the japanese gmp regulations 2003

The Japanese GMP Regulations 2003 Yakuji Nippo, Ltd.

2 December 2004

© 2004 Drumbeat Dimensions, Inc. All rights reserved.

DRUMBEAT DIMENSIONS, INC. P.O. Box 100, West Mystic, CT 06388-0100 USA

Fax: (860) 536-9419 Phone: (860) 572-7255 e-mail: [email protected]

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I. Regulations for Buildings and Facilities of Pharmacies etc.

(MHW Ministerial Ordinance No. 2 dated February 1, 1961; Amended: MHL Ministerial Ordinance No. 16 dated may 20, 2003)

The Regulations for Buildings and Facilities for Pharmacies etc. shall be revised as follows, in accordance

with the provisions of Article 6, Item 1 (including cases where it shall apply mutatis mutandis under Article 26, Paragraph 2); Article 13, Paragraph 2, Item 1 (including cases where it shall apply mutatis

mutandis under Article 23); Article 28, Paragraph 3, Item 1; and Article 39, Paragraph 2 of the Pharmaceutical Affairs Law (Law No. 145, 1960)

TABLE OF CONTENTS

Chapter 2 Manufacture of Drugs etc. (Articles 5 - 14-4)

Supplementary Provisions

Chapter 2 Manufacture of Drugs etc. DRUMBEAT

Concept (Buildings and Facilities of Manufacturing Sites for Drugs to Which Standards for Manufacturing Control and Quality Control Shall Not Apply)

Article 5 The buildings and facilities of manufacturing sites for drugs (excluding drugs specified by the government ordinance pursuant to Article 13, Paragraph 2, Item 2 of the Law, including cases where it shall apply mutatis mutandis under Article 18, Paragraph 2 of the law; the same in the next article, Article 5-3, and Articles 14 to 14-3 inclusive) shall meet the following requirements.

(1) To have adequate facilities and equipment for manufacturing drugs at the manufacturing site [including a material manufactured in the intermediate process which must undergo further processes before a final product (hereinafter referred to as “intermediate product”); excluding the provisions of Article 10, Item 2; the same hereinafter].

9.01 10.01

(2) The area for manufacturing operations (hereinafter referred to as “work area”) shall meet the following requirements. Proviso: This provision shall not apply to the requirements D, E and G when the manufacturing process is carried out prior to the final purification of drugs as active ingredients (hereinafter referred to as “active pharmaceutical ingredient”) intended for use in manufacturing drugs, and manufacturing facilities for such process have an encloses structure.


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A. To be adequately lighted, illuminated, ventilated and clean.

9.03.01 9.04

B. To be distinctly separated from living quarters and other

unsanitary areas.

9.02

C. To have an adequate area for operations to be performed.

9.01

D. To have facilities for the control of dust, insects, and rodents.

1.09 9.03.01 9.05.02 9.07.02

E. To have floors made of wood, concrete or equivalent materials.

9.07

F. To have facilities or equipment for the disposal of sewage and waste.

1.19.01 9.10

G. To have disinfection facilities for personnel.

9.06

H. To have facilities for the disposal of poisonous gases if generated in manufacturing any particular item of product.

9.03 9.10

(3) Among the work areas, work rooms for the weighing operations of raw materials, and the formulating, filling or sealing operations of drugs (including work rooms for active pharmaceutical ingredients where the filling to sealing operations of intermediate products in containers after the final purification are performed) shall meet the following operations.

A. Work tables in the work room shall be constructed so as not to hinder the smooth, proper operations.

9.07

B. To be constructed so as not to allow passage for personnel other than those working in the room. Proviso: This provision shall not apply so long as there is no risk of contamination to drugs by personnel other than those working in the room that can be locked.

11.01 12.02.09

C. To have entrances, exits and windows of the room that can be locked.

11.01 12.02.09

D. To have ceilings made of wood, concrete or materials equivalent

thereto so as to prevent dust and dirt from falling.

9.07 9.07.02


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E. To have floors made of concrete, tile, mortar or wood with a smooth surface free from crevices, or of cleanable materials equivalent thereto.

9.07

F. To have pipes and ducts in the room constructed so as to prevent accumulation of dust and dirt on their surfaces. Proviso: This provision shall not apply so long as these pipes and ducts can be easily cleaned.

9.07.02

(4) To have adequate facilities for the sanitary and safe storage of raw materials, packaging and labeling materials, and products.

7.01

(5) To have adequate facilities and equipment for the inspection and testing of raw materials, packaging and labeling materials, and products. Proviso: This provision shall not apply so long as the inspection and testing of drugs undergoing only repackaging are performed on the manufacturer’s own responsibilities using other testing institutions and this is confirmed to present no problem and to be unavoidable.

9.02.08 9.12

(Buildings and Facilities of Manufacturing Sites for Drugs Other Than Active Pharmaceutical Ingredients to Which the Standards for Manufacturing Control and Quality Control of Drugs Shall Not Apply)

Article 5-2 The buildings and facilities of manufacturing sites for drugs other than active pharmaceutical ingredients (limited to drugs specified by the government ordinance pursuant to Article 13, Paragraph 2, Item 2 of the Law) shall meet the following requirements.

(1) To have adequate facilities and equipment for manufacturing drugs at the manufacturing site.

9.01 10.01

(2) To be appropriately positioned so as to facilitate the smooth and proper operations, and cleaning.

9.01 10.01

(3) Work areas shall meet the following requirements.

A. To be adequately lighted, illuminated, ventilated and cleaned.

9.03.01 9.04


unsanitary areas.

9.02

C. To have an adequate area for performing the operations.

9.01


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D. To have facilities for the control of dust, insects and rodents.

1.09 9.03.01 9.05.02

E. To have facilities or equipment for the disposal of sewage and

waste.

1.19.01 9.10

F. To have disinfection facilities for personnel.

9.06

G. To have facilities for the disposal of poisonous gases, if generated in manufacturing any particular item of product.

9.03 9.10

H. Among the work areas, the work room shall be provided with structures and facilities for prevention of contamination by dust or microorganisms according to the type, dosage form and manufacturing process of intended drugs. Proviso: This provision shall not apply so long as the same effects are obtained from the functions of the manufacturing facilities.

9.03.01

I. When a drug which is easily dispersed and causes anaphylaxis in minute amounts or a drug which is suspected to have serious effects on other drugs by cross-contamination is manufactured simultaneously with other drugs, the work room and air-treatment system shall be separated from those used for other drugs.

5.28 5.28.01

6.18

J. To have washing and toilet facilities and dressing rooms.

9.06

K. Among the work areas, the work room for the weighing operations of raw materials, and the formulating, filling or sealing operations of drugs shall meet the following requirements.

(i) Work tables in the work room shall be constructed so as not to hinder the smooth and proper operations.

9.07

(ii) To be constructed so as not to allow the passage of personnel other than those working in the room. Proviso: This provision shall not apply so long as there is no risk of contamination to drugs by personnel other than those working in the room.

11.01 12.02.09


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(iii) To have no entrances or exits opening to the exterior, except for emergency exits, shall be provided.

9.01 11.01

12.02.09

(iv) To have entrances, exits and windows of the room that can be locked.

11.01 12.02.09

(v) Water discharging facilities in the room shall be

constructed so as to prevent contamination of the room.

9.07.01 9.08

9.08.01

(4) To have adequate facilities for the sanitary and safe storage of raw materials, packaging and labeling materials and drug products that are separated.

7.01

(5) To have facilities for supply of water of the amount and quality required for manufacture (including water for cleaning facilities and equipment as well as containers; the same in the next article) according to the type of drugs.

5.19 9.08

9.08.01

(6) To have facilities and equipment for the inspection and testing of raw materials, packaging and labeling materials, and products. Proviso: This provision shall not apply to the facilities and equipment for the following inspection and testing so long as the inspection and testing are performed on the manufacturer’s own responsibilities using the following testing facilities or institutions and this is confirmed to present no problem and to be unavoidable.

9.02.08 9.12

A. Inspection and testing of drugs undergoing only repackaging: Other testing institutions.

B. Inspection and testing of raw materials, and packaging and labeling materials: Other testing facilities of the manufacturer or testing institutions specified under Article 11, Paragraph 1 of the Enforcement Regulations.

C. High level physicochemical or animal tests of drugs: Other testing facilities of the manufacturer or testing institutions specified under Article 11, Paragraph 1 of the Enforcement Regulations.

