Watch the webinar here: https://bit.ly/2lLquKk Since 2017 Chinese Health Authority has published new regulation for Co-Review procedure of API, excipient and packaging material. Focusing on the unique regulatory requirement for registration of excipient we will give you an overview about the dossier requirement, ChP compliance and impact for the pharmaceutical industry. If you want to market your drug into China, are you aware that excipient used in your drug need to be registered and to be compliance wtih Chinese pharmacopoeia? Since 2017 Chinese Health Authority has published new regulation for Co-Review procedure of API, excipient and packaging material. Focusing on the unique regulatory requirement for registration of excipient we will give you an overview about the dossier requirement, ChP compliance and impact for the pharmaceutcal industry. In this webinar, you will learn: - Current Chinese regulation for excipient registration - Chinese pharmacopoeia as standard for the excipients - Impact of excipient regulation for pharmaceutical industries

1. The life science business of Merck operates
as MilliporeSigma in the U.S. and Canada.
China Co-Review &
Chinese
Pharmacopoeia
July 2019

2. Agenda
1
2
3
China National Medical Products Administration (NMPA)
& Evolution of Regulations for Excipients
Impact on Global Drug Manufacturers
Our Strategy & Approach

3. China National Medical
Products Administration
(NMPA) & Evolution of
Regulations for
Excipients

4. New regulation
& global pharma
manufacturer
needs for China:
Chinese
Pharmacopoeia
(ChP) compliance
& co-review of
API/excipients are
prerequisites for
pharma and
biopharma to
submit drugs
applications in
China.
Germany
China
Greenland
Canada
United States
Sweden
Russia
Brazil
South Africa
China Co-Review & Chinese Pharmacopoeia | July 20194

5. China NMPA & How It Works
5
NMPA
Other Divisions
Center for Food and
Drug Inspection (CFDI)
GMP drafting and inspection on drug,
medical device and cosmetics
Center for Drug
Evaluation (CDE)
New Regulation/guidance draft
evaluation on drugs including excipients/API
Registration Division
Coordinate on drug review and approval
reform
ChP Commission
ChP revision/new add
with the support from NIFDC and local IFDC
National Institutes for
Food and Drug Control
(NIFDC)
ChP monograph establishment & sample
testing etc.
Pre-approval
technical
review
Overall
administration
coordination
Product
specification
NMPA=National Medical Products Administration
China Co-Review & Chinese Pharmacopoeia | July 20195

6. Evolution of Excipient Regulations in China
Before 2016 Aug 2016 Nov 2017 Dec 2017 Jun 2018 Jul 2018 Apr 2019
Bundling Review
Excipient change from alone
review to bundling reviewed
with drug application
1st Deep
Dive Training
2nd Deep
Dive Training
Global
Webinar
Co-Review
Announcement on co-
review
IDL
Import Drug License
2nd Update Draft
Excipient dossier
requirement based on
classification
1st Update Draft
Co-review management
regulation for
API/excipient/packaging with
finished drug
3rd Update Draft
Announcement on the matters
related to filing and co-review
& approval
4th Update Draft
Announcement on further
improving the co-review and
approval
China Co-Review & Chinese Pharmacopoeia | July 20196

7. Opportunities and Challenges for Pharma Manufacturers
• NMPA notice adopted the regulatory registration procedure as US DMF
for stand-alone registration of excipient
• Foreign and domestic industries have the "same" chance to go to China
market for excipients
• Excipient and API suppliers with broad portfolio can leverage synergies
from registration process and have higher probability of success
Opportunities
• Excipient registration is mandatory only in China. No transition time for
industry to implement, lot of industries are not prepared
• Dossier requirements are very detailed as for API, or even extended,
industries have concern about confidential information
• ChP compliance is mandatory and ChP is not harmonized with USP/EP
Challenges
China Co-Review & Chinese Pharmacopoeia | July 20197

8. Impact on Global
Drug Manufacturers

9. Chinese Dossier Requirements for Excipients
China Dossier Section Required Content Comments
1
General company
information
company name, address etc.
company certificate documents,
storing address of study documents
Storing address of study documents can be
provided, however it is GMP information, not
required for registration dossier in EU/US
2
General information of
excipients
name, structure, characteristics,
approval and usage information,
status of being included in
pharmacopoeia
It is challenging to provide the approval and usage
information world wide, since only in China the
registration of excipient is needed, no other official
approval information is available
3
Manufacturing
information
manufacturing process, control of
materials,
process control, critical steps, list of
equipment,
process validation and developement
It is challenging to provide very detailed information
about manfuacturing and raw materials and list of
equipment due to confidentiality; validation of
manufacturing process for excipient is not
mandatory in EU/US
4 Characterization
structure and physicochemical
properties,
functional characteristics,
impurity study
For compendia substance it is challenging to provide
raw data, spectrums as proof of structure;
complete impurity profile study for compendia
excipient is not required EU/US
China Co-Review & Chinese Pharmacopoeia | July 20199

