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Part 1 “Regulations for Structures and Facilities of Pharmacies”

構造設備規則　Article 6 General classification

BFR6-1 (General classification manufacturing plant structure and equipment) [Question] Regarding the provisions of Article 6, Item 3 of the Building and Facilities Regulations, where should "toilets and changing places" be located?

[Answer] "Toilets and places for changing clothes" must be installed in the manufacturing facility, but as stated in Chapter 2, Section 2, 1(7) and (8) of the Enforcement Notification, toilets may be located in the front room or passageway. It is separated from the operational room by, for example, Changing areas do not necessarily require a dedicated room for changing. In addition, toilets and changing rooms should be equipped with hand-washing facilities and appropriate equipment that takes hygiene management into consideration.

BFR6-2 (General classification manufacturing plant structure and equipment) [Question] Article 6, Item 4, A of the Construction and Facilities Regulations stipulates that workplaces must have appropriate lighting. For example, in a workplace where the manufacturing process before the final purification of a drug substance product is carried out, is it necessary to install lighting equipment even if the illuminance can be ensured by daylighting?

[Answer] Make sure that the necessary illuminance, including daylighting, can be secured depending on the type of work so that the work is not hindered.

BFR6-3 (Structures and equipment of general classification manufacturing plants) [Question] Regarding the provisions of Article 6, Item 4, D of the Regulations on Buildings and Facilities, are reaction vessels, filters, and crystallization vessels used in the manufacture of pharmaceutical products that are active pharmaceutical ingredients considered to have a "closed structure"?

[Answer] Generally speaking, it can be considered a "closed structure." However, care must be taken to prevent contamination when opening the lid during operations such as adding seed crystals.

BFR6-4 (Structures and equipment of general classification manufacturing plants) [Question] Regarding the provisions of Article 6, Item 4 (d) of the Regulations on Buildings and Facilities, for workplaces where manufacturing processes are performed prior to the final purification of products related to pharmaceutical ingredients, there are special exceptions if the manufacturing equipment has a closed structure. Is it permissible to use outdoor equipment that has not been properly protected against insects and insects?

[Answer] If the manufacturing equipment is of a closed structure and the drug substance product is not exposed to the outside air by opening or closing the lid during manufacturing operations, it may be allowed to be used.

BFR6-5 (General classification manufacturing plant structure and equipment) [Question] Article 6, Item 6 of the Regulations on Structures and Facilities states that "(manufacturing sites) must have the necessary equipment to separate and store products, etc. and materials in a sanitary and safe manner." Is it correct to understand that there is no need to install special equipment by storing the materials separately in a section of the central hallway or operational room under the same cleanliness level environment for a short period of time?

[Answer] "Equipment" as used in "Equipment necessary for sanitary and safe storage" includes, for example, equipment such as storage shelves, as well as warehouses. Therefore, in principle, it is not allowed to store products in a central hallway or a section of a operational room, but if a central hallway or a section of a operational room is used temporarily, it may cause confusion and contamination with other products, etc. and materials. and if necessary measures are taken to prevent cross-contamination.

BFR6-6 (General classification manufacturing plant structure and equipment) [Question] Article 6, item 5 (b) of the Building and Facilities Regulations states that ``doorways and windows (of operational rooms) must be able to be closed.'' Is it okay to install a ventilation fan?

[Answer] As stipulated in Article 6, Item 5, A of the Structures and Facilities Regulations, the structure and equipment must be necessary to prevent contamination from outdoors. When installing, protective measures against solvents and dust and external Measures are taken to prevent contamination from

BFR6-7 (General classification manufacturing plant structure and equipment) [Question] Article 6, Item 5 of the Regulations on Structures and Facilities states that it is a "operational room for products related to active pharmaceutical ingredients, where work is performed to fill containers with intermediate products that have undergone final purification and close them." What specifically does "filling and closing" refer to in the manufacturing process of products that are active ingredients?

[Answer] Generally, this applies to everything from removing the product to directly filling and closing the container or envelope (including the inner bag).

BFR6-8 (General classification manufacturing plant structure and equipment) [Question] According to Article 6, Item 5, E of the Structural Facilities Regulations, ``Indoor pipes, ducts, and other equipment must be constructed to prevent dirt from accumulating on their surfaces.However, this does not apply if they are easy to clean. What does "if it is easy to clean" mean?

[Answer] "If it is easy to clean" means that the equipment has a structure that allows for sufficient cleaning within the scope of daily cleaning. For example, even if pipes, ducts, etc. are horizontal, if debris can be easily removed through daily cleaning and debris is prevented from accumulating, this can be interpreted as "a case where cleaning is easy." do not have.

BFR6-9 (General classification manufacturing plant structure and equipment) [Question] Please specifically explain the difference between the terms "division," "divide," and "distinguish" as referred to in Chapter 2, Section 2, 1(12) of the Enforcement Notification.

[Answer] Regarding the provision of "Equipment necessary for separating and storing products, etc. and materials..." in Article 6, Paragraph 1, Item 6 of the Regulations on Structures and Facilities, Enforcement Notice Chapter 2, Section 2 1(12) refers to a fixed area divided by walls, partition boards, etc. "Separate" refers to separating certain places or objects by drawing lines, markings, etc. "Distinguish" refers to separating places and things into categories in order to identify them. The specific form in which these should be realized should be determined in each case according to its purpose.

BFR6-10 (General classification manufacturing plant structure and equipment) [Question] According to Article 6, Item 7 of the Regulations on Structures and Facilities, there is no problem in conducting tests and inspections on products, etc. and materials using other test and analytical equipment of the manufacturer, etc. or other test and inspection institutions. If so, is it not necessary for the manufacturing facility to have these test and analytical equipment?

[Answer] There is no problem even if you are not prepared.

Testing and analytical equipment

BFR6-11 (testing and analytical equipment) [Question] Article 6, Item 7 of the Regulations on Structures and Facilities states that "equipment and equipment necessary for testing and inspection of products, etc. and materials shall be provided." Can this be interpreted as being excluded?

[Answer] Although not a requirement for permission (certification), equipment necessary for testing and inspection that has been established as a voluntary standard should be appropriately managed under GMP.

BFR6-12 (testing and analytical equipment) [Question] If some of the test and inspection items for raw materials, etc. are omitted by meeting the prescribed conditions, is it not necessary to provide the test and analytical equipment and instruments necessary for the omitted items?

[Answer] It is difficult to obtain a rational basis for omission unless the test and analytical equipment and instruments necessary for the test and inspection items to be omitted are provided (see GMP 11-4). Even testing equipment and instruments related to inspection items must be provided. However, this does not apply when using other test and inspection facilities of the manufacturer or other test and inspection institutions.

BFR6-13 (Testing and analytical equipment) [Question] When accepting products manufactured at another manufacturing facility and manufacturing them from the next process onwards, if the prescribed conditions are met, it is possible to use the test and inspection results conducted at the other manufacturing facility to produce your own product. If some testing and inspection items are omitted at a manufacturing facility, is it not necessary to provide the testing and analytical equipment and instruments necessary for the omitted testing and inspection items?

[Answer] Even in the case of questions, testing equipment and equipment necessary for the omitted testing items must be provided (see BFR6-12). However, this does not apply when using other test and inspection facilities of the manufacturer or other test and inspection institutions.

構造設備規則　Article 7　Sterile category

BFR7-1 (Structures and equipment of sterile division manufacturing facility) [Question] Can the "work control area" referred to in Article 7, Item 1, A of the Building and Facilities Regulations include operational rooms for products other than sterile pharmaceutical products?

[Answer] Among the work management areas for products related to sterile pharmaceuticals, operational rooms or work areas where drug preparation work, filling work, or work after preparation work (excluding labeling and packaging work) performed for sterilization of products is performed. According to the provisions of Article 23, Item 4 (a) and (b) of the GMP Ministerial Ordinance, the controlled area must be separated from non-sterile pharmaceutical work areas, and must be separated from work areas where preparation work is performed, filling work, or closure work. The room must be private.

However, even when working in a operational room for non-sterile pharmaceutical products, the cleanliness level required according to the type, dosage form, and manufacturing process of the product is maintained in the work control area for sterile pharmaceutical products. If there is a reasonable basis that there is no risk of contamination or cross-contamination of the operational room or work control area for products related to sterile pharmaceutical products, and this is specified in advance in the Standard Operating Procedures, etc. It may be acceptable to design it as a question.

BFR7-2 (Structural and equipment of sterile division manufacturing facility) [Question] In the work management area, is it necessary to store injectable products that have already been filled into ampoules and closed in a storage room with the same level of cleanliness as the filling and closing room?

[Answer] It is not necessarily necessary to store them at the same cleanliness level, but it is necessary to take sufficient care to ensure that there is no change in quality.

BFR7-3 (Structural and equipment of sterile division manufacturing facility) [Question] Article 7, Item 2(b) of the Regulations for Structures and Facilities states that "equipment and utensils must be capable of sterilization or disinfection," but what about freeze dryers that cannot be sterilized with high-pressure steam? Should I respond to this?

[Answer] For freeze dryers located in operational rooms or work control areas where sterile pharmaceutical products are filled and closed, it is desirable to sterilize them using high-pressure steam sterilization. However, "Guidelines for the manufacture of sterile pharmaceuticals using aseptic techniques" (2010 Health, Labor and Welfare Scientific Research Research on the introduction of new test methods to ensure the microbiological quality of pharmaceuticals) "Guidelines for the manufacture of sterile pharmaceuticals using aseptic techniques" If sterility can be guaranteed by referring to the latest version of related guidelines, etc., other methods may be used.

構造設備規則　Article 8　Specified biological drugs

BFR8-1 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1 (a) (2) of the Construction and Facilities Regulations states that "drainage facilities shall be of an appropriate structure to prevent pollution by harmful wastewater." Does "Structure" include drainage traps and backflow prevention devices at drain outlets?

[Answer] Included.

BFR8-2 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1, A (2) of the Regulations for Structures and Facilities states that "drainage facilities shall be of appropriate structure to prevent pollution by harmful wastewater." Does waste liquid containing unactivated pathogens (BSL2 or higher) fall under "hazardous waste liquid"?

[Answer] In the case of the question, substances that have an impact on the human body or the environment, such as pathogens (BSL2 or higher) before they are inactivated, fall under "hazardous waste fluid."

BFR8-3 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1, B (1) of the Regulations for Structures and Facilities states that ``Drains must have a trap that is easy to clean and a device to prevent backflow of wastewater.'' What are some examples of "devices to prevent backflow"?

[Answer] For example, the piping leading to the terminal drain should not be directly inserted into the waste liquid in the drain outside the manufacturing area, and the structure should have physical or mechanical backflow prevention measures that do not reduce the effectiveness of the drain trap. However, in addition to backflow prevention devices, connections such as ensuring that the piping leading to the end drainage outlet are not directly inserted into the waste liquid in the drains outside the manufacturing area and that it does not become a source of backflowing wastewater, etc. It is necessary to design the structure of the piping that will be used. The structure must prevent not only the backflow of water but also the backflow of contaminated air from the piping.

BFR8-4 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] According to Article 8, Paragraph 1, Item 1, B (3) of the Structural Facilities Regulations, ``The floor groove is shallow and easy to clean, and is connected to the outside of the manufacturing area through a drainage outlet.'' Is it correct to understand that this includes structures that prevent wastewater from stagnation, structures that are easy to disinfect, and structures that prevent microbial contamination from occurring from outside the manufacturing area through drains?

[Answer] Article 8, Paragraph 1, Item 1(b) of the Regulations for Structures and Facilities stipulates that drains shall not be installed in clean areas, and cases (1) to (3) are listed as cases where it is deemed unavoidable. These conditions must be met. Although the floor grooves and drains are separate, they are connected to the outside of the manufacturing area to prevent contamination from outside the manufacturing area from entering the floor grooves. ) and (2) describe requirements for drains and traps.

BFR8-5 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1, C (1) of the Structural and Facilities Regulations states that ``no drains shall be installed'' in sterile areas. Does this need to be removed?

[Answer] If a drainage outlet is already installed in the existing structure and equipment, in addition to removing the drainage outlet, measures should be taken to prevent pollution by creating a structure that can be sealed during manufacturing operations. There is no problem. However, the procedures, etc. for this purpose must be stipulated in advance in a Standard Operating Procedures, etc.

BFR8-6 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1 of the Building and Facilities Regulations states that "areas where pathogenic microorganisms, etc. are handled shall have the necessary structure and equipment for appropriate negative pressure management." Is it correct to assume that this refers to areas where pathogens are directly handled, and does not apply to areas where raw materials that may contain pathogens are handled?

[Answer] Negative pressure control should be carried out as necessary, not only in areas where pathogens are handled for manufacturing purposes, but also in areas where raw materials that may be contaminated with pathogens are handled.

BFR8-7 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1 of the Building and Facilities Regulations states that "areas where pathogenic microorganisms, etc. are handled shall have the necessary structure and equipment for appropriate negative pressure management." Do areas where potentially pathogenic microorganisms are handled include areas where potentially pathogenic microorganisms are cultured?

[Answer] Included.

BFR8-8 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1 of the Building and Facilities Regulations states that the building shall have the necessary structure and equipment for appropriate negative pressure management. Is it correct to think that if negative pressure is applied to the front room, hallway, etc. around the operational room, it is not necessarily necessary to apply negative pressure to the outside air?

[Answer] No problem. Pathogenic microorganisms must be handled in accordance with containment requirements. Please refer to the latest version of the National Institute of Infectious Diseases Pathogen Safety Management Regulations, the WHO Biosafety Manual, or related regulations.

BFR8-9 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1 of the Building and Facilities Regulations states that "areas where pathogenic microorganisms, etc. are handled shall have the necessary structure and equipment for appropriate negative pressure management." What should I pay attention to when storing pathogenic microorganisms?

[Answer] Storage management should be performed according to the biosafety level of the pathogen. When storing pathogenic microorganisms, etc., use containers that do not allow the contents to leak outside, and take appropriate measures to prevent their spread. When selecting a direct storage container, consideration should be given to ensuring the container's airtightness under the operations and conditions necessary for storing the pathogenic microorganism, such as preservation treatment such as freezing and storage temperature.

In addition, even in the event of leakage from the direct storage container, measures should be taken to prevent the leakage and dispersion of pathogenic microorganisms by using encapsulation, etc., and establishing appropriate inactivation and cleaning methods to prevent it from spreading easily. Furthermore, in addition to physical restrictions such as restricting access to the storage room, the microorganisms to be stored are 114), it is necessary to carry out appropriate management. In that case, structural equipment for negative pressure management is not necessarily required.

BFR8-10 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] What specifically refers to "pathogenic microorganisms, etc." in Section 8, Paragraph 1, Item 1, and "Infectious microorganisms, etc." in Item 1, G of the Building and Facilities Regulations? .

[Answer] It refers to what is generally called pathogenic microorganisms and infectious microorganisms. Regarding the pathogenicity and infectivity of microorganisms, their handling, etc., please refer to the latest editions of the National Institute of Infectious Diseases Pathogen Safety Management Regulations, the WHO Biosafety Manual, or related regulations.

BFR8-11 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] According to Article 8, Paragraph 1, Item 1-H of the Building and Facilities Regulations, "Rooms and equipment used for handling smallpox pathogens, acute poliomyelitis pathogens, spore-forming pathogens, or tubercle bacilli used in manufacturing are classified by product type. Is it correct to think that this provision does not apply to equipment that handles toxins, etc. after bacterial cells have been removed?

[Answer] In principle, it is not allowed. However, even in cases such as questions, it may be permitted if there is a reasonable basis that it does not require specific use for each type of product, and if it is stipulated in advance in the Standard Operating Procedures, etc. .

BFR8-12 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1, Li (1) of the Building and Facilities Regulations, ``Having an appropriate structure to prevent contamination of products by microorganisms, etc.'' refers to air conditioning equipment in sterile areas. Can this be considered a provision limited to

[Answer] It is not limited to air conditioning equipment in sterile areas. It stipulates the requirements to be met for air treatment systems at manufacturing facilities for products related to specified biological drugs, etc.

BFR8-13 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] According to Article 8, Paragraph 1, Item 1, Li(2) of the Regulations for Buildings and Facilities, air treatment systems must be properly installed to prevent the spread of the microorganisms through the air when handling pathogenic microorganisms, etc. However, is it correct to think that this only applies when pathogenic microorganisms themselves are used as raw materials?

[Answer] In addition to cases where they are used as raw materials, this also includes cases where pathogenic microorganisms are used in tests, etc.

BFR8-14 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1, Li(3) of the Regulations for Buildings and Facilities states that ``Air discharged from an area where pathogenic microorganisms, etc. are handled must be discharged after the microorganisms, etc. are removed by a high-performance air filter. However, is it necessary to test the filter's performance using a testing method that uses pathogenic microorganisms as an indicator?

[Answer] It is not necessary to use a testing method that uses pathogenic microorganisms as an indicator, as long as the testing method can confirm that the filter maintains the specified performance.

BFR8-15 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] According to Article 8, Paragraph 1, Item 1, Li(4) of the Building and Facilities Regulations, the structure shall not allow recirculation of air exhausted from the operational room where there is a risk of leakage of pathogenic microorganisms, etc. However, this does not apply if the structure specified in (3) has sufficiently removed the microorganisms, and it is recognized that recirculation is unavoidable.'' If the bacteria belong to risk level 2 or lower as specified in the manual and measures are taken to prevent contamination, is it okay to have a recirculating structure?

[Answer] According to WHO's "Biosafety Guidelines for Personnel Engaged in the Production of Vaccines and Biological Products for Medical Use" and "Laboratory Biosafety Manual," in the case of risk level 2, the exhaust port of gas generated from the culture process is HEPA filters must be installed. The facility meets these regulations, has basic biosafety equipment, ensures that microorganisms are sufficiently removed by managing HEPA filters and air conditioning equipment, and establishes operational room management methods. It is necessary to take measures in case of leakage. In addition, if the quality of pharmaceuticals, etc. is ensured, and if it is deemed unavoidable, a structure that recirculates air in the operational room may be used.

BFR8-16 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1, Li(5) of the Regulations for Structures and Facilities stipulates that the air treatment system "shall be separated for each operational room as necessary." If there is no contamination of products etc. by the air treatment system, is it not necessary to use it exclusively?

[Answer] It should be exclusive. However, if there is reasonable evidence that there is no contamination or cross-contamination due to the characteristics of the product, it may not be necessary to make it exclusive.

BFR8-17 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1, Rule (1) of the Regulations on Structures and Facilities states that "the area for testing animals used shall be isolated from other areas." What is the reason for this? .

[Answer] In order to prevent newly brought in animals from being contaminated with pathogenic factors, etc., animals brought in are not allowed to be brought in until the results of the inspection at the time of acceptance are known. This requires an area to be provided to separate the animals to be used from the animals currently being used.

BFR8-18 (Structures and equipment of specified biological pharmaceutical manufacturing facilities) [Question] Article 8, Paragraph 1, Item 1, Rule (1) of the Regulations on Structures and Facilities states that "the area for testing animals used shall be isolated from other areas." , Is it correct to consider that equipment for housing the animal is included until the inspection is completed?

[Answer] No problem.

構造設備規則　Article 10　Packaging classification

BFR10-1 (Structural equipment of packaging manufacturing facility) [Question] Is it correct to understand that any of the provisions of Articles 6 to 9 of the Structural and Establishment Regulations apply to manufacturing facilities that only perform subdivision packaging, rather than the provisions of Article 10 of the Structural and Establishment Regulations?

[Answer] No problem. Furthermore, subdividing does not fall under the manufacturing act that can be performed under a manufacturing license for packaging, etc. categories, since the direct filling of containers or packaging (including inner bags) has not been completed.

Part 2: Cases related to “Ministerial Ordinance on Manufacturing Control and Quality Control Standards for Pharmaceuticals and Quasi-drugs”

改正GMP省令　General matters

GMP0-1 (general matters) [Question] Regarding the manufacturing control and quality control of products related to drugs that are active ingredients in Section 2, Manufacturing control and quality control of drugs that are active ingredients (Articles 21-22), in the third notification of the promulgation of the revised ministerial ordinance. It states that ``manufacturing control and quality control shall be focused on the final purification process and other processes that have a significant impact on the product quality of the drug substance.'' Please give a concrete example.

[Answer] The manufacturing process for products that are active pharmaceutical ingredients usually consists of the process of obtaining the desired ingredient from raw materials containing impurities through chemical synthesis, extraction, etc., and increasing the purity while removing impurities. has been done. Therefore, as specific examples of "other processes that have a significant impact on the product quality of the drug substance," the final reaction process, intermediate purification process, and crystallization process also decisively control the quality of the product related to the drug substance. If it is classified as a process, it is covered.

Even if the product is related to the same drug substance, if the raw materials, manufacturing methods, manufacturing equipment, etc. are different, the processes that affect the quality may differ. "Processes that have a significant impact on the drug substance" should be appropriately determined in advance by the manufacturer, etc., depending on the type of drug substance, manufacturing procedure, etc. However, processes that are required to be described in the manufacturing and marketing approval document must be followed.

In addition, when appropriately determining in advance "other processes that have a significant impact on the product quality of the drug substance," a quality risk management method that identifies potential risks to quality in the manufacturing process and scientifically evaluates them should be adopted. This is effective.

GMP0-2 (general matters) [Question] How should I handle the various technical information listed in the Japanese Pharmacopoeia Reference Information?

[Answer] Technical information, such as the characteristics of the drug product and the characteristics of the manufacturing process, should be appropriately utilized and referenced depending on the risk. In addition, it is stated in "Handling of reference information deleted due to enactment of the 17th revised Japanese Pharmacopoeia Second Supplement" (June 28, 2019, Pharmaceutical Evaluation and Management Division, Administrative Communication of the Monitoring and Guidance and Narcotics Countermeasures Division) As mentioned above, "Parametric release of terminally sterilized pharmaceuticals," "Medium filling test (process simulation)," and "Environmental monitoring method for sterile pharmaceutical production areas," which have been deleted from the Japanese Pharmacopoeia reference information, can also serve as a reference for operations. To be.

GMP0-3 (general matters) [Question] Manufacturers in the category of Article 25, Paragraph 1, Item 5 of the Enforcement Regulations, foreign manufacturers in the category of Article 35, Paragraph 1, Item 5 of the Enforcement Regulations, and only those subject to storage in Article 13-2-2 of the Act. Which provisions of the GMP Ministerial Ordinance should be applied in cases where only storage operations are carried out at a manufacturing facility that conducts storage operations or that only performs storage operations as specified in Article 13-3-2 of the Act?

[Answer] As stated in Section 3(4) of the Notice of Promulgation of the Revised Ministerial Ordinance, the provisions of each article of the GMP Ministerial Ordinance, including operations related to storage at a manufacturing facility that only performs storage, apply to the manufacturing control of pharmaceuticals at the manufacturing facility, It is applied to the extent necessary to appropriately carry out work related to quality assurance and testing and inspection (hereinafter referred to as manufacturing/quality control related work) or work related to manufacturing control and quality control of quasi-drugs. Something.

GMP0-4 (general matters) [Question] Is it permissible for a marketing authorization holder to apply for a GMP compliance investigation regarding the manufacture of export drugs?

[Answer] Article 80, Paragraph 1 of the Pharmaceutical Affairs Law stipulates that "manufacturers of pharmaceuticals for export, etc." must undergo an investigation, and not manufacturers and distributors.

GMP0-5 (general matters) [Question] Manufacturers apply for and renew manufacturing licenses every five years, but GMP compliance surveys to maintain approval for each item are outsourced by, for example, multiple manufacturers. Is it permissible for a manufacturer to submit the applications of the relevant marketing authorization holder all at once?

[Answer] Regarding the GMP compliance investigation in the example in the question, the marketing authorization holder who has obtained manufacturing and marketing approval for the item would apply. GMP compliance surveys to maintain approval for each item must be submitted by manufacturers every five years after approval; There is no problem for the manufacturer, etc. to submit the applications of multiple marketing authorization holders at the same time (before the deadline for undergoing GMP compliance inspections every five years from the date of marketing approval).

GMP0-6 (general matters) [Question] Regarding the responsibilities of a "manufacturer, etc." stipulated in the GMP Ministerial Ordinance, is it possible for the manufacturer, etc. to have a person designated in advance perform the duties?

[Answer] At least with regard to the operations of manufacturers, etc. stipulated in Article 3-3, Article 5, Paragraph 2, and Article 6, Paragraphs 1 to 3 of the GMP Ministerial Ordinance, if the manufacturer, etc. is a corporation. This should be carried out primarily by the executives responsible for pharmaceutical affairs, including the representative of the corporation. If the manufacturer, etc. has a person designated in advance perform work other than these, an appropriate person with the ability to properly and smoothly carry out the work shall be appointed, and the content and scope of the work shall be determined according to GMP standards. This shall be clarified in the document specified in Article 6, Paragraph 4 of the Ministerial Ordinance, and the document shall be stored in accordance with Article 20 of the GMP Ministerial Ordinance. Even if the manufacturer, etc.'s work is performed by a person designated in advance by the manufacturer, the ultimate responsibility for such work shall be the responsibility of the pharmaceutical affairs-related work, including the representative of the manufacturer, etc. who is a corporation. The liability shall be borne by the officer with the following qualifications.

改正GMP省令　Site master file

GMP0-7 (site master file) [Question] The documents to be attached when applying for a drug compatibility investigation include the Cabinet Order pursuant to the enforcement of part of the Act to amend the Act on Ensuring the Quality, Efficacy, and Safety of Pharmaceuticals and Medical Devices, etc.; Chapter 2, Section 2-8 of the Establishment and Revision of Ministerial Ordinances (Yakusho Kanma No. 0713 No. 12, July 13, 2021). (3) Classification suitability survey o. , a site master file or equivalent material is mentioned, but what is a "site master file"?

[Answer] About the concept when utilizing the PIC/S GMP guidelines (Administrative communication of the Monitoring and Guidance/Narcotics Control Division dated February 1, 2012) Attachment (1) As set forth in Chapter 4 of Part 1 of the PIC/S GMP Guidelines This is a document that describes the work activities related to GMP of the manufacturing facility that is being implemented, and is useful when conducting an audit (on-site or in writing) of the manufacturing facility, as it can clearly show an overview of the activities including the manufacturing facility's quality system. . See PIC/S Interpretation Memorandum (“EXPLANATORY NOTES FOR PHARMACEUTICAL MANUFACTURERS ON THE PREPARATION OF A SITE MASTER FILE” PE 008-4 1 Annex1 January 2011).

Please note that manufacturers who may be subject to inspections by overseas authorities should use this term as much as possible, as they may be required to present documents that correspond to this concept during inspections, etc. by overseas authorities. It is advisable to prepare corresponding documents.

GMP0-8 (site master file) [Question] What items should be included in the site master file? Also, to what extent should each item be described?

[Answer] As a result of research on international harmonization of GMP, QMS, GCTP, and pharmaceutical excipient guidelines in 2018, a mock site master file was created and posted on the PMDA website for reference. thing. Please note that the actual state of manufacturing control and quality control at pharmaceutical manufacturing facilities differs from one manufacturing facility to another, so it should be prepared according to the actual situation at each manufacturing facility.

改正GMP省令　Article 2　Definition

GMP2-1 (definition of raw materials) [Question] Regarding "raw materials" in Article 2, Paragraph 4 of the GMP Ministerial Ordinance, Article 3, Section 2(4) of the Notification of Promulgation of the Revised Ministerial Ordinance states, ``Raw materials'' are those used in the manufacture of products related to pharmaceuticals or quasi-drugs at manufacturing facilities. (including materials that do not remain in the product, but excludes materials and intermediate products)", but what exactly is meant by "raw materials that do not remain in the product"?

[Answer] Examples include water used in the manufacturing process that does not end up in the product, and substances such as solvents that volatilize during drying and other processes. Examples of such solvents include ethanol, isopropanol, and solvents used in freeze-drying, which are used in the granule manufacturing process. These materials are included as raw materials because their quality directly affects the quality of the product, and it is thought that they need to be managed in the same way as the raw materials that will ultimately be included in the product. It's for a reason.

GMP2-2 (definition of raw materials) [Question] Regarding "raw materials" as stipulated in Article 2, Paragraph 4 of the GMP Ministerial Ordinance, "raw materials" of products related to drug substances are defined as "raw materials" of products related to drug substances that are manufactured in a manner that affects the quality of products related to drug substances. Can it be considered only substances used in the process and subsequent processes?

[Answer] All substances used in manufacturing, including starting materials, fall under the category of raw materials for products that are active pharmaceutical ingredients. Regarding the manufacturing control and quality control of products related to active pharmaceutical ingredients based on the provisions of the GMP Ministerial Ordinance, as the series of manufacturing processes of products related to active pharmaceutical ingredients progress, risks to the quality of the products are considered, In principle, strict handling of raw materials is also required.

GMP2-3 (definition of raw materials) [Question] Filter aids, ion exchange resins and their regenerants, sterilizing agents for equipment, cleaning agents for instruments and containers, etc. are generally not included in "raw materials" in Article 2, Paragraph 4 of the GMP Ministerial Ordinance. How should this be managed?

[Answer] Consider the risks to the quality of the product and manage it according to its characteristics, purpose of use, method of use, etc.

GMP2-4 (definition of raw materials) [Question] Should antioxidants, pH regulators, etc. used in small quantities other than main raw materials be treated as "raw materials" under Article 2, Paragraph 4 of the GMP Ministerial Ordinance?

[Answer] Treat it as a raw material.

GMP2-5 (definition of raw materials) [Question] If the manufacturing process includes a fermentation process, does the culture medium need to be managed as a "raw material" under Article 2, Paragraph 4 of the GMP Ministerial Ordinance?

[Answer] If the quality of the product could be seriously affected, the culture medium and its components should be managed as raw materials.

GMP2-6 (definition of instrument calibration) [Question] Does “calibration of instruments” in the Notification of Promulgation of Revised Ministerial Ordinance No. 3-2(25)① include adjusting the difference between the value indicated by the instrument and the true value when there is a difference? May I understand?

[Answer] "Calibration of an instrument" refers to determining the relationship between the value indicated by the instrument and the true value by using appropriate standards, standard samples, etc., taking into account the required accuracy. , "adjustment" is not included

GMP2-7 (definition of intermediate products) [Question] I would like you to be more specific about "intermediate products."

[Answer] Intermediate products are those that are manufactured in intermediate manufacturing processes within a manufacturing facility, and that become products shipped from the manufacturing facility after passing through subsequent manufacturing processes. Specifically, intermediate products are those for which the final packaging at the manufacturing facility has not been completed.

GMP2-8 (definition of intermediate products) [Question] When factory A manufactures a "formulation bulk" and factory B receives it and packages it in subdivisions, should this "formulation bulk" be treated as a raw material, an intermediate product, or a finished product?

[Answer] In the case of the question, "preparation bulk" is a product produced at "Factory A" and is a raw material produced at "Factory B" as stated in Part 3, 2(4) of the amended ministerial ordinance promulgation notice.

GMP2-9 (definition of intermediate products) [Question] In the case of GMP2-8, what kind of tests and inspections should be conducted on the "bulk drug product" at "Factory B"?

[Answer] “Raw materials” as stipulated in the GMP Ministerial Ordinance are “raw materials for a manufacturing facility” and refer to those that are received at the manufacturing facility and have not yet undergone the manufacturing process at the manufacturing facility. In addition to the specifications and test methods stipulated in the manufacturing and sales approval (notification) document, the testing and inspection of raw materials conducted at the manufacturing facility is based on the standards necessary for manufacturing control and quality control at the manufacturing facility. , it is acceptable to carry out appropriate tests and inspections.

GMP2-10 (definition of intermediate products) [Question] Unground products after drying of crystals (wet products) produced in the final stage of the refining process in the middle of a series of manufacturing processes at a certain manufacturing facility, and crushed and sieved products thereof (at the relevant manufacturing facility, (items that are subdivided and packaged) are considered "intermediate products" as defined in Article 2, Paragraph 1 of the GMP Ministerial Ordinance?

[Answer] In the case of the question, both "unground products" and "crushed and sieved products" are intermediate products. See GMP 2-7.

GMP2-11 (other) [Question] Please explain the difference between a manufacturing site, a workshop, and a operational room.

[Answer] A manufacturing facility as referred to in the GMP Ministerial Ordinance is one that has been granted permission under Article 13 of the Act or certification under Article 13-3 of the Act, or has been registered under Article 13-2-2 of the Act, or Refers to those registered under Article 3-2. A workplace is defined in Article 2, Paragraph 16 of the GMP Ministerial Ordinance as a "place where manufacturing work is performed" and includes offices, testing and inspection rooms, etc. that are directly connected to the manufacturing work site. A operational room refers to an individual room in a work place where manufacturing work is performed.

GMP2-12 (other) [Question] If all the work or operations stipulated in Article 2, Paragraph 18 of the GMP Ministerial Ordinance are performed inside a clean booth, is it okay to limit the "sterile area" to the inside of the clean booth?

[Answer] No problem

GMP2-13 (definition of materials) [Question] Do plastic films and aluminum foils for PTP packaging and packs for suppositories fall under the category of "containers" or "encapsulations" under Article 2, Paragraph 3 of the GMP Ministerial Ordinance?

[Answer] We understand that plastic films and aluminum foils used for PTP packaging, SP packaging, etc., as well as suppository packs, are encapsulated. Since these items come into direct contact with the product, they must be managed according to the risks.

GMP2-14 (definition of materials) [Question] Is the desiccant contained in the container included in the "materials" in Article 2, Paragraph 3 of the GMP Ministerial Ordinance?

[Answer] Desiccants like the ones in the question are not normally included in the materials specified in Article 2, Paragraph 3 of the GMP Ministerial Ordinance, but should be handled in accordance with the management of materials stipulated in the GMP Ministerial Ordinance. In particular, if there is a possibility that the desiccant may come into direct contact with the product, it must be managed to prevent contamination.

GMP2-15 (definition of materials) [Question] In the case of pharmaceuticals that are active ingredients, what is meant by the package insert that is a material in Article 2, Paragraph 3 of the GMP Ministerial Ordinance?

[Answer] Regarding pharmaceuticals exclusively for manufacturing, the provisions of Article 52, Paragraph 2, Item 1 of the Act do not apply pursuant to the provisions of Article 214, Paragraph 2 of the Enforcement Regulations, so package inserts are not required for most pharmaceuticals that are active ingredients. do not.

However, for pharmaceuticals included in the Japanese Pharmacopoeia, matters stipulated by the Japanese Pharmacopoeia to be written on documents attached to them or on their containers or encapsulates, and pursuant to the provisions of Article 42, Paragraph 1 of the Act. For pharmaceuticals for which standards have been established, when writing in the package insert the matters stipulated by the standards to be written on the accompanying document or on its container or encapsulation, the respective stipulated items shall be included. A complete package insert is required.

GMP2-16 (definition of materials) [Question] If a drug substance as a drug substance is placed in a polyethylene bag, etc. that does not contain the matters stipulated in Article 50 of the Act and is enclosed in a fiber drum, etc. and distributed, how should the polyethylene bag, etc. be handled? .

[Answer] Regarding the "polyethylene bags, etc." in the case of the question, it corresponds to the inner bag under Article 57, Paragraph 1 of the Act, and under the provisions of the same paragraph, pharmaceuticals are not allowed to be used in containers or containers that may make pharmaceuticals dangerous to health and hygiene. Considering that it must not be contained in packaging (including inner bags), it is necessary to manage it appropriately based on the provisions of the GMP Ministerial Ordinance. In addition, the "fiber drum" in the case of the question corresponds to the "direct container" under the law.

GMP2-17 (definition of lot) [Question] Please provide an example of the composition of a "lot" as defined in Article 2, Paragraph 4 of the GMP Ministerial Ordinance.

[Answer] Lot composition cases are not uniformly determined, but should be determined after considering manufacturing conditions, work methods, etc. for each product. For product lots related to biological products, please refer to the General Rules for Biological Products Standards.

GMP2-18 (definition of lot) [Question] According to Article 2, Paragraph 4 of the GMP Ministerial Ordinance, a lot is defined as “products and raw materials (hereinafter referred to as “products, etc.”) that are manufactured to have homogeneity through a series of manufacturing processes within one manufacturing period. A group. ", but how long should we consider "one manufacturing period" in this case?

[Answer] The manufacturing period varies depending on the type of product, dosage form, working style, structure and equipment, and other differences, and cannot be determined unconditionally.

GMP2-19 (definition of lot) [Question] What is the condition of "products and raw materials manufactured to have homogeneity"?

[Answer] "Products and raw materials that are manufactured to have homogeneity" means that there is reasonable evidence (validation data, etc.) that they are manufactured to have homogeneity, and that the quality department has confirmed this. This refers to cases where it is specified in advance in Pharmaceutical Product Standard Code documents, etc.

GMP2-20 (definition of lot) [Question] What is the acceptable range (variation) of "homogeneity" in lot composition as stipulated in Article 2, Paragraph 4 of the GMP Ministerial Ordinance?

[Answer] The range may vary depending on the type of each product and the testing method used to confirm homogeneity, so it cannot be determined unconditionally.

GMP2-21 (definition of lot) [Question] When allocating lots for products that are active pharmaceutical ingredients, to what extent is the "homogeneity" within the lots required?

[Answer] The required homogeneity varies depending on the type of product for each drug substance, the testing method used to confirm homogeneity, etc., and cannot be determined unconditionally. In addition, one method is to mix appropriately to improve homogeneity, as long as it does not violate the prerequisites for mixing according to GMP2-31.

GMP2-22 (lot composition) [Question] If intermediate products from the same manufacturing lot are continuously filled and packaged using the same manufacturing conditions and equipment over a long period of time, can they be treated as the same lot?

[Answer] In the case of the question, if there is a risk that the homogeneity of the lot will be lost due to filling and packaging being carried out over a long period of time, this is not acceptable. Regarding the lots of products that have gone through the filling and packaging process, each unit is considered to have been filled and packaged to have homogeneity, and each lot must be based on rational evidence (validation data) that shows that each lot is manufactured to be homogeneous. etc.) shall be confirmed by the quality department and specified in advance in the Pharmaceutical product standard code, etc.

In addition, cleaning at appropriate intervals is necessary to prevent the formation of contaminants and their carryover (in the manufacture of products related to active pharmaceutical ingredients, cleansing must be carried out at appropriate intervals to prevent the formation of contaminants and their carryover). Take care to avoid causing carryover of microbial contamination.) Generally, if the content of the work is clear, it is common to stipulate time limits in Pharmaceutical Product Standard Code documents, etc. (excluding work to be completed).

GMP2-23 (lot composition) [Question] Is it permissible to further divide intermediate products from the same lot into several lots during the packaging process at the final product manufacturing facility?

[Answer] No problem. However, the relationship between the lot number of the "intermediate product" and the manufacturing number or manufacturing code displayed on the final product must be clarified, and manufacturing records must be created to enable bidirectional tracking.

GMP2-24 (lot composition) [Question] When manufacturing multiple lots of the same product continuously during the same manufacturing period, even if residue from the previous lot remains in the hopper or pipe, the theoretical classification of each lot will result in a difference between the lots. Is it okay to separate?

[Answer] Even when multiple lots of the same product are manufactured continuously during the same manufacturing period, it is a general rule to clearly classify the lots, but in the case of liquids, granules, etc. The following items should be taken into account, and the risk to quality should be taken into account.

1. There must be reasonable evidence that the product will be manufactured to be homogeneous, and this must be confirmed by the quality department and specified in advance in the Pharmaceutical product standard code, etc.

2. When recalling products due to the occurrence of defective products, etc., handle multiple lots that may remain from the previous lot at once.

3. Cleaning at appropriate intervals necessary to prevent the formation and carryover of contaminants (in the manufacture of drug substance products, decomposition products or microbial contamination that could adversely affect the impurity profile) Please be careful not to cause carryover.)

GMP2-25 (lot composition) [Question] In the manufacturing of products related to oral liquids, etc., when the drugs in one mixing tank are filled over several days under the same conditions and using the same manufacturing equipment, Is it okay to group all filled products into one lot and give them the same lot number? Also, at what point is it appropriate to take samples for testing and inspection of the product?

[Answer] It is acceptable if the following conditions are met.
1. There is reasonable evidence (validation data, etc.) that the product is manufactured to be homogeneous, and this has been confirmed by the quality department.
2. It must be specified in advance in the Pharmaceutical product standard codes, etc.
3. Time limits should be specified in drug product standards documents, etc.

Also, take note of GMP2-22. Note that sampling must be performed at a time when accurate test and inspection judgments can be made on a representative sample of the lot.

GMP2-26 (lot composition) [Question] Is it correct to think that lot management is not necessary when manufacturing water for injection as manufacturing water continuously?

[Answer] In difficult cases, there is no need to perform so-called lot management. However, based on the validation results, it is necessary to conduct tests and inspections on necessary items as frequently as necessary for quality control. In addition, if a recall is to be carried out due to the occurrence of defective products, etc., it is necessary to handle them as a unit to the extent that they can be classified on reasonable grounds.

GMP2-27 (lot composition) [Question] Water for injection in the Japanese Pharmacopoeia is manufactured by continuously producing distilled water, filling and closing ampoules, etc., during the same manufacturing period, under the same manufacturing conditions, and using the same manufacturing equipment. If there is reasonable evidence that the product will be manufactured to be homogeneous by taking the necessary measures for quality control, the quality department has confirmed this, and it is specified in the drug product standard document, etc. , may a lot be formed by a fixed period or a fixed unit quantity?

[Answer] There is no problem with the lot composition in the case of the question.

GMP2-28 (lot composition) [Question] Can intermediate products (preparations) of different batches manufactured in a series of manufacturing processes during the same manufacturing period be made into the same lot composition at the packaging stage after confirming homogeneity?

[Answer] If there is scientific evidence that the product lot composition has been manufactured to be homogeneous, the quality department has confirmed this, and it is specified in the Pharmaceutical product standard code, etc. , a group of items may be treated as the same lot. In addition, when evaluating homogeneity, not only the conformity of the intermediate product to the specifications, but also the test and inspection results related to in-process control should be evaluated.

GMP2-29 (lot composition (raw materials)) [Question] Even if the same lot of raw materials is received over multiple days, can the manufacturing unit at the supplier of the raw materials be treated as one lot of raw materials at the receiving manufacturing facility?

[Answer] In cases such as the question where raw materials from the same lot are delivered in installments, the general rule is to manage each batch as a separate lot, taking into account changes in quality during transportation. However, taking into account changes in quality during transportation, it may be handled as one lot within the range that has been confirmed to be homogeneous through testing and inspection at the time of acceptance. Please refer to GMP11-12 for testing and inspection of each lot of raw materials in the example in the question.

GMP2-30 (lot composition (raw materials)) [Question] How should lot management of crude drug raw materials be performed?

[Answer] For example, if it is presumed to be homogeneous through testing and inspection at the time of acceptance, it is okay to treat the same imported unit as one lot. There is no problem in treating items that are estimated to have homogeneity in corresponding units as one lot. However, if homogeneity is suspected through visual inspection or other testing at the time of acceptance, it should be handled as a separate lot.

GMP2-31 (mixing of lots, etc.) [Question] Please provide a model for GMP2-19's ``rational evidence that shows that product lots are manufactured to be homogeneous'' for pharmaceutical products that are active ingredients.

[Answer] Next, we will show an example of ``rational grounds that show that lots are manufactured to be homogeneous'' and ``the concept of whether lots can be mixed.''

Examples of reasonable grounds to demonstrate that a lot is manufactured to be homogeneous

No.		Ⅰ		II
classification		Lot-to-lot homogeneity		Homogeneity within lots
Case classification	Preparation amount	Same between lots	Varies between lots
	Final process			With mixing operation	No mixing operation However, the centrifugation operation is performed once or multiple times. Single final crystallizer Multiple drying machines (same type) *If there are multiple final crystallizers (different sizes), there will be "no homogeneity".
Conditions for manufacturing processes, etc. when using the “reasonable grounds” below	Manufacturing process operating procedures (people)	Unit operation procedures, including mother liquor and intermediate recovery procedures, have been established and process control standards have been established in advance. Yield calculations are clear.	For each ordered quantity, unit operation procedures are established, including mother liquor and intermediate recovery procedures, and process control standards are set in advance. Yield calculations are clear.	Unit operation procedures are established and process control standards are set in advance.	Same as left
	Raw materials and materials	Products that meet standards are used.	Same as left	Same as left	Same as left
	Equipment, etc.	Predetermined equipment, equipment, etc. are used. When active ingredients are shared in the production of different products, cleaning methods and evaluation methods have been established.	Predetermined equipment and equipment are used for each ordered quantity. When active ingredients are shared in the production of different products, cleaning methods and evaluation methods have been established.	Predetermined equipment, equipment, etc. are used.	Same as left
	time limit	The time is determined by operating conditions such as each work shift, each day, and each week.	Same as left	Same as left	Same as left
reasonable basis	item ◎Required items ○Implemented as necessary	◎Regulatory approved information such as content ○Particle size, specific volume, crystal polymorphism, crystal habit, angle of repose, solubility, etc.	Same as left	◎ Necessary items such as content to determine mixing time and mixing speed	◎Drying conditions (time, temperature, etc.) ◎Necessary items such as content, loss on drying, particle size, etc. to determine grinding conditions (feed rate, screen size)
	judgement	There should be no difference in the data obtained from multiple lots using established sampling methods.	There should be no difference between lot sizes or between lots in the multiple data obtained for each ordered quantity using established sampling methods.	There should be no difference in the data obtained within a lot using the established collection method.	Same as left

Concept of whether or not lots can be mixed

Preconditions (mixing fractions from one lot in the process according to a predetermined procedure (at the point when the lot number for the process is determined) (e.g. dividing one lot into multiple parts, centrifuging and drying them) ) is not considered "mixing" here.)

1. Lots that are found to be out of specification as a result of testing shall not be mixed for the purpose of conforming to the specifications.
2. Each lot to be mixed shall be manufactured according to a predetermined process, tested and inspected, and confirmed to comply with specifications.
3. The mixing process should be well controlled and documented. Mixed lots shall be tested and inspected as necessary to determine whether they conform to predetermined standards
4. Manufacturing records related to the mixing process should be created to enable tracing to each lot that made up the mixture
5. If the physical characteristics of the product are important, the blending process should be validated to demonstrate the homogeneity of the blended lot. The validation should include verification of important properties that can be affected by the mixing process (e.g. particle size distribution, bulk density, etc.).
6. The expiration date, expiration date, or retest date of a mixed lot shall be based on the manufacturing date of the oldest of the lots that make up the combination or mixture.

GMP2-32 (mixing of lots, etc.) [Question] I would like to combine multiple batches of pharmaceutical products that are active ingredients manufactured under the same manufacturing conditions and equipment to form one lot. Is testing and inspection of all items necessary for multiple batches before mixing?

[Answer] Before mixing, it shall be confirmed that the "batch" conforms to the specifications, and items deemed necessary for quality control shall be set in the specifications for the batch, and testing and inspection shall be conducted.

GMP2-33 (mixing of lots, etc.) [Question] In the manufacturing of products related to infusion preparations, several batches are often combined to form one lot, so please provide some general points to keep in mind.

[Answer] Regarding the points to keep in mind regarding the lot composition when batches that have been sterilized in multiple batches in the manufacturing process of infusion preparations are combined into one lot, the following matters should be confirmed by the quality department and the pharmaceutical product This should be specified in advance in the standard document, etc.

1. Reasonable basis to show that it is manufactured to be homogeneous

2. Simultaneously conduct process monitoring of the sterilization process, keep it as a record, and if a defect in the sterilization process is suspected in the final product, investigate all potentially related sterilization batches. Provisions for appropriate treatment

GMP2-34 (mixing of lots, etc.) [Question] Is it possible to mix fractions of one lot with another lot to make one lot for products related to pharmaceutical products that are active ingredients?

[Answer] Products must not be mixed together for the purpose of concealing the nonconformity of a particular lot, but it is acceptable to combine fractional items from lots that conform to the specifications into one lot. Ensure that the lot is homogeneous and conforms to specifications before mixing. In addition, the quality department should confirm the method, write it down in advance in the Pharmaceutical product standard code, etc., and create records so that the lot history can be confirmed.

GMP2-35 (mixing of lots, etc.) [Question] One lot, which has gone through a series of manufacturing processes up to the final stage, is divided into two parts in the final process after crystallization to produce a drug product that is an active pharmaceutical ingredient. Can these be combined and treated as one lot?

[Answer] It is necessary that the product conforming to appropriate process control be made into a drug product that is an active pharmaceutical ingredient through a uniform process. There is reasonable evidence that the product related to the drug substance after crystallization has been manufactured to have homogeneity, and this has been confirmed by the quality department and specified in advance in the drug product standard document, etc. In some cases, it may be treated as one lot.

GMP2-36 (mixing of lots, etc.) [Question] If a lot that has gone through a series of manufacturing processes is divided and mixed using multiple mixers under the same conditions, can they be combined and treated as one lot?

[Answer] There is reasonable evidence (validation data, etc.) that the "multiple mixers" have the same mixing effect and are manufactured to be homogeneous, and the quality department confirms this, If it is specified in advance in the Pharmaceutical product standard code, etc., it may be treated as one lot.

GMP2-37 (mixing of lots, etc.) [Question] Is it okay to divide a lot that has gone through a series of manufacturing processes and integrate the parts that have been sterilized using different types of high-pressure steam sterilizers and treat them as one lot?

[Answer] Traceability of sterilization units must be ensured. When handling as a single lot, it is acceptable as long as records for each sterile unit are properly prepared and homogeneity is validated. Regarding sterilization validation, please refer to "Handling of reference information deleted due to enactment of the 17th revised Japanese Pharmacopoeia Second Supplement" (June 28, 2019, Pharmaceutical Evaluation and Management Division, Surveillance and Guidance/Narcotics Countermeasures Division Administrative Communication) ).

GMP2-38 (mixing of lots, etc.) [Question] If it is possible to clearly trace the relationship between the packaged product lot and the concentrate preparation batch or compounding batch for a drug product, one lot of the packaged product corresponds to multiple concentrate preparation batches or compounding batches. Can it be something?

[Answer] Please refer to GMP 2-28.

