1 implementation of quality-by-design: ogd initiatives implementation of quality-by-design: ogd...
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ImplementationImplementationof Quality-by-Design:of Quality-by-Design:
OGD InitiativesOGD InitiativesLawrence Yu, PhDLawrence Yu, PhDDirector for ScienceDirector for Science
Office of Generic DrugsOffice of Generic DrugsFood and Drug AdministrationFood and Drug Administration
Advisory Committee for Pharmaceutical Science October 5, 2006
Advisory Committee for Pharmaceutical Science October 5, 2006
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What is Quality by Design?What is Quality by Design?
Pharmaceutical Quality by Design (QbD) Pharmaceutical Quality by Design (QbD) – QbD means designing and developing QbD means designing and developing
formulations and manufacturing processes to formulations and manufacturing processes to ensure predefined product qualityensure predefined product quality
Understanding and controlling formulation and Understanding and controlling formulation and manufacturing process variables affecting the manufacturing process variables affecting the quality of a drug productquality of a drug product
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Question-based ReviewQuestion-based Review
Question-based Review (QbR) is a general Question-based Review (QbR) is a general framework for a science and risk-based framework for a science and risk-based assessment of product qualityassessment of product qualityQbR contains the important scientific and QbR contains the important scientific and regulatory review questions toregulatory review questions to– Comprehensively assess critical formulation and Comprehensively assess critical formulation and
manufacturing process variablesmanufacturing process variables– Set regulatory specifications relevant to qualitySet regulatory specifications relevant to quality– Determine the level of risk associated with the Determine the level of risk associated with the
manufacture and design of the productmanufacture and design of the product
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Questions Come FirstQuestions Come First Say What You Do and Do What You SaySay What You Do and Do What You Say
Questions guide reviewers Questions guide reviewers – Prepare a consistent and comprehensive evaluation Prepare a consistent and comprehensive evaluation
of the ANDAof the ANDA– Assess critical formulation & manufacturing variablesAssess critical formulation & manufacturing variables
Questions guide industry Questions guide industry – Recognize issues OGD generally considers critical Recognize issues OGD generally considers critical – Direct industry toward QbDDirect industry toward QbD
Questions inform readers of the reviewQuestions inform readers of the review– How QbD was used in the ANDAHow QbD was used in the ANDA– Provide the basis for a risk assessmentProvide the basis for a risk assessment
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Generic Sponsor: Implementing
QbD in developmentand manufacturing
FDA OGD:Developed a Question-based Review System
that assesses sponsor’s QbD ANDAs
FDA’s Pharmaceutical cGMPfor the 21st Century
QbD Initiative
QbR Questions Embodies QbD
Qualityby
Design
What attributes should the drug product possess?
QbR Questions Embodies QbD
Qualityby
Design
How was the product designed to have these attributes?
Were alternative formulations or mechanisms investigated?
How were the excipients selected?
How was the final formulation optimized?
QbR Questions Embodies QbD
Qualityby
Design
What are the unit operations in the drug product manufacturing process?
Why was the manufacturing process selected?
How are the unit operations related to the drug product quality?
QbR Questions Embodies QbD
Qualityby
Design
How were the critical process parameters identified, monitored, and controlled?
In the proposed scale up plan what operating parameters will be adjusted to ensure the product meets all in-process and final product specifications?
What evidence supports the plan to scale up the process to commercial scale?
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Why is QbD for Generic Drugs Why is QbD for Generic Drugs Unique?Unique?
Target product quality Target product quality profile well defined profile well defined such as dissolution, such as dissolution,
purity, uniformity, and purity, uniformity, and stabilitystability
Biopharmaceutical Biopharmaceutical properties of drugs properties of drugs
already known such as already known such as polymorphism, polymorphism, absorption, and absorption, and
pharmacokinetics pharmacokinetics informationinformation
Extensive formulation Extensive formulation and manufacturing and manufacturing experience for many experience for many generic manufacturersgeneric manufacturers
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Quality by End Product TestingQuality by End Product Testing
Unit OperationsMixing
CompressionCoating…
Drug Substance
Excipients
AssayUniformityImpurity
MetalRes Solvents
MoistureDiss
MeetSpec? Yes
No
10/30 out of 10,000,000
CFR 314.70Change Guidance
?
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Quality by DesignQuality by Design
Unit OperationsMixing
CompressionCoating…
Drug Substance
Excipients
AssayUniformity
PurityDiss
“Always” Meet Spec
PAT
Clinical Relevance
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QbD More Information to ReviewQbD More Information to Review
0
200
400
600
800
1000
2001 2002 2003 2004 2005
ANDAs
EmployeesQuality By
Testing
Quality by
Design
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Quality Assessment under Old Quality Assessment under Old CMC Review?CMC Review?
