Current Issues in QA of Medicinal Products Date: February 17, 2006 Time: 10:00 – 15:10 Venue: Kudan Kaikai Hall, Tokyo Organizer: The Society of Japanese Pharmacopoeia (SJP) (Incorporated Foundation) Sponsors: • Japan Federation of Pharmaceutical Manufacturersf Associations (JFPMA) • Japan Pharmaceutical Manufacturer Association (JPMA) • The Pharmaceutical Manufacturersf Association of Tokyo (PMAT) (Incorporated Association) • Osaka Pharmaceutical Manufacturers Association (OPMA) • Japan Medical Association (JMA) (Incorporated Association) PROGRAM 10:00-10:10 Opening Address from the Organizer Society of Japanese Pharmacopoeia (SJP) 10:10-11:10 International Harmonization and Future Trends of Japanese Pharmacopoeia (JP) Pharmaceuticals and Medical Devices Agency Adviser Mr. Takao Hayakawa 11:10-12:10 Current GMP Audit Practice after the Recent Amendments of Pharmaceutical Affaires Law Pharmaceuticals and Medical Devices Agency Office of Compliance and Standards GMP Expert Mr. Koji Nagashima Lunch Break 13:10-14:10 Future Development of Measures agains Illicit Drugs Ministry of Health, Labor and Welfare Pharmaceutical and Food Safety Bureau Compliance and Narcotics Division Assistant Manager Mr. Toshinari Teruoka Break (Cont.) 14:10-14:20 Current Issues of Drug Surveillance Ministry of Health, Labor and Welfare Pharmaceutical and Food Safety Bureau Compliance and Narcotics Division GMP Officer Mr. Yasuo Iimura Related reports Disclaimer Note: The Information Meeting gCurrent Issues in QA of Medicinal Productsh has been carried out also in Osaka on February 23, 2006 under the same program as the meeting in Tokyo, only the GMP presentation above was made by an alternative speaker. Key illustrations Table 1. Fundamental policies in the maintenance of Japanese Pharmacopoeia (JP) Table 2. Documents, which should be added as appendix to the GMP audit application forms for every 5 yearsf renewal of approvals Table 3. For manufacturing facilities abroad) Table 4. There are some documents required to be submitted before GMP audit applications including Table 5. Procedures of GMP audits for facilities located abroad Opening Address from the Organizer Society of Japanese Pharmacopoeia (SJP) (Gist) The progress in the research and development of medicinal products in our country is remarkable; however a number of difficulties have appeared recently. In this foundation (The Society of Japanese Pharmacopoeia) we selected some recent topics affecting the development of medicinal products, and with guidance and support we organized this information meeting and hope even small this would be helpful for all of you in the audience. We also would like to thank to our sponsors and to all participants. Note: The first of the series of information meetings was carried out on January 29, 1999 in Tokyo with the purpose to provide direct clarification for a number of current topics (organizational changes, acceptance of ICH Guidelines, GCP and the conduct of clinical trials). The title gNew Drug Evaluation Division Meetingh reflects the name of the current Evaluation and Licensing Division (ELD) back in 1999. Since then totally 50 meetings have been held as follow: Title No. New Drug Evaluation Division Information Meetings 22 Periodic ICH Information Meetings 13 Problems with Safety of Drugs 8 Problems with QA of Drugs 6 Japanese Pharmacopoeia 1 Total as of February 2005 50 International Harmonization and Future Trends of Japanese Pharmacopoeia (JP) Pharmaceuticals and Medical Devices Agency Adviser Mr. Takao Hayakawa 1 The presentation reflected the changes implemented prior to the adoption of the new XV Edition of the JP from the view point of the pharmaceutical affairs administration (regulatory agency) Key points of the presentation: The purpose of Japanese Pharmacopoeia (JP) is to indicate, in concert with state-of-the-art science and technology and medical demands, the official ggolden standardsh necessary to ensure the quality of domestic pharmaceuticals. JP is to clarify the criteria to judge of pharmaceuticalsf quality which are to be medically important. JP also specifies standards and test methods in order to comprehensively assure quality of medicinal products in general. JP also has a role as a mean for disclosure of information on pharmaceuticals and achieving greater public accountability. The JP is to be revised every five years and during this five-year interval supplement(s) may be issued, if necessary. JP XIV was adopted in April 2001 and followed by two supplements in January 2002 and January 2005. Now the JP XV is to be issued in April 2006. The fundamental policies to generate/revise JP have five main points as follows, which are