TFDA’s Strategies in Enhancing Drug Quality
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.
2011.04.29
The Orange Book, Generic Drugs and Bioequivalence
1
Outline
Organization and Responsibility
Management of Drug Quality-product
Life Cycle Management
Pre-Marketing Approval
Post-Marketing Management
Regulation strategies in Enhancing Drug
Quality
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
Establish Taiwan Food and Drug
Safety Management System
Drug
Medical Devices/cosmetics
Food
Risk
Management
And
Quality
Assurance
Center for
Regional
Administration
TFDA
Controlled
Drug
Research &
Analysis
55
5
Statistics on Pharmaceutical Licenses
(2010)
Generic drug
New drug
新藥
1649件
學名藥
22875
23201 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 (88)
2702 (12)
23201 (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 Quality-product
Life Cycle Management
9
Quality
Quality
The suitability of either a drug substance or drug product for
its intended use. This term includes such attributes as the
identity, strength, and purity.
-ICH Q6A ,ICH Q8
Quality objective
The holder of a manufacturing authorization must manufacture
medicinal products so as to ensure their products：
1.Fit for their intended use, comply with the requirements of
the marketing authorization
2. Do not place patients at risk due to inadequate safety,
quality or efficacy
-PIC/S GMP Guide 2007
10
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
11
11
Milestones on Drug Regulation
1980
1982
GMP
2000
1990
1999
cGMP
1987
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
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
GLP, GCP, cGMP
Labeling（direction of use）
14
BE studies
15
Bioequivalence
IND/NDAs
Establish links between
(1) Early and late clinical trial formulations
(2) Formulations used in clinical trial and stability studies, if
different
(3) Clinical trial formulations and to-be-marketed drug product;
and
(4) Other comparisons, as appropriate.
ANDAs
BE is a primary element in the determination of therapeutic
equivalence BE, together with the determination of PE allows a
regulatory conclusion of therapeutic equivalence
16
Therapeutic Equivalence
Pharmaceutical equivalence (PE)
Bioequivalence (BE)
Proper labeling
CMC/cGMP/GLP/GCP
FDA deemed two products therapeutic
equivalence-PE+BE+ proper labeling
+CMC/cGMP /GLP-GCP
17
BE Requirement
Product Quality and in vivo Performance
BE study is required once therapeutic outcome
demonstrated
BE is required whenever changes are significant
enough so that they lead to questions of product
quality/performance or therapeutic outcome
 Pre-approval
—Pilot formulation vs pivotal clinical formulation
—Pivotal clinical formulation vs final market formulation
—Generic product vs RLD
 Significant post-approval changes
BE requirement should be applied to both the brand
name and the generic products
18
Regulatory requirement on BE studies
Regulations
 Guideline of Bioavailability and Bioequivalence 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
19
Licenses of BE products in Taiwan
Innovative or BE
products
Products wavied for BE
studies (IV、oral soln,
BCS class I drug etc.)
OTC products
Products not conducting
BE studies*
Total
* Products approved before 1983
Number of
Licenses
Percentage of
Licenses(%)
5367
21.1
7605
29.9
8266
32.5
4197
16.5
25435
100
20
Post-marketing Management
21
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.
22
Post-approval commitment
Surveillance on Safety and Efficacy
 Post-marketing Surveillance, Phase-IV trial
 ADR/quality defect reporting and investigation
 REMS/RMP
Maintenance for Drug Quality-Life Cycle
Management
 Well controlled process and quality system
— batch to batch release
 On-going stability protocol
 Post-approval changes, annual report
 Inspection
23
The role of Government and Industry in ensuring
Drug quality
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
* It is majorly the responsibility of industry to ensure product quality throughout
product life cycle
24
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
25
25
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
26
26
National Drug Quality surveillance and Testing
Survey on Marketed Drug Product Quality
(1989-2009)
(~1989)
GMP implemented
Fail to meet the
specificationAssay
Fail to meet the
specificationDissolution
5.9%
21.7%
(1990~2000)
GMP to cGMP
(2001~2009)
cGMP fully
implemented
3.9%
0.6%
( 33.9% )
( 84.6%)
11.7%
0.7%
( 46.1%)
( 94.0%)
27
Therapeutic Inequivalence Reporting
in Taiwan
Establishing" Drug Therapeutic Inequivalence Reporting System
in Taiwan“ since 2009
Establishing committee for identification and evaluation of
reports
Summarizing 70 reports from 2009 to 2010
 One brand name drug (thyroxin)：
— Formulation and manufacturing site changed
— Following a switch, unexpected AE (allergy) occurred in
patients
— TFDA investigation and ongoing review
 One injectable drug（iron sucrose complex）
— AE (allergy) occurred in patients
— Suspect difference in structure and particle size
 Others: poor data (ex insufficient information, lack of lab
28
data) or single case
Therapeutic Inequivalence Reporting
in US FDA
Therapeutic Inequivalence Action Coordinating
Committee (TIACC) in CDER to evaluate these reports
For example: Bupropion（Antidepressant）
Brand name drug (Wellbutrin XL 300 mg) vs.generic drug (Budeprion XL 300 mg)
 In 2007, FDA received 85 AE reports following a switch
 US FDA's evaluation and conclusion
—The generic form of bupropion bioequivalent and
therapeutically equivalent to the brand name drug
—The number of AE reports following a switch
were fewer than the drug and placebo groups in
clinical trials
—Natural history of disease：The AE may occur
throughout the course of the therapy, even patients
on a stable dose of medicine or receiving placebo.