D. Inspection and testing of products, excluding the tests in C: Other testing facilities of the manufacturer.


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DRUMBEAT Concept

(Buildings and Facilities of Manufacturing Sites for Active Pharmaceutical Ingredients to Which the Standards for Manufacturing Control and Quality Control Shall Not Apply)

Article 5-3 The buildings and facilities of manufacturing sites for active pharmaceutical ingredients (limited to drugs specified by the government ordinance pursuant to Article 13, Paragraph 2, Item 2 of the Law) shall meet the following requirements.

(1) To have adequate facilities and equipment for manufacturing drugs at the manufacturing site.

9.01

(2) To be properly positioned so as to facilitate the smooth and proper operations, cleaning and maintenance.

9.01

(3) To have washing and toilet facilities and dressing rooms.

9.06

(4) Work areas shall meet the following requirements: Proviso: This provision shall not apply to the requirements D and F when the manufacturing process is carried out prior to the final purification, and manufacturing facilities for such process have an enclosed structure.

A. To be adequately lighted, illuminated, ventilated and cleaned.

9.03.01 9.04


unsanitary areas.

9.02

C. To have an adequate area for performing operations.

9.01

D. To have facilities for the control of dust, insects and rodents.

1.09 9.03.01 9.05.02

E. To have facilities or equipment for the disposal of sewage and

waste.

1.19.01 9.10

F. To have disinfection facilities for personnel.

9.06

G. To have facilities for the disposal of poisonous gases if generated in manufacturing any particular item of product.

9.03 9.10


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H. Manufacturing facilities for active pharmaceutical ingredients where substances causing anaphylaxis in minute or those suspected to have serious effects on other drugs by cross-contamination are produced in the intermediate process. When a drug which is easily dispersed and causes anaphylaxis in minute amounts shall have the functions to prevent other drugs from contamination of such substances.

5.28 5.28.01

6.18

(5) The work area for performing manufacturing processes subsequent to the final purification shall meet the following requirements in addition to those in A to H of the preceding item.

A. Among the work areas, work rooms shall be provided with structures and facilities for prevention of contamination by dust or microorganisms according to the type, dosage form, physical properties and manufacturing process of intended drugs. Proviso: This provision shall not apply so long as the same effects are obtained from the functions of the manufacturing facilities, etc.

9.03.01

B. When a drug which is easily dispersed and causes anaphylaxis in minute amounts or a drug which is suspected to have serious effects on other drugs by cross-contamination is manufactured simultaneously with other drugs, the work room and air-treatment system shall be separated from those used for other drugs.

5.28 5.28.01

6.18

C. Among the work areas, the work room for the filling to sealing operations of intermediate products in containers which have undergone the final purification shall meet the following requirements.

(i) Work tables in the work room shall be constructed so as not to hinder the smooth and proper operations.

9.07

(ii) To be constructed so as not to allow the passage of personnel other than those working in the room. Proviso: This provision shall not apply so long as there is no risk of contamination to drugs by personnel other than those working in the room.

11.01 12.02.09

(iii) To have no entrances or exits opening directly to the exterior, except for emergency exits.

11.01 12.02.09


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(iv) To have entrances, exits and windows of the room that can be locked.

11.01 12.02.09

(v) The water discharging facilities in the room shall be

constructed so as to prevent contamination of the room.

9.07.01 9.08.01

(6) To have facilities for the sanitary and safe storage of raw materials, packaging and labeling materials and products which are separated.

7.01

(7) To have facilities for supply of water of the quality and quantity needed for manufacturing according to the type of drugs.

5.19 9.08

9.08.01

(8) To have facilities and equipment for the inspection and testing of raw materials, packaging and labeling materials and products. Proviso: This provision shall not apply to the facilities and equipment for the inspection and testing of the following matters so long as the inspection and testing are performed on the manufacturer’s own responsibilities using the following testing facilities or institutions A to D and this is confirmed to present no problem and to be unavoidable.

9.02.08 9.12

A. Inspection and testing of drugs undergoing only repackaging: Other testing institutions.

B. Inspection and testing of raw materials, and packaging and labeling materials: Other testing facilities of the manufacturer or testing institutions specified under Item 6-B of the preceding article.

C. High level physicochemical or animal tests of drugs: Other testing facilities of the manufacturer or testing institutions specified in Item 6-C of the preceding article.

D. Inspection and testing of products (excluding the tests in C) Other testing facilities of the manufacturer.


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(Buildings and Facilities of Manufacturing Sites for Sterile Products) Article 6 The buildings and facilities of the manufacturing sites for sterile products [(injectable drug products, excluding blood products not constituting a lot pursuant to Article 1, Paragraph 2 of the Regulations for Manufacturing Control and Quality Control of Drugs and Quasi-drugs (MHW Ministerial Ordinance No. 16, 1999), eye drops, eye ointment or biological products (excluding blood products not constituting a lot, and drugs intended for exclusive use in the diagnosis of diseases and those directly used in the human body; the same in this article and Article 7), and water for injections; the same hereinafter) shall meet the following requirements in addition to those specified under Article 5-2.


A. Among the work areas, the work room or working control area (the area consisting of work rooms, passage, etc. that are controlled so as to maintain a uniform quality of cleanliness; the same hereinafter) shall be provided with adequate structures and facilities for maintaining appropriate temperature, humidity and cleanliness according to the type, dosage form and manufacturing process of intended sterile products.

1.12 9.03

9.03.01

B. The work room for the weighing operations of raw materials and for the washing operations of containers shall have an enclosed structure for protection against dust.

9.03.02

C. The work room for the drying and sterilization operations of containers after washing shall be used exclusively for that purpose. Proviso: This provision shall not apply so long as there is no risk of contamination of containers after washing.

1.12.03 9.02.10

D. The work room or work control area for the formulating, filling or sealing operations of drugs shall meet the following requirements.

(i) To be separated from the work area for drugs other than sterile products and sterile active pharmaceutical ingredients (refer to active pharmaceutical ingredients that are sterile, excluding intermediate product; the same hereinafter). Proviso: This provision shall not apply so long as there is no risk of contamination of sterile products.

9.02


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(ii) The ceilings, walls and floors of the room shall have surfaces made of materials able to withstand spray washing with disinfectant solutions.

9.07

(iii) To have facilities and equipment that allow sterilization and disinfection.

9.01 10.01

(iv) The work room for the formulating operations and for the

filling or sealing operations shall be used exclusively for their respective purposes. Proviso: When the formulating and filling operations, or the formulating, filling or sealing operations are performed continuously in a closed system, these operations may be performed in the same room. When the filling and sealing operations of sterile products other than injections are performed in a closed system, both operations may be performed in the same room as the formulating operations. Separate rooms for the preparing operations and for the filling or sealing operations of radiopharmaceuticals shall not be used.

1.12 9.02

(v) When injectable drug products and other sterile products are manufactured in the same room, manufacturing facilities for injectable drug products shall be in a closed system and used exclusively for that purpose.

1.12 9.02

E. To have dressing rooms for exclusive use by personnel engaging in operations in C. Proviso: This provision shall not apply with the following facilities.

9.06

(2) Work areas shall be provided with the following facilities.

A. Facilities for drying, sterilization and storage of containers after washing.

1.12.03 9.02.10

B. Facilities for formulating drugs. Among these facilities, an open

filtration system shall be provided with a cover, and a closed filtration system with purification equipment for air replenished.

9.03

C. Facilities for filling drugs.

9.02.07

D. Facilities for sealing containers.

9.02.07


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E. In the case of liquid injectable drug products, purification equipment for air replenished in a tank for storing stock solutions.

5.30.01

F. Purification equipment for air replenished in containers of injectable drug products.

5.30.01

(3) To have sterilization equipment for manufacturing according to the type of intended sterile products.

10.01

(4) To have indoor facilities for manufacturing distilled water, etc. (including cleaning water for facilities and equipment, and containers; the same hereinafter) of the quality or quantity needed for manufacturing according to the type of sterile products. Proviso: It is not necessary to install these facilities indoors when they have an enclosed system.

5.19

(5) Facilities such as pipes to supply distilled water, etc. for manufacturing shall be constructed so as to prevent contamination of distilled water, etc. by foreign matter or microorganisms.