GMP2-39 (lot and serial number, etc.) [Question] The number attached to each product for each lot to perform lot management based on the provisions of the GMP Ministerial Ordinance, and the manufacturing number written on the direct container or direct packaging of the drug as prescribed in Article 50, Item 3 of the Act. Do the numbers or manufacturing codes have to be the same?

[Answer] If the relationship between the lot number and the manufacturing number or manufacturing code at the manufacturing stage is clarified and manufacturing records are created to enable bidirectional tracking, then the numbers or symbols do not necessarily need to be the same. There isn't.

GMP2-40 (lot and serial number, etc.) [Question] By using the abbreviation of the manufacturing date as the manufacturing number or manufacturing code, is it possible to display the same manufacturing number or manufacturing code on another item that has the same active ingredient but a different content? Okay?

[Answer] In the case of the question, it is easy to identify whether the production lot is subject to recall because the items are clearly different, and there is no problem with recall (because it is difficult to identify as a result) (Please note that if there is a problem with collection, the responsibility may fall to the person who made the display.) However, the relationship between the lot number at the manufacturing stage and the manufacturing number or manufacturing code displayed on the final product must be clarified, and records must be created to enable bidirectional tracking.

GMP2-41 (lot and serial number, etc.) [Question] I would like to add an “identification symbol” to individual packaging boxes to distinguish them from products of the same lot that have already been shipped, such as when replacing the package insert for a product that has not yet been determined to be shipped from a manufacturing facility. Is it not necessary to add notes to containers, etc.?

[Answer] There is no need to write it directly on the container, etc., as long as it is not confusing with the serial number or manufacturing code.

GMP2-42 (lot and serial number, etc.) [Question] When intermediate products from the same manufacturing lot are packaged into several types of packaging units during the packaging process, is it permissible to display the same manufacturing number or manufacturing code on the different packaging units or packaging formats?

[Answer] In the case of the question, even if the same manufacturing number or manufacturing symbol is displayed, the items are clearly different and it is easy to identify whether the product lot is subject to recall or not, and there is no problem with recall, etc. (It should be noted that if the product is difficult to identify as a result and the product collection is hindered, the responsibility may be attributed to the person who made the labeling.) If the product has the same serial number or It is acceptable to display the manufacturing symbol.

However, the relationship between the lot number at the manufacturing stage and the manufacturing number or manufacturing code displayed on the final product must be clarified, and manufacturing records must be created to enable bidirectional tracking.

(example)

① It is permissible to display the same manufacturing number or manufacturing symbol on bottles of 100 tablets and bottles of 1,000 tablets.

② It is acceptable to display the same manufacturing number or manufacturing code on 100-tablet bottles and 100-tablet PTP packages.

management unit

GMP2-43 (management unit) [Question] What is the scope of the material management unit defined in Article 2, Paragraph 8 of the GMP Ministerial Ordinance?

[Answer] For example, if the quality standards, manufacturing methods, etc. of the raw materials (materials) of the material supplier are the same, and the material is confirmed to be homogeneous based on the results of testing and inspection at the time of receiving the material, etc. Within the scope specified above, any of the following units may be considered as a management unit.

1. Manufacturing unit at material supplier
2. Unit for management of raw materials (materials) at material suppliers
3. Unit of delivery to manufacturers, etc. by material suppliers

GMP2-44 (Corrective actions and preventive actions) [Question] How should we judge the appropriateness of "measures to eliminate the situation" stipulated in Article 2, Paragraphs 14 and 15 of the GMP Ministerial Ordinance?

[Answer] For example, one possible method is to use quality risk management to confirm that the risk of recurrence of detected nonconformities and other undesirable situations has been reduced to an acceptable level. In addition, the effectiveness of the measures should be appropriately evaluated by confirming that similar events do not occur again.

改正GMP省令　Article 3-2　Compliance with regulatory approved information

GMP3 2-1 (Compliance with regulatory approved information) [Question] What do I need to keep in mind when manufacturing in accordance with the regulatory approved information?

[Answer] Manufacturers, etc. should obtain information regarding the manufacturing method and testing method of the product's manufacturing and marketing approval (notification) form from the product's marketing authorization holder, and ensure that there are no discrepancies between the approved content and the actual manufacturing status. thing. Furthermore, pursuant to the provisions of Article 10, Paragraph 5 of the GQP Ministerial Ordinance, marketing authorization holders are required to provide manufacturers, etc. with information regarding appropriate and smooth manufacturing control and quality, including the contents of the marketing approval (notification) form. Therefore, manufacturers should work closely with manufacturers and distributors to always obtain the latest information. In particular, information must be obtained reliably at the time of manufacturing and sales approval, approval of partial changes to manufacturing and sales approval items, confirmation of change plans related to manufacturing and sales approval items (hereinafter referred to as "partial change approval, etc."), and notification of minor changes. thing. In addition, if you are registered with the Register of Active Pharmaceutical Ingredients (hereinafter referred to as "MF"), you must ensure that there are no discrepancies between the MF registration contents and the actual manufacturing status based on the MF usage agreement with the marketing authorization holder. . Specifically, manufacturers, etc. should keep track of the latest MF registration content, and if they intend to make changes that affect or are likely to affect the MF registration content, they should contact the marketing authorization holder at an appropriate time (manufacturer etc.). (Including communication through the MF domestic administrator, etc. based on arrangements with distributors.) Changes must be implemented after obtaining confirmation from the manufacturer/seller.

改正GMP省令　Article 3-3　Pharmaceutical Quality System

GMP3 3-1 (Pharmaceutical Quality System) [Question] If I have already established a quality management system based on ISO9001, etc., is it necessary to establish a pharmaceutical quality system again based on the GMP ministerial ordinance?

[Answer] If a "quality management system" based on ISO9001, etc. has already been constructed and operated, and if the quality management system is sufficient compared to the pharmaceutical quality system specified in the GMP ministerial ordinance, It's good to continue doing that.

GMP3-3-2 (Responsibilities of manufacturers, etc.) [Question] If a company has multiple manufacturing facilities, is it necessary to establish a separate pharmaceutical quality system for each manufacturing facility, or is it okay for the pharmaceutical company to construct and operate one pharmaceutical quality system?

[Answer] The construction of a pharmaceutical quality system can be handled flexibly depending on the size of the company. An independent pharmaceutical quality system may be established as a manufacturing site, or a single pharmaceutical quality system may be constructed including multiple manufacturing sites. However, when building a single pharmaceutical quality system that includes multiple manufacturing sites, it is necessary to clearly define the responsibilities of the company-wide pharmaceutical quality system in addition to the GMP organization chart established for each manufacturing site.

GMP3 3-3 (Pharmaceutical Quality System) [Question] It says, "Build an effective pharmaceutical quality system," but what does an effective pharmaceutical quality system mean?

[Answer] It is necessary for the manufacturer, etc. to have a quality manual, etc., and operate it so that it fulfills its responsibilities stipulated in the management commitment of the Q10 guideline, which serves as a reference for the pharmaceutical quality system of the GMP ministerial ordinance. In addition, established quality policies, quality targets, and internal systems must be made known by the manufacturer to all relevant employees, and an appropriate information communication system must be in place. The design of a pharmaceutical quality system is defined as the elements of a pharmaceutical quality system (monitoring system for manufacturing process performance and product quality, corrective action and preventive action (CAPA) system, change management system, management review). There are certain functions that are designed to enhance GMP activities and promote continuous improvement. The specific procedures and methods must be appropriately established and operated by the manufacturer, etc.

GMP3 3-4 (Pharmaceutical Quality System) [Question] It states that ``the quality policy must be established in writing, and the components of the pharmaceutical quality system, such as procedures, must be indicated in the document.'' What kind of items need to be established in writing?

[Answer] The document concerned is the "Guidelines for Pharmaceutical Quality Systems" (February 19, 2010, Pharmaceutical Food and Drug Administration Bureau No. 0219 No. 1/Pharmaceutical Food and Drug Administration Bureau No. 0219 No. 1) (hereinafter referred to as the Q10 Guidelines) and It corresponds to the quality manual in the PIC/S GMP guidelines and describes the pharmaceutical quality system including the following items.

·quality policy
Scope of application of pharmaceutical quality system
Identification of pharmaceutical quality system processes and their sequence, relationships and interdependencies
Responsibilities of manufacturers, etc. within the pharmaceutical quality system

The quality manual must include the elements of the pharmaceutical quality system (monitoring system for manufacturing process performance and product quality, CAPA system, change management system, management review), and the basic concept of these elements is shown below. .

1. Manufacturing process performance and product quality monitoring system

Planning and implementing a system for monitoring manufacturing process performance and product quality to ensure that the manufacturing process maintains its ability and control to produce a product of set quality.

2. CAPA system

A structured approach to the investigation process to identify root causes, leading to improvements and deeper understanding of products and manufacturing processes.

3. change management system

Systematic efforts to appropriately evaluate proposed changes using knowledge management, quality risk management, experts in related fields, etc. to confirm that the objectives have been achieved and that there are no negative effects on product quality after implementation of the changes. provides a high degree of assurance that changes will not have unintended consequences.

Four. management review

Product quality management reviews are conducted to evaluate the quality of each product and the effectiveness of manufacturing processes, and to promote continuous improvement of product quality, and the continuity of the pharmaceutical quality system by evaluating the effectiveness of each element of the quality system. There are two types of management reviews of pharmaceutical quality systems that are carried out to improve performance. Manufacturers, etc. evaluate the operational performance of manufacturing processes, product quality, and the results of periodic reviews of pharmaceutical quality systems, and continuously improve both product quality and the pharmaceutical quality system that is the mechanism to guarantee it.

GMP3 3-5 (Pharmaceutical Quality System) [Question] Please explain your quality policy.

[Answer] In addition to Article 3-5(1) of the Notice of Promulgation of Revised Ministerial Ordinance, the established quality policy must be communicated and understood by all levels of personnel involved in pharmaceuticals, so it must be communicated to all personnel through posting, distribution, education, etc. It is necessary to make this information widely known. In addition, the ongoing effectiveness of the quality policy must be reviewed periodically, such as during management reviews, and revised as necessary.

GMP3 3-6 (Pharmaceutical Quality System) [Question] Section 5(1) of the Notification of Promulgation of Revised Ministerial Ordinance states that one of the elements that the quality policy should include is "meeting the requirements of the GMP Ministerial Ordinance." What does this include? .

[Answer] etc. include related regulatory requirements and guidelines, such as the Act, the Japanese Pharmacopoeia, standards for biological raw materials, ICH notifications, GMP guidelines for PIC/S, and domestic guidelines (“Aseptic Possible examples include "Guidelines for the manufacture of pharmaceuticals" and "Guidelines for the manufacture of sterile pharmaceuticals using terminal sterilization methods," or the latest version of related guidelines.

GMP3 3-7 (Pharmaceutical Quality System) [Question] If the manufacturer, etc. and the marketing authorization holder are the same corporation or group company, is it okay for the manufacturer, etc. to share the quality policy established by the marketing authorization holder?

[Answer] Good.

GMP3 3-8 (Pharmaceutical Quality System) [Question] The GMP Ministerial Ordinance stipulates that manufacturers, etc. must have a The manufacturing supervisor or an organization in charge of quality assurance activity set quality goals at their manufacturing facility based on the quality policy. Is it okay to set quality goals for each department and organization?

[Answer] Each department and organization may set quality goals according to their respective operations. Furthermore, the The manufacturing supervisor or the organization in charge of quality assurance shall manage the creation of appropriate quality objectives in these departments.

GMP3 3-9 (Pharmaceutical Quality System) [Question] The GMP Ministerial Ordinance says to "achieve quality goals," but how can we determine whether quality goals are being achieved?

[Answer] As one method for evaluating the degree of achievement of quality goals, the Q10 guideline, which serves as a reference for the pharmaceutical quality system of the GMP Ministerial Ordinance, describes ``performance evaluation indicators to measure progress toward quality goals.'' Performance evaluation indicators, also known as KPIs (Key Performance Indicators), are set for the purpose of monitoring the progress toward quality goals, and standards for evaluating the degree of achievement are established when setting quality goals, and are checked periodically. This will be reported at the management review. As a result of evaluation based on KPIs, management reviews confirm and verify what was not achieved, the reasons for it, and whether horizontal development is being carried out.Based on the commitment there, we continuously improve system and product quality. The key is to run the PDCA cycle. Furthermore, if possible, the objectivity of the evaluation can be increased by quantifying the KPI.

GMP3 3-10 (Pharmaceutical Quality System) [Question] What are the resources needed to establish and implement a pharmaceutical quality system? Also, what exactly does it mean to allocate resources?

[Answer] According to Article 3-3, Item 4 of the GMP Ministerial Ordinance, resources are defined as the knowledge and skills possessed by individuals, as well as technology, equipment, and other resources utilized for manufacturing control and quality control at manufacturing facilities. This includes, for example, organizations, personnel, budgets, and information, and refers to all management resources considered necessary to realize the establishment, implementation, maintenance, and continuous improvement of a quality management system. Note that the equipment includes software. Allocating resources means that manufacturers clarify and provide the necessary resources based on management reviews, escalation, etc.

GMP3 3-11 (Pharmaceutical Quality System) [Question] What does "regularly check the pharmaceutical quality system" specifically refer to?

[Answer] “Regularly check the pharmaceutical quality system” refers to management reviews in the Q10 guidelines and the PIC/S GMP guidelines. Management reviews are conducted periodically to confirm that the pharmaceutical quality system continues to be appropriate and effective. Manufacturers, etc. will evaluate the operational performance of manufacturing processes and product quality, as well as the results of periodic reviews of pharmaceutical quality systems. The quality manual should describe the frequency of management review meetings, information input, and output from manufacturers, etc. It is also the responsibility of manufacturers, etc. to ensure that management reviews are conducted.

Examples of inputs include:

1. Product quality inspection results
・Information regarding product quality (complaints, recalls, etc.)
・Results and considerations of process control and product quality control (including trend analysis)
・Results of effectiveness evaluation of changes

2. Evaluation of the effectiveness of pharmaceutical quality systems
・Status of complaint management, deviation management, CAPA and change management
・Status of outsourced work
・Risk assessment status
・Appropriateness of work related to quality assurance

3. Factors influencing pharmaceutical quality systems
・Response to new regulations and guidelines
・Status of quality issues (internal and external environment)
・Changes in the business environment
・Status of development and technological innovation
・Issues regarding succession, patents, and trademarks

4. Results of inspections by authorities and response status, results of external audits and self-inspections

5. Follow-up from previous management review

Possible output examples include the following:

1. Instructions for improving manufacturing processes and products
2. Instructions for improving pharmaceutical quality systems
3. Instructions for sharing necessary knowledge
4. Resource allocation (review), instruction on education and training
5. Instructions for revising quality goals
6. Sharing of management review results (effective horizontal deployment)

GMP3 3-12 (Pharmaceutical Quality System) [Question] Q10 Guidelines, which serve as a reference for pharmaceutical quality systems in the GMP Ministerial Ordinance, mention knowledge management as a method for achieving a pharmaceutical quality system.What is this?

[Answer] Knowledge management is a systematic effort to acquire, analyze, accumulate and disseminate information on products, manufacturing processes and component materials, and its specific ideas and methods. has been published on the PMDA's website as a result of research on international harmonization of GMP, QMS, and GCTP guidelines (Explanatory materials on knowledge management (2019)).

GMP3-3-13 (Pharmaceutical Quality System) [Question] When making changes to the pharmaceutical quality system, such as changes to quality policies, quality targets, quality manuals, etc., is it necessary to comply with Article 14 of the GMP Ministerial Ordinance?

[Answer] Article 14 does not necessarily have to be followed when changing the pharmaceutical quality system, but if the change is to raw materials, materials, or product specifications or manufacturing procedures (including regulatory approved information), Article 14 must be followed. Follow.

改正GMP省令　Article 3-4　Quality Risk Management

GMP3 4-1 (Quality Risk Management) [Question] Article 3-4, Paragraph 2 of the GMP Ministerial Ordinance stipulates that documents related to quality risk management implementation procedures and other necessary matters must be prepared, but is an independent Standard Operating Procedures necessary?

[Answer] Although an independent Standard Operating Procedures is not required, a document specifying quality risk management is necessary. Create and store procedures for implementing quality risk management and other necessary documents and records.

GMP3 4-2 (Quality Risk Management) [Question] Your company carries out CAPA, but can you say that quality risk management is being carried out?

[Answer] Quality risk management is a systematic process consisting of assessment, control, communication, and review of risks related to drug quality throughout the product lifecycle. CAPA is not just one type of quality risk management, but these processes should be utilized in quality system activities that include CAPA.

GMP3 4-3 (quality risk management) [Question] The article states, "Use quality risk management to build a pharmaceutical quality system." How should quality risk management be utilized?

[Answer] The Q10 guideline, which serves as a reference for the pharmaceutical quality system of the GMP ministerial ordinance, states that quality risk management can provide independent efforts to identify, scientifically evaluate, and control potential risks to quality. is defined as a method to facilitate the achievement of the objectives of a pharmaceutical quality system. With one of the objectives being "establishing and maintaining a controlled state," quality risk management is used to identify monitoring and control systems. Another objective, ``Promoting Continuous Improvement,'' is used to identify and prioritize areas for continuous improvement. Please note that the "Guidelines for Quality Risk Management" (September 1, 2006, Pharmaceutical and Food Safety Bureau No. 0901004) provides examples of principles and methods for quality risk management that can be applied to various aspects of pharmaceutical quality. /Pharmaceuticals, Food and Drug Administration No. 0901005), "Question and Answer Collection (Q&A) Regarding 'Guidelines for Pharmaceutical Development,' 'Guidelines for Quality Risk Management,' and 'Guidelines for Pharmaceutical Quality Systems.'" (September 2010) Please also refer to "Regarding the Utilization of Quality Risk Management in Pharmaceutical Quality Systems" (Administrative Communication of the Monitoring and Guidance/Narcotics Control Division dated July 7, 2017), etc. thing.

改正GMP省令　Article 4　Manufacturing Department and Quality Department

GMP4-1 (quality department) [Question] What kind of organization does the "organization in charge of quality assurance activity" defined by the quality department stipulated in Article 4, Paragraph 3, Item 1 of the GMP Ministerial Ordinance have to be?

[Answer] The "organization in charge of quality assurance-related work" is required to be objective as a function responsible for quality assurance, and to be an organization independent from the manufacturing department. In addition, depending on the size and structure of the organization, the "quality department" may have separate "organizations in charge of work related to quality assurance" and "organizations in charge of work related to testing and inspection," or both . An organization may take the form of a single organization or a group. Please refer to Section 7(3) of the Revised Ministerial Ordinance Promulgation Notice No. 3 regarding concurrent positions with employees of organizations in charge of operations related to testing and inspection. In addition, each company may appropriately determine its name. An example of an organization chart is shown below.

GMP4-2 (quality department) [Question] Is it possible to replace the ``organization responsible for quality assurance-related work'' with the head office quality assurance department, etc.?

[Answer] Instead of establishing an "organization in charge of quality assurance-related work" within the manufacturing site's organization, the work that should be performed by the "organization in charge of quality assurance-related work" is outsourced to the quality assurance department of the head office, etc. It is not allowed to do so. However, as long as it does not interfere with quality assurance-related work, employees belonging to the head office quality assurance department, etc. may concurrently serve in the "organization responsible for quality assurance-related work" at the manufacturing site. In this case, the responsibilities of employees belonging to the head office quality assurance department, etc. should be clearly stated in the document set forth in Article 6, Paragraph 4 of the GMP Ministerial Ordinance.

GMP4-3 (quality department) [Question] Is it possible for the person in charge of the “organization responsible for work related to quality assurance” and the person in charge of the “organization responsible for work related to testing and inspection” to concurrently hold the same position?

[Answer] As the "organization in charge of quality assurance-related work" is required to be objective as a function responsible for quality assurance, it is desirable to avoid concurrently serving as the person in charge of both organizations. However, if it is necessary for a person to serve as both managers due to the size of the company, etc., the duties of the person responsible for each organization should be clearly differentiated. In addition, the responsibilities, etc. should be clearly stated in the document specified in Article 6, Paragraph 4 of the GMP Ministerial Ordinance.

GMP4-4 (quality department) [Question] When creating Pharmaceutical Product Standard Code and Standard Operating Proceduress, is it necessary to have their contents verified by the organization in charge of quality assurance activity?

[Answer] Although it is not necessarily necessary to obtain confirmation from the organization in charge of quality assurance activity, in accordance with Article 5, Paragraph 1, Item 3 of the GMP Ministerial Ordinance, manufacturing procedures, etc. should be made to ensure that they do not differ from regulatory approved information. Considering that it is required that the organization in charge of work related to quality assurance manage the work, when creating Pharmaceutical Product Standard Code and Standard Operating Proceduress, the organization in charge of work related to quality assurance confirms the contents. It is desirable to receive

改正GMP省令　Article 5　The manufacturing supervisor

GMP5-1 (The manufacturing supervisor) [Question] Is it permissible for the The manufacturing supervisor to be the person in charge of the manufacturing department or the quality department?

[Answer] A person is not allowed to be in charge of the manufacturing department, but if there is no problem with management, he or she may be in charge of the quality department.

Assisting manufacturing supervisor with their work

GMP5-2 (assistance of manufacturing supervisor's work) [Question] If the scale of a manufacturing facility becomes large and there are separate buildings for different dosage forms on the same premises, is it okay to appoint multiple The manufacturing supervisors? If there must be one person, is it okay to appoint more than one deputy The manufacturing supervisor (assistant)?

[Answer] There shall be one The manufacturing supervisor per manufacturing site. In a manufacturing facility that is large in scale and handles a wide variety of products, it is acceptable to appoint an assistant in case a situation arises in which the The manufacturing supervisor is unable to perform his or her duties (if it is deemed unavoidable). However, the scope of the auxiliary work, the method of reporting to the The manufacturing supervisor, etc. must be clearly specified in the document stipulated in Article 6, Paragraph 4 of the GMP Ministerial Ordinance.

Acting on behalf of the manufacturing supervisor

GMP5-4 (acting on behalf of The manufacturing supervisor) [Question] Is it okay to appoint a substitute in case the The manufacturing supervisor is absent due to business trips, hospitalization, etc.?

[Answer] In the case of questions, if it is deemed that there will be no hindrance to business operations, there is no problem in appointing a representative.

However, the agent must have the same qualifications as a The manufacturing supervisor (qualifications stipulated in Article 17, Paragraph 5 of the Act), and the responsibilities of the agent at the time of acting on behalf of the agent must be written in the document stipulated in Article 6, Paragraph 4 of the GMP Ministerial Ordinance. Please specify. In addition, if the period of absence is extremely long, there is a risk of disruption to the operations of the manufacturing plant, so the The manufacturing supervisor should be replaced rather than the substitute.

GMP5-5 (acting on behalf of The manufacturing supervisor) [Question] In a manufacturer where the manufacturing site and the head office (the main office of the corporation) are far apart, if the The manufacturing supervisor often travels to the head office to carry out his/her duties, it is permissible to appoint a substitute. mosquito.

[Answer] In the case of questions, if it is deemed that there will be no hindrance to business operations, there is no problem in appointing a representative.

However, the agent must have the same qualifications as a The manufacturing supervisor (qualifications stipulated in Article 17, Paragraph 5 of the Act), and the responsibilities of the agent at the time of acting on behalf of the agent must be written in the document stipulated in Article 6, Paragraph 4 of the GMP Ministerial Ordinance. Please specify.

GMP5-6 (acting on behalf of The manufacturing supervisor) [Question] Since the The manufacturing supervisor is busy with work at the head office, etc., is it acceptable to appoint a substitute and fully delegate the work of the The manufacturing supervisor for a long period of time?

[Answer] Not allowed. The manufacturing supervisors need to manage the manufacturing site on-site. Change the manufacturing supervisor.

GMP5-7 (acting on behalf of The manufacturing supervisor) [Question] If a representative is appointed for the manufacturing supervisor, is it okay to use the seal for signing and affixing the name and seal as that of the representative?

[Answer] It should belong to the agent. However, the responsibilities, etc. related to the signature or affixing of name and seal of the agent must be clearly stated in the document as stipulated in Article 6, Paragraph 4 of the GMP Ministerial Ordinance.

改正GMP省令　Article 6　Staff

GMP6-1 (staff) [Question] Does the material storage department need not belong to the manufacturing department in terms of internal organization?

[Answer] The act of storing materials for manufacturing is also subject to the GMP Ministerial Ordinance, and the department that conducts this must be included in the manufacturing department under GMP. Furthermore, it is desirable that the responsibilities and management system of manufacturing plant personnel as stipulated in Article 6, Paragraph 4 of the GMP Ministerial Ordinance are consistent with the "in-house organization" in both name and reality, but it is important to properly implement the management stipulated in the GMP Ministerial Ordinance. As long as it is possible and the mutual relationship is made clear, there is no problem even if the name, etc. of the "internal organization" does not necessarily match.

GMP6-2 (staff) [Question] What kind of person does the "responsible person" in Article 6 of the GMP Ministerial Ordinance specifically refer to?

[Answer] A responsible person is a person appointed by a manufacturer, etc. according to the scale of the manufacturing facility and the type of work, etc. in order to carry out manufacturing and quality-related operations appropriately and smoothly. In addition to the person in charge of the quality department, this includes the person in charge of each task (e.g., person in charge of validation, etc.) as indicated in the notification of promulgation of the revised ministerial ordinance. If the manufacturer, etc. is a corporation, the executive responsible for pharmaceutical affairs, including the corporation's representative, will take the initiative to ensure that appropriate responsible persons are responsible through securing resources and confirming the GMP system through management reviews. It is necessary to secure a system for engaging in work.

GMP6-3 (staff) [Question] What kind of person is appropriate to be responsible for work related to quality assurance?

[Answer] The person responsible for quality assurance-related work must have the ability to properly and smoothly carry out quality assurance-related work. Therefore, candidates are required to have knowledge of manufacturing/quality-related operations or quality control operations under the GQP ministerial ordinance, appropriate understanding and judgment, and to be familiar with operations related to quality assurance.

改正GMP省令　Article 7　Pharmaceutical Product Standard Code

GMP7-1 (Pharmaceutical product standard code general matters) [Question] Article 7 of the GMP Ministerial Ordinance states that manufacturers, etc. are required to create and store Pharmaceutical Product Standard Code for pharmaceutical products. does it have to be done?

[Answer] It requires that it be prepared and operated under the control of the manufacturer, etc. (in the case of a corporation, as a corporation), and when creating a new one or revising it, document management is required based on the provisions of Article 20 of the GMP Ministerial Ordinance. It may be carried out by a person (organization, etc.) who is authorized by the document set forth in Article 6, Paragraph 4 of the GMP Ministerial Ordinance, in accordance with the method. The same applies to the Standard Operating Procedures in Article 8 of the GMP Ministerial Ordinance. Furthermore, Pharmaceutical Product Standard Code must be approved by the quality department, and other procedures that affect product quality must be confirmed by the quality department and documented.

GMP7-2 (Pharmaceutical product standard code general matters) [Question] When undergoing a pre-approval GMP compliance investigation, it is necessary to prepare Standard Operating Proceduress stipulated in the GMP Ministerial Ordinance, but when creating a drug product standard document under Article 7 of the GMP Ministerial Ordinance, there are matters regarding materials. Do we also need to stipulate that?

[Answer] By the time a pre-approval GMP compliance survey is submitted, matters related to materials such as specifications for containers, packaging, and labeling, and testing and inspection methods must be written in advance in the drug product standards document for the product for which the survey application is being applied. It is necessary to keep it. However, in manufacturing facilities that handle labeled materials, when undergoing a pre-approval GMP compliance investigation, a draft drug product standard document containing the items that should be stipulated at that time (checked by the quality department) is required. However, since the display items, etc. specified by the manufacturing and marketing approval will be included in the drug product standard document, they should be finalized immediately after the manufacturing and marketing approval. .

GMP7-3 (ingredients and amounts) [Question] The section on injections in the Japanese Pharmacopoeia's General Rules for Preparations states that ``If this drug uses an aqueous solvent, sodium chloride or other additives may be added to make it isotonic with blood or body fluids, and the pH may be adjusted. To do this, an acid or alkali can be added." Is it okay to add these substances to the Japanese Pharmacopoeia's Pharmaceutical Product Standard Code for Injectable Products even if they are not listed in the manufacturing and marketing approval (notification) form? What about products related to injections outside the Japanese Pharmacopoeia?

[Answer] In either case, addition is not permitted unless it is stated in the manufacturing and marketing approval (notification) document.

GMP7-4 (ingredients and quantities) [Question] If an ingredient listed as “Japanese Pharmacopoeia ○○○” in the “Ingredients and Quantity or Essence” column of the manufacturing and marketing approval (notification) form continues to be listed in the revised Japanese Pharmacopoeia, the GMP Ministerial Ordinance will apply. Article 7, Notification of Promulgation of Revised Ministerial Ordinance No. 3-10(3) ① A. Components of the product and raw materials used in its manufacture (if the components are unknown, their essence) Regarding "amounts, specifications, and testing and inspection methods," are they based on the standards of the old pharmacopoeia or the new pharmacopoeia? What if an ingredient listed as "Appended Standard ○○○" is newly listed in the revised Japanese Pharmacopoeia? Furthermore, what if it is listed in something other than the official standard?

[Answer] Handle it based on the notification regarding handling etc. due to the revision of the Japanese Pharmacopoeia. Items other than the compendial standards (Japanese Pharmacopoeia, biological product standards, and radiopharmaceutical standards), specifically non-Japanese Pharmacopoeia drug standards, pharmaceutical excipient standards, non-Japanese Pharmacopoeia crude drug standards, and raw materials for in vitro diagnostics. For standards, pesticide guidelines, food additive standards, standards for quasi-drug raw materials, etc., it may be possible to state component standards in accordance with the official standards, but in this case, the same shall apply to the official standards. It is necessary to consider whether the standards are appropriate, taking into consideration whether the drug is listed, the route of administration, and the purpose of use of the proposed drug.

GMP7-5 (ingredients and amounts) [Question] Regarding products related to Chinese herbal extract preparations, the “manufacturing” in Chapter 3, Section 3-7(4) G of Partial Amendment Enforcement Notification as Items to be Included in Product Standards in Article 7 of the GMP Ministerial Ordinance for Pharmaceuticals and Quasi-Drugs ``Methods and Manufacturing Procedures'', if the content of the main ingredient of the product is insufficient even though crude drugs that meet the specifications are used as raw materials, ingredients that are not listed in the manufacturing and marketing approval (notification) form may be used as the missing ingredient. Is it permissible to add a corresponding amount?

[Answer] Not allowed.

GMP7-6 (ingredients and amounts) [Question] If Japanese Pharmacopoeia ○○○ is listed as the specification in the "Ingredients and Quantity or Essence" column of the manufacturing and marketing approval (notification) form, it is a pharmaceutical product under Article 7 of the GMP Ministerial Ordinance regarding the product concerned. Notice of Promulgation of Revised Ministerial Ordinance No. 3-10(3) ① as Items to be Included in Standards: Components of products and raw materials used in their manufacture (if the components are unknown, their essence), quantities, specifications, and tests Is it permissible to use raw materials that meet the Japanese Pharmacopoeia standards but are not labeled with the Japanese Pharmacopoeia in the "Inspection Methods" and (E) "Manufacturing Methods and Procedures"?

[Answer] Priority should be given to those labeled as “Japanese Pharmacopoeia.” If it is unavoidable to use raw materials that are not labeled in the Japanese Pharmacopoeia, please confirm that they are equivalent to or higher than the standards of the Japanese Pharmacopoeia, and apply additional standards and testing methods as necessary. Please carefully check the quality of raw materials before use. In addition, similar measures should be taken for other raw materials that are subject to compendial standards.

GMP7-7 (specifications and test methods) [Question] Concerning crude drugs used as raw materials for manufacturing products related to Chinese herbal extract preparations, amended Ministerial Ordinance promulgation notification No. 3-10(3) ① A. What points should be kept in mind in terms of quality control regarding the ingredients of products and raw materials used in their manufacture (or their essence if the ingredients are unknown), quantities, specifications, and testing and inspection methods?

[Answer] Raw materials used as crude drugs are tested and inspected according to the standards of the Japanese Pharmacopoeia, the standards for crude drugs outside the Japanese Pharmacopoeia, and the attached specifications for manufacturing and marketing approval (notification) forms. Care should be taken to use crude drugs of appropriate quality by setting the following items and conducting tests and inspections as necessary.

1. Property tests (appearance, microscopic examination, etc.), confirmation tests, quantitative tests, etc.

2. Particle size test of cut crude drug

3. appraisal test

Four. Purity test (foreign substances, pesticide residue test, heavy metal test, arsenic test, aristolochic acid test)

Five. Other required tests

(1) Ingredients other than the Japanese Pharmacopoeia, non-Japanese Pharmacopoeia standards for herbal medicines, manufacturing and marketing approval (notification) document attached specifications, extract content, loss on drying, ash content and acid-insoluble ash content tests, etc.

(2) Confirmation of processing methods and remedies for crude drugs

(3) Tests based on the characteristics of individual crude drugs (microbial limit test, aflatoxin test, powder physical property test of crude drug powder, lucidin and lucidin-3-O- of madder root (including what is called madder root, madder grass, etc.) exams related to primeveroside), etc.

GMP7-8 (specifications and test methods) [Question] In the GMP Ministerial Ordinance Article 7, Pharmaceutical Product Standard Code, there is a statement in Article 7 of the GMP Ministerial Ordinance Promulgation Notice No. 3, 10(3) ①A, “Ingredients of products and raw materials used in their manufacture (if the ingredients are unknown, the ``Essence) and quantity, specifications, and testing and inspection methods''; (a) ``Container specifications and testing and inspection methods''; When describing the standards and testing and inspection methods for raw materials or materials as "standards and specifications for materials containing necessary matters such as dosage, efficacy, or effects, and precautions for use or handling," the raw materials or materials concerned. Please indicate the need to obtain information on manufacturing methods from those suppliers.

[Answer] When it comes to raw materials and other products manufactured at other factories, it is important to try to obtain information about their manufacturing in order to ensure the quality of products manufactured at your own factory. In particular, be sure to obtain information on the manufacturing method of raw materials, as this is closely related to the quality of the raw materials. If it is clear that the changes have been made, it is necessary to set additional standards and test and inspection methods as necessary, carefully confirm the quality of raw materials, and perform appropriate change management.

GMP7-9 (specifications and test methods) [Question] GMP Ministerial Ordinance No. 7 when using raw materials, such as solvents, that are listed only in the manufacturing method column of the product's manufacturing and marketing approval (notification) and do not fall under the product components in the manufacturing process of a certain product. I would like to know the precautions to be taken when creating standard documents for pharmaceutical products under Article 1.

[Answer] Regarding the raw materials mentioned in the question, the description in the Pharmaceutical product standard code should be based on the raw materials that correspond to the components of the product, and care should be taken to ensure that the raw materials used during the manufacturing process remain. Furthermore, similar measures should be taken when using raw materials that do not correspond to the ingredients of the product for over-the-counter drugs, etc. for which a specific method is not required to be described in the manufacturing method column.

GMP7-10 (specifications and test methods) [Question] If it is determined that changing some of the manufacturing and sales regulatory approved information in order to conform to the revised Japanese Pharmacopoeia's general test methods will result in an improvement of the drug product, please refer to the Pharmaceutical product standard code under Article 7 of the GMP Ministerial Ordinance. Is it okay to reflect this change in the product and pass the test if it is determined to pass using the revised test method, even if it is determined to fail using the general test method of the Japanese Pharmacopoeia at the time of approval?

[Answer] Not allowed. Take necessary measures in accordance with Article 11, Paragraph 1, Item 8 of the GMP Ministerial Ordinance. In addition, in the case of the question, if it is determined that some of the manufacturing and sales regulatory approved information should be changed at the manufacturing site in order to conform to the general test methods specified in the revised Japanese Pharmacopoeia, In addition to following the relevant notifications regarding handling, etc., contact the marketing authorization holder in advance to apply for partial change approval, etc. (notification of minor changes, if applicable).

GMP7-11 (specifications and test methods) [Question] When incoming crude raw materials are further refined and the resulting material is used as a raw material for a product (preparation) and specifications and test and inspection methods are specified, what should be stated in the Pharmaceutical product standard code under Article 7 of the GMP Ministerial Ordinance? In the revised Ministerial Ordinance Promulgation Notice No. 3, 10(3) ①, "Manufacturing method and manufacturing procedure," it is prohibited to describe a manufacturing method that consistently processes from refining the crude raw material to formulation into a formulation without taking out the raw material. Is it recognized?

[Answer] The "crude raw materials" mentioned in the question should also be tested and inspected in advance to confirm that they are appropriate before being accepted. If such an integrated manufacturing method is clearly specified in the manufacturing and marketing approval (notification) document, it is acceptable.

GMP7-12 (specifications and test methods) [Question] Regarding the information listed as reference information that is not used as criteria for determining compliance in the properties section of the "Specifications and Test Methods" column of the manufacturing and marketing approval (notification) form, please refer to the Pharmaceutical Product Standard Code stipulated in Article 7 of the GMP Ministerial Ordinance. Is it not necessary to conduct tests and inspections on the documents?

[Answer] Decide whether to conduct tests or inspections by considering the risks to product quality.

GMP7-13 (specifications and test methods) [Question] Concerning intermediates in the manufacturing process of products related to pharmaceuticals that are active pharmaceutical ingredients, the revised Ministerial Ordinance Promulgation Notice No. 3-10(3)①E “Manufacturing method and Manufacturing procedures (including in-process inspections, specifications for intermediate products, testing and testing methods, and evidence to demonstrate the validity of the standards and testing and testing methods based on the results of identifying and evaluating quality risks) Should I set the following items?

[Answer] Although it cannot be determined in general, in the case of the question, the process capability up to the production of the "intermediate" and the impact on the quality of the product related to the drug substance are evaluated, and the Appropriately set items that can control the quality of pharmaceutical products according to risks.

GMP7-14 (specifications and test methods) [Question] According to Article 7 of the GMP Ministerial Ordinance, what kind of tests and inspections need to be conducted on intermediate products?

[Answer] In cases where the specifications and testing and inspection methods of intermediate products are not specified in the manufacturing and marketing approval (notification) document or compendial formula, the amended Ministerial Ordinance Promulgation Notice No. 3-10(3)(1) A and B(C) Based on the results of identifying and evaluating the standards, testing and testing methods, and quality risks, the standards and testing methods are to be established voluntarily as necessary for management purposes. This should be specified in advance in the drug product standard document before implementation.

GMP7-15 (specifications and test methods) [Question] To what extent should the specifications and testing and inspection of gases used to ensure product quality, such as nitrogen gas for sealing, be stipulated in the Pharmaceutical Product Standard Code document under Article 7 of the GMP Ministerial Ordinance?

[Answer] Tests and inspections for these gases should be stipulated taking into consideration the impact they may have on product quality.

GMP7-16 (specifications and test methods) [Question] In the "Ingredients and Quantity or Essence" column of the manufacturing and marketing approval (notification) form, it is stipulated that the standards of the Japanese Pharmacopoeia shall be applied mutatis mutandis as the specifications for the ingredients. However, due to subsequent revisions to the Japanese Pharmacopoeia, is deleted from the Japanese Pharmacopoeia, is it okay to continue using the standards listed before the revision in the drug product standards set forth in Article 7 of the GMP Ministerial Ordinance?

[Answer] Follow the notification regarding handling, etc. due to the revision of the Japanese Pharmacopoeia. In addition, if necessary, contact the marketing authorization holder to promptly apply for approval of partial changes (notification of minor changes, if applicable).

GMP7-17 (manufacturing method and manufacturing procedure) [Question] Regarding the recovery of solvents for reuse in the production of subsequent lots in the manufacturing process of products that are active pharmaceutical ingredients, what is the case in the case stipulated in Article 7 of the GMP Ministerial Ordinance? I would like to know the points to keep in mind.

[Answer] Based on the information stated in the manufacturing and marketing approval (notification) document, the organization responsible for quality assurance operations confirms the manufacturing method, etc., and specifies it in advance in the Pharmaceutical Product Standard Code, etc., and performs within the scope. thing. For recovered solvents, standards should be set according to the purpose of use, such as the process in which they will be used. Monitor and control validated recovery processes to ensure that recovered solvents meet specifications before reuse or mixing with new compliant solvents. Appropriate testing should be performed to demonstrate that the reused or mixed solvent is compatible with all manufacturing processes in which it is used. Appropriate manufacturing records should be created regarding reuse of solvents and mixing with new compliant solvents. In order to prevent negative effects on product quality due to the accumulation of unexpected impurities that cannot be detected using established test methods, the collected solvent is regularly disposed of and cut off by appropriately setting the number of collections and the period of use. Take that into account. When using recovered solvents, extreme care must be taken from the perspective of preventing cross-contamination, taking into account the risks of the process in which they are used. Particularly when sharing collection facilities with other companies, care should be taken to prevent cross-contamination.

GMP7-18 (manufacturing method and manufacturing procedure) [Question] In the manufacturing process of products related to granule preparations, for example, large particles and small particles remain as work in progress, but are they mixed into the next lot under Article 7 of the GMP Ministerial Ordinance? Is it okay to specify that?

[Answer] It is necessary to confirm through appropriate validation that the quality of the product after mixing is ensured. It is acceptable if the upper limit of the mixing amount of the backlog and the number of mixing times are validated and stated in the drug product standard document. In this case, the number of lots to which unprocessed items are added should be specified to ensure that lots are not mixed continuously.

GMP7-19 (standard preparation amount) [Question] Among the matters to be described in the standard document for pharmaceutical products under Article 7 of the GMP Ministerial Ordinance, what is the standard amount of preparation for weighing, preparation, filling, etc. and its How should we think about the basis for demonstrating validity (validation results stipulated in Article 13 of the GMP Ministerial Ordinance, etc.)?

[Answer] The “standard amount” that should be stated in the drug product standard document refers to the amount that the final product should be prepared in, taking into account losses in the manufacturing process. Refers to the amount of preparation determined so that it will match. In addition, when correcting the amount of drug substance used for each lot based on purity (content, potency) during the formulation process, the scope and conditions under which the correction can be made should be stated in the drug product standard document. There is a need.

On the other hand, "evidence showing validity" is the basis showing the validity of the "standard preparation amount" (including the scope and conditions under which the above amendments can be made), and is the basis that shows the validity of the "standard preparation amount" (in the case of making the above amendments, the scope and conditions under which the amendments can be made). Data that shows that it is possible to consistently manufacture products that meet the descriptions of "components and quantities or essence" and "specifications and test methods" in the document is applicable. Specifically, in addition to data such as technical studies and validation during prototyping and scale-up, we also provide information such as dissolution profiles and impurity profiles that cannot be proven simply by meeting the "specifications and test methods" of the manufacturing and marketing approval . Examples include data showing consistency of quality between the investigational drug and the drug manufactured on a commercial scale. However, the required data will differ depending on the characteristics of the item, the purpose of inclusion of the ingredients for setting the standard preparation amount, physical properties, etc.

GMP7-20 (standard preparation amount) [Question] When a sudden problem occurs in the manufacturing process, such as an increase in losses (dropping of pharmaceutical ingredients from bag filters, dust collection, adhesion to equipment, etc.) in the manufacturing process, what should be done as specified in the Pharmaceutical Product Standard Code? Can I change the amount of preparation from the standard amount given?

[Answer] Regarding unexpected problems, deviations should be managed in accordance with the provisions of Article 15 of the GMP Ministerial Ordinance. When changing the amount of preparation as a corrective or preventive measure for deviations, if the change affects or is likely to affect product quality or regulatory approved information as specified in Article 14, Paragraph 1, Item 2 of the GMP Ministerial Ordinance. When making changes, please contact the marketing authorization holder in advance regarding the need to apply for partial change approval (notification of minor changes, if applicable) and receive confirmation.

GMP7-21 (standard preparation amount) [Question] Ingredients listed as "trace amount" in "Ingredients and quantity or essence" in the marketing approval document should not be added in the drug product standard document under Article 7 of the GMP Ministerial Ordinance, as this includes cases in which they are not added. Is it okay to stipulate that

[Answer] Not adding it is not acceptable.

GMP7-22 (standard preparation amount) [Question] How should an ingredient listed as "appropriate amount" in "Ingredients and Quantity or Essence" in the marketing approval document be described in the drug product standard document under Article 7 of the GMP Ministerial Ordinance?

[Answer] In principle, it should be stated as something that should be added, but for example, if the manufacturing and marketing approval states that pH adjuster is an "appropriate amount," it may be written in the drug product standard document that it may not be added. Regarding the types and specific names of ingredients that can be described as "appropriate amount" in the manufacturing and marketing approval application, please refer to the "Matters to be included in the drug approval application" (February 8, 2000, Pharmaceutical No. 39), which states that ``For pH adjusters and sugar coating agents for tablets, the amounts of multiple ingredients may be described as ``appropriate amounts.'''' In addition, when making changes within the scope of the approval application regarding the amount of ingredients described as "appropriate amount" or "trace amount", manufacturing method, etc., it is the applicant's responsibility to submit materials that support the validity of the changes. It is also indicated that manufacturers should prepare and preserve the ingredients, and when making the above changes to ingredients that are described as "appropriate amount" or "trace amount," they should contact the applicant, the marketing authorization holder. and provide the necessary materials.

GMP7-23 (standard preparation amount) [Question] In the Pharmaceutical Product Standard Code set forth in Article 7 of the GMP Ministerial Ordinance regarding the manufacture of products related to injectables, what is commonly used to maintain pH within the specification or indicated value range of the manufacturing and marketing approval? Can I add a new pH adjuster (hydrochloric acid, sodium hydroxide, etc.) to the water?

[Answer] When adding a new substance, consult with the marketing authorization holder to apply for partial change approval, etc

GMP7-24 (other) [Question] At a manufacturing facility that performs manufacturing processes from bulk drug manufacturing to subdivided packaging, the revised Ministerial Ordinance Promulgation Notice No. 3, 10(3), At which of the following points should the shelf life of "product storage conditions and shelf life or retest date and evidence showing their validity (stability test results, etc.)" begin? 1) Preparation bulk manufacturing work days 2) Date of passing the drug bulk test 3) Subdividing and packaging work days 4) Product test passing date

[Answer] The validity period is often stated starting from the manufacturing date, but it is difficult to determine it unconditionally. In either case, it is necessary to determine the shelf life based on stability test results, etc. so that quality can be guaranteed.

GMP7-25 (other) [Question] When describing ``dosage and administration'' and ``indications or effects'' in a product standard document, a copy of the manufacturing and marketing approval (notification) document is often cited and attached, but other than that, other package inserts are cited. Is it okay to attach it?

[Answer] It is acceptable as long as all the necessary information is listed. However, even if there are changes or substitutions to the cited and attached documents, it is necessary to obtain approval from the quality department in advance as a revision of the product standard.

GMP7-26 (other) [Question] Tests in lieu of test and inspection methods in official compendials or specification books as specified in Article 7 of the GMP Ministerial Ordinance, Notification of Promulgation of Revised Ministerial Ordinance No. 3-10(3) ① A and B-(B) What should we keep in mind regarding the basis of the method?

[Answer] It is necessary to check the basis for accuracy, precision, specificity, range, etc. according to the purpose, referring to the provisions of the Japanese Pharmacopoeia's general rules. For example, if the specificities are the same, it is necessary to confirm that there is no difference in the mean values and that the standard deviations are the same or smaller.

In addition, if there is any doubt about the quality of the product, please be sure to confirm that the judgment of pass/fail is based on the test method specified in the official compendium or specification book referred to in the manufacturing and marketing approval (notification) document. This should be confirmed by the organization in charge of warranty-related work and specified in the Standard Operating Procedures, etc. in advance.

GMP7-27 (other) [Question] In the manufacture of products related to pharmaceuticals that are active pharmaceutical ingredients, in the GMP Ministerial Ordinance Article 7, Pharmaceutical Product Standard Code, the Revised Ministerial Ordinance Promulgation Notice No. 3, 10(3) ①A, ``Components of products and raw materials used in their manufacture'' Is it necessary to stipulate testing and inspection at the time of receipt of raw materials as (if the ingredients are unknown, their essence), quantities, specifications, and testing and inspection methods?

[Answer] It is necessary to stipulate it in advance.

GMP7-28 (other) [Question] The “evidence showing their validity (stability test results, etc.)” in No. 3-10(3)① of the Notice of Promulgation of the Revised Ministerial Ordinance refers to whether the stability test materials, etc. submitted at the time of application for manufacturing and marketing approval are If it continues to be the basis and is appropriate, can I interpret it as sufficient to quote and attach it?

[Answer] If stability testing was in progress at the time of application for approval, the results of the tests that were conducted and submitted until the time of approval, and if stability tests were conducted after approval, the results, etc. should also be covered. Please refer to "Revision of Stability Testing Guidelines" (Pharmaceutical Review No. 0603001, June 3, 2003), etc.

GMP7-29 (other) [Question] For products that do not specify a shelf life or retest date in the manufacturing and marketing approval (notification) document, official compendium, or specification book, and for which there is no stability test data, test reference sample that have been stored for three years or more. However, if no change over time is observed in the results, the results of the relevant test may be used in place of the stability test as the items to be described in the standard document for pharmaceutical products under Article 7 of the GMP Ministerial Ordinance, Article 3, Section 10(3) of the Notice of Promulgation of the Revised Ministerial Ordinance. )① Q: Can it be described in the drug product standard document as "product storage conditions and shelf life or retest date"?

[Answer] In principle, it is necessary to conduct a stability test. However, in the case of old products without stability test data, if the Reference sample has been properly stored under "appropriate storage conditions," the results of stability monitoring may be used in addition to methods such as questions. It doesn't matter how you use it. If changes over time are observed, it is necessary to conduct another stability test and take necessary measures.

GMP7-30 (other) [Question] Regarding the amended Ministerial Ordinance Promulgation Notice No. 3-10(3)③C, it states, “The details of the arrangements that the marketing authorization holder of the product has made with the manufacturer or foreign manufacturer (in addition, at the request of the GMP investigation conductor) "The manufacturer is required to be able to present a copy of the relevant agreement document.)" However, what should be kept in mind when making an agreement with a marketing authorization holder?

