TFDA’s Strategies in Enhancing Drug Quality
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Transcript of TFDA’s Strategies in Enhancing Drug Quality
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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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