5.19.01 5.19.02

(6) The following facilities and equipment for the inspection and testing of the following matters shall be provided. In such cases, the proviso in Item 6, Article 5-2 shall apply mutatis mutandis.

9.02.08 9.12

A. Facilities and equipment for the inspection and testing of in the hermetic condition where necessary.

B. Facilities and equipment for the inspection and testing of a foreign matter.

C. Facilities and equipment for the physicochemical inspection and testing of raw materials, packaging and labeling materials, and products.

D. Facilities and equipment for the sterility tests.

E. Facilities and equipment for the pyrogen tests where necessary.

F. Facilities and equipment for the biological tests where necessary.


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(Buildings and Facilities of Manufacturing Sites for Sterile Active Pharmaceutical Ingredients)

Article 6-2 The buildings and facilities of manufacturing sites for sterile active pharmaceutical ingredients shall meet the following requirements in addition to those specified under Article 5-3.


A. Among the work areas, the work room or working control area shall be provided with adequate structures and facilities for maintaining appropriate temperature, humidity and cleanliness according to the type, physical properties and manufacturing process of intended sterile active pharmaceutical ingredients.

1.12 9.03

9.03.01

B. The work room for washing containers (limited to those used in the operations subsequent to the preparing operations intended for sterilization; the same in this article) shall have an enclosed structure for protection against dust.

1.12.03 9.02.10

C. The work room for the drying or sterilization operations of containers after washing shall be used exclusively for that purpose. Proviso: This provision shall not apply so long as there is no risk of contamination of containers after washing.

9.02

D. The work room for operations (excluding labeling and packaging operations) subsequent to the preparing operations intended for sterilization shall meet the following requirements. Proviso: This provision shall not apply so long as microbial proliferation can be inhibited in the formulating conditions.

(i) To be separated from the work area for drugs other than sterile products and sterile active pharmaceutical ingredients. Proviso: This provision shall not apply so long as there is no risk of contamination of sterile active pharmaceutical ingredients.

9.02

(ii) The ceilings, walls and floors of the room shall have their surfaces made of materials able to withstand spray washing with disinfectant solutions.

9.07

(iii) To have facilities and equipment that allow sterilization and disinfection.

9.01 10.01


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E. To have dressing rooms for exclusive use by personnel engaged in operations in specified in D.

9.06

(2) The work area shall be provided with the following facilities and equipment.

A. Facilities for drying, sterilization and storage of containers after washing.

9.02.10

B. Facilities for preparation intended for sterilization.

9.02

C. Facilities or equipment for filling sterile active pharmaceutical ingredients.

1.12

D. Facilities or equipment for sealing containers.

1.12 9.02.07

(3) To have sterilization facilities for manufacturing according to the type of

sterile active pharmaceutical ingredients.

9.02 9.15

(4) To have indoor facilities for manufacturing distilled water, etc. of the quality and quantity needed for manufacturing according to the type of sterile active pharmaceutical ingredients. Proviso: It is not necessary to install these facilities indoors when they have an enclosed structure.

5.19

(5) Facilities such as pipes to supply distilled water, etc. required for manufacturing shall be constructed so as to prevent contamination of distilled water, etc. by foreign matter or microorganisms.

5.19.01 5.19.02

(6) To have the following facilities and equipment for inspection and testing. In such cases, the proviso of Article 5-3, Item 8 shall apply mutatis mutandis.

9.02.08 9.12

A. Facilities and equipment for inspection and testing in the hermetic condition, where necessary

B. Facilities and equipment for the inspection and testing of a foreign matter

C. Facilities and equipment for the physicochemical inspection and testing of raw materials, packaging and labeling materials, and products


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D. Facilities and equipment for sterility tests

E. Facilities and equipment for pyrogen tests, where necessary

F. Facilities and equipment for biological tests, where necessary.

(Buildings and Facilities of Manufacturing Sites for Biological Preparations) Article 7 The buildings and facilities of manufacturing sites for biological preparations shall meet the following requirements in addition to those specified under Articles 5-2 and 6.

(1) The work area for biological preparations shall be provided with the following facilities. Proviso: The facilities confirmed it unnecessary to manufacture the preparations according to the type, manufacturing method, etc. of biological preparations shall be excluded.

A. Storage facilities for microorganisms.

9.02.15

B. Facilities for keeping animals for use in manufacturing or in testing after inoculation of microorganisms.

9.11

C. Facilities for treating animals for use in manufacturing or in testing

9.11

D. Facilities for inoculating microorganisms into culture media etc.

9.02.15

E. Facilities for cultivating microorganisms

9.02.15

F. Facilities for collecting, inactivating and sterilizing cultured microorganisms

9.02.15

G. Facilities for preparing diluents for stock solutions.

9.02.15

H. Facilities for diluting and subdividing stock solutions and for sealing containers.

9.02.15

I. Facilities for disinfecting devices and equipment that have been used in manufacturing or in testing

1.04


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(2) The facilities specified under the preceding item shall be provided with rooms which are distinctly separated from other rooms, and rooms provided with the facilities indicated in A, B, D or I of the preceding item, which are used to treat smallpox viruses, acute poliomyelitis viruses, spore-forming pathogens or Mycobacterium tuberculosis, shall be used exclusively for treating each type of biological preparation and strictly isolated from other rooms.

5.28.01 6.18

(3) The ceilings, walls and floors of the room provided with the facilities indicated Item 1, B to D, and F to H shall have their surfaces constructed so as to allow washing and disinfection.

9.07

(4) The room provided with the facilities indicated in Item 1, D and F to H inclusive and the room provided with the facilities for the sterility tests, among the facilities for testing raw materials, labeling and packaging materials, shall meet the following requirements.

A. Work rooms shall be aseptic. Proviso: This provision shall not apply so long as a room provided with an aseptic box where aseptic operations can be carried out, according to the type, manufacturing method, etc. of biological preparation.

1.12 1.12.01

B. The aseptic room in A shall have an adjacent anteroom which allows exclusive passage of personnel to and from the work room and whose entrances and exits are not opening directly to the exterior.

1.12

(5) The work area shall be provided with the following facilities in addition to those specified in Item 1.

A. Facilities for breeding and managing animals for use in manufacturing or in testing.

9.11

B. Facilities for preparing culture media and diluents for the media.

C. Facilities for washing and sterilization of equipment/instruments, containers, etc. which are used in manufacturing or in testing.

9.02.23

D. Facilities for incinerating animal carcasses and other biological waste as well as for purifying sewage.

1.19.01 9.10

E. Dressing rooms and bathrooms for exclusive use by personnel.

9.06


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(6) Storage facilities shall be provided with thermostats, self-recording thermometers and other required meters.

7.01 10.04

(Buildings and Facilities of Manufacturing Sites for Blood Products Not Constituting a Lot)

(Test deleted, not applicable)

(Buildings and Facilities of Manufacturing Sites for Biological Preparations etc.) Article 8-2 Specified biological products specified under Article 2, Paragraph 6 of the Law (hereinafter referred to as “specified biological product”), biological preparations specified under Article 15-4, Paragraph 2, Item 2-A of the Enforcement Ordinance of the Law, drugs designated by the Minister pursuant to the provisions of Article 43, Paragraph 1 of the Law, drugs manufactured by application of gene recombination technology, drugs provided as source materials drugs manufactured by application of gene recombination technology, drugs manufactured by application of incubation technology of human or animal cells, drugs provided as source materials drugs manufactured by application of incubation technology of human or animal cells, or cellular/tissue based drugs (hereinafter referred to as “biological preparation etc.”), for which the buildings and facilities of manufacturing sites shall meet the following requirements in addition to those specified under Article 5-2 to Article 8 inclusive.


A. Clean areas (refer to the clean areas specified under Article 1, Paragraph 5 of the Regulations for Manufacturing Control and Quality Control of Drugs and Quasi-drugs; the same in this item) and aseptic areas (refer to the aseptic areas specified under Article 1, Paragraph 6 of the Regulations for Manufacturing Control and Quality Control of Drugs and Quasi-drugs; the same in this item) shall meet the following requirements.

(i) The ceilings, walls and floors with a smooth surface and free from crevices shall be constructed so as to prevent dust and dirt from falling.

9.07 9.07.02

(ii) Water discharging facilities shall have adequate structures for prevention of contamination with poisonous sewage.

