Marketing Authorization Procedures and Quality
Management for Generics in Taiwan
Meir-Chyun Tzou, Ph.D.
Director, Division of Drugs and New Biotechnology Products,
Taiwan Food and Drug Administration,
Department of Health,
Taiwan, R.O.C.
2011.06.03
Generic Medicines in the Legal Systems of the Republic
of China and the Federal Republic of Germany
1
Outline
Organization and Responsibility
Management of Drug Quality-product
Life Cycle Management
Pre-Marketing Approval
Post-Marketing Management
Issues of Intellectual Property Right for
Drug Approval
Future perspectives
2
Establishment of Taiwan FDA
Taiwan FDA (TFDA) was
inaugurated on Jan. 1, 2010
TFDA supersedes the following 4
bureaus of Department of Health
 Bureau of Food Safety
 Bureau of Pharmaceutical Affairs
 Bureau of Food and Drug Analysis
 Bureau of Controlled Drugs
33
3
TFDA Organization Chart
44
4
Core Value of TFDA
From Product Centered to Consumer Centered
Consumer Protection
Risk Analysis and
risk communication
Food Management
Drug
Management
5
Statistics on Pharmaceutical Licenses
(2010)
Generic drug
New drug
新藥
1649件
學名藥
22875
22857 84.13%
84.13%
API
原料藥
2318
8.53%
Biologics
生物藥品
309 件
1.14%
罕見疾病藥品
35 件
Orphan Drugs
6
Statistics on Pharmaceutical Licenses
(2010)
Domestic (%) Import (%)
Total (%)
493 (30)
1156 (70)
1649 (100)
20499 (90)
2358 (10)
22857 (100)
560 (24)
1758 (76)
2318 (100)
Total no. of Licenses
21552 (79)
5616 (21)
27168 (100)
ratio
~1:42:1.2
~1:2.3:1.5
~1:14:1.4
New Drug
Generic Drug
API
Domestic
13449
Import
3239
Total
16688
Non-Rx drug
7543
619
8162
Total
Rx: Non-RX
20992
1.8:1
3858
5.2:1
24850
2:1
Rx drug
77
7
Statistics on drug registration and post-approval ch
(Jan~Dec.2010)
category
NCE
cases Domestic
NDA non-NCE
total
prescription
ANDA OTC
total
post-approval
changes
license
extensions
Import
total
1
26
27
279
90
369
1731
27
80
107
60
22
82
1433
28
106
134
339
112
451
3164
815
551
1366
8
Management of Drug Qualityproduct Life Cycle Management
9
Management of Drug Quality-product Life
Cycle Management
Basic
research
Review
Preclinical
Clinical
Trials
Product
Launch
Production
Marketing
& Sales
CTD：Safety、Efficacy 、Quality
(審查)
GLP、GCP
GPvP
Inspection
(稽查)
Analysis
(檢驗)
GMP/GTP
Testing / Trial/Analysis
10
Milestones on Drug Regulation
1980
1982
GMP
2000
1990
1999
cGMP
1983
BA/BE
1993
1996
Local
clinical trial GCP
1998
GLP
2000
BS *
Evaluation
/ICH E5
2010
2009
DMF
2010
PIC/S
GMP
2001
Pivotal trial/
early phase trial
*Bridging Study Evaluation in accordance with ICH E5
1983
PV/PMS
1998
ADR
1998
CDE
2008
GPvP
2001
TDRF
2010
TFDA
11
11
Milestones on Drug Regulation
1982 Good Manufacturing Practice (GMP)
1987 Bioavailability / Bioequivalence Guideline (BA/BE)
1993 Safety monitoring system-the requirement of local clinical trial
1996 Good Clinical Practice (GCP)
1998 Good Laboratory Practices (GLP)
1999 Establishment of Adverse Drug Reaction reporting system
1999 Amendment of current GMP (cGMP)
2004 Implementation of bridging study evaluation (BSE)
2005 Revision of Pharmaceutical Affairs Act (Data Exclusivity &
compulsory requirement of serious ADR reporting)
2008 Good Pharmacovigilance Practice (GPvP)
2008 Guideline for Biosimilar Product Review and Approval
2009 Drug Master File (DMF)
2010 Implementation of PIC/S GMP
2010 Amendment of Guideline for Biosimilar Product Review and Approval
2010 Develop strategies for review guidelines of tNCE and Botanical New
Drug (in process)
2010 Relaxation of CPP requirement (draft)
12
12
12
Pre-Marketing Approval
13
Pre-marketing review
New Drug
Safety
Efficacy
Quality
Pharm / Tox
PK/PD/BA/BE
Clinical trials
Generic drug
Bioequivalence (BE) as a surrogate
to clinical trial
Chemistry, Manufacturing and Controls, CMC
 Including Active Pharmaceutical Ingredient (API) ,
excipients, process control, validation, stability, etc.
