Enterprise-wide Use License - Current Issues in QA of Medicinal Products Date: February 18, 2005 Time: 9:50 - 15:00 Venue: Kudan Kaikai Hall, Tokyo Organizer: The Society of Japanese Pharmacopoeia (SJP) (Incorporated Foundation) Sponsors: * Japan Federation of Pharmaceutical Manufacturers' Associations (JFPMA) * Japan Pharmaceutical Manufacturer Association (JPMA) * The Pharmaceutical Manufacturers' Association of Tokyo (PMAT) (Incorporated Association) * Osaka Pharmaceutical Manufacturers Association (OPMA) * Japan Medical Association (JMA) (Incorporated Association) PROGRAM 9:50-10:00 Opening Address from the Organizer Society of Japanese Pharmacopoeia (SJP) Mr. M. Uchiyama 10:00-10:30 Second supplement to the Fourteenth Edition of the Japanese Pharmacopoeia (administrative viewpoint) MHLW, PFSB, Evaluation and Licensing Division Division Head Mr. Akira Kawahara 10:30-11:15 Second Supplement to the Fourteenth Edition of the Japanese Pharmacopoeia (reviewer viewpoint) National Institute of Health Sciences Deputy Director Mr. Takao Hayakawa 11:15-11:25 Break 11:12-12:15 GMP compliance for medicinal products Tokyo Metropolitan Government, Bureau of Social Welfare and Public Health, Medical Welfare Division, Division Head Ms. Miki Machida Lunch Break (Afternoon Program continues on the next page) 13:20-14:10 Recent trends in GMP National Institute of Health Sciences Division of Drugs, Third Section Head Mr. Yukio Hiyama Break 14:10-15:00 Current issues of the pharmaceutical inspections: Recall of the medicinal products and the violations of the Pharmaceutical Affairs Law Ministry of Health, Labor and Welfare Pharmaceutical and Food Safety Bureau Compliance and Narcotics Division GMP Officer Mr. Yasuo Iimura Disclaimer Note: The Information Meeting "Current Issues in QA of Medicinal Products" has been carried out also in Osaka on February 24, 2004 under the same program as the meeting in Tokyo, only the two GMP presentations above were made by alternative speakers. Key illustrations Table 1. Official Monographs in JP XIV Figure 1. Overview of the changes in licensing system for medicinal products (diagram 1) Figure 2. Overview of the changes in licensing system for medicinal products (diagram 2) Opening Address from the Organizer Society of Japanese Pharmacopoeia (SJP) Mr. M. Uchiyama (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 "New Drug Evaluation Division Meeting" reflects the name of the current Evaluation and Licensing Division (ELD) back in 1999. Since then totally 44 meetings have been held as follow: Title No. New Drug Evaluation Division Information Meetings 20 Periodic ICH Information Meetings 11 Problems with Safety of Drugs 7 Problems with QA of Drugs 5 14th Japanese Pharmacopoeia 1 Total as of February 2005 44 Second Supplement to the Fourteenth Edition of the Japanese Pharmacopoeia (administrative viewpoint) MHLW, PFSB, Evaluation and Licensing Division Division Head Mr. Akira Kawahara The presentation reflected the changes and implications after the introduction of the Second Supplement from the view point of the pharmaceutical affairs administration (regulatory agency) Key points of the presentation: * Absorbent gauze and absorbent cotton: from medicinal products to medical devices (after April 1, 2005) * Adhesive plaster: to be excluded from the category and assigned as general merchandises (after April 1, 2005) * Powdered processed Aconite root: Added to the category * Medical devices: to be controlled under more stricter laws (e.g. GMP, GLP) * Partial amendments for the international harmonization of JP, EP and USP * General Tests: Collection amount test for injections: newly added * Additional revisions following the above * Announcement in June, implementation in July 2005 * Key changes in the Fourteenth Edition of the Japanese Pharmacopoeia (JP XIV) * Full-fledged revisions of General Notices * Categorization of General Tests * Configuration changes of Official Monographs for more flexibility * Additional descriptions of symbols to indicate the international harmonization: JP, EP, USP * Revisions of Japanese names * Website of the Japanese Pharmacopoeia * The Japanese Pharmacopoeia, Fourteenth Edition: online * The Japanese Pharmacopoeia, Fourteenth Edition (English Version): online * The First Supplement to the Japanese Pharmacopoeia, Fourteenth Edition: online * The First Supplement to the Japanese Pharmacopoeia, Fourteenth Edition (English Version): March 2005 * The Second Supplement to the Japanese Pharmacopoeia, Fourteenth Edition: May 2005 * The Second Supplement to the Japanese Pharmacopoeia, Fourteenth Edition (English Version): in 2005 Second Supplement to the Fourteenth Edition of the Japanese Pharmacopoeia (reviewer viewpoint) National Institute of Health Sciences Deputy Director Mr. Takao Hayakawa The presentation reflected the changes and implications after the introduction of the Second Supplement from the view point of the Pharmaceutical Affairs and Food Sanitation