5.19 9.08

B. The outlet for discharge shall not be provided with the clean area.

Proviso: This provision shall not apply so long as the requirements in the following (i) to (iii) are met and this is confirmed to present no problem.


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(i) The outlet for discharge shall be provided with drainage trap that is easy to clean, and equipment for preventing water from flowing backward.

5.19 9.07.01 9.08.02

(ii) The trap shall have structures that can be disinfected.

9.07.01 9.08.02

(iii) The grooves of the floor shall be shallow, easy to clean and

connect through the outlet for discharge to the outside of the manufacturing area (refer to a site for performing the operations to incubate, extract and purify, weigh raw materials, wash and dry containers, formulate and fill drugs, and to seal and package containers, as well as a site for dressing; the same in this item).

9.07 9.07.01

C. Aseptic areas shall meet the following requirements:

(i) The outlet for discharge shall not be provided with the aseptic area.

1.12

(ii) The sink shall not be provided with the aseptic area.

1.12

D. The area for performing tests using animals and microorganisms, and for treating animal tissues and microorganisms that are not used in manufacturing biological preparations etc. shall be distinctly separated from other areas for manufacturing biological preparations etc., and air handling systems shall be exclusively provided.

9.02.08 9.02.15

E. The area for performing aseptic operations shall be provided with structures and facilities for controlling positive pressure.

9.03.01

F. The area for treating pathogenic microorganisms shall be provided with structures and facilities for the proper control of negative pressure.

9.03.01

G. The area for treating infectious microorganisms shall be provided with facilities for the washing, sterilization and disinfection of the equipment that have been used in the area, as well as that for the disposal of discharged liquids.

1.19.01 9.01 9.10


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H. The area for manufacturing drugs with human blood or plasma as raw materials shall be distinctly separated from other areas and shall be provided with facilities and equipment exclusively for manufacturing such drugs. Proviso: This provision shall not apply to the area for performing the processes subsequent to the virus inactivation or elimination.

9.02

I. The equipment/instruments used in the work room for treating smallpox viruses, acute poliomyelitis viruses, spore-forming pathogens or Mycobacterium tuberculosis for use in manufacturing shall be labeled according to the type of products and exclusively used for that purpose.

5.28.01

(2) Air handling systems shall meet the following requirements.

A. To have adequate structures for preventing raw materials or products from contaminating with microorganisms, etc.

5.28 9.03.01

B. When pathogenic microorganisms, etc. are used, adequate structures for preventing such microorganisms from spreading into the air shall be provided.

5.28.01

C. To have the structures constructed so as to discharge the air emitted from the area for treating pathogenic microorganisms, etc. after removal of such microorganisms through the high-efficiency particulate air filter (HEPA).

5.28.01 9.03.01

D. To have the structures constructed so as not to cause recirculation of the air in the work room for the operations that are suspected to cause leakage of pathogenic microorganisms, etc. Proviso: This provision shall not apply so long as such microorganisms etc. are completely removed from the air as specified in C of this paragraph and it is confirmed that such recirculation is unavoidable.

5.28 9.03.01

E. Air handling systems shall be provided exclusively with respective work rooms where necessary.

9.03.01

(3) Pipes, valves and bent filters shall be constructed so as to facilitate cleaning and sterilization according to the purpose of use.

10.01


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(4) Facilities for keeping animals for use in manufacturing or in testing (including donor animals; hereinafter, refer to as “use animals” in this item) shall meet the following requirements.

9.11

A. To have quarantine areas for use animals are separated from other areas.

B. To have storage facilities for feed that cannot be invaded by insects.

C. To have breeding rooms for animals for use in manufacturing that are separated from those for animals for use in testing.

D. To have air handling systems provided with breeding rooms for use animals that are separated from those for other areas. Proviso: This provision shall not apply to animals considered it proper to be bred outside.

E. To have rooms for inoculating antigens into animals, where necessary. In such cases, rooms for inoculation shall be separated from those for autopsy.

(Buildings and Facilities of Manufacturing Sites for Cellular/Tissue Based Drugs) (Text deleted, not applicable)

(Buildings and Facilities of Manufacturing Sites for Radiopharmaceuticals) (Text deleted, not applicable)

(Buildings and Facilities of Manufacturing Sites for Absorbent Gauze and Absorbent Cotton)

(Text deleted, not applicable)


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(Buildings and Facilities of Manufacturing Sites for Quasi-drugs to Which Standards for Manufacturing Control and Quality Control Shall Not Apply)

Article 12 To the buildings and facilities of manufacturing sites for quasi-drugs (excluding quasi-drugs stipulated by the government ordinance pursuant to Article 13, Paragraph 2, Item 2 of the Law), the provisions of Article 5 (excluding Item 5) shall apply mutatis mutandis, and adequate facilities and equipment for the inspection and testing of raw materials, labeling and packaging materials, and products shall be provided. Proviso: This provision shall not apply to the facilities and equipment for the inspection and testing of the following matters so long as the inspection and testing are performed on the manufacturer’s own responsibilities using the following testing facilities or institutions and this is confirmed to present no problem to the proper testing.

9.01 10.01

(1) Inspection and testing of quasi-drugs undergoing only repackaging: other testing facilities

(2) High level physicochemical or animal tests: other testing facilities for the manufacturer or testing institutions specified under Article 11, Paragraph 1 of the Enforcement Regulations.

(Buildings and Facilities of Manufacturing Sties for Quasi-drugs to Which Standards for Manufacturing Control and Quality Control Shall Apply)

Article 12-2 The provisions of Article 5-2 (excluding Item 3-I) shall apply mutatis mutandis to the buildings and facilities of manufacturing sites for quasi-drugs stipulated by the government ordinance pursuant to Article 13, Paragraph 2, Item 2 of the Law.

(Buildings and Facilities of Manufacturing Sites for Cosmetics) Article 13 The buildings and facilities of manufacturing sites for cosmetics shall meet the following requirements.

(1) To be provided with adequate facilities and equipment for manufacturing of products at the manufacturing site.

9.01 10.01

(2) To have work areas which shall meet the following requirements.

A. To be adequately lighted, ventilated and clean.

9.03.01 9.04


unsanitary areas.

9.02

C. To have adequate areas for performing the proper operations.

9.01


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D. To be provided with facilities for the control of dust, insects and rodents.

1.09 9.03.01 9.05.02

E. To have floors made of wood, concrete or materials equivalent

thereto.

9.07

F. To have adequate facilities or equipment for the disposal of discharged water and waste materials.

1.19.01 9.10

(3) To be provided with adequate facilities for the sanitary and safe storage of raw materials, labeling and packaging materials, and products.

7.01

(4) To be provided with adequate facilities and equipment for the inspection and testing of raw materials, labeling and packaging materials, and products. Proviso: This provision shall not apply to the facilities and equipment for the inspection and testing of the following matters so long as the inspection and testing are performed on the manufacturer’s own responsibilities using the following testing facilities or institutions and this is confirmed to present no problem to the proper testing.

9.02.08 9.12

A. Inspection and testing of cosmetics undergoing only repackaging: other testing facilities

B. High level physicochemical or animal tests: other testing facilities of the manufacturer or testing institutions specified under Article 11, Paragraph 1 of the Enforcement Regulations.


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Concept (Date of Enforcement) 1. This ordinance shall come into effect on the date of enforcement (February 1,

1961).

Attached Table

Sign Size Location of Sign On radioactivity signs as specified under Article 17, Paragraph 1 of the Japan Industrial Standards in accordance with the Industrial Standardization Law (Law No. 185, 1949), the upper part shall indicate “Storage Room” and the lower part “Unauthorized Entry Prohibited.”

Radioactivity signs shall have a radius of at least 10 cm.

The sign shall be posted at the entrance or exit of the storage room or its vicinities.


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II. Regulations for Manufacturing Control and Quality Control of Drugs and Quasi-drugs

(MHW Ministerial Ordinance No. 16 dated March 12, 1999;

Amended: MHLW Ministerial Ordinance No. 95 dated May 20, 2003) In accordance with the provisions of Article 13, Paragraph 2, Item 2 (including cases where it shall apply mutatis mutandis under Article 18, Paragraph 2) of the Pharmaceutical Affairs Law (Law No. 145, 1960),

the whole text of the Regulations for Manufacturing Control and Quality Control of Drugs and Quasi-drugs shall be revised as stated below.

