Agenda. The current state of Pharmaceutical Excipients in Japan -JPE, JP, DMF, GAB (GMP Auditing Board)- Pharmaceutical Excipients

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1 The current state of Pharmaceutical Excipients in Japan -JPE, JP, DMF, GAB (GMP Auditing Board)- Dr. Keiji Kijima, Secretary General, IPEC Japan April 26, 2012 Agenda JPE (Japanese ) JP (Japanese Pharmacopoeia) MF (Master File System) GAB (GMP Auditing Board) others are substances(s) other than drug substance(s) contained in preparations which are used to increase the utility of the preparation, to enable manufacturing of drug products easy, to keep product s integrity, to improve the appearance of a formulation and so forth. For these purposes, suitable excipients may be added in the drug manufacturing. The excipients used, however, must be non-toxic, harmless and pharmacologically inactive in the amount administered and must not interfere with the therapeutic efficacy or the quality test of the preparations. (JP16) 1

2 Notification JPE Public consultation Study Committee Proposal IPEC Japan (Council) Japanese Pharmaceutical Excipient (JPE) As preparation technologies are advanced and preparation designs are diversified, the role of pharmaceutical excipients is increasing in the characteristics such as dissolution, stability, solubility, etc. Japanese Pharmaceutical Excipient (JPE) Ministry of Health, Labor and Welfare (MHLW) announced the standards of the pharmaceutical excipients not included in Japanese Pharmacopoeia by the publication of Japanese. Total Monogrphs Japanese monographs Japanese Pharmaceutical Excipients/Supplement monographs supplied and 1 monograph deleted ---Total 297 monographs 2

3 Total Monogrphs Total Monogrphs JPE monographs supplied Total monographs 396 Japanese monographs supplied and 2 monographs deleted ---Total 436 monographs Japanese monographs added and 1 monographs deleted ---Total 479 For the Revised Japanese (JPE) 2012 For the Revised Japanese (JPE) 2012 MHLW started the committee for the revision of JPE in The committee has been held 9 times till Dec [Expected: Revised---approx. 40 monographs; New---approx. 12 monographs] The public comment will be collected in spring of A notification will be given by a chief of the bureau in charge in summer. 3

4 Situation of Japanese (JPE) Situation of Japanese Pharmaceutical Excipients (JPE) JPE consists of pharmaceutical excipients not included in Japanese Pharmacopoeia as well as those having precedent use and often used for the marketable pharmaceutical preparations. There are also pharmaceutical excipients specified in attachment in the application of approval of medicines Therefore, it is useful for pharmaceutical companies to apply for the approval of medicines. The pharmaceutical excipients, not applied to GMP, are applicable to SELF-IMPOSED STANDARDS FOR MANUFACTURING CONTROL OF PHARMACEUTICAL EXCIPIENTS (SELF- IMPOSED GMP). Judgment of advisability Judgment of advisability JPE is provided to determine the standards concerning General Notices, Preparations, Descriptions, Storages, etc. The pharmaceutical excipients are to be tested according to the provisions given in General Notice, General Tests and the pertinent monographs. The items of the Description in the monographs are given for the information, and should not be taken as indicating standards for conformity. 4

5 Situation of Japanese Pharmaceutical Excipients (JPE) Situation of Japanese Pharmaceutical Excipients (JPE) Unless otherwise specified in General Notices, General Tests and the pertinent monographs, the provisions given in General Notice, General Tests in JP 16 shall be applied. For pharmaceutical excipients specified in JPE Monographs which are manufactured as source materials derived from animals, the relevant animals must be healthy in principle, unless otherwise specified. Pursuant to Paragraph 1, Article 41 of the Pharmaceutical Affairs Law (Law No.145, 1960), the Japanese Pharmacopoeia (hereinafter referred to as new Pharmacopoeia ), which has been established as follows*, shall be applied on April 1, *The term as follows here indicates the contents of the Japanese Pharmacopoeia Sixteenth Edition from General Notices to Ultraviolet-visible Reference Spectra (pp ) The official name of this pharmacopoeia is 第十六改正日本薬局方, and may be abbreviated as 日局十六, 日局 16, JP XVI or JP 16. The English name of the pharmacopoeia is The Japanese Pharmacopoeia, Sixteenth Edition. 5

6 JP Edition Publication Outline Monographs JP 年 272 JP Supplement I partial revision Glycerin (DEG) 1567 partial revision Heparin Sodium (OSCS) 1567 partial revision Supplement II partial revision JP JP 16 th Edition carries 1764 articles, owing to the addition of 106 articles and the deletion of 15 articles. Ministerial Notification based on Pharmaceutical Affairs Law Final Draft JP Public consultation JP Committee PMDA (Expert Committee) The following items in General Tests, Processed and Apparatus were revised: 2.01 Liquid Chromatography 2.46 Residual Solvents Test 2.51 Conductivity Measurement 2.54 ph Determination 2.58 X-Ray Powder Diffraction Method 3.01 Determination of Bulk and Tapped Densities and so on. Total 15 items 6