Council (PAFSC) - a deliberation committee to the MHLW Key points of the presentation: * Background of the Second Supplement to the Fourteenth Edition of the Japanese Pharmacopoeia * Fourteenth Edition: implemented in April 2001 * The First Supplement to Fourteenth Edition: implemented in January 2003 * The Second Supplement to Fourteenth Edition: implemented in January 2005 * Fifteenth Edition: to be implemented in April 2006 * Key changes in the Second Supplement to the Fourteenth Edition of the Japanese Pharmacopoeia 1. General Tests: new (1 item), revision (6 items) 2. Official Monographs: * The First Part: new (27 items), revision (53 items), omission (1 item) * The Second Part: new (12 items), revision (22 items), omission (9 items) 3. General Rules for Crude Drugs; amendment (1 item) Listed below for easy reference are the changes - including revised texts and newly introduced parts after the Second Supplement 1.1 General Tests - Biological Tests Revision: 15. Bacterial Endotoxins Test (for international harmonization) Gel-clot techniques (2) Limit Test. 47. Pyrogen Test (for consistency with EP) Test animals, apparatus and instruments, test procedures, interpretation of the results. 59. Sterility Test (for international harmonization) Full-fledged revision: Microorganisms for growth promotion test; Number of items to be taken from the lot; Minimum quantity taken from each medium, etc. 1.2 General Tests - Physicochemical Tests Revision: 8. Nuclear Magnetic Resonance Spectroscopy Wider range of nuclide, the new registry of apparatus, instruments and measurement conditions, the revisions of verification procedures and each test procedure of 1H NMR and 13C NMR. 16. Residue on Ignition Test (for international harmonization) Revisions of crucible materials, temperature and time of ignition process, etc. 1.3 General Tests - Physical Property Tests New: 74. Determination of Powder Particle Density (Listed on EP and USP) Method to determine the particle density of powdered medicinal products with gas displacement pycnometer Revision: 53. Specific Surface Area Determination Additional explanations for the test method, provisions of the constants, etc. 2.1 Official Monographs - Number of items Table 1. Official Monographs in JP XIV Items First Section Second Section New 27 12 Revised 53 22 Deleted 1 9 Total in Section 907 484 Total number of Monographs 1,391 Note: After the implementation of the Second Supplement 2.2 Official Monographs - for international harmonization Medicinal Additives ? Carmellose Calcium July 2003 ? Wheat Starch October 2001 ? Cellulose Acetate Phthalate October 2001 ? Corn Starch October 2001 ? Potato Starch October 2001 ? Benzyl Alcohol July 2003 2.3 Official Monographs - Transitions from other regulations (for international harmonization) ? From The Japanese Pharmaceutical Codex 2002 (First Section) Alprostadil, Etoposide, Eperisone Hydrochloride, Tizanidine hydrochloride, Pirenzepine Hydrochloride, Glutathione, Cisplatin, Serrapeptase, Nicorandil, Nilvadipine, Piroxicam (11 items) (Second Section) Tiaramide Hydrochloride Tablets, Trichlormethiazide Tablets, Furosemide Tablets, Flopropione Capsules, Metoclopramide Tablets (5 items) ? From The Japanese Standards for Herbal Medicine (1989) Termeric, Lindera Root, Lycium Fruit, Lycium Bark, Tribulus Fruit, Cnidium Monnieri Fruit, Sappan Wood, Lonicera Leaf and Stem (8 items) ? From The Japanese Pharmaceutical Codex, Third Section "Dissolution for Preparations" Tiaramide Hydrochloride Tablets, Benidipine Hydrochloride Tablets, Trichlormethiazide Tablets, Nilvadipine Tablets, Furosemide Tablets, Metoclopramide Tablets (6 items) ? From The Japanese Pharmaceutical Codex, Fourth Section "Antibiotics Drugs" Azithromycin Hydrate, Flomoxef Sodium for Injection, Cefepime dihydrochloride for Injection (3 items) 2.5 Official Monographs - Newly added to the Japanese Pharmacopoeia (First Section) Benidipine Hydrochloride, Oxytocin, Methylprednisolone Succinate, Tranexamic Acid Capsules, Tranexamic Acid Tablets, Tranexamic Acid Injection, (Flopropione Capsules) (7(6) items) (Second Section) Epimedium Herb, Processed Ginger, Processed Aconite Root, Powdered Processed Aconite Root (4 items) 2.5 Official Monographs - Excluded from the Japanese Pharmacopoeia (First Section) Santonin Tablets (Second Section) Absorbent Gauze, Sterile Absorbent Gauze, Absorbent Cotton, Purified Absorbent Cotton, Sterile Absorbent Cotton, Sterile Purified Absorbent Cotton (→medical devices) Digitalis, Powdered Digitalis Adhesive Plaster (to be treated as general merchandise) 3. General Information - International harmonization status update (1) Carmellose Calcium, Wheat Starch, Cellulose Acetate Phthalate, Corn Starch, Potato Starch, Benzyl Alcohol (2) Amino Acid Analysis (Completely harmonized) (3) Capillary Electrophoresis (Completely harmonized) (4) Protein Determination (Partially harmonized) (5) Isoelectric Focusing (Completely harmonized) (6) Peptide Mapping (Completely harmonized) (7) Rapid Identification of Microorganism by Gene Analysis (New, Japan original) (8) Density of Solids or Powder Particles (In progress) GMP compliance for medicinal products Tokyo Metropolitan Government Bureau of Social Welfare and Public Health Medical Welfare Division Division Head Ms. Miki Machida The presentation focused on the pending amendments in the Pharmaceutical Affairs Law (PAL) due to enter into effect from April 2005, as the most significant changes shall affect the current manufacturing and import license system to be replaced with new types of licenses. Key points of the presentation: ? Key changes in the GMP of Medicinal Products under the revised Pharmaceutical Affairs Law ? If any plants do not comply with GMP of medicinal products - Approval for manufacturing and sales are not to be granted. ? Medicinal Products exempted from GMP compliance: (1) Active substances for human drug use for extermination and prevention of rat infestation, or for sterilization and disinfection, not directly applied to the body / animal use drugs to be included. (2) Medicinal products for in vitro diagnostics, not directly applied to the body → animal drugs only, human use drugs to be excluded. ? Category of medicinal products for in vitro diagnostics: Medicinal Products to be re-categorized as Medical Devices ? Documentation to be prepared and stored by manufacturers: (to be revised) ? Manufacturing at two or more plants: GMP Agreements with import suppliers: GMPI License holders of drug manufacturing and selling license to arrange agreements with manufacturers and to specify the obligations to the manufacturers ? Advance application of license renewal - timeline for submission ? Drug manufacturer's licenses and drug import and sales licenses expiring within 2005 - by February 4, 2005 ? Pre-manufacturing and selling notifications, etc by February 10, 2005 ? Advance application of manufacturer's licenses, etc. ? Application for Drug manufacturer's license: (Warehouse Branches should apply) ? Drug manufacturing and selling license ? Application for conformity inspections Note: See the Figures 1 and 2 (next pages) for further details Figure 1. Overview of the changes in licensing system for medicinal products (diagram 1) Source: Tokyo Metropolitan Government Bureau of Social Welfare and Public Health (modified) Figure 2. Overview of the changes in licensing system for medicinal products (diagram 2) Source: Tokyo Metropolitan Government Bureau of Social Welfare and Public Health (modified) Recent trends in GMP National Institute of Health Sciences Division of Drugs, Third Section Head Mr. Yukio Hiyama The presentation summarized the implications of the amendments in the pharmaceutical regulations in Japan in term of GMP requirements. Three relevant guidelines explained in details. Key points of the presentation: ? Key points of revised Pharmaceutical Affairs Law > Introduction of license holder (wholesaler) approval system > Manufacturing approval, import approval > Sales approval License Holders: Responsible for an entire process of supply of medicinal products * Feasibility of full contract manufacturing: regulatory flexibility for business models * Manufacturing processes: to be described on the certificate of approval * GMP compliance: necessary requirement for approval GMP guideline for preparation of medicinal products ? Overviews of GMP guideline for preparation of medicinal products * Directly targeted for new medicinal drugs, recommended for other drugs * All the GMP requirements (incl. GQP Ordinances) included * Contract manufacturers of medicinal products postulated * Practical procedures for GMP compliance at plants ? Framework of GMP guideline for preparation of medicinal products 1. Preface 2. Quality management 3. Employees 4. Structures and facilities 5. Process facilities 6. Documentations and Records 7. Management of primary materials 8. Management of manufacturing and other processes 9. Packaging and identification labeling 10. Storage and shipment 11. Management of testing laboratories 12. Validation 13. Change control 14. Rejection and reuse of products 15. Complaints 16. Recall 17. Contract manufacturers (incl. Testing institutions) 18. Distributors and sales intermediaries Guideline for technology transfers ? Overviews of guideline for technology transfers * Ensuring the quality consistency from development to manufacturing. * Reproductability of the design quality * Quality consistency with the standards. * Document management and updating of technical information ? Framework of guideline for technology transfers * Process outline of technology transfers * Procedures and formats * Exemplification of information following technology transfers * Documentations of technology transfers Guideline for management of testing laboratories ? Overviews of guideline for management of testing laboratories * Implementation of Good Practice based on the actual conditions of testing