TABLE OF CONTENTS

Chapter 1 General Provisions (Article 1)

Chapter 2 Manufacturing Control and Quality Control of Drugs

Section 1 General Rules (Articles 2 - 4) Section 2 Manufacturing Control (Articles 5 and 6) Section 3 Quality Control (Articles 7 and 8) Section 4 Other Duties Related to the Manufacturing Sites (Articles 9 - 14) Section 5 Manufacture at Two or More Manufacturing Sites (Articles 15 and 16 Section 6 Miscellaneous Provisions (Article 16-2)

Chapter 3 Manufacturing Control and Quality Control of Quasi-drugs (Article 17)


Chapter 1 General Provisions DRUMBEAT

Concept (Definitions) Article 1 The term “labeling and packaging materials” used in this ordinance means containers, wrappers and package inserts of a product, and labels pasted on the containers and wrappers.

2. The term “lot” used in this ordinance means a batch of products manufactured so as to have a uniform quality during a series of manufacturing processes within a unit of manufacturing period [including a material manufactured during the process which must undergo subsequent processes before a final product is obtained (hereinafter referred to as “intermediate product”; the same under Article 3, Paragraph 1, Item 2; Article 6, Paragraph 1, Item 2-D and Paragraph 2, Item 1-A, G and J; and Article 8, Paragraph 1, Item 1-A and B) and raw materials.


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3. The term “control unit’ used in this ordinance means a batch of labeling and packaging materials which are confirmed to have a uniformity quality.

4. The “validation” used in this ordinance means to validate and document that anticipated results yield from the buildings and facilities at manufacturing sites as well as operating procedures, processes and other methods of manufacturing control and quality control (hereinafter referred to as “the operating procedures etc”).

5. The term “clean area” used in this ordinance means, among the areas for performing manufacturing operations (hereinafter referred to as “work area”), a place for performing the weighing operations of raw materials and the preparing operations of drugs, and a place where containers after washing are exposed to the air in the work area.

6. The term “aseptic area” used in this ordinance means, among the work area, a place where drugs being sterile and containers after sterilization are exposed to the air in the work area, a place for performing the filling operations of drugs and the sealing operations of containers, as well as a place for performing aseptic operations such as sterility tests etc.

7. The term “cellular/tissue based drug” used in this ordinance means drugs composed of human or animal cells or tissues (excluding human blood and drugs composed of ingredients manufactured with human blood).

8. The term “donor” used this ordinance means an individual providing her (his) cells or tissues as raw materials of cellular/tissue based drugs (excluding cells or tissues derived from the human body with brain death as specified under Article 6, Paragraph 2 of the Law on Organ Transplantation (Law No. 104, 1997).

9. The term “donor animal” used in this ordinance means an animal providing its cells or tissues as the source materials of cellular/tissue based drugs.


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Chapter 2 Manufacturing Control and Quality Control of Drugs

DRUMBEAT

Concept Section 1 General Rules (Manufacturing Control Manager and Quality Control Manager) Article 2 A manufacturer of drugs (hereinafter referred to as “manufacturer”) shall designate, at each manufacturing site, a person responsible for the manufacturing control unit as the manufacturing control manager and a person responsible for the quality control unit as the quality control manager, who perform their duties under the supervision of a product security pharmacist (hereinafter referred to as “product security pharmacist”).

13.01 13.02 13.11

2. The quality control unit shall be independent of the manufacturing control unit.

3. The manufacturing control manager shall not hold a position as the quality control manager concurrently.

(Product Security Pharmacist) Article 3 The product security pharmacist shall perform the following duties.

13.11

(1) To supervise the manufacturing control manager and the quality control manager.

(2) To decide, through appropriate evaluation of results of the manufacturing control and quality control, whether or not to release the product out of the manufacturing site.

6.07.03

(3) To ensure that the validation, self-inspection and training, as well as the confirmation specified under Article 15, Paragraph 5, Item 1, are properly carried out, by documents reported as specified under Article 10, Paragraph 1, Item 2; Article 13, Paragraph 1, Item 2; Article 14, Paragraph 1, Item 2; and Article 15, Paragraph 5, Item 2.

(4) The duties specified under Article 11 and 12.

2. The manufacturer shall make efforts for the effective performance of the duties assigned to the product security pharmacist.

(Product Master Formula) Article 4 The manufacturer shall prepare, at each manufacturing site involved in the manufacture of the drug, a product master formula, for each product, describing the following matters.

5.02


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(1) Terms concerning manufacturing approval;

(2) Manufacturing procedures;

(3) In cases where drugs intended for manufacture are biological products specified under Article 2, Paragraph 5 of the Law (Law No. 145, 1960) (hereinafter referred to as “biological product”), biological preparations indicated in Item 2-A, Paragraph 2, Article 15-4 of the Enforcement Ordinance of the Law (Government Ordinance No. 11, 1961), drugs designated by the Minister pursuant to the provisions of Article 43, Paragraph 1 of the Law, drugs manufactured by application of gene recombination technology, drugs provided as the source materials drugs manufactured by application of gene recombination technology, drugs manufactured by application of incubation technology of human or animal cells, or drugs provided as the source materials drugs manufactured by application of incubation technology of human or animal cells, or cellular/tissue based drugs (hereinafter referred to as “biological preparations etc.”), describe the following matters.

A. Name, essence, description, ingredients and their contents, and other specifications of a drug obtained from humans, animals, plants or microorganisms provided as the source materials.

B. Specifications of animals for use in manufacturing or in inspection and testing (including methods of breeding and keeping animals) (including donor animals; hereinafter referred to as “use animal”).

(4) Other necessary matters.

Section 2 Manufacturing Control (Manufacturing Control Standard Code and Manufacturing Hygiene Control Standard Code)

Article 5 The manufacturer shall prepare, at each manufacturing site, a manufacturing control standard code describing storage of raw materials etc., control of the manufacturing process and other necessary matters, as well as at each work area, a manufacturing hygiene control standard code describing the sanitation and hygiene of the buildings and facilities (excluding those provided for inspection and testing; the same hereinafter), and personnel, and other necessary matters.

1.02 7.01 12.02


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(Duties of Manufacturing Control Manager) Article 6 The manufacturer shall have the manufacturing control manager perform appropriately the following duties related to the manufacturing control of drugs in accordance with the product master formula, the manufacturing control standard code or the manufacturing hygiene control standard code.

13.05

(1) To prepare a manufacturing order describing instructions, precautions and other necessary matters during the manufacturing process.

5.01

(2) To perform by herself/himself, or according to the type of duties, to have a person, designated beforehand, perform the following duties.

A. To manufacture drugs in accordance with the manufacturing order.

B. To prepare records of manufacturing drugs by lot (by manufacturing number in case of drugs not constituting a lot; the same hereinafter).

5.03

C. To confirm whether or not the labeling and packaging of product are properly performed for each lot, and to prepare records of the confirmation results.

5.03.02

D. To store appropriately raw materials and products by lot, and labeling and packaging materials by control unit, manage receipt/distribution of such materials and products, and to prepare the records thereof.

3.01 3.02 3.10 4.01 4.02

E. To confirm cleanliness of the buildings and facilities, and to

prepare records of the confirmation results.

1.01

F. To perform the sanitation and hygiene of personnel, and to prepare the records thereof.

12.02.01

G. To perform the periodical inspection for maintenance of the buildings and facilities (including calibration of meters), and to prepare the records thereof

2.02 2.02.04

H. Other necessary duties.


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(3) To confirm from records of storage, receipt/distribution, as well as those of the manufacturing hygiene control that the manufacturing control is properly performed, and report the results of the confirmation in writing to the product security pharmacist.

8.01.01

(4) To retain records of manufacture, storage, receipt/distribution, as well as those of the manufacturing hygiene control, for the following periods from the date of preparation.

A. Three years for drugs other than biological products or cellular/tissue based drugs (hereinafter referred to as “biological products etc.”) [when a drug related to the records is obliged to bear an expiry date or the date of expiry (hereinafter referred to as “expiry date”), a period of the expiry date plus one year].

B. A period of the expiry date plus 30 years for specified biological products prescribed under Article 2, Paragraph 6 of the Law (hereinafter referred to as “specified biological product”) or for biological products manufactured with human blood as the source material [refer to the source of materials for use in manufacturing; the same hereinafter (including those for use during the manufacturing process; the same hereinafter)] (hereinafter referred to as “product containing human blood derived material”).