summarized in Table 1: Table 1. Fundamental policies in the maintenance of JP I. In order to enrich JP, fully list up pharmaceuticals important for healthcare: • Considering USP and EP, review practical rules for pharmaceuticals to be listed up in JP • Review the organization of JP (e.g. classification of Part I and Part II) • Review relatedness of JP to other pharmaceuticals standards Cont. II. Upon necessity (e.g. new safety information, international harmonization by Pharmacopoeial Discussion Group (PDG)), prompt partial revision and operation III. Promote International Harmonization • Address the international harmonization actively and incorporate harmonized issues promptly • Internationalize (through, e.g. PDG) testing methods defined in JP • As a part of internalization, investigate measures to enhance JPfs credibility • Promote internalization of pharmaceutical excipients and general testing methods IV. Ensure transparency and generalization of JP • More effective methods/means to generalize JP • Disclosure on the web • Easy-to-understand JP (easily understandable terms/description) • Incorporation of advantages of USP and EP into JP • Improvement of additional information, such as references, appendix, index Cont. V. Introduce up-to-date analysis methods, which are accompanied with amendment of the General Rules, the Preparation Rules, the General Test Procedures, and promoting establishment of standards. Especially, introduction of testing methods which are listed up in the other pharmacopoeia such as USP, EP, or internationally harmonized, but not listed up yet in JP; and establishment of integrated nomenclature common to JP, Japanese Accepted Names (JAN) and International Nonproprietary Name (INN). For the revision for JP XV, the Ministry of Health, Labor and Welfare (MHLW) of Japan and the Pharmaceuticals and Medical Devices Agency (PMDA) had cooperated based on the policies described above, the former deciding inspection policies related to JP, while the latter dealing with practical affairs related to the revision. As a result, especially in the light of the trend of international harmonization, some testing procedures, reference information, pharmaceutical excipients, items in the General Rules, Preparation Rules, Part 1, Part 2 will be revised or added in JP XV. Another significant revision is for the organization of JP (See Fig. 2). In JP 15, the General Rule, the Preparation Rules, and the General Testing Procedures, which were included in Part 1 (including frequently used bulk drugs and fundamental preparations) and Part 2 (including mixed preparations and their bulk drugs, and also natural medicines and Rules, therefore) respectively in JP XIV, are integrated into single the gGeneral Rulesh, the gPreparation Rulesh and the gGeneral Testing Proceduresh. Pharmaceuticals are categorized gchemical pharmaceuticalsh and gnatural medicinesh. Some of the reference information (on UV and IR spectroscopy) for Part 1 and Part 2 in JP XIV are also integrated into single gUV spectroscopy reference informationh and gIR spectroscopy reference informationh. Comments of the JKS Analyst: The efforts above should be appreciated, including catching up with rapid development of science and technology by, e.g., incorporating up-to-date analyses and accommodating trend toward globalization / borderless, which are essential for todayfs world. The accessibility to contents of JP, that is, drug information, through the internet may help people learn more about pharmaceuticals. Nevertheless, these amendments are not really gprompth enough to be gup-to-dateh. The methods listed up in JP should have the universality and simplicity so that they could be performed without expensive equipments and complicated procedures, so it would be possible to incorporate them in JP earlier. Continuous information collection and more frequent revision would be helpful - to do so, simplification of revision procedure or staff increase may be helpful. Current GMP Audit Practice after the Recent Amendments of Pharmaceutical Affairs Law Pharmaceuticals and Medical Devices Agency Office of Compliance and Standards GMP Expert Mr. Koji Nagashima The presentation reflected the changes and implications after the enforcement of the revised Pharmaceutical Affairs Law (PAL) on April 1, 2005, as the Good Manufacturing Practice (GMP) – for both medicines (pharmaceuticals, biologicals) and medical devices is one of the areas most profoundly affected. Key points of the presentation: After the amendment of the Pharmaceutical Affairs Law, new GMP standards were imposed for pharmaceuticals and medical devices manufactures and marketing companies. Firstly, the responsibilities