Watch the webinar recording: https://bit.ly/2SE4DkZ Abstract: If you want to market your drug in China, are you aware that the excipients used in your drug need to be registered and to be compliant with the Chinese Pharmacopoeia? Since 2017, Chinese Health Authority has published new regulations for Co-Review procedure of API, excipient and packaging material. NMPA and CDE are developing the pharmaceuticals regulations continuously. Focusing on the unique regulatory requirements for the registration of excipients, we will give you an update on the recent changes in excipient regulations, the published ChP 2020 and the regulatory trends for excipients in China. In this webinar, you will learn: • Recap of the history of excipient regulations in China • Recent changes of regulations for excipient registration • ChP 2020 • Regulatory trends for excipients in China

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
New developments
of excipient
regulations in China
Cloris Tian, Yuwei Heinzel
October 8th, 2020

2. The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada.

3. Cloris Tian
Senior Regulatory Manager
Greater China, Shanghai
Yuwei Heinzel
Head of Pharma Registration
Germany, Darmstadt

4. Agenda
1
2
3
Recap of the history –
China excipient regulation
Recent development in
regulation for excipients
About Chinese
Pharmacopoeia and
ChP2020
4 Regulatory trends for
excipients

5. Recap of the history –
China excipient
regulation

6. New developments of excipient regulations in China | October 8, 20206
China NMPA and the main departments
Relevant for excipient registration and supervisionTheCentralGovernmentof
China
NMPA
(National Medical
Products
Administration)
Other Divisions
CFDI
GMP drafting and inspection on drug,
medical device and cosmetics
CDE
(Center for Drug
evaluation)
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
NIFDC
ChP monograph establishment &
Sample testing etc.
Local MPA
(Province, City)
Pre-approval
Technical
review
Overall
administration
coordination
Product
specification
Domestic excipient manufacture
daily supervision

7. New developments of excipient regulations in China | October 8, 20207
Continuous changing and developing (2016 - April 2019)
Evolution of Regulations of Excipients (1)
Before 2016 Aug 2016 Nov 2017 April 2019 continuing
Bundling Review
Announcement for Excipient
to be bundle-reviewed with
drug application
Global
Webinar
Co-Review
Announcement on co-
review for
API/Excipient/Packaging
(2017 No. 146)
IDL
Regulation about IDL:
Import Drug License
Draft for Comment
Announcement on further
improving the co-review and
approval with drug product and
its related supervision matters
No more valid
No more valid

8. New developments of excipient regulations in China | October 8, 20208
August 2019 Nov 2019 Dec 2019 April 2020 June 2020 Developing
Draft for Comment
about classification, review
and variation of chemical
drugs
1st Deep
Dive Training
Global
Webinar
ChP 2020
ChP 2020 is published
in CN
China Drug
Administration Law
Implementation of MAH system
Draft for Comment
about Guidelines for post-
approval changes
on further improving the co-
review and approval with drug
product
Announcement
2019, No. 56
Continuous changing and developing (since August 2019)
Evolution of Regulations of Excipients (2)

9. New developments of excipient regulations in China | October 8, 20209
How to Register Excipient in China
From IDL to Co-Review
Drug application
submitted
Drug
Acceptance No.
Excipient
submission
Excipient
submission Registration No.
Bundling
Review
Co-Review
LOA*
IDL*
Excipient Application
（Local FDA*，
CFDA*） Approved License
Before
Aug 2016
Aug
2016-Nov
2017
Since
Nov 2017
(No. 146)
Excipient
as
component
in
imported
drugs
Required
Drug
Application
*IDL: Import Drug License
*Local FDA and CFDA: local, central food and drug administration
*LOA: Letter of Authorization

10. Stand alone registration of AEP*, to be co-reviewed with Drug
New developments of excipient regulations in China | October 8, 202010
What is Co-Review Procedure?
After drug application being accepted by CDE
Co-review procedure triggered, timeline depends on drug application status
AEP*dossier
review ALL
responses
received and
passed
review
CDE
Co-review
Drug dossier
review
* AEP stands for API/Excipient/Packaging material
Deficiency
letters
Deficiency
letter
Drug
application
approved
AEP* status
in CDE as “A”
− CDE will send deficiency letter to excipient applicant directly, drug applicant will be notified.
− Drug applicant need to ensure AEP* suppliers respond timely, otherwise drug approval
timeline will be impacted.