[Answer] In the GMP Ministerial Ordinance, Articles 14 and 15 stipulate matters that require responses to manufacturers and distributors, and agreements with manufacturers and distributors also apply to manufacturing control and quality control at manufacturing facilities. Since this is an important element, it is necessary for manufacturers, etc., to proactively confirm the details of their agreements with manufacturers and distributors and to ensure that no deficiencies occur. Furthermore, it is necessary to attach or link a "copy of the agreement document" to the drug product standard document.

改正GMP省令　Article 8　Standard Operating Procedures

GMP8-1 (Standard Operating Procedures) [Question] Regarding the "Standard Operating Procedures" in Article 8, Paragraph 1 of the GMP Ministerial Ordinance, if procedures have been created that allow for proper implementation of manufacturing control and quality control, it is not necessary to create separate Standard Operating Proceduress for each. Is it okay? Also, is it okay to follow the specifications of each manufacturer for the name of the Standard Operating Procedures?

[Answer] It is assumed that document management based on Article 20 of the GMP Ministerial Ordinance (see GMP 20-1, etc.) is carried out appropriately, and that the contents are clear and easy to understand (necessary and appropriate) for all personnel implementing the relevant procedures. (In some cases, it is acceptable to assume that the applicant has received education and training.), as long as the procedure ensures that the procedure is carried out reliably . However, make sure you know where each procedure stipulated in the GMP ministerial ordinance is listed. Please obtain confirmation from the quality department regarding any content that may affect the quality of the product.

GMP8-2 (Standard Operating Procedures) [Question] Article 8, Paragraph 1 of the GMP Ministerial Ordinance states that documents are to be created for each manufacturing facility. For example, is it okay to separately specify procedures for the manufacturing department and procedures for the quality department within a manufacturing site? .

[Answer] As long as it does not interfere with document control, manufacturing control, and quality control as stipulated in Article 20 of the GMP Ministerial Ordinance, there is no problem.

GMP8-3 (equipment of Standard Operating Procedures) [Question] Article 8, Paragraph 1 of the GMP Ministerial Ordinance states that "Standard Operating Proceduress must be prepared and properly prepared at the relevant manufacturing facility." Is it okay to create one document with specific procedures and place it at each manufacturing site?

[Answer] There is no problem as long as each manufacturing site is able to respond appropriately. However, it is necessary to have a Standard Operating Procedures that is appropriate to the actual circumstances of each manufacturing facility, and such a Standard Operating Procedures must be installed at the manufacturing facility in question.

GMP8-4 (General procedures regarding hygiene management of structures, equipment and personnel) [Question] I would like to know the precautions and general format for writing procedures regarding hygiene management of structures, facilities, and staff as stipulated in Article 8, Paragraph 1, Item 1 of the GMP Ministerial Ordinance in the Standard Operating Procedures.

[Answer]

1. Procedures regarding the hygiene management of structures, equipment, and staff should be established in accordance with the actual circumstances of each manufacturing facility, and include all relevant content listed in GMP ministerial ordinances, revised ministerial ordinance promulgation notices, etc.

2. The following items should also be included in the revised ministerial ordinance promulgation notification No. 3-11(1)①C(a) "Procedures for sanitary management of structures and equipment".

(1) List of structures and equipment covered by the procedure.

(2) Assignment of responsibilities for implementing procedures;

3. Items that should be stated as ``interval'' in ``Procedures for sanitary control of structures and equipment'' in ``Procedures for sanitary control of structures and equipment'' in ``C.'' (A) include, for example, the following items:

(1) Establishment of a schedule for cleaning structures and equipment that should ensure cleanliness and, if necessary, a schedule for sterilization and disinfection work (sanitization)

(2) Measures to prevent contamination of cleaned structures and equipment before use

(3) If necessary, the maximum allowable time for cleaning of the used structures and equipment and the period of validity of the cleaning after the cleaning of the structures and equipment has been carried out.

(4) Even when manufacturing the same product continuously or for a limited period of time, cleaning at appropriate intervals is necessary to prevent the formation of contaminants and their carryover. In manufacturing pharmaceutical products, avoid causing carryover of decomposition products or microbial contamination that could adversely affect impurity profiles.)

Four. The revised Ministerial Ordinance Promulgation Notice No. 3-11(1)①C(A)((A)) "Procedures for cleaning, maintenance, sterilization, etc. of structures and equipment" includes, for example, the following matters:

(1) Procedures necessary for personnel to perform cleaning, maintenance, sterilization, etc. in an effective and reproducible manner.

(2) Procedures for disassembling and assembling each part of the structure and equipment, as necessary.

(3) Procedures for removing or erasing markings of preceding lots

(4) Cleaning procedures and cleaning agent selection methods depending on residues or contaminants;

Five. For example, the following are examples of "procedures related to cleanliness" and ((c)) "procedures related to maintenance and management of cleanliness": Includes matters.

(1) Judgment criteria for residues

(2) Where possible, inspection of structures and equipment for cleanliness before use;

GMP8-5 (General procedures regarding hygiene management of structures, equipment and personnel) [Question] When manufacturing products related to external sterilizing disinfectants, is it necessary to pay attention to microbial contamination in the procedures for sanitary management of structures, equipment, and personnel as stipulated in Article 8, Paragraph 1, Item 1 of the GMP Ministerial Ordinance?

[Answer] Even when manufacturing products related to disinfectants, it is necessary to pay sufficient attention to hygiene management to prevent microbial contamination.

GMP8-6 (General procedures regarding hygiene management of structures, equipment and personnel) [Question] Regarding the provisions of Article 8, Paragraph 1, Item 1 of the GMP Ministerial Ordinance, please indicate the points to note regarding hygiene management in the manufacture of products related to sterile preparations that undergo a sterilization process after filling and closing.

[Answer] Even if the product is a sterile preparation using the final sterilization method, ensuring the sterility of the product is not left solely to the final sterilization process, but rather measures to prevent foreign material contamination, dust (fine particle) control, and microbial contamination during the manufacturing process. It is necessary to pay sufficient attention to the prevention of

GMP8-7 (General procedures regarding hygiene management of structures, equipment and personnel) [Question] The scope of application of the procedures regarding hygiene management of structures and equipment and personnel in Article 8, Paragraph 1, Item 1 of the GMP Ministerial Ordinance includes testing and testing laboratories related to quality control as well as testing and testing laboratories related to in-process control. Can you do it?

[Answer] Included.

GMP8-8 (General procedures regarding hygiene management of structures, equipment and personnel) [Question] Regarding the procedures for cleaning structures and facilities at the time of lot change in the procedures for hygiene management of structures and facilities and personnel in Article 8, Paragraph 1, Item 1 of the GMP Ministerial Ordinance, what are the procedures for cleaning structures and facilities for injections, internal solutions, and external solutions? For products, instead of washing with distilled water, they are washed with filling liquid (co-washing), and after filling the previous lot, the remaining liquid is drained as much as possible, and the filling machine is filled with the next lot's chemical liquid and discharged. Is it okay to repeat this process once or twice before moving on to filling the next lot? (Washing with distilled water may actually increase the chance of contamination and may dilute the initial filling of the next lot.) Therefore, cleaning with filling liquid is considered safer.)

[Answer] Based on each item of GMP 8-4, the procedure is to ensure that the method of asking the questions achieves the purpose of cleaning, is validated according to the characteristics of the product, and does not affect product quality, etc. There is no problem if it is stipulated in advance in the document, etc.

Hygiene management of structures, equipment and personnel

GMP8-9 (hygiene management of structures, equipment and staff) [Question] Please indicate the precautions to be taken when stipulating procedures regarding the hygiene management of structures, equipment, and personnel regarding the use of disinfectants for sterilization and disinfection work (sanitization) of sterile rooms, etc.

[Answer] When selecting a disinfectant, carefully consider whether it has the desired effect or not. It is necessary to take measures in advance to prevent this. In addition, it is necessary to pay attention to preventing the emergence of bacteria that have acquired resistance to disinfectants, and to monitor the effectiveness of disinfectants depending on the type of microorganisms. These precautions must be stipulated in advance in the Standard Operating Procedures, etc.

GMP8-10 (hygiene management of structures, equipment and staff) [Question] Amended Ministerial Ordinance Promulgation Notice No. 3-11(1) ①C(B)((C)) as a stipulation for procedures regarding hygiene management of structures and facilities and personnel as set forth in Article 8, Paragraph 1, Item 1 of the GMP Ministerial Ordinance Please indicate the points to keep in mind regarding the "procedures for understanding the health status of employees."

[Answer]

1. Procedures such as health examinations, interviews, declarations, etc. that allow us to identify any health conditions (infectious diseases, lacerations, etc.) that may reduce the reliability of product quality, and follow the hygiene standards stipulated in the GMP Ministerial Ordinance. It shall be implemented using procedures that fully utilize the purpose of management.

2. Furthermore, if a person is found to have an obvious disease or laceration as observed by a medical practitioner or supervisor, if the disease or laceration is likely to have an adverse effect on the quality of the product, check whether the condition has recovered or not. , or do not engage in work until it has been determined that engaging in work will not compromise the safety or quality of the product.

GMP8-11 (hygiene management of structures, equipment and staff) [Question] Notification No. 3-11(1)①C(A)((B)) of the amended Ministerial Ordinance promulgation as a stipulation of procedures regarding hygiene management of structures, facilities, and personnel in Article 8, Paragraph 1, Item 1 of the GMP Ministerial Ordinance Regarding "Procedures related to cleanliness" and ((c)) "Procedures related to maintenance and management of cleanliness" 1. How should the confirmation method regarding cleanliness be set? 2. Will cleanliness checks be conducted every day? 3. Is it sufficient to judge the appearance with the naked eye? Four. What are the points to keep in mind when creating confirmation records after cleaning?

[Answer]

1. Appropriate methods should be established that match the structure and equipment of each manufacturing facility.

2. This will vary depending on the content of the confirmation, so it must be decided on a case-by-case basis.

3. Judging appearance with the naked eye is not the only method of confirmation, but it can be used as a means of confirmation.

Four. The cleanliness record should record the items checked, the place checked, the results of the check, the date and time of the check, the person in charge of cleaning, the person checking, etc.

General procedures regarding the management of manufacturing processes, manufacturing equipment, raw materials, materials, and products

GMP8-12 (General procedures regarding the management of manufacturing processes, manufacturing equipment, raw materials, materials, and products) [Question] I would like to know the precautions and general format for creating documents that describe procedures related to manufacturing processes, manufacturing equipment, and management of materials and products. I would also like to see general points to note regarding ``Procedures related to control values necessary for process control'' in Section 11(1)②B(C)((C)) of the Notification of Promulgation of Revised Ministerial Ordinance No. 3.

[Answer]

1. Documents describing procedures for the management of manufacturing processes, manufacturing equipment, materials, products, etc. should be appropriate to the actual situation of each manufacturing site and include all relevant content indicated in GMP ministerial ordinances, revised ministerial ordinance promulgation notices, etc. to create something.

2. The ``general format'' cannot be determined in general, but must be created in accordance with the actual circumstances of each manufacturing facility.

3. In addition to the matters stipulated in the approval document, "general considerations" include, for example, the following specific matters:

(1) Process control and its judgment criteria shall be established based on information obtained during the development stage or actual data.

(2) The criteria, types, and scope of tests and inspections related to process control should be established taking into account the characteristics of the product, the stages of the manufacturing process, the degree to which the manufacturing process affects the quality of the product, etc.

(3) Matters related to important process control and its monitoring shall be confirmed by the quality department and documented, including control matters and control methods (including process adjustments based on test and inspection results related to process control).

(4) A Standard Operating Procedures shall be prepared for the method of collecting samples related to products, etc., and the plan and procedure for collecting such samples shall be based on rational and appropriate methods.

(5) Samples shall be collected using procedures that prevent mutual contamination and cross-contamination between the collected sample and other products, etc., and ensure the integrity of the sample after collection.

(6) Usually, in tests and inspections related to process control, investigations are conducted regarding results that do not conform to standards (hereinafter referred to as OOS).

General procedures regarding test and test equipment, specimen management, and other appropriate test and test implementation

GMP8-13 (general procedures regarding test and test equipment, specimen management, and other appropriate test and test implementation) [Question] Please explain the precautions and general format for creating a document describing procedures for testing and testing equipment, specimen management, and other appropriate testing and testing implementation as stipulated in Article 8, Paragraph 1, Item 3 of the GMP Ministerial Ordinance. I want you to.

[Answer] Documents describing testing equipment, specimen management, and other procedures for conducting appropriate testing and testing shall be documents that include all relevant information from GMP ministerial ordinances, amended ministerial ordinance promulgation notices, etc. Create something that matches the actual situation of the manufacturing facility.

GMP8-14 (general procedures regarding test and test equipment, specimen management, and other appropriate test and test implementation) [Question] Regarding the stipulations of testing equipment, specimen management, and other appropriate testing and testing implementation procedures stipulated in Article 8, Paragraph 1, Item 3 of the GMP Ministerial Ordinance, amended Ministerial Ordinance Promulgation Notice No. 3-11(1)③B ( g) Are there any necessary procedures other than ((a)) and ((b)) shown in "Other necessary procedures for conducting appropriate tests and inspections"?

[Answer] For example, this applies to the breeding management of rabbits used in pyrogenic substance tests before use, management matters such as rest periods for reuse, and management procedures for test bacteria used in microbiological potency testing methods for antibiotics. There are cases.

GMP8-15 (general procedures regarding test and test equipment, specimen management, and other appropriate test and test implementation) [Question] If the cleaning of the glass bottles used as materials is left to the bottle supplier, to what extent should the Standard Operating Procedures stipulate the evaluation of the cleanliness of the bottles upon acceptance by the manufacturer, etc., and the checks on the supplier's manufacturing facilities? Okay?

[Answer] The cleaning of glass bottles, which are materials, should not be left to the "bottle supplier" and manufacturers, etc. should not use them without testing and inspecting them upon acceptance. Even if the bottles have been cleaned by the "bottle supplier," it is the responsibility of the manufacturer, etc. to establish an evaluation test and inspection method for cleanliness, conduct tests, and clean the bottles again if necessary. . In addition, checks on the supplier's manufacturing facilities shall be carried out by on-site confirmation, obtaining relevant documents and confirming them using such documents, or other appropriate methods.

Inspection and maintenance of test and analytical equipment and calibration of instruments

GMP8-16 (Inspection and maintenance of test and analytical equipment and calibration of instruments) [Question] Amended Ministerial Ordinance Promulgation Notification No. 3-11(1)③B as stipulations of testing equipment, specimen management, and other appropriate procedures for implementation of testing and testing under Article 8, Paragraph 1, Item 3 of the GMP Ministerial Ordinance. H) I would like to see precautions in specifying "procedures for inspection and maintenance of equipment and instruments related to testing and inspection, calibration of instruments, etc."

[Answer] Describe matters related to inspection and maintenance (e.g. name of test and analytical equipment, equipment identification number, inspection items, inspection method, frequency, etc.), matters related to calibration, etc. (refer to GMP11-33, etc.), and perform inspection and maintenance. , proofreading, etc. must be carried out appropriately.

GMP8-17 (Reference standard, etc.) [Question] Amended Ministerial Ordinance Promulgation Notification No. 3-11(1)③B as stipulations for procedures regarding testing and testing equipment, specimen management, and other appropriate testing and testing implementation under Article 8, Paragraph 1, Item 3 of the GMP Ministerial Ordinance. (g) Please indicate the precautions to be taken when specifying the "procedures for the management of Reference standard, reagents, test water, etc. for testing and testing" in ((a)).

[Answer] Reference standard for testing (substances used as standards in quantitative or qualitative measurements of pharmaceuticals, etc., and equivalent to the "reference standard" in the PIC/S GMP guidelines; the same shall apply hereinafter), reagents For example, the following items are necessary for properly managing test liquids, test water, etc. In addition, Reference standard for testing and inspection are substances that are shown to have a set quality and purity by comparison with primary Reference standard, and are used as standards in daily laboratory analysis (hereinafter referred to as "secondary Reference standard"). "Reference standard") are included.

1. Reference standard, reagents, test water, etc. for testing shall be prepared according to procedures, labeled, and have appropriate expiration dates.

2. Suppliers of so-called primary Reference standard should be determined in advance in writing. Primary standards shall be used and stored in accordance with predetermined procedures, and records shall be created. (If stored in accordance with established procedures, it can generally be put into use without testing.)

3. If a primary standard cannot be obtained from an officially certified supplier, a “homemade primary standard” should be established. For "homemade primary Reference standard", conduct appropriate tests and inspections to prove identity and purity, create records, and keep them.

Four. So-called secondary standards should be appropriately obtained, prepared, tested, approved, and stored. The suitability of each lot of secondary Reference standard should be determined by comparison with the primary standard product before its first use. Each lot of secondary standards should be requalified periodically according to a predefined implementation plan.

11 of “Guidelines for GMP of APIs” (Yakuhin No. 1200, November 2, 2001). Exam room management should also be referred to.

GMP8-18 (Ensuring the reliability (integrity) of documents and records) [Question] What should I keep in mind to "continuously ensure the reliability of Standard Operating Proceduress, etc. and the records specified in this chapter" as required by Article 8, Paragraph 2 of the GMP Ministerial Ordinance?

[Answer] This section is a provision regarding ensuring data integrity, and it is required to ensure that recorded data is correct throughout its lifecycle*. To this end, it is necessary to ensure that the data is collected correctly and has not been altered, that any modifications made are appropriate, that responsibility is clear, that correct records are maintained, and that the records are correct. Reproducibility is required. The ALCOA+ principles (1 to 9 below) are generally known as data integrity requirements. These requirements apply to documents and records, whether paper or electronic.

In addition, when using documents and records using electronic media (hereinafter referred to as "electronic data" in this section), the computerized system that generates the electronic data must have the ability to meet the requirements shown in the ALCOA+ principles. ``Guidelines for Proper Management of Computerized Systems in Pharmaceutical and Quasi-drug Manufacturers, etc.'' (Yakusho Kanma Hatsu No. 1021 No. 11, October 21, 2010) Perform and verify computerized system validation in accordance with the indicated methodology . Note that functions that can satisfy the requirements shown in the ALCOA+ principles include an audit trail function, a function to prevent data overwriting and tampering, and a function to set operational authority for each user, but it is necessary to have any of these functions. The determination of whether there is such a system and the extent to which computerized system validation is required should be made after conducting a risk assessment that takes into account the importance of the generated data in terms of product quality, the complexity of the system, etc.

No.	requirements	Content
1	Attributable	The creator, recorder, confirmer, approver, etc. of documents and records can be identified.
2	Legible	Be able to read and understand.
3	Contemporaneous	When something is carried out, it should be recorded immediately.
Four	Originality	Be in the initial state.
Five	Accurate	No errors.
6	Complete	All necessary information is present.
7	Consistent	Do not contradict.
8	Enduring	Must be usable without being lost, destroyed, or damaged.
9	Availability	Can be taken out at any time.

*The life cycle of data refers to all the periods during which data is retained, including data collection, recording, verification, approval, use as a basis for decision-making (shipment judgment, validation judgment, deviation investigation, etc.), storage, and disposal. It refers to a stage.

改正GMP省令　Article 9　Structures and equipment

Structures and equipment of manufacturing facilities for products related to pharmaceutical products as active pharmaceutical ingredients

GMP9-1 (Structures and equipment of manufacturing facilities for products related to drug substances) [Question] Can raw materials for pharmaceutical products that are active pharmaceutical ingredients be stored in outdoor storage tanks?

[Answer] If the "storage tank" itself can protect the raw material in a sufficiently hygienic and safe manner, there is no problem. When using the raw materials, care should be taken as necessary regarding cleanliness.

GMP9-2 (operational room cleanliness) [Question] Regarding the provisions of Article 9, Paragraph 1, Item 3 and Article 24, Item 1 of the GMP Ministerial Ordinance, please indicate the cleanliness classification of each operational room in the manufacturing facility.

[Answer] Although there is no specific numerical value regarding the cleanliness classification of each operational room, etc., the classification shown below has been generally used in the past, so please refer to it.

Category 1: Preparation room, filling/closure room, etc. for products related to sterile preparations

Category 2: Weighing room, preparation room, filling closed room, intermediate product storage area for products related to general preparations (however, storage areas for intermediate products that are stored in appropriate sealed containers and are completely protected from contamination) , some cases do not necessarily fall into this category), raw material collection rooms, etc.

Category 3: Packaging room (packaging room for filled and closed products), product storage room, raw material storage room, changing room (initial stage room where casual clothes are changed into work clothes), etc.

Category 4: Entrance hall, guest room, power machine room, power distribution room, etc.

The above classifications are provided as a rough guideline and may be changed according to the actual circumstances of each manufacturing facility.

For sterile preparations, refer to the "Guidelines for the manufacture of sterile pharmaceuticals using aseptic procedures" and "Guidelines for the manufacture of sterile pharmaceuticals using terminal sterilization methods," or the latest version of related guidelines.

GMP9-3 (structural equipment of operational room) [Question] Regarding the provisions of Article 9, Paragraph 1, Item 3 and Article 24, Item 1 of the GMP Ministerial Ordinance, regarding the filling/closing to packaging integrated line for PTP packaging, SP packaging, etc., is it possible to install a bulkhead in the middle of the integrated line? It seems to be common to have separate operational rooms for the filling/closing process and the packaging process, but it is difficult due to structural and equipment considerations to divide the integrated line into different cleanliness categories. In cases where work efficiency is significantly hindered, measures can be taken to prevent contamination and cross-contamination of lids, covers, casters, etc. in parts related to the filling and closing process, even if the entire line is run in the same operational room. Okay?

[Answer] "Measures to prevent contamination and cross-contamination" ensure that "parts related to the filling and closing process" are managed according to the desired cleanliness category, and contamination and cross-contamination from "parts related to the packaging process" are prevented. As long as this has been done, there is no problem. It is assumed that basic measures to prevent contamination and cross-contamination, such as cleaning and systematic implementation of education and training, are properly taken.

GMP9-4 (structural equipment of operational room) [Question] According to Article 9, Item 1, Item 3 of the GMP Ministerial Ordinance, ``Operational rooms in workplaces have the structure necessary to prevent contamination by dust or microorganisms, depending on the type of product, dosage form, and manufacturing process. 13(1)(3)(a) of the Revised Ministerial Ordinance Promulgation Notification indicates that ``having a operational room for weighing raw materials, preparing products, filling work, or closing work "The operational room shall be separated from the operational room where other manufacturing operations are performed." How should this be interpreted when it is difficult to distinguish between a operational room where cleaning work is performed and a operational room where filling and closing work is performed?

[Answer]

1. As in the case below, if product contamination and cross-contamination are prevented during manufacturing operations, the proviso to Article 9, Paragraph 1, Item 3 of the GMP Ministerial Ordinance states, ``However, due to the functions of manufacturing equipment, etc., "This does not apply if the same degree of effect can be obtained."

(1) If the manufacturing equipment is a closed type, and measures are taken to prevent product contamination and cross-contamination during weighing, preparation, or filling/closure operations.

(2) When laminar flow equipment, etc. installed in the operational room or manufacturing equipment is used to prevent product contamination and cross-contamination during weighing, preparation, or filling/closure work.

(3) In cases where the filling/closing work and packaging work for the capsule product after capsule filling are performed by a continuous machine, and measures are taken to prevent contamination in the parts involved in the filling/closing work.

2. It is assumed that basic measures to prevent contamination and cross-contamination, such as cleaning and systematic implementation of education and training, are properly taken.

GMP9-5 (structural equipment of operational room) [Question] According to Article 9, Paragraph 1, Item 3 of the GMP Ministerial Ordinance, ``Operational rooms in workplaces have the structure necessary to prevent contamination by dust or microorganisms, depending on the type of product, dosage form, and manufacturing process.'' What kind of structure and equipment should a operational room where work that generates dust be carried out have?

[Answer]

1. This is necessary for operational rooms where raw materials are weighed, operational rooms where preparation work is performed with solids such as powders that generate dust, or operational rooms where filling and closing work with solids such as powders that generate dust are performed. Each operational room shall be equipped with a dust removal device and have its own dedicated operational room.

2. However, products with the same active ingredient (different dosage forms (oral solid preparations (note: tablets, capsules, granules, fine granules, powders are the same dosage form as oral solid preparations), oral liquid preparations, etc.) are excluded. ), based on risk assessment (confirming that there is no impact through environmental monitoring, etc.), appropriate measures should be taken to ensure that weighing, preparation, filling and closing operations do not affect each operation. If the work is carried out in a divided area, there is no problem even if each work is carried out in the same operational room.

3. It is assumed that basic measures to prevent contamination and cross-contamination, such as cleaning and systematic implementation of education and training, are properly taken.

GMP9-6 (structural equipment of operational room) [Question] If the same staff member is responsible for both weighing and preparation work, and each work involves handling products with different active ingredients, is it possible for the same staff member to enter both the weighing room and the preparation room? Is it okay to do so?

[Answer] In principle, this is not allowed. However, basic measures to prevent contamination and cross-contamination (including the necessity of changing clothes and changing procedures), such as cleaning, systematic implementation of thorough education and training, etc., must be strictly taken, and contamination through such personnel must be taken seriously. If there is reasonable evidence that there is no cross-contamination or cross-contamination, and these are stipulated in advance in the Standard Operating Procedures, etc., this may be permitted. In addition, care should also be taken to prevent confusion between different active ingredients due to mistakes.

GMP9-7 (structural equipment of operational room) [Question] Is it acceptable to use the same operational room as a weighing room in the morning, a preparation room in the afternoon, and a filling/closing room the next day?

[Answer]

1. There is no problem when manufacturing products with the same active ingredients after establishing procedures for cleaning and clearance after work and validating that there is no impact on each work.

2. For products with different active ingredients, procedures for cleaning and clearance after work and procedures for checking cleanliness and clearance immediately before the start of work are established, and if these procedures are followed, there will always be no cross-contamination by products with different active ingredients. After validating this, we will ensure that basic contamination and cross-contamination prevention measures are taken appropriately, such as cleaning, switching to a product with a different active ingredient, confirming cleanliness immediately before starting work, and implementing thorough education and training in a planned manner. If there is evidence to demonstrate that there is no contamination or cross-contamination, and this is stipulated in advance in the Standard Operating Procedures, etc., it may be accepted.

GMP9-8 (structural equipment of operational room) [Question] Based on GMP 9-7, for example, for products with the following formulations, if weighing work, preparation work, and filling/closure work are performed in separate areas, can each work be performed in the same operational room? Does it apply to the product? ① Ouren 1g ② Ouren 2g ③ Ouren 1g Gennoshoko 1g ④ Ouren 1g Gennoshoko 1g Keihi 1g ⑤ Ouren 2g Gennoshoko 1g Keihi 1g Products related to extract preparations made by adding excipients to extracts made from each.

[Answer] The combinations of ① and ②, ④ and ⑤ each fall under the category of products that can be performed in the same operational room (including cases where the types of excipients are different). All other combinations do not correspond to products where the relevant work can be performed in the same operational room.

GMP9-9 (operational room structure and equipment) [Question] According to Section 13(1)③ of the Notice of Promulgation of Revised Ministerial Ordinance, ``Operational rooms in workplaces must be designed to prevent contamination by dust or microorganisms, depending on the type of product being manufactured, the dosage form, and the manufacturing process. products with the same active ingredients. ), if weighing, preparation, filling, or closing work is performed in a space that is appropriately divided so as not to affect each work, each work is performed in the same operational room. Is it safe to assume that there is no need for dust removal equipment? In addition, if no dust is generated during any of the operations such as weighing raw materials, preparation, filling, and closing, and if a dust removal device is provided as necessary, all of these operations should be performed in the same operational room. Can this be interpreted as "weighing, preparation, filling/occlusion"?

[Answer] Even if the product contains the same active ingredients, it is necessary to provide a dust removal device as necessary. Regarding the latter question, if the products have the same active ingredients but generate dust, the weighing chamber must be dedicated for "weighing", "preparation (classification), filling/closing", etc. If the product has the same active ingredients and no dust is generated, it may be referred to as "weighing (classification), preparation (classification), filling/occluding". However, it is necessary to prove through environmental monitoring results that no dust will be generated.

GMP9-10 (flow line of people and materials) [Question] Regarding the provisions of Article 9, Paragraph 1, Item 4 of the GMP Ministerial Ordinance, if bulk drug products are transported from the preparation operational room to the filling operational room via work control areas with different levels of cleanliness, such as corridors and packaging operational rooms. May I do so?

[Answer] In principle, this is not allowed. However, this is not a problem if the cleanliness level of the air that comes into contact with the "preparation bulk" is maintained during transportation and loading, and sufficient prevention of mix-up, contamination, and cross-contamination is ensured (for changing clothes, transportation equipment, loading equipment, etc.) (Please also take into consideration the following.)

GMP9-11 (flow line of people and materials) [Question] Is an anteroom for changing clothes necessary for operational rooms where preparation work for products related to oral drugs that are neither sterile drugs nor biological products, and operational rooms where filling and closing work is performed? Also, is there a need for a section between changing and undressing in the changing room?

[Answer] Regarding the installation of a front room after changing and the division of changing rooms, as in the question, each manufacturer, etc. should decide according to the actual situation of each manufacturing site, depending on the risk, from the perspective of preventing contamination and cross-contamination. We should respond accordingly.

GMP9-12 (Products that are easily dispersed and can cause hypersensitivity reactions even in minute amounts) [Question] Article 9, Paragraph 1, Item 5-a of the GMP Ministerial Ordinance states, ``When handling products that are easily dispersed and can cause hypersensitivity reactions in minute amounts.'' Is it correct to think that even if a substance causes a hypersensitivity reaction, the capsule formulation after filling does not fall under this category?

[Answer] For capsules that have been filled and the drug attached to the outside of the capsule has been removed through a polishing process, etc., the provisions of Article 9, Paragraph 1, Item 5 A of the GMP Ministerial Ordinance do not necessarily apply. Although not applicable, there is a possibility that the drug may scatter due to breakage of the capsule during handling, etc., so measures to prevent leakage of the product, such as dedicating a operational room and installing a separate air treatment system, etc. It is desirable to take

GMP9-13 (Products that are easily dispersed and can cause hypersensitivity reactions even in minute amounts) [Question] Article 9, Paragraph 1, Item 5-a of the GMP Ministerial Ordinance states, ``When handling products that are easily dispersed and can cause hypersensitivity reactions in minute amounts.'' Is it correct to assume that even if a substance causes a hypersensitivity reaction in tablet form, this does not apply to the product?

[Answer] Since there is a possibility that the powder may scatter even for products made into tablets, measures will be taken to prevent the product from leaking, such as dedicating a operational room and installing a separate air handling system. There is a need. However, this does not apply to items that have been properly coated and are in a state where they cannot scatter, but as there is a possibility that the chemicals may scatter due to damage to the coating during handling, a dedicated operational room will be provided. It is desirable to take measures to prevent leakage of the product, such as installing a separate air treatment system.

GMP9-14 (Products that are easily dispersed and can cause hypersensitivity reactions even in minute amounts) [Question] Please indicate the precautions to be taken when handling "products, etc. that are easily dispersed and can cause hypersensitivity reactions in minute amounts" as per Article 9, Paragraph 1, Item 5-a of the Non-GMP Ministerial Ordinance.

[Answer] Considering the risk of hypersensitivity reactions, etc., in addition to hard containment measures such as dedicating operational rooms and separate air conditioning systems, we will also appropriately implement soft containment measures such as monitoring. Take measures to prevent cross-contamination of products.

In addition, when manufacturing substances such as penicillins and cephalosporins that can cause hypersensitivity reactions in minute amounts, monitoring here refers to confirming that the product does not leak from the work area and checking that the product does not leak from the manufacturing area. This purpose is to confirm whether there is any contamination or not, and to confirm that there is no impact on pharmaceuticals manufactured in other manufacturing areas.

When monitoring, it is necessary to determine the monitoring points, frequency, monitoring method, etc., taking into account the flow of workers and materials that come and go in the manufacturing area, work procedures, air flow, exhaust and drainage, etc. . Specific monitoring methods include the swab method, rinse method, and suction method (filter collection method), but the sampling method and quantitative method are based on factors such as the strength of sensitization of the product being monitored. It is necessary to take these settings into account. Also, set alert levels and action levels in advance, and document procedures for what to do when those levels are exceeded.

GMP9-15 (Products that are easily dispersed and can cause hypersensitivity reactions even in minute amounts) [Question] How should documents and records created within the dedicated manufacturing area for products that cause hypersensitivity reactions in trace amounts or brought in from outside be handled?

[Answer] The documents and records mentioned in the question may contain trace amounts of substances that can cause hypersensitivity reactions, so they should not be taken out carelessly. It is necessary to handle documents and records by analyzing the quality risk of cross-contamination due to removal work, inspection of documents, and records, etc. Also, confirm through monitoring, etc. that documents and records are being handled appropriately. Possible ways to reduce the quality risk of cross-contamination due to transporting documents and records include using fax machines, electronic files, etc., and transporting documents in plastic bags.

GMP9-16 (products that are easily dispersed and can cause hypersensitivity reactions even in minute amounts) [Question] In Article 9, Paragraph 1, Item 5 of the GMP Ministerial Ordinance, "the operational room (excluding operational rooms where only products stored in airtight containers are handled; the same shall apply in the next paragraph) shall be used exclusively" means that Is it enough to just divide the area, or do I need to take other measures as well, such as creating negative pressure?

[Answer] It is not permitted to manufacture products related to penicillins, cephalosporins, etc. and other products in the same operational room. Each operational room should be separate, that is, it should be divided into rooms, and the air treatment system should be separate. In addition to ensuring that people and objects do not cross each other, there should be sufficient space for air flow, etc. You need to be careful. Please refer to GMP9-14.

GMP9-17 (Products that are easily dispersed and can cause hypersensitivity reactions in small amounts) [Question] Please explain in detail what is meant by "separate air treatment system" as stipulated in Article 9, Paragraph 1, Item 5 of the GMP Ministerial Ordinance.

[Answer] "Separate air handling system" means that the air that has passed through the operational room where penicillins, cephalosporins, etc. are handled does not pass through other rooms, as shown in the example diagram below. This is what it says. Even if you are not handling materials that can cause hypersensitivity reactions in trace amounts, appropriate measures should be taken to minimize the risk of contamination and cross-contamination when air is recirculated into the workplace.

GMP9-18 (shared use of equipment) [Question] GMP9-18 (Sharing of equipment) Please explain how to determine whether or not operational rooms can be shared for pharmaceutical manufacturing equipment.

[Answer] Regarding the sharing of operational rooms, an example is shown in the decision tree in Attachment 1. The final decision on whether or not to share the product must be made based on the results of risk assessment based on scientific data from toxicological evaluation. Note that operational rooms that only handle samples collected from products, etc. are not required to be dedicated, but materials taken out of the operational room, manufacturing equipment and products are handled through test and analytical equipment, workers, etc. Care must be taken to avoid cross-contamination.

GMP9-19 (shared use of equipment) [Question] How is the toxicological evaluation of products, etc. performed when manufacturing facilities for pharmaceuticals are to be shared?

[Answer] Various indicators are known for toxicological evaluation (e.g. maximum no-observed-effect level (NOEL)). In setting limit values based on toxicological evaluation, in addition to the PIC/S related guidance documents listed in Section 13(1)(5)(a) of Revised Ministerial Ordinance Promulgation Notice No. 3, "Guidelines for Residual Solvents in Pharmaceuticals" ( "Guidelines for Elemental Impurities in Pharmaceuticals" (Pharmaceuticals and Food Safety and Drug Administration No. 0930 No. 4, September 30, 2015) (hereinafter referred to as ICH Q3D) ), “Guidelines for the evaluation and management of DNA-reactive (mutagenic) impurities in pharmaceuticals to reduce potential carcinogenic risks” (November 10, 2015 (Pharmaceutical Review and Review Notification No. 1110 No. 3) ICH M7) etc. should be used as a reference.

GMP9-20 (shared use of equipment) [Question] Who should conduct the toxicological evaluation when sharing equipment?

[Answer] It is desirable that a toxicology expert etc. conduct this. When entrusting toxicological evaluation to external experts, the manufacturer, etc. should confirm their suitability in advance and keep a record of this.

GMP9-21 (shared use of equipment) [Question] What points should be kept in mind when coordinating with manufacturers, etc. and marketing authorization holders when attempting to share pharmaceutical manufacturing equipment?

[Answer] If the product to be consigned is a drug or quasi-drug, the manufacturer, etc. should obtain information regarding the handling of the item from the manufacturing contractor (or ordering party). On the other hand, manufacturers should provide manufacturers, etc. with the information they possess so that contract manufacturers, etc. can set appropriate residual tolerance limits.

If the item to be shared is not covered by the GMP ministerial ordinance, collect the information yourself or from the manufacturer to determine whether or not it can be shared.

Based on the information obtained and collected as described above, manufacturers should appropriately evaluate whether or not structures and equipment can be shared, referring to the decision tree shown in GMP 9-18, and take appropriate measures to prevent cross-contamination. It is necessary to establish this.

If equipment is to be shared, the manufacturer, etc. must inform the manufacturer, etc. of the reason why the product in question can be shared regardless of whether the GMP ministerial ordinance applies (including appropriate measures to prevent cross-contamination). Contact should be made in advance, and the manufacturer/seller shall receive the contact, evaluate whether equipment sharing is possible if necessary, and notify the manufacturer, etc. of the results. Additionally, manufacturers should consider agreeing on the conditions for shared use with manufacturers, etc. based on the provisions of the GQP Ministerial Ordinance.

GMP9-22 (shared use of equipment) [Question] Article 9, Paragraph 2 of the GMP Ministerial Ordinance states that "manufacturing work for products to which this Ministerial Ordinance does not apply shall not be carried out in operational rooms where products are handled." What should I keep in mind when carrying out manufacturing work in a operational room that handles products related to pharmaceutical products? 1. Raw materials for pharmaceuticals that serve as active pharmaceutical ingredients 2. Intermediates for pharmaceuticals that serve as active ingredients for export 3. Active ingredients and their raw materials and intermediates at the drug development stage

[Answer] Regarding 1 and 2, it is okay to judge whether or not to dedicate a operational room based on the provisions of Article 9, Paragraph 1, Item 5 of the GMP Ministerial Ordinance.

On the other hand, regarding item 3, like investigational drugs, it is considered to be a product to which the GMP Ministerial Ordinance does not apply, and the provisions of Article 9, Paragraph 2 of the GMP Ministerial Ordinance apply. As per 2), when manufacturing a drug-related product and using the product in combination with or diverting it to products to which the GMP Ministerial Ordinance does not apply, Article 9 of the GMP Ministerial Ordinance is required, as in 1 and 2. Based on the provisions of Paragraph 1, Item 5, there is no problem in determining whether or not to dedicate a operational room.

Please refer to GMP 9-18 and 9-21 for the feasibility and points to keep in mind when sharing equipment.

GMP9-23 (shared use of equipment) [Question] Article 9, Paragraph 1, Item 5 of the GMP Ministerial Ordinance states, “Working rooms (excluding operational rooms where only products stored in sealed containers are handled and operational rooms where only samples collected from products, etc. are handled. The same product is used exclusively for the same product), but is it possible to share the freeze dryer with other products?

[Answer]

1. As the risk of scattering under reduced pressure cannot be denied, it should be used exclusively for this purpose in principle.

2. However, depending on the type of product, the manufacturing date may differ, and there is reasonable evidence (cleaning validation (refer to GMP 13-55) data, etc.) that the product is in a state where it cannot be dispersed or cross-contaminated. It may be possible to share a freeze dryer if it is stipulated in advance in the Standard Operating Procedures, etc.

3. It is assumed that basic measures to prevent contamination and cross-contamination, such as cleaning and systematic implementation of education and training, are properly taken.

GMP9-24 (shared use of equipment) [Question] The changing room for staff in the operational room for products related to penicillins, cephalosporins, etc. is shared with the changing room for staff in the operational room for other products (air showers are for their own use.) Is it okay to do so?

[Answer] Not allowed.

GMP9-25 (shared use of equipment) [Question] What kind of operational room does "operational room where only products stored in sealed containers are handled" in Article 9, Paragraph 1, Item 5 of the GMP Ministerial Ordinance refer to?

[Answer] Refers to a operational room where products, etc., such as those packaged in PTP packaging or after bottling, are handled only in closed containers that do not cause leakage or contamination during normal handling. .

GMP9-26 (shared use of equipment) [Question] The testing laboratory for quality control of products such as products related to penicillins, cephalosporins, etc. that are subject to Article 9, Paragraph 1, Item 5 of the GMP Ministerial Ordinance is the testing laboratory for other products, etc. Can I share it with

[Answer] As long as there is no cross-contamination of "other products, etc.", there is no problem in sharing testing and testing laboratories related to quality control, which are usually separated from work sites, but testing and testing rooms related to in-process control, etc. shall not share products related to products that may cause cross-contamination with products related to "other products, etc." In order to prevent "other products, etc." from being contaminated with penicillins, cephalosporins, etc., for example, the testing and inspection room and the manufacturing operational room of "other products, etc." should not have the same air conditioning system; Measures should be taken to prevent cross-contamination of manufacturing operational rooms for "other products, etc." by staff members, collected products, documents, etc.

GMP9-27 (shared use of equipment) [Question] Article 9, Paragraph 1, Item 3 of the GMP Ministerial Ordinance: “Working rooms in workplaces have the necessary structure and structure to prevent contamination by dust or microorganisms, depending on the type of product, dosage form, and manufacturing process. With regard to the provision of ``having equipment,'' if 5 to 6 dryers, tableting machines, etc. are installed together, dust removal equipment, etc. shall be installed in units of drying zones, tableting zones, etc. Should I think about how to respond? Or will it be necessary to deal with each dryer, tablet machine, etc.? (Excluding products related to penicillins, cephalosporins, etc.)

[Answer] In the case of the question, assuming that products with different active ingredients are not handled at the same time in each "zone", if work management is carried out to prevent cross-contamination, dust removal equipment can be installed in each "zone". There is no harm in considering countermeasures such as installation or dedicating a operational room.

GMP9-28 (shared use of equipment) [Question] Structures and facilities for manufacturing products related to pharmaceutical products to which GMP Ministerial Ordinance is applied, as well as products related to products to which GMP Ministerial Ordinance does not apply (drugs or quasi-drugs, medical devices, cosmetics, veterinary drugs, food, etc.) Can I share it with others?

[Answer]

1. Decisions on whether products to which GMP is not applicable can be shared must be based on scientific evidence based on GMP9-19, GMP13-56, etc. If it is determined that the substance can be shared, measures will be taken to prevent cross-contamination of other products by the verified process of inactivating or removing the substance or by cleaning the structure and equipment, and measures will be taken to prevent cross-contamination of other products. Manufactured under the same level of manufacturing control and quality control as the product, and provided with reasonable evidence (cleaning validation (GMP13)) that there is no confusion, contamination, or cross-contamination with pharmaceutical products. -Refer to 55 and 56) data, etc.) must be specified in advance in the Standard Operating Procedures, etc.

2. In this case, it is assumed that basic measures to prevent contamination and cross-contamination, such as cleaning and systematic implementation of education and training, are properly taken.

3. Regardless of whether appropriate measures are taken to prevent cross-contamination, sharing is prohibited in the following cases:

(1) When handling substances that are easily dispersed and can cause hypersensitivity reactions in minute amounts during the manufacturing process of the product.

(2) The article is not intended for use on the human body, and it is not clear that its ingredients do not have strong pharmacological effects or toxicity.

Four. In addition, it is stated in Section 13(2) of the Revised Ministerial Ordinance Promulgation Notice that ``It is acceptable to use or divert the product to products to which GMP is not applied (e.g., veterinary drugs, drugs subject to clinical trials, etc.). ”.

GMP9-29 (shared use of equipment) [Question] What kind of processes are involved in "inactivation" and "removal," which are measures to prevent cross-contamination when manufacturing equipment is shared with materials to which the GMP ministerial ordinance does not apply?

[Answer] Examples of typical inactivation/removal processes include the following.

1. Heating (e.g. liquid 60℃, 12-24 hours)

2. Organic solvent/surfactant treatment

3. Acid treatment/alkali treatment

Four. Radiation irradiation (γ-ray irradiation)*, autoclave, etc.*

Five. Extraction/adsorption treatment

*In the case of this inactivation treatment, it is expected that the enzyme activity will be inactivated and the microorganisms will be inactivated by killing them, but since the enzyme protein and the dead microorganisms will not be removed, the remaining proteins and microorganisms will not be removed. Body mass also needs to be taken into consideration.

GMP9-30 (shared use of equipment) [Question] What does "inactivation" and "removal" mean, which are measures to prevent cross-contamination when manufacturing equipment is shared with materials to which the GMP ministerial ordinance does not apply?

[Answer] "Inactivation" refers to the loss of pharmacological effects, toxicity, etc., and "removal" refers to the removal of substances that have pharmacological effects, toxicity, etc.

GMP9-31 (shared use of equipment) [Question] How should the degree of inactivation be evaluated?

[Answer] Regarding the degree of inactivation, the concept of residual permissible limit value for cleaning (washing) should be applied mutatis mutandis.

Education and training on cross-contamination prevention

GMP9-32 (Education and training on cross-contamination prevention) [Question] What kind of education and training should be implemented regarding cross-contamination prevention?

[Answer] Causes of cross-contamination (e.g., powder adhering to workers scatters as workers move, powder spilled on the floor adheres to the wheels of trolleys and scatters inside and outside the operational room, etc.), Provide specific training on work procedures to prevent contamination in accordance with the manufacturing management of the manufacturing facility, and educate employees so that they fully understand the importance of working correctly according to established procedures. Education and training should be conducted not only for workers engaged in manufacturing, but also for all related workers who enter the production area, such as those engaged in cleaning work.

Structures and equipment related to manufacturing water

GMP9-33 (structures and equipment related to manufacturing water) [Question] Regarding the provisions of Article 9, Paragraph 1, Item 6 of the GMP Ministerial Ordinance, to what extent should water used in the manufacture of pharmaceutical products that are active ingredients for non-sterile oral preparations be managed? In addition, in the manufacture of pharmaceutical products that are active ingredients that are purified by distillation in the final purification process, how should the quality of water used in the pre-distillation process be regulated and to what extent should it be controlled? Is there one?

[Answer] The ``Guidelines for GMP for APIs'' (Ipaku No. 1200, November 2, 2001) states that ``Unless there is a justifiable reason, at least the water quality standards based on the Water Supply Act or the World Health Organization (WHO) drinking water quality guidelines. In addition, if it has been confirmed in advance that the drinking water standards of each country comply with the water quality standards based on the Water Supply Act or the WHO drinking water quality guidelines, we will confirm that the drinking water standards of each country comply with the drinking water standards. You can also do that. In addition, regarding the selection of manufacturing water for products related to drug substances, please refer to the Japanese Pharmacopoeia reference information "Quality control of pharmaceutical water." In addition, in order to ensure the quality of manufacturing water, it is necessary to monitor it at appropriate intervals, taking into account the use of the manufacturing water and the status of maintenance, including sterilization of water treatment equipment.

GMP9-34 (structures and equipment related to manufacturing water) [Question] The scope of application of water in Article 9, Paragraph 1, Item 6 of the GMP Ministerial Ordinance includes water for washing equipment, instruments, and containers used in manufacturing, and water for testing and inspection at manufacturing facilities for products related to pharmaceuticals that are active pharmaceutical ingredients. Does it include the water used?

[Answer] Included.

GMP9-35 (structures and equipment related to manufacturing water) [Question] Article 9, Paragraph 1, Item 6 of the GMP Ministerial Ordinance stipulates that water supply equipment of the quality and quantity required for product manufacturing must be provided. Can I purchase it from and use it as is?

[Answer] When purchasing water for manufacturing from outside, conduct acceptance tests regarding the necessary quality for each management unit and confirm that it conforms to the requirements before use (e.g., according to the Japanese Pharmacopoeia drug monograph. (Implementation of test items for "purified water (container)"). For tap water, acceptance tests regarding the necessary quality are not required, but the water quality standards based on the Water Supply Law or the World Health Organization (WHO) drinking water quality guidelines (drinking water standards of each country are If it has been confirmed in advance that the water conforms to the water quality standards based on the WHO drinking water quality standards or the WHO drinking water quality guidelines, confirm that it complies with the drinking water standards of each country).

改正GMP省令　Article 10　Manufacturing Control

GMP10-1 (manufacturing instructions) [Question] Regarding the "expected yield" and "standard yield" indicated in Article 10, Item 1 of the GMP Ministerial Ordinance, as specified in the revised Ministerial Ordinance Promulgation Notice No. 3, 14(1)⑥, as items to be stated in the manufacturing instructions Please explain.

[Answer] Generally, the expected yield refers to the 100% yield that can be calculated in advance from the amount of raw materials charged based on the Pharmaceutical product standard code. The expected yield is the yield calculated stoichiometrically based on the amount of raw materials charged. In addition, standard yield (yield) is the standard (average) yield (yield) when actually manufactured based on the Pharmaceutical product standard code, based on experimental data, pilot scale data, or actual data. refers to the appropriate range determined based on the In general, regarding the amount of production (actual yield), if there is a deviation in yield, the impact or risk of such deviation on the quality of the lot affected by the deviation must be clarified.

GMP10-2 (manufacturing instructions) [Question] When manufacturing the same product, in the same quantity, and using the same manufacturing method every day, please omit the common items and write only the necessary information such as the instruction date, lot number, or manufacturing number on a paper medium or Is it okay to use electronic media as a manufacturing instruction set forth in Article 10, Item 1 of the GMP Ministerial Ordinance?

[Answer] Omitting even common items can cause lot confusion and other mistakes, so it is necessary to include all necessary items in the manufacturing instructions.

GMP10-3 (manufacturing instructions) [Question] Is it okay to create manufacturing instructions for each process under Article 10, Item 1 of the GMP Ministerial Ordinance?

[Answer] As long as manufacturing instructions are properly prepared based on Pharmaceutical Product Standard Code, etc., manufacturing instructions may be created for each process or for all processes at once.

GMP10-4 (manufacturing instructions) [Question] Article 10, Item 3 of the GMP Ministerial Ordinance stipulates that, in principle, a group of products manufactured based on one manufacturing instruction should be manufactured in one lot. When manufacturing, can it be issued every few days or every month?

