drug approval system in Malaysia, NPRA

1. 1
DRUG APPROVAL SYSTEM
IN MALAYSIA
Rosilawati Ahmad
Deputy Director, Centre for Product Registration
National Pharmaceutical Regulatory Agency (NPRA), Malaysia
2019 K-Pharma Academy (KPA) for ASEAN

2. Sharing content
Intro-
Pharmaceutical
Services Program&
NPRA
Categories of
Products &
Registration
requirements
Registration
process &
timelines
Issues Identified in
Korean product dossier
assessed at NPRA
Summary
2

3. Sharing content
Intro-
Pharmaceutical
Services Program
& NPRA
Regulatory
activities
Registration
requirements &
process
Challenges &
Regulatory reform
Summary
3

4. Organisation Chart – Ministry of Health, MALAYSIA

5. Organisation Chart - Pharmaceutical Services Program
Senior Director of
Pharmaceutical Services
Program
National Pharmaceutical
Regulatory Agency (NPRA)
Pharmacy Enforcement
Division
Pharmacy Practice &
Development Division
Pharmacy Policy &
Strategic Planning
Division
Pharmacy Board Malaysia
Pharmacy and pharmaceutical services, Clinical & Technical, MoH
Drug Formulary, Special Drug Request approved by DG, Technical
support in medicines tender, Price control, Patients education
Strategic plans and policies, Human resources, National Medicines
Policy, ICT related, intra-agency, inter-agency and
international communication
Enforcement and prevention activities, control of licensing,
monitoring activities and consumer awareness activities,
advertisement
Registration of Pharmacists
NRA for medicines and cosmetics in Malaysia. Ensuring the QSE of
medicines through the registration and licensing scheme, post-
market activities

6. Poisons Act 1952 (Revised 1989)
Sales of Drugs Act 1952 (Revised 1989)
Dangerous Drugs Act 1952 (Revised 1980)
Registration of Pharmacists Act 1952 (Revised 1989)
Medicine (Advertisement & Sale) Act 1956 (Revised 1983)
Legislation

7. Legislation
Control of Drugs and Cosmetics Regulations
CDCR 1984, Regulation 7(1) states:
• No person shall manufacture, sell, supply,
import, possess or administer any product
unless:
• (a) the product is a registered product, and
• (b) the person holds the appropriate
license required & issued under these
Regulations.

8. VISION
To be an internationally renowned
regulatory authority for medicinal
products and cosmetics
MISSION
To safeguard the nation’s health
through scientific excellence in the
regulatory control of medicinal
products and cosmetics
OBJECTIVE
To ensure that therapeutic
substances approved for the local
market are safe, effective and of
quality and also to ensure that
cosmetic products approved are safe
and of quality
REGULATORY SYSTEM
Role of
National Pharmaceutical
Regulatory Agency

9. ORGANISATION
CHART
81
Pharmacy
Assistants
329
Pharmacists
Total staff : 490
Staff Strength
Centre for Quality Control
DEPUTY DIRECTOR
Centre for Post Product
Registration and
Cosmetic Control
DIRECTOR
DEPUTY DIRECTOR
Centre for
Investigational New
Product
DEPUTY DIRECTOR
Centre for Product
Registration
DEPUTY DIRECTOR
Centre for Compliance
and Licensing
DEPUTY DIRECTOR
Centre for Development
and Strategic Planning
80
Administrative
& Support Staff
1
3
2
4
5
6
DEPUTY DIRECTOR

10. NPRA’s international presence
10
Member
Non-member
Ad-hoc
Inter-agency collaboration
• WHO Collaborating Centre for Regulatory Control of Pharmaceuticals
• WHO Programme for International Drug Monitoring
• PIC/S
• ACCSQ-PPWG
• Network of Official Medicines Control Laboratories (NOMCoL)
• OECD GLP Mutual Acceptance of Data (MAD)
• ICH Observer
• Joint assessments
• Parallel reviews
• Bilateral meetings

11. Sharing content
Intro-
Pharmaceutical
Services Program&
NPRA
Categories of
Products &
Registration
requirements
Registration
process &
timelines
Issues Identified in
Korean product dossier
assessed at NPRA
Summary
11