between manufacturers and manufacturing and marketing companies (MMMC) were divided clearly, and manufacturing and marketing companies were stipulated as entities who owe last responsibilities before products entering into market. MMMC have to observe GMP, which became more important and strict than ever in order to monitor the quality and safety of products. Licensing and authorization system has been redeemed according to the newly amended law. According to the revisions, MMMC are required to abide new ordinances such as GQP (Good Quality Practice) and GVP (Good Vigilance Practice), which were enacted separately in order to obtain licensing. Manufacturing companies or facilities have to meet the standard of Quality Management Systems (QMS) and facility standards. Foreign manufacturers or facilities need to obtain authorization in Japan. Manufacturing facilities and manufacturing and marketing companies have to agree mutually before manufacturing new products. GMP audits are subject to procedures, documents and facilities and manufacturing companies or facilities are subject to audit for licensing before obtaining license. GMP audits for biological preparation, radioactive products, radioactive vitro examination products, products which need techniques of genetically modification and cell cultivation, specified biological derived products or tissue or cell related products, new drugs before reexaminations and manufacturing facilities abroad are undertaken by PMDA. Quasi drugs, cosmetic products and other pharmaceutical products mentioned above, local authorities are responsible for GMP audits. PMDA conduct regular GMP audits once every two years and specific on demand audits considered required of reexamination for cases of recalls or equivalency approval of products. Generally GMP audits are on-site basis; however, in some cases document based audits are undertaken. These decisions are made depending on risk levels of products or past inspection histories. The decisions are based on types of products, process of manufacturing, productsf equivalency audit histories and their facilities and so on. First step of GMP compliance on-site audits is for manufacturing and marketing companies to submit application forms to the Office of Review Administration of PMDA. Then GMP Audit Division negotiates the schedule with manufacturing and marketing companies, the GMP audits are conducted by qualified inspectors dispatched from PMDA. The results of audits are fed back to manufacturing companies or facilities directly and if there are points necessary to be improved, they will submit final report after adequate revisions. Upon completion, the official documents are issued from PMDA, and the manufacturing companies have to store the documents on their side. PMDA issue result report to MHLW, local authorities or other authorities who will issue authorizations for manufacturers. In this process, manufacturing and marketing companies have to be careful about timing and duration of GMP audits. Generally, GMP audit application must be issued 6 months before drug or other productsf approval. However, for new drugs subject to a priority review, the schedule may be discussed with PMDA before submissions of applications for GMP audit. One of the PMDAfs missions is to conduct GMP audits and examinations for licensing for manufacturing facilities, and it has to conduct approval audits for manufacturing facilities abroad. Also PMDA conducts other audits, including inspections of manufacturers or those in abroad. When manufacturing and marketing companies submit GMP audit applications, they always have to be careful about timing of the productfs approval: preparations should be done adequately; otherwise audit schedule will be delayed. In order to obtain manufacturing and marketing approval from authorities, all of manufacturing facilities should be undertaken GMP audits before approval. It should be noted that GMP audits vary themselves depending on types of products and manufacturing facilities, and the amount of the audit fees. The MMMC submitting audit applications are required to undertake full scale validations. Generally, it is recommended that 3 lots for validations are completed, before submitting an audit application. According to the new GMP regulations, the MMMC should take responsibilities for facilitiesf GMP inspections. For the drugs before reexaminations, PMDA undertake GMP audits, as it is necessary to submit applications 6 months in advance to the renewal of the products. The MMMC have to check authorities where applications should be submitted for each active ingredient, which their facilities are manufacturing, since the authorities