C. A period of the expiry date plus 10 years for biological products etc. (excluding products in B).

2. In manufacturing biological preparations etc., the manufacturer shall, in addition to the duties specified in the preceding paragraph, have the manufacturing control manager perform properly the following duties related to the manufacturing control of biological products etc. in accordance with the product master formula, the manufacturing control standard code, or the manufacturing hygiene control standard code.



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A. When source materials or products are inactivated, or microorganisms etc. contained in the source materials and products are inactivated or eliminated, during the manufacturing process, to take action necessary for preventing contamination by the source materials or products that are inactivated or eliminated in such a way.

5.28

B. When biochemical technology such as fermentation etc. is applied during the manufacturing process, to perform continuous measurements of temperature, hydrogen ion index, etc. necessary for the control of manufacturing process.

5.12

C. When equipment for column chromatography is used during the manufacturing process, to take action required to prevent contamination of the equipment by microorganisms, and to perform measurements of endotoxins, where necessary.

5.28

D. In employing the culture method to provide a continuous supply of culture media to an incubation tank and to perform a continuous discharge of liquid media during the manufacturing process, to take action required to maintain incubation condition in the incubation tank during the incubation period.

E. To restrict as much as possible for personnel other than those who are engaged in manufacturing to go in or out of the work area.

12.02.09

F. To perform the following duties related to the sanitation and hygiene of personnel.

(i) To restrict as much as possible for personnel to go in our out of the aseptic area or the clean area where actual operations are carried out.

12.02.09

(ii) To have personnel engaged in manufacturing not assign to the position to keep use animals (excluding those for use in manufacturing).

1.12.02

G. To perform the following duties related to the sanitation and hygiene of personnel working in the aseptic area or in the clean area:


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(i) To have personnel engaged in manufacturing wear work clothes, shoes, caps and masks that have been disinfected.

1.12.02 12.02.05 12.02.06

(ii) To have personnel undergo medical checkups at intervals

not exceeding 6 months in order to confirm that they do not have diseases that are suspected to contaminate raw materials or products by microorganisms etc.

12.02.11

(iii) When personnel having their conditions that are suspected to contaminate raw materials or products with abnormal numbers or types of microorganisms (including infectious diseases such as skin or hair, cold, wound, or symptoms such as diarrhea or fevers without causes), to have each personnel notify the fact.

12.02.02

H. In addition to breeding use animals (limited to those for use in manufacturing; the same hereinafter) under constant, proper care, to take care not to use animals with infectious diseases or animals not appropriate for use in manufacturing through observations of their physical conditions before use.

6.27

I. To dispose of all the things (limited to those contaminated during the manufacturing process) and animal carcasses that have been contaminated by microorganisms so as not to cause hazards to the public health and hygiene.

1.19

J. To prepare the following records in handling of microbial strains for use in manufacturing, and to retain the records thereof for 5 years from the date of preparation (when the drug related to the records is a specified product or a product containing human blood derived material, a period of the expiry date plus 30 years, or when the drug related to the records is a different biological product etc., a period of the expiry date plus 10 years).

8.01.01

(i) Name of microorganisms and number given to each container.

(ii) Date of being transferred and, name and address of a person who has transferred (in case a corporation, name and address).


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(iii) Biological properties and date of testing.

(iv) Status of subculture.

K. In manufacturing other products, to prohibit to use the equipment/instruments of the work room for treating small pox viruses, acute poliomyelitis viruses, spore-forming pathogens or Mycobacterium tuberculosis, with the labels attached to them for each type of product.

5.28.01

L. For materials derived from organisms (excluding plants) for use in manufacturing of biological products (hereinafter referred to as “biologically derived source material”, the manufacturer shall confirm that the biologically derived source material is an appropriate article by reference to the product master formula of the drug, prepare records of the confirmation results, and retain the records thereof for the following periods.

(i) A period of the expiry date plus 30 years for specified biological products or for products containing human blood derived material.

8.01.01

(ii) A period of the expiry date plus 10 years for biological products (excluding products indicated in (i)).

8.01.01

M. The manufacturer shall retain herself/himself records of biologically derived source materials for use in manufacturing of biological products for the following periods as specified by the Minister, or close a contract with a person collecting materials of the biologically derived source material (hereinafter referred to as “source material collecting firm etc.”), and the records shall be retained appropriately by the source material collecting firm etc. based on the contract.

(i) A period of the expiry date plus 30 years for specified biological products or for products containing human blood derived material.

8.01.01

(ii) A period of the expiry date plus 10 years for biological products (excluding products indicated in (i)).

8.01.01

(2) To prepare records specified in Item 4 of the preceding paragraph and L and M indicated in the preceding item from each lot of intended biological products etc., and to retain the records thereof.

8.01


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3. In manufacturing cellular/tissue based drugs, the manufacturer shall, in addition to the duties in Paragraph 2, have the manufacturing control manager perform properly the following duties related to the manufacturing control of cellular/tissue based drugs in accordance with the product master formula, the manufacturing control standard code, or the manufacturing hygiene control standard code.


A. In handling of the cells or tissues collected from different donors or donor animals, to take necessary action to prevent mixture and cross-contamination of the cells or tissues.

5.28

B. To confirm from records on the following matters that cells or tissues as source materials are appropriate articles, when received, by reference to a drug master formula of the drug, and to prepare records of the confirmation results.

(i) Facilities where the cells or tissues have been collected;

(ii) Date on which the cells or tissues have been collected;

(iii) When the cells or tissues are derived from humans, the status of diagnosing donors through their health checking and testing for the donor screening (refer to a decision of, from the results of the health checking and testing of donors, whether or not such donors are fully eligible to provide their cells or tissues as source materials of cellular/tissue based drugs.

(iv) When cells or tissues are derived from animals, the status of receiving donor animals, as well as conditions of the inspection and testing, and breeding and keeping of such animals for the donor screening (refer to a decision of, from the results of the health checking and testing of donor animals, whether or not such donors are fully eligible to provide their cells or tissues as source materials of cellular/tissue based drugs).

(v) Records of collecting the cells or tissues.


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(vi) Requirements for ensuring the quality of cellular/tissue based drugs, in addition to those indicated in (i) to (v) above.

C. In collecting cells or tissues as source materials from donor animals, to take necessary action to prevent contamination by microorganisms during the collection, and to prepare records of the action taken.

D. When personnel meet any of the following conditions, not to have the personnel work in the clean area or in the aseptic area.

(i) When personnel have their physical conditions suspected to contaminate source materials or products with abnormal numbers or types of microorganisms (including infectious diseases of the skin or the hair, cold, wound, or symptoms of diarrhea or fevers of unknown causes)

12.02.02

(ii) When personnel treat microorganisms etc. suspected to contaminate cells or tissues immediately before their collection or processing.

E. For products, to grasp, for each product, the name of the destination facilities and date of distribution, and lots, and to prepare the records thereof.

7.02

F. For distribution, to take necessary action to ensure the quality of products, and prepare records of the action taken.

7.02

G. To prepare records of breeding and keeping donor animals after their acceptance.

6.27

(2) To prepare records specified in B, C, E, F and G of the preceding item by lot (by product for records in E of the same item), and to retain the records thereof for a period of the expiry dates plus 10 years from the date of preparation (a period of the expiry date plus 30 years when a drug related to the records is a specified biological product or a product containing human blood derived material).

8.01.01


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4. Records of biological products specified in the preceding three paragraphs shall be retained appropriately so as to confirm a series of records biologically derived source materials provided in manufacturing to a product manufactured with the biologically derived source materials.

8.01.01

Section 3 Quality Control (Quality Control Standard Code) Article 7 The manufacturer shall prepare, at each manufacturing site, a quality control standard code describing methods of collecting samples and of evaluation test results, and other necessary matters.

6.01 6.07

(Duties of Quality Control Manager) Article 8 The manufacturer shall have the quality control manager perform systematically and appropriately the following duties related to the quality control of drugs in accordance with the product master formula or the quality control standard code.

13.06

(1) To perform by herself/himself or, according to the type of duties, to have a person, designated beforehand, perform the following duties.

A. To collect samples of raw materials and products by lot, and those of labeling and packaging materials by control unit, and to prepare the records thereof.