GLP, GCP, cGMP
Labeling（direction of use）
14
Regulatory requirement on BE studies
Regulations
 Guideline of Bioavailability and Bioequivalence (BA/BE)
studies (1987)
 Regulations of BA/BE Studies (2009)
Drug Application
 New drugs
 Generic drugs
—Since 1983
—Retrospectively request BE studies for drugs approved before
1983 with BE concern
e.g., Diltiazem 、Glyburide、Furosemide、Isosorbide dinitrate、Atenolol、
Nifedipine、Rifampin、Digoxin、Carbamazepine
15
BA/BE studies inspection
Implement inspection from 2002
Clinical phase should follow GCP
Laboratory phase should follow GLP
Other Regulations of BA/BE Studies
Reviewer initiated inspection
16
Milestones of Pharmaceutical GMP Development
in Taiwan
GMP
600
500
cGMP
PIC/S GMP
number of domestic pharmaceutical manufacturer
550
400
300
211
200
230
163
165
100
0
◆
◆
◆
◆
1982
1988
1999
2005
21 pharmaceutical
manufacturers are in
compliance with
PIC/S GMP
◆
2010.11
Overseas Inspection since 2002
17
Regulatory requirement on Active
Pharmaceutical Ingredients (API)
DMF for API of NDA and biological products
2002 GMP Guide for Active Pharmaceutical
Ingredients
2009 Announced DMF technical information review
form and application notes for API.
18
Post-marketing Management
19
Regulation on post-approval
changes
Types of Post-approval Changes
 Scale of manufacturing, Manufacturing process, equipment,
site, manufacturer, etc.
 Particle size, crystalline form, polymorphs, in-process,
controls, product release specification, etc.
 Synthetic procedures, source of API and excipients,
supplier, etc.
Regulation Requirement
Scale-Up and Post Approval Changes (SUPAC) （2001 public Announcement ）
 For products that have passed the BE testing and registered
for marketing, any changes, depending on the level and
extent of change are required to submit Bioequivalence
testing report or Dissolution Rate Profile to assure and
verify its quality.
20
Post-approval commitment
Surveillance on Safety, Efficacy and Quality
 Post-marketing Surveillance, Phase-IV trial
 ADR/quality defect reporting and investigation
 REMS/RMP
Maintenance for Drug Quality-Life Cycle
Management (industry’s role)
 Well controlled process and quality system
— batch to batch release
 On-going stability protocol
 Post-approval changes, annual report
 Inspection
21
The role of Government and Industry in ensuring
Drug quality
It is mainly the industry’s responsibility, not the government’s,
to ensure product quality throughout product life cycle
Government’s role
Industry’s role
Review
Review to ensure S、E&Q
Testing
Batch release for biologics
No testing for other drugs
(with exceptions)
In process control and batch to batch release
for drugs and biologics
Inspection to assure
compliance
Comply with GXPto assure data integrity and honest
communication
Inspection
Provide data for S、E&Q
non-clinical, clinical trial, CMC
22
Post-marketing Management System
Post-marketing Management system
Post-approval
changes
Safety
Pharmacovigilance
Quality
surveillance
GMP
Post-approval
commitment
ADR
reporting system
Product quality
defect reporting
system
Compliance
Review/
Testing
Inspection
Review
Review
23
23
Post-marketing Safety and Quality
Surveillance-Risk Management
Quality
surveillance
Passive
Drug Product quality defect
reporting system
Therapeutic Inequivalence
Reporting System
Surveillance
Post-marketing
product quality
and safety
surveillance
Active
Safety
surveillance
Passive
Active
Reassessment / Inspection
Labeling change
 Withdrawal/Recall
National Quality surveillance
Program
National ADR reporting
system
Manufacturer：Drug safety
report on a regular
basis(PSUR)
Government：ADR active
Monitoring Network
24
24
Issues of Intellectual Property Right
for Drug Approval
25
Issues of Patent
Issues of
Intellectual
Property Right
for Drug
Approval
Issues of Research Exemption
Issues of Exclusivity
Issues of Copyright
26
Issues of Patent
Disclosure of patent
Declaration of patent non-infringement
The review of generic drug and the
information of patents are normally linked
Review of patent infringement casesIntellectual Property Court
27
Issues of Patent
Disclosure of patent
 Pharmaceutical Affairs Act Article 40-2 (since
2005 )
 While granting the certificate of pharmaceutical product,
the central health competent authority shall announce the
disclosed patent number or patent application number
provided by the applicant.