11. Recent development
in regulation for
excipients

12. New developments of excipient regulations in China | October 8, 202012
Announcement No. 56 on Co-Review of AEP (1)
Valid since 15th August 2019 – What is New?
API, excipient and packaging material should be registered via Co-REV dossier submission to
CDE, MAH holds the responsibility of drug product and should ensure all the suppliers (AEP) are
appropriately audited.
Transparent information on CDE database for AEP Co-REV status:
I (registered but inactive – not yet Co-Rev approved);
A (registered and active – Co-Rev approved)
Note: For former approved imported and domestic produced excipient under IDL, the status
transferred to “A” without co-reviewed with drug application, however if these approved
registrations are linked with new registration application, the supplier will need to supplement
additional data.
Annex 1: Classification of the excipient 1,2,3 and related requirement of dossier content for Class
-> some reduction of dossier requirement for 2.3 USP/EP/BP/JP excipient and 2.4 ChP
excipient
Annex 4: General instructions for annual report - A summary of changes and all LoAs shall be
reported in the annual report, to be submitted in the first quarter of each year.
1
2
3
4

13. New developments of excipient regulations in China | October 8, 202013
1
2
3
4
5
Exemption list
for low risk
excipient
Pigments (Colorants), Inks
 Iron oxide, plant carbon
black, Cochineal
 Benzene-free inks (for oral)Flavors and Essences
Orange flavor, banana
flavor, Vanillin
* Follow GB National Food
Safety Standards if listed
pH adjusters
 Several inorganic acids
 Some organic acids
 Used in injections
Corrigents
(sweeting agents)
 Sucrose, glucose, …
 Mannitol, sorbitol, …
 Saccharin Na, Sucralose,
etc.
Inorganic salts
“With simple preparation
process and stable
physicochemical properties”
Injectable appl.
included
Note: The final exemption of registration need to be confirmed by CDE depends on the usage of excipient and risk of drug product
Announcement No. 56 on AEP Co-REV (2)
Annex 3 – Exempted Excipients

14. New developments of excipient regulations in China | October 8, 202014
Revised China Drug Administrative Law
Effective since 1st of Dec. 2019
History:
First issued in 1984, revised in 2001, complete revision in Aug 2019
Scope:
Ensure drug safety and to improve healthcare system in China
Key contents of this revision of Law:*1+2
1. To implement MAH (Marketing Authorization Holder) system in China, MAH has whole responsibility of
the drug, including API/Excipient/Packaging material (consistent with Co-REV Announcement No. 56);
2. To reform “Drug Approval System” and encourage innovative drug development in China (for example:
fast track);
3. To further improve supervision of drugs to cover the whole process - drug development,
manufacturing, marketing, strengthen measures and penalties;
4. To realize risk based assessment for post approval change, significant change need to be approved ->
more guideline will be developed for implementation.
*1 Based on NMPA Director presented to NPC (National People’s Congress) for review and approval.
*2 NMPA officer’s comment in Xinhua News in 27th Aug. 2019 on “China Focus: China revises law to ensure drug safety”

15. New developments of excipient regulations in China | October 8, 202015
Impact for Pharmaceutical Industry
Regulatory responsibility
CDE
(Center of Drug Evaluation)
Drug owner/ MAH AEP Owner/ Registrant
Co-review dossier
REG.No
Deficiency
Letter
LOA/Change notification
New Drug Application
(NDA)/Abbreviated NDA
Annual Report/Variation
Deficiency
Letter
Response letter
Response
letter
Drug owner/MAH is responsible for the quality of final drug product
(used excipients should be covered)
Annual Report/
Supplement
Approval/
Rejection
Sample testing/
On site inspection
if needed
 Owner of Database
API/Excipients/Packaging
 Review of registration dossier
Request/Communication

16. About Chinese
Pharmacopoeia
and ChP2020

17. New developments of excipient regulations in China | October 8, 202017
* Means drug registration standards that approved by NMPA,
as well as other historical standards etc.
Drug Administration Law of the People’s Republic of China- issued in 26th
Aug. 2019 (effective in 1st Dec. 2019)
Article 28: Finished drugs must meet National Drug Standard. Chinese
Pharmacopeia and drug standard* published by China drug authority are National
Drug Standard.
Article 98 (…) In one of the following circumstances, it is a inferior drug:
(…)
(7) Other drug don’t comply with (National) Drug Standard.
ChP legal base