[Answer] Not allowed. However, if several lots of products are repeatedly manufactured within the same day according to the same instruction content (including the content shown in Section 14(1) ③ to ⑧ (excluding the time of ③) of Revised Ministerial Ordinance Publication Notice No. 3). In this case, it is acceptable to have one sheet of instructions with all the lot numbers to be manufactured within the same day written in the lot number column as instructions for several lots.

GMP10-5 (manufacturing instructions) [Question] Article 10, Item 1 of the GMP Ministerial Ordinance, Article 10, Item 1 of the Notification of Promulgation of the Revised Ministerial Ordinance No. 3, 14(1) ⑥ “Batch size of products (including intermediate products) in the manufacturing process, expected Cases in which the recovered mother liquor is carried forward and used in the next lot in the manufacture of products related to drug substances, with regard to the yield (standard yield if it is difficult to determine the expected yield) and acceptable yield limits. Therefore, it may not be possible to accurately record the amount of recovered mother liquor in the manufacturing instructions. In this case, is it okay to describe the amount of recovered mother liquor as an approximate amount? Also, since it is difficult to manage by yield on a lot-by-lot basis, is it okay to manage by yield over a continuous period of time?

[Answer]

1. Regarding the questions in the first part, if it is unavoidable, there is no problem. However, the preparation amount must be described within the scope of the manufacturing and marketing approval (notification) document, mother liquor control values (e.g. content rate, etc.), and the mother liquor should be managed including the yield for each lot.

2. Regarding the yield control in the question in the second half, the principle is to follow manufacturing instructions for each lot. However, if it is difficult to specify the yield for each lot and give manufacturing instructions, and if it is unavoidable, at least give instructions based on standards that serve as a guideline for the yield for each lot based on actual data, etc. The production volume and yield of multiple consecutive lots during one manufacturing period shall be recorded in the manufacturing record, and if there is a deviation in the yield of multiple lots, the impact or risk thereof on the quality of the lots related to the deviation shall be recorded. There is no problem if it is clearly stated, confirmed by the quality department, and specified in advance in the Pharmaceutical product standard code, etc.

3. In general, the amount of output (actual yield) is compared at a predetermined stage of the manufacturing process, and when there is a deviation in yield related to an important process, the quality of the lot affected by the deviation is compared. Clarify the impact or risk of such impact on

GMP10-6 (manufacturing instructions) [Question] In Article 10, Item 1 of the GMP Ministerial Ordinance, Article 10, Item 1 of the Notification of Promulgation of the Revised Ministerial Ordinance No. 3, 14(1)⑥ states, “Expected yield (if it is difficult to determine the expected yield)” "Standard yield) and yield tolerance limits", but it is not completely accurate for consecutive lots of the same drug substance manufactured in the same manufacturing period, under the same manufacturing conditions, and with the same manufacturing equipment. If the yield varies from lot to lot as a result of not properly cleaning the equipment, how much variation in yield is acceptable?

[Answer]

1. The standard yield range for each lot cannot be determined unconditionally because it may vary depending on the product, manufacturing method, manufacturing equipment, etc. An appropriate control range is set from the perspective of understanding deviations that may affect product quality based on performance data, etc., and this is confirmed by the quality department, specified in advance in Pharmaceutical Product Standard Code, etc., and the process is started. Appropriate management.

2. In addition, in general, the amount of output (actual yield) shall be compared at a predetermined stage in the manufacturing process, and if there is a deviation in yield related to an important process, the quality of the lot affected by the deviation Clarify the impact or risk of such impact on

3. Even when manufacturing the same product continuously or for a limited period of time, cleaning must be carried out at appropriate intervals to prevent the formation of contaminants and their carryover (products related to pharmaceuticals that are active ingredients). (2) to avoid causing carryover of decomposition products or microbial contamination that could adversely affect the impurity profile.

GMP10-7 (manufacturing instructions) [Question] Regarding ingredients whose quantities are listed in "mass (volume)" on the manufacturing and marketing approval (notification) document, in the manufacturing instructions in Article 10, Item 2 of the GMP Ministerial Ordinance, when weighing in actual work, it is converted by specific gravity. Can I instruct them to weigh by "capacity (mass)"? However, the specific gravity of each component at each temperature has been thoroughly investigated and specified in advance in the Pharmaceutical Product Standard Code.

[Answer] No problem. In general, important weighing work should be performed in the presence of someone other than the worker (unless equivalent control can be achieved by other methods). In addition, when performing conversion processing from time to time in instructions and records, double-check or alternative confirmation to prevent conversion errors.

GMP10-8 (manufacturing instructions) [Question] In the manufacturing and marketing approval (notification) document, the content of a liquid or injection drug is stated in volume (mL), but in the manufacturing of products related to the drug, the manufacturing instructions under Article 10, Item 2 of the GMP Ministerial Ordinance are not followed. Is it okay to instruct that the filling amount be measured by mass and converted to volume (mL) using specific gravity? However, the specific gravity of each component at each temperature has been thoroughly investigated and specified in advance in the Pharmaceutical Product Standard Code.

[Answer] No problem. In general, important weighing work should be performed in the presence of someone other than the worker (unless equivalent control can be achieved by other methods). In addition, when performing conversion processing from time to time in instructions and records, double-check or alternative confirmation to prevent conversion errors.

GMP10-9 (manufacturing instructions) [Question] Regarding the process of continuously subdividing and packaging intermediate products of the same lot of products related to capsules over a long period of time using the same manufacturing conditions and the same manufacturing equipment, the manufacturing process stipulates Article 10, Item 2 of the GMP Ministerial Ordinance. Can instructions (see GMP 10-3) be carried out using a single manufacturing instruction?

[Answer] In the case of the question, subdivided packaging is permitted within the scope of being considered the same lot (see GMP 2-23). Please refer to GMP10-4.

GMP10-10 (manufacturing instructions) [Question] Regarding several processes in which the same lot of intermediate products is manufactured under the same manufacturing conditions and with the same manufacturing equipment over a long period of time, is it possible to use a single manufacturing instruction sheet to comply with the manufacturing instructions set forth in Article 10, Item 2 of the GMP Ministerial Ordinance? May I go?

[Answer] In the case of the question, products that have gone through "several steps" are permitted within the scope of being considered the same lot (see GMP 2-23). Please refer to GMP10-4.

GMP10-11 (manufacturing instructions) [Question] Article 10, Item 1 of the GMP Ministerial Ordinance states, "Documents containing instructions, precautions, and other necessary matters in the manufacturing process (hereinafter referred to as "manufacturing instructions") must be prepared and kept." However, is it okay for the organization in charge of quality assurance-related work to keep it?

[Answer] When storing manufacturing instructions, it is not necessarily necessary for the manufacturing department to store them, but it should be stated in the Standard Operating Procedures that the organization in charge of quality assurance operations will store them, and the manufacturing instructions will be stored based on that. There is no harm in doing so.

GMP10-12 (manufacturing record) [Question] Can the names of products, etc. and materials listed in manufacturing records be written using the abbreviations used internally by the manufacturer, etc.?

[Answer] Necessary measures such as making it possible to identify the latest revision status of the relationship between official names and "abbreviations" and implementing systematic education and training are necessary to ensure that there is no risk of confusion. There is no problem as long as the quality department confirms that there are reasonable grounds for doing so, and that these are specified in advance in the drug product standard documents, etc.

GMP10-13 (manufacturing record) [Question] Is it okay to fill in the manufacturing record for several lots on one sheet under Article 10, Item 4 of the GMP Ministerial Ordinance?

[Answer] In principle, records should be created for each lot so that if there is a problem with that lot, a follow-up investigation can be conducted to determine the cause. Furthermore, for records for which it is not necessarily rational to manage each lot (for example, daily inspection records, operational room monitoring records, etc.), even if they are managed in a separate volume, the relationship with each lot can be traced. There is no problem as long as it is done as follows.

GMP10-14 (manufacturing record) [Question] Is it acceptable to prepare manufacturing records in English as per Article 10, Item 4 of the GMP Ministerial Ordinance?

[Answer] In principle, manufacturers are not allowed to prepare manufacturing records in English. Please note that it is acceptable to write both Japanese and English texts. For foreign manufacturers, it may be prepared in a language that is easily understood by the responsible person and other employees.

GMP10-15 (manufacturing record) [Question] Article 10, Item 4 of the GMP Ministerial Ordinance, Article 10, Item 4, Notification of the Promulgation of the Revised Ministerial Ordinance No. 3, 14(4) ⑤ “Names and lot numbers of raw materials used in the manufacturing process (raw materials that do not constitute a lot)” (manufacturing number), control unit number, and quantity used (actual measured value), if the solvent used in the manufacturing process of a drug product that is an active pharmaceutical ingredient is collected and used repeatedly, what is the amount to be prepared? Should I think like this?

[Answer] In the case of the question, record the amount of recovered solvent reused and the amount of newly mixed solvent. Note that it is necessary to confirm that reused solvents and newly mixed solvents comply with the standards before mixing.

GMP10-16 (manufacturing record) [Question] Article 10, Item 4 of the GMP Ministerial Ordinance, Article 10, Item 4, Notification of the Promulgation of the Revised Ministerial Ordinance No. 3, 14(4) ⑤ “Names and lot numbers of raw materials used in the manufacturing process (raw materials that do not constitute a lot)” Regarding "manufacturing number), control unit number, and quantity used (actual value)," when using an automatic weigher to weigh different lots of raw materials consecutively, it is important to know how much of each lot's raw materials were used in the product. How should I create manufacturing records when I am unsure?

[Answer] As a general rule, manufacturing instructions should include accurate descriptions of the amount of raw materials to be mixed or prepared, including the units of measurement. At a minimum, manufacturing records must include all lot numbers and total amounts of raw materials used.

GMP10-17 (manufacturing record) [Question] With regard to Article 10, Item 4 of the GMP Ministerial Ordinance, Notice of Promulgation of Revised Ministerial Ordinance No. 3-14(4), ① “Name,” ④ “Name or initials,” and ⑧ “Name or initials.” Is it okay to replace the name of the person in charge, employee name, and work chief entered in the manufacturing record with the employee number?

[Answer] Not allowed.

GMP10-18 (acceptance and storage) [Question] Please indicate the precautions to be taken when accepting and storing products, etc. and materials based on the provisions of Article 10, Items 5 and 6 of the GMP Ministerial Ordinance.

[Answer]

1. Examples of precautions for receiving and storing products, etc. and materials

(1) Individual containers or groups of containers for products, etc. and materials shall be identified using identification codes, lot numbers or management unit numbers, receipt numbers, etc., and the placement, movement, etc. of each lot or each management unit shall be indicated using such numbers. To manage. In addition, the management status of each lot or management unit (e.g., "under testing", "passed product", "rejected product", "return", "waiting for shipping decision", "shippable", "shippable") , "recovered items", "disposal", etc.).

(2) Products and materials shall be handled and stored in a manner that prevents decomposition, contamination, and cross-contamination.

(3) In principle, containers in which products and materials are stored (fiber drums, boxes, etc.) should not be placed directly on the floor, and should not be cleaned and inspected unless this can be done by other means. Provide appropriate spacing if necessary for this purpose.

(4) Products, etc. and materials shall be stored under conditions and periods that do not adversely affect their quality, and storage and delivery shall be managed so that the oldest items are used first.

(5) Products and materials determined to be rejected shall be identified and stored separately to prevent them from being used for manufacturing without permission.

2. Examples of precautions for receiving and storing raw materials, etc.

(1) Incoming raw materials, etc. must be accompanied by appropriate labeling before acceptance (if the name of the supplier and the name of the manufacturer, etc. are different, the relationship shall be inspected). ), and confirm by visual inspection that there is no damage to the container, damage to the seal, or evidence of unauthorized tampering or contamination.

(2) When raw materials are received by transport by non-dedicated tank truck, etc., receipt of a certificate showing that the tank truck, etc. has been cleaned, testing and inspection, supplier audit (on-site or in writing), etc. Appropriate measures should be taken to prevent cross-contamination.

(3) Large storage containers, their associated piping, and piping for filling or discharging the containers shall be identified.

3. Examples of precautions for receiving and storing materials

(1) Access to the label storage area shall be limited to authorized personnel.

(2) Check the balance of the amount of labels issued, used, and returned, and if they do not match, investigate the cause and have it checked by the quality department.

(3) All surplus labels displaying lot numbers and other lot-related items must be destroyed.

(4) Old versions and expired labels must be discarded.

GMP10-19 (storage) [Question] As an interpretation of Article 10, Item 6 of the GMP Ministerial Ordinance, it is stated in Section 14(6)① of the Notification of Promulgation of the Revised Ministerial Ordinance that ``For products, etc., by lot (for products, etc. that do not constitute a lot, by serial number), ``Materials shall be appropriately stored and delivered in each management unit.'' However, for packaging, filled and closed intermediate products must be clearly separated by lines etc. in the packaging operational room and temporarily stored. Is it okay? I would also like to know how products and materials are handled when stored in the Rack Building warehouse.

[Answer]

1. GMP10-18 1. Procedures, etc. based on the precautions are prescribed in advance in Standard Operating Proceduress, etc., and systematic implementation of education and training for staff engaged in work in the "packaging operational room" is carried out to prevent confusion, contamination, and cross-contamination. There is no problem if the necessary measures are taken.

2. When storing in a so-called rack building warehouse, it is okay to manage one pallet as one category.

GMP10-20 (storage) [Question] In accordance with the GMP Ministerial Ordinance, there is a method of managing products, raw materials, etc. in the same storage area by separating them into pallets and displaying them as "under testing," "passing products," "rejecting products," etc. Is it considered to be "appropriately stored" under Section 14(6)① of the Revised Ministerial Ordinance Promulgation Notice No. 3 as an interpretation of Article 10, Item 6?

[Answer]

1. This shall be considered if sufficient measures are taken to prevent confusion, contamination, and cross-contamination. In addition, for products, raw materials, etc. that have been determined to fail (it is desirable to take action as soon as possible when OOS is obtained (see GMP 11-60)), return, dispose, etc. are necessary. Until such measures are taken, measures should be taken to ensure the prevention of mix-up, such as moving the product to a location where it can be stored in an isolated manner as soon as possible.

2. In addition, records regarding the final disposition of items determined to be rejected shall be created and retained.

GMP10-21 (storage) [Question] Regarding the provisions of Article 10, Item 6 of the GMP Ministerial Ordinance, if a storage location is specified for each product, raw material, etc., for example, if the storage location for raw materials is temporarily used as the storage location for products, etc. I would like to know what to keep in mind when storing items other than these.

[Answer] Take sufficient measures to prevent confusion, contamination, and cross-contamination, and ensure that the quality department confirms the procedures and stipulate them in advance in the Standard Operating Procedures, etc. Regarding the necessity of submitting change notifications related to manufacturing licenses and certifications, please follow the notices and administrative communications issued by the Pharmaceutical Examination and Management Division, Pharmaceutical and Environmental Health Bureau, Ministry of Health, Labor and Welfare.

GMP10-22 (storage) [Question] Regarding the provisions of Article 10, Item 6 of the GMP Ministerial Ordinance, is it okay to clearly classify different types or different lots of products, raw materials, etc. and then mix them on the same pallet?

[Answer] GMP10-18 1. The quality department confirms the procedures, etc. based on the precautions of This is acceptable as long as it is clearly separated and the necessary measures are taken to prevent confusion, contamination, and cross-contamination. However, mixing with rejected products is not permitted. Items undergoing testing and inspection (temporary storage) should not be mixed with passed items, but should be placed on at least a separate "pallet".

GMP10-23 (storage) [Question] Regarding the interpretation of Article 10, Item 6 of the GMP Ministerial Ordinance, Article 3 of the Notification of Promulgation of the Revised Ministerial Ordinance, Section 14(6) ②C states, In storage, the materials are classified by item and labeled with the item name or item symbol of the material in question at each storage location.''However, if there is a label indicating the item name of the material in question on the packaging. Can this be replaced by displaying the storage location?

[Answer] The quality department has confirmed the procedures, etc. based on GMP10-19 and GMP10-22, and the procedures are stipulated in advance in the Standard Operating Procedures, etc., and necessary measures are taken to prevent confusion, such as systematic implementation of employee education and training. If this is the case, this can be replaced by displaying the storage location. However, it is necessary to display information such as revisions of displayed content, management numbers for managing first-in, first-out, and status management before and after inspection.

GMP10-24 (storage) [Question] In 3-14(6)②C of the Notice of Promulgation of Revised Ministerial Ordinance, points to keep in mind regarding the storage of materials for which matters stipulated by the law are stated are indicated. I would like to know the points to keep in mind when managing materials for which only other items are displayed.

[Answer] Even if materials are labeled only with matters other than those stipulated by the law, they should be managed in the same way as materials that are labeled with matters stipulated by the law.

GMP10-25 (storage) [Question] Regarding the provisions of Article 10, Item 7 of the GMP Ministerial Ordinance, it is complicated to carry raw materials into the weighing room each time they are weighed and then return them to the raw material warehouse after weighing. Also, can it be stored in the weighing room if care is taken to avoid contamination and cross-contamination?

[Answer] Storage in the weighing room is not permitted. Measures should be taken by setting up a warehouse for dispensing raw materials near the weighing room.

GMP10-26 (storage) [Question] Please indicate the points to keep in mind when manufacturing drugs designated by the Minister of Health, Labor and Welfare as addictive based on the provisions of Article 50, Item 11 of the Act (hereinafter referred to as "addictive drugs"). want.

[Answer] Due to the characteristics of addictive drugs, there is a high probability of health and hygiene hazards occurring if they are mixed with other drugs. "Thorough reinforcement of unannounced on-site inspections based on the above" (Notice No. 0209, Supervisory Guidance/Narcotics Countermeasures Division Chief of the Yakusho Kanma Department, February 9, 2021)3. In addition to thoroughly implementing the manufacturing control described in , care should be taken regarding storage management, such as storing the product clearly separated from other products or raw materials and creating records of entering and exiting the storage area.

Storage records and accounting records

GMP10-27 (storage records and accounting records) [Question] Regarding the interpretation of Article 10, Item 6 of the GMP Ministerial Ordinance, Section 14(6) (2) of the Notice of Promulgation of the Revised Ministerial Ordinance No. 3 states, ``For materials, for each management unit, the date and quantity of materials received, the amount taken during storage, "Measures taken, date of shipment, and quantity must be recorded," but is it necessary to create one for all materials?

[Answer] All items that require GMP management are subject to this. At least materials whose specifications and test methods are specified in the manufacturing and sales approval (notification) document, and materials with matters specified by law, will be accepted and stored in accordance with GMP10-18, and storage and delivery will be conducted. To create records.

GMP10-28 (storage records and accounting records) [Question] Manufacturers who are entrusted with determining whether or not to ship products to the market must keep records of storage and disbursements of products as required by Article 10, Item 6 of the GMP Ministerial Ordinance, and keep records of product storage and disbursements as required by the GQP Ministerial Ordinance. May I use this information as a record of drug sales (brand name, lot number, quantity, shipping destination, etc.) required for "records related to shipments to destination markets?"

[Answer] The products approved in the determination of whether or nn of whether or not to be shipped to the market as pharmaceuticals without going through any manufacturing process, and the determination of whether or not to be shipped from the manufacturing facility and the mar

GMP10-29 (hygiene management record) [Question] Hygiene management records related to manufacturing, such as cleanliness confirmation result records for structures and equipment under Article 10, Item 7 of the GMP Ministerial Ordinance, and hygiene management records for personnel under Item 8 of the same article, must be kept in the manufacturing record form under Item 4 of the same article. Can I record it inside?

[Answer] The necessary matters specified in the GMP Ministerial Ordinance, the Notice of Promulgation of the Rev etc. are stated, and it is clear which (multiple) lots of which product the "sanitatiouring" corresponds to. Yes, there is no problem as long as it does not hinder the implementation of the provisions of the GMP Ministerial Ordinance, such as deviation control, shipping decision, recall response, etc.

GMP10-30 (hygiene management record) [Question] Please indicate the precautions and general format for creating records of cleanliness confirmation results for structures and equipment as stipulated in Article 10, Item 7 of the GMP Ministerial Ordinance.

[Answer]

1. Confirm that cleaning has been carried out based on each item of GMP 8-4, and confirm the date (time, if necessary) of cleaning, the name and lot number of the product manufactured using the relevant structure and equipment, and Enter the serial numbe and the name of the person who performed the cleaning.

2. The ``general format'' cannot be determined in general, but must be created in accordance with the actual circumstances of each manufacturing facility.

GMP10-31 (hygiene management record) [Question] Article 10, Item 7 of the GMP Ministerial Ordinance states that "confirm the cleanliness of structures and equipment," but what level of cleanliness is required?

[Answer] The cleanliness level should be determined according to the risk of the product, and the basis thereof should be stipulated in advance in the Standard Operating Procedures, etc.

GMP10-32 (hygiene management record) [Question] What exactly should be recorded under Article 10, Item 8 of the GMP Ministerial Ordinance, “carrying out hygiene management of employees and recording it”? Also, can records created based on the provisions of the Industrial Safety and Health Act be used?

[Answer] Matters related to the procedures in Section 11(1)(1)C(b) of the Notification of Promulgation of Revised Ministerial Ordinance, namely, "Restriction on entry to the workplace by persons other than staff engaged in manufacturing work" and "Restriction on access to the workplace by persons other than employees engaged in manufacturing work" , changing clothes and washing hands when entering and exiting, wearing protective equipment, etc., ``Understanding the health status of employees'' (see GMP 8-10), ``Restrictions on belongings and makeup, prohibition of eating, drinking, and smoking in the workplace, etc.'' Refers to records related to etc. If the necessary matters specified in the GMP Ministerial Ordinance, the Notice of Promulgation of Revised Ministerial Ordinance, etc. are entered, the necessary management (matters stipulated in Article 20, etc.) is carried out, and there are no problems in the operation of the Industrial Safety and Health Act. There is no problem in managing and utilizing "records created based on the provisions of the Industrial Safety and Health Act" as GMP documents.

GMP10-33 (calibration record) [Question] Hygiene management records related to manufacturing, such as cleanliness confirmation result records for structures and equipment under Article 10, Item 7 of the GMP Ministerial Ordinance, and hygiene management records for personnel under Item 8 of the same article, must be kept in the manufacturing record form under Item 4 of the same article. Can I record it inside?

[Answer] Manufacturers, etc. should determine risks to product quality based on the type, characteristics, purpose of use, frequency of use, etc. of the meter.

GMP10-34 (calibration record) [Question] Regarding "calibration of instruments" in Article 10, Item 9 of the GMP Ministerial Ordinance, which instruments should be calibrated and by what method? Also, for all items related to measurement for which national standards exist, is it necessary to ensure traceability to those standards?

[Answer] Ensure the following points.

1. We create a list of instruments and determine which instruments need to be calibrated, how they are calibrated, how often they should be calibrated, etc., based on the type of instrument, its characteristics, purpose of use, and frequency of use, and take into account the risk of adverse effects on product quality. The manufacturer shall calibrate at least the instruments that may affect the quality of the product.

2. For important instruments, the calibration status should be made clear (e.g., by attaching a label with the date of the next calibration scheduled, etc.). Instruments that do not meet the calibration standards and instruments whose next calibration date has passed have been marked as "unusable."

3. If an important instrument deviates from predetermined standard (limit) values during its calibration, the impact on the quality of products manufactured using the instrument since the previous calibration will be assessed and determined. and take necessary measures.

Four. If a so-called national standard exists, it is necessary that calibration be performed using a method that can be traced back to that standard. If a so-called national standard does not exist, the basis for calibration must be recorded.

GMP10-35 (calibration record) [Question] Can regular inspections of measuring instruments stipulated in the Measurement Act be interpreted as periodic inspection and maintenance of instruments? To what extent are periodic inspections and maintenance performed for concentration meters and other instruments that are not required by the Measurement Act?

[Answer] Among the matters related to inspection and maintenance of structures and equipment under Article 10, Item 9 of the GMP Ministerial Ordinance, regarding measuring instruments, apart from the inspection according to the Measurement Act, product It is necessary for manufacturers, etc., to conduct inspections, taking into account the risks to quality.

GMP10-36 (Report to organization in charge of quality assurance-related work) [Question] Is it okay to collectively report the status of manufacturing, storage, delivery, and hygiene management as a mechanism for document reporting to the organization in charge of quality assurance operations under Article 10, Item 10 of the GMP Ministerial Ordinance?

[Answer] Information related to manufacturing control and quality control that is necessary for shipping decisions should be reported before deciding whether to ship the lot from the manufacturing facility. In this case, check the individual management status of manufacturing, storage, delivery, and hygiene management, including the manufacturing records of the products created for each lot, and then report to the organization in charge of quality assurance operations. Other information that is regularly managed may be reported in bulk on a regular basis, except in the case of abnormalities

GMP10-37 (other) [Question] Regarding products that are active pharmaceutical ingredients, is it permissible to add a sieving or filtration process that is not listed in the manufacturing method section of the approval document for the purpose of removing foreign substances? It has been verified that sieving or filtration of the drug substance, which is the drug substance, does not affect the quality of the product.

[Answer] Please obtain confirmation from the marketing authorization holder in advance regarding the addition of this step, as it may affect regulatory approved information. In addition, when adding the relevant process, change management shall be conducted in accordance with the provisions of Article 14 of the GMP Ministerial Ordinance.

改正GMP省令　Article 11　Quality Control

GMP11-1 (test inspection) [Question] After importing a pharmaceutical product that is an active pharmaceutical ingredient manufactured at a foreign manufacturing facility, it is stored at packaging, etc. classification manufacturer A without any modification, including packaging and labeling (no Japanese labels, etc. affixed to containers, etc.). ) Delivered to domestic formulation manufacturer B. The drug manufacturer B manufactures a drug product using the drug substance, and decides whether or not it can be shipped from the manufacturing site as well as whether it can be shipped to the market. In this case, is it necessary for packaging, etc. classification manufacturer A to conduct testing and inspection on the test items that pharmaceutical product manufacturer B performs at the time of acceptance?

[Answer] Only if all of the following conditions are met, "Packaging, etc. Classification Manufacturer A" will conduct tests and inspections on items whose storage operations will not affect the product, and "Formulation Manufacturer B" will conduct testing upon acceptance. It is not necessary to carry out tests and inspections (excluding visual inspections) related to the items.

1. The marketing authorization holder shall comply with the provisions of the GQP Ministerial Ordinance with regard to the storage of the drug substance, which is the drug substance, with the "Packaging, etc. Classified Manufacturer A" and with respect to the manufacture of the product related to the said drug product with the "Formulation Manufacturer B." We have concluded an agreement based on the above, in which changes in storage conditions, etc. at "packaging, etc. class manufacturer A" are made with the agreement of both "packaging, etc. class manufacturer A" and "formulation manufacturer B". and that this fact is specified in advance in the drug product standard documents, etc.

2. The agreement based on the provisions of the GQP Ministerial Ordinance describes the rational basis for demonstrating that the storage operations of "Packaging, etc. Category Manufacturer A" do not affect the quality of the products guaranteed in the relevant test and inspection items. , and this fact must be specified in advance in the drug product standard documents, etc.

GMP11-2 (other testing and inspection bodies) [Question] The tests and inspections stipulated in Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance shall be carried out in accordance with Article 6, Item 7 of the Regulation on Buildings and Facilities and the Act on Partial Amendment of the Pharmaceutical Affairs Act and the Blood Collection and Blood Donation Brokerage Control Act. Regarding Enforcement (Pharmaceutical and Food Safety No. 0709004, July 9, 2004), what are the matters when using other testing and inspection institutions based on the provisions of Part 3, 10, Partial Outsourcing of Manufacturing Activities? Should we be careful about this?

[Answer]

1. Manufacturers, etc. shall enter into appropriate agreements based on Article 11-5, Paragraphs 1 and 2 of the GMP Ministerial Ordinance, and collect and store samples (see GMP 11-44) related to the use of the external testing laboratory. and transmission, implementation of testing and inspection (see Revised Ministerial Ordinance Promulgation Notice No. 3-15(1)④), inspection and maintenance of testing and testing equipment (see GMP11-38), preparation of test and inspection report, test and inspection record ( (Refer to Section 15(1) ④ A) of the Notice of Promulgation of the Revised Ministerial Ordinance (Refer to Section 3-15(1) ④ A) (including work necessary to ensure the reliability of records), reporting of test and inspection results, etc. This must be stipulated in advance in the Standard Operating Procedures, etc.

2. The following items shall be included in the test and inspection report. In addition, if the standard values and test and inspection results are obtained in numerical values, the numerical values shall be clearly indicated.

(1) Name (in the case of a corporation, name) and contact information, etc. of the external testing and inspection agency concerned

(2) Date of implementation of the test and inspection by the external test and inspection agency.

(3) Name (in the case of a corporation, name) and contact information of the manufacturer, etc.

(4) Results of testing and inspection by the external testing and inspection organization and date of judgment by the manufacturer, etc.

3. Manufacturers, etc., shall provide the following information regarding the product: 1. At the same time, prepare a document that describes the matters listed above, and inform the person designated in advance, and if necessary, the person in charge of the test and inspection of the relevant external test and inspection organization, of the technical matters necessary and matters to be noted when conducting the test and inspection. etc., and conclude an agreement (specifying that, in principle, so-called "subcontracting" shall not be carried out). In addition, documents related to the agreement shall be retained by both the manufacturer, etc. and the external testing and inspection organization.

Four. Manufacturers, etc. shall, as necessary, have a person designated in advance confirm on-site that tests and inspections are being conducted appropriately at the external testing and inspection organization based on the contents of the documents mentioned in 3 above, and create records thereof. be stored above.

Five. Manufacturers, etc. should conduct on-site inspections of the test and inspection facilities of the relevant external test and inspection organization, and conclude agreements as necessary so that they can use them promptly and appropriately.

6. Either the manufacturer, etc. or the relevant external testing and inspection organization shall retain the original copy of the test and inspection report, and the other party shall retain a copy thereof so that it can be used immediately.

7. Changes in test and inspection methods, etc. should not be made unless the manufacturer, etc. is informed of the change and approves it.

Omission of some tests and inspections, etc.

GMP11-3 (partial omission of testing, etc.) [Question] If a single tank is used to receive liquid raw materials such as organic solvents, acids, and alkalis used in product manufacturing, multiple lots of the raw materials will be mixed in the tank. What is the matter?

[Answer] When mixing newly arrived liquid raw materials with existing inventory (e.g. existing solvents in large capacity storage containers), it is necessary to confirm that the incoming raw materials are suitable in advance. The product must be tested and inspected before use. Regarding storage of liquid raw materials, care must be taken to avoid quality deterioration, and depending on the possibility of contamination during transfer of liquid raw materials to tanks, consumption amount, stability, etc., liquid raw materials in tanks may be stored as necessary. monitoring at appropriate intervals.

GMP11-4 (partial omission of testing, etc.) [Question] Regarding the provisions of Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance, manufacturers, etc. can confirm the test results for some items of testing and inspection at the time of receiving raw materials, etc. by checking the test report of the supplier of the raw materials, etc. If there are any cases where this can be done in place of implementation, please provide examples.

[Answer] All of the conditions listed below are met, and there is a reasonable basis to show that the quality of the product will not be affected even if testing and inspection of some items are replaced by confirmation of the supplier's test report. If this is specified in advance in the drug product standards document, etc., the manufacturer, etc. may check the test report of the supplier of raw materials, etc. instead of conducting tests and inspections for the item in question. No problem. However, acceptance tests stipulated as regulatory approved information must be conducted in accordance with the regulatory approved information.

1. Based on the provisions of Article 11-4, Paragraph 1 of the GMP Ministerial Ordinance, manufacturers, etc. must manage their suppliers appropriately and implement appropriate and smooth manufacturing control and quality to ensure a continuous supply of raw materials that meet specifications. Confirm that the product is manufactured under controlled conditions.

2. Manufacturers, etc. have conducted tests and inspections on all items in at least 3 lots or 3 management units, etc., in lots according to the risk, before confirming the supplier's test report and conducting tests and inspections on the relevant items. , and conduct their own testing and inspection on a regular basis, confirming the test and inspection results by the supplier and their own acceptance test and inspection results at regular intervals, and confirming that there is a continuous correlation. The item must be

3. The item must be one for which the manufacturer, etc. has confirmed that the results of their own acceptance test and inspection are stable and that there is no risk of failure in terms of the standard range.

Four. The item must be tested at the supplier using the same test method as the test and inspection at the time of acceptance by the manufacturer, etc.

Five. Items that have been confirmed to be unaffected by transportation after the tests and inspections used have been conducted.

6. Regardless of the above, the manufacturer, etc. must conduct the external inspection and confirmation test themselves.

7. Manufacturers, etc. should understand changes that affect or may affect the quality of the raw materials, etc. through appropriate methods such as arrangements with raw material suppliers or manufacturers, and comply with Article 14 of the GMP Ministerial Ordinance. Be subject to change management.

GMP11-5 (partial omission of testing, etc.) [Question] Regarding the provisions of Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance, if the raw material is labeled as compliant with the Japanese Pharmacopoeia, the Official Standards of Food Additives, JIS, etc., this is the reason. Is it possible to partially omit testing and inspection upon receipt of these raw materials?

[Answer] Even for products labeled with official standards such as the Japanese Pharmacopoeia, Food Additives Standards, JIS, JAS, etc., this cannot be used as a reason for partially omitting tests and inspections at the time of acceptance.

GMP11-6 (partial omission of testing, etc.) [Question] If the raw material is a narcotic, is it possible to omit the testing and inspection at the time of receiving the raw material as stipulated in Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance?

[Answer] If the drug used as the raw material is an opiate drug, most of the test and inspection items can be omitted. However, possible tests and inspections such as appearance inspections should be conducted. Furthermore, when using narcotics derived from poppy shell concentrate (CPS) as a raw material, it is not permitted to omit testing and inspection upon receipt of the raw material based on the relevant QA.

GMP11-7 (partial omission of testing, etc.) [Question] Regarding raw materials for stimulants, is it possible to omit the testing and inspection at the time of acceptance pursuant to Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance?

[Answer] Not allowed.

GMP11-8 (partial omission of testing, etc.) [Question] Even if products that have passed national certification are used as raw materials, is testing and inspection required at the time of receipt of raw materials as stipulated in Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance? If it is not necessary, is testing and analytical equipment also unnecessary?

[Answer] In principle, most tests and inspections can be omitted. However, in addition to confirmation tests and visual inspections, it is necessary to conduct minimum tests such as potency measurements as necessary, and a system for conducting tests and tests for this purpose is necessary.

GMP11-9 (partial omission of testing, etc.) [Question] Regarding the provisions of Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance, if the quality of crude drugs used as raw materials can be checked by visual inspection, etc., the confirmation test stated in the manufacturing and marketing approval (notification) Can I omit the implementation?

[Answer] In principle, this is not allowed.

GMP11-10 (partial omission of testing, etc.) [Question] When preparing multiple lots of the same raw material at one time, the amount taken from each lot according to the ratio of the amounts to be prepared must be mixed and used as a sample, and one test and inspection will comply with Article 11 of the GMP Ministerial Ordinance. Is it acceptable to perform testing and inspection for each lot as described in Paragraph 1, Item 4?

[Answer] Not allowed. Tests and inspections must be conducted for each lot used.

GMP11-11 (partial omission of testing, etc.) [Question] Is it okay to grade raw material suppliers based on certain criteria and use this as a basis for omitting testing and inspection at the time of receiving raw materials as stipulated in Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance?

[Answer] Not allowed. It does not prevent companies from conducting internal, unofficial grading, but it is not permitted to omit part of the test/inspection based solely on the grading.

GMP11-12 (partial omission of testing, etc.) [Question] When raw materials or materials in the same lot or in the same management unit (see GMP 2-29) are delivered in parts, if the first delivery conforms to the specifications, for subsequent deliveries, Is it possible to omit all the tests and inspections specified in Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance?

[Answer] It is not permitted to omit all testing and inspections for subsequent deliveries. For example, tests and confirmation tests related to quality changes during transportation are required.

GMP11-13 (partial omission of testing, etc.) [Question] If the same supplier continues to deliver the same raw materials, if the test results by the supplier and the test and inspection results at the time of acceptance by the manufacturer, etc. for the first delivery match, then the supply May the results of tests and tests conducted by a person be used as the test and test results under Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance?

[Answer] Omission is not permitted only if the test and inspection results of the first delivery match.

GMP11-14 (partial omission of testing, etc.) [Question] If special equipment and technology are required to conduct testing and inspection of raw materials for products that are active pharmaceutical ingredients at the time of acceptance due to the explosiveness or toxicity of the raw materials, the testing and inspection shall be conducted. Can I omit it?

[Answer] Obtaining and confirming the results of testing and inspection of raw materials by the supplier may be able to replace the testing and inspection at the time of receiving raw materials as stipulated in Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance. In that case, the supplier's testing and inspection reports should be appropriately evaluated and stored in an organized manner. In addition, the quality department should confirm the valid reason for omission and clearly state it in advance in the Pharmaceutical product standard code, etc. In addition, confirmation by external inspection, etc. must be carried out.

GMP11-15 (partial omission of testing, etc.) [Question] If a preliminary sample from a raw material supplier meets the specifications, is it okay to omit all testing and inspection for the actual delivered material?

[Answer] Even if the sample is sealed and transportation conditions are guaranteed, this does not guarantee that the sample itself is the same as the actual delivered batch and is representative of the batch in question. In principle, they are not accepted as samples for testing and inspection for acceptance. However, in cases such as GMP11-16 or in other cases where the identity of the preceding sample and the actual delivered raw material can be guaranteed, some testing and inspection may be omitted.

GMP11-16 (partial omission of testing, etc.) [Question] When a manufacturer of the same corporation receives the same lot of raw materials at two or more of its manufacturing sites, the test and inspection results of one manufacturing site are used to determine the GMP regarding the same test items at the time of acceptance at the other manufacturing sites. Is it possible to replace the test and inspection specified in Article 11, Paragraph 1, Item 4 of the Ministerial Ordinance?

[Answer] All of the following conditions are met, and there is reasonable evidence that omitting or simplifying the testing and inspection of some items will not affect the quality of products using the raw materials. There is no problem if the quality department confirms this and it is specified in advance in the Pharmaceutical product standard code, etc. However, it is necessary to conduct verification regarding quality changes during transportation, as well as visual inspection and confirmation tests.

1. The manufacturer has confirmed the supplier of raw materials based on the provisions of Article 11-4, Paragraph 1 of the GMP Ministerial Ordinance.

2. The manufacturing facility that conducts the testing and inspection must be subject to the GMP Ministerial Ordinance.

3. Testing and inspection shall be conducted appropriately by the organization in charge of work related to testing and inspection at the relevant manufacturing facility.

Four. Even if the results of tests and inspections conducted at the manufacturing site are used, there is no risk of affecting the quality of the products at the other manufacturing site.

Five. The other manufacturing facility must share its sampling records and testing and inspection records for items for which testing is omitted. Note that a copy of the record may be kept at the other manufacturing facility.

GMP11-17 (partial omission of testing, etc.) [Question] If raw materials are received and subdivided and packaged before being used in the manufacturing of products, the testing and inspection conducted at the manufacturing facility at the time of receipt before subdivision shall be carried out in accordance with Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance. Can it be used for product testing and inspection?

[Answer] In the case of the question, there is a reasonable basis to show that the "subdivision" work does not affect the quality of the raw material, and this has been confirmed by the quality department and specified in advance in the Pharmaceutical product standard code, etc. In such cases, the results of testing and inspection at the time of raw material acceptance may be used.

GMP11-18 (partial omission of testing, etc.) [Question] If Manufacturer A is supplied with raw materials or materials by Manufacturer B, the same corporation as the manufacturing/distributor that outsources the product, Manufacturer A will enter into an agreement with another manufacturer (in this example, Manufacturer A and Manufacturer B conclude an agreement (excluding cases where the GQP agreement between the marketing authorization holder and Manufacturer A includes matters related to the above acceptance test). As Manufacturer A, we can use the test and inspection results of the manufacturing facility (including the results of external testing and inspection institutions commissioned by Manufacturing Plant B), and as Manufacturer A, we can use the Is it acceptable to carry out testing and inspection at the time of acceptance?

[Answer] No problem. However, if transportation conditions, etc. may affect the quality of raw materials or materials, Manufacturer A must conduct necessary tests and inspections. In addition, acceptance tests stipulated as approved items shall be conducted in accordance with the approved items.

GMP11-19 (partial omission of testing, etc.) [Question] The quantitative test and the confirmatory test are based on the same principle, and there is a rational basis for conducting one test and testing for the other. In cases where it is specified in advance in product standards, etc., is it acceptable to conduct tests and inspections on one side as tests and inspections on the other? (example)
	Quantitative test	Confirmation test
	UV absorption	UV spectrum
	colorimetric	Coloration
	Gas chromatography	retention time
	liquid chromatography	retention time
	atomic absorption	spectrum
	fluorescence absorption	spectrum

[Answer] There is no problem if it can be considered that a confirmation test was conducted as part of a series of test operations related to a quantitative test.

GMP11-20 (partial omission of testing, etc.) [Question] When an organization in charge of testing and inspection related to the in-process control of intermediate products during the integrated manufacturing process conducts testing and inspection, obtaining and confirming the results indicates that all manufacturing processes at the manufacturing site have been completed. Is it okay to test and inspect products that have been manufactured?

[Answer] In principle, samples should be taken from products that have undergone all the manufacturing processes at the manufacturing facility, and tests should be conducted.

However, if there is a rational basis (validation data, etc.) that the results of the testing and inspection and the quality characteristics of the product related to the testing and inspection will not change even after subsequent processes, the quality department confirms this, and the pharmaceutical product standard Regarding the items specified in advance in the documents, etc., the results of testing and inspection related to in-process control of the intermediate product may be used as part of the testing and inspection results of the product that has completed all the manufacturing processes at the manufacturing facility.

GMP11-21 (partial omission of testing, etc.) [Question] Samples are collected for testing under Article 11, Paragraph 1, Item 1 of the GMP Ministerial Ordinance, not from products that have completed all the manufacturing processes at the manufacturing facility, but from products immediately before packaging (for example, from products in the middle of packaging). ) Can it be collected from intermediate products?

[Answer] In principle, samples should be taken from products that have undergone all the manufacturing processes at the manufacturing facility and tested. However, if there is a reasonable basis for this, the quality department confirms it, and it is specified in advance in the Pharmaceutical Product Standard Code, etc., intermediate products immediately before packaging may be used as samples. However, for label confirmation inspections that can only be performed by collecting samples from products that have gone through all the manufacturing processes at the manufacturing facility, tests should be conducted using samples that have gone through all the manufacturing processes.

GMP11-22 (partial omission of testing, etc.) [Question] In a manufacturing facility that only performs the process of filling raw materials (powder) into vials, etc., if the test and inspection items at the time of receiving the raw materials are the same as the test and inspection items for the product filled in the vials, etc., Is it permissible to omit the relevant test items based on the results of testing and inspection at the time of raw material acceptance?

[Answer] There is a rational basis (validation data, etc.) that the results of the test and inspection and the quality characteristics of the product related to the test and inspection will not change even after the filling process, and the quality department has confirmed this and established the pharmaceutical product standard. For items specified in advance in documents, etc., the results of testing and inspection at the time of raw material acceptance may be included as part of the results of testing and inspection of the product.

GMP11-23 (partial omission of testing, etc.) [Question] If a collection volume test is conducted for in-process control during the filling process of a product related to an injectable drug, the results for each lot have been confirmed, and the relevant item for the product that has completed all the manufacturing processes at the manufacturing site is confirmed. Is it acceptable to conduct such a test/inspection?

[Answer] There is reasonable evidence (validation data, etc.) that there will be no change in the results of the test and inspection related to the item and the quality characteristics of the product related to the test and inspection, even after subsequent processes, and the quality department has confirmed this. However, if it is specified in advance in the drug product standard document, etc., there is no problem.

However, testing and inspection related to this in-process control should be treated as important in-process control related to general handling (see GMP 8-12).

GMP11-24 (partial omission of testing, etc.) [Question] Tests and inspections related to in-process control performed by collecting intermediates, recovered solvents, etc. during the manufacturing process of pharmaceutical products that are active pharmaceutical ingredients are carried out by a person other than the test and inspection implementer of the organization in charge of tasks related to testing and inspection. Can this be carried out by a person?

[Answer] No problem. Furthermore, the quality department shall provide appropriate education and training to the person and certify them. In addition, as a general rule, the quality department needs to confirm the results of in-process tests, including raw data. However, in principle, these tests and inspections cannot be considered as tests and inspections stipulated in Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance.

GMP11-25 (partial omission of testing, etc.) [Question] If mass deviation tests and disintegration tests related to in-process control are conducted in the tableting process of tablets (if the product is uncoated tablets), the results of these tests for each lot are confirmed. Is it acceptable to conduct tests and inspections related to the relevant items for products that have completed all manufacturing processes?

[Answer] No problem. See GMP 11-20.

GMP11-26 (partial omission of testing, etc.) [Question] Regarding raw materials that are expensive and require a large amount for testing and inspection compared to the amount used in the manufacturing process, this is the reason why the lot-by-lot Can testing and inspection of raw materials be omitted?

[Answer] Omissions based solely on the reason for the question are not permitted.

GMP11-27 (partial omission of testing, etc.) [Question] There are cases where the raw material specifications of the manufacturing and marketing approval (notification) document stipulate pyrogenic substance tests and toxicity tests in the same way as raw materials for injections, even though the product is a preparation for use on the skin, etc. In such a case, if the manufacturer deems it unnecessary for the product to be applied to the skin, etc., the product should be tested for pyrogenic substances and toxicity based on the provisions of Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance. Can I omit it?

[Answer] It cannot be omitted. If pyrogenic substance testing and toxicity testing are not required, contact the manufacturer to request changes to the manufacturing and marketing approval items.

GMP11-28 (partial omission of testing, etc.) [Question] Among the quality control test items for crude drugs, for items where the test values are not expected to increase or change after preparation of the crude drug (purity test (residual pesticides, heavy metals, arsenic)), Manufacturer A is using other manufacturers. When receiving a crude drug (manufacturer B's product) from B as a raw material, manufacturer A must include the test and inspection results of manufacturer B in the test and inspection stipulated in Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance at the time of receiving the crude drug. Can I use it?

[Answer] In principle, omission of some tests and inspections complies with GMP11-4. However, in the case of the question, if the following conditions are met, "Manufacturer A" may use the test and inspection results of "Manufacturer B" for its own tests and inspections when receiving raw materials.

1. Arrangements to be made between the marketing authorization holder and “Manufacturer A” and “Manufacturer B” based on the provisions of the GQP Ministerial Ordinance, and between the marketing authorization holder and the manufacturer pursuant to the provisions of the GQP Ministerial Ordinance. Except for the following matters, in the contract concluded directly between "Manufacturer A" and "Manufacturer B" (the contract must be kept by both "Manufacturer A" and "Manufacturer B"): be stipulated.

(1) “Manufacturer B” shall supply crude drugs manufactured under appropriate manufacturing control and quality control.

(2) “Manufacturer B” must confirm that the storage management of the crude drug concerned is appropriate.

(3) “Manufacturer B” shall confirm that the test and inspection results for the relevant test and inspection items are values that take into account the homogeneity of the lot.

(4) “Manufacturer B” must keep the test results of the crude drug in such a way that they can be disclosed to “Manufacturer A” at any time.

2. “Manufacturer A” must confirm in advance that the testing and testing methods are appropriate when using the results of testing and testing of the crude drug by “manufacturer B.”

3. "Manufacturer A" shall create and retain a document regarding the test and inspection results that includes the following items in order to ensure lot traceability regarding the test and inspection results of its products.

(1) Sample name and lot number or manufacturing number or control number

(2) Test and inspection items, date of test and inspection, name of person in charge of test and inspection, and test and inspection results

(3) Judgment of test and inspection results, date of judgment, and name of judge

Four. "Manufacturer A" will be able to quickly trace the lot of the crude drug in question, in order to quickly track the lot of the crude drug in question, "Manufacturer A" will provide the name of the crude drug it accepts, the name (in the case of a corporation, name) of "Manufacturer B", etc., "Manufacturer B", etc. The test and inspection items for the crude drug concerned by "Manufacturer B", the lot and corresponding quantity assigned to the crude drug by "Manufacturer B", the new lot and corresponding quantity assigned by "Manufacturer A", the "manufacturer A "List of historical information related to the use of testing and inspection results of herbal medicines" containing the confirmation results of the person in charge of the quality department of "A" should be created and stored using the format shown below as a reference.

Five. Is "Manufacturer A" conducting appropriate and smooth manufacturing control and quality control of raw materials, etc. for "Manufacturer B" based on the provisions of Article 11-4, Paragraph 1, Item 3 of the GMP Ministerial Ordinance? During periodic checks, it shall be confirmed that the relevant tests and inspections are being conducted properly, and records thereof shall be created and kept in accordance with the provisions of Item 4 of the same paragraph. As a general rule, such confirmation shall be conducted on-site, and if the manufacturer conducts the confirmation, a copy of the confirmation record may be confirmed and kept; however, the above It should be noted that if it cannot be determined from the confirmation records of the relevant marketing authorization holder whether or not the matters shown in 2. have been confirmed, omission of the relevant tests and inspections is not permitted.

List of historical information related to the use of crude drug test results

The history of using test results of crude drugs is as follows.

Name of crude drug	lot	amount of usage	Quality department manager confirmation	Date confirmed

GMP11-29 (partial omission of testing, etc.) [Question] When Manufacturer A, who manufactures products related to simple herbal medicines, receives herbal medicines (products of Manufacturer B) from Manufacturer B as raw materials, Manufacturer A must comply with the drug/quasi-drug GMP standards for the said herbal medicines. Can I use Manufacturer B's test results regarding pesticide residues, heavy metals, and arsenic for the test and test of products under Article 11, Paragraph 1, Item 4 of the Ministerial Ordinance?

[Answer] In principle, omission of some tests and inspections complies with GMP11-4. However, in the case of the question, when manufacturing products related to single crude drugs, it is thought that there is usually no change in the amount of residual pesticides, heavy metals, and arsenic in the crude drugs that are the raw materials, If it is ensured that there is no contamination or cross-contamination by products, etc., and all of the items 1 to 5 listed in the answer to GMP11-28 are met, then "Manufacturer B"'s pesticides, heavy metals, arsenic, etc. There is no problem in using such test and inspection results for testing and inspection of your own products.