12. 12
#RegulatoryReform
Pre marketing Post marketing
Regulatory Functions
Product
Life
cycle
Drug
Discovery
Preclinical Clinical trials Regulatory Review
Approval &
Launch
Post-
Marketing
Surveillance
National Regulatory System
Regulatory Inspection
Licensing premises
Laboratory access and Testing
Clinical Trial’s Oversight
Marketing authorization
Vigilance
Market surveillance and Control
Lot Release

13. NPRA registers products that fulfil
registration criteria
New Drug Products
Biologics
Health Supplements
Generics
Natural/herbal
Veterinary
QUALITY
EFFICACY SAFETY
13

14. New Drug Product
Any pharmaceutical product that has not been previously registered in
accordance with the legal provisions in Malaysia

15. Types of New Drug Product
New Chemical Entities
Hybrid
15
Product containing an active moiety/ radiopharmaceutical
substance that has not been registered in any
pharmaceutical product [full product dossier required]
Other products, e.g. combination of registered NCEs, new
dosage form, new strength, new route of administration
[abbreviated product dossier allowed]

16. Biologics
Biologic product refers to a product
whose active substance is made by or
derived from a living organism (plant,
human, animal or microorganism)
May be produced by biotechnology
methods and other sophisticated
cutting-edge technologies.
The product imitates natural
biological substances in our bodies
such as hormones, enzymes or
antibodies.
Therapeutics made out of proteins
that can differ in size (large) and
structural complexity
E.g. Vaccines
Blood/Plasma derived medicinal products
Biotechnology products including biosimilar
Cell and Gene Therapy Products (CGTPs)

17. Generics
A generic product is a product that is essentially similar to a currently registered product in
Malaysia. Classified into two groups:
Scheduled Poison
(Known as Controlled
Medicine/ Controlled Poison)
Products containing poisons
as listed in the First Schedule
under Poisons Act 1952
Non-scheduled Poison
(Known as Non-Poison or
“Over-the-Counter”, OTC)
Products containing active
ingredients which are not listed
in the First Schedule under
Poisons Act 1952; and is
excluding active ingredient
which is categorized under
health supplements or natural
products or cosmetics

18. PROCEDURES FOR REGISTRATION

19. 2

20. QUEST MEMBERSHIP REGISTRATION
• Product registration application is via QUEST3+ online submission system which enables its
users to conduct secured online activities (eg. Product registration, cosmetic notification etc.).
20
Submission of Quest3+ Membership Registration
application via https://quest3plus.bpfk.gov.my/
Received USB Token that contains a User Digital
Certificate from MSC Trustgate.com Sdn. Bhd.
Access to QUEST online system for
product registration application

21. REQUIREMENTS FOR REGISTRATION
21

22. Registration requirements for
pharmaceutical products
International
WHO
ICH
EMA
US FDA
Regional
ASEAN Guidelines for:
Stability
Process validation
Variation
Local
Drug Registration Guidance Document
NPRA Guidelines
DCA Directives
Circulars 22

23. GUIDELINES
 Drug Registration Guidance
Document(DRGD)
 ASEAN Guidelines on Process Validation
 ASEAN Guidelines for the Conduct of
BA/BE Studies
 ASEAN Guidelines for Drug Product
Stability Study
 ASEAN Guidance on ACTD
 Other guidilines may be applicable ) as
and when needed

24. NPCB
MOH
Registration Application Format
 ASEAN Common Technical Dossier / ASEAN
Common Technical Requirements ( ACTD/ACTR)
- adopted and adapted from ICH requirements
 Implemented since July 2003

25. Registration Application Format
 ASEAN Common Technical Dossier / ASEAN
Common Technical Requirements ( ACTD/ACTR)
- adopted and adapted from ICH requirements
 Implemented since July 2003