7 Master File System for Drug Substances The harmonized General Tests and Monographs among the Japanese Pharmacopoeia, the European Pharmacopoeia and the United States Pharmacopeia are preceded by the statement as such. The parts of the test, being not harmonized, are surrounded by the symbols( ). Based on the Revised Pharmaceutical Affairs Law which was enforced on April 1, 2005, Master File Systems (MF) had been implemented ever since in Japan. Master File System for Drug Substances However, concerning existing pharmaceutical excipients, it is considered appropriate to refrain from submitting application of MF in Japan at present based on the PFSB/ELD Notification No issued by Ministry of Health, Labor and Welfare on February 10, Scope of MF Utilization Applications of MF registrations and changes to registered contents and notifications of minor changes to the registered contents shall be submitted to the Pharmaceuticals and Medical Devices Agency (hereinafter referred to as PMDA ), pursuant to the procedures and forms specified in the Enforcement Regulations of the Pharmaceutical Affairs Law (MHW Ministerial Ordinance No.1, 1961). 7

8 Items for registration The following raw materials to be used for the manufacture of pharmaceuticals and medical devices can be registered in MF. Items for registration 1. Drug substances, intermediates and pharmaceutical product materials (materials of pharmaceutical products with special dosage form, etc.) 2. New excipients and pre-mix excipients with a different composition ratio from existing ones 3. Materials for medical devices 4. Containers / packaging materials Items for registration Drug substances, intermediates and pharmaceutical product materials (materials of pharmaceutical products with special dosage form, etc.) used for OTC drugs (excluding OTC with new active ingredients or those with their active ingredients still in the reexamination period) are not appropriate for registration in MF, as it is considered that their quality and safety are already established even with existing specification and test methods. SELF-IMPOSED STANDARDS FOR MANUFACTURING CONTROL OF PHARMACEUTICAL EXCIPIENTS (SELF-IMPOSED GMP) As the pharmaceutical excipients in JP 16 are generally classified as Medicine, they should follow the GMP standard. Among them, 108 monographs receive the application of the GMP HARDWARE, but avoid the application of GMP SOFTWARE. IPEC Japan started the work to edit SELF- IMPOSED GMP since The process is as follows: 8

9 SELF-IMPOSED GMP GMP SOFTWARE SELF-IMPOSED GMP GMP HARDWARE Established April 1, 1996 Established April 1, 1998 The 1 st revised version October 1, 2006 The 1 st revised version October 1, 2006 The 2 nd revised version December 7, 2006 SELF-IMPOSED GMP VALIDATION STANDARDS SELF-IMPOSED GMP COLLECTION OF Q & A Change of management, Deviation of management and Addition of Q & A about the validation standards Established October 1, 2006 Established April 1,

10 SELF-IMPOSED GMP GUIDANCE BOOK FOR PLACTICE <Revision> Established December 1, 2010 In order not to interfere with enforcing the selfimposed GMP, explanatory information, matters to be checked or attended, and Q&A are supplemented to each articles. English Version English version of SELF-IMPOSED GMP AND ITS EXPLANATION was completed on December 1, 2011 to inform our GMP to foreign countries. In addition, the GMP Committee of IPEC Japan is making a comparison of SELF- IMPOSED GMP with ICH Q7 or IPEC Joint GMP to understand GMP at the level of the international standard. GMP Auditing Board for According to MHLW Ministerial Ordinance about GQP; The manufacturers of APIs shall ensure that the production duties at the factory concerned are conducted properly and efficiently with manufacturing control and quality control. GMP Auditing Board for However, As for pharmaceutical excipients, the production duties are not established as legal requirements. 10

11 GMP Auditing Board for Pharmaceutical excipients are often used in common at plural pharmaceutical companies. In that case, It is a good policy for the pharmaceutical companies to reduce an audit burden by using audit result of the 3 rd party. GMP Auditing Board for The manufactures of pharmaceutical excipients can reduce a burden to accept an audit from every company that is using the same product, too. GMP Auditing Board for GMP Auditing Board for GMP Auditing Board for Pharmaceutical Excipients is established in 2005 to secure the quality of pharmaceutical excipients of our country and to raise the reliability of the manufacturers of pharmaceutical excipients. The Board evaluates the GMP situation enforced by the manufactures based on SELF-IMPOSED GMP STANDARDS, edited by IPEC Japan, and then performs appropriate authorization. 11

12 Outline of GMP Auditing Board for Advantage of GMP Auditing Board for The board audits the pharmaceutical excipients company whether the company conducts production duties at the manufacturing site concerned properly and efficiently with manufacturing control and quality control. Therefore, the pharmaceutical company might secure the good quality and reliability of the pharmaceutical excipient product effectively if passed the audition. Japanese Directory by IPEC Japan The number of Pharmaceutical excipients, which have been used so far, is 1228 monographs according to Japanese Directory But among them, about 200 monographs are listed in JP 16. Japanese Directory by IPEC Japan Pharmaceutical excipients which are generally used in the process of dosage form formulation play an important role in securing the quality, efficacy and safety through maintaining the dosage form and stabilizing the drug. In association with higher levels of pharmaceutical technology and diversified dosage forms in recent years, the role of pharmaceutical excipients has been increasing. For the purpose of appropriate use of pharmaceutical excipients, the Japanese edition of Japanese Pharmaceutical Excipients Directory (JPED) was published on the basis of collective investigations of the available information on definitions, properties, specifications, uses, maximum dose and so forth related to approval drugs. 12