GMP11-30 (partial omission of testing, etc.) [Question] What does "confirm that storage management is appropriate" in GMP11-28 mean?

[Answer] In order to prevent mix-up, contamination, and cross-contamination between lots of crude drug products, containers are used to prevent the crude drug from scattering, and the name and lot number of the crude drug are displayed on the container. This refers to confirming that the medicinal products are properly identified, that they are stored in warehouses appropriate for the herbal medicine to prevent insect damage and mold growth, and that storage and disbursement records are appropriately created. be.

GMP11-31 (partial omission of testing, etc.) [Question] What does GMP11-28 mean by "confirm that the test and inspection results for the relevant test and inspection item are values that take into account the homogeneity of the lot"?

[Answer] Since herbal medicines are natural products, the characteristics and morphology of each part of the plant (leaves, roots, rhizomes, fruits, etc.) should be determined by referring to the ``Sampling'' section of the Crude Drugs Testing Method in the Japanese Pharmacopoeia General Tests. (cut herbal medicines, powdered herbal medicines, etc.), etc., the manufacturer shall manage test and test equipment and samples, and perform other appropriate tests and tests as stipulated in the Standard Operating Procedures, etc. for the implementation of appropriate tests and tests. This refers to confirming that appropriate sampling is being carried out with due consideration to lot homogeneity through testing and inspection procedures related to the implementation of the process.

GMP11-32 (other) [Question] Is it necessary to display the expiry date of reagents used for testing and testing on both opened and unopened products?

[Answer] For unopened products, display the expiration date based on the quality guarantee expiration information provided by the reagent supplier. After opening, consider the frequency of use, etc., and if there is a problem with quality deterioration, set a separate deadline for handling. Also, the expiration date should be clearly stated in the Standard Operating Procedures, etc.

GMP11-33 (calibration of instruments and management of equipment) [Question] Regarding the calibration of instruments related to testing and inspection pursuant to Article 11, Paragraph 1, Item 7 of the GMP Ministerial Ordinance, which instruments should be calibrated and by what method?

[Answer]

1. Manufacturers, etc. should create a list of instruments and determine the instruments that require calibration, the calibration method, the frequency of calibration, etc., taking into account the risks to test and inspection results, depending on the type, characteristics, purpose of use, and frequency of use of the instruments. . Calibration should be performed at least on instruments that may affect test and inspection results.

2. For important instruments, the calibration status should be made clear (e.g., by attaching a label with the date of the next calibration scheduled, etc.). Instruments that do not meet the calibration standards and instruments whose next calibration date has passed have been marked as "unusable."

3. If an important instrument deviates from the standard calibration value, evaluate the impact on the quality of products manufactured using the instrument since the previous calibration, make a determination, and take necessary measures.

Four. If a so-called national standard exists, it is necessary that calibration be performed using a method that can be traced back to that standard. If a so-called national standard does not exist, the basis for calibration must be recorded.

GMP11-34 (sampling) [Question] GMP 11-34 (Specimen collection) Revised Ministerial Ordinance Promulgation Notice No. 3-15(1) ①A states that ``With regard to the work of collecting samples, the independence of the quality department as stipulated in Article 4, Paragraph 2 of the said Ordinance. As long as the sampling is maintained, there is no problem in having employees of the manufacturing department who handle the raw materials, supplies, and products take the samples under the supervision and instructions of the quality department. What should you keep in mind?

[Answer] In principle, samples should be collected by a person in the quality department in order to objectively evaluate the quality of products, etc. If manufacturing department personnel are required to perform sampling work, the quality department shall be responsible for providing necessary education and training to manufacturing department personnel using appropriate methods approved by the quality department (see GMP 11-36). Based on the above, it is necessary to ensure that sampling operations are being carried out appropriately, such as by confirming that sampling operations are being carried out appropriately by the manufacturing department, as necessary.

GMP11-35 (sampling) [Question] If a product or raw material is contained in multiple containers (packages), the quality department should collect samples of the product or raw material under Article 11, Paragraph 1, Item 1 of the GMP Ministerial Ordinance from one package. Is it correct to think that this refers to the sampling of the required amount for testing and does not include the act of selecting containers (packaging) for sampling?

[Answer] The act of selecting from multiple containers (packaging) is also included in sampling. When collecting samples for products, raw materials, etc. as specified in Article 11, Paragraph 1, Item 1 of the GMP Ministerial Ordinance, everything from selecting a container (packaging) from multiple containers (packaging) to sampling the required amount for testing and inspection is carried out. Point.

GMP11-36 (sampling) [Question] What should we keep in mind when collecting samples under Article 11, Paragraph 1, Item 1 of the GMP Ministerial Ordinance?

[Answer] The method for collecting samples should be in accordance with the current scientific and technological standards, taking into account the characteristics of the specimen, test items, etc., while paying attention to the prevention of confusion, contamination, and cross-contamination. etc. shall be stipulated in advance. Please note the following regarding regulations regarding specimen collection and specimen collection under Article 11, Paragraph 1, Item 1.

1. The samples to be collected should be representative of the lot or management unit, and the number of containers to be sampled, the sampling locations in the target containers, and the amount to be sampled from each container should be carefully considered in order to minimize the risk to product quality. Determine the method of collection taking into consideration the following.

2. The number of containers to be collected and the number of samples to be collected (sample size) are based on the importance of the products and materials to be collected, the degree of variation in quality, the history of the quality of products supplied by the supplier in the past, and It shall be determined based on the amount necessary for proper testing and inspection.

3. Samples should be collected at predetermined locations using procedures that prevent contamination of the collected products, etc., materials, and cross-contamination with other products, materials, and other objects.

Four. Carefully open the container for specimen collection, and seal it immediately after specimen collection.

Five. The containers (packaging) of products, etc. and materials from which samples were collected must be labeled to the effect that samples have been collected (e.g., affixed with a label stating "Sample collected").

GMP11-37 (sampling) [Question] GMP11-36 3. , it is stipulated that samples should be collected at predetermined locations to prevent cross-contamination, but samples of raw materials used in the manufacturing process of products related to drug substances may also be collected at storage locations. mosquito.

[Answer] No problem. In that case, a storage location is designated in advance as the specimen collection location, and procedures are taken to prevent contamination of the collected "raw materials" and cross-contamination with other products, materials, and other objects at that location. thing.

GMP11-38 (sampling) [Question] Concerning samples stipulated in Article 11, Paragraph 1, Item 1 of the GMP Ministerial Ordinance, raw material For materials, etc., it is necessary to determine a specific method for collecting samples to represent a lot or management unit and to accurately judge test results. I would like to know the standard amount of samples to be collected.

[Answer] It can vary depending on the type of product, quantity, individual test and inspection items, etc., and cannot be determined unconditionally. As a manufacturer, etc., you must specify the appropriate (see GMP 11-36).

GMP11-39 (sampling) [Question] When collecting a sample for raw material testing, is it necessary to write on the sample container (collection container) so that it can be seen from which container (package) the sample was collected?

[Answer] When collecting a sample, it is not necessarily necessary to write directly on the "collection container," but it should be indicated on the container (packaging) that the sample was collected. When collecting multiple samples, traceability of the containers (packaging) in which the samples were collected and their test results should be ensured as necessary. See GMP 11-36.

GMP11-40 (sampling) [Question] Regarding the “name of the person in charge of collection” in Article 11, Paragraph 1, Item 1 of the GMP Ministerial Ordinance, as specified in Article 11, Paragraph 1, Item 1 of the Notification of Promulgation of Revised Ministerial Ordinance No. 3, 15(1) ①, as a matter to be recorded in the specimen collection record, If there is no choice but to have multiple specimen collectors due to the long time involved, is it okay to list the name of only one person in charge?

[Answer] It is not acceptable to record only the name of one person in charge. Each time a sample is collected, it is necessary to include the name or initials of the person who actually collected the sample, the time of collection, etc., as well as to be able to identify the sample.

GMP11-41 (Management of samples and Reference standard) [Question] Article 11, Paragraph 1, Item 2 of the GMP Ministerial Ordinance requires proper storage of samples and Reference standard for testing and testing.What are the matters to keep in mind for management?

[Answer] It is necessary to establish management procedures according to the importance of test samples and Reference standard. It is necessary to objectively ensure proper management of especially important samples and Reference standard, such as final product samples at each manufacturing site and Reference standard used in quantitative tests. Each manufacturing facility should prescribe the content of management in a Standard Operating Procedures, etc., taking into consideration the following points.

1. Perform accounting management. Each time it is used, record the date of use, user, purpose of use, amount used, etc. to ensure traceability.

2. Compare the actual remaining amount after use with the theoretical remaining amount to confirm that there are no unexplained excesses or deficiencies.

3. Record that the remaining amount has been properly disposed of. It should be noted that test samples are not required to be stored for a long period of time even after the test is completed.

Four. Consider storage conditions such as temperature, humidity, and light until use so as not to affect testing. For temperature conditions, see GMP11-49 and 50.

GMP11-42 (test inspection record) [Question] Is it permissible to proceed with the manufacturing process without waiting for the results of testing and inspection under Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance regarding raw materials, materials, and intermediate products (including intermediates)?

[Answer] As a general rule, proceed with the manufacturing process after obtaining quality confirmation. However, if the quality department deems it appropriate after considering the risk to subsequent test and inspection results, it is permitted to proceed with the manufacturing process without waiting for the test and inspection results. Even in such a case, the decision as to whether or not to ship the product from the manufacturing facility must, in principle, be made only after all these results are available and the suitability of the product can be determined. It should be stipulated that if the test results are inappropriate, measures such as disposal of the manufactured product will be taken.

GMP11-43 (test inspection record) [Question] The names of products, raw materials, or materials, test and inspection items, etc. to be recorded in the test and inspection records under Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance are written using abbreviations used internally by the manufacturer, etc. May I do so?

[Answer] We will make it possible to identify the latest revision status of the relationship between official names and "abbreviations," and take necessary measures such as systematic implementation of education and training to ensure that there is no risk of confusion. There is no problem as long as the basis is approved by the quality department and specified in advance in the Pharmaceutical product standard code, etc.

GMP11-44 (test inspection record) [Question] In Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance, as stated in Article 11, Paragraph 1, Item 4 of the Notification of Promulgation of the Revised Ministerial Ordinance, No. 3, 15(1) ④, the name or initials of the staff member (external testing and inspection agency) In the case of ``○○ (name or initials of the staff member)'' and ``○○ (name of the external testing and inspection institution)'' in each case, ), ○○ (name or initials of the person in charge)", if you create a list of the names or initials of each staff member, as well as the names or initials of the external testing and inspection agency and the person in charge, Is it okay to write something like “according to attached table ○○”?

[Answer] Not allowed. Write the name or initials of the employee who was engaged in each case (in the case of an external testing and testing organization, the name of the external testing and testing organization and the name or initials of the person in charge).

GMP11-45 (Reference sample storage) [Question] If the same lot of intermediate products corresponds to two or three types of packaging units (for example, 100 tablets, 500 tablets, and 1,000 tablets), only one representative of the lot should be kept as a Reference sample. Is it okay to use it as a packaging unit? Or do you need to store all packaging units?

[Answer] When storing the Reference sample in the case of the question, it is not necessarily necessary to store all the packaging units, and for large packaging products, a small sample is stored in a packaging form with the same function as the final product (for example, small packaging). There is no problem in storing materials such as individual packages and package inserts of large packaged products that display expiration dates and serial numbers, etc. Although the final product (packaged product with contents) is equivalent to other packaging units (individual packaging), printing materials, etc. are different and cannot be substituted, so the materials must be stored.

A Reference sample is a sample for analytical testing in preparation for the possibility of future quality evaluation such as defects after shipment to the market, so if the quality of the contents is common, a representative packaging unit should be used as a Reference sample. It is better to keep it.

Preserved products are samples used to confirm the identity of products on the market, and can be shared with reference sample, but if they are shared, the Reference sample should be a representative sample of multiple packaging units. It is sufficient to store only the packaging unit, but since all packaging units are required as Retention samples, packaging materials in the same packaging form as the final product should be stored for all packaging units other than the representative packaging unit stored as Reference samples. There is a need to.

GMP11-46 (Reference sample storage) [Question] According to Article 11, Paragraph 1, Item 5 of the GMP Ministerial Ordinance, the storage amount of reference sample is set to be more than twice the amount required for the prescribed tests and inspections. Is it necessary to store twice the amount?

[Answer] There is no problem in storing at least twice the amount required for other tests excluding sterility tests and pyrogen tests. However, the amount must be stored so that tests and inspections can be carried out appropriately.

GMP11-47 (Reference sample storage) [Question] When a product related to a formulation is manufactured at Factory A, packaged at Factory B, and used to determine whether it can be shipped to the market, should reference sample be stored at Factory A or Factory B?

[Answer] Either is fine. In addition to stipulating the rules regarding the storage and use of reference sample in the Standard Operating Procedures, etc., and entering into agreements stipulated in Article 11-5, Paragraph 1 of the GMP Ministerial Ordinance, even if the reference sample are stored at "Factory A", , be stored under the direction and responsibility of the quality department of "Factory B", and take care to ensure that there are no hindrances to the GMP compliance investigation.

GMP11-48 (Reference sample storage) [Question] Is it permissible to centrally manage the storage of reference sample based on the provisions of Article 11, Paragraph 1, Item 3 of the GMP Ministerial Ordinance at other manufacturing sites of the same manufacturer, etc. (corporation)?

[Answer] The purpose of storing reference sample is to prepare for the possibility of evaluating product quality in the future. If so, there is no problem in centrally managing it at other manufacturing sites of the same manufacturer, etc. (corporation). In this case, the rules, etc. shall be stipulated in advance in a Standard Operating Procedures, etc., and shall be kept under the direction and responsibility of the quality department of the manufacturing facility, which makes decisions on whether or not to ship to the market upon commission from the manufacturer, and Care must be taken to ensure that there are no hindrances during GMP compliance surveys, etc.

GMP11-49 (Reference sample storage) [Question] “Appropriate storage conditions” for reference sample in Article 11, Paragraph 1, Item 5 of the GMP Ministerial Ordinance are “normal room temperature” or “conditions specified in the storage method column of the manufacturing and marketing approval (notification) form”. Should one of the conditions be met?

[Answer] Section 15(1) ⑤ A of the Notice of Promulgation of the Revised Ministerial Ordinance states that ``storage conditions under normal distribution conditions must also be taken into account'', If storage conditions are specified in the `` column, store under those conditions, otherwise store at normal room temperature, but avoid extreme high temperature and humidity, or extreme low temperature and low humidity. Also, be sure to check the storage conditions by temperature monitoring. Note that storage of samples for stability monitoring is different from storage of reference materials.

GMP11-50 (Reference sample storage) [Question] There is no air conditioning in the storage room for reference sample, but the room temperature is within the range of 18 to 28 degrees Celsius throughout the year. Even if the environment is equivalent to one controlled by air conditioning, can this be considered storage conditions under normal distribution?

[Answer] No problem.

GMP11-51 (Reference sample storage) [Question] Regarding the “appropriate storage conditions” for reference sample in Article 11, Paragraph 1, Item 5 of the GMP Ministerial Ordinance, it is stated in Section 15(1) ⑤ A of the Revised Ministerial Ordinance Promulgation Notice that “the form in which it was shipped to the market (at the time of shipment) In cases where it is unavoidable due to storage reasons, such as when the packaging unit of the product is large, the final product should be packaged in a package with the same functionality as that shipped to the market). Can it be stored in a functional packaging form (for example, a small packaging form)?

[Answer] No problem.

GMP11-52 (Reference sample storage) [Question] Please indicate the range of items that should be kept as Reference samples.

[Answer] From the perspective of guaranteeing the quality of products distributed in the market, this is essential for final products and pharmaceuticals that are active ingredients. Other raw materials and materials should be determined by the manufacturer, etc. or marketing authorization holder, taking into account health and hygiene risks. For example, biological raw materials such as human serum albumin, which are used as stabilizers for biological medicines, are important from the standpoint of safety measures against unknown infectious diseases.

In addition, from the same point of view, in biological products, viruses, prions, unknown substances, etc. related to infectious diseases can be detected with higher sensitivity from the stage of the final product and the product related to the drug substance. In addition to storing the drug substance, it is also necessary to consider storing intermediates at appropriate stages. Note that solvents, gases, and water used in the manufacturing process are not included.

GMP11-53 (Reference sample storage) [Question] I would like to confirm the drug substance, which is the active ingredient of the product, and which should be kept as a Reference sample as stipulated in Article 11, Paragraph 1, Item 6 of the GMP Ministerial Ordinance. Pursuant to Article 21 of the GMP Ministerial Ordinance, drug substance manufacturers, etc. keep drug substances as reference sample, but is it possible to use them as reference sample for drug manufacturers?

[Answer] Substitutions cannot be made unless an appropriate storage period (at least 2 years after the release decision of the product in which the drug substance was last used) has been established with the drug substance manufacturer, etc. In addition, in order to set an appropriate storage period with the drug substance manufacturer, etc., and to substitute reference sample stored at the drug substance manufacturer, etc., the manufacturer, etc. of the drug substance drug, etc. and the GMP Ministerial Ordinance Article 11. 5. If the manufacturer of a drug product needs to use a Reference sample of a drug substance for investigation, it will promptly provide the required amount of drug substance. What is prescribed to be done.

GMP11-54 (Reference sample storage) [Question] Please provide a specific example regarding setting the storage period for reference sample such as raw materials as stipulated in Article 11, Paragraph 1, Item 6 of the GMP Ministerial Ordinance.

[Answer] By fixing the usage period after the arrival of raw materials, etc. and the period from the time the raw materials are used until the product is shipped, and adding the storage period as a Reference sample to these periods, it is possible to You can set a storage period at any time. In addition, raw materials are to be stored for two years from the date of shipment of the used product, but this period is subject to the stability period according to PIC/S GMP Guideline Annex 19, excluding biological raw materials. It is said that it may be shortened if it is shorter.

GMP11-55 (Reference sample storage) [Question] Please specifically indicate what kinds of raw materials or materials other than the drug substance that are considered to "affect the quality of the product."

[Answer] Raw materials are determined based on risks depending on the characteristics of the product. Regarding materials, materials that come into direct contact with the product are considered necessary to ensure the quality of the shipped product, materials that have the function of protecting the contents by preventing the permeation of moisture, oxygen, etc. even without direct contact, and display materials. etc. are applicable. Regarding materials, if the amount necessary for testing and inspection is secured by storing the final product, the materials are also considered to be stored.

GMP11-56 (Reference sample storage) [Question] Is it necessary to store reference sample for products shipped in bulk formulations in the same way as final products?

[Answer] At the discretion of the manufacturing facility that ships the bulk drug product, it is permissible to keep reference materials for the bulk drug product shipped as necessary for management purposes. Furthermore, as stated in GMP 2-8, at the receiving manufacturing facility, the bulk drug product becomes the raw material used in the manufacturing of the product at that manufacturing facility, so it is subject to Article 11 of the GMP Ministerial Ordinance as something that affects the quality of the product. It is considered that it will be stored in accordance with the provisions of Paragraph 1, Item 6.

Record of receipt and delivery of Reference samples and Retention samples

GMP11-57 (reference/retention sample storage) [Question] Appropriate storage of reference sample and preserved products is required under Article 11, Paragraph 1, Items 5 and 6 of the GMP Ministerial Ordinance.What are the matters to be kept in mind for management?

[Answer] In order to objectively guarantee proper management status, the contents of management should be stipulated in the Standard Operating Procedures, etc. in advance, taking into consideration the following points.

1. Perform accounting management. Each time it is used, record the date of use, user, purpose of use, amount used, etc. to ensure traceability.

2. Compare the actual remaining amount after use with the theoretical remaining amount to confirm that there are no unexplained excesses or deficiencies.

3. Proper disposal of the remaining amount beyond the storage period shall be recorded.

GMP11-58 (storage of Retention samples) [Question] How should I store large quantities of Retention samples?

[Answer] When storing large-capacity preserves, it is not necessarily necessary to store them in large packages as final products, but in large packages with individual packaging that displays expiration dates, manufacturing numbers, etc., and package inserts, etc. There is no problem in storing individually packaged products containing the required amount of product as reference sample

GMP11-59 (OOS) [Question] If the standard document for pharmaceutical products under Article 7 of the GMP Ministerial Ordinance specifies standards for testing and inspection that are stricter than the standards stated in the manufacturing and marketing approval (notification) document, will the product deviate from the standards? If so, how should the necessary measures be taken to determine whether or not the product in question can be shipped from the manufacturing facility?

[Answer] For products that deviate from the ``independent standards,'' it is necessary to conduct sufficient investigation such as re-examining the manufacturing process control and retesting, and carefully judge the final approval or failure. The handling of such cases shall be stipulated in advance in the Standard Operating Procedures, etc.

Regarding Pharmaceutical Product Standard Code, as stated in Section 10(3) ① A and B(A) of Revised Ministerial Ordinance Promulgation Notification No. 3, if standards are set that are stricter than the standards for approved items, the standards shall be The basis must be clearly stated in advance.

In addition, product quality will be checked periodically or from time to time, and if the specifications and test methods stated in the manufacturing and marketing approval (notification) are found to be insufficient in light of the current related notifications, scientific and technological standards, etc., we will promptly review the product quality. Contact the marketing authorization holder to apply for department change approval, etc. (notification of minor changes, if applicable).

GMP11-60 (OOS) [Question] When an OOS occurs, what should we keep in mind when investigating the cause?

[Answer] When an OOS occurs, it is necessary to promptly investigate according to predetermined procedures and determine the cause of the occurrence. When conducting an investigation, it is common to first check for laboratory errors (malfunctions in equipment, conformity of standards and reagents to specifications, operational errors, etc.). If no laboratory error is found, there may be a problem with the product itself, and an expanded investigation will be required to cover raw materials, manufacturing equipment, manufacturing processes, etc. Until the presence or absence of a laboratory error is determined, all test equipment and samples used should be retained, and all activities in the investigation (e.g. data from investigative tests, resampling records, etc.) and the basis for decision-making should be documented. It is necessary to pay attention to the following.

GMP11-61 (OOS) [Question] How should I handle it if the OOS turns out to be due to a lab error?

[Answer] If it is determined that the cause of OOS is a lab error, the test can be retested after correcting the cause of the lab error, and the results can be accepted as the test results. In addition, in cases where it is not possible to retest the sample in which OOS was obtained, such as in a sterility test or microbial limit test, if it can be clearly proven that the OOS was due to a cause unrelated to the test product (e.g., A retest using a different specimen may be performed only if the test can be determined to be "invalid" according to the General Testing Methods <4.06> Sterility Testing Methods. In addition, when actually implementing the process, the above must be stipulated in advance in the Standard Operating Procedures, etc.

GMP11-62 (OOS) [Question] What should I do when it is not clear whether the cause of OOS is a lab error?

[Answer] Take measures according to predetermined procedures. After the laboratory error investigation, it is necessary to conduct an expanded investigation targeting raw materials, manufacturing equipment, manufacturing processes, etc., and use it as material for considering the reliability of the data that became OOS. In addition, during the expanded investigation, it is assumed that consideration will be given to retesting using the same sample used at the time of OOS occurrence, resampling using the same method as the initial sampling, and retesting using that sample. When retesting is performed, it is important to evaluate the test results of the lot by combining the OOS and retest results, and the results of the retest cannot be invalidated without valid scientific grounds. shall not be adopted. Samples should be retained until the presence or absence of a laboratory error is determined, and all activities in the cause investigation (e.g., investigative test data, resampling records, etc.) and the basis for decision-making should be documented. In addition, care must be taken to maintain the test equipment used.

GMP11-63 (special exceptions such as MRA) [Question] According to the special provisions for quality control in Article 11, Paragraph 2 of the GMP Ministerial Ordinance, confirming the records of tests and inspections conducted by foreign manufacturers in the importing country will replace the test and inspection in Paragraph 1, Item 4 of the same article. If so, may the confirmation results of items 1 and 2 of Paragraph 2 of the same article be made using the confirmation results by the marketing authorization holder of the item related to the product in question?

[Answer] No problem. Please note that confirmations under Article 11, Paragraph 2, Items 1 and 2 of the GMP Ministerial Ordinance are required to be carried out as a manufacturer in cooperation with the marketing authorization holder, based on the arrangements based on the provisions of the GQP Ministerial Ordinance. Be what you are. Even if the confirmation results by the manufacturer are used in cases such as questions, the manufacturer must determine whether the confirmation details are appropriate, and the procedures for use should be stipulated in advance in the Standard Operating Procedures, etc. thing.

GMP11-64 (special exceptions such as MRA) [Question] If MRA or MOU special provisions apply and the results of tests conducted in the applicable country can be used, and product quality can be guaranteed by confirming the test results, test and inspection items Is it not necessary to provide the necessary test and analytical equipment and instruments?

[Answer] It is desirable to maintain test equipment at the domestic manufacturing facility that accepts the product, but procedures have been established in the event that there are doubts about the results. If investigation and retesting are possible and are specified in the agreement, they do not necessarily have to be provided.

GMP11-65 (special exceptions such as MRA) [Question] I would like to see a clarification on the scope of application of special provisions for the omission of tests such as MRA.

[Answer] Note 4 of ``Partial Revision of the Agreement on Mutual Recognition between Japan and the European Community'' (Pharmaceuticals, Food and Drug Administration, No. 0718, July 18, 2018). Regarding batch certificates, etc. (Related to Part A 4 and 5 of the Annex by Pharmaceutical Field), pharmaceuticals manufactured at manufacturing facilities located in MRA-applicable countries (for drug products, the raw materials used) (excluding pharmaceutical products), facilities that manufacture pharmaceuticals to be exported to Japan and manufacturing facilities that issue certificates for each lot (batch certificate) of pharmaceuticals to be exported to Japan are subject to MRA. In addition, for exemption from examination by MRA, it is the responsibility of the applicant to ensure that at least each of the conditions in Part A 4(a) to 4(b) of the Sector-Specific Annex are met. The same applies to the handling of drugs, manufacturing locations, certificates, etc. related to the application of MOUs, etc. in exchange countries.

GMP11-66 (special exceptions such as MRA) [Question] If the scope of MRA, etc. and the conditions for omission are met, a foreign manufacturer in the importing country can perform testing and inspection (excluding visual inspection) stipulated in Article 11, Paragraph 1, Item 4 of the GMP Ministerial Ordinance. Can this be replaced by checking the test and inspection records that reflect the regular tests/skip tests, etc. conducted?

[Answer] If a periodic test/skip test, etc. is used to determine the results of a manufacturing facility test/inspection, it is determined that the imported product lot is guaranteed even if the test is applied. There is no problem if the batch certificate was issued at the foreign manufacturer's manufacturing facility.

GMP11-67 (special exceptions such as MRA) [Question] In accordance with Article 11, Paragraph 2 of the GMP Ministerial Ordinance, when testing and inspection (excluding appearance tests) are replaced by confirming the records of testing and inspection conducted by the foreign manufacturer in the importing country, reference sample and preserved products I would like the handling of the issue to be clarified.

[Answer] Regarding reference sample, if the final products, raw materials, etc. can be promptly investigated and retested at the foreign manufacturing facility where the relevant tests were conducted, and if these are specified in the arrangements based on the GQP Ministerial Ordinance, they cannot be imported. It is acceptable for the foreign manufacturer in the destination country to store more than double the amount required for testing and inspection, but it must be managed as an outsourced storage company in accordance with the provisions of Article 11-5 of the GMP Ministerial Ordinance. Domestic manufacturers must store stored products in accordance with Article 11, Paragraph 1, Item 5 of the GMP Ministerial Ordinance.

GMP11-68 (special exceptions such as MRA) [Question] When a domestic manufacturer sells a final product manufactured by a foreign manufacturer that is subject to an MRA or MOU to the market after the domestic manufacturing facility has made the import/storage/shipment decision, is the product only stored as a manufacturing act? Is it acceptable for a domestic packaging, etc. classification manufacturing facility to make a shipping decision based on the results of visual inspection and confirmation of the test and inspection records of the foreign manufacturer conducted by the marketing authorization holder?

[Answer] Since it is the responsibility of the manufacturer to determine whether a product is released from a manufacturing facility under GMP, it is necessary to check the testing and inspection records of foreign manufacturers themselves.

GMP11-69 (special exceptions such as MRA) [Question] GMP11-69 (Special Provisions for MRA, etc.) Revised Ministerial Ordinance Promulgation Notice No. 3-15(2)② states, Even in cases where this can be replaced by confirming the records of tests and inspections conducted by the foreign manufacturer of the imported product, the appearance inspection of the imported product, Article 11-2, Paragraph 1, Item 4 of the said Ordinance, or When doubts arise about the quality based on the stability monitoring evaluation pursuant to the provisions of Article 21-2, Paragraph 1, Item 4, and the quality information pursuant to Article 16 of the same order, necessary tests and inspections are required. However, if there is any doubt about the quality, the foreign manufacturing facility that conducted the test can promptly carry out the necessary investigation and retesting, and if this is specified in the agreement, it is not necessarily the case that the domestic manufacturing facility Is it okay to understand that I don't have to take the test?

[Answer] That understanding is fine.

GMP11-70 (special exceptions such as MRA) [Question] In Article 11, Paragraph 2 of the GMP Ministerial Ordinance, "tests and inspections conducted by foreign manufacturers in the importing country" are not only tests and inspections conducted by manufacturing facility A immediately before import, but also tests and inspections conducted by manufacturing facility B that preceded it. Does this also apply to tests and inspections conducted by It is assumed that manufacturing sites A and B are located in MRA applicable countries.

[Answer] The test and inspection carried out by Manufacturer B are tests and inspections of imported products, and it is within the GMP of the importing country that the product is shipped (exported) at Manufacturer A after confirming the batch certificate issued by Manufacturer B. It is not necessarily limited to the tests and inspections conducted by Manufacturing Plant A immediately before import, as long as they are carried out appropriately in accordance with regulations.

GMP11-71 (special exceptions such as MRA) [Question] If MRA or MOU special provisions apply, and if the results of a test conducted in the applicable country can be used, and product quality can be guaranteed by confirming the test results, testing and inspection is not required. Is it not necessary to provide the testing and analytical equipment and instruments necessary for the item?

[Answer] Although it is desirable to maintain test equipment at domestic manufacturing facilities that accept products, there are procedures in place in the event that there are doubts about the results, and the foreign manufacturing facility where the test was conducted should promptly investigate and retest. If it is possible to do so and it is specified in the agreement, it is not necessary to have it.

改正GMP省令　Article 11-2　Stability Monitoring

GMP11 2-1 (stability monitoring) [Question] Items in the specifications that are easily affected by storage and items that are considered to affect the efficacy or safety of the product if they do not comply, as referred to in Article 11-2, Paragraph 1, Item 2 of the GMP Ministerial Ordinance. What is it?

[Answer] Select items that are easily affected by temperature, humidity, etc., based on the knowledge obtained from design, prototype studies, and stability tests conducted during the research and development stage. Note that items that are considered to have no obvious change over time, such as heavy metals and arsenic, may be omitted.

GMP11 2-2 (stability monitoring) [Question] The amended Ministerial Ordinance Promulgation Notice No. 3, 16(1) ① requires records of the "validity of the selection." Please explain your approach to lot selection.

[Answer] For each final drug product, at least one lot should be included in the stability monitoring plan each year (unless there is no production in that year). In addition, even if the changes are temporary, changes that affect stability or lots that have been processed for deviations should be added to the plan.

GMP11 2-3 (stability monitoring) [Question] Please explain the concept of measurement intervals.

[Answer] Tests should be conducted at least every 12 months. It is necessary to be able to provide a sufficient amount of data for each test item to enable evaluation of compliance with the standards over the validity period, and this is determined for each product based on data from the development stage or subsequent evaluation. thing.

GMP11 2-4 (stability monitoring) [Question] Where are the product selection and sampling methods stipulated?

[Answer] Stability monitoring procedures should be specified in advance or specified in the drug product standard document.

GMP11 2-5 (stability monitoring) [Question] What storage conditions should stability monitoring be used under?

[Answer] From the perspective of evaluating compliance with the specifications over the shelf life or retest period, the following ICH Q1A (referred to as (R2)), it is preferable to store the long-term storage test under the storage conditions described in (R2). If the storage conditions differ from those stated in ICH Q1A(R2), the storage conditions may be used. If the storage conditions are different from either the conditions stated in ICH Q1A(R2) or the storage conditions of the long-term storage test submitted as evidence for setting the shelf life or retest period at the time of application for manufacturing and marketing approval, the validity The quality of the product shall be confirmed by the quality department and clearly stated in the Standard Operating Procedures, etc. During storage , temperature and humidity should be monitored and consideration should be given to measurements at representative points in the storage environment. However, humidity control is not necessarily required for items that are not affected by humidity or for packaging that is not affected by humidity.

GMP11 2-6 (stability monitoring) [Question] Stability monitoring of water-based formulations in semi-permeable containers shows that there is no change in the risk of water permeability compared to the lot of formulation used in long-term storage studies at the time of application for approval. Even if not, is it necessary to store it under the conditions of 25°C ± 2°C and 40% RH ± 5% RH as stated in ICH Q1A(R2)?

[Answer] In such cases, it may be stored at 25℃±2℃ and 60%RH±5%RH.

GMP11 2-7 (stability monitoring) [Question] Can the bracketing method or matrixing method be applied to the stability monitoring of multiple preparations containing the same active ingredient, such as preparations with different contents or dosages, or preparations with different primary packaging?

[Answer] If there is scientific validity, it may be included in stability monitoring plans, etc. When applying the bracketing method or matrixing method, please refer to the "Application of bracketing method and matrixing method to stability testing of drug substances and drug products" (Pharmaceuticals and Drug Administration Notification No. 0731004, July 31, 2002). The principles shall be followed.

GMP11 2-8 (stability monitoring) [Question] It is stated that the principles of bracketing method and matrixing design may be applied when there is scientific validity in stability monitoring plans, etc., but in what specific cases? .

[Answer] When conducting a reduction test, the type and degree of validity shown differs depending on each product. Please refer to "Application of bracketing method and matrixing method to stability testing of drug substances and drug products" (Pharmaceutical Review No. 0731004, July 31, 2002).

GMP11 2-9 (stability monitoring) [Question] What should be the conditions for stability monitoring when the product storage conditions are not room temperature storage but specify specific temperature and humidity conditions?

[Answer] Storage conditions for stability monitoring follow ICH Q1A(R2), but for products that have storage conditions other than storage at room temperature (1-30°C) and storage in the refrigerator/freezer, Either store it under the test conditions, or monitor it for a period that can sufficiently guarantee the specified shelf life, etc. by setting the upper limit of the specified temperature condition to -2℃ and keeping it at the set temperature condition of ±2℃ and humidity condition of ±5%. shall be carried out.

GMP11 2-10 (stability monitoring) [Question] If the manufacturing process is divided between multiple manufacturing sites, please explain the concept of the manufacturing site that conducts stability monitoring and the manufacturing site that stores its records.

[Answer] Stability monitoring is, in principle, carried out by the manufacturer of the final product (drug) and the drug substance (drug substance). It is possible to perform storage and testing at other manufacturing facilities, external testing agencies, or other outsourcing companies. Although storage of collected samples and implementation of testing and testing may be outsourced to others, the manufacturer, etc. shall be responsible for the appropriate implementation of stability monitoring. In addition, the agreement should include necessary matters such as the method of communication with the contractor, the necessary technical conditions for outsourcing stability monitoring, and the method of quality control during transportation of collected samples.

GMP11 2-11 (stability monitoring) [Question] When it comes to stability monitoring of formulations with different concentrations, if a higher-risk ingredient can be identified during the development stage or subsequent evaluation, is it okay to conduct stability monitoring only for that ingredient?

[Answer] If the bracketing method can be applied, there is no problem. However, if a higher-risk content results in non-compliance, all other formulations with different concentrations are judged to be non-compliant, or if the affected formulations and lots can be scientifically identified, the rationale for the validity is Determine which objects are nonconforming based on the

GMP11 2-12 (stability monitoring) [Question] Article 11-2, Paragraph 1, Item 4 of the GMP Ministerial Ordinance states, "Based on the results of the test and inspection in the previous item, evaluate the impact on the quality of the drug concerned." Which is better, the organization in charge of the department's testing and inspection-related work or the organization in charge of quality assurance-related work?

[Answer] Regarding the evaluation in Article 11-2, Paragraph 1, Item 4 of the GMP Ministerial Ordinance, since objective evaluation is necessary, the organization in charge of quality assurance activity in the quality department should conduct the evaluation. is desirable.

GMP11 2-13 (stability monitoring) [Question] Regarding stability monitoring, are there any matters that should be recorded in the records stipulated in Article 11-2, Paragraph 1, Item 5 of the GMP Ministerial Ordinance other than No. 3-16(1)⑤ of the Notice of Promulgation of the Revised Ministerial Ordinance?

[Answer] Examples include the following.

・Records regarding input into and removal from storage

・Records regarding temperature and humidity during storage

改正GMP省令　Article 11-3　Verification of product quality

GMP11 3-1 (Verification of product quality) [Question] Why is product quality verification necessary?

[Answer] Even in a validated process, as manufacturing results are accumulated, there may be cases where improvements to improve product quality are discovered.For example, the following cases may occur.

1. Because it may be desirable to change manufacturing conditions, etc. due to changes in the physical properties of raw materials, etc.

2. If abnormalities, deviations, or unfavorable trends are observed, it is necessary to take necessary measures.

GMP11 3-2 (Verification of product quality) [Question] How should product quality be checked?

[Answer] When conducting inspections, follow the procedures and keep the following points in mind.

It should be noted that it is not necessary for the organization in charge of quality assurance-related work to carry out all product quality verification activities; instead, the manufacturing department or the organization in charge of testing and inspection-related work can conduct quality assurance after analyzing trends. It is acceptable for the organization responsible for the work related to the final review and approval to be carried out.

1. This should be done at least once a year.

2. The results of the review should be evaluated and the need to take corrective, preventive, or revalidation actions should be considered. If corrective action or revalidation is determined to be necessary, records should be created regarding the reasons and details.

3. If the measures are grouped by product type according to risk, scientific validity must be demonstrated.

GMP11 3-3 (Verification of product quality) [Question] By when do product quality inspection results need to be reported to the The manufacturing supervisor?

[Answer] The inspection should be completed by the date that does not interfere with the purpose of product quality inspection, and should be reported to the The manufacturing supervisor. As the situation varies depending on the manufacturing schedule of the target item, it is not possible to predict a general deadline, but the manufacturing site should set an appropriate deadline and complete the inspection by that date.

GMP11 3-4 (Verification of product quality) [Question] How will product quality be checked for products that have not been manufactured or have only been manufactured in 1 or 2 lots due to production conditions such as temporary production suspension?

[Answer] Even if the product is not manufactured during the period covered by the product quality review, it may be necessary to review deviations during storage, changes to the product, stability monitoring, etc. Furthermore, as long as there are products on the market, it is necessary to check information regarding the quality of the products after they are shipped from the market. For other items, the manufacturer, etc. should appropriately decide in advance the number of lots to be inspected and the number of years to conduct inspections even if the number of lots is not reached, and stipulate this in the procedure. Then, once the preset number of production lots has been reached, product quality should be checked. In addition, even if the number of manufacturing lots is less than the preset number of lots, if a preset number of years has passed, the number of lots from the past can be added and used to check trends in process control values, etc. One method is to check product quality.

GMP11 3-5 (Verification of product quality) [Question] GMP11-3-2 3. In what cases is "grouping by product type" acceptable?

[Answer] If there is a scientific basis, instead of checking each product individually, for example, it is possible to check the product quality of a group of products with the same dosage form manufactured using manufacturing equipment based on the same principle. . GMP11 3-6 3.5.7.8.9. and 11. It is thought that there are some items that can be grouped and checked regardless of the product.

GMP11 3-6 (Verification of product quality) [Question] What are the inspection items for product quality?

[Answer] The subject of inspection is thought to include at least the following items, but manufacturers, etc. should set and implement appropriate items according to the actual situation of the manufacturing site.

1. Verification of test and inspection results upon receipt of raw materials, etc.

2. Verification of important process control and final product quality control results

3. Review of all batches that were non-conforming to established standards and their investigation

4. Review of all significant deviations or nonconformities, their associated investigations, and the effectiveness of any resulting corrective or preventive actions taken.

5. Review of any changes made to processes or analytical methods

6. Inspection of changes in manufacturing and sales regulatory approved information (including changes in export notification matters) that have been contacted by manufacturers and distributors.

7. Review of stability monitoring results and any unfavorable trends

8. Review of all quality-related returns, quality information and recalls, as well as investigations into causes conducted at the time.

9. Review of the adequacy of corrective actions taken on processes or equipment

Ten. Review of post-marketing commitments regarding new manufacturing and marketing approvals and partial changes to manufacturing and marketing regulatory approved information, which have been contacted by marketing authorization holders.

11. Qualification status of related equipment and utilities

12. If outsourced, check the management of the outsourced company

In addition, 6. and 10. , manufacturers, etc. should appropriately obtain and check information regarding the relevant manufacturing facility from the marketing authorization holder in accordance with the arrangements set forth in Article 7 of the GQP Ministerial Ordinance.

GMP11 3-7 (Verification of product quality) [Question] Please provide examples of specific verification methods for the verification items listed in GMP11 3-6.

[Answer] Please refer to "Examples of Product Quality Inspection Reports" (June 13, 2014, Administrative Communication of the Surveillance and Guidance/Narcotics Countermeasures Division).

GMP11 3-8 (Verification of product quality) [Question] GMP11 3-6 1. Does "raw materials, etc." in ``raw materials, etc.'' include all raw materials and materials used at the manufacturing facility?

[Answer] Product quality verification is carried out for the purpose of verifying the validity of the manufacturing process and the specifications of raw materials, materials, and products, as stated in Section 17(1) ① of the Revised Ministerial Ordinance Promulgation Notice No. 3. be. To achieve this objective, utilize quality risk management, appropriately select raw materials and materials to be subject to product quality inspection, and describe them in Standard Operating Proceduress, etc. At least important raw materials listed in GMP11 4-4 must be subject to inspection.

GMP11 3-9 (Verification of product quality) [Question] Does checking process control include simple control using process control charts that are used on a daily basis?

[Answer] It also includes management such as questions. One way to carry out "verification of process control" is to record in-process control data, test and inspection data, etc. on a process control chart for lots produced in the past and perform a chronological analysis.

GMP11 3-10 (Verification of product quality) [Question] Of the inspection items listed in GMP11 3-6, 2. Regarding verification of the results of important process control and quality control of final products, if there are a large number of product lots, is it okay to select the lots to be investigated in the verification of important process control?

[Answer] Although it is desirable to check all manufacturing lots for a certain period of time for the relevant inspection items, it is acceptable for the manufacturer, etc. to appropriately set the implementation method and stipulate it in the Standard Operating Procedures, etc. do not have. When selecting an extraction method, it is necessary to keep in mind that there is no bias in the production period and that it is possible to evaluate seasonal fluctuations.

GMP11-3-11 (Verification of product quality) [Question] GMP11-3-6 11. What is the “qualification status of related equipment and utilities”?

[Answer] The objective is to check the operating status of manufacturing equipment and manufacturing support systems such as air conditioning and manufacturing water equipment, based on the results of daily inspections, periodic inspections, and tests of these systems. The target manufacturing equipment shall be determined by the manufacturer, etc., taking into account the risks to product quality depending on its type, characteristics, purpose of use, frequency of use, etc.

GMP11-3-12 (Verification of product quality) [Question] The herbal medicines that are the raw materials for products such as dried extract powders and soft extracts (for manufacturing purposes only) are natural products and there are variations in quality even within the same lot. If control based on the value ±3σ becomes difficult, what method should be used to verify process control as part of product quality verification?

[Answer] Each manufacturing process (extraction, concentration, spray drying, etc.) for products related to dry extract powder, soft extract, etc. was carried out using the specified equipment and under the specified manufacturing conditions (see "Kampo extract products" below). (Refer to "Example Table of Manufacturing Process Control Items.") from manufacturing records, etc., and if it is confirmed that the variation in the in-process control value is within the specified range, the average value between lots. Even if ±3σ is not controlled, it is acceptable to select necessary items in advance from indicator components, extract content, loss on drying, etc., and to confirm that the target lot is within the range of approved standards. .

Example table of Chinese herbal extract product manufacturing process control items

Process		Contents of management items, etc. (examples)
Dry extract manufacturing process	①Herbal medicines arrived	・Identification, morphological quality (refer to the standards for manufacturing control and quality control of crude drug and Chinese herbal medicine preparations (voluntary standards of the Japan Federation of Pharmaceutical Manufacturers) ・Origin, production area, residual pesticides, etc.
	② Cutting	・Correlation between whole herbal medicines and chopped processed products (things containing essential oils, water-soluble ingredients, ash content, loss on drying) ・Storage conditions for cut herbs
	③Weighing	・Confirmation of compounding amount and lot (in case of mixing multiple lots, the compounding ratio of each lot)
	④Extraction	・Extraction machine number, amount of preparation, order of adding crude drugs, particle size of cut crude drugs, type and amount of extraction solvent, heating temperature, extraction temperature, extraction time (if there is a filtration process, filter management method, etc.)
	⑤ Concentration	・Concentrator number, concentration temperature, concentration time, degree of vacuum, concentrated extract liquid volume (concentration adjustment before spray drying)
	⑥Drying	・Spray drying machine number, air supply (exhaust) temperature, air flow rate, spray nozzle diameter, (concentrated) extract liquid feeding speed (flow meter or pressure gauge), spray liquid volume, time required for spraying
	⑦Dried extract powder	・Confirmation of homogeneity (indicator components, extract content, loss on drying, and specific bulk volume are sampled and investigated in chronological order). If a final mixing process is included, it should be carried out in accordance with ⑨. ・Tests related to yield and manufacturing and marketing approval specifications (collection and testing of one sample per lot is acceptable)
Extract granule manufacturing process	⑧Weighing	・Confirmation of compounding amount and raw material lot (when using multiple lots of raw material dry extract powder, mix it in advance and check the uniformity of at least the indicator components within the lot → Regular process control) (Required when accumulating data for verification.)
	⑨Mixture	・Mixer number, amount of preparation, raw material input order, particle size and moisture content of each raw material, mixing speed (rotation speed), mixing time ・Confirmation of uniformity (After mixing for a certain period of time, collect a certain amount from a pre-specified location and evaluate: Select the indicator component with the highest analysis accuracy.)
	⑩ Granulation (dry)	- Granulator number. In the case of the wet method, how to check the amount of water, dropping speed, and granulation end point, etc. In the case of the dry method, control of compression roller speed and pressure, etc. ・Reuse of sieve residue (in case of wet method, input method and limit of sieve residue input amount) ・In the case of wet method, drying conditions (temperature, time, air volume) and drying procedure, etc.
	⑪Crushing/classification	・Equipment number, vibration speed, sieve mesh size, yield ・Confirm homogeneity (samples may be collected in chronological order) Each indicator component, extract content, loss on drying, bulk volume, particle size distribution, disintegration, etc.
	⑫Filling/occlusion	・Measure the mass of each package at the beginning, middle, and late stages of the filling process. ・Equipment number used, mass deviation test (for SP packaged products, seal integrity is confirmed by water pressure, etc.), material quality, yield, approved standard test, etc.

改正GMP省令　Article 11-4　Management of suppliers of raw materials

GMP11-4-1 (Management of suppliers of raw materials, etc.) [Question] What kind of person does "supplier" in Article 11-4 of the GMP Ministerial Ordinance specifically refer to?

[Answer] Suppliers include those who manufacture raw materials, etc., as well as agents, intermediaries, traders, distributors, etc. who can obtain accurate information on raw materials, etc., and manufacturers who use the raw materials, etc. This includes those deemed necessary.

GMP11-4-2 (Management of suppliers of raw materials, etc.) [Question] What specific procedures are required for "selection after evaluating suitability" in Article 11-4, Paragraph 1, Item 2 of the GMP Ministerial Ordinance?

[Answer] Since selection in this item refers to the act of approval, procedures regarding evaluation (including audits (on-site or in writing), analysis results of the raw materials, etc. of the raw materials, etc.) of suppliers of raw materials, etc. and management should be written in advance. Organizations responsible for quality assurance-related work need to select suppliers in accordance with these procedures. In addition, for individual raw materials, etc., specific approved suppliers should be listed in the drug product standards according to the procedures. In addition, in the case of general-purpose raw materials, etc., the selected supplier may be described in a document common to all products, independent of the Pharmaceutical Product Standard Code. In addition, if a manufacturer evaluates and selects suppliers of raw materials, etc., the manufacturer etc. may confirm the details and make a selection. Furthermore, when changing raw materials and their suppliers, it is necessary to follow an appropriate change management process.

GMP11-4-3 (Management of suppliers of raw materials, etc.) [Question] What are the matters to be kept in mind when concluding an agreement stipulated in Article 11-4, Paragraph 2 of the GMP Ministerial Ordinance?

[Answer] For general-purpose raw materials, etc., it may be difficult to convey information regarding a specific lot even if you make direct arrangements with the manufacturer. , make arrangements with agents, etc., so that appropriate information can be obtained. Regarding the management of raw materials, etc., organizations in charge of quality assurance operations should make arrangements with suppliers from which they can obtain the necessary information in order to properly carry out the operations stipulated in Article 11-4, Paragraph 1 of the GMP Ministerial Ordinance. It does not require arrangements with all suppliers.

GMP11-4-4 (Management of suppliers of raw materials, etc.) [Question] What does "raw materials, etc. that affect product quality" in Article 11-4, Paragraph 2 of the GMP Ministerial Ordinance refer to?

[Answer] It refers to raw materials, etc. that are important for quality assurance, and refers to those determined in advance by the organization in charge of quality assurance operations depending on the risk.

For example, raw materials used as active ingredients of pharmaceuticals, pharmaceutical excipients, and containers or packaging that come into direct contact with the product contents may be considered to have an impact on product quality. See GMP11-55.

GMP11 4-5 (Management of suppliers of raw materials, etc.) [Question] Article 11-4, Paragraph 2 of the GMP Ministerial Ordinance states that "necessary arrangements must be concluded in writing with suppliers," but arrangements between the head office (purchasing department) and suppliers of raw materials, etc. are sufficient. mosquito.