29
Regulation Strategies in Enhancing Drug
Quality
30
Strategies on BE approaches
Regulation
Strategies in
Enhancing
Drug Quality
Strategies for API and Generic Drug
Strategies for Post-Approval Changes
Strategies for GMP regulation
31
Strategies on BE approaches
Initiatives on BE studies
BE issues for certain drug products
Alternative approaches for in vivo performance
evaluation
Drugs with special dosage forms
32
Initiatives on BE studies
Retrospectively request BE studies for drugs
approved before 1983
Products with special concern on therapeutic
equivalence
BE Study Inspections
Primarily Domestic Inspection, Foreign
Inspections in plans
33
Initiatives on BE studies
Therapeutic Inequivalence Action
Coordinating Committee (TIACC)
Establishment on April, 2009
Provide a systematic evaluation of therapeutic
failure and toxicity
Strengthen CRO management
Guidance for organizations performing
bioequivalence studies
(Announced on April 18, 2011)
34
BE issues for certain drug products
Alternative approaches for in vivo performance
evaluation
Nasal aerosols or Nasal sprays
Metered-dose inhalers or metered dose spray
 In vitro studies
 PK/PD/clinical study
Oral drugs rarely absorbed by GI tract
 e.g., Sevelamer (phosphate binder )
 In vitro studies
Topical and vaginal antifungals
 In vitro studies (Franz cell system)
 Potential in vivo performance evaluation methods is still developing
35
BE issues for certain drug products
Drugs with special dosage forms
Transdermal patches
Single or Multiple doses
Liposome products
 Bioanalytical Methods
Encapsulated and uncapsulated
36
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
 Communication with the industry association
 Training /Education
37
Implement API’s DMF for Generic Drug
Implementation status of API’s DMF
Area Europe
Management model
EDMF:
nonpharmacopoeia
products
U.S.A.
Japan
DMF Type I
DMF Type II
DMF Type III
DMF Type IV
DMF Type V
J-DMF
C0S:
pharmacopoeia
products
38
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
39
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
40
40
Strategies for
Post-Approval Changes
Revise Post-Approval Change Guideline, based on
SUPAC (USA), BACPAC (USA) and variation
regulation (EMA)
Strengthen post-approval changes regulation system,
based on EMA’s regulation-Annual Product Quality
Review(PIC/S GMP)
 Industry’s duty: be responsible for drug product quality,
and make commitment to the drug quality assurance.
— Major change: submit data for pre-approval
— All quality related changes: annual product quality review
41
Product Quality Review (PIC/S GMP)
Drug Product(PIC/S GMP Part 1 1.4)
2009.09.01
API(PIC/S GMPPart 2 1.5)
2009.09.01
1.A review of staring materials and packaging materials used for the product,
especially those from new sources.
2.A review of critical in-process controls and finished product results.
1.A review of critical in-process control and critical
API test results.
3.A review of all batches that failed to meet established specification (s)and
their investigation.
2.A review of all batches that failed to meet established
specification (s).
4.A review of all significant deviations or non-conformances, their related
investigations, and the effectiveness of resultant corrective and preventive
actions taken.
3.A review of all critical deviations or nonconformance
and related investigations.
5.A review of all changes carried out to the processes or analytical methods.
4.A review of any changes carried out to the processes
or analytical methods.
6.A review of Marketing Authorization variations submitted/granted/refused,
including those for third country (export only) dossiers.
7.A review of the results of the stability monitoring programmed and any
adverse trends.
5.A review of results of the stability monitoring
program.
8.A review of all quality-related returns, complaints and recalls and the
investigations performed at the time.
6.A review of all quality-related returns, complaints
and recalls.
9.A review of adequacy of any other previous product process or equipment
corrective action
7.A review of adequacy of corrective actions.
10.For new marketing authorizations and variations to marketing authorizations,
a review of post-marketing commitments.
11.The qualification status of relevant equipment and utilities, e.g. HVAC,
Water, compressed gases etc.相
12.A review of Technical agreements to ensure that they are up to date.
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
Evolution of Quality concept
Quality
Systems
Quality
by
Testing-
Quality
by
Manufacturing
process-
Quality
by
Design
Quality
Assurance
Quality
Control
1970s
1980s
1990s
2000s
45
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
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
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