conducting the GMP audits might be different depending on the active ingredients. Note: The Tables 2 to 5 list documents required for submission to the authorities in various cases of GMP audits. Cont. Table 2. Documents to be added as appendices to the GMP audit application forms for every 5 yearsf renewal of approvals: 1) Copy of GMP auditfs result undertaken within 2 years 2) Copy of an approval letter of manufacturing and marketing of the product including appendix 3) Copy of an approval for equivalencies (Complete-change recognition document) within 5 years and of an application of slight modifications (partial change) within 5 years 4) If applications were made concurrently, classify them according to each facility, area and work place of the products 5) Recall histories if any within 5 years, 6) Form of declaration, and 7) Other documents if examiners will require. Table 3. For manufacturing facilities abroad 1) Copies of GMP audit report in the country or GMP inspection reports, 2) Certification document issued by WHO, and 3) Others required by auditors in Japan. Cont. Table 4. Documents required to be submitted prior the GMP audit applications including 1) Summary description of facilities 2) Layout drawing of the manufacturing facilities which shows their environment and layout 3) Plain view of the facility which shows work flow lines for personnelfs and materials, management levels for environment, pressure difference between rooms or others 4) GMP organization chart and documents of QA systems 5) GMP flow chart 6) Documents describing manufacturing process such as manufacturing process, test or examination context within the process, specifications and test procedures of raw materials or intermediate products, and acceptance test and specifications for raw materials 7) Documents describing validation tests and their result such as records of full scale validation tests undertaken for 3 lots, validation tests for cleanings 8) Deviation control procedures and their results 9) Equivalency audit procedures and their results 10) Shipment records from the facilities 11) Standard compliance report for biological derived materials 12) Past GMP inspection history including those undertaken abroad and their results. Table 5. Procedures of GMP audits for facilities located abroad 1) Similar methods undertaken in Japan and 2) Inspections are generally a group of 2 staffs for 3) Generally period of about 3 days, and 4) Notification of audits will be made from 3 to 6 weeks before the audits, and 5) Required documents for applications have to be made available one to two weeks before the audits application 6) Audits will be undertaken based on the documents focusing on important points. Special considerations that have to be made are: a) to apply equivalent method undertaken in Japan b) to hire adequate interpreter specialized in this field c) to translate documents if necessary d) to make efficient audit schedule e) to apply same standards adopted in Japan. According to new GMP audits, the important points are divided into major 6 categories: 1) management control audit, 2) facilities and equipments control audit, 3) storage control audit of bulk materials, 4) manufacturing process control audit, 5) packaging control audit, and 6) test procedure controls audit, as further detailed below: 1) By management control audit, deviation control such as QA divisionsf management, communication system, research of causes and countermeasures to avoid recurrence are examined. Equivalency audit including communication between QA divisions is also important factor to be monitored. Another factor is self-inspection practices which follow regulations and undertake amendment if necessary and storage of records. Communications between QA divisions are also monitored. If management control is undertaken by subcontractors, inspections of them are also required, including following the GMP by these agents is also monitored. Document control is one of key factors: storage of the original documents, their reevaluation, and distribution methods are also inspected. Conforming GMP procedure manuals and implementation of validation before and approval of the products are also checked, and the education systems are examined as well. 2) Facility and equipment control audit covers: implementation of insect control if necessary, repair of flaws of facility or equipment and implementation of countermeasures for biohazard areas. For aseptic laboratories or rooms isolation procedures are also checked. 