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TFDA’s Strategies in Enhancing Drug QualityTFDA’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

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OutlineOutline

Organization and Responsibility

Management of Drug Quality-product Life Cycle ManagementPre-Marketing ApprovalPost-Marketing Management

Regulation strategies in Enhancing Drug Quality

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Taiwan FDA (TFDA) was inaugurated on Jan. 1, 2010

TFDA supersedes the following 4 bureaus of Department of Health Bureau of Food SafetyBureau of Pharmaceutical AffairsBureau of Food and Drug AnalysisBureau of Controlled Drugs

Establishment of Taiwan FDAEstablishment of Taiwan FDA

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TFDA Organization ChartTFDA Organization Chart

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Risk Management

And Quality

Assurance

TFDA

Food DrugMedical Devices/cosmetics

ControlledDrug

Research & Analysis

Center for Regional

Administration

Establish Taiwan Food and Drug Establish Taiwan Food and Drug Safety Management SystemSafety Management System

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學名藥22875

84.13%原料藥23188.53%

罕見疾病藥品35 件

新藥1649件

生物藥品309 件1.14%

Statistics on Pharmaceutical LicensesStatistics on Pharmaceutical Licenses(2010)(2010)

New drugGeneric drug

API

Biologics

Orphan Drugs

23201 84.13%

777

Statistics on Pharmaceutical LicensesStatistics on Pharmaceutical Licenses (2010) (2010)

Domestic Import TotalRx drug 13449 3239 16688

Non-Rx drug 7543 619 8162

Total 20992 3858 24850

Rx: Non-RX 1.8:1 5.2:1 2:1

　 Domestic (%)

Import (%) Total (%)

New Drug 493 (30) 1156 (70) 1649 (100)

Generic Drug 20499 (88) 2702 (12) 23201 (100)

API 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

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Domestic Import total

NCE 1 27 28non-NCE 26 80 106total 27 107 134prescription 279 60 339OTC 90 22 112total 369 82 451post-approval post-approval changeschanges

1731 1433 3164

license license extensionsextensions

815 551 1366

casescategory

NDA

ANDA

Statistics on drug registration and post-approval Statistics on drug registration and post-approval changes changes (Jan~Dec.2010)(Jan~Dec.2010)

Statistics on drug registration and post-approval Statistics on drug registration and post-approval changes changes (Jan~Dec.2010)(Jan~Dec.2010)

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Management of Drug Quality-product LifManagement of Drug Quality-product Life Cycle Managemente Cycle Management

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QualityQuality

Quality The suitability of either a drug substance or drug product for i

ts 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 manufactur

e medicinal products so as to ensure their products：1.Fit for their intended use, comply with the requirements of the marketing authorization2. Do not place patients at risk due to inadequate safety,

quality or efficacy

-PIC/S GMP Guide 2007

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Management of Drug Quality-product Life Cycle Management of Drug Quality-product Life Cycle ManagementManagement

Basic research

Pre- clinical

ClinicalTrials

Product Launch

ProductionMarketing

& Sales

Review

Inspection

CTD ： Safety 、 Efficacy 、 Quality

GMP/GTP

GLP 、 GCP GPvP

Analysis Testing / Trial/Analysis

( 審查 )

( 稽查 )

( 檢驗 )11

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1980 1990 2000 2010

Milestones on Drug RegulationMilestones on Drug Regulation

1982GMP

1982GMP

1987BA/BE

1987BA/BE

1999cGMP

1999cGMP

2009DMF

2009DMF

2010PIC/S GMP

2010PIC/S GMP

1993Local

clinical trial

1993Local

clinical trial1996 GCP

1996 GCP

1998GLP

1998GLP

*Bridging Study Evaluation in accordance with ICH E5*Bridging Study Evaluation in accordance with ICH E5

2000BS *

Evaluation /ICH E5

2000BS *

Evaluation /ICH E5

2001Pivotal trial/

early phase trial

2001Pivotal trial/

early phase trial

1998CDE

1998CDE

2001TDRF

2001TDRF

2010TFDA

2010TFDA

1983PV/PMS

1983PV/PMS

1998ADR

1998ADR

2008GPvP

2008GPvP

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Pre-Marketing ApprovalPre-Marketing Approval

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Pre-marketing reviewPre-marketing review

New Drug Generic drug

Safety

Efficacy

Pharm / Tox

PK/PD/BA/BE

Clinical trials

Bioequivalence (BE) as a surrogate to clinical trial

Quality Chemistry, Manufacturing and Controls, CMC

GLP, GCP, cGMP Labeling （ direction of use ）

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BE studiesBE studies

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BioequivalenceBioequivalence

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

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Therapeutic EquivalenceTherapeutic Equivalence

Pharmaceutical equivalence (PE)Bioequivalence (BE)Proper labelingCMC/cGMP/GLP/GCP

FDA deemed two products therapeutic equivalence-PE+BE+ proper labeling +CMC/cGMP /GLP-GCP

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BE Requirement BE Requirement Product Quality and in vivo PerformanceProduct Quality and in vivo Performance

BE study is required once therapeutic outcome demonstratedBE 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

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Regulatory requirement on BE studiesRegulatory requirement on BE studies

Regulations Guideline of Bioavailability and Bioequivalence studies

(1987) Regulations of BA/BE Studies (2009)

Drug ApplicationNew drugs Generic drugs

—Since 1983—Retrospectively request BE studies for drugs approved before 19

83 with BE concerne.g., Diltiazem 、 Glyburide 、 Furosemide 、 Isosorbide dinitrate 、 Ate

nolol 、 Nifedipine 、 Rifampin 、 Digoxin 、 Carbamazepine

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Licenses of BE products in TaiwanLicenses of BE products in Taiwan

Number of Licenses

Percentage of Licenses(%)

Innovative or BE products

5367 21.1

Products wavied for BE studies (IV 、 oral soln, BCS class I drug etc.)

7605 29.9

OTC products8266 32.5

Products not conducting BE studies*

4197 16.5

Total 25435 100

* Products approved before 1983

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Post-marketing ManagementPost-marketing Management

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Regulation on post approval changesRegulation 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, cont

rols, product release specification, etc.Synthetic procedures, source of API and excipients, supp

lier, 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.

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Post-approval commitmentPost-approval commitment

Surveillance on Safety and EfficacyPost-marketing Surveillance, Phase-IV trialADR/quality defect reporting and investigationREMS/RMP

Maintenance for Drug Quality-Life Cycle ManagementWell controlled process and quality system

— batch to batch releaseOn-going stability protocolPost-approval changes, annual report Inspection

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The role of Government and IndustryThe role of Government and Industry in ensuring in ensuring Drug qualityDrug quality

Government’s role Industry’s role

Review Review to ensure S 、 E&Q Provide data for S 、 E&Qnon-clinical, clinical trial, CMC

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 Inspection to assure compliance

Comply with GXP-

to assure data integrity and honest communication

* It is majorly the responsibility of industry to ensure product quality throughout product life cycle

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Post-marketing Post-marketing ManagementManagement System System

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Post-marketing Management systemPost-marketing Management system

Post-approval changes

Post-approval changes

Post-approvalcommitment

Post-approvalcommitment

ADR reporting system

ADR reporting system

Product quality defect reporting

system

Product quality defect reporting

system

Compliance Compliance

GMPGMPSafety

PharmacovigilanceSafety

Pharmacovigilance

ReviewReview ReviewReviewReview/Testing

Review/Testing

InspectionInspection

Quality surveillance

Quality surveillance

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Post-marketing product quality

and safety surveillance

Post-marketing product quality

and safety surveillance

Quality surveillance

Quality surveillance

Safety surveillance

Safety surveillance

Drug Product quality defect reporting system

Drug Product quality defect reporting system

ActiveActive

ActiveActive

National Quality surveillance Program

National Quality surveillance Program

National ADR reporting system

National ADR reporting system

Manufacturer ： Drug safety report on a regular basis(PSU

R)

Manufacturer ： Drug safety report on a regular basis(PSU

R)

Government ： ADR active Monitoring Network

Government ： ADR active Monitoring Network

Reassessment / InspectionLabeling change

Withdrawal/Recall

Reassessment / InspectionLabeling change

Withdrawal/Recall

SurveillanceSurveillance

Post-marketing Safety and Quality Post-marketing Safety and Quality Surveillance-Risk ManagementSurveillance-Risk Management

PassivePassive

PassivePassive

Therapeutic Inequivalence Reporting System

Therapeutic Inequivalence Reporting System

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(~1989)GMP implemented

(1990~2000)GMP to cGMP

(2001~2009)cGMP fully implemen

ted

Fail to meet the specification-Assay

5.9%

3.9%

( 33.9% )

0.6%

( 84.6%)

Fail to meet the specification-Dissolution

21.7%

11.7%

( 46.1%)

0.7%

( 94.0%)

Survey on Marketed Drug Product QualitySurvey on Marketed Drug Product Quality(1989-2009)(1989-2009)

National Drug Quality surveillance and TestingNational Drug Quality surveillance and Testing

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Therapeutic Inequivalence Reporting Therapeutic Inequivalence Reporting in Taiwanin Taiwan

Establishing" Drug Therapeutic Inequivalence Reporting System in Taiwan“ since 2009Establishing 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 data) or single case

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Therapeutic Inequivalence ReportingTherapeutic Inequivalence Reporting in US FDA 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.