laboratories * Both in-house testing laboratories and contract testing laboratories included * Subordinate of GMP guideline for preparation of medicinal products * Two main categories: Recommendations for management and technical recommendations ? Framework of guideline for management of testing laboratories (Draft) * Preface * Recommendations for management * Technical recommendations ? Certificate of approval under revised Pharmaceutical Affairs Law * Manufacturing process is included to the qualification of medicinal products. * Minor modifications defined in Certificate of approval: * Supplemental NDA - with Notification * Object of Supplemental NDA: ? Items that require double-check by the regulations ? Items that cannot be assessed with the evaluation method of manufacturing process adopted at the time of the application of the approval ? Registration patterns of range, target value / preset value * Range described on the certificate of approval, with no acceptable range * Target value / preset value described on the certificate of approval, with acceptable range descried in SOP * Range described on the certificate of approval, with acceptable range descried in SOP ? Regulations of modification control under revised Pharmaceutical Affairs Law (Q8, P2) * Major modifications that have a strong probability to affect the quality: ? To submit Supplemental NDA and required documents to the regulatory authorities and to obtain an approval prior to implementation. Revised P2 documents and other required documents might be submitted as appropriate * Minor modifications that have a least probability to affect the quality: ? To confirm that the modifications do not affect the quality and to notify the details of the modifications to the regulating authorities within 30 days from the implementation. Current issues of the pharmaceutical inspections: Recall of the medicinal products and the violations of the Pharmaceutical Affairs Law Ministry of Health, Labor and Welfare Pharmaceutical and Food Safety Bureau Compliance and Narcotics Division GMP Officer Mr. Yasuo Iimura The presentation was prompted and dealt with the recent surge of imports of unauthorized medicinal products and borderline products with unauthorized claims. Key points of the presentation: ? Unapproved and unauthorized drugs * Healthy foods (Supplements) that contain pharmaceutical ingredients * Healthy foods (Supplements) that claim for pharmaceutical effects or imitate pharmaceutical designs * Medicinal products that are not yet approved nor authorized (Excluding investigational drugs, laboratory reagents) * Foreign-made medicinal products without import and sales licenses * Imitation drugs * Unregulated drugs Manufacturing approval, import approval To be replaced with Sales approval License holders: to be responsible for the entire process of the supply of medicinal products ? Testing institutions * Designation system - change to Registration system * Renewal of the registration: every 6 years * Changes of names, address, operation ranges: Prior notifications required * Test operating rules: Prior notifications required * Operating books: to be furnished * Cessation/suspension of the operation: Prior notifications required * Financial statements, etc: to be furnished * Operation rages: 1. Testing of medicinal products requested by pharmacies and general sellers 2. Testing of medicinal products, quasi-drugs and cosmetics, toilet articles, requested by manufacturers: > Testing of primary materials and other materials > Advanced physicochemical tests related to the products and animal tests ? Name indication of License holders of drug manufacturing and selling * Names and addresses legally to be indicated * When to indicate other company names, the name of license holder should be clearly identifiable * License holders should be indicated with the term manufacturer and seller * Other companies names should not be associated with the terms such as "total" or "responsible" > When using the term "original" to indicate the sellers, the manufacturer and seller should also be indicated with "original" __________________________________________________________ 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 regulatory@jouhoukoukai.com 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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Worldwide Copyright (c) 2001-2005 by JKS LLC Reproduction in whole or part without permission is forbidden. www.jouhoukoukai.com JP, Japanese Pharmacopoeia; EP, European Pharmacopoeia; USP, US Pharmacopoeia The texts from JP are accessible online at the following URL: http://www.mhlw.go.jp/topics/bukyoku/iyaku/yakkyoku/index.html Current Issues in QA of Medicinal Products February 2005 JM_I_015 - 3 - Current Issues in QA of Medicinal Products February 2005 JM_I_015 - 17 - Current Issues in QA of Medicinal Products February 2005 JM_I_015 - 19 - Current Issues in QA of Medicinal Products February 2005 JM_I_015 - 27 -