3.03 6.01

6.01.05

B. To perform the inspection and testing of the collected samples by lot or by control unit, and to prepare the records thereof. Proviso: This provision shall not apply so long as the following inspection and testing are performed on the manufacturer’s own responsibilities using the following testing facilities or institutions without causing hindrance to the proper testing.

6.02

(i) Inspection and testing of drugs undergoing only repackaging: Other testing institutions.

(ii) Inspection and testing of raw materials, and labeling and packaging materials: Other testing facilities of the manufacturer or the testing institutions specified under Article 11, Paragraph 1 of the Enforcement Regulations of the Pharmaceutical Affairs Law (MHW Ministerial Ordinance No. 1, 1961; referred to as “the Enforcement Regulations” in (iii)”).


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(iii) High level physicochemical and animal tests of the product: Other testing facilities of the manufacturer, or the testing institutions specified under Article 11, Paragraph 1 of the Enforcement Regulations.

(iv) Inspection and testing of the product [excluding the inspection and testing in (iii)]: Other testing facilities of the manufacturer.

C. To store a reserve sample, under proper conditions of storage, from each lot of product (in the case of specified biological product not constituting a lot, for biologically derived source material which has been provided in manufacturing of the product, for each manufacturing number of the product or from each lot of the biologically derived source material), consisting of at least twice the quantity needed for all the required tests, for the following periods from the date of manufacturing. Proviso: This provision shall apply neither to drugs under a contract, already closed between the manufacturer and a source material collecting firm etc., specifying that the source material collecting firm etc. shall store a reserve sample for the following periods nor to drugs not constituting a lot other than specified biological products. For specified biological product constituting a lot or cellular/tissue based drugs, after three years have passed [when a drug as the product is obliged to bear an expiry date, a period of the expiry date plus one year (one month for radiopharmaceuticals)], storage of the biologically derived source material which has been provided in manufacturing of the product may be substituted for storage of the product.

6.03

(i) Three years for drugs other than specified biological products or cellular/tissue based drugs [when a drug as the product is obliged to bear an expiry date, a period of the expiry date plus one year (plus one month for radiopharmaceuticals)].

(ii) A period of the expiry date plus 10 years for specified biological products.

(iii) Appropriate duration of cellular/tissue based drugs (excluding products in (ii)).


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D. To perform the periodical inspection for maintenance of the testing facilities and equipment (including calibration of meters), and to prepare the records of the inspection.

2.02 2.02.04

6.12

E. Other necessary duties.

(2) To report evaluation of test results in writing to the product security pharmacist and the manufacturing control manager.

6.16

(3) To retain records of test results for the following duration from the date of preparation.

8.01.01

A. Three years for drugs other than biological products etc. [when the drug related to the records is obliged to state the expiry date, a period of the expiry date plus one year].

B. A period of the expiry date plus 30 years for specified biological products etc. (excluding products indicated in B).

2. In manufacturing biological preparations etc., the manufacturer shall, in addition to the duties in the preceding paragraph, have the quality control manager perform appropriately the following duties related to the quality control the biological preparations etc. in accordance with the product master formula or the quality control standard code.

(1) To perform herself/himself or, according to the type of duties, to have a person, designated beforehand, perform the following duties.

A To separate samples by the proper labeling of identification in order to prevent mixture and cross-contamination of the samples.

5.28

B. To perform, at the proper stage of manufacturing, the inspection and testing required from the quality control and impracticable in the product.

5.12 6.02

C. In addition to breeding of use animals (limited to animals for use in the inspection and testing; the same in this paragraph), under constant, proper conditions, to take care not to use animals with infectious diseases and other animals inappropriate for use through observations of their physical conditions before use.

6.27


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D. To dispose of all the articles which have been contaminated with microorganisms (limited to those contaminated during the inspection and testing) and carcasses of use animals so as not to cause hazards to the public health and hygiene.

1.19

E. To prepare the following records in handling of microbial strains for use in inspection and testing, and to retain the records thereof for 5 years after the date of preparation (when a drug related to the records is a specified biological product or a product containing human blood derived material, a period of the expiry date plus 30 years, or when a drug related to the records a different biological product etc., a period of the expiry date plus 10 years).

8.01.01

(i) Name of microorganisms and number given to each container.

(ii) Date of being transferred, and name and address of a person who has transferred (in the case of a corporation, name and address).

(iii) Biological properties and date of testing.

(iv) Status of subculture.

(2) To prepare and retain records specified in Item 3 of the preceding paragraph from each lot of the intended biological preparation.

3. In manufacturing cellular/tissue based drugs, the manufacturer shall, in addition to the duties specified in the Paragraph 2, have the quality control manager perform the following duties related to the quality control of cellular/tissue based drugs in accordance with the product master formula or the quality control standard code.

13.06

(1) To perform by herself/himself the inspection and testing of donor animals at the time of or after their receipt and other necessary duties, or to have a person, designated beforehand, perform the following duties according to the type of duties (when the drug related to the records is a specified biological product or a product containing human blood derived materials, a period of the expiry date plus 30 years).

6.27


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(2) To prepare records of the duties in the preceding item, and to retain the records thereof for a period of the expiry date plus 10 years (when a drug related to the records is a specified biological product or a product containing human blood derived material, a period of the expiry date plus 30 years.

8.01.01

4. Records of biological products specified in the preceding three paragraphs shall be retained appropriately so as to confirm a series of records from biologically derived source materials provided in manufacturing to a product manufactured with biologically derived source materials.

8.01

Section 4 Other Duties Related to Manufacturing Control and Quality Control (Operating Procedures for Validation etc.) Article 9 The manufacturer shall prepare, at each manufacturing site, written operating procedures for validation, complaint management, recall action, self-inspection, and training (hereinafter referred to as “operating procedures”), in order to perform properly the duties specified under Articles 10 to 14 inclusive.

1.06 1.15 1.16 1.17 1.18 2.05 5.06 5.16 6.12 6.13 7.05 8.03

(Validation) Article 10 The manufacturer shall have a person, designated beforehand, perform the following duties in accordance with the operating procedures.

(1) To perform validation in the following cases.

A. When manufacturing of drugs is started at the manufacturing site.

5.16

B. When there are changes made in the operating procedures, which might have serious effects on the quality of drugs.

5.04.01

C. When it is considered necessary to perform properly the manufacturing control and quality control of drugs.

5.16

(2) To report in writing to the product security pharmacist the results of validation.

17.04


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(3) To retain records of validation for the following periods from the date of preparation.

8.01.01

A. Three years for drugs other than biological products etc.

B. A period of the expiry date plus 30 years for specified biological products or products containing human blood derived material.

C. A period of the expiry date plus 10 years for biological products etc. (excluding products indicated in B).

2. The manufacturer shall take all the required action when it is found necessary to improve the manufacturing control and quality control from the results of the validation in Item 1 of the preceding paragraph, prepare records of the action taken, and to retain the records thereof for the following periods from the date of the preparation.

8.01.01

(1) Three years for drugs other than biological products etc.

(2) A period of the expiry date plus 30 years for specified biological products or products containing human blood derived material.

(3) A period of the expiry date plus 10 years for biological products etc. (excluding products indicated in the preceding item).

(Complaint Management) Article 11 When there is a complaint regarding the quality etc. of drugs, the manufacturer shall have the product security pharmacist perform the following duties in accordance with the operating procedures, excluding cases where the complained matter is not obviously attributable to the manufacturing site.

6.13

(1) To investigate into the cause of the complaint, and to take all the required action when it is found necessary to improve the manufacturing control and quality control.

6.21.06

(2) To prepare records of the complaint management describing the details of the complaint, clarified cause, and the correction action taken, and to retain the records thereof for the following periods from the date of preparation.

6.13 8.01.01



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(Recall Action) Article 12 The manufacturer shall, when taking a recall action for the reason the quality etc. of drugs, have the product security pharmacist of the manufacturing site perform the following duties in accordance with the operating procedures, excluding cases where the recall is not obviously attributable to the manufacturing site.

7.05

(1) To investigate into the cause of the recall, and to take all the required action when it is found necessary to improve the manufacturing control and quality control.

6.21

(2) To store by separation of the recalled products for a given period, and to properly dispose of them.

7.04.02

(3) To prepare records of the recall action taken describing the details of the recall, clarified cause, and the correction action taken, and to retain the records thereof for the following periods from the date of preparation.