[Answer] There is no problem as long as the appropriate content is specified. However, the details of the agreement should also be understood at the relevant manufacturing facility.

GMP11-4-6 (Management of suppliers of raw materials, etc.) [Question] The Revised Ministerial Ordinance Promulgation Notice No. 3-18(1)③ states, “Based on the agreement with the marketing authorization holder regarding the product using the raw materials, the marketing authorization holder shall comply with the provisions of Article 10, Item 1 of the GQP Ministerial Ordinance. "There is no problem in sharing the results of regular confirmation by the manufacturer, etc." However, even if the manufacturer, etc. receives the results of regular confirmation from the manufacturer, the manufacturer, etc. may overlap and comply with Article 11-4 of the GMP Ministerial Ordinance. Is it necessary to confirm Paragraph 1, Item 3?

[Answer] In that case, the manufacturer, etc. does not need to conduct the confirmation themselves, but they may check the contents of the confirmation records shared by the marketing authorization holder and copies of the necessary quality information obtained by the marketing authorization holder. First, keep a record of it.

GMP11-4-7 (Management of suppliers of raw materials, etc.) [Question] Article 11-4, Paragraph 1, Item 3 of the GMP Ministerial Ordinance states that "confirm periodically", but how should this be carried out?

[Answer] For example, the following responses can be considered. Planned audits (on-site or in writing) to determine whether the manufacturing control and quality control of the raw materials, which are the products of the raw material suppliers, are appropriate, depending on the degree of impact the raw materials have on product quality and the supplier's evaluation. Check whether the quality of the raw materials, etc. is being properly ensured, and identify any issues that need improvement in advance. If so, check whether those items have been appropriately improved. If the organization in charge of quality assurance operations determines that it is necessary based on the results and risks, additional audits (on-site or in writing) of the suppliers of the raw materials, etc. will be conducted to ensure the manufacturing management and control of the raw materials, etc. Check quality control methods.

In addition, in cases where the marketing authorization holder has concluded an agreement with a supplier (such as a drug substance manufacturer, etc.), such as for pharmaceuticals that are active ingredients, confirmation can also be made using the method described in GMP 11 4-6.

GMP11-4-8 (Management of suppliers of raw materials, etc.) [Question] Is it necessary for the manufacturing company of the drug product to obtain and store the results of stability monitoring of the drug substance?

[Answer] At the very least, if an unfavorable trend is confirmed in the stability monitoring of the drug substance, or if OOS or the risk of OOS occurs, as stipulated in the agreement for supplier management of raw materials, etc. It is necessary to establish a system that allows business operators to quickly obtain information.

改正GMP省令　Article 11-5　Management of external contractors

GMP11 5-1 (Management of external contractors) [Question] What types of outsourcing companies are included in Article 11-5 of the GMP Ministerial Ordinance?

[Answer] An outsourcing company under Article 11-5 of the GMP Ministerial Ordinance includes, for example, a person who is entrusted with the following operations in addition to the operations indicated in Section 19(1)② of the Notice of Promulgation of the Revised Ministerial Ordinance (other businesses of the same corporation). ) is also applicable.

・Inspection and maintenance of structures and equipment and calibration of instruments as stipulated in Article 10, Item 9 of the GMP Ministerial Ordinance

・Disinfection and sterilization of work clothes

・Storage and processing of raw materials, materials, and products deemed nonconformance for use or shipment as stipulated in Article 17, Paragraph 2 of the GMP Ministerial Ordinance

Furthermore, management methods for external contractors should be appropriately set depending on the risks of the outsourced work.

GMP11 5-2 (Management of external contractors) [Question] If a marketing authorization holder has concluded an agreement with an external contractor, the manufacturer, etc. must confirm the suitability and ability as per Article 11-5, Paragraph 2, Item 1 of the GMP Ministerial Ordinance, and perform periodic checks as per Item 2 of the same. How should I carry out this confirmation?

[Answer] If the marketing authorization holder has already evaluated and periodically confirmed the suitability and ability of the outsourced contractor, obtain the audit report prepared by the marketing authorization holder, check it, and check the evaluation results. By recording the information, it is possible to confirm the manufacturing site. In addition, the scope of responsibility regarding the management of outsourcing companies should be clarified in agreements with manufacturers, etc. so that manufacturers, etc. can obtain such information.

GMP11 5-3 (Management of external contractors) [Question] According to Article 11-5, Paragraph 1 of the GMP Ministerial Ordinance, the tasks that can be outsourced to external contractors are limited to those that are deemed to cause no problem in having other companies perform the tasks. When outsourcing to an external contractor (external testing and inspection organization), what kind of person should be selected?

[Answer] It is important that operations related to quality assurance and testing are managed at the same level as in manufacturing facilities at external testing and inspection institutions. Therefore, it is necessary to select people who understand the GMP Ministerial Ordinance, build systems such as quality systems that allow testing and inspection operations to be carried out properly and smoothly, and who can fully comply with each article of the GMP Ministerial Ordinance.

The quality system may be constructed with reference to not only ICH Q10 but also ISO 9001 (Quality Management System - Requirements) or ISO/IEC 17025 (General Requirements for the Competence of Testing and Calibration Laboratories). It would also be helpful to check whether the product has participated in quality control tests conducted by the Ministry of Health, Labor and Welfare or the Japan Pharmaceutical Association, or whether there has been a GMP compliance investigation by the authorities, and the results of those investigations.

GMP11 5-4 (Management of external contractors) [Question] Article 11-5, Paragraph 2, Item 1 of the GMP Ministerial Ordinance states that when making arrangements with external contractors, their suitability and ability should be checked.What does this mean?

[Answer] Depending on the degree of impact of the outsourced work on product quality, etc., measures such as conducting an audit (on-site or in writing), interviewing the vendor, or checking the vendor materials, and documenting the results, etc. be.

GMP11 5-5 (Management of external contractors) [Question] Article 11-5, Paragraph 2, Item 2 of the GMP Ministerial Ordinance states that external contractors are to periodically check whether they are properly and smoothly carrying out the outsourced manufacturing and quality-related operations. Do you mean something like that?

[Answer] Depending on the degree of impact of the outsourced work on product quality, there are measures to be taken such as conducting audits (on-site or in writing), conducting interviews, and documenting the results. Furthermore, regarding outsourced work carried out within the manufacturing facility, the above-mentioned periodic confirmation can be replaced by documenting the status and results of the work.

GMP11 5-6 (Management of external contractors) [Question] Regarding the arrangements under Article 11-5, Paragraph 1 of the GMP Ministerial Ordinance, are forms such as purchase orders and invoices acceptable?

[Answer] There is no problem as long as the manufacturer, etc. specified in Article 11-5, Paragraph 2 of the GMP Ministerial Ordinance can appropriately carry out the work that should be performed by the outsourcing company.

改正GMP省令　Article 12　Shipping Management

GMP12-1 (determination of whether or not to ship from the manufacturing site) [Question] Article 12, Paragraph 1 of the GMP Ministerial Ordinance states, "Evaluate each lot appropriately to determine whether manufacturing and quality-related operations have been performed appropriately." What organization is in charge of quality assurance operations? Is it necessary to evaluate the content (results) of the degree?

[Answer] The so-called manufacturing records under Article 10, Item 4 of the GMP Ministerial Ordinance, the testing and inspection records under Article 11, Paragraph 1, Item 4, etc., should be appropriately confirmed, and the manufacturing control from the manufacturing department under Article 10, Item 10 should be confirmed. Confirmation based on the provisions of Article 11, Paragraph 3 regarding the reporting of contents (results) that have been confirmed to have been carried out appropriately, and determination of the results of testing and inspection under Article 11, Paragraph 1, Item 8, or Article 11 It is necessary to properly evaluate the confirmation in paragraph 2. The level of evaluation content cannot be determined unconditionally, as it varies depending on the actual circumstances of the manufacturing facility, the product, etc.

GMP12-2 (determination of whether or not to ship from the manufacturing site) [Question] Is it necessary to clearly indicate the result of the decision on whether or not a product can be shipped from the manufacturing site on the individual label of the product?

[Answer] It should be possible to check the management status of individual containers or groups of containers for products (e.g., "waiting for decision on whether or not to ship", "can be shipped", "unshippable", etc.) (GMP10) ―18).

GMP12-3 (determination of whether or not to ship from the manufacturing site) [Question] Manufacturer B, who handles the secondary packaging and subsequent processes, receives a product that has already been primarily packaged (PTP packaging for tablets, filling containers for liquid medicine, etc.) from pharmaceutical manufacturer A, and is commissioned by the manufacturer. When making a market release determination, can the content test results from pharmaceutical manufacturer A be used as part of manufacturer B's final product release testing?

[Answer] In principle, final product shipping tests should be conducted by collecting samples from Manufacturer B, but if it has been confirmed that all of the following conditions are met, and if the agreement with the marketing authorization holder is met, As long as it is agreed upon by Manufacturer B, it is permissible for Manufacturer B to use the content test results of Pharmaceutical Manufacturer A to determine its release on the market. However, tests specified in the manufacturing and marketing approval (notification) document to be conducted by Manufacturer B must be conducted by that manufacturer. On the other hand, in accordance with the provisions of Article 11, Paragraph 2 of the GMP Ministerial Ordinance, when replacing the imported product by confirming the test and inspection records conducted by the foreign manufacturer, the provisions of Items 1 to 4 of the same article must be followed.

1. Formulation manufacturer A must be a domestic manufacturing facility.

2. It has been proven that there is no impact on product quality due to transportation, packaging/labeling work, storage period, etc. after the test and inspection used, and it has been evaluated in conjunction with Manufacturer B's test data related to packaging and labeling. That's what I'm doing.

3. Manufacturer B is responsible for determining the results of the tests and inspections used.

GMP12-4 (determination of whether or not to ship from the manufacturing site) [Question] Regarding the shipment of products at a manufacturing facility other than the manufacturing facility that manufactures final products, or export drugs or quasi-drugs for export (so-called final products) that are subject to the decision to be shipped overseas, manufacturing and sales Is it permissible to carry out the procedure before approval or before a GMP compliance investigation has been conducted and it is determined that the product is compliant?

[Answer] No problem.

改正GMP省令　Article 13　Validation

GMP13-1 (purpose of validation) [Question] Amended Ministerial Ordinance Publication No. 4 (hereinafter referred to as "Validation Guidelines") 2(1) (Purpose of Validation, etc.) What does verification mean?

[Answer] Verification refers to confirming that products of the desired quality can be consistently manufactured using predetermined evaluation standards and evaluation methods.

GMP13-2 (purpose of validation) [Question] Validation Guideline 2(1) (Purpose of validation, etc.) states, "Verify that it has the expected effect." However, as a verification item, there are no stipulations in manufacturing and marketing approval (notification) matters, compendial documents, etc. Is it okay for manufacturers, etc. to set "evaluation standards" that have not yet been established?

[Answer] No problem. For example, in validation, the number of samples and test items are often increased compared to commercial production in order to demonstrate that the product can be consistently manufactured using predetermined evaluation standards and evaluation methods. There is a need. For this reason, manufacturers, etc. should set appropriate verification items and "evaluation criteria" on their own, including the adoption of "evaluation criteria" that are not stipulated in manufacturing and marketing approval (notification) matters and compendial documents. be described in the validation plan as part of the "effects" referred to in the validation guidelines.

When adopting "evaluation criteria" that are not specified in manufacturing and marketing approval (notification) matters or compendial documents, etc., the basis for setting them should be clarified in advance, and the basis for setting them should be clarified in advance, and confirmed by the quality department and written in the validation plan.

it is desirable to adopt generally accepted standards, such as the sterility assurance level of "10-6 or less" for terminal sterilization methods, as the standard.

GMP13-3 (purpose of validation) [Question] Validation Guidelines 2(1) (Purpose of Validation) states, ``Knowledge accumulated over the life cycle of a drug (process design of the drug concerned, daily process confirmation during commercial production, Article 3 of the GMP Ministerial Ordinance) (including the results obtained from quality risk management pursuant to the provisions of Paragraph 1 of Article 11-3 of the same Order and product quality inspection pursuant to the provisions of Paragraph 1, Item 1 of Article 11-3 of the same Order). , if the product development or production technology establishment for the drug concerned is being conducted at a site other than the manufacturing site, the drug marketing authorization holder will appropriately and smoothly contact the manufacturer, etc. pursuant to the provisions of Article 10, Paragraph 5 of the GQP Ministerial Ordinance. ``It requires the transfer of related knowledge and technology, such as the provision of quality information necessary for implementation of quality manufacturing control and quality control.'' What does "technology transfer" (hereinafter referred to as "technology transfer") refer to?

[Answer] The life cycle of a drug is defined in the Q10 guidelines as the entire process of drug development, technology transfer, commercial production, and product termination. In addition, the goal of technology transfer in the same guidelines is "to transfer knowledge of pharmaceutical products and manufacturing processes between development and production departments and within or between manufacturing sites in order to achieve product realization." ing. This knowledge forms the basis for manufacturing processes, control strategies, process validation efforts and continuous improvement to reduce risks to product quality. Furthermore, as long as a drug is sold, it is necessary to maintain a validated state, so validation throughout the drug's life cycle is required.

In order to establish a process, it is important to accumulate data from the time of drug development, and the starting point for the knowledge and information accumulated throughout a drug's life cycle is at the time of development, when data acquisition activities begin. If the department that carried out this activity is different from the production department, technology will be transferred from the different department to the production department. Although drug development activities are not subject to GMP controls, they are science-based and cannot be properly documented without proper documentation.

The knowledge that is generally transferred includes knowledge regarding manufacturing technology and analytical technology, and it is desirable to transfer as much knowledge and information as possible prior to technology transfer, with reference to the following items.

1. Development history

2. Manufacturing process and important parameters

3. Product quality characteristics such as impurities and physical properties

Four. Cleaning method

Five. Specifications and test methods and their validity basis

6. Information on stability test results and storage conditions

Validation master plan

GMP13-4 (Validation Master Plan) [Question] Validation can cover a wide variety of items such as structures, equipment, procedures, processes, and other manufacturing control and quality control methods, but the validation master plan referred to in the validation guidelines should be created for all of these items for each product. Is that necessary? Also, is it necessary to report all verification results to the organization in charge of quality assurance activity for each product?

[Answer] The content of the validation master plan may be created as common to multiple products at each manufacturing site. On the other hand, as a general rule, validation plans created based on validation procedures must be created for each product, and validation reports referred to in the validation guidelines must also be reported for each product. However, validation plans related to the validation of "equipment, system, or equipment" and "work such as cleaning" may be prepared for each facility or device.

GMP13-5 (Validation Master Plan) [Question] Can the validation master plan specified in Validation Guidelines (1) be considered a document with the same content as the validation master plan required by the PIC/S GMP guidelines?

[Answer] No problem.

GMP13-6 (Validation Master Plan) [Question] In the validation master plan, who should approve the validation plan? In particular, in the case of process validation, is it okay to stipulate that the person in charge of the research and development department is the person in charge?

[Answer] This is the "pre-designated person" in Article 13, Paragraph 1 of the GMP Ministerial Ordinance, that is, the person responsible for validation as defined in the validation guidelines. However, if a deputy person in charge of validation is appointed for each field, the responsibility and authority etc. stipulated in the document in Article 6, Paragraph 4 of the GMP Ministerial Ordinance shall be assigned to the deputy person in charge of validation. There is no problem.

GMP13-7 (Validation Master Plan) [Question] Regarding the Validation Master Plan, Article 3 of the Notice of Promulgation of Revised Ministerial Ordinance No. 11(1) ⑨A states that it is the "overall policy regarding validation at the manufacturing facility." What should be stipulated?

[Answer] The overall policy, purpose, and approach regarding validation as a manufacturing facility should be clearly and concisely defined.

GMP13-8 (Validation Master Plan) [Question] Regarding the Validation Master Plan, Article 3 of the Notification of Promulgation of the Revised Ministerial Ordinance No. 11(1) ⑨A states that "the responsibilities and management system of employees engaged in work related to validation at the manufacturing site". Does this apply to employees of the organization?

[Answer] This applies to employees of manufacturing departments, quality departments, research and development departments, and organizations involved in the design and development of structural equipment or computerized systems.

GMP13-9 (Validation Master Plan) [Question] Validation Guidelines 2(3) states that "validation plans shall be created based on the validation master plan", but how should I specifically describe the timing of individual validations? mosquito.

[Answer] The validation master plan stipulates that ``the implementation period shall be determined and stated in the validation plan,'' and the specific implementation timing of each individual validation can be stated in the relevant validation plan. In addition, when the scope of validation is wide and there are multiple individual plans, such as a large-scale project, consideration should be given to documenting the project that summarizes the entire validation.

GMP13-10 (Validation Master Plan) [Question] Regarding the Validation Master Plan, Article 3 of the Notice of Promulgation of the Revised Ministerial Ordinance No. 11(1) ⑨K states "Other procedures necessary to properly and smoothly conduct validation". What are the specifics?

[Answer] Risk assessment methods for determining the scope of validation and important control items, matters related to the use of knowledge and information accumulated throughout the product life cycle including drug development and daily process confirmation, and product quality checks, and revalidation. It stipulates the matters necessary to carry out validation. Each manufacturer, etc. shall determine and enter the necessary items as appropriate.

GMP13-11 (validation manager) [Question] Does the "pre-designated person" in Article 13, Paragraph 1 of the GMP Ministerial Ordinance, that is, the employee who is the "person in charge of validation" as defined in the validation guidelines, have to be a person who belongs to the manufacturing facility in question?

[Answer] If you are an employee of a manufacturer, etc., you do not necessarily have to belong to the manufacturing facility. However, the responsibilities, authority, etc. of the relevant personnel shall be stipulated in advance in the documents set forth in Article 6, Paragraph 4 of the GMP Ministerial Ordinance and in the Validation Master Plan, and the education and training set forth in Article 19, Paragraph 1 shall be provided so that they can carry out their responsibilities without hindrance. to do.

GMP13-12 (validation manager) [Question] Is it acceptable for the "person designated in advance" in Article 13, Paragraph 1 of the GMP Ministerial Ordinance, that is, the "person in charge of validation" as referred to in the validation guidelines, to concurrently serve as the The manufacturing supervisor? Also, is it possible to concurrently serve as a "person designated in advance" under other provisions of the GMP Ministerial Ordinance? Is it correct to understand that the "person designated in advance" in Article 13, Paragraph 1 of the GMP Ministerial Ordinance does not have to be a person in charge of the internal organization, and there are no special qualification requirements?

[Answer] There is no problem with holding any of the concurrent positions mentioned in the question, as long as it does not interfere with other duties and can be done fairly. As stated in Section 21(1) of the Revised Ministerial Ordinance Promulgation Notice, an official who is familiar with the work should be designated as the person responsible for validation. In addition, the responsibilities, authority, etc. of the relevant personnel shall be properly stipulated in advance in the documents stipulated in Article 6, Paragraph 4 of the GMP Ministerial Ordinance and in the Standard Operating Procedures regarding validation, so that the operations stipulated in Article 13 can be carried out smoothly.

GMP13-13 (validation manager) [Question] Can there be multiple "persons designated in advance" in Article 13, Paragraph 1 of the GMP Ministerial Ordinance, that is, "Persons Responsible for Validation" as defined in the Validation Guidelines? , manufacturing-related, testing/inspection-related, equipment-related, etc., it may not be possible for one person to cover the entire situation).

[Answer] The person responsible for validation is the person who is responsible for the entire validation, and it is not allowed to have more than one person at one manufacturing facility. However, since a wide variety of staff from various departments may be involved in the implementation of validation, it is acceptable to have a deputy person in charge of validation for each field. In that case, the responsibilities, authority, etc. of each deputy person in charge of validation should be appropriately defined and clarified in advance in the document set forth in Article 6, Paragraph 4 of the GMP Ministerial Ordinance and in the validation master plan.

GMP13-14 (validation plan, etc.) [Question] The "pre-designated person" in Article 13, Paragraph 1 of the GMP Ministerial Ordinance, that is, the The manufacturing supervisor who also serves as the "person in charge of validation" as defined in the validation standards, is the person in charge of the manufacturing department, the person in charge of the quality department, etc. Is it okay to hold a "validation committee" organized by the organization to evaluate and approve the validation plan and validation results?

[Answer] The person responsible for validation as the “pre-designated person” in Article 13, Paragraph 1 of the GMP Ministerial Ordinance must be a person who has the responsibility and authority regarding the implementation of validation. Therefore, even if a "validation committee" is held as in the question and discussions are held to approve the validation plan, the person ultimately responsible for implementing validation is the person responsible for validation.

GMP13-15 (validation plan, etc.) [Question] Does the validation plan have to be prepared ``by the person designated in advance'' under Article 13, Paragraph 1 of the GMP Ministerial Ordinance, that is, the ``person responsible for validation'' as referred to in the Validation Guidelines? Or is it okay to have each person in charge (practical person in charge) check and approve the documents prepared?

[Answer] The person in charge of creating the validation plan is the person in charge of validation, and must also bear ultimate responsibility for the work related to the preparation carried out by the personnel in charge under his or her instructions. At least the person responsible for validation must confirm and approve the creation, changes, etc. of the validation plan.

GMP13-16 (validation plan, etc.) [Question] Validation Guidelines (3) ⑤ states that "verification methods (data to be collected for verification, methods and standards for evaluating that data, etc.)" are specified in the validation plan. How should the suitability of test methods used for manufacturing process control, etc. (excluding standard tests) be ensured?

[Answer] Validate the test method to be adopted or obtain validation data. If validation is not performed, the suitability of the test method shall be demonstrated under actual conditions of use and recorded. The degree of validation should reflect the purpose of the test and the stage of the manufacturing process to which the test method is applied. Consider appropriate qualification of test and testing equipment before starting validation. When making changes to the test method, validation should be carried out according to the degree of change. In addition, test methods listed in compendials such as the Japanese Pharmacopoeia and other recognized reference documents are general methods and cannot necessarily be applied to all test subjects without problems, so analytical method validation Its suitability must be verified using other appropriate methods.

GMP13-17 (validation plan, etc.) [Question] What should we keep in mind when creating a validation report? Also, when creating validation plans and validation reports, is it okay to combine the formats as a "plan/report"?

[Answer]

1. The validation report corresponding to the validation plan should summarize the results obtained during the validation, comment on any deviations identified (the causes or reasons for the deviations should be appropriately stated), and properly document the results. Summarize your conclusions and include any recommended changes or other suggestions for remediating deficiencies.

2. As in the question, there is no problem even if the validation plan and validation report are formally integrated and created as a "plan/report." However, this should be defined in advance in the validation master plan and approval of the plan should be obtained before implementation.

GMP13-18 (validation plan, etc.) [Question] How should I describe "verification methods (data to be collected for verification, methods and standards for evaluating that data, etc.)" as a matter stipulated in the validation plan in Validation Guidelines (3) ⑤? . For example, should I state "based on statistical methods"?

[Answer] When creating a validation plan, the target products and implementation items have already been concretely determined, so the verification method should not be described in an abstract manner such as "based on statistical methods" as in the question. Please be specific. For example, the locations or measurement points where samples are taken during verification, the number of measurements, the method of testing and testing, the handling of analysis results (adoption of average, maximum or minimum values, specific statistical calculation methods, etc.), testing and testing results. Specific evaluation criteria, etc. should be described to ensure that the validation plan is effective.

GMP13-19 (qualification assessment) [Question] Validation Guidelines (5) ① states that ``properly calibrated measuring instruments should be used.'' What is calibration?

[Answer] Calibration is the process of determining the relationship between the value expressed by the measuring instrument used during manufacturing and the true value using appropriate standards and standard samples, taking into account the required accuracy. say. Appropriate standards and standard samples include so-called national standards or standards calibrated using such standards, standards specified in the Japanese Pharmacopoeia, and standards that comply with the standards of official compendials or manufacturing and marketing approval (notification) documents. etc.

GMP13-20 (qualification evaluation) [Question] What is the so-called challenge testing method for performance qualification (PQ) that confirms that expected results are achieved at the upper or lower limits of process tolerances within Standard Operating Procedures? Is it possible to use it?

[Answer] It is possible. Depending on the purpose and content of the challenge test, there are those that need to be conducted in commercial production facilities and those that are conducted during industrialization research that does not involve commercial production facilities.

GMP13-21 (qualification evaluation) [Question] When changing manufacturing equipment and it is considered that the changed equipment falls under the operating principle stated in the manufacturing and marketing approval (notification) document, the change management prescribed in Article 14 of the GMP Ministerial Ordinance must be followed. Can I change it according to the instructions?

[Answer] No problem. If necessary, we will consult with the GMP compliance authority and conduct design qualification (DQ), equipment installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). ).

GMP13-22 (qualification assessment) [Question] For movable manufacturing equipment such as crushers that are used in any operational room, is it necessary to conduct a qualification assessment each time it is moved?

[Answer] Once it is confirmed that the initial and periodic qualification evaluations are being conducted appropriately, and the results are available for use, it is necessary to conduct qualification evaluations again each time there is movement within the same manufacturing facility, etc. There isn't. Appropriately manage the equipment, taking into account the effects of moving the equipment, inspect it during use, check the operating status, and create records.

GMP13-23 (qualification assessment) [Question] Regarding the calibration of the load cell of a preparation tank with a capacity of several tons, it is difficult to calibrate using a reference weight that has traceability to the measurement standard. Is it okay to use water that has been drained?

[Answer] There is no problem as long as the required accuracy is ensured.

GMP13-24 (qualification evaluation) [Question] Can you use the same high-pressure steam sterilizer to sterilize several types of products with different formulations under the same temperature, same time, same container material (form), same volume, and same load? When performing performance qualification (PQ) for a process performed using sterilization methods, is it okay to use data related to a representative product of the process in place of performance qualification (PQ) for other products?

[Answer] If the maintenance and inspection of the high-pressure steam sterilization equipment and the calibration of the instruments have been carried out appropriately, and the evaluation of quality other than sterility and non-pyrogenicity has been completed, and each product related to the process If properties such as heat permeability and drug viscosity can be investigated to ensure equivalency in sterilization effectiveness between products, it is acceptable to conduct evaluations using data related to "representative products." In this case, the rationale should be clearly stated in the validation plan in advance.

GMP13-25 (qualification evaluation) [Question] I would like to transfer an in-house developed test method that has already been validated from Company A's equipment to Company B's equipment, but is it necessary to carry out all the analytical method validation items?

[Answer] If you have carried out equipment qualification and have confirmed in your company that there is no difference in basic performance, it is not necessarily necessary to carry out all the analytical method validation items again. After fully understanding the characteristics of the test method and assessing the risks, it may be sufficient to verify some items of analytical method validation as necessary. In that case, document the content that was implemented and the basis for selecting the items.

GMP13-26 (process validation) [Question] What method should be used to evaluate content uniformity in the manufacture of tablet products for which formulation uniformity (content uniformity test) is not specified in the marketing approval (notification) document?

[Answer] For example, when formulation uniformity (mass deviation test) is applied, 10 tablets are collected at each of the early, middle and late stages of the tabletting process, the mass of each tablet is measured, and the manufacturing and marketing approval ( The active ingredient was determined using the quantitative method described in the notification), and the estimated content of each tablet in the initial, middle, and late stages was calculated from the mass of each tablet and the quantitative value of the active ingredient. Statistics were obtained on the data obtained. There is also an alternative method of processing and evaluating content uniformity. Before the tabletting process, the mass deviation of the product is considered as a content deviation based on the evaluation of content uniformity, and the mass of each product is measured and determined by the quantitative method specified in the manufacturing and marketing approval (notification) document. When estimating "content uniformity" using the obtained active ingredient content (refer to the Japanese Pharmacopoeia), manufacturing and marketing approval (notification) is required at each of the early, middle, and late stages of the tableting process. Take the number of tablets required for the quantitative determination (for example, 20 tablets) as described in the book, take 10 tablets from the initial 20 tablets, measure the mass of each tablet, and grind the initial 20 tablets (W1, W2...W10). Another method is to quantify the substance according to the method described in the manufacturing and marketing approval (notification) and calculate the judgment value using the formula below, and if this value does not exceed 15.0%, it is deemed to be compliant.

Judgment value = |M-A|+ks

M: Display amount (100.0%)

A: Average content per tablet determined by quantitative determination (% of labeled amount)

1…10: Estimated amount of active ingredient contained in one tablet (i)

1=W1×A/W

W1…W10: Mass of each tablet (Wi)

W=W1…Average value of W10

k: Judgment coefficient In this case k=2.4

s = standard deviation of 10 tablets

GMP13-27 (process validation) [Question] Validation Guidelines (5) ② A and B (C) state that "PV is, in principle, repeatedly manufactured in three lots of the product on a commercial production scale." When filling containers of the same quality, does the filling process require process validation for each capacity?

[Answer] Regarding the filling process for products with different capacities such as different sizes for the same drug, even if the equipment is the same, filling time and filling speed can be factors that can cause process fluctuations, so the process should be done separately for each capacity. Validation is required. However, for products with different capacities, there is no problem as long as the necessary validation is performed in consideration of the variable factors and product characteristics.

GMP13-28 (process validation) [Question] The answer to GMP13-27 states that "process validation is required for each volume." Therefore, if the same equipment is used, is it okay to perform process validation at the maximum and minimum capacity of the product?

[Answer] No problem. However, the filling performance and other characteristics of all capacities must be confirmed in advance using an appropriate method. Also, evaluate in advance the impact on product quality, such as material and shape.

GMP13-29 (process validation) [Question] When filling the same product with the same volume using multiple equipment with the same specifications, is it necessary to perform process validation using each equipment?

[Answer] Even if the model and specifications are the same, if the equipment is different, process validation is generally required for each equipment. However, if the equipment, system, or device has been qualified and the equivalence between each piece of equipment has been confirmed, it may be possible to perform process validation using one piece of equipment and omit the other. .

GMP13-30 (process validation) [Question] Validation Guidelines (5) ② A and B (D) state that ``Normally, for products that have undergone the relevant process, PV must be completed before deciding whether or not to ship them from the manufacturing site.'' However, for example, even if a product is produced only once a year, is it necessary to perform process validation on three lots in principle before shipping the product?

[Answer] If there is a rational basis for conducting concurrent validation as process validation and it is specified in advance in the validation plan, process validation should not be conducted in three lots before shipping the product. In some cases, it may be accepted. Consult with the GMP compliance investigation authority. For drugs designated as orphan drugs, concurrent validation is adopted, and one lot is confirmed on a commercial production scale before conducting a GMP compliance investigation, and the remaining two lots are commercially produced after approval is obtained. There is no problem in checking on a production scale. However, the rationale for implementing concurrent validation and the lot structure should be clearly stated in the validation plan in advance.

GMP13-31 (process validation) [Question] When producing several products with the same dosage form and active ingredient but different concentrations (or contents) and volumes, is it necessary to conduct process validation for each concentration (or content) and volume? Is there one?

[Answer] If the drug properties and the effects of each process on product quality can be considered similar, the rationale for grouping and selecting representative products should be clearly stated in the validation plan in advance. After that, process validation can be performed on the representative product.

Grouping refers to groups of products that can be considered to be similar in formulation characteristics (biological activity, physicochemical properties, quality standards, amount of active ingredients, etc.) and the effects of each process on product quality. This refers to a collective evaluation. For example, there may be products with generally similar formulation characteristics, such as products with the same manufacturing process but slightly different amounts of active ingredients, or products with slightly different types and amounts of ingredients other than active ingredients.

When grouping products, the range of products and rational basis for selection should be specified in advance in the validation plan. In particular, carefully consider whether it is appropriate to evaluate products by grouping them, especially for products with little past manufacturing experience. Even if the products are similar, it is necessary to perform process validation for each product if it is expected that there will be no common variation factors in process control, etc.

GMP13-32 (process validation) [Question] Is it okay to perform process validation for a process that uses the same manufacturing equipment to manufacture the same product at manufacturing scales of 200kg, 500kg, and 1,000kg only on the smallest scale of 200kg?

[Answer] The purpose of process validation is to verify that the manufacturing scale in commercial production does not affect the quality of the product, so in the case of the question, in principle, there are three types: 200 kg, 500 kg, and 1,000 kg. Validation needs to be carried out at any commercial production scale.

However, if there is a reasonable reason why the lot size does not affect the quality of the product and it is specified in the validation plan in advance, then in the case of the question, for 500 kg of the three types of commercial production scale. can be omitted.

GMP13-33 (process validation) [Question] In process validation, how should the locations and amounts of samples used in tests to evaluate content uniformity be set?

[Answer] Regarding the location of collection, depending on the formulation characteristics of the target product, for example, in the tabletting process, it is chronological, and in the mixing process, the lot is determined by taking into account the capacity of the mixer and the input amount. Appropriate representative locations and number of locations shall be established. The amount to be collected should be determined taking into consideration the method of testing the content of the active ingredient, analytical accuracy, etc. The location and amount of sampling should be specified in advance in the validation plan.

GMP13-34 (process validation) [Question] How should we evaluate the "uniformity of content" of tablet products containing enzymes such as diastase as active ingredients?

[Answer] When the width of the specifications in the manufacturing and marketing approval (notification) document exceeds the labeled amount ±25%, such as with enzyme preparations such as diastase, or when it is difficult to evaluate uniformity from the viewpoint of analytical accuracy, After evaluating the uniformity of the mixing process, which is the pre-process, according to the standards set by the manufacturer, etc., the quantitative values obtained according to the method in the manufacturing and marketing approval (notification) form of samples taken in chronological order during the tableting process are determined to be within the standard range. After confirming that the weight is within the range, it is okay to evaluate the weight of each compressed product by performing statistical processing on a time-series basis.

GMP13-35 (process validation) [Question] How should I perform process validation of the pill-making process for pill-related products?

[Answer] At the beginning, middle, and later stages of the round-making process, confirm that the variation in individual mass of a fixed quantity dried as per the normal process is within the expected range. However, if the mass deviation test standard is not stated in the manufacturing and marketing approval (notification) document, it is sufficient to confirm that the variation in single doses is within the expected value set by the manufacturer, etc. . However, in addition to the impact on the pill-making process due to changes in the viscosity of the kneaded mass as necessary, the product related to pills immediately after being made contains a large amount of water, so the product related to pills after drying may be Pay attention to weight (content) control.

In addition, if a disintegration test is set as a standard in the manufacturing and marketing approval (notification) document, the disintegration property should also be evaluated.

GMP13-36 (process validation) [Question] Old approval documents for herbal herbal medicine preparations may specify a quantitative method such as the persimmon method using thin layer chromatography. In such cases, may validation be performed using an appropriate quantitative method other than the method described in the manufacturing and marketing approval (notification) document, such as HPLC?

[Answer] In addition to the method described in the manufacturing and marketing approval (notification) document for process validation, it is acceptable to perform validation using HPLC methods, etc., which have high analytical accuracy, for quantitative methods. In addition, if the test method described in the manufacturing and marketing approval (notification) document is deemed to be insufficient in light of the current related notifications, scientific and technological standards, etc., an application for partial change approval, etc. (if applicable, minor (Notification of changes)

GMP13-37 (process validation) [Question] In process validation, if a verification method based on "results of repeated manufacturing of 3 lots" is adopted, do 3 consecutive lots have to be compliant?

[Answer] In principle, three consecutive lots must meet the criteria. If the expected results are not obtained, it is necessary to investigate the cause, perform process validation on three consecutive lots again under conditions that eliminate the cause, and perform evaluation.

However, when it is confirmed that there was an obvious operational error after conducting an OOS investigation according to the prescribed procedures, or when the cause is a special matter that is clearly not related to manufacturing process control, such as a power outage or equipment failure. etc., excluding that lot and adding the remanufactured lot to make 3 lots can be considered as "repeated production of 3 lots." Please note that pharmaceuticals developed in accordance with the "Revision of Guidelines for Pharmaceutical Development" (Pharmaceuticals and Food Safety Review No. 0628 No. 1, June 28, 2010) and whose manufacturing process stipulates continuous process confirmation. For this, please refer to GMP13-50 to GMP13-54.

GMP13-38 (process validation) [Question] When sharing equipment to manufacture multiple products, it may be difficult to manufacture three consecutive lots of the same product. Even in such a case, does process validation have to be performed by serially manufacturing three lots of the product on a commercial production scale?

[Answer] Commercial scale manufacturing of three lots of the same product does not necessarily have to be continuous without manufacturing other products; in other words, it may be performed in between the production of other products. However, you must meet the criteria three times in a row.

As a prerequisite, basic contamination and cross-contamination prevention measures must be taken appropriately, such as checking the cleanliness of equipment and implementing education and training in a planned manner.

GMP13-39 (process validation) [Question] If the manufacturing equipment used when creating the application data for manufacturing and sales approval is the same as the equipment that will carry out commercial production after manufacturing and sales approval, is it possible to use the data from the manufacturing of the industrialized research product for application using that equipment for process validation? Is it possible to treat it as such?

[Answer] The suitability of the manufacturing equipment is maintained, and the manufacturing conditions, etc. (manufacturing scale is commercial production scale, etc.) at the time of obtaining the "data at the time of manufacturing the industrialized research product for application" in the question are confirmed. In some cases, if the process validation is the same as the process validation to be performed, it may be sufficient to specify these matters in advance in the validation plan to be performed.

GMP13-40 (process validation) [Question] If manufacturing equipment with the same specifications is installed at another manufacturing site of the same corporation to manufacture the same product, is process validation required at both manufacturing sites? If the manufacturing equipment has the same specifications, is it okay to perform process validation for three lots at only one manufacturing site?

[Answer] Even if the manufacturing equipment has the same specifications, they are different manufacturing equipment due to differences in operating performance. Additionally, since the manufacturing environment, GMP organizational structure, etc. are different, it is necessary to perform process validation for both manufacturing facilities.

GMP13-41 (process validation) [Question] When relocating existing manufacturing equipment related to important processes of the same product within the same manufacturing facility or establishing new manufacturing equipment with the same specifications as the relevant manufacturing equipment, process validation is required for lots smaller than 3 lots. Is it okay to evaluate by manufacturing numbers?

[Answer] As with GMP13-40, even if the manufacturing equipment has the same specifications, it will be different manufacturing equipment due to differences in operating performance, so in principle, process validation for 3 lots is required. However, in the case of relocation, there is no problem if all of the following requirements are met and this is clearly stated in the validation plan in advance.

1. Regarding the "relocated manufacturing equipment", design qualification (DQ) is conducted in advance, and after relocation, equipment installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) are conducted. ), and ensure equivalence of the equipment before and after relocation.

2. It has been confirmed that there is no change in the pre-identified variable factors and that the process is stable based on the accumulated product quality verification results for the manufacturing process related to the "manufacturing equipment before relocation."

3. There shall be no changes in the lot size, manufacturing procedures, etc. of the process related to the manufacturing equipment before and after relocation.

GMP13-42 (process validation) [Question] Regarding pharmaceuticals that are active ingredients used for process validation of drug products, is it necessary to use three separate lots and conduct validation related to the drug product process?

[Answer] When performing process validation for the "formulation process" at the manufacturing facility, the lot of the drug substance that will be used for validation is determined by considering the knowledge and information acquired from the time of drug development, the quality characteristics of the product, etc. This is desirable.

GMP13-43 (process validation) [Question] Can process validation be performed without using active drugs?

[Answer] Process validation is the process of verifying that the allowable conditions for pre-specified variable factors that affect product quality are appropriate for consistently manufacturing products that meet the desired quality. It is something to be verified. Therefore, confirmation is performed using actual medicine.

GMP13-44 (process validation) [Question] Is it necessary to conduct process validation for all manufacturing processes? Also, what should be considered when selecting a manufacturing process for process validation?

[Answer] It is not necessarily necessary to carry out process validation for all manufacturing processes, but based on the knowledge and information acquired during drug development, it is possible to conduct process validation based on the quality characteristics of the product. The selection and implementation of a certain important process by a manufacturer, etc. Examples of important processes are shown in the table below, but even processes not shown in the table should be validated according to the quality risk (e.g. coating process in dissolution evaluation).

GMP13-45 (process validation) [Question] When applying for new manufacturing and marketing approval, if manufacturing is performed using existing equipment, is it not necessary to conduct a new qualification assessment of the existing equipment, and only process validation can be performed?

[Answer] Depending on the product being manufactured, some manufacturing equipment may require changes in usage conditions; for example, there may be cases where equipment qualification needs to be re-evaluated. Therefore, it is necessary to assess whether the results of qualification assessments that have already been carried out can be used.

GMP13-46 (process validation) [Question] Can performance qualification (PQ) conducted before the start of process validation be performed using small-scale data from the time of recipe design or manufacturing method review? Or is performance qualification (PQ) not considered complete until a manufacturing method is established at commercial production scale? Also, is it correct to understand that there are no specific regulations regarding the number of production lots required for this performance qualification (PQ)?

[Answer]

1. As a general rule, performance qualification (PQ) is ultimately performed on a commercial production scale, and the manufacturing procedures, etc. established based on the results of industrialization research, etc. are verified as intended over the entire range of expected operating conditions. This is to confirm that it is working.

2. However, if sufficient knowledge regarding the manufacturing process has been accumulated through industrialization research, etc., and the fluctuation factors such as important parameters are understood, performance qualification (PQ) may be conducted on a commercial production scale. There are cases where it is not necessary.

3. The number of lots required for performance qualification (PQ) should be determined appropriately according to variables such as accumulated knowledge and important parameters. When analyzing variation factors, statistical methods should be used as necessary.

GMP13-47 (process validation) [Question] In process validation, what does it mean to ``verify that the process is a valid process that consistently produces products of the required quality''? For example, can "verification" be defined as passing a product's standards?

[Answer] The purpose of process validation is not to simply evaluate the validity of the manufacturing process based on whether the product meets or fails the product's specifications, but also to evaluate the variable factors that affect product quality (physical properties of raw materials, operating conditions, etc.) that have been specified in advance. ) is to confirm and document that the process that operates under the permissible conditions set in consideration of the above is appropriate for consistently manufacturing products that meet the desired quality.

Therefore, in process validation, it is not always sufficient to confirm that a product that has completed all the manufacturing processes at a manufacturing site passes its specifications; it also includes in-process management, including monitoring, so that the operational performance of the process can be evaluated. By appropriately determining the content of such tests and inspections (locations and times of sampling) and conducting various evaluations, structures, equipment, procedures, processes, and other manufacturing control and quality control methods should have the expected effects. need to be confirmed.

GMP13-48 (process validation) [Question] The table of GMP13-44 (examples of important processes) lists the tableting process and granulation process as processes that affect dissolution as a quality characteristic of solid dosage forms, but is it necessary to obtain manufacturing and marketing approval (notification)? Is it necessary to include dissolution in the validation of the process even if dissolution testing is not specified in the standard?

[Answer] It is not necessarily a requirement unless it is specified in the standards of the manufacturing and marketing approval (notification) document, but it is desirable to implement it in order to understand the process from a quality assurance perspective and grasp the trends of variable factors. For products subject to quality re-evaluation, please refer to GMP13-66.

GMP13-49 (process validation) [Question] How should I perform process validation of a manufacturing process that affects the uniformity of content of a liquid formulation in which ingredients are dispersed?

[Answer] When assuming a general manufacturing process for a product like the one in the question, it is necessary to evaluate the mixing process, dispersion process, filling process, etc. as important processes. The processes to be evaluated shall be selected based on quality risk management evaluation, and the validity of acceptable conditions shall be verified with respect to pre-identified variable factors that affect product quality. For example, when evaluating content uniformity in the filling process, the sampling method (location, frequency, amount, etc.) should be appropriately set at the beginning, middle, and late stage of the process based on scientific grounds. Do this with the sample.

Continuous process confirmation

GMP13-50 (continuous process confirmation) [Question] What kind of method is meant by "a method that is equivalent or better" in Validation Guidelines (5) ② (c)?

[Answer] For example, for products whose formulations were developed based on the ``more advanced QbD method'' of the ``Revision of Guidelines for Formulation Development'' (Pharmaceutical and Food Safety Review No. 0628 No. 1, June 28, 2010), This refers to the case where the manufacturing process is verified by incorporating a method of process confirmation. However, before shipping commercial products, it is necessary to demonstrate that products of the quality required on a commercial production scale can be produced continuously.

GMP13-51 (continuous process confirmation) [Question] What steps can be taken to introduce continuous process confirmation?

[Answer] Develop formulations based on the ``more advanced QbD method'' of ``Revision of Guidelines for Formulation Development'' (Pharmaceutical and Food Safety Review No. 0628 No. 1, June 28, 2010), and manage continuous process confirmation. It is possible to introduce it if a strategy is established. Even when introducing an existing product for which continuous process confirmation has not been established, the manufacturing process and control strategy should be developed based on the "Guidelines for Formulation Development."

GMP13-52 (continuous process confirmation) [Question] How should process validation be performed for products that incorporate continuous process confirmation?

[Answer] "Question and Answer Collection (Q&A) regarding 'Guidelines for Pharmaceutical Development,' 'Guidelines for Quality Risk Management,' and 'Guidelines for Pharmaceutical Quality Systems.'" (September 17, 2010, Review Management Division/Monitoring and Guidance As shown in 1.1Q3 of the Narcotics Countermeasures Division Administrative Communication), the process design, process qualification, and daily process confirmation stages of process validation need to be operated throughout the product lifecycle. During implementation, it should be stated in the validation plan that continuous process confirmation will be applied. In addition, data obtained through continuous monitoring can be used to verify process consistency and to check product quality throughout the product lifecycle.

GMP13-53 (continuous process confirmation) [Question] Is process validation of 3 lots on a commercial production scale necessary for manufacturing processes that have introduced continuous process confirmation?

[Answer] For manufacturing processes that have introduced continuous process confirmation, process validation of three lots on a commercial production scale is not necessarily required.

GMP13-54 (continuous process confirmation) [Question] How should process validation be performed for a product that consists of a series of manufacturing processes in which continuous process confirmation has been introduced and manufacturing processes in which it has not been introduced?

[Answer] Continuous process verification is applied to each manufacturing process based on the control strategy for drug product development. Continuous process confirmation may be included in a series of manufacturing processes. There may be cases where there are some items that are not included. Process validation for such manufacturing processes should be performed in three lots on a commercial production scale, in accordance with conventional validation evaluation methods, for processes to which continuous process confirmation is not applied. The validation evaluation method to be applied to the manufacturing process must be determined in advance in the validation plan.

GMP13-55 (cleaning validation) [Question] To what extent should cleaning validation be implemented in the validation guidelines?

[Answer] Cleaning validation should be carried out keeping in mind the following points.

1. This should be done for all equipment that comes into contact with the product. In dedicated equipment, for manufacturing processes where generation of decomposed products or carryover cannot be ruled out, consideration should be given to degraded residues such as decomposed products.

2. For cleaning methods subject to validation, ensure that the amount of residue remains below the contamination limit considering the lot size of products manufactured thereafter, and reflect the validated cleaning methods in Standard Operating Proceduress, etc. .

3. The validation plan for cleaning validation includes information on the target equipment, procedures, products related to the equipment, acceptable levels, parameters for monitoring and control, testing methods, the manner of samples to be collected, and the collection and collection of the samples. Describe the method of display. The procedure should include sampling locations and time limits for equipment cleaning (dirty hold time and clean hold time). Consider the maximum length (time and/or number of batches) when manufacturing campaigns without cleaning between batches.

Four. The test method should be valid with specificity and sensitivity through analytical method validation so that it can sufficiently detect residues equivalent to the limit value.

Five. Collection methods should include swabbing, rinsing or alternative methods (e.g. direct extraction) as appropriate to detect both insoluble and soluble residues. The sampling method used should be one that allows quantitative determination of the level of residue remaining on equipment surfaces after cleaning.

6. Limits (tolerable residual limits) for residues or contaminants (including cleaning agents) should be set based on standards based on the safety of the product to be manufactured next (see GMP 13-56).

7. When considering procedures for equipment cleaning work and sterilization work (sanitization), if the work requires controlling the number of microorganisms or the amount of endotoxins in the product, or if contamination by microorganisms or endotoxins may be a problem. These should be taken into account.

8. Cleaning validated cleaning procedures should be monitored at appropriate intervals after validation to ensure that the cleaning procedures are effective during normal manufacturing. See GMP 13-60.

9. When residues of raw materials and carryover of contaminants are removed during the purification process, such as in the case of drug substances, the process to be subject to cleaning validation should be determined after assessing the risk of impact on the quality of the drug substance. .

GMP13-56 (cleaning validation) [Question] What should we keep in mind when conducting cleaning validation and setting acceptable residual limits?

[Answer] Manufacturers, etc. should set appropriate residual tolerable limits for each product they manufacture to prevent cross-contamination due to exposure to components of other products or other items.

When setting the allowable residue limit value, since the material properties (solubility, potency, toxicity) etc. of residues or contaminants (including cleaning agents) differ, it is necessary to determine the health hazard to patients based on the principles of quality risk management. Setting values to appropriately control risk.

In addition, properly conduct cleaning validation, record the results, and reflect the validated cleaning method in Standard Operating Proceduress, etc.

Note that the following methods are known for calculating the residual permissible limit value for cleaning validation, and these ideas serve as a reference, but are not limited to these.

・Method using permissible daily exposure (PDE/ADE) or permissible daily intake (ADI)

・Method based on occupational exposure limits (OEL)

・Mixed concentration 10ppm or less

・1/1000 of the minimum daily dose

Please also refer to the following related documents:

・“Q&A regarding API GMP guidelines” (Administrative communication from the Monitoring and Guidance/Narcotics Control Division, March 8, 2016), 4. Structural equipment – containment

・GUIDELINE ON SETTING HEALTH BASED EXPOSURE LIMITS FOR USE IN RISK IDENTIFICATION IN THE MANUFACTURE OF DIFFERENT MEDICINAL PRODUCTS IN SHARED FACILITIES, PI 046-1, PIC/S

・QUESTIONS AND ANSWERS ON IMPLEMENTATION OF RISK‐BASED PREVENTION OF CROSS‐CONTAMINATION IN PRODUCTION AND 'GUIDELINE ON SETTING HEALTH‐BASED EXPOSURE LIMITS FOR USE IN RISK IDENTIFICATION IN THE MANUFACTURE OF DIFFERENT MEDICINAL PRODUCTS IN SHARED FACILITIES', PI 053‐1, PIC /S

・AIDE-MEMOIRE, INSPECTION OF HEALTH BASED EXPOSURE LIMIT (HBEL) ASSESSMENTS AND USE IN QUALITY RISK MANAGEMENT, PI 052-1, PIC/S

・ICH M7

・"Revision of the guidelines regarding impurities in drug substances for drugs containing new active ingredients" (December 16, 2002, Pharmaceutical Affairs Bureau No. 1216001) (ICH Q3A(R2)))

Please refer to GMP9-18 and GMP9-28 regarding whether equipment can be shared.

