GMP IN THE CURRENT REGULATORY EMVIRONMENT Industry perspective of Japan

ICH Q7A (GMP for API) arrived at final agreement and Step 4 sign off on 10Th November 2000 at San Diego ICH-5. The Q7A document will be enforced by April 2001 in all of three regions ( USA, EU & Japan ). In Japan, the Q7A document is now under translation into Japanese and the Japanese version of the Q7A document will be published as a notification.

Status of this document (Guide) This document(Guide) is the guidance, not the regulation. This document should be applied not only for new submission drugs but also for already marketed drugs. This document should exert an influence on all manufacturers that would supply an API to the ICH three regions.

Table of Content Section Title 1 Introduction 2 Quality Management 3 Personnel 4 Buildings and Facilities 5 Process Equipment 6 Documentation and Records 7 Materials Management 8 Production and In-Process Controls 9 Packaging and Identification Labelling of APIs and Intermediates 10 Storage and Distribution 11 Laboratory Controls 12 Validation 13 Change Control 14 Rejection and Reuse of Materials 15 Complaints and Recalls 16 Contract Manufacturers (including Laboratories) 17 Agents, Brokers, Traders, Distributors, Repackers, and Relabellers 18 Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 19 APIs for Use in Clinical Trials 20 Glossary

Scope This Guide applies to the manufacture of APIs for use in human drug (medicinal) products.　 In this Guide “manufacturing” is defined to include all operations of receipt of materials, production, packaging, repackaging,labelling, relabelling, quality control, release, storage and distribution of APIs and the related controls.

The company should designate and document the rationale for the point at which production of the API begins. For synthetic processes, this is known as the point at which "API Starting Materials" are entered into the process. For other processes ( e.g.fermentation, extraction, purification, etc), this rationale should be established on a case-by-case basis.

Current Japanese GMP system 　GMP for Medical drug (API and drug product) and 　 　quasi drug [ministerial ordinance] 　 ・Regulation for Manufacturing control and 　　 Quality control (Soft) ・Regulation for Building and Facilities for Pharmacies etc., (Hard) 　 Regulation for Quality Assurance of Imported Drugs (GMPI) [ministerial ordinance] In Japan, Compliance with GMP is a requirement for a marketing license and license renewal.

GMP(complementary) ・Biological preparation [Notification] 　　・Ethical Extract product in Kampo medicine 　　 　　　Formulation [voluntary standard] 　　・General herb medicine in Kampo Formulation 　　 　 [voluntary standard] 　　・Ethical Molded poultices [voluntary standard] 　　・in vitro Diagnostic [voluntary standard] Other ・GMP for Drug use for Clinical trials [Notification] ・GMP for Medical excipient [voluntary standard] ・Technical Guideline for Manufacturing and Quality 　 　control of Cosmetics [voluntary standard] ・GMP for Medical Devices [ministerial ordinance]

After Q7A( GMP for API) enforcement Current J-GMP API Notification based on (basically) ICH Q7 document Drug product There are some difference between current J-GMP and ICH Q7A document, such as Quality management, Containment, Impurity profile, Contract manufacturer, API for use in clinical trials et.al.,

Quality management Manufacturing control manager Product security pharmacist (Production department ) (Manufacturing manager) Activity Quality control manager Releasing and rejecting (Quality department) Approving all procedure, Specification,changing * Prescription in the Pharmaceutical Affair Law (Production department) Manufacturing control manager (Quality unit) Product security pharmacist Quality control manager

Containment Current J-GMP When a drug which is easy to disperse and causes anaphylaxis in small quantities (that means an antibiotic of penicillin group) is manufactured simultaneously with other drugs, its manufacturing room and air-handling system shall be separated from those used for other drugs. Q7A document Dedicated production areas, which include facilities, air handling equipment and/or process equipments, should be employed in the production of highly sensitizing materials such as penicillins or cephalosporins.

Companies'requirements in order to meet need for dedicated production area No. companies responding(N=44) % Sufficient 13 29.5 Some remodeling/amendment 14 31.8 is necessary Difficult 17 38.7

Impurity profile will be required for a marketed drug Impurity profile data Level of data No. companies responding(n=67) % All products have sufficient data 9 13.4 Some product(s) do not have sufficient data: 58 86.6 a) Impurity is examined, but not for an impurity profile 50 74.6 b) Impurity is not examined 8 13.4

Option No.of respondents In the case of having only insufficient data Option No.of respondents (n=57) % Some lots should be examined to confirm an impurity profile 44 77.2 by appropriate methods On account of the nature of the product, it is difficult to perform 13 22.8 an examination of impurity profile

Future actions regarding impurity testing No. of Option respondents (n=61) The impurity profile is set a routine (lot) test 14 The impurity profile is to be certain frequency 40 Other(at the time of process changing, first 3 lots et al.,) 5 Impossible 2

Contact manufacturer Contract manufacturer is not available for API on current J-GMP. Japanese companies expect to be de-regulated after enforcement of this ICH document. APIs for use in clinical trials In Japan, other GMP than medical drug should be applied to an API for use in clinical trials. Japanese company want to apply this document to an API for use in clinical trials.

Foresight It clarifies Control items, Standards, Criteria, etc., GMP controlled under same standards throughout the three ICH regions. Increase in the level of quality assurance (include countries out of the ICH regions) It accelerates MRA of GMP. (include countries out of the ICH regions) It reduces barriers for export/import, facilitating the import/export of APIs. Importation of major and good quality material assured