26. GMP Requirements
CANADA
AUSTRALIA
Malaysia -Member since 2002
ARGENTINA LATVIA
AUSTRALIA LIECHTENSTEIN
AUSTRIA LITHUANIA
BELGIUM MALAYSIA
CANADA MALTA
CYPRUS NETHERLANDS
CZECH REP. (SUKL) NEW ZEALAND
CZECH REP. (ISCVBM) NORWAY
DENMARK POLAND
ESTONIA PORTUGAL
FINLAND ROMANIA
FRANCE (ANSM) SINGAPORE
FRANCE (ANSES) SLOVAK REPUBLIC
GERMANY SLOVENJIA
GREECE SOUTH AFRICA
HUNGARY SPAIN
ICELAND SWEDEN
INDONESIA SWITZERLAND
ISRAEL TAIWAN
IRELAND UKRAINE
ITALY UNITED KINGDOM
JAPAN UNITED STATES
KOREA
Pharmaceutical Inspection
Cooperation Scheme
•PIC/s standards (also known as the Pharmaceuticals Inspection Cooperation
Scheme ).
•If > 1 manufacturer involved, GMP certification should be available for all
manufacturers
26

27. Sharing content
Intro-
Pharmaceutical
Services Program&
NPRA
Categories of
Products &
Registration
requirements
Registration
process &
timelines
Issues Identified in
Korean product dossier
assessed at NPRA
Summary
27

28. Registration process
Step 6
Step 5
Step 4
Step 3
Step 2
Step 1
TECHNICAL
ASSESSMENT
• Evaluator’s
review
• Expert opinion-
KOL (for NCE
and Biologics
only)
• Correspondence
with applicant
DCA MEETING
Final report
presented at
Drug Control
Authority (DCA)
ACCEPTANCE OF
DOSSIER
Acceptance
of Dossier for
full evaluation
ASSESSMENT
COMPLETE
Evaluation report
presented at
NPRA Evaluation
Committee
FINAL DECISION
Approval
(MAL no.)
rejection
SCREENING
Screening of
application
received via
QUEST 3+
online system
Normal Timeline:
Generics: 210wd
NCEs, Biologics: 245 wd

29. TIMELINE FOR REGISTRATION
Type of Application Timeline
Full
Evaluation New Drug Products & Biologics
245 working days
Full
Evaluation
Generic (Scheduled & Non-Scheduled
Poison)
210 working days
Abridged
Evaluation
Generic (Non-Scheduled Poison)
• Single active ingredient
• Two or more active ingredients
• 116 working days
• 136 working days

30. FEES FOR REGISTRATION
Product Classification Processing
Fees
(RM)
Analysis Fees
(RM)
Total Fees (RM)
(USD)
a) New Drug
Products
b) Biologics
1000.00 Single active
ingredient :
3000.00
4000.00
(950)
Two or more
active ingredients
: 4000.00
5000.00
(1200)
Generic
(Scheduled Poison)
1000.00 Single active
ingredient :
1200.00
2200.00
(525)
Two or more
active ingredients
: 2000.00
3000.00
(715)

31. Facilitating Approval to new/innovative
medicines/generics/biosimilars– alternative registration pathway
PRIORITY REVIEW
(i) Unmet medical needs with
no treatment options locally
available
(ii)Life-saving with no
treatment options locally
available
(iii)first *generic/ biosimilar
product, or first locally
manufactured
generic/biosimilar product.
CONDITIONAL REGISTRATION
• Products for unmet need
supported by early clinical
data such as phase II clinical
data (based on fully
validated surrogate
endpoints)
• Conditionally registered for 2
years period with specific
conditions
FACILITATED REGISTRATION
PATHWAY
• Leveraging on a Stringent
Regulatory Authority
decision and information -
rely on assessment
report issued by the
reference agencies
• Abbreviated and
Verification Review

32. To allow promising new medicines to
reach patients with unmet need
earlier based on early phase data
such as phase II clinical data to
support the efficacy and safety.
To provide guidance on the
application necessary for
implementation of conditional
registration
To ensure that appropriate measures
are in place to manage the risks
inherent as additional data are still
required.
32
Guidelines on Conditional
Registration for NCEs and Biologics
NPRA National Pharmaceutical Regulatory Agency
1
2
3
NPRA National Pharmaceutical Regulatory Agency
Published May 2018
NPRA National Pharmaceutical Regulatory Agency