18. 18 New developments of excipient regulations in China | October 8, 2020
New Committee establishment Next Committee establishment
Committee plenary
meeting to review
compilation outline
Collect and
establish research
subjects
Standard drafting
Standard
verification
Finalize the
Standard draft
Approve by
corresponding
expert committee
Promulgate for
public comments
Approve by NMPA
and publish the
standard
ChP
Implementation
and evaluation
Effort from ChP Commission to encourage industry
involvement
ChP2020 Working Procedure with adjustments

19. New developments of excipient regulations in China | October 8, 202019
ChP’s goal and revision
timeline
 ChP aims for the most
stringent standard and
harmonization with
other international
compendial is not one of
ChP’s top priorities;
 ChP revise every 2-3
years (mid of every 5
years) while EP is every
3 months and USP is 6
months, industry have
to wait for long time for
revision.
ChP working procedure and
communication with industry
 For ChP2015-2020 over 2000
monographs new/revised,
limited timeline (3 moths)for
industry to provide samples
and verification data when
draft publicized for comments;
 Lack of mechanism for industry
on involvement, as the overall
revision process is long (2-3
years) and it’s a challenge for
industry to follow up closely
with ChP institutes.
Challenge
for industry
Challenges for industry to work on ChP Compliance

20. ChP2020 Working Procedure with adjustments
New Committee establishment Next Committee establishment
Committee plenary
meeting to review
compilation outline
Collect and
establish research
subjects
Standard drafting
Standard
verification
Finalize the
Standard draft
Approve by
corresponding
expert committee
Promulgate for
public comments
Approve by NMPA
and publish the
standard
ChP
Implementation
and evaluation
20
Industry early
involvement
Strengthen
communication
and discussion
with industry
New developments of excipient regulations in China | October 8, 2020
Effort from ChP Commission to encourage industry
involvement

21. New developments of excipient regulations in China | October 8, 202021
 Encourage industry on early involvement and expert
panel participation during ChP2020 new and revision
process;
− More and more excipients monographs have gone through 2~3
round of expert panel meetings if dissent still maintained.
 11th May 2020, ChP issued notice of “Recommend
on Excipent Standard Expert”
− To encourage experts from industry, university and drug control
institutes etc. to participant in excipient standard and
physicochemical test method new and revision tasks.
 17th Jun. 2020, ChP Commission issued “Excipient
Monograph Guardian Management” to help
industry to implement ChP2020
− The listed experts for corresponding excipient monograph will
be responsible to answer query/question from industry with
clear guidance.
* Image taken from ChP publication and webpage: www.chp.org.cn
Effort from ChP Commission to encourage industry
involvement and facilitate ChP2020 implementation

22. Volume IV
Volume IV:
335 excipients are included.
212 (63%) monographs are revised.
65 (19%) monographs are newly added.
58 (18%) monographs are unchanged.
Pharmaceutical Excipients
58
65
212
unchanged added revised
Vol.IV
monographs
63%
19% 18%
0
36%
50%
13%
1%
0%
10%
20%
30%
40%
50%
60%
70%
revised newly added unchanged delete
ChP 2020 vs ChP 2015
 ChP2020
 ChP2015  Total 270 excipient Monographs
 Total 335 excipient Monographs
New developments of excipient regulations in China | October 8, 202022
ChP Basic information – Vol. IV on excipient

23. Compare with the notice for ChP2015, following key content
included:
 ChP is important part of national drug standards;
 Drug registration standards vs. ChP standards:
For some case, when there is discrepancy between the two
standards, shall implement the approved registration standards, and
notify ChP to revise.
 Post approve change (PAC) due to ChP2020 implementation
If PAC initiated due to ChP2020 implementation, MAH or
manufacture shall conduct related evaluation and change through
process of approval, do after filing or reporting.
 Implementation body
Drug MAH, manufacture and drug applicant agent shall implement
ChP2020.
ChP implementation
Notices issued by NMPA in 2020
* Based on NMPA publication and webpage: www.nmpa.gov.cn.
23 New developments of excipient regulations in China | October 8, 2020