GMP13-57 (cleaning validation) [Question] Does cleaning validation need to be repeated three times?

[Answer]

1. Cleaning validation generally requires data from three replicates.

2. Even for new products, if there is reasonable evidence that the properties, such as the amount of residue, are similar to existing products that share manufacturing equipment with respect to cleaning validation, this should be specified in advance in the validation plan. If so, there is no problem in using the cleaning validation results for the existing product. However, it must be confirmed that the new product has the same cleaning effect at least once using the new cleaning method.

3. If the new equipment is structurally similar to the existing equipment and is considered to have the same cleaning effect, if the rationale for this is specified in advance in the validation plan, the cleaning of the equipment There is no harm in using the validation results. However, confirm that the cleaning method has the same cleaning effect at least once.

GMP13-58 (cleaning validation) [Question] In cleaning validation, is it okay to evaluate using only index components based on rational grounds?

[Answer] The purpose of cleaning validation is to ensure that contamination and cross-contamination of products can be sufficiently prevented by performing the work in question. Therefore, when selecting components to serve as indicators, consider the solubility of each component, difficulty in removal by the relevant cleaning method, residual limit, physiological activity, dosage, content, etc. to achieve the objective. It is necessary to verify that it can be done. The basis for selecting indicator components, the basis for setting residual limits for indicator components, etc. should be clearly stated in the validation implementation plan in advance.

GMP13-59 (cleaning validation) [Question] How should shared manufacturing equipment equipped with automatic cleaning systems that have undergone cleaning validation and established cleaning methods be managed on a daily basis?

[Answer] In addition to conducting daily management in accordance with the procedures for sanitary management of structures, equipment, and personnel that reflect the knowledge obtained through cleaning validation (see GMP 8-4), we also ensure that the cleaning procedures that underwent cleaning validation are effective during normal manufacturing. Monitoring should be performed at appropriate intervals after validation to ensure that See GMP 13-60. Additionally, instruments used for cleaning work should be calibrated regularly.

Furthermore, if you plan to change the cleaning method or other operations, "validation at the time of change" must be carried out.

GMP13-60 (cleaning validation) [Question] What test methods should be used for cleaning validation and daily management?

[Answer] Verify that the test method used for cleaning validation is sufficient to achieve its purpose and has appropriate detection sensitivity even when the residue or contaminant being tested is below the limit value. It is necessary to do so. Visual confirmation may also be substituted for quantitative testing if these points are met. In addition, visual confirmation may be used in daily management.

In the case of visual confirmation, it is necessary to take appropriate measures in advance, such as systematic implementation of education and training, to prevent variations in evaluation among observers.

GMP13-61 (cleaning validation) [Question] When using detergents (surfactants) to clean manufacturing equipment, is it necessary to check whether detergent components remain?

[Answer] When cleaning with detergents, it is necessary to confirm through quantitative tests during cleaning validation that there are no residual detergent components using the specified cleaning method (rinsing, etc.). When using detergents that are easy to remove, visual confirmation after drying may be used as long as the conditions of GMP13-60 are met and the residual limit value can be sufficiently detected by visual confirmation.

GMP13-62 (cleaning validation) [Question] Regarding the cleaning validation of multiple manufacturing equipment from preparation to filling in the manufacturing process of products related to internal liquids, the concentration of residues or contaminants in the final cleaning solution is below the limit value using the rinsing method. Is it correct to think that it is sufficient to confirm that this is the case?

[Answer] Regarding the sampling method for cleaning validation, it is preferable to collect samples directly from the equipment surface (swab method). However, if the validity of the rinsing method has been verified by the swab method, etc. by disassembling and cleaning it in advance, there is no problem in using the rinsing method. See GMP 13-55.

GMP13-63 (cleaning validation) [Question] There are multiple manufacturing facilities with the same specifications that manufacture the same product. Can the results of cleaning validation for one manufacturing facility be used for cleaning validation for other manufacturing facilities?

[Answer] When conducting cleaning validation for manufacturing equipment with the same specifications, it is acceptable to use cleaning validation data for one manufacturing equipment for cleaning validation for other manufacturing equipment. The rationale should be clearly stated in the validation plan in advance.

revalidation

GMP13-64 (revalidation) [Question] Validation Guidelines 2(5)④ states, “The necessity, timing, and items for revalidation include the equipment, equipment, or system, manufacturing process, cleaning work, or product manufacturing frequency related to testing and inspection. In addition, for products related to pharmaceuticals, stability monitoring evaluation pursuant to the provisions of Article 11-2, Paragraph 1, Item 4 and Article 21-2, Paragraph 1, Item 4 of the GMP Ministerial Ordinance, and Article 11 of the same Ordinance. 3.It should be determined by the manufacturer, etc. based on the results of product quality inspection, etc. pursuant to the provisions of Paragraph 1, Item 1.'' However, I would like to see examples where revalidation may be deemed unnecessary.

[Answer] Regarding the manufacturing process of non-sterile pharmaceuticals, if it is determined that there are no problems with the product quality inspection results and no events that affect the reproducibility of the process are observed, revalidation must be performed. There is no problem. However, if equipment requirements change due to process changes, qualification must be performed. On the other hand, with regard to processes related to sterility assurance of sterile pharmaceuticals, periodic revalidation is carried out regardless of the results of product quality inspections, as the operational performance of the manufacturing process may directly affect product quality. thing.

GMP13-65 (revalidation) [Question] When implementing a sterilization process based on a terminal sterilization method (for example, moist heat sterilization including high-pressure steam sterilization), even if the temperature distribution of the sterilizer has already been confirmed in an unloaded state as part of the equipment performance, Is revalidation necessary?

[Answer] It is necessary. In the moist heat sterilization process, heat distribution tests under load and heat permeability tests are conducted to ensure that the temperature and time of all objects placed in the sterilizer satisfy the sterilization conditions stipulated by the Japanese Pharmacopoeia. Must be verified through testing. For other terminal sterilization methods, please refer to the "Guidelines for the manufacture of sterile pharmaceuticals using terminal sterilization methods" and the latest editions of related guidelines.

GMP13-66 (validation when changing) [Question] How should validation be performed for products that are subject to quality re-evaluation?

[Answer]

1. For products that are subject to quality re-evaluation, it is necessary to confirm the quality in response to the review of dissolution properties. Therefore, for products for which process validation has not been performed regarding dissolution properties, process validation should be performed for each product once an official dissolution test method has been established.

2. If dissolution is to be changed due to a change in formulation or manufacturing method, the process that affects dissolution (coating process, etc.) must be understood at the study stage, and the manufacturing method for commercial production must be established and the dissolution Perform process validation with respect to performance.

3. Regarding quality re-evaluation, please refer to "Regarding the implementation of re-evaluation regarding the quality of ethical drugs" (Ipaku No. 634, July 15, 1998).

GMP13-67 (validation when changing) [Question] Are there any regulations regarding the number of lots for process validation to be carried out as validation at the time of change? If it is possible to verify by manufacturing one lot based on the manufacturing conditions of similar products, is it okay to manufacture only one lot?

[Answer] From the viewpoint of reproducibility, process validation of three lots is required in principle. However, if it can be reasonably explained based on knowledge related to similar products that it is predicted that the changes will not affect the quality of the product, the basis for this can be clearly stated in the validation plan in advance, so that concurrent Validation (3 lots in principle) may be accepted.

GMP13-68 (validation when changing) [Question] If the raw materials, materials, procedures, manufacturing equipment, etc. are the same, but only the lot size is changed, is it necessary to perform validation at the time of the change?

[Answer] Even if the raw materials and other conditions are the same, if changing the lot size may affect quality, validation should be performed at the time of the change. In addition, if the standard preparation amount or lot size is specified in the manufacturing and marketing approval document, the change may affect product quality or regulatory approved information as specified in Article 14, Paragraph 1, Item 2 of the GMP Ministerial Ordinance, or Since there is a high possibility that this will be the case, please consult with the marketing authorization holder regarding the necessity of applying for partial change approval (notification of minor changes if applicable) when making changes.

GMP13-69 (validation of manufacturing support system) [Question] Of the validation of "devices or systems that support manufacturing," to what extent should validation be carried out for devices or systems that supply water for manufacturing?

[Answer] Validation of equipment or systems that supply manufacturing water should be carried out to ensure that the manufacturing water produced by the equipment or system consistently satisfies the intended quality standards at all points of use. to do. Furthermore, the quality of raw water should be checked periodically.

GMP13-70 (Validation of manufacturing support system) [Question] Do qualification evaluations and cleaning validation of manufacturing equipment shared by multiple products, such as manufacturing support systems, have to be performed for each product?

[Answer] For manufacturing equipment that is shared in the manufacturing of multiple products, it is not necessarily necessary to perform qualification evaluation and cleaning validation for each product, and it is fine to perform these for each manufacturing equipment. In addition, before implementation, the rational basis for grouping, etc. should be specified in the validation plan in advance.

GMP13-71 (Validation of manufacturing support system) [Question] If the equipment or system for supplying water for production or the equipment or system for air conditioning in the workplace is subject to daily process control by specifying items, locations, timings, etc. to be monitored, are regular Is qualification assessment necessary?

[Answer] Apart from daily monitoring, periodically confirm that there are no problems with the suitability of equipment or systems and the calibration of measuring instruments. Furthermore, equipment or systems that support manufacturing related to sterility and non-pyrogenicity should be periodically revalidated. However, if all equipment or system qualification items have been confirmed and documented during "monitoring" in the case of the question, there is no need to conduct it again.

GMP13-72 (Validation of manufacturing support system) [Question] Regarding the validation of equipment or systems for air conditioning in workplaces, to what extent should validation be carried out?

[Answer] Considering the characteristics of the intended "equipment or system for air conditioning in a workplace," it is possible to permanently guarantee the expected quality of the air supplied by the "equipment or system." Implement to a certain degree.

Special provisions for application of validation guidelines

GMP13-73 (Special application of validation guidelines) [Question] When undergoing a pre-approval GMP compliance survey for a product that is subject to national certification, is it necessary to perform validation in the same way as for other pharmaceutical products?

[Answer] It is necessary. However, as stated in Validation Guidelines (7), the Minister of Health, Labor and Welfare has designated the product as requiring certification based on the provisions of Article 43, Paragraph 1 of the Act on Ensuring the Quality, Efficacy, and Safety of Pharmaceuticals and Medical Devices, etc. Regarding the validation of products related to pharmaceuticals, etc. (Ministry of Health and Welfare Notification No. 279 of 1968), the quality risks of the product are identified and evaluated, without necessarily following the validation guidelines. It is said that there is no problem in using an appropriate method based on the results.

GMP13-74 (Special application of validation guidelines) [Question] Regarding products related to pharmaceuticals that use opiate drugs as raw materials, Validation Guideline (7) states, ``Not necessarily based on this Validation Guideline, but using appropriate methods based on the results of identifying and evaluating the risks of the product. However, what should be done specifically?

[Answer]

1. For pharmaceutical products that use opium narcotics as raw materials, from the perspective of appropriate management of supply and demand of opium narcotics raw materials under the Narcotics and Psychotropic Substances Control Act, etc., this is conducted when undergoing a pre-approval GMP compliance survey. It is not required to carry out process validation for the manufacturing process. However, "qualification evaluation" must be conducted (for "qualification evaluation", the method of setting operating conditions etc. with reference to the confirmation results related to similar products, and the use of dummies with similar physicochemical properties) There are methods to check the validity of the conditions, etc.).

2. Confirmation of manufacturing procedures, etc., such as production support systems, cleaning operations, etc., that will not interfere with the supply and demand of opium-based drug raw materials should be conducted. Furthermore, after approval for manufacturing and sales, measures deemed necessary to ensure quality should be taken, such as verifying the stability and validity of the process through product quality checks and implementing concurrent validation.

GMP13-75 (Special application of validation guidelines) [Question] The main testing items stipulated in the Japanese Pharmacopoeia for ethanol extract preparations of crude drugs, such as bitter tinctures, are confirmation tests and alcohol content. How should the uniformity of content be evaluated and determined in the manufacturing process of pharmaceutical products for which clear standard values for crude drug extract content have not been indicated?

[Answer] In the case of the question, in addition to the "alcohol content," the manufacturer should set the extract content and other specifications as much as possible before making an evaluation. Furthermore, the obtained product must meet all the items of the Japanese Pharmacopoeia Standards. In addition, if there is no quantitative method for determining the uniformity of herbal medicine extracts in light of the current state of the art, it may be necessary to confirm that no matter which part of the product is sampled and a confirmation test is performed, the result will be positive. There is no harm in verifying it.

GMP13-76 (Validation of SP packaging or PTP packaging for tablets and capsules from filling to packaging) [Question] What is the appropriate way to handle validation of the process from filling to packaging, such as SP packaging or PTP packaging for tablets and capsules?

[Answer] The basic idea regarding handling performance qualification (PQ)/process validation is as follows.

PTP packaging will be described below as an example, but SP packaging is handled in the same way as PTP packaging. Targeted processes include the PTP filling process alone using a PTP packaging machine (blister packaging machine), as well as the PTP filling process and packaging process using a pillow packaging machine, cartoning machine, etc. This also includes cases where this is done consistently.

The quality of the final product consists of the following three points.

1. Quality of tablets, capsules, etc. (hereinafter referred to as "tablets, etc.") to be injected

2. The quality of the filling condition, such as damage such as cracks, chips, etc., and stains on tablets, etc.

3. Packaging quality (the correct number of tablets, etc. are filled and properly sealed, etc.)

1. is verified through process validation of the formulation process, and 2. and 3. is verified through appropriately configured continuous monitoring and process controls of the filling and packaging process.

Furthermore, based on the results of stability evaluation, there is no impact on product quality due to exposure to the process work environment from the time the tablets, etc. are loaded into the packaging machine until the filling is completed. It is necessary to be able to guarantee that.

Regarding PTP packaging and SP packaging of tablets, etc., the following two points can be considered, so manufacturers can determine the necessity of process validation according to the characteristics of the product, including the packaging form.

・The quality of the preparations to be filled (content, dissolution, etc.) has already been determined in the formulation process, and the quality risks that may occur over time due to the operation of this process (when packaging preparations such as powders) (segregation, etc.) is generally low.

- The process has large mechanical elements (molding, sealing, slitting, stamping, punching, inspection, etc.), and the main task is to fill tablets, etc. of confirmed quality into packaging containers.

In addition, regardless of whether process validation is implemented, 1. as shown in GMP13-78. ～4. It is necessary to obtain knowledge, etc.

GMP13-77 (Validation of SP packaging or PTP packaging for tablets and capsules from filling to packaging) [Question] In the performance qualification (PQ) of the process from filling to packaging of SP packaging or PTP packaging for tablets and capsules, is it conducted without using packaging materials labeled for active drug or commercial production? Is it okay?

[Answer] Based on the concept shown in GMP13-76 and the [Concept for formulations and packaging materials used in performance qualification (PQ)] shown below, based on quality risk management, Performance qualification (PQ) may be performed using packaging materials that mimic the Furthermore, depending on the item to be evaluated, it is also possible to evaluate without using a preparation (actual drug or simulant). For performance qualification (PQ) lot scales, see GMP 13-46.

[Concept of formulations and packaging materials used in performance qualification (PQ)]

Depending on the quality item being evaluated, a drug product can be evaluated using a simulant instead of the active drug, or without using either the active drug or the simulant. However, for areas where there is a possibility that different behavior may be exhibited on the manufacturing line due to the difference between the actual drug and the simulated drug (e.g., preparation transportation, filling area, etc.), it is desirable to evaluate using the actual drug. Furthermore, since packaging materials for commercial production are generally not available at the time of performance qualification (PQ), packaging materials that mimic those for commercial production are often used. If active drugs or packaging materials for commercial production are not used, an explanation that the evaluation can be made without the use of these materials is required.

GMP13-78 (Validation of SP packaging or PTP packaging for tablets and capsules from filling to packaging) [Question] Is it acceptable that the performance qualification (PQ) and process validation of the process from filling to packaging for SP packaging or PTP packaging for tablets and capsules and the implementation scale or operating time must be on a commercial production scale?

[Answer] Based on the concept of performance qualification (PQ)/process validation shown in GMP13-76, a standard commercial production scale does not necessarily exist due to the characteristics of the process. ) Regardless of the scale, based on the knowledge below, perform performance qualification (PQ)/process validation by running the filling/packaging line at least from the start of operation (work start) to stable operation. If it can be verified, it may be possible to adopt the idea that quality can be guaranteed even if the product is operated continuously for a long time beyond the operating time.

1. Knowledge regarding the quality characteristics (including stability evaluation) of the drug concerned

2. Knowledge about the quality of filling conditions such as cracks, chips, etc. damage and stains on tablets, etc.

3. If airtightness significantly affects the quality of the drug product, knowledge regarding the packaging quality related to airtightness of SP packaging or PTP packaging evaluated at the stage up to performance qualification (PQ).

Four. Knowledge regarding the characteristics of the manufacturing equipment based on the manufacturing experience of the relevant filling/packaging line or similar filling/packaging lines.

However, based on the results of performance qualification (PQ)/process validation, it is necessary to specify the items, methods, or scope of control for continuous monitoring or process control during commercial production.

In addition, if it is predicted that quality risks will increase when restarting a filling/packaging line after it has been stopped or when switching packaging materials, performance qualification (PQ)/process shall be conducted with such work as the worst case. It is an effective means to import and verify data during validation.

When implementing the process based on the above-mentioned concept, it is acceptable to implement the process on a lot (batch) scale or at the minimum operating time, which can be determined to be guaranteed even if the system is operated for a long time.

In addition, based on the results of performance qualification (PQ), etc., by identifying items, methods, control ranges, etc. for continuous monitoring or process control during commercial production, it is possible to Process validation can be omitted if it can be scientifically demonstrated in documentation that product quality, including labeling, can be guaranteed.

GMP13-79 (Validation of SP packaging or PTP packaging for tablets and capsules from filling to packaging) [Question] Does performance qualification (PQ) of the process from filling to packaging of SP packaging or PTP packaging for tablets and capsules have to be repeated three times in principle?

[Answer] Based on the concept of performance qualification (PQ)/process validation shown in GMP13-76 and the [concept of repetition of performance qualification (PQ)] shown below, what is necessary for performance qualification (PQ)? The number of lots can be determined appropriately according to varying factors such as accumulated knowledge and important parameters. When analyzing variation factors, statistical methods should be used as necessary.

[Performance qualification (PQ) repetition concept]

1 shown in GMP13-78, which was basically evaluated at the stage up to performance qualification (PQ). ～4. The number of repetitions of performance qualification (PQ) is set based on the knowledge of Further, the number of repetitions may be changed depending on the quality item to be evaluated.

GMP13-80 (Validation of SP packaging or PTP packaging for tablets and capsules from filling to packaging) [Question] Regarding the process from filling to packaging of SP packaging or PTP packaging for tablets and capsules, what items should be prepared for pre-approval GMP compliance investigation?

[Answer] At the time of pre-approval GMP compliance investigation, it is necessary to prepare the following items.

・Qualification evaluation of processes from filling to packaging (OQ, PQ, etc.)

・Process validation report or basis for determining that products of sufficient quality can be consistently manufactured even if process validation is not completed

・Documents necessary for manufacturing processes from filling to packaging (manufacturing procedures, process control procedures, etc.) or their drafts

Furthermore, "grounds for determining that products of sufficient quality can be consistently manufactured even if process validation has not been completed" is defined in 1. of GMP13-78. ～4. Based on the knowledge of This refers to scientifically demonstrating that product quality, including labeling, can be guaranteed.

GMP13-81 (validation (other)) [Question] Will the concept of retrospective validation, in which test and inspection results and manufacturing records accumulated for well-established manufacturing processes are analyzed using statistical methods, etc., be accepted in the future?

[Answer] Retrospective validation was provisionally allowed when validation standards were introduced, and there is currently no opportunity to conduct retrospective validation.

GMP13-82 (validation (other)) [Question] How should process validation be performed when it is difficult to keep the lot size constant due to manufacturing reasons such as order-made production?

[Answer] Generally, changes in lot size are considered to have an impact on process variation factors and, ultimately, product quality, so validation must be performed at the time of change. First, evaluate the degree to which the manufacturing process depends on lot size, and if the manufacturing process does not depend on lot size but is expected to fluctuate on a daily basis, process validation ( In principle, it may be possible to take measures by conducting 3 lots of each product and confirming equivalence within that range. In addition, in processes that depend on lot size, it is necessary to limit the fluctuation range of lot size or divide the lot size range into several parts and adjust the operating parameters for each, and then perform separate process validation. be.

GMP13-83 (validation (other)) [Question] If Manufacturer A manufactures the bulk drug product and Manufacturer B performs the filling, packaging, and labeling processes, ① If only the processes performed by Manufacturer B are transferred to another manufacturer, ② If manufacturing and sales approval is transferred without changing the processes performed by both manufacturers, is it necessary to perform validation at the time of change in either of the above?

[Answer] In the case of question 1, process validation should be performed for the transferred process at the manufacturing site of "another manufacturer." In the case of question ②, there is no need to perform validation at the time of change in principle, but the GMP organizational structure, etc. should also be considered.

GMP13-84 (validation (other)) [Question] What kind of specific content should be carried out in the validation of products related to sterile preparations?

[Answer] It is important to ensure sterility and non-pyrogenicity in the manufacturing process of products related to sterile preparations such as injections, eye drops, eye ointments, and water for injection (limited to formulations). Regarding the handling of reference information deleted due to the enactment of the Second Supplement to the Pharmacopoeia” (June 28, 2019, Pharmaceutical Evaluation and Management Division/Supervision and Guidance/Narcotics Countermeasures Division Administrative Communication) and PIC/S GMP guidelines, etc. Please refer to the guidelines and implement them appropriately.

GMP13-85 (validation (other)) [Question] Should process validation also be performed for the packaging labeling process?

[Answer] In general, for the packaging process (excluding primary packaging) and labeling process, if the suitability of the expiration date, printing of lot numbers, inclusion of package inserts, etc. is confirmed separately, process validation is not necessarily required. There is no need to do so.

GMP13-86 (validation (other)) [Question] If only the name of the manufacturer, etc. listed in the manufacturing method column of the manufacturing and sales approval (notification) document has changed due to a corporate merger, etc., please review the process for important processes at the manufacturing site of the manufacturer, etc. after the change. Is it necessary to perform validation?

[Answer] If the GMP system has not changed and documents and records have been inherited as in the question, if process redaction has been carried out by the manufacturer, etc. before the name change and constancy has been ensured, the structures, equipment, and Unless there are changes in procedures, processes, or other manufacturing control and quality control methods, there is no need to perform process validation again.

GMP13-87 (validation (other)) [Question] If you intend to manufacture and sell a drug that has already been manufactured and sold after receiving manufacturing and sales approval with a new name that is different from the current name, process validation will be conducted for important steps of the product related to the drug with the new name. Do you need to?

[Answer] Unless there are changes in the structure and equipment of the manufacturing facility, procedures, processes, and other manufacturing control and quality control methods, process validation has already been completed for products related to "drugs that have already received manufacturing and marketing approval and are being manufactured and sold." If it has been carried out, there is no need to perform process validation again for products related to "drugs with new names." However, if there is a change in the marking or shape of the tablet, it is necessary to perform process validation again after that step.

GMP13-88 (validation (other)) [Question] Is it possible to request another company to perform validation?

[Answer] Under the responsibility of the manufacturer, etc. and the person in charge of validation, the scope of work to be outsourced to "other companies" is clarified, and the validation master plan includes general matters and is created for each individual validation. After stipulating specific matters in the plan, it is acceptable to outsource some of the validation work, such as analysis and statistical processing, to ``other companies.''

GMP13-89 (validation (other)) [Question] For products manufactured under the same manufacturing conditions for the purpose of validation, in addition to lots that underwent process validation, after manufacturing and sales approval, confirmation is made that these products are manufactured according to the manufacturing method stated in the approval document. Is it permissible to ship products to the market after appropriately determining whether or not they can be released from the manufacturing site, such as by confirming that they comply with the standards?

[Answer] In addition to lots that have undergone process validation, lots manufactured through performance qualification (PQ) may also be approved for shipment. In this case, in addition to the conditions in the question, the manufacturing conditions have been determined in the same way as for the lot that underwent process validation, and the standards for shipping have been set in the validation plan in advance, and the verification results indicate that the manufacturing conditions are met. If this is confirmed, shipment will be approved.

GMP13-90 (validation (other)) [Question] If multiple manufacturers are preparing and seeking approval for a drug as an active ingredient in order to reduce risks to the stable supply of drugs, is the manufacturing facility that manufactures the drug product subject to pre-approval GMP compliance inspection? Is it necessary to perform process validation using drug substances from all multiple manufacturers?

[Answer] Regarding drug substances from manufacturers that are not scheduled to be supplied at the time of approval, for example, the equivalence of the formulation and the manufacturing method and standards for formulation, taking into account the presence of crystal polymorphs, differences in solvents, and differences in manufacturing methods. Process validation is not required at the time of investigation, etc. in cases where the impact on etc. has been confirmed through laboratory-scale verification, PQ, etc.

改正GMP省令　Article 14　Changes control

GMP14-1 (Changes control) [Question] When changing the manufacturing location, manufacturing method, etc. at a manufacturing facility, is it necessary for the manufacturer, etc. to contact the marketing authorization holder?

[Answer] Based on the agreement with the marketing authorization holder, if there is a possibility that the product quality or regulatory approved information will be affected or may be affected, as stated in Section 22(1)② of the Notification of Promulgation of the Revised Ministerial Ordinance, Advance notice is required. It is desirable that the agreement includes criteria that take the above into account.

The above also applies to foreign drug substance manufacturers that have received MF registration, but based on the agreement with the manufacturer, the MF domestic administrator may contact the manufacturer in advance. It is possible. In this case, care must be taken to ensure that notification of changes is made without delay. For details, please also refer to the GQP Ministerial Ordinance and related notifications.

GMP14-2 (Changes control) [Question] In change management, what should we keep in mind regarding the impact on approval items?

[Answer] Examples include the following cases.

1. Manufacturers, etc. should obtain the latest approval information and confirm whether the changes may affect the approval items. Domestic manufacturers with MF registration should also refer to the latest version of their MF registration to confirm the impact of the change. Foreign drug substance manufacturers who have received MF registration should also obtain the latest registration information from the MF domestic administrator, etc., and confirm the impact of the change. (Refer to GMP3 2-1 for handling of regulatory approved information in case of MF registration.)

2. The impact on approval items shall be evaluated by the organization in charge of operations related to the quality assurance department.

GMP14-3 (Changes control) [Question] Please indicate the matters that should be kept in mind regarding contacting and confirming with manufacturers and distributors in change management.

[Answer] Examples include the following cases.

1. The matters to be contacted and confirmed with the marketing authorization holder, as well as the method and responsible person, etc., shall be specified in the agreement, etc. with the marketing authorization holder.

2. For changes that may affect product quality or regulatory approved information, the criteria for judgment should be established in the agreement with the marketing authorization holder so that the authorization can be appropriately communicated and confirmed to the authorization holder.

3. In order to properly contact and confirm with the manufacturer, 1. and 2. Arrangements should also be made to review this as necessary.

Furthermore, it is important that the above-mentioned reports be made in a timely manner by the manufacturer, etc. to the marketing authorization holder based on the agreement.

GMP14-4 (Changes control) [Question] Please tell us about the matters that should be kept in mind regarding change management.

[Answer] Examples of matters that should be generally kept in mind regarding change management include the following:

1. All GMP-related changes must be drafted by the appropriate department and approved by the organization responsible for quality assurance activities.

2. The procedures for managing changes in Article 14 of Article 8, Paragraph 1, Item 10 of the GMP Ministerial Ordinance shall include the following matters:

(1) In assessing the impact on product quality under Article 14, Paragraph 1, Item 1 of the GMP Ministerial Ordinance, the need for revalidation and the need for additional tests and inspections necessary to justify changes should be evaluated. to include.

(2) The evaluation method and evaluation criteria for product quality after the change shall be determined in advance before the change.

(3) Determine in advance the methods for revising or abolishing documents related to the change and for educating and training staff, and ensure that such document revisions and abolition and education and training are carried out reliably.

(4) As other necessary measures under Article 14, Paragraph 1, Item 4 of the GMP Ministerial Ordinance, check in advance whether or not there is a need to revise standards, test and inspection methods, expiration dates, expiration dates, retest dates, and labeling before making any changes. Decide.

(5) Evaluate the impact on regulatory approved information.

3. After implementation of the change, evaluation pursuant to Article 14, Paragraph 2, Item 1 of the GMP Ministerial Ordinance shall cover multiple lots starting from the first lot manufactured or tested under the change.

In addition, in order to clarify change management procedures and practices, the following materials should also serve as a reference for establishing an effective pharmaceutical quality system.

・How to Evaluate and Demonstrate the Effectiveness of a Pharmaceutical Quality System in relation to Risk-based Change Management, PI 054-1, PIC/S

GMP14-5 (Changes control) [Question] Article 14, Paragraph 1, Item 5 of the GMP Ministerial Ordinance states that "the implementation status of the tasks listed in each of the preceding items must be reported in writing to the organization in charge of quality assurance-related tasks and the The manufacturing supervisor." However, is it necessary for The manufacturing supervisors to report each time change management is implemented, just like organizations responsible for quality assurance-related work?

[Answer] Organizations in charge of work related to quality assurance need to understand the implementation status of individual work in a timely manner. On the other hand, The manufacturing supervisors do not necessarily need to receive reports on the implementation status of change control projects each time, as long as it does not interfere with the operations stipulated in Article 5 of the GMP Ministerial Ordinance. For example, in consideration of the degree of impact or risk of impact on product quality or regulatory approved information, standards for change control cases that should be reported each time and change control cases that should be reported periodically are set in advance to The manufacturing supervisors. It may be possible to stipulate this in a Standard Operating Procedures, etc., and report to the The manufacturing supervisor at an appropriate time accordingly.

改正GMP省令　Article 15　Management of deviations

GMP15-1 (Management of deviations) [Question] Article 15, Paragraph 1 of the GMP Ministerial Ordinance states that "in the event of deviation from manufacturing procedures, etc.", how should we consider the concept of "deviation"?

[Answer] In No. 3-23(1)① of the Notification of Promulgation of the Revised Ministerial Ordinance, it is stated that ``the structure and equipment of the manufacturing facility shall be A deviation is defined as "when procedures, processes, and other manufacturing control and quality control methods are not maintained in the expected state."

GMP15-2 (deviation control) [Question] Article 15, Paragraph 1, Item 1 of the GMP Ministerial Ordinance states that "the effects of deviations shall be investigated." What kind of matters are included in this investigation of effects?

[Answer] The purpose of the investigation here is to identify the impact on product quality, but it is important to clarify the severity of the impact, the items affected, and their quantities. be. Depending on the cause of the deviation, it may affect not only the manufacturing lot where the deviation occurred, but also the manufacturing lots of the same item or other items manufactured in the past. Additionally, for lots for which an impact has been confirmed or determined to be undeniable, measures such as eliminating defects in the lot or canceling shipment or use are required. In addition, in order to accurately understand the impact on product quality, it is considered necessary to identify the cause of the deviation.

GMP15-3 (deviation control) [Question] Article 15, Paragraph 1, Item 2(b) of the GMP Ministerial Ordinance states that in the event of a significant deviation, the manufacturer of the product related to the deviation shall be promptly notified. What should we keep in mind when doing so?

[Answer] "When a serious deviation occurs" refers to a case that is determined to be serious based on the results of the investigation under Article 15, Paragraph 1, Item 1 of the GMP Ministerial Ordinance. "Products related to the deviation" refers to the product lots that were identified in the investigation as being affected by the deviation, and after promptly identifying the affected area, the manufacturer and distributor related to the product lot We request that you contact us.

Furthermore, regarding deviations that occur in common equipment and facilities such as utilities and warehouses, related manufacturers should also be notified based on their respective agreements.

GMP15-4 (deviation control) [Question] When deviations from manufacturing procedures, etc. occur, is it necessary to implement CAPA for all deviations?

[Answer] As per Article 15, Paragraph 1, Item 2, C of the GMP Ministerial Ordinance, if a significant deviation occurs, the necessary CAPA should be taken. For other deviations, it is desirable to consider CAPA based on the results of impact studies. In either case, evaluate the effectiveness of CAPA after implementation. Regardless of whether or not CAPA is implemented, the results of the impact investigation of deviations that occur must be reported in writing to the organization in charge of quality assurance activity, pursuant to Article 15, Paragraph 1, Item 1 of the GMP Ministerial Ordinance. There is a need to.

改正GMP省令　Article 16　Processing of quality information, quality defects

GMP16-1 (quality information, etc.) [Question] What does "information regarding quality, etc. (hereinafter referred to as "quality information")" in Article 16, Paragraph 1 of the GMP Ministerial Ordinance specifically refer to?

[Answer] Quality information is provided by manufacturers, users, medical institutions, suppliers of raw materials, other manufacturers, and related information overseas (overseas regulatory authorities and academic societies related to the product, similar products, manufacturing processes, etc.). information, or if the manufacturer has requested an investigation regarding the quality information from overseas product manufacturers or formulation manufacturers of the drug substance, and has received a report on the cause investigation and the results of CAPA, etc. A system must be established to appropriately obtain related information, such as quality information obtained from manufacturers, etc.

GMP16-2 (quality information, etc.) [Question] If a company decides to initiate a voluntary recall after obtaining information on the quality of the product from the exporter of the product, is a recall report necessary?

[Answer] Report in accordance with the provisions of Article 68-11 of the Act and Article 228-22 of the Enforcement Regulations.

GMP16-3 (quality information, etc.) [Question] If a quality defect or a risk thereof is found, is there an obligation to report it to the manufacturing license holder?

[Answer] Determine based on the content of quality information. Quality information may also be closely related to efficacy and safety, and manufacturers must comply with the GQP Ministerial Ordinance or the Ministerial Ordinance on Standards for Post-Marketing Safety Management of Cosmetics and Medical Devices (September 22, 2004). After taking appropriate measures based on the provisions of Ministry of Health, Labor and Welfare Ordinance No. 135 (GVP Ministerial Ordinance), if it falls under Article 68-10 of the Act (reporting of side effects, etc.), please notify the Minister of Health, Labor and Welfare, and If Article 68-11 (report of recall) applies, a report must be made to the Minister of Health, Labor and Welfare or the prefectural governor (Article 228-22 of the Enforcement Regulations).

GMP16-4 (quality information processing) [Question] In the Revised Ministerial Ordinance Promulgation Notice No. 3-24(1), it is stated that "quality information regarding a product shall include information regarding the quality of raw materials used in the manufacture of the product." Is it okay to handle quality information regarding defects during the manufacturing of raw materials, etc. under the category of "deviation management"?

[Answer] No problem.

GMP16-5 (quality information processing) [Question] In 24(1)② of the Revised Ministerial Ordinance Promulgation Notice, it states, ``Except in cases where it is clear that the matter related to the quality information is not caused by the manufacturing site, the cause shall be investigated and manufacturing and quality ``If improvements are needed in related operations, necessary Corrective actions and preventive actions must be taken.'' However, what happens when the cause lies in the supplier of raw materials used by the manufacturing facility? Is there a need for some kind of response?

[Answer] If necessary, it is necessary to investigate the cause and give necessary instructions for improvement to suppliers of raw materials, etc., as well as confirm the results.

GMP16-6 (quality information processing) [Question]) Regarding records of "Corrective actions and preventive actions" in Article 16, Paragraph 1, Item 3 of the GMP Ministerial Ordinance, Article 3 of the Notice of Promulgation of the Revised Ministerial Ordinance, Section 24(1)(3), states "Regarding records of Corrective actions and preventive actions." "The measures will be taken gradually in accordance with the progress schedule of the relevant measures." However, if the manufacturer, etc. takes any action, even if the problem is not attributable to the manufacturing facility, such as dirty transportation containers or damage due to user error, etc. If such measures have been taken, should the status of such measures be recorded in the record?

[Answer] As specified in Article 16, Paragraph 1, Item 2 of the GMP Ministerial Ordinance, if the matter is related to quality information that is clearly not attributable to the manufacturing facility, the manufacturer, etc. There is no need to create records containing CAPAs related to quality information. However, the measures taken by the manufacturing facility as a result of their judgment as necessary for manufacturing control or quality control shall be recorded.

GMP16-7 (quality information processing) [Question] Please indicate the scope of matters that should be recorded among the matters related to the obtained quality information. For example, in cases where we received information from the market about symptoms such as nausea, fever, and eczema, and when we conducted quality tests at our manufacturing facility, there were no abnormalities, and as a result, it was clear that the problem was not caused by the manufacturing facility. Is it correct to consider that matters related to quality information that has become a product are not subject to the content of quality information, the results of investigation into causes, and the creation of CAPA records as defined in Article 16 of the GMP Ministerial Ordinance?

[Answer] Record that it has become clear that the problem is not caused by the manufacturing site. For example, since it is possible that the cause is a quality problem that cannot be detected with the accuracy of normal testing and inspection, it is possible that the manufacturer's quality It is extremely important to cooperate with the warranty department and investigate the cause. In addition, if the cause has been investigated by conducting quality testing as in the example in the question, records containing the results of the cause investigation must be created and kept.

GMP16-8 (quality information processing) [Question] Article 16, Paragraph 2 of the GMP Ministerial Ordinance states, ``If a manufacturer, etc. finds a quality defect or a risk of it as a result of the confirmation in item 3 of the preceding paragraph, it shall notify the organization in charge of quality assurance activity of procedures. The relevant matters shall be reported in writing to the The manufacturing supervisor based on the relevant quality information.　Also, promptly contact the manufacturer of the product related to the quality information, and provide information necessary for making a decision on product recall. In addition to taking the necessary measures such as provision of personal information, records related to such measures must be created and kept.'' In what cases does this apply?

[Answer] For example, the following cases may be subject to reporting, but there may be other cases that require response, so it is important to understand them appropriately through arrangements with manufacturers, distributors, etc. .

- Regarding quality information from a manufacturer/seller, if the cause is determined to be due to the manufacturer's own manufacturing facility.

・When information is obtained from suppliers of raw materials, etc.

・When information regarding the product, similar products, manufacturing process, etc. (information from domestic and international regulatory authorities, academic societies, etc.) is obtained.

・When necessary information is obtained due to laws and regulations, issuance of related notices, amendments, etc.

改正GMP省令　Article 17　Processing of recall

GMP17-1 (scope of recall) [Question] Does a return related to quality information constitute a recall?

[Answer] The content of "returned materials related to quality information" is not clear, but it does not necessarily comply with the GMP Ministerial Ordinance for a quality information applicant to receive a product for the basis of the information when providing quality information. This does not fall under " recall " as referred to in Article 17.

GMP17-2 (processing such as recall) [Question] What are the operations related to recall processing carried out by a person designated in advance by the manufacturer, etc. under Article 17 of the GMP Ministerial Ordinance (Processing of recalls, etc.) and the operations performed by the quality assurance manager under Article 12 of the GQP Ministerial Ordinance (Recall processing)? What is the difference?

[Answer] A person designated in advance by the manufacturer, etc. shall carry out work based on the procedures for managing the storage of recovered products at the relevant manufacturing site. The quality assurance supervisor provides instructions to manufacturers, etc. regarding storage, processing, etc. related to recall.

GMP17-3 (storage of products and materials deemed nonconformance) [Question] Article 17, Paragraph 2 of the GMP Ministerial Ordinance states that "the provisions of the preceding paragraph shall apply mutatis mutandis", and raw materials, materials, and products that are deemed nonconformance for use or shipment must be stored separately, but are they stored in a separate room? Do I have to?

[Answer] A separate room is preferable. However, if necessary measures such as systematic implementation of education and training are taken and there are no problems in preventing mix-up, contamination, or cross-contamination, at least physical separation will be made and clearly defined by labeling, delineation, labeling, etc. of each package. There is no problem in storing rejected products in another area of the same room that has been clearly designated as a "rejected product storage area."

改正GMP省令　Article 18　Self-inspection

GMP18-1 (self-inspection) [Question] The self-inspection stipulated in Article 18 of the GMP Ministerial Ordinance is applicable to cases where the manufacturer, etc. who intends to conduct the self-inspection and the marketing authorization holder who manufactures and sells the item related to the product are the same corporation, and the said marketing authorization holder is subject to the GQP Ministerial Ordinance. Is it okay to consider that the periodic confirmation of GMP at a manufacturing facility conducted pursuant to the provisions of Article 10 constitutes self-inspection by the manufacturer, etc.?

[Answer] If the content stipulated in the self-inspection Standard Operating Procedures for the manufacturer, etc. is met, the manufacturer, etc. is responsible for verifying the content through GMP periodic confirmation conducted by the same legal entity, the marketing authorization holder. After approval, it may be substituted for the self-inspection under Article 18 of the GMP Ministerial Ordinance.

GMP18-2 (self-inspection) [Question] Regarding the “pre-designated person” in Article 18, Paragraph 1 of the GMP Ministerial Ordinance, Article 26 (1) of the revised Ministerial Ordinance Promulgation Notice states that “a person from an objective standpoint who is not engaged in work subject to self-inspection” However, if it is unavoidable, is it okay to hire someone from the same department who is involved in the work?

[Answer] Regarding the “pre-designated person” in Article 18, Paragraph 1 of the GMP Ministerial Ordinance, Article 26 (1) of the revised ministerial ordinance promulgation notification No. In cases where it is unavoidable, such as when there is no one other than those in the same department who is familiar with the content of the work that is subject to self-inspection, in relation to the fact that an employee is designated in advance as the person responsible for the self-inspection. As long as they are from the same department, there is no problem. However, even in that case, as stipulated in Article 26 (1) of the Notification of the Promulgation of the Revised Ministerial Ordinance, the employee shall not be engaged in the work that is subject to the self-inspection, and the suitability of the employee shall be evaluated in advance. Things to do.

Additionally, it is preferable that employees conducting self-inspections not be in charge of self-inspections related to the work they are engaged in, but they may be treated in the same way as ``persons designated in advance.''

GMP18-3 (self-inspection) [Question] When conducting periodic self-inspections, is it necessary to conduct and keep records of all the matters stipulated in Section 26(1)① of the Revised Ministerial Ordinance Promulgation Notice each time?

[Answer] It is not necessarily necessary to conduct a self-inspection of all the matters stipulated in Section 26(1)① of the Revised Ministerial Ordinance Promulgation Notice No. 3 every time. If the implementation is to be carried out in several parts, an implementation plan must be prepared in advance to ensure that all the specified items are completed within the specified period, and records must be kept. In addition, The manufacturing supervisors and organizations in charge of quality assurance-related operations must confirm that self-inspections are being conducted, and the results of self-inspections are the responsibilities of manufacturing plant personnel as stipulated in Article 6, Paragraph 4 of the GMP Ministerial Ordinance. In addition, in the management system, report to the manufacturer, etc., or staff members in a position to manage and supervise the manufacturing site, and draw their attention.

GMP18-4 (self-inspection) [Question] As stated in Article 3-26(1) of the Revised Ministerial Ordinance Promulgation Notification, ``If part of the work related to self-inspection is outsourced to an external contractor, appropriate management shall be carried out in accordance with the provisions of Article 11-5 of the said Ordinance. What kind of cases are assumed to be "required," and what should be noted in such cases?

[Answer] For example, it is assumed that the work will be outsourced to an outside expert. Even if the self-inspection is outsourced, the manufacturer, etc. is responsible for conducting the self-inspection. Therefore, the manufacturer, etc. should evaluate the suitability of the external contractor based on the purpose of the self-inspection before entrusting it to the outsourcing company, and report the results of the self-inspection. You need to decide for yourself.

改正GMP省令　Article 19　Education and Training

GMP19-1 (education and training) [Question] I believe that the amount of time for education and training cannot be determined in general depending on the content of the work, but what is the minimum number of hours that should be spent on training?

[Answer] The content of education and training can vary greatly depending on the type of product being manufactured, the content of the work, etc., so it cannot be determined in general. Manufacturers, etc., evaluate the effectiveness and decide on the content, time, timing (if changes to work etc. are planned, make sure to do so with sufficient time before implementing the change), etc. be established and implemented in a planned manner.

GMP19-2 (education and training) [Question] I understand that the term "staff" in Article 19, Item 1 of the GMP Ministerial Ordinance also applies to staff in charge of maintenance, etc., but does it also include workers from outside construction (equipment) contractors?

[Answer] Persons engaged in work that may affect product quality must be provided with education and training, and records of implementation must be kept for five years.

GMP19-3 (education and training) [Question] What does the revised ministerial ordinance promulgation notification No. 3-27(1) ② (a) “GMP overview” and b “hygiene management overview” specifically mean?

[Answer] "GMP Overview" refers to an overview of the purpose, concept, etc. of the GMP Ministerial Ordinance, including related laws and regulations, and "Sanitation Management Overview" refers to an overview of the purpose, concept, etc. of hygiene management stipulated in the GMP Ministerial Ordinance. say.

GMP19-4 (education and training) [Question] Is it necessary to keep teaching materials together with the records of the implementation of education and training pursuant to Article 19, Item 3 of the GMP Ministerial Ordinance?

[Answer] Not necessarily. There is no problem in saving the teaching materials used for education and training so that they can be checked.

GMP19-5 (education and training) [Question] Article 19, Item 4 of the GMP Ministerial Ordinance states that ``the effectiveness of education and training should be regularly evaluated.'' How often should we consider ``regularly'' to be considered? Also, what concrete measures should be taken to "evaluate effectiveness"?

[Answer] Regarding the frequency of education and training, for example, manufacturers can determine the frequency of on-the-job training depending on the type of product being manufactured, the structure and equipment used, etc., depending on the actual situation. In addition, "effectiveness evaluation" refers to evaluating whether the content of education and training is accurately reflected in practice as a manufacturer, etc. (e.g., evaluation using mock operations to confirm changing procedures, etc.) etc).

GMP19-6 (education and training) [Question] Article 19, Item 4 of the GMP Ministerial Ordinance states that ``the effectiveness of education and training should be periodically evaluated and improvements should be made as necessary.'' What kind of evaluation should be used to make improvements?

[Answer] Evaluate whether employees understand and have the ability to perform their duties and responsibilities, and whether the current education and training system is effective, and consider the necessity of updating education and training materials and the frequency of implementation. , consider improvement measures regarding methods, etc.

改正GMP省令　Article 20　Management of documents and records

GMP20-1 (Management of documents, etc.) [Question] Please indicate the points to be noted when creating and revising Standard Operating Proceduress, etc.

[Answer] When creating or revising procedures, etc. as stipulated in the GMP Ministerial Ordinance, manufacturers, etc. must, in accordance with the provisions of Article 20 of the GMP Ministerial Ordinance, approve, distribute, and store the procedures, etc. to a person designated in advance. In addition, the date of creation or revision must be recorded in the Standard Operating Procedures, etc., and the history of previous revisions must be kept. Also, be sure to be able to identify the latest revision status.

Regarding the history of revisions, past revision dates, revised items, etc. must be kept for at least 5 years (if the period of validity of the product related to the Standard Operating Procedures, etc. plus 1 year is longer than 5 years, then the revision history) The period of validity plus one year) must be made retroactive. In addition, if a copy of the Standard Operating Procedures, etc. exists (measures such as identification should be taken to prevent confusion with the original), all necessary measures should be taken, such as distributing and replacing copies at the same time as correcting the original. ensure that the copies are corrected. Furthermore, when abolishing a document, it is necessary to prevent the abolished document from being used against the intended purpose.

GMP20-2 (Management of documents, etc.) [Question] Regarding the storage of manufacturing records and test and inspection records, Article 20 of the GMP Ministerial Ordinance stipulates that they must be stored for a specified period of time, but in view of the capacity of the storage facility at the manufacturing facility, records that have been in use for more than two years. Is it okay to store the information only at the manufacturer's headquarters?

[Answer] In principle, records should be kept at the manufacturing facility within the period specified by the GMP Ministerial Ordinance, but if the records are easily available at the manufacturing facility and are Questions may be used as long as they do not interfere with manufacturing control or quality control. In this case, the rules should be specified in advance in the Standard Operating Procedures, etc., and the product should be stored under the direction and responsibility of the manufacturing department or quality department of the manufacturing facility where the product was manufactured. Also, care must be taken to ensure that there are no hindrances to GMP compliance surveys, etc.

GMP20-3 (Management of documents, etc.) [Question] When storing records related to manufacturing control or quality control on magnetic media, etc., is it acceptable to store them in a computer instead of preserving the original handwritten records?

[Answer] A computerized system that is appropriately managed in accordance with the "Guidelines for Appropriate Management of Computerized Systems for Manufacturing and Distributing Manufacturers" (Pharmaceuticals, Food and Drug Administration No. 1021 No. 11, October 21, 2010) The requirements of the "Guidelines for the Use of Electromagnetic Records and Electronic Signatures Regarding Applications for Permits, etc." (Appendix No. 0401022 of the Pharmaceutical and Food Safety Bureau, April 1, 2005) (hereinafter referred to as the "ER/ES Guidelines") are met. Even if it is decided to store the records under strict conditions, the original "handwritten records" must also be stored separately from the perspective of ensuring data integrity.

GMP20-4 (Management of documents, etc.) [Question] Please provide an example of what constitutes "raw data," which is a record that includes the original data used to obtain the final results and the process that led to the final results.

[Answer] The raw data must be such that it can be verified that the final results were obtained correctly. For example, raw data related to testing and inspection includes the following:

1. Data output from measuring equipment using print function

2. A chart output from a recorder or a record of read values

3. A written down of the value displayed on a measuring device

Four. A record of observations

Five. A file that electronically records waveform data such as charts

6. photograph

7. A record of the process of calculation, conversion, etc. using the above data, etc.

Furthermore, from the perspective of data integrity, "raw data" should be stored so that it can be used in the state in which it was obtained.