33. Full Registration (Normal Regulatory Approval) vs
Conditional Registration (early access)
Clinical trial
(evaluating of efficacy and safety)
Approval Marketing
33
Clinical
Research
Clinical
Research
Clinical trial
(prediction of
efficacy and
assurance of
safety)
Conditional
approval for
a limited
time period
(2 years)
Marketing
Confirmation of
efficacy and safety
in the post
marketing stage
Full
registration or
Revocation of
the
conditional
registration
Continued
marketing
(if
approved)
Submission
of renewal
application
within the
limited time
period
Conditional Registration Pathway
*Faster access of patients to new product is expected
• Based on the clinical data from limited number of patients, efficacy is predicted in a shorter time compared with the conventional process
• Acute-phase adverse reactions etc. can be evaluated for safety in a short period of time
Normal Regulatory Approval Pathway

34. 34
Guidelines on Facilitated Registration Pathway:
Abbreviated and Verification Review
NPRA National Pharmaceutical Regulatory Agency
NPRA National Pharmaceutical Regulatory Agency
NPRA National Pharmaceutical Regulatory Agency
Published March 2019
ensure innovative medicines addressing
current unmet medical needs can be
accessible to patients in need in a
timely manner
reduce duplication, especially for
products where safety and efficacy have
already been confirmed by Stringent
Regulatory Authorities
drive greater focus toward risk-based
evaluations, focusing on what is locally
critical versus what can be leveraged/relied
upon from decisions made by SRAs
1
2
3

35. a) New Drug Products
b) Biologics including Biosimilar
.
Scope
Abbreviated review - approved by at
least 1 reference drug regulatory
agency
Verification Review - Approved by 2
reference drug regulatory agencies
Routes
US FDA & EMA
WHO Prequalified Medicinal Products
covered by the alternative listing
procedure (evaluated by US FDA and
EMA)
Reference Agencies
Facilitated Registration Pathway
“RELIANCE….an act whereby a regulatory authority in one jurisdiction may take into
account/give significant weight to work performed by another regulator or other trusted
institution in reaching its own decision….”

36. Documents required
-Complete Common Technical Document-stability study complies with ASEAN stability guideline
-Protocol of Analysis & analytical method validation –checklist as Appendix
FULL DOSSIER
Complete assessment report including assessment on the Q&A documents between the PRH and
reference DRA and all annexes.
Note: may consider accepting public assessment reports accompanied by redacted information and Q&A
provided that the applicant has shown proof and effort to obtain the unredacted assessment reports
PROOF OF
APPROVAL
Proof of approval from the chosen reference DRA-
DECLARATION LETTER
Relevant declaration letter(s) issued by the product owner/PRH- all aspects of the DS & DP quality and
intended direction(s) for use, including but not limited to the formulation, manufacturing site(s), release and
shelf life specifications, primary packaging and active pharmaceutical ingredient(s) source are identical to
that currently approved by the chosen reference drug regulatory agency at the time of submission
ASSESSMENT REPORT
1
4
3
2

37. Full Dossier
Approved by any
regulatory agency
Full evaluation:
quality, non-clinical &
clinical
245 w.d.
Normal Registration Pathway
Facilitated / Abbreviated Registration Pathway
Facilitated / Verification Registration Pathway
Conditional Registration Pathway
Full Dossier
Approved by any
regulatory agency
Evaluation: quality,
non-clinical & early
clinical data (phase II)
245 w.d.
Full Dossier +
Reference agency
assessment report
Approved by EMA
/ US FDA
Abridged evaluation:
quality & clinical
120 w.d.
Full Dossier +
Reference agency
assessment report
Approved by both
EMA & US FDA
Reference agency
assessment report
90 w.d.
37
Full Dossier
Approved by any
regulatory agency
Full evaluation:
quality, non-clinical &
clinical
120 w.d.
Priority Review
TIMELINES COMPARISON- NCEs & Biologics