-DOH made an announcement on October, 2005 notifying applicants who are applying
or have been granted marketing approval for pharmaceutical products after Feb. 2005, to
submit registered patent number/ affidavit of patent.
 These information are available on website.
(http://www.fda.gov.tw/Bgradation_index.aspx?site_content_s
n=38)
28
Issues of Patent
Declaration of patent non-infringement
 Review Regulations for Registration and Market
Approval of Pharmaceuticals Article 19
 Applicants should submit an affidavit to declare that the
applicant has full legal responsibility if the applied product
infringe the patent of others.
The review of generic drug and the information
of patents are normally linked.
29
Issues of Patent
Review of patent infringement casesIntellectual Property Court
 According to Taiwan’s Patent Act, within valid patent
protection period, generic drug cannot enter the market or
be sold.
 Patent infringement will be granted by the patentee if the
generic drug applicants violate the rule.
 Patent-related litigation and the quality of review had been
enhanced and accelerated since the Intellectual Property
Court was established on July 1st, 2008.
30
Issues of Research Exemption
Exemption for Research use
 Pharmaceutical Affairs Act Article 40-2 Paragraph 5
The patent right of the new drug shall not be applicable to
researches, teachings, or testing prior to the application for
registration by the pharmaceutical firms.
 Patent Act Article 60(Amending)
31
Issues of Exclusivity
Historical exclusivity analogy
 1993 Safety monitoring system-the requirement of local
clinical trial for NDA (Taiwan-US Intellectual Property
Right Agreement)
 Pipeline protection of new drug before the Patent Act was amended
in 1986.
 Barrier for generic drug application
 Within five years after the issuance of a license for new drug , the
second applicant is required to submit the same scale of clinical trial
data as the first applicant.
 1997 New indication
 2004 Implementation of bridging study evaluation (BSE)
32
Issues of Data exclusivity
Pharmaceutical Affairs Act Article 40-2
Within five years after the issuance of a license for new drug of new
chemical entity, any other pharmaceutical firm may not apply for
evaluation and registration of the same items by citing the data submitted
by the licensee without such licensee’s authorization.
After three years of the issuance of a license for new drug of new chemical
entity, other pharmaceutical firm may apply for registration of drugs of the
same substance, the same dosage form, the same dose, and the same dose
unit according to this Act and related laws or regulations; the drug license
may be issued on the next day to the expiration of five years after the
issuance of license to such new drug of new chemical entity.
33
Issues of Data exclusivity
Pharmaceutical Affairs Act Article 40-2
 The second paragraph hereof can only be applicable
with the compliance that application for registration
of a new drug of new chemical entity shall be made to
the Central Competent Health Authority within three
years after it is first approved for marketing in any
country.
34
Issues of Copyright
Generic drug labeling
 Review Regulations for Registration and Market
Approval of Pharmaceuticals Article 20
Generic drug labeling of the surveillance drugs*, should
follow the first approved labeling; labeling of the nonsurveillance drugs** should be translated according to the
innovator’s labeling.
 But drug labeling has not been excluded from the
copyright act, which might cause the lawsuit.
*surveillance drugs: chemical entity first approved after 1983.
**non-surveillance drugs : chemical entity first approved before 1983.
35
Issues of Copyright
Drug labeling – fair use for public benefit
 Copyright Act Article 65
Fair use of a work shall not constitute infringement on economic rights in the work.