Use of computers, etc.

GMP20-5 (computer use, etc.) [Question] Does “instructions in writing” stipulated in the GMP Ministerial Ordinance include instructions in electronic media using a computerized system, etc.?

[Answer] That understanding is fine. Furthermore, the content of instructions in electronic media must be accurately stored and, like instructions in paper format, must be preserved for the period specified by the GMP Ministerial Ordinance. The same applies to "defined in a document," "reported in a document," and "prepared a document."

GMP20-6 (computer use, etc.) [Question] Test and inspection records are created using a computer, printed on paper, and kept with a stamp. Are the ER/ES guidelines applicable in this case as well?

[Answer] When raw data is transcribed and a list of test results is created and stored in paper media as the original copy of a document that is required to be stored by the GMP ministerial ordinance, and electromagnetic records are also stored. It is desirable to base these guidelines as much as possible. Furthermore, regardless of whether or not this guideline is applied, raw data must also be managed appropriately. On the other hand, this guideline applies to records created by electronically transmitting data generated by measuring instruments, and when secondary processing or judgment is performed within a computer.

GMP20-7 (computer use, etc.) [Question] Can records stipulated by the GMP Ministerial Ordinance be stored on microfilm or microfiche?

[Answer] No problem. However, when using reduction techniques such as microfilm, make sure that necessary information can be easily retrieved and hard copies can be obtained.

GMP20-8 (computer use, etc.) [Question] Are there any documents stipulated in the GMP Ministerial Ordinance that can be stored, created, issued, etc. using a computerized system?

[Answer] Documents stipulated in the GMP Ministerial Ordinance that are permitted to be stored as electromagnetic records are the "Act on the Use of Information and Communication Technology in the Storage of Documents Performed by Private Business Operators, etc." (Act No. 149 of 2004). No.) Based on Article 3 of the "Ministerial Ordinance Concerning the Use of Information and Communication Technology in the Storage of Documents Performed by Private Business Operators, etc. Based on the Provisions of Laws and Regulations Under the Jurisdiction of the Ministry of Health, Labor and Welfare" (March 25, 2005 Ministry of Health, Labor and Welfare Ordinance No. (No. 44) (hereinafter referred to as the "e-Document Ministerial Ordinance") As stipulated in Article 3, basically all documents and records stipulated in the GMP Ministerial Ordinance can be created, stored, and delivered using a computerized system. You can think that it can be done.

However, if these documents are created, recorded, and delivered using a computerized system, the computerized system must meet the requirements stipulated in the ER/ES Guidelines and comply with the ``Guidelines for Proper Management of Computerized Systems for Manufacturers/Authors''. (Pharmaceuticals, Food and Drug Administration Notification No. 1021 No. 11, October 21, 2010). Note that delivery here means reporting, instructions, and distribution as defined in the GMP Ministerial Ordinance through electronic media.

GMP20-9 (computer use, etc.) [Question] When creating a manufacturing instruction (copy of the original) using a computer, is it necessary to write the date of the instruction and sign or affix the name and seal of the person instructing the instruction on the printed version?

[Answer]

1. When manufacturing instructions are prepared in writing, the date of the instructions may be mechanically printed. However, the signature or name and seal of the person who is to issue the manufacturing instructions (a printed name is acceptable) is required.

2. If manufacturing instructions are to be electronically recorded instead of written instructions, the person in charge of the manufacturing department must provide an electronic signature in accordance with the e-document ministerial ordinance and the ER/ES guidelines.

GMP20-10 (computer use, etc.) [Question] If the quality department uses a computer-generated report to report to the manufacturing department the results of tests and inspections related to raw materials and materials, is the quality department's signature or name and seal required?

[Answer] When reporting in writing, it must be signed or affixed with a name and seal. Reports of test and inspection results determined by the quality department to the manufacturing department can be made in writing or by electromagnetic means on a computer. A digital signature is required.

GMP20-11 (computer use, etc.) [Question] Can quality be judged by a system that inputs test and inspection results and compares them with pre-stored standards, and automatically outputs a pass if each item falls within the standards?

[Answer] There is no problem with "outputting" the product, but the quality department needs to review the test and inspection results again to determine suitability.

GMP20-12 (computer use, etc.) [Question] Is validation necessary when developing and using computerized systems for manufacturing control and quality control at manufacturing plants? Also, what are the rules to be observed in doing so?

[Answer] If a computerized system is developed and used for manufacturing management and quality control, computerized system validation (CSV) is necessary, but in addition, it is necessary to properly manage the system from development to operation and disposal. It is necessary to do so. When managing computerized systems, follow the "Guidelines for Appropriate Management of Computerized Systems for Manufacturing and Distributing Manufacturers" (Pharmaceuticals, Food and Drug Administration, No. 1021 No. 11, October 21, 2010) and the latest versions of related guidelines.

GMP20-13 (computer use, etc.) [Question] How should entries, changes, and deletions of records be recorded when using electronic media?

[Answer] Records that are entered, changed, or deleted correspond to the "Audit Trail" in the PIC/S related guidance document PI041, and records must be kept to ensure the authenticity of electromagnetic records. Point. This concept requires that records be kept of all entries and modifications. In addition, if changes or deletions are made, a record of the reason is also required.

改正GMP省令　Article 21　Quality Control of Drug Substances

GMP21-1 (Reference sample storage for pharmaceutical ingredients) [Question] Regarding the storage of reference sample for pharmaceuticals that are active ingredients under Article 21 of the GMP Ministerial Ordinance, is it okay to store them in a container that is different from the material of the container for the active pharmaceutical ingredients?

[Answer] Any container is acceptable as long as it provides the same or better protection than the container for the drug substance.

GMP21-2 (Storage of reference sample for drug substances) [Question] If a drug as an active pharmaceutical ingredient is manufactured at Factory A of the manufacturer, etc., and the entire quantity is delivered to Factory B of the same manufacturer, etc., and formulated at Factory B, is there a storage of reference sample for the drug as an active ingredient? Can the location be either Factory A or Factory B?

[Answer] In the case of the question, as a general rule, it should be stored at "Factory A". However, the rules regarding the storage and use of reference sample at "Factory B" (storage shall be carried out under the responsibility of the quality department of "Factory A" and under its instructions) shall be stipulated in advance in the Standard Operating Procedures, etc., and the GMP Ministerial Regulations If consideration has been made to ensure that there is no hindrance to the GMP compliance investigation at "Factory A" due to the conclusion of an agreement stipulated in Article 11-5, it may be stored at "Factory B".

GMP21-3 (Storage of reference sample for drug substances) [Question] What does "shipment completed" in Article 21, Paragraph 1, Item 1 of the GMP Ministerial Ordinance mean?

[Answer] Please refer to the following statement in "Q&A regarding API GMP guidelines" (Administrative communication from the Monitoring and Guidance/Narcotics Countermeasures Division, March 8, 2016).

Q6.1

``[ICH Q7, 6.13] states that ``These records shall be retained for at least three years after the shipment of the applicable lot has been completely completed.'' What does ``shipment have been completely completed'' mean? What do you mean? ”

A6.1

“For drug substances that have a retest date, [ICH Q7, 6.13] requires that records related to manufacturing, testing, and release be maintained for at least three years after the drug substance lot is ``fully released.'' I plan to save the above. "Shipment is completely completed" is understood to mean that one drug substance lot is shipped by the manufacturer of the drug substance to the next party in the supply chain.

Additionally, in the case of drug substances handled by agents, intermediaries, traders, distributors, repackers, and relabelers [ICH Q7, 17], "completely shipped" means that all of the drug substances received are This refers to the shipment of a drug lot. ”

The intent of ICH Q7 is to maintain records for the period that the drug substance is considered on the market for investigation of any issues or product complaints. Although accepted industry practice at the time ICH Q7 was written did not envisage manufacturers setting retest dates beyond three years, this section of ICH Q7 By stating "at least 3 years", it also covers a longer retention period for records. This aligns with basic GMP principles and local requirements that records are kept for the entire period that the drug substance is available on the market.

It is good industry practice to consider preserving records of the drug substance for as long as the drug product in which it is used is expected to be available on the market.

Retest date of drug substance

GMP21-4 (retest date of drug substance) [Question] What should I do if I exceed the retest date?

[Answer] If a lot of a drug substance that has been stored under specified conditions is to be used for manufacturing a product beyond the retest date, it must be tested and inspected again to ensure that it conforms to the specified specifications. Please make sure that it is available and use it promptly. Such reconfirmation may be carried out multiple times if there is a rational basis (stability test data, etc.) for one lot of the drug substance, even after the first time, and it is stipulated in advance in the Standard Operating Procedures, etc. There is no problem in doing so. In other words, even after the retest date, the remaining drug substance that has been used can be used if it is reconfirmed that it complies with the prescribed standards through testing.

GMP21-5 (retest date of drug substance) [Question] What kind of drugs are active ingredients for which a retest date can be set?

[Answer] It can be applied to drugs that are active ingredients whose quality is guaranteed for a considerable period of time under specified storage conditions, as shown by the results of stability tests, etc. Pharmaceuticals that are active ingredients that are known to be physically or chemically unstable should not be considered for setting a retest date, but should have a shelf life (period of use) set as before.

Article 21-2 (stability monitoring)

GMP21 2-1 (Stability monitoring of drug substance) [Question] How should stability monitoring be carried out for drugs that are active ingredients?

[Answer] In principle, stability monitoring of drug substances is carried out at the manufacturing site of the drug substance. For specific implementation methods, detailed explanations are provided in 11.5 Stability Monitoring of APIs of the "Guidelines for GMP of APIs" (Yakuhin No. 1200, November 2, 2001). It is desirable to use a method that complies with this. Even if the manufacturing site for the drug substance is the same as the manufacturing site for the drug product, stability monitoring of the drug substance must be performed.

GMP21-2-2 (Stability monitoring of drug substance) [Question] Article 21-2, Paragraph 1, Item 1 of the GMP Ministerial Ordinance states that the necessary amount of specimen must be collected. Is it okay to use a container made of a different material from the product to hold the collected specimen?

[Answer] In principle, it should be made of the same material as the product's container. However, this does not apply if it is confirmed that the effects of different container materials on the product are the same, and this is clearly stated in the Standard Operating Procedures, etc.

GMP21 2-3 (Stability monitoring of drug substance) [Question] Items in the specifications that are likely to be affected by storage and that are considered to affect the efficacy or safety of the product in case of non-compliance, as referred to in Article 21-2, Paragraph 1, Item 2 of the GMP Ministerial Ordinance. What is it?

[Answer] Select items that are easily affected by temperature, humidity, etc., based on the knowledge obtained from design, prototype studies, and stability tests conducted during the research and development stage. Note that items that are considered to have no obvious change over time, such as heavy metals and arsenic, may be omitted.

GMP21 2-4 (Stability monitoring of drug substance) [Question] GMP21 2-4 (Stability Monitoring of Pharmaceutical Ingredients) Are "chopped herbal medicines" and "powdered herbal medicines" subject to stability monitoring among the pharmaceuticals that are active ingredients of herbal medicines and herbal herbal medicine preparations?

[Answer] Due to the characteristics of crude drugs, pharmaceuticals that are active ingredients for "chopped crude drugs" and "powdered crude drugs" are not subject to stability monitoring. Note that crude drug extracts and compounded extracts fall under this category.

GMP21 2-5 (Stability monitoring of drug substance) [Question] Article 21-2, Paragraph 1, Item 4 of the GMP Ministerial Ordinance states, "Based on the results of the tests and inspections in the previous item, evaluate the impact on the quality of the drug concerned." Which is better, the organization in charge of the department's testing and inspection-related work or the organization in charge of quality assurance-related work?

[Answer] Regarding the evaluation under Article 21-2, Paragraph 1, Item 4 of the GMP Ministerial Ordinance, as with GMP 11-2-12 (stability monitoring), objective evaluation is required, so within the quality department, It is desirable that the organization in charge of quality assurance activity conducts the evaluation.

改正GMP省令　Article 22　Storage of documents and records

GMP22-1 (Storage of documents and records) [Question] When revising a product Standard Operating Procedures, etc. for a drug that is an active pharmaceutical ingredient, the date of revision should be written on the Standard Operating Procedures, etc. based on Article 20, Paragraph 1, Item 2 of the GMP Ministerial Ordinance, and the previous Is it correct to think that it is sufficient to keep a history of revisions and that there is no need to keep all old Standard Operating Proceduress, etc. before revisions?

[Answer] As stipulated in Article 22 of the GMP Ministerial Ordinance, "old Standard Operating Proceduress, etc." prior to revision must be stored for a specified period from the date they are no longer used. Furthermore, when abolishing a document, it is necessary to prevent the abolished document from being used against the intended purpose.

改正GMP省令　Article 23　Structures and equipment of sterile manufacturing facilities

GMP23-1 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] Article 23 of the GMP Ministerial Ordinance stipulates the structure and equipment of sterile pharmaceutical manufacturing facilities. Does this apply to manufacturing facilities for products related to sterile pharmaceutical products?

[Answer] Sterile pharmaceuticals refer to injections, eye drops, eye ointments, water for injection (preparations only), and items for which sterility-related standards have been set as part of manufacturing and marketing approval (notification). The provisions of the ministerial ordinance referred to in 2013 apply to manufacturing facilities for products related to all of these items.

GMP23-2 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] What does "degree of cleanliness" in Article 23, Item 1 of the GMP Ministerial Ordinance specifically mean?

[Answer] Please refer to the latest version of "Guidelines for the manufacture of sterile pharmaceuticals using aseptic techniques" and "Guidelines for the manufacture of sterile pharmaceuticals using terminal sterilization methods" or related guidelines.

GMP23-3 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] Regarding the provisions of Article 23, Item 2 of the GMP Ministerial Ordinance, it is stated that the operational room for drying or sterilizing containers after cleaning of products related to sterile pharmaceutical products is dedicated. Does it not have to be exclusive?

[Answer] It is desirable that it be dedicated for cleaning work and for products related to sterile pharmaceuticals. However, if there is no risk of contamination of the containers of products related to sterile drugs, and if the containers of products related to drugs other than sterile drugs are also cleaned at the cleanliness level of the cleaning operational room for products related to sterile drugs, It does not need to be dedicated to cleaning containers for sterile pharmaceutical products.

GMP23-4 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] Article 23, Item 2 of the GMP Ministerial Ordinance states, ``However, this does not apply in cases where there is no risk of contamination of the container after cleaning.'' Please show me an example.

[Answer] For example, it may be stored in a special storage box with measures taken to prevent contamination.

GMP23-5 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] Article 23, Item 3(b) of the GMP Ministerial Ordinance states that ``sterilized pharmaceutical products must be equipped with the necessary sterilization equipment for manufacturing them depending on the type of product.'' I would like to know the points to keep in mind.

[Answer]

1. Materials for sterilization filters and filters for other purposes should be those that have as little reaction with and adsorption of components in the filtrate as possible, and that are free from the possibility of releasing filter components such as fibers into the filtrate. Use less material (asbestos is not allowed).

2. Regarding the performance of the filter, in addition to validating the filtration sterilization process to confirm that the expected results are obtained, we also ensure that the intended performance of the filter is always fully demonstrated through daily process control, etc. Take care to ensure that it is used in the correct condition.

3. Please refer to the latest editions of "Guidelines for the manufacture of sterile pharmaceuticals using aseptic procedures" and "Guidelines for the manufacture of sterile pharmaceuticals using terminal sterilization methods" or related guidelines.

GMP23-6 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] What kind of work specifically refers to "drug preparation work, filling work, or work after preparation work performed for sterilization of products" in Article 23, Item 4 of the GMP Ministerial Ordinance?

[Answer] For example, it refers to operations such as sterilization by filtration, freeze-drying, melting, capping, and wrapping.

GMP23-7 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] Regarding the provisions of Article 23, Item 4, B and C of the GMP Ministerial Ordinance, if the filling operational room and container cleaning operational room are managed at the same cleanliness level in the manufacture of products related to injectables, the filling work is Is it permissible for the staff performing the container cleaning work to change their clothes in the same changing room?

[Answer] According to the provisions of Article 23, Item 4 (b) of the GMP Ministerial Ordinance, the operational room where filling work is performed is to be dedicated, and according to the provisions of Article 23, Item 4 (c), there is a dedicated changing room for the staff performing the work. As a general rule, this is not permitted.

GMP23-8 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] Regarding the provisions of Article 23, Item 4 (b) and (c) of the GMP Ministerial Ordinance, in a workplace that manufactures products related to injections that are manufactured by heat sterilization, the weighing operational room and the preparation operational room must be maintained at the same cleanliness level. When under control, is it possible for staff who perform weighing work and staff who perform preparation work to change clothes in the same changing room and enter and leave the weighing operational room and the preparation operational room respectively through the central corridor? However, there is a dust removal device in the weighing operational room.

[Answer] According to the provisions of Article 23, Item 4, B and C of the GMP Ministerial Ordinance, this is not allowed in principle. However, in the case of the question, the "weighing room" is dedicated to weighing raw materials whose sterility is guaranteed (hereinafter referred to as "sterile raw materials") or raw materials for products related to sterile pharmaceuticals that are handled in the same way as sterile raw materials. A room that can be maintained at the same cleanliness level as the "preparation operational room" even during weighing work, and that there is no risk of contamination or cross-contamination of the "preparation operational room". If there is a basis for this and it is stipulated in advance in the Standard Operating Procedures, etc., it may be acceptable to manage changing clothes and flow lines as in the question.

GMP23-9 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] Can a operational room where ampoules and rubber stoppers are cleaned be included in the work management area for sterile pharmaceutical products?

[Answer] If there is a reasonable basis that the cleaning work of ampoules and rubber stoppers will not cause contamination or cross-contamination of the controlled area for sterile pharmaceutical products, and this is stipulated in advance in the Standard Operating Procedures, etc. , no problem. Please pay attention to the provisions of Article 23, Item 4 (b) and (c) of the GMP Ministerial Ordinance.

GMP23-10 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] If the preparation work and the filling/closing work are performed in a closed facility, and if the cleaning work of containers, etc. is performed in a separate area, the cleaning work is carried out in the same place as the closed facility. Can I do this in my operational room?

[Answer] As a general rule, closed equipment that performs preparation work, filling and closing work, and cleaning of containers should be done in separate rooms, not in "separate areas." However, even during the cleaning work of containers, etc., the cleanliness level of the preparation work and filling/closing work will not be affected and there is no risk of contamination or cross-contamination of the preparation work and filling/closing work. If there is a basis for this and it is stipulated in advance in the Standard Operating Procedures, cleaning work for containers, etc. may be carried out in a separate area within the same operational room as the "closed equipment".

GMP23-11 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] Regarding the provisions of Article 23, Item 5 of the GMP Ministerial Ordinance, it is stated in Section 32(2)⑤ of the Revised Ministerial Ordinance Promulgation Notice that "distilled water, etc. (in addition to distilled water, includes purified water, water for injection, etc.)" Yes, but does this "water for injection, etc." include water for injection made by ultrafiltration?

[Answer] Included. In addition, ultrafiltration method (a method of filtering water using a cross-flow filtration method using a reverse osmosis membrane, an ultrafiltration membrane, or a membrane filtration device that combines these membranes with the ability to remove all types of microorganisms and endotoxins) ) When preparing water for injection, be careful of microbial contamination.

GMP23-12 (Structures and equipment of sterile pharmaceutical manufacturing facilities) [Question] Regarding the provisions of Article 23, Item 5 of the GMP Ministerial Ordinance, ``Distilled water, etc. (in addition to distilled water, includes purified water, water for injection, etc.)'' in Article 32(2)⑤ of the revised Ministerial Ordinance promulgation notification. However, should this "purified water" be interpreted as sterile purified water?

[Answer] According to the question in the notification of promulgation of the revised ministerial ordinance, sterile purified water is considered to be included in "water for injection, etc." Note that even equipment that supplies sterile purified water needs to have a structure necessary to prevent contamination by foreign substances or microorganisms.

改正GMP省令　Article 24　Sterile manufacturing control

GMP24-1 (Manufacturing control of products related to sterile pharmaceuticals) [Question] What are the specific points that should be kept in mind when manufacturing products related to sterile preparations?

[Answer] For example, the following should be noted. In addition, refer to the latest editions of "Guidelines for the manufacture of sterile pharmaceuticals using aseptic techniques" and "Guidelines for the manufacture of sterile pharmaceuticals using terminal sterilization methods," or related guidelines.

1. Matters related to preparation work, filling and closing work

(1) For operational rooms or work control areas where preparation work or filling/closing work is performed, staff must enter through the front room, and raw materials, materials, etc. must be brought in through a pass box or auxiliary room. thing. At this time, staff members should change their clothes appropriately and disinfect their hands before entering the room, and surfaces of raw materials and supplies should be cleaned before bringing them in.

(2) Before starting preparation work or filling/closure work, the manufacturing equipment to be used should be sterilized or cleaned with sterilized purified water, etc. as necessary. When using a filtration device, pass a small amount of the chemical solution through it first.

(3) After completion of preparation work and filling/closure work, each manufacturing equipment used is cleaned to ensure that no chemical remains, and final cleaning is performed with sterilized or sterilized purified water as necessary. Dry or sterilize as necessary.

(4) After completing the preparation work and filling/closing work, clean and maintain the operational room and pay attention to environmental conservation.

2. Matters related to sterilization work

Sterilize products and containers that require sterilization by appropriately controlling temperature, time, etc. In addition, in particular, sterilized and unsterilized items should be clearly separated and managed.

3. Matters related to work related to foreign object inspection and sealing status inspection

(1) Foreign object inspections shall be conducted by skilled personnel or equipment with comparable performance, and re-inspections shall be conducted by designated personnel at any time by sampling.

(2) The sealing condition of injectables filled in ampoules shall be inspected using an appropriate method.

(3) If the results of foreign object inspection and sealing condition inspection show that the rate of non-standard items is abnormally high, check all processes, investigate the cause, and take appropriate measures.

4. Matters related to container cleaning work, etc.

(1) When cleaning containers, do so in a operational room that is easy to clean, and use cleaning equipment with high cleaning capacity. Also, when performing final cleaning, use purified water that has been sterilized or sterilized as necessary.

(2) When drying and sterilizing containers, use methods that do not damage the materials. However, containers for injectable products that require heat sterilization should be sterilized and dried immediately after cleaning and stored appropriately.

5. Matters regarding working hours

As a general rule, the work from preparation to filling and closing (sterilization if there is a sterilization process) must be completed within one day's control time. However, when working on products that cannot be completed in one day during normal manufacturing processes, sufficient measures must be taken to prevent contamination and quality deterioration.

GMP24-2 (Manufacturing control of products related to sterile pharmaceuticals) [Question] Is it necessary to purchase empty containers with guaranteed sterility and re-clean and sterilize the containers before filling them at a manufacturing facility that manufactures products related to sterile preparations such as injections?

[Answer] There are rational grounds and validated procedures that can maintain sterility assurance and prevent the contamination of insoluble foreign substances, and the quality department has confirmed these and established them in Pharmaceutical Product Standard Code documents, etc. If specified in advance, it is not necessarily necessary to clean and sterilize the empty container again.

GMP24-3 (Manufacturing control of products related to sterile pharmaceuticals) [Question] Regarding the provisions of Article 23, Item 3, C and Article 24, Item 1 of the GMP Ministerial Ordinance, please indicate the points to note regarding the maintenance and management of air conditioning equipment in operational rooms, etc. for products related to sterile preparations.

[Answer] Monitor as appropriate to ensure that predetermined conditions such as temperature, relative humidity, cleanliness level, air volume, necessity for unidirectional airflow, ventilation frequency, and differential pressure between rooms, etc. are met. take appropriate measures to ensure that the capacity of air conditioning equipment is fully utilized (e.g., not to disturb the airflow) when arranging manufacturing equipment in operational rooms, and ensure that the integrity of HEPA filters is maintained. Examples include checking during installation and periodically. Please refer to the latest editions of "Guidelines for the manufacture of sterile pharmaceuticals using aseptic techniques" and "Guidelines for the manufacture of sterile pharmaceuticals using terminal sterilization methods," or related guidelines.

GMP24-4 (Manufacturing control of products related to sterile pharmaceuticals) [Question] Regarding the provisions of Article 24, Items 1 and 3 of the GMP Ministerial Ordinance, when installing germicidal lamps, what precautions should be taken regarding how to install them, their capabilities, etc.? Also, is it necessary to install germicidal lights?

[Answer] Determine the installation method and irradiation conditions (wavelength, etc.) depending on the purpose (sterilization), and be aware that sterilization efficiency varies depending on the type of microorganisms. In addition, sufficient management should be carried out taking into consideration the performance, lifespan, and prevention of harm to staff of germicidal lamps. Please note that the installation of germicidal lamps is not mandatory.

GMP24-5 (Manufacturing control of products related to sterile pharmaceuticals) [Question] GMP24-1 4. (1) states, ``When performing final cleaning, use purified water, etc. that has been sterilized or sterilized as necessary,'' but what does ``as necessary'' mean? Also, what does "etc." in "purified water, etc." refer to?

[Answer] "As necessary" means, for example, that containers that are not heat sterilized after cleaning are subjected to a final cleaning using purified water that has been sterilized or sterilized. Moreover, "etc." corresponds to, for example, sterilized air used when air cleaning is performed on containers of products related to eye drops.

GMP24-6 (Manufacturing control of products related to sterile pharmaceuticals) [Question] Regarding the provisions of Article 24, Item 5 of the GMP Ministerial Ordinance, validation regarding the production of water for injection, water produced by ultrafiltration method (RO (reverse osmosis) water, UF (ultrafiltration) water, etc.) and sterile purified water. What are the points to keep in mind when doing this?

[Answer] Please refer to the latest version of "Guidelines for the manufacture of sterile pharmaceuticals using aseptic techniques" and "Guidelines for the manufacture of sterile pharmaceuticals using terminal sterilization methods" or related guidelines.

GMP24-7 (Manufacturing control of products related to sterile pharmaceuticals) [Question] GMP24-1 5. Regarding the manufacture of products related to sterile preparations, it is stated that ``the work from preparation to filling and closing (sterilization for products that involve a sterilization process) should be completed within one day's control time in principle,'' but the scope of operation is limited. I would like you to show me.

[Answer]

1. Generally, if the content of the work is clear, a time limit should be specified in the Pharmaceutical product standard code, etc. (work that ends when it is confirmed that a certain goal has been achieved through testing and inspection related to in-process control) except for.).

2. If manufacturing work exceeds one day's control time due to unavoidable technical reasons, and there is a reasonable basis that does not impede the guarantee of sterility, the work related to quality assurance may be carried out by the quality department. If the organization in charge has confirmed this and it is specified in advance in the Pharmaceutical Product Standard Code, etc., it does not necessarily have to be "within one day's management time."

3. Even if it is necessary to take samples and test them before filling, and it may take several days to obtain the results, in principle, filling should be carried out immediately. It is preferable not to store the product for several days while waiting for the results of the test.

Four. In principle, if the manufacturing equipment's capacity for filling and closing work is low compared to the production volume of the product related to the injection to be prepared, and the filling and closing work takes several days, etc., the reason is a lack of capacity of the manufacturing equipment. It is not accepted as such.

GMP24-8 (Manufacturing control of products related to sterile pharmaceuticals) [Question] Please explain your thoughts on foreign material inspection during the manufacturing process of injectable products.

[Answer] The standards for foreign substance testing should be in accordance with the Japanese Pharmacopoeia. In addition, A6.4 of the "Guidelines for the manufacture of sterile pharmaceuticals using aseptic procedures". Please refer to the latest version of visual inspection and "Guidelines for manufacturing sterile pharmaceuticals using terminal sterilization methods" or related guidelines. Originally, it is not a good idea to simply eliminate defective products through process inspection, and it is necessary to take necessary measures to prevent contamination, etc. in the manufacturing process based on the provisions of Article 24, Item 3 of the GMP Ministerial Ordinance. There is.

GMP24-9 (Manufacturing control of products related to sterile pharmaceuticals) [Question] Regarding the provisions of Article 24, Item 2 of the GMP Ministerial Ordinance, is it permissible to use the Japanese Pharmacopoeia's testing methods for foreign substance inspections performed as part of in-process control in the manufacturing of injectable products?

[Answer] As long as it does not violate the manufacturing and marketing approval (notification) document, it is determined by the manufacturer, etc., and if the purpose of preventing the shipment of products contaminated with foreign substances is achieved, the inspection method may be used. It is not limited to a specific method.

GMP24-10 (Manufacturing control of products related to sterile pharmaceuticals) [Question] Regarding the provisions of Article 24, Item 2 of the GMP Ministerial Ordinance, when conducting foreign substance inspections related to in-process control of manufacturing of products related to powder injections and eye drops, is it permissible to do so by sampling?

[Answer] In principle, all products should be inspected for the purpose of preventing the shipment of products contaminated with foreign substances. The method of testing and the method of determining results should be determined by the manufacturer, etc., and stipulated in advance in the Standard Operating Procedures, etc.

GMP24-11 (Manufacturing control of products related to sterile pharmaceuticals) [Question] Regarding the provisions of Article 24, Item 2 of the GMP Ministerial Ordinance, foreign substance inspections performed as part of in-process control for manufacturing products related to injectables are not necessarily conducted by persons belonging to the organization responsible for testing and inspection. (For example, if the foreign object inspection department belongs to the manufacturing department).

[Answer] The foreign matter inspection mentioned in the question is performed as part of in-process control, and can be performed by the manufacturing department.

GMP24-12 (Manufacturing control of products related to sterile pharmaceuticals) [Question]) Regarding the provisions of Article 24, Item 2 of the GMP Ministerial Ordinance, what methods are available for inspecting the sealing status of products related to ampoule injections?

[Answer] For example, there are the following methods for sealing status inspection.

1. Method of checking for leakage by inverting the ampoule in the device and reducing the pressure

2. A method to check that the contents of the ampoule do not become colored when the ampoule is submerged in a dye aqueous solution in a pressurized device, or when the ampoule is submerged in a dye aqueous solution in a device, the pressure is reduced, and then the pressure is returned to normal pressure.

3. A method in which electrodes are placed at the tip and other parts of the ampoule, the ampoule is laid down horizontally, and leakage is checked by changes in conductivity caused by pinholes.

GMP24-13 (Manufacturing control of products related to sterile pharmaceuticals) [Question] How should we think about the seal inspection of vial injection products?

[Answer] The integrity of the container must be maintained until use. Defects in containers or closures can cause loss of integrity and should be confirmed through routine control tests or 100% testing. Containers of sterile preparations should be sealed using an appropriately validated method, and equipment operating conditions should be appropriately controlled. The integrity test method should be determined appropriately for the container and closure. Please refer to A6.3 of the "Guidelines for the manufacture of sterile pharmaceuticals using aseptic procedures." Please refer to the latest version of container integrity and "Guidelines for the manufacture of sterile pharmaceutical products using terminal sterilization methods" or related guidelines.

GMP24-14 (Cleanliness standards and measurement methods) [Question] Regarding the provisions of Article 24, Item 1 of the GMP Ministerial Ordinance, please provide a model for the cleanliness level of operational rooms, etc. for products related to sterile pharmaceuticals.

[Answer] As a manufacturer, etc., we establish standards according to the actual situation of each manufacturing site (e.g., appropriate cleanliness levels based on equipment/facilities, product characteristics, environmental management methods, risks, etc.) and check with the quality department. to get. Please refer to the latest editions of "Guidelines for the manufacture of sterile pharmaceuticals using aseptic procedures" and "Guidelines for the manufacture of sterile pharmaceuticals using terminal sterilization methods" or related guidelines.

GMP24-15 (Cleanliness standards and measurement methods) [Question] Regarding the provisions of Article 24, Item 1 of the GMP Ministerial Ordinance, please provide a method for measuring the cleanliness of operational rooms where sterile pharmaceutical products are manufactured.

[Answer] Methods for measuring the cleanliness of sterile pharmaceutical products in operational rooms, etc. are: (1) Fallen bacteria measurement method, (2) Suspended particle measurement method, (3) Airborne microorganism measurement method, and (4) Wipe test method for work tables, etc. , etc. For details on these methods, see, for example, "Handling of reference information deleted due to enactment of the 17th revised Japanese Pharmacopoeia Second Supplement" (June 28, 2019, Drug Review and Management Division, Monitoring and Guidance Please refer to the Environmental Monitoring Law for Sterile Pharmaceutical Manufacturing Areas, etc. of the Narcotics Control Division Administrative Liaison).

改正GMP省令　Article 25-2　Pharmaceutical Product Standard Code for Biological Drugs

GMP25-2-1 (Pharmaceutical product standard codes related to biological drugs, etc.) [Question] Regarding the matters to be described in the Pharmaceutical product standard code related to biological drugs, etc. under Article 25-2 of the GMP Ministerial Ordinance, to what extent should it be described in the Pharmaceutical product standard code?

[Answer] Pharmaceutical Product Standard Code for products related to biological drugs, etc. must also include the matters stipulated in Article 25-2 of the GMP Ministerial Ordinance, in addition to Article 3-10(3) of the Notice of Promulgation of the Revised Ministerial Ordinance. As stated in 3-35(2)① of the Notice of Promulgation of Revised Ministerial Ordinance, the necessary information regarding raw materials stipulated in the standards for biological raw materials, the name of the country where the raw material blood was collected, and whether it is blood donation or non-donation. (Biological products whose active ingredient is human blood or products obtained from it as stipulated in Article 233 of the Enforcement Regulations (Special Provisions for the Labeling of Biological Products, etc. Containing Human Blood as an Active Ingredient) (In the case of specified biological products manufactured using blood as a raw material), etc., should also be described.

GMP25-2-2 (Pharmaceutical product standard code general matters related to biological drugs, etc.) [Question] Regarding the GMP Ministerial Ordinance Article 25-2, Item 1, “Name, essence, properties, ingredients, content, and other specifications of products obtained from humans, animals, plants, or microorganisms used as raw materials” For crude drugs, there are examples in which the Japanese Pharmacopoeia has multiple bases, and these are used singly or in combination. In this case, is it okay to include multiple bases that may be used in the drug product standard document?

[Answer] No problem. However, it must be possible to trace the origins of the raw materials actually used through manufacturing records, testing and inspection records, etc.

GMP25-2-3 (Pharmaceutical product standard codes related to biological drugs, etc.) [Question] Regarding the "name, essence, properties, ingredients, content, and other specifications of products obtained from humans, animals, plants, or microorganisms used as raw materials" in Article 25-2, Item 1 of the GMP Ministerial Ordinance. Although the purpose is to clarify the origin, properties, etc. of the raw materials, is it permissible for manufacturers, etc., to independently define the matters necessary to confirm the quality of the raw materials?

[Answer] As shown in 3-35(2)①(a) of the Notice of Promulgation of Revised Ministerial Ordinance, the necessary matters related to raw materials stipulated in the standards for biological raw materials are included in the Pharmaceutical Product Standard Code as matters related to this article. must be included in Regarding other matters necessary to confirm the quality of raw materials, such as those specified in laws and regulations and notifications, suppliers must make their own judgments and respond based on risks.

GMP25-2-4 (Pharmaceutical product standard code general matters related to biological drugs, etc.) [Question] Article 25-2, Item 2 of the GMP Ministerial Ordinance states "Standards for animals used in manufacturing or testing (including breeding management methods)". Is it correct to think that it only refers to the method of breeding management in

[Answer] It also includes breeding management methods at animal producers.

GMP25-2-5 (Pharmaceutical product standard codes related to biological drugs, etc.) [Question] What specifically is the "standards for animals used in manufacturing or testing and inspection" in Article 25-2, Item 2 of the GMP Ministerial Ordinance?

[Answer] Examples include the breeding lineage of the animal, infectious diseases that are guaranteed to be free from the disease, and the breeding environment. The quality department shall confirm the necessary specifications according to the intended use of animals and specify them in advance in the drug product standard document.

改正GMP省令　Article 26　Structures and equipment for biological drugs

GMP26-1 (Structures and equipment of manufacturing facilities for biological drugs, etc.) [Question] The structures and equipment of manufacturers of products related to "biological products" as defined in Article 80, Paragraph 2, Item 3, A of the Law Enforcement Order must comply with Article 26 of the GMP Ministerial Ordinance (Manufacturing facilities for biological drugs, etc.). Is it correct to consider that the following applies?

[Answer] Yes. Furthermore, Article 9 (structures and equipment) and Article 23 (structures and equipment of sterile pharmaceutical manufacturing facilities) of the GMP Ministerial Ordinance also apply. However, as stated in Section 36(2)② of the Notice of Promulgation of the Revised Ministerial Ordinance, if the manufacturing work of blood products that do not constitute a lot is carried out in a so-called closed system and sterility is ensured, The provisions of Article 23 shall not apply.

GMP26-2 (Structures and equipment of manufacturing facilities for biological drugs, etc.) [Question] The provisions of Article 26 of the GMP Ministerial Ordinance require that all manufacturing facilities for products related to subject biological drugs, etc. be separated from manufacturing facilities for products related to other drugs and dedicated. Is it correct to think that it is not?

[Answer] No problem. However, in order to prevent cross-contamination between biological drugs, etc. at the manufacturing stage where living organisms are used, additional preventive measures are required, such as the use of specialized facilities and equipment, campaign manufacturing, and closed systems. becomes.

GMP26-3 (Structures and equipment of manufacturing facilities for biological drugs, etc.) [Question] What exactly is meant by "a room clearly separated from others" in Article 26, Item 1, A of the GMP Ministerial Ordinance?

[Answer] Here, it is meant to be distinguished from parts related to the manufacture of products related to pharmaceuticals other than biological medicines.

GMP26-4 (Structures and equipment of manufacturing facilities for biological drugs, etc.) [Question] Article 26, Item 3 of the GMP Ministerial Ordinance states that ``areas where products made from human blood or plasma are manufactured must be clearly separated from other areas and must be dedicated to the manufacturing. "However, this does not apply to manufacturing processes after the process of inactivating or removing viruses." Is it correct to consider that the equipment and equipment used to manufacture pharmaceutical products purchased from plasma-derived products manufactured through the above process as raw materials do not need to be dedicated?

[Answer] No problem.

GMP26-5 (Structures and equipment of manufacturing facilities for biological drugs, etc.) [Question] Article 26, Item 3 of the GMP Ministerial Ordinance states that ``areas where products made from human blood or plasma are manufactured must be clearly separated from other areas and must be dedicated to the manufacturing. Is it correct to think that this provision does not apply to the equipment and equipment used to manufacture the dissolution solution (water for injection) that is attached to plasma-derived products?

[Answer] No problem.

改正GMP省令　Article 27　Biological Manufacturing Control

GMP27-1 (Manufacturing control of products related to biological drugs, etc.) [Question] Article 27, Paragraph 1, Item 1 of the GMP Ministerial Ordinance states, ``In the manufacturing process, when products, etc. are inactivated, or when microorganisms, etc. contained in products, etc. are inactivated or removed, or take necessary measures to prevent contamination from products, etc. that have not been removed." However, when using sealed containers, this can be done by clearly labeling and separating them. Is it okay to think that there is?

[Answer] There is no problem as long as appropriate measures are taken to prevent mix-up, contamination, and cross-contamination of the products, etc. handled, including preventing contamination from outside the container or through workers. The basis for the measures to be taken shall be clearly stated in the Standard Operating Procedures, etc.

GMP27-2 (Manufacturing control of products related to biological drugs, etc.) [Question] Article 27, Paragraph 1, Item 4 of the GMP Ministerial Ordinance states, ``In the manufacturing process, if a culture method is used in which the culture medium is continuously supplied to the culture tank and the culture solution is continuously discharged, "Take necessary measures to maintain culture conditions in the culture tank during the culture period." What is the purpose of this provision?

[Answer] This regulation aims to maintain the quality of the target product by maintaining the culture conditions during the culture period. Specific examples of measures include the growth status of microorganisms during culture, etc. monitoring, etc.

GMP27-3 (manufacturing control of products related to biological drugs, etc.) [Question] Article 27, Paragraph 1, Item 5 C of the GMP Ministerial Ordinance states, ``Employees engaged in manufacturing operations shall not be engaged in operations related to the management of working animals (excluding those currently used in the manufacturing process). What is the purpose of this provision?

[Answer] The purpose of this regulation is to prevent contamination or cross-contamination of the manufacturing process through personnel engaged in work related to the management of animals used in processes other than manufacturing processes such as testing and inspection.

GMP27-4 (Manufacturing control of products related to biological drugs, etc.) [Question] Article 27, Paragraph 1, Item 6, A of the GMP Ministerial Ordinance states that "employees engaged in manufacturing work must wear disinfected work clothes, work footwear, work caps, and work masks." Is it correct to think that depending on the characteristics of the product and work, there may be cases where it is not necessary to use unsterilized work clothes or to not wear a mask?

[Answer] No problem. When working with biological products, there are some tasks such as weighing raw materials that do not necessarily require disinfected work clothes, so the reason and rationale for this should be clearly stated in the Standard Operating Procedures, etc. in advance. However, even if not sterilized, work clothes that can maintain the cleanliness required for the work in question must be worn.

GMP27-5 (Manufacturing control of products related to biological drugs, etc.) [Question] Article 27, Paragraph 1, Item 8 of the GMP Ministerial Ordinance states, ``All products contaminated with microorganisms (limited to those contaminated during the manufacturing process) and the carcasses of animals used must be treated in a manner that poses no health and hygiene hazard. What does it mean to "take measures so that there is no risk of health and hygiene problems"?

[Answer] This refers to taking appropriate microbial sterilization measures and keeping records of them. The basis for the measures you decide to take should be clearly stated in the Standard Operating Procedures, etc.

GMP27-6 (Manufacturing control of products related to biological drugs, etc.) [Question] What is the standard for biological raw materials specified in Article 27, Paragraph 1, Item 12 of the GMP Ministerial Ordinance, “as specified by the Minister of Health, Labor and Welfare,” Paragraph 4, Section 3 (Animal-derived raw material standards), (6)? Among the matters that must be recorded so that the information necessary to ensure quality and safety can be confirmed for raw materials of animal origin, "the progress of work to produce raw materials" refers to manufacturing process records. Are you there? If so, since it is difficult to obtain each lot, is it okay to conclude a consignment contract and have the raw material supplier do the work?

[Answer] As indicated in Article 27, Paragraph 1, Item 12 of the GMP Ministerial Ordinance and ``Administrative Handling, etc. Associated with Partial Amendments to the Enforcement Regulations of the Pharmaceutical Affairs Law'' (Pharmaceutical and Pharmaceutical Affairs Bureau No. 0520001, May 20, 2003). As shown in the above, manufacturers, etc. may entrust the storage of records of questions to biological raw material collectors, etc. by concluding an agreement with them. The agreement shall stipulate that records will be managed to prevent deletion, loss, and mix-up, and to enable raw material collectors, etc. to promptly provide necessary records upon request from manufacturers, etc. The contents of this arrangement should be specified in advance in the drug product standard document.

GMP27-7 (manufacturing control of products related to biological drugs, etc.) [Question] Regarding records of GMP 27-6 questions, if it is difficult for the raw material collector to keep the records, the biological raw material manufacturer, etc. should keep the records appropriately for the period specified in Article 30 or Article 31 of the GMP Ministerial Ordinance. Is it okay to do so?

[Answer] No problem. However, in addition to Article 11-4 of the GMP Ministerial Ordinance, manufacturers, etc. themselves must periodically evaluate the suitability of biological raw material manufacturers, etc.

GMP27-8 (Manufacturing control of products related to biological drugs, etc.) [Question] In the record regarding the handling of microorganism strains used in manufacturing as stipulated in Article 27, Paragraph 1, Item 9 of the GMP Ministerial Ordinance, regarding the "biological properties and testing date" of the strain, the strain used is Can I use the test results from the source?

[Answer] Regarding the strains of microorganisms used in manufacturing, manufacturers must confirm that they are appropriate strains through biological property tests, etc. before using them.

改正GMP省令　Article 28　Biological Quality Control

GMP28-1 (quality control of products related to biological drugs, etc.) [Question] Article 28, Paragraph 2, Item 1 of the GMP Ministerial Ordinance states that "samples should be separated with appropriate identification labeling in order to prevent sample confusion and cross-contamination." Is it okay?

[Answer] An example of this is to display the sample name, lot number, and date of collection on the container containing the sample. Biohazard information shall be displayed as necessary.

GMP28-2 (quality control of products related to biological drugs, etc.) [Question] Article 28, Paragraph 2, Item 2 of the GMP Ministerial Ordinance states, "Tests and inspections that are important for quality control and cannot be performed on the product should be performed at an appropriate stage of the manufacturing process." However, is it correct to think that tests and inspections of undiluted solutions correspond to this?

[Answer] Yes, it is. One of the characteristics of products related to biological drugs, etc. is that in some cases it is difficult to evaluate product quality only by testing and inspecting products that have completed all the manufacturing processes at the manufacturing site. It clearly indicates the obligation to conduct tests, and includes, for example, testing of culture extracts in addition to questions.

GMP28-3 (quality control of products related to biological drugs, etc.) [Question] Article 28, Paragraph 2, Item 5 of the GMP Ministerial Ordinance states that ``Regarding the handling of strains of microorganisms used in tests and inspections...records must be created and kept.'' What are the target microorganisms? , Is it correct to consider that only microorganisms are used mainly for quantitative determination? Or are indicator bacteria used in microbial tests (including microbial limit tests, sterility tests, etc.) also covered?

[Answer] This applies not only to microorganisms used for quantitative determination, but also to indicator bacteria used in performance tests of culture media used in microbial tests. The strains of microorganisms to be used should be specified in advance in the Standard Operating Procedures, etc.

GMP28-4 (quality control of products related to biological drugs, etc.) [Question] Article 28, Paragraph 2, Item 5, C of the GMP Ministerial Ordinance states "biological properties and the date of their inspection." What are the inspection items related to biological properties? Also, in this case, is it okay to use the test results from the source of the strain used?

[Answer] Test items related to biological properties generally include confirmation of the morphology of the microorganism, Gram staining, various other stains, colony shape, auxotrophy, etc., but depending on the type of microorganism, special tests may be required. Inspection items cannot be determined unambiguously because different items may be required. Please refer to GMP 27-8 regarding the use of test results by the source of the strain used.

GMP28-5 (quality control of products related to biological drugs, etc.) [Question] According to Article 28, Paragraph 1 of the GMP Ministerial Ordinance, storage of reference sample of biological raw materials used in the manufacture of final products of specified biological drugs that constitute a lot and specified biological drugs that do not constitute a lot is prohibited. The period of validity plus 10 years is required from the date the certificate is issued. The amount to be stored is said to be more than twice the amount required for the prescribed tests and inspections. Is it correct to interpret this as an amount sufficient to allow microbiological tests to be carried out?

[Answer] According to 3-38(1)③ of the Notice of Promulgation of the Revised Ministerial Ordinance, “an amount more than twice the amount required for the prescribed test and test” refers to the amount required for the test and test related to the investigation of the cause of infectious diseases such as viruses. "This refers to an amount that is more than twice the amount required." Therefore, for reference sample such as products after the expiration date plus one year, storage of twice the amount required for a complete test and inspection such as manufacturing and sales approval standards is required. isn't it.

改正GMP省令　Article 29　Biological education and training

GMP29-1 (biological education and training) [Question] Article 29, Item 1 of the GMP Ministerial Ordinance states that "education and training in microbiology, medicine, veterinary medicine, etc. shall be provided to personnel engaged in the manufacturing or testing and testing of biological drugs, etc." Is it okay to select and implement the areas of education shown here that are necessary depending on the product being handled?

[Answer] No problem. However, the rational basis for this should be clearly stated in the Standard Operating Procedures, etc. in advance.

GMP29-2 (biological education and training) [Question] Regarding personnel who work in areas that require precautions against contamination, such as "sterile areas and areas where pathogenic microorganisms are handled, etc." as referred to in Article 25, Item 2 and Article 29, Item 2 of the GMP Ministerial Ordinance. What kind of education should be provided for this?

[Answer] For example, by referring to the WHO biosafety manual, the National Institute of Infectious Diseases Pathogen Safety Management Regulations, etc., manufacturers can appropriately determine the content of training based on the manufacturing process, product characteristics, etc. No problem.

改正GMP省令　Article 30　Storage of documents and records

GMP30-1 (Management of biological documents, etc.) [Question] Regarding the storage period for manufacturing-related records, Article 30 of the GMP Ministerial Ordinance stipulates that in the case of manufacturing products related to specified biological drugs and biological drugs manufactured using human blood as raw materials, the shelf life + 30 In the case of manufacturing products related to other biological products and cell tissue drugs, the shelf life is stipulated as 10 years plus the shelf life. Should I think of it like this?

[Answer] Products related to active pharmaceutical ingredients, which are ingredients designated by the Minister of Health, Labor and Welfare as biological products based on the provisions of Article 2, Paragraph 10 of the Act, are also subject to the “specified biological drugs and human ``Products related to biological drugs manufactured using blood as a raw material'' or ``Products related to biologically derived/cell tissue drugs'' (excluding those that fall under the former), and their manufacturers, etc. As such, documents and records must be retained for the respective specified periods.

GMP30-2 (Management of biological documents, etc.) [Question] When manufacturing a product using ingredients that are subject to the Biological Raw Materials Standards but are not designated as biological products (e.g. gelatin used in oral preparations), what is the retention period for records? How should we think about this in light of the provisions of Article 30 of the GMP Ministerial Ordinance?

[Answer] Five years from the date of creation (however, if the effective period plus one year is longer than five years, the effective period plus one year).

GMP30-3 (Management of biological documents, etc.) [Question] This is a genetically modified drug that is designated as a biological product because human serum albumin, etc. is used only as a medium component during the production of Master Cell Bank and Working Cell Bank, and the manufacturing process of its drug substance and drug product. We believe that products that do not contain any human-derived ingredients do not fall under the category of "biological pharmaceutical products manufactured using human blood as raw materials" as stipulated in Article 30, Item 1 of the GMP Ministerial Ordinance. Is it okay?

[Answer] If human serum albumin, etc. is used even in the production of master cell banks and working cell banks, it falls under "products related to biological drugs manufactured using human blood as raw materials." Therefore, documents and records related to the product are required to be kept for a period of ``validity period plus 30 years''.