38. Statistics
27%
7%
3%
52%
11%
212,568
Notified
Cosmetics
As of 10-09-19
444
Importers
As of 31-08-19
1,386
Wholesalers
As of 31-08-19
23,254
Registered Products
As of 03-09-19
545
Manufacturers
as of 31-08-19
77 Pharma 173 TMHS
11 Veterinary 284 Cosmetics
12,208
Traditional
(T)
1,603
Non
Prescription
(X)
6,122
Prescription
(A)
2,554
Health
Supplement
(N)
767
Veterinary
(H)
1,158 Pharma 198 TMHS
30 Veterinary
179 Pharma 229 TMHS
36 Veterinary
7,725 Pharma 14,762 TMHS
767 Veterinary

39. A comparison of new drug approval
timelines, 2015-2017 (CIRS, London)
3. marketing authorisation (MA) time (time between submission and approval, which includes company
and agency time). These time points are influenced by a number of factors, one of which is the
regulatory landscape within different jurisdictions (Figure 1).
Figure1: Overall medianrollout time to AsiancountriesforNASs approved2015-2017and factorsinfluencing
their rollout.
(n1,n2) = number of NASs, number of companies
39
EM: emerging market

40. Sharing content
Intro-
Pharmaceutical
Services Program&
NPRA
Categories of
Products &
Registration
requirements
Registration
process &
timelines
Issues Identified in
Korean product dossier
assessed at NPRA
Summary
40

41. New Drug Products: Issues Identified in
Korean product dossier assessed at NPRA
Quality
Clinical
41
• Inconsistent information on product composition and specifications among
different sections of the dossier
• No data on degradation products of active pharmaceutical ingredient (API) and
drug product (e.g. stress stability testing)
• No justification on proposed drug product quality control test specifications
• Incomplete process validation report (e.g. no sampling plan)
• Incomplete stability data (e.g. no photostability study, only 3 months’ real time
stability data with a proposed shelf life of 36 months)
• Limited clinical data from Phase III studies to support efficacy and safety of all
proposed indications – this led to DCA approval of one out of all proposed
indications
• Clinical trial did not include active comparators with established use in treating
a particular disease
• Transdermal patch product did not include studies on adhesion (including the
influence of external factor such as heat and/or under other ‘in-use conditions’),
skin irritation and sensitisation

42. Biologics: Issues Identified in Korean
product dossier assessed at NPRA (based on
limited no. of products)
General
Clinical
42
• Translation issue from Korean to English- some may not be accurate
e.g. related clinical study protocol-impact on the different conduct of
the Clinical Trial
• Translation of NPRA queries from English to Korean and vice versa –
lost in translation-the true meaning of the questions raised were not
direct effectively to the applicant. Hence, unsatisfactory response

43. Generics: Issues Identified in Korean
product dossier assessed at NPRA
Quality
Clinical
43
• Test for degradation products is not conducted
• Test parameters are not included as per ASEAN Guideline on Stability study
of Drug Product. (e.g. Microbial limit test, drug release rate for transdermal
patches)
• Process validation: Media Fill report with insufficient number of containers
filled, incomplete media fill incubation information, filter validation report
and information for tunnel sterilization
• In-use stability data /Compatibility Data upon dilution is not provided
• Final concentration of diluted product is different from innovator product

44. Sharing content
Intro-
Pharmaceutical
Services Program&
NPRA
Categories of
Products &
Registration
requirements
Registration
process &
timelines
Issues Identified in
Korean product dossier
assessed at NPRA
Summary
44

45. Summary – NPRA regulatory strengthening
Structured training programs in collaboration
with industry, academia and other DRA’s
important for capacity building
Organisational change, upgrading of systems
and guidelines to support implementation of
regulatory frameworks
Collaboration with other NDRA’s to overcome
regulatory oversights and improve application
time
Use of new approaches in regulatory practice
towards efficient use of resources and avoid
duplication of work
Reliance and mutual trust with other NRA’s to
ensure sustainability of collaboration,
convergence, harmonisation efforts
1
2
3
4
5

46. Further reference
• Address : Lot 36, Jalan Universiti, 46200 Petaling Jaya,
Selangor, Malaysia.
• Telephone : +603-78835510
• Fax : +603-79581312
• Email: rosilawati.a@npra.gov.my
• Website : www.npra.gov.my

47. 47