10. Chinese Dossier Requirements for Excipients
China Dossier Section Required Content Comments
5
Quality Control
Specifications,
description and validation of analysis methods,
list of equipment for testing,
justification of specifications
ChP compliance mandatory for product described
in ChP current version, validation and cross-
validation for test methods of excipientis
challenging; list of testing equipment is not
required for registration in EU/US
6 Batch Test Report 3 consecutive CoAs Comparable with batch analysis
7
Stability Study stability summary
stability data
packaging of excipients
CDE expects stability study to cover
most/complete parameters of final release,
whereas only stability indicating parameters are
covered in stability study
8
Pharmacology and
Toxicological Study
In general, the pharmacology and toxicology study
data or literature to be provided:
summary of pharmacology and toxicology study,
pharmacodynamic effect of the drug products
which intends to use the excipient, non-clinical
pharmacokinetic study, safety pharmacology
study, single/repeated dose toxicity etc.
For compendia substances Pharmco. and
Toxico. data are not required in EU/US
China Co-Review & Chinese Pharmacopoeia | July 201910

11. Related NMPA Announcement No. 134 – Exemption
The final decision if a registration of an excipient is necessary or not needs to be
confirmed with CDE by the product owner/marketing authorization applicant
As stipulated in Attachment 1 of Announcement No. 134, 2016: What are the pharmaceutical
excipients excluded from the co-review?
(I) Correctives (sweeteners): such as sucrose, syrupus simplex, mannitol, sorbitol, sodium saccharin, aspartame, sucralose, stevioside,
glucose, xylitol, maltitol etc. This variety is limited to be used as flavoring agent (sweetener) in preparations.
(II) Essences and fragrances: such as orange essence, banana essence, vanillin and so on. For the food standard implementation, the
requirements in the current editions of GB 2760 National Food Safety Standard - Standards for Uses of Food Additives, GB 30616 National
Food Safety Standard - Essences used in Food and GB 29938 National Food Safety Standard - General rules for fragrances used in Foods
should be met.
(III) Pigment (colorant): such as ferric oxide, vegetable carbon black, cochineal etc.. For the food standard implementation, the requirements
in the current edition of GB 2760 National Food Safety Standard - Standards for Uses of Food Additives.
(IV) pH adjuster(including pH adjuster in injections): such as malic acid, fumaric acid, acetic acid, sodium acetate, citric acid (sodium,
potassium salt), tartaric acid, sodium hydroxide, concentrated ammonia solution, hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid,
potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate etc.
(V) Inorganic salts only used as excipients, prepared with simple manufacturing process and having stable physical and chemical properties
(including those used in injections): such as calcium carbonate, sodium carbonate, potassium chloride, calcium chloride, magnesium chloride,
calcium phosphate, calcium hydrogen phosphate, calcium sulfate and sodium bicarbonate etc.
(VI) Non-benzene ink used for oral preparation printing.
China Co-Review & Chinese Pharmacopoeia | July 201911

12. Issuing Letter of Authorization is Required for Drug
Application
Information needed from
Excipient owner
•Excipient (or authorized) company
•Excipient product name
•Excipient registration no. at CDE
Drug Information needed
from Drug applicant
•Name of MAH holder
•Drug name with dosage form
•Administration route of Drug
Product
For request on Letter of Authorization, your business partner will be
happy to assist
China Co-Review & Chinese Pharmacopoeia | July 201912

13. Drug Administration Law of the People’s Republic
of China- issued in 28th Feb. 2001
Article 32: Finished drugs must meet National Drug Standard. Chinese
Pharmacopoeia and drug standard published by China drug
authority are “National Drug Standard”.
Article 49: Any drug product with a pharmaceutical component not
compliant with “National Drug Standard”, will be regarded as
“inferior medicine”.
Legal Basis for Chinese Pharmacopeia (ChP) Compliance
* Imagesource: www.chp.org.cn
China Co-Review & Chinese Pharmacopoeia | July 201913