24. Regulatory trends
for excipients

25. New developments of excipient regulations in China | October 8, 202025
NMPA- ICH Office
 Established in 12th Jul.2017 under CDE, members including CDE, NIFDC, ChP Commission, NIFDI,
CCFDIE, Chinese Pharmaceutical Association etc. , based on task needs, may invite other industry
associations, universities, institutes join in working group;
 Participate in ICH coordination; transfer and implement ICH guidelines; training on guidelines; liaison
between ICH and regulatory bodies;
 Currently with following approaches:
Transfer and implement
directly
 Well recognized and widely
implemented Guidelines;
 Example: ICH Q1- Q11
(except Q4 on pharmacopeia)
Integrated into
regulation/notice/Adiminis
trative guidance
 Need procedural process or
administrative guidance;
 Example: ICH Q12 (Lifecycle
management); M4 for eCTD
Implement through other
technical guidance
 Coordinate with other
subordinate organization;
 Example: ICH Q3C and ICH
Q3D to be implanted in Chinese
Pharmacopeia.
1 2 3
It’s a long journey for China to fully harmonize with ICH Guidelines !
How are ICH Guidelines adopted or integrated into China
Regulation System

26. CDE（10 notices）
 Notice on draft for comment of <Administrative
Measures of Bundling Review of drug application
with API, Exipient and Packaging Material>;
 <Notes for the Drafting of the Guide for the Acceptance
and Review of Chemical Drug Substances (Draft for
Comment)>
 <Notice on publicly soliciting opinions on "Technical Data
Requirements for New Coronavirus Neutralizing Antibody
Drugs (Pharmacy) (Draft for Comment)">
 <Notice on publicly soliciting opinions on "Guiding
Principles for the Administration of Drug Clinical Trials
during the New Coronary Pneumonia Outbreak (Draft for
Comment)“>
 …
NPMA(4 notices)
 <Registration Classification and
Requirements for Application Dossiers of
Chemical Drugs> (Post Approval Change
included);
 <Registration Classification and
Requirements for Application Dossiers of
Biologic Drugs>(Post Approval Change
included);
 <Registration Classification and
Requirements for Application Dossiers of
Chinese Traditional Drugs>(Post
Approval Change included);
 …
Deadline for comments submission is end of May, target to be finalized before 1st Jul. to support
DRR (Drug Registration Regulation)and DMR (Drug Manufacture Regulation) implementation. Most
of above drafts finalized and became effective before 1st Jul.
Draft on excipient hasn’t be finalized yet.
26 New developments of excipient regulations in China | October 8, 2020
Drafts issued for public comments on 30th Apr. 2020
New Guidance/Notice from NMPA, CDE

27. Trend: Exemption Product List Simplified Dossier Product List
New developments of excipient regulations in China | October 8, 202027
If excipient company chooses not to
register annex 1-4 excipients, it could
provide excipient dossier to drug applicant
to support drug registration
including: basic manufacturer info, basic product
info, excipient specification, COA, usage
statement, etc.
21 Annex 1-4 Simplified Dossier Product
List
Article 30 (Product with Simplified
Dossier)
The excipients and packaging material that with long
usage history in food and drug, with established safety,
and the usage, dosage and function are within the
routine usage status, instead of product registration,
simplified dossier can be prepared and submitted together
with drug product.
I. The non-high risk excipients which already listed in
USP-NF, Ph.Eur., JP, BP and Ch.P;
II. The excipient which already used in food industry with
GB standard and used in oral drug product;
III. The excipient which already used in cosmetic industry
with international cosmetic or industrial standard and
used in topical drug product;
IV. Corrigents (sweetening agents), flavors, spices,
pigments (colorants), pH adjusters, inorganic salts
with simple preparation technology and stable
physicochemical properties, and benzene free ink for
printing on oral preparations. (The same as the
exemption product list described in No. 56 of 2019)
Not effective and implemented yet
Excipient Co-Review Regulation Draft for Comments

28. New developments of excipient regulations in China | October 8, 202028
* AEP stands for “API, Excipient and Packaging material”
 AEP* co-review registration is
mandatory and being
strengthened further.
 Exemption list for excipient need
to be communicated with CDE for
confirmation when necessary.
 If excipient not listed in
ChP/EP/USP/JP, suggest to check
early on registration plan with
the supplier.
Review on
excipient status
 ChP is a basic ongoing quality
requirements for MAH;
 Individual company has varied
interpretation and diversified
approach on ChP compliance.
Basic quality
control – ChP
Compliance
 Willingness and capability to
register the excipient, with
technical and analytic capability
to answer query from CDE;
 Quality system including change
control management, etc.;
 Annual report
Supplier
Management
1 2 3
How can your drug enter into China Market
Take Away

29. Contact:
The vibrant M and SAFC are trademarks 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.
© 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.
Yuwei.Heinzel@emdgroup.com
Cloris.Tian@emdgroup.com
Disclaimer:
Views and opinions expressed in
this talk are those of the speaker
and should not be taken as views
of Merck KGaA, Darmstadt,
Germany.