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Regulation Strategies in Enhancing Drug Regulation Strategies in Enhancing Drug QualityQuality

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Regulation Strategies in Enhancing

Drug Quality

Strategies on BE approaches

Strategies for API and Generic Drug

Strategies for GMP regulation

Strategies for Post-Approval Changes

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Strategies on BE approachesStrategies on BE approaches

Initiatives on BE studies

BE issues for certain drug products Alternative approaches for in vivo performance

evaluationDrugs with special dosage forms

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Initiatives on BE studiesInitiatives on BE studies

Retrospectively request BE studies for drugs approved before 1983 Products with special concern on therapeutic

equivalence

BE Study InspectionsPrimarily Domestic Inspection, Foreign

Inspections in plans

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Initiatives on BE studiesInitiatives on BE studies

Therapeutic Inequivalence Action Coordinating Committee (TIACC)Establishment on April, 2009Provide a systematic evaluation of therapeutic fail

ure and toxicity

Strengthen CRO managementGuidance for organizations performing bioequival

ence studies (Announced on April 18, 2011)

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BE issues for certain drug productsBE issues for certain drug products

Alternative approaches for in vivo performance evaluationNasal 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

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Drugs with special dosage forms Transdermal patches

Single or Multiple doses

Liposome products Bioanalytical Methods

Encapsulated and uncapsulated

BE issues for certain drug productsBE issues for certain drug products

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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

Strategies for API and Generic DrugStrategies for API and Generic Drug

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Europe U.S.A. Japan

EDMF:

non-pharmacopoeia products

C0S: pharmacopoeia products

DMF Type I

DMF Type II

DMF Type III

DMF Type IV

DMF Type V

J-DMF

Implement API’s DMF for Generic DrugImplement API’s DMF for Generic Drug

Implementation status of API’s DMF

Managem

ent model

Area

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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

included

included

not included

not included

* with the exception of blood and blood components

Common Technical Document (CTD)Implementation Coordination Group

presented in June 13 `02General Information on the CTD

organized by:Implementation Coordination Group Members

plus members in CTD-Q, CTD-S, CTD-E & eCTD

Implement Common Technical Document for Implement Common Technical Document for generic druggeneric drug

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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 ReviewRegulation Strategy for management of product

license

Strategies for Strategies for Post-Approval ChangesPost-Approval Changes

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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, a

nd make commitment to the drug quality assurance.— Major change: submit data for pre-approval— All quality related changes: annual product quality review

Strategies for Strategies for Post-Approval ChangesPost-Approval Changes

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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.

Product Quality Review (PIC/S GMP)Product Quality Review (PIC/S GMP)

43434343

Strategies for GMP regulationStrategies for GMP regulation

Quality Assurance for Drug ManufacturingQuality Assurance for Drug Manufacturing

Good Manufactory Practice (GMP)

Documentations, SOP, QC, QACurrent GMP (cGMP)

Validations- analytical method, process, data treatment

PIC/S GMP by 2014

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PIC/S GMP

1982◆

1999◆

cGMPGMP

◆2010.11

◆1988

◆2005

211 230163

165

550

0

100

200

300

400

500

600

21 pharmaceutical manufacturers are in

compliance with PIC/S GMP

Milestones of Pharmaceutical GMP Development in Milestones of Pharmaceutical GMP Development in TaiwanTaiwan

number of domestic pharmaceutical manufacturer

Overseas Inspection since 2002

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Quality by

Testing- Quality Control

Quality by

Manufacturing process- Quality

Assurance

1970s 1980s 1990s 2000s

Quality by

Design

Quality Systems

Evolution of Quality conceptEvolution of Quality concept

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Internationalize quality guidelinesInternationalize 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

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New Quality InitiativeNew Quality Initiative

How to do What to do

Product

-1970s

QualityControl

Process

1980s~1990s

Systems

21st Century

QualitySystems

QualityAssurance

Fixed controls state Dynamic controls state

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The three-way winThe three-way win

Consumer

Industry Government

Ensure Drug quality,

safety& efficacy

International harmonization

on drugmanagement

Increase international

competitiveness

GoalGoal

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