In determining whether the exploitation of a work complies with the provisions of Articles
44 through 63, or other conditions of fair use, all circumstances shall be taken into
account, and in particular the following facts shall be noted as the basis for determination.
 The court decision for lawsuit cases : Drug labeling
should refer to Copyright Act Article 52 “Within a
reasonable scope, it may be used for necessary or
other legitimate purposes”
Drug labeling excluding from copyright
TFDA is planning to amend the Pharmaceutical Affairs Act Article 48-2, to stipulates the
suitability of excluding drug labeling from Copyright Act.
36
Future perspectives of Intellectual
Property Right for Drug Approval
Exemption for research use
-amendment of Patent Act
Drug labeling excluding from copyright
-amendment of Pharmaceutical Affairs Act
Data exclusivity for new indication?
37
Future perspectives
38
Strategies for API and Generic Drug
Future perspectives
in Enhancing
Drug Quality
Strategies for Post-Approval Changes
Strategies for GMP regulation
39
Strategies for API and Generic Drug
Establishing the review strategies for DMF of
API and CTD of Generic Drugs
 Time-line and action plans
to implement API’s DMF and CTD for Generic Drug
 Implement DMF and CTD by stages.
Stage 1: With NHI drug price incentives, encouraging companies to
implement DMF, starting from Oct. 1st, 2009
Stage 2: Compulsory implementation of DMF and CTD
-Implement by stages, by items
40
Implement Common Technical Document for
generic drug
New chemical entities
New biologic
New indication
New dosage forms
New route of administration
Generics
OTC
EU
FDA
MHLW
included
included
included
included
included*
included
included
included
included
included
included
included
included
included
included
included
included
not included
included
included
not included
* with the exception of blood and blood components
Common Technical Document (CTD)
Implementation Coordination Group
organized by:
Implementation Coordination Group Members
plus members in CTD-Q, CTD-S, CTD-E & eCTD
presented in June 13 `02
General Information on the CTD
41
Strategies for
Post-Approval Changes
Regulation strategies for post-approval changes
 Establish DMF database of API
 Monitor and inspect API changes
 Revise guideline for Scale-Up and Post
Approval Changes (SUPAC)
 Strengthen regulation on Post-Approval
Changes-Product Quality Review
Regulation Strategy for management of product
license
42
42
Strategies for GMP regulation
Quality Assurance for Drug Manufacturing
Good Manufactory Practice (GMP)
Documentations, SOP, QC, QA
Current GMP (cGMP)
 Validations- analytical method, process, data
treatment
PIC/S GMP by 2014
43
43
43
Milestones of Pharmaceutical GMP Development in
Taiwan
GMP
600
500
cGMP
PIC/S GMP
number of domestic pharmaceutical manufacturer
550
400
300
211
200
230
163
165
100
0
◆
◆
◆
◆
1982
1988
1999
2005
21 pharmaceutical
manufacturers are in
compliance with
PIC/S GMP
◆
2010.11
Overseas Inspection since 2002
44
Internationalize quality guidelines
Implementation status of ICH quality Guidelines in Taiwan
Q1
Stability
Adopt
Q2
Analytical Validation
Adopt
Q3
Impurities
Accept
Q4
Pharmacopoeias
Accept
Q5
Quality of Biotechnological products
Accept
Q6
Specifications
Accept
Q7
Good Manufacturing Practice(原料藥GMP)
Adopt
Q8
Pharmaceutical Development
Accept
Q9
Risk Management system
Accept
Q10
Pharmaceutical Quality system
Accept
45
Evolution of Quality concept
Quality
Systems
Quality
by
Testing-
Quality
by
Manufacturing
- Quality
Quality
by
Design
Assurance
Quality
Control
1970s
1980s
1990s
2000s
46
New Quality Initiative
How to do
What to do
Fixed controls state
Dynamic controls state
Product
Process
Systems
-1970s
1980s~1990s
21st Century
Quality
Control
Quality
Assurance
Quality
Systems
47
Goal
The three-way win
Consumer
Ensure
Drug quality,
safety&
efficacy
Industry
Increase
international
competitiveness
International
harmonization
on drug
management
Government
48
49