7.05.01 8.01.01




(Self-inspection) Article 13 The manufacturer shall have a person, designated beforehand, perform the following duties in accordance with the operating procedures.

(1) To perform the periodical self-inspection of the manufacturing control and quality control of drugs at the manufacturing site.

6.12

(2) To report the results of the self-inspection in writing to the product security pharmacist.


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(3) To prepare records of the self-inspection results, and to retain the records thereof for the following periods from the date of the preparation.

8.01.01




2. The manufacturer shall take all the required action when it is found necessary to improve the manufacturing control and quality control from self-inspection results in Item 1 of the preceding paragraph, and prepare records of the action taken, and to retain the records thereof for the following periods from the date of preparation.

6.12 8.01.01

(1) Three years for drugs other than biological products etc.

(2) A period of the expiry date plus 30 years for specified biological products or products containing human blood derived material.

(3) A period of the expiry date plus 10 years for biological products etc. (excluding products indicated in B).

(Training) Article 14 The manufacturer shall have a person, designated beforehand, perform the following duties in accordance with the operating procedures.

(1) To conduct systematically training of personnel regarding the manufacturing control and quality control.

5.06

(2) To report the status of the training in writing to the product security pharmacist.

5.06.03

(3) To prepare records of the training, and to retain the records thereof for 3 years from the date of preparation.

5.06.03 8.01.01

2. In manufacturing biological products etc., the manufacturer shall, in addition to the duties specified in the preceding paragraph, have a person, designated beforehand, perform the following duties in accordance with the operation procedures.


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(1) To conduct training of personnel engaging in the manufacturing or inspection and testing of biological products etc. in microbiology, medicine, veterinary medicine, etc.

5.06

(2) To conduct training of personnel working in the aseptic area or other areas where pathogenic microorganisms are treat, for taking action to prevent contamination by microorganisms.

1.12.02 5.06.05

Section 5 Manufacture at Two or More Manufacturing Sites (Manufacture at Two or More Manufacturing Sites) Article 15 One manufacturer (hereinafter referred to as “contractor”) who commissions part of the manufacturing process to another manufacturer (hereinafter referred to as the “contract acceptor”) shall close a contract with the contract acceptor regarding the following matters in order to ensure the proper conduct of manufacturing control and quality control during the manufacturing process.

14.01

(1) Scope of the commissioned process

(2) Technical conditions for the manufacture covered by the contract (hereinafter referred to as “contract manufacture”).

(3) Periodical confirmation by the contractor of the proper conduct of the contract manufacture at the manufacturing site of the contract acceptor.

14.01.03

(4) Instructions of the contractor given to the contract acceptor with respect to the contract manufacture.

(5) When the contractor gives instructions specified in the preceding item that any necessary action should be taken to improve the manufacturing control or quality control of the contract manufacture, confirmation by the contractor that such action has been taken.

(6) A method of quality control during transportation/delivery.

(7) Other matters required to ensure the proper conduct of the manufacturing control and quality control of the contract manufacture.


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2. The contractor and the contract acceptor shall document matters for the contract specified in the preceding paragraph in the product master formula, manufacturing control standard code, manufacturing hygiene control standard code, quality control standard code, and operating procedures. Proviso: In such cases, each of the contractor and the contract acceptor should document only the processes performed by herself/himself, notwithstanding the provisions of Article 4, 5, 7, and 9.

14.01.02

3. The contractor shall give written instructions specified in Paragraph 1, Item 4.

14.01

4. The contract acceptor shall report in writing to the contractor that the security pharmacist of the contract acceptor has released the products through appropriate evaluation of the manufacturing control and quality control of the contract manufacture.

14.01.02

5. The contractor shall have a person, designated beforehand, perform the following duties.

(1) To obtain confirmation specified in Paragraph 1, Items 3 and 5.

(2) To report in writing to the product security pharmacist of the contractor the confirmation results in the preceding item.

(3) To prepare records after the date of expiration specified in Item 1, and to retain the records thereof for the following periods after the date of preparation.

8.01.01




Article 15-2 The contractor may provide instructions, instead of written instructions specified in Paragraph 3 of the preceding article, by using an electronic system of information processing or by the following methods utilizing information communication technologies (hereinafter referred to as “electromagnetic methods” in this article) after having obtained the consent of the contract acceptor as specified in Paragraph 4. In such cases, it shall be recognized that the contractor has provided written instructions.

14.01


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(1) The following method A or B among the methods of using an electronic system of information processing shall be used.

2.06.03

A. The method to transmit instructions through an electric communication line connected between the user computer of the contractor and the user computer of the contract acceptor, and to enter in the files equipped with the user computer of the destination.

B. The method to provide, through an electric communication line, the contract acceptor with direct access to the instructions entered in the files equipped with the user computer of the contractor, and to enter in the files equipped with the user computer of the contract acceptor (when the contract acceptor provides consent or rejection as to whether to obtain instructions by electromagnetic methods, the method to enter the consent or the rejection in the files equipped with the user computer of the contractor.

(2) The method to distribute instructions entered in the files prepared with means capable of providing a safe entry to given matters, including a magnetic disk, CD-ROM or other equivalent means.

2.06.03

2. The methods specified in the preceding paragraph shall allow the contract acceptor to prepare a document by output of data entered in the files.

3. The term “electronic system of information processing” used in Paragraph 1, Item 1 means an electronic system of information processing, which connects, through an electronic communication line, the user computer of the contractor with the computer of the contract acceptor.

4. The contractor shall, when intending to give instructions specified in Paragraph 3 of the preceding article pursuant to the provisions of Paragraph 1, present the following matters to the contract acceptor beforehand, and obtain the consent of the contract acceptor in written or by electromagnetic methods.

(1) The method available to the contractor among the methods specified in Paragraph 1.

(2) The method to enter in computer files.


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5. When the contractor obtaining the consent specified in the preceding paragraph is informed in written or by the electromagnetic methods that the contract acceptor refuses to obtain instructions by electromagnetic methods, the contractor shall not give instructions specified in Paragraph 3 of the preceding article by electromagnetic methods. Proviso: This provision shall not apply when the contract acceptor has given the consent specified in the preceding paragraph.

6. The provisions of Paragraphs 1 to 5 inclusive shall apply mutatis mutandis to the written report specified in Paragraph 4 of the preceding article. In such cases, “contractor” in these provisions shall read “contract acceptor”, and “contract acceptor” shall read “contractor”.

Article 16 When the manufacturing process is performed at two or more manufacturing sites of the manufacturer, the manufacturer shall establish methods of quality control during transportation/delivery, and other necessary matters required to ensure the proper conduct of the manufacturing control and quality control of the manufacturing process.

2. The manufacturer shall document the matters established in the preceding paragraph in the product master formula, the manufacturing control standard code, the manufacturing hygiene control standard code, the quality control standard code and in the operating procedures. Proviso: In such cases, each of the contractor and the contract acceptor should document only the matters on the process performed by herself/himself, notwithstanding the provisions of Articles 4, 5, 7 and 9.

Section 6 Miscellaneous Provisions (Exceptions in Retention of Records) Article 16-2 Notwithstanding the provisions of Article 6, Article 8, Article 10 to Article 13 inclusive, and Article 15, the manufacturer or the contractor shall have the manufacturing control manager, the quality control manager or a person, designated beforehand, retain records specified under Article 6, Article 8, Article 10 to Article 13 inclusive, and Article 15 of biological products designated by the Minister for the periods specified by the Minister. Proviso: This provision shall not apply to cases where a contract has been closed between the manufacturer or the contractor and a source material collecting firm etc. for the relevant period based on the contract.

8.01.01


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Chapter 3 Manufacturing Control and Quality Control of Quasi-drugs

DRUMBEAT

Concept (Manufacturing Control and Quality Control of Quasi-drugs) Article 17 The provisions in Chapter 2 (excluding Article 4, Item 3; Article 6, Paragraph 2; Article 8, Paragraph 2; and Article 14, Paragraph 2) shall apply to quasi-drugs. In this case, “product security pharmacist (hereinafter referred to as “product security pharmacist”) under Article 2, Paragraph 1 shall read “responsible engineering manager”, and “product security pharmacist” in Chapter 2 (excluding Article 2, Paragraph 1) shall read “responsible engineering manager”.


DRUMBEAT

Concept (Date of Enforcement) 1. This ordinance shall come into effect on March 31, 1999.

the japanese gmp regulations 2003

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