3) Storage control of bulk materials includes: temperature control, facilities for storage, installation of temperature indicators and their position, implementation of labeling of materials during storage, adopting adequate storage method, implementation of insect control, adopting of anti-contamination measures, storage of shipment log books and so on. 4) Manufacturing process control audit covers: bulk materials control especially for biological, cell- or tissue-derived materials, contamination control during manufacturing process, manufacturing procedure including documentation of procedures, documentation of management of inadequate products, documentation of specification of filters used for anti-virus, air-conditioning, documentation of exchange of resin parts for purification columns, sanitation control of facilities including usage of adequate disinfections, adaptation of environmental control and insect control and so on, implementation of labeling within manufacturing facilities such as clean rooms, biohazard labeling, labels for pipes etc, aseptic methods if necessary, construction materials used for facilities, installation of alarms, implementation of validation for sterilization autoclaves, temperature control for cultivation bath, control of service water including regular monitoring, installation of procedure manuals, compliance with standards etc, shipment control including shipping conditions, installation of shipping logs. 5) Package control audit covers: management of inadequate products, control of labeling materials. 6) Test procedure control audit covers management of test procedures. For examples, it should be monitored when antibodies and radioactive markers are deployed, procedures or specifications of preparations and marking are adequately used; examination whether the purified water meets the standards and labels of test samples, agents, solvents and their expiration date; checking the undertaken packaging materials acceptance tests. Provision of examples of defective products for visual checks is required. Accuracy of facilities or equipments used for test or audit including microbial test incubator temperature distributions, sterilization autoclavesf calibration or check-up of a pair of scales should be examined. Aseptic test conditions, compliance of standards for animal tests such as adequacies of animal passages, adaptation of accumulation period, selections of animals, data controls, procedure for inadequate animals, conditions of autopsy rooms, and procedures after autopsies shall be examined. For record controls, implementation of double checks, records of equipments, preparation of agents should also be inspected. Future Development of Measures against Illicit Drugs Ministry of Health, Labor and Welfare Pharmaceutical and Food Safety Bureau Compliance and Narcotics Division Assistant Manager Mr. Toshinari Teruoka The presentation provides insights on the measures taken by the authorities in a response to the recent confirmation of sales of more than 100 different glaw-evading drugsh 2 in the country. Key points of the presentation: 1. What are the illegal drugs (so-called law-evading drugs)? • Products in sale assumed to be able to produce euphoria and generally pleasant feelings • Products (substances) not approved as drugs • Products sold mainly in so called adult shops or online 2. Health damage, hazards and accidents related to illegal drugs • Murder carried by a person in state of intoxication • Death of a person admitted in emergency unit where the exhibited symptoms were misinterpreted • Acute poisoning due to overdose 3. Control under the current system • Repeal of the sales and license cancellations under the Pharmaceutical Affairs Law • Reporting the distributors of the product gRushh (containing nitrites) to the Tokyo Metropolitan Police Department for opening a case. 4. Difficulty of the control under the existing system • Violations of the PAL have become increasingly sophisticated 5. Problems of the existing system • Inefficiencies of the existing control and management • The import of drugs for personal use is not restricted in the present drug legislation. 