14. ChP Development and Current Version of ChP
Key information
 Since 1953, so far 10 versions of
Chinese Pharmacopeia published
 Since 1985, ChP Committee publish
new version every 5 years
 Since 2005, ChP also issued EN
version
 ChP 2010: ~132 excipients
 ChP 2015: ~ 270 excipients (97
revised, 137 added)
* Based on ChP publication and webpage: www.chp.org.cn
The 11th ChP committee had been established in 2017 for ChP 2020. More
monographs will be added and revised, estimated ChP 2020 publish in Q2/2020
China Co-Review & Chinese Pharmacopoeia | July 201914

15. Example of our Product Specification
ChP declaration
is visible in
product name
Specification includes
ChP requirements
China Co-Review & Chinese Pharmacopoeia | July 201915

16. Our Strategy &
Approach

17. Challenges and Strategy
1. Constantly changing regulatory landscape in China
2. Contracted items
− Details of critical manufacturing steps, critical process parameters are required for submission and need raw material
supplier’s support. Many are not willing to move forward under current guidelines and expectations
− Current focus of our in-house produced items
3. ChP compliance
− English version of ChP 2015 not published until 2017
− ChP is often not harmonized with USP, EP, BP and JP
− More than 400 Excipients & APIs need to be reviewed, methods developed, cross-validated, etc
Long term strategy
− Analytical method verification/validation according to ChP 2015/2020 is supported by QC Wuxi lab, China
− New product launches including ChP and addition of ChP & co-review readiness to existing excipients; We are adding
significant regulatory and QC resources to prioritize registration needs
− We are striving to collaborate with customers to understand long-term product needs for registration and ChP
compliance
China Co-Review & Chinese Pharmacopoeia | July 201917

18. Successfully Registered Products
 A&F products registered in China can be checked at:
http://www.cde.org.cn/yfb.do?method=main
 From 2018 to Q2/2019, more than 200 letters of authorization (LoA)
were issued globally
Registered Products
Month of
Registration
100892 Sucrose low in endotoxins EMPROVE® exp Ph Eur,BP,JP,NF Aug 2017
108386 Tris (Trometamol) EMPROVE® exp Ph Eur,BP,JPC,USP Sep 2017
100201 Phenol EMPROVE® ESSENTIAL Ph Eur,ChP,JP,USP Feb 2018
106143 Meglumine low in endotoxins EMPROVE® API Ph Eur,ChP,JP,USP Apr 2018
100805 Titanium(IV) oxide EMPROVE® exp Ph Eur,BP,USP,JP,E 171 Apr 2018
137096 D(-)-Mannitol EMPROVE® EXPERT Ph Eur,BP,USP,JP Jun 2018
112635 Parteck®DeltaM (Mannitol)EMPROVE® ESSENTIAL Ph Eur,BP,USP,JP,E 421 Jul 2018
100494 Parteck® M 100 (Mannitol) EMPROVE® ESSENTIAL Ph Eur,BP,JP,USP,E 421 Sep 2018
100419 Parteck® M 200 (Mannitol) EMPROVE® ESSENTIAL Ph Eur,BP,JP,USP,E 421 Sep 2018
817081 Sodium caprylate suitable for use as excipient EMPROVE® exp Ph Eur,NF Jan 2019
103583 Parteck® SI 150 (Sorbitol) EMPROVE® ESSENTIAL Ph Eur,BP,JP,NF,JSFA,E 420 Apr 2019
108800 Zinc acetate dihydrate EMPROVE® ESSENTIAL Ph Eur, USP Jul 2019
Successfully
co-reviewed
with
customers:
Tris (108386)
China Co-Review & Chinese Pharmacopoeia | July 201918

19. Multicompendial Excipients & APIs with ChP on label
Multicompendial Excipients & APIs with ChP on label
106143 Meglumine low in endotoxins EMPROVE® API Ph Eur,ChP,JP,USP
100201 Phenol EMPROVE® ESSENTIAL Ph Eur,ChP,JP,USP
141355 Polyvinyl alcohol 18-88 EMPROVE® ESSENTIAL Ph Eur,ChP,USP,JPE
141353 Polyvinyl alcohol 40-88 EMPROVE® ESSENTIAL Ph Eur,ChP,USP,JPE
141517 Parteck® COAT (Polyvinylalkohol) EMPROVE® ESSENTIAL Ph Eur,ChP,JPE,USP
103789 Saccharose EMPROVE® EXPERT Ph Eur,ChP,JP,NF
China Co-Review & Chinese Pharmacopoeia | July 201919

20. Global Webinar 2019
Watch our interactive Webinar now:
www.emdmillipore.com/china-excipients-regulation
China Co-Review & Chinese Pharmacopoeia | July 201920

21. The vibrant M is a trademark of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information
on trademarks is available via publicly accessible resources.
© 2019 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.