Ch. Pharmacopoeia 2015

Chinese Pharmacopeia 2015 New Milestone of Excipients Standards in China Jessica Zheng Chair, Industry Liaison Committee, IPEC China Regulatory Manager China, Merck [email protected]

IPEC Europe Annual Seminar Nice, Feb. 5, 2015

Content: Chinese Pharmacopeia (ChP) regulatory position in China Overview of ChP 2015 Features of Excipients standards in ChP 2015 ChP approach in harmonization and industry involvement

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ChP Regulatory Position in China ChP Compliance is very important for excipient regulatory compliance in China! Drug Administrative Law (No.45, 2001)

•Active ingredients, excipients used in drug manufacturing must meet the requirements for pharmaceutical application •Drug administrative law is under revision process, intend to further clarify the requirements of excipients

Administrative Regulation of Drug Registration (No. 28, 2007)

•National drug standards are Chinese Pharmacopeia, drug registration standards and other drug standards issued by CFDA. •Drug registration standards should not be lower than monograph requirements in ChP. •The setting of test items and test methods in drug registration standards should meet the basic requirements of ChP.

Regulation of Strengthening Supervision on Excipients (2012)

•For excipients already have national drug standards, must meet the requirements of national drug standards •CFDA organize ChP committee to formulate, revise and issue national excipients standards. To research and issue the recommended excipients standards. 3

ChP Regulatory Position in China ChP Compliance is very important for excipient regulatory compliance in China! CFDA notice about renew registration of imported drug (No.18, 2009)

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Because of ChP or local pharmacopeia update, the registration standards of imported drug need to update accordingly. The applicant need to submit the supplementary application separately before the renew application.

CFDA notice about implement ChP 2010 (No.43, 2010)

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For any drug registration standard which not meet the ChP requirements, the drug manufacturer should submit the supplementary application to change the drug registration standards.

Chinese Pharmacopeia (2010)

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General notice No. 22: The drug substances and excipients used in preparations or dosage forms should comply with the requirements stated in the individual monographs of this edition of Pharmacopoeia. 4

Content: Chinese Pharmacopeia (ChP) regulatory position in China Overview of ChP 2015 Features of Excipients standards in ChP 2015 ChP approach in harmonization and industry involvement

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Overview of ChP 2015 Recent Time Schedule : Finalize* Manuscript

2014.6

Public Comment

Unify Manuscript

2014.7

Issue Implement

Print

2014.8

Press Proofread

2014.12

2015.1

2015.7

Publish ChP 2015

*: Draft and revision finalized by local drug institute and submitted to ChP committee Page 6-10: data from ChP 2015 Compilation Situation, Wei Zhang, General Secretary of ChP Committee, 2014 Joint ChP-USP Science and Standards Symposium

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Overview of ChP 2015 The total No. of monographs in ChP 2015 is 5682, the growth reach 24.4% The No. of monograph standards improvement is 2831

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Overview of ChP 2015 ChP main structure change: 3 volumes

4 volumes

Volume I: Traditional Chinese Medicine Volume II: Chemical Medicine

Volume III: Biologics Volume IV: General chapters (appendices), Guidances and excipients monographs

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Overview of ChP 2015 New encoding system for general chapters Coding Series

Category

0100 Series

General Chapter for Drug Formulation

0200 Series

Other General Chapter

0300 Series

General Identification Test

0400 Series

Spectroscopic Methodology

0500 Series

Chromatography

0600 Series

Physical Constants Test Method

0700 Series

Other test Method

0800 Series

Limit Test

0900 Series

Physical Properties Test method

1000 Series

Molecular Biological Technique

1100 Series

Biological Test Method

1200 Series

Biological Activity Test Method

2000 Series

Traditional Chinese Medicine Related Test Method

3000 Series

Biological Product Related Test Method

8000 Series

Reagents and Standard Substance

9000 Series

Guidance 9

Overview of ChP 2015 Pharmacopeia Supplement Edition ChP will continue to issue supplement edition for ChP 2015 Three Pharmacopeia Supplement Editions for ChP 2010 have been issued by ChP

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Content: Chinese Pharmacopeia (ChP) regulatory position in China Overview of ChP 2015 Features of Excipients standards in ChP 2015 ChP approach in harmonization and industry involvement

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Features of Excipients Standards in ChP 2015 1. The number of excipients monographs increase significantly

The No. of excipients monographs in ChP 2015 will be around 271, new added 139, the growth will reach 105% 12

Features of Excipients Standards in ChP 2015 2. Increase the safety and functional requirements on excipients Revise general chapter for excipients (0251)  Added classification description about chemical structure and drug dosage form  Emphasize excipient GMP and GDP  Emphasize the sterility and microbial limit requirements on excipients for injection and eye drops  Emphasize the label indicate “pharmaceutical excipient” and route of administration New draft guidance of research on functionality-related characteristics of pharmaceutical excipients (9701)

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Features of Excipients Standards in ChP 2015 3. Excipient monographs for injection will be separately adopted 1

Propylene Glycol for Injection

丙二醇（供注射用）

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Polysorbate 80 for Injection

聚山梨酯 80（供注射用）

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Macrogol 300 for Injection

聚乙二醇300（供注射用）

included in the up to date list

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Macrogol 400 for Injection

聚乙二醇400（供注射用）

of excipients plan to adopted

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Sodium Chloride for Injection

氯化钠（供注射用）

by ChP 2015 (Sep. 2014). In

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Soya Lecithin for injection

大豆磷脂（供注射用）

addition, there are 6

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Egg yolk lecithin for Injection

蛋黄卵磷脂（供注射用）

excipient monographs

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Activated Charcoal for Injection

活性炭（供注射用）

included specification for

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Poly(lactide-co-glycolide)for Injection_5050

丙交酯乙交酯共聚物（5050）(供注射用)

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Poly(lactide-co-glycolide)for Injection_7525

丙交酯乙交酯共聚物（7525）(供注射用)

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Poly(lactide-co-glycolide)for Injection_8515

丙交酯乙交酯共聚物（8515）(供注射用)

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Glycerol for Injection

甘油(供注射用)

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SoybeanOil (For Injection)

大豆油(供注射用)

There are total 13 excipient monographs for injection are

injection. http://www.chp.org.cn/cms/business/ add-acc/accessory/000020.html

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Features of Excipients Standards in ChP 2015

Example: Polysorbate 80

Test Appearance Specific gravity 25°C Viscosity Acid value Saponification value Hydroxyl value Iodine value Peroxide value Identification pH value UV absorbance: - at 225 nm - at 267 nm Color Ethylene glycol Diethylene glycol Triethylene glycol Ethylene oxide Dioxane Freezing test Water content Ashes Heavy metals Arsenic Composition of fatty acids Myristic acid Palmitic acid Palmitoleic acid Stearic acid Oleic acid Linoleic acid Linolenic acid Bacterial endotoxin Asepsis

Polysorbate 80 Conform 1.06-1.09 350-550mm2/s