6. Summary of the proposal by the "Study Committee Concerning the Ideal Way for Measures against Law Evading Drugs" • Clear identification of ingredient as an illegal drug and clarification of regulation grounds • Limiting the risk of health damage by measures against products suspected to be illegal • Uniform regulations of the personal import of drugs and limiting the acquisition opportunities for illegal drugs as much as possible. Current Issues of Drug Surveillance Ministry of Health, Labor and Welfare Pharmaceutical and Food Safety Bureau Compliance and Narcotics Division GMP Officer Mr. Yasuo Iimura The presentation presents updates on the issues of pharmacovigilance, new guidelines and implementation to yield more practical results. As a background, in the recent years, a number of products – predominantly imported form China, with diet, slimming and weight-lose effects claimed, have been reported to have cause liver and other organ damages. In many case, those products belong to a grey regulatory zone – permitting both unrestricted import and unregulated claims. Key points of the presentation: 1. About the pharmacovigilance • Number of the pharmaceutical inspectors in the whole country – comments • Pharmaceutical inspector's business – duties, activities 2. Concerning the monitoring of unapproved medicinal products and food products • Appetite-controlling products and diet foods • Appetite-controlling products and diet foods falling under the PAB Notification N. 46 3 • Examples of advertisements of ghealthy foodsh in violation of the PAL • Hazard and health damages caused by unapproved medicinal products and food products, and their reporting • Cases of Chinese diet foods – reported in the summer of 2002 • Examples of health impairment due to use of the unapproved abortion preparation RU486 and dieting drug Tentensu • Cases with inclusion of Sildenafil 4 in a health foods for inducing vigor (stamina) and an example of mixture of structural analogs • Concerning the illicit drugs (so called law-evading drugs) • Types of illegal drugs, the actual sale situation, healthy damage examples • Control of the illegal drugs and future measures • Problems specifically related to Internet 3. Monitoring of adulterated drugs • Voluntary recall of adulterated medicines • Schemes of voluntary recall adulterated medicines • Transition of voluntary recall numbers adulterated medicines • Main recent collection cases • Review of the national authorization standards Related reports The repost listed below and previously published by JKS contain presentations and / or references to the topics of the present report: New Drug Evaluation Division Regular Meetings • Current Issues of QA of Medicinal Products (held in 2005): Available in the JKS Document Store Cont. • Individual reports on the New Drug Evaluation Division Regular Meetings – 18th, 19th and 20th (held in 2004), 21st and 22nd (held in 2005): Available in the JKS Document Store • 13th ICH Immediate Briefing (held in 2005): Available in the JKS Document Store • Report on the gDrugs and Medical Devices Safety Update Seminarh held in Tokyo on September 16, 2005 Available in the JKS Document Store __________________________________________________________ For further references on QA, GMP and other relevant issues of medicinal products in Japan, the readers can browse the online JKS Document Store or to send inquiries to Disclaimer This publication is based on information obtained through in-house research and from sources available to public and it is not a complete analysis of every material fact. 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Jouhou Koukai Services LLC and its business Jouhou Koukai Publishing provide information and intelligence on the Japanese pharmaceutical market in the fields of medicine, pharmaceuticals, patents, licensing, copyrights and data protection, business and corporate development, information technology, including e-health, and medical communication, however, this information does not constitute for nor can it be used as such for a substitute of medical, legal or investment advice. Worldwide Copyright © 2001-2006 by JKS LLC Reproduction in whole or part without permission is forbidden. 1 Mr. Takao Hayakawa is a former Deputy Director of the National Institute of Health Sciences. See also the previous presentation in the report gCurrent Issues in QA of Medicinal Products 2005h – in the JKS Document Store: ( 2 Law-evading drugs (also called ganalog drugsh) could cause the same effects as certain illicit substances, but are difficult to be designated as illegal narcotics because their chemical structure is modified so to slightly differ from recognized illegal drugs. Law-evading drugs often are commonly sold under the guise of chemicals not intended for human use, such as air fresheners, video head cleaners, etc. 3 Notification of the (now defunct) Ministry of Health and Welfare Pharmaceutical Affairs Bureau gGuidance on the control of unapproved impermissibility medicinal products" dated June 1, 1971 4 Sildenafil is the active ingredient of Viagra (approved in Japan) – see more in Japan Approvals Database, JAD) ( ?? ?? ?? ?? Current Issues in QA of Medicinal Products February 2006 JM_I_030- 3 - Current Issues in QA of Medicinal Products February 2006 JM_I_030- 26 - Current Issues in QA of Medicinal Products February 2006 JM_I_030- 35 -