Chinese Pharmacopeia 2015New Milestone of Excipients Standards
in China
Jessica ZhengChair, Industry Liaison Committee, IPEC China
Regulatory Manager China, [email protected]
IPEC Europe Annual SeminarNice, 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 Compliance is very important for excipient regulatory compliance in China!
ChP Regulatory Position 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.
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ChP Regulatory Position in China
Chinese Pharmacopeia (2010)
• 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.
CFDA notice about implement ChP 2010 (No.43, 2010)
• 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.
ChP Compliance is very important for excipient regulatory compliance in China!
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CFDA notice about renew registration of imported drug (No.18, 2009)
• 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.
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
5
Overview of ChP 2015
Finalize*Manuscript
UnifyManuscript
PrintIssue
Implement
*: Draft and revision finalized by local drug institute and submitted to ChP committee
2015.72015.12014.122014.82014.72014.6
PublicComment
PublishChP 2015
PressProofread
Recent Time Schedule :
Page 6-10: data from ChP 2015 Compilation Situation, Wei Zhang, General Secretary of ChP Committee, 2014 Joint ChP-USP Science and
Standards Symposium6
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 chaptersCoding 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
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Overview of ChP 2015
Pharmacopeia Supplement Edition
Three Pharmacopeia Supplement Editions for ChP 2010 have been issued by ChP
ChP will continue to issue supplement edition for ChP 2015
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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%
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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)
2 Polysorbate 80 for Injection 聚山梨酯 80(供注射用)
3 Macrogol 300 for Injection 聚乙二醇300(供注射用)
4 Macrogol 400 for Injection 聚乙二醇400(供注射用)
5 Sodium Chloride for Injection 氯化钠(供注射用)
6 Soya Lecithin for injection 大豆磷脂(供注射用)
7 Egg yolk lecithin for Injection 蛋黄卵磷脂(供注射用)
8 Activated Charcoal for Injection 活性炭(供注射用)
9 Poly(lactide-co-glycolide)for Injection_5050 丙交酯乙交酯共聚物(5050)(供注射用)
10 Poly(lactide-co-glycolide)for Injection_7525 丙交酯乙交酯共聚物(7525)(供注射用)
11 Poly(lactide-co-glycolide)for Injection_8515 丙交酯乙交酯共聚物(8515)(供注射用)
12 Glycerol for Injection 甘油(供注射用)
13 SoybeanOil (For Injection) 大豆油(供注射用)
There are total 13 excipient
monographs for injection are
included in the up to date list
of excipients plan to adopted
by ChP 2015 (Sep. 2014). In
addition, there are 6
excipient monographs
included specification for
injection.
http://www.chp.org.cn/cms/business/
add-acc/accessory/000020.html
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Test Polysorbate 80 Polysorbate 80 for injection
Appearance Conform Conform
Specific gravity 1.06-1.09 1.06-1.09
25°C Viscosity 350-550mm2/s 350-450mm2/s
Acid value <=2.2 <=1
Saponification value 45-60 45-55
Hydroxyl value 65-80 65-80
Iodine value 18-24 18-24
Peroxide value <=10 <=3
Identification Conform Conform
pH value 5.0-8.0 5.0-7.5
UV absorbance:- at 225 nm- at 267 nm
NA<=1
<=0.1
Color Conform Conform
Ethylene glycol NA <=0.01%
Diethylene glycol NA <=0.01%
Triethylene glycol NA <=0.01%
Ethylene oxide <=1ppm <=1ppm
Dioxane <=10ppm <=10ppm
Freezing test Conform Conform
Water content <=3% <=0.5%
Ashes <=0.2% <=0.1%
Heavy metals <=10ppm <=10ppm
Arsenic <=2ppm <=2ppm
Composition of fatty acids
Myristic acid NA <=0.5%
Palmitic acid NA <=0.5%
Palmitoleic acid NA <=0.5%
Stearic acid NA <=0.5%
Oleic acid NA >=98%
Linoleic acid NA <=0.5%
Linolenic acid NA <=0.5%
Bacterial endotoxin NA <0.012EU
Asepsis NA Conform
Features of Excipients Standards in ChP 2015
Example: Polysorbate 80
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Features of Excipients Standards in ChP 2015
Specific panel discussion of Polysorbate 80 for injection monograph was
held in Nov. 2014 by ChP committee, discussion group included people from
ChP, industry experts, Excipient makers and users. Representative of IPEC
China attended this discussion too.
Polysorbate 80 for injection monograph will be adopted by ChP 2015
separately, keep the specification of Oleic acid purity >=98%
For some specific drug formation needs, excipient user can define the
specific excipient standards needs based on usability and safety.
Propose CFDA to postpone the date of implement for excipients for
injection monographs, give industry enough time to verify in practices.
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Features of Excipients Standards in ChP 2015
4. Atypical Active
In ChP 2010, there are some problems existing about atypical actives
monographs, such as inaccurate adoption, repeated adoption in API and
Excipient part, not consistent in test methods etc.
Possible situation in ChP 2015:
• Keep consistent test methods for same test item in atypical active
monograph adopted in API part and excipient part.
• Will still adopt atypical actives both in API part and excipient part.
• Keep necessary same standards for monograph in API part and excipient
part.
• Different supervision requirements on atypical actives used as API and
excipient
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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
18
Page from International Harmonisation, Dr Samantha Atkinson , BP Commission, 2014 Joint ChP-USP Science and Standards Symposium
China signed MOU of Pharmacopeia harmonization, but not official member of PDG
Harmonization
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ChP Update Process and Industry Involvement
ChP Committee
Drug Institutes
Other Drug Institutes
ChP Committee
CFDA
• Review revision and new draft monographs
• Publish on ChP website for public consultation
• Collect public comments• Evaluate, adopt or reject suggestions• Finalize and issue ChP 2015
• Implement ChP 2015
• Propose ChP 2015 excipients list (387)
• Clarify responsibility of each drug institute
2012.7.23
2015.7
3 months
• Collect and test samples• Test method verification• Propose revision and new draft
• Continue communication
• comply with current ChP monograph requirements
• IPEC China provide comments on proposed list
• Actively provide samples• Actively communication for
specifications and test methods
• Review the draft or revision• Submit official amending
suggestions to ChP directly or through IPEC China
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ChP Feedbacks
ChP provided 2 batches official feedbacks for the ChP 2015 excipients public consultation. IPEC China coordinate the members comments submission.
http://www.chp.org.cn/cms/business/add-acc/accessory/000021.html
http://www.chp.org.cn/cms/business/add-acc/accessory/000018.html
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Appreciate the comments from
Hannah Han (IPEC China)
Cloris Tian (IPEC China)
Colin Li (IPEC China)
Daniel Liu (IPEC China)
Nicol Fan (IPEC China)
Meredith Ge (IPEC China)