Reviewers prepare a summary of the Reviewers prepare a summary of the applicationapplication
Write deficiency letters in response to Write deficiency letters in response to missing information or insufficient missing information or insufficient specificationsspecifications
No pharmaceutical development No pharmaceutical development information in ANDAsinformation in ANDAs
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Quality Assessment under QbRQuality Assessment under QbR
The QbR quality review includesThe QbR quality review includes
– Comprehensively evaluate sponsor’s Quality Comprehensively evaluate sponsor’s Quality by Designby Design
– Set regulatory specifications relevant to Set regulatory specifications relevant to qualityquality
– Determine the level of risk associated with the Determine the level of risk associated with the manufacture and design of the productmanufacture and design of the product
– Explain the reason for each deficiencyExplain the reason for each deficiency
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Old CMC Review to QbR Old CMC Review to QbR AssessmentAssessment
Old QbR
Assessment
Summary
Body of DataSponsor
Reviewer
Assess specperformance
SummaryQbD
Body of DataQbD
Assess spec
Summary
Body of Data
Reviewer
Sponsor
No PD InfNo PD Info Assess QbD
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Diagram of the ICH Common Technical Document
QOSSummary of Critical CMC Elements
Body of DataCMC SubmissionPackage
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OGD Model QOSOGD Model QOS
Model QOS for ER Product (1/2006)Model QOS for ER Product (1/2006)– http: //www.fda.gov/cder/ogd/http: //www.fda.gov/cder/ogd/
OGD_Model_Quality_Overall_Summary.pdf OGD_Model_Quality_Overall_Summary.pdf
Model QOS for IR Product (3/2006)Model QOS for IR Product (3/2006)– http: //www.fda.gov/cder/ogd/http: //www.fda.gov/cder/ogd/
OGD_Model_QOS_IR_Product.pdfOGD_Model_QOS_IR_Product.pdf
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QbR: Where Are We Today?QbR: Where Are We Today?
Generic Drug Industry On Board Generic Drug Industry On Board – GPhA Technical Committee QbR WGGPhA Technical Committee QbR WG
Over 35 QbR ANDAsOver 35 QbR ANDAs– Over 20 Generic CompaniesOver 20 Generic Companies
First QbR ApprovalFirst QbR Approval– CMC Review Time = 4 months, 1 cycleCMC Review Time = 4 months, 1 cycle– Total Review Time = 8 monthsTotal Review Time = 8 months
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Experience with Assessment of Experience with Assessment of QbR ANDAs: Technical AdvantagesQbR ANDAs: Technical Advantages
““Enhanced product and review assessmentEnhanced product and review assessment– Critical formulation and manufacturing process Critical formulation and manufacturing process
variables identified and controlled in QbR-QOSvariables identified and controlled in QbR-QOS
Insight into sponsor’s development plansInsight into sponsor’s development plans– Product & Process Design, and DevelopmentProduct & Process Design, and Development
– Directly address the Directly address the OGD’s questionsOGD’s questions
Better understanding of sponsors' rationale for Better understanding of sponsors' rationale for decisions and therefore, less decisions and therefore, less
misunderstandingsmisunderstandings””
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Experience with Assessment of Experience with Assessment of QbR ANDAs: Documentation AdvantagesQbR ANDAs: Documentation Advantages
““Primary reviewer saves time (~20%) Primary reviewer saves time (~20%) – Summary of applicationSummary of application
Facts findingFacts finding
Tables & chartsTables & charts
Chemical structuresChemical structures
Specifications etcSpecifications etc
No transcriptional errorsNo transcriptional errors””
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FDA’s cGMP Initiative and Initiation of QbRQbR Questions draftedGPhA Technical Advisory Committee MeetingOGD GPhA Technical Advisory Committee Joint MeetingGPhA Technical Advisory Committee Meeting OGD QbR White PaperOGD GPhA Technical Advisory Committee Joint MeetingGPhA Fall Technical WorkshopANDA Submission ChecklistExample Quality Overall SummaryGPhA Technical Advisory Committee MeetingGPhA QbR WebcastGPhA Teleconference on Quality of QOSOGD QbR RetreatFirst QbR ANDA ApprovalFull implementation of QbR
20041/20052/20056/20056/20058/2005
10/200510/2005
1/20061/20062/20065/20067/20069/20069/20061/2007
Question-based Review: Question-based Review: Progress/CommunicationProgress/Communication
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ChallengesChallenges
Quality of QOS prepared by sponsorsQuality of QOS prepared by sponsors– Too longToo long
Non-critical data; Multiple tables: same dataNon-critical data; Multiple tables: same data
Analytical Validation: USP methodsAnalytical Validation: USP methods
– Leaving out questionsLeaving out questions– Inconsistencies between QOS and body of dataInconsistencies between QOS and body of data
OGD’s ActionsOGD’s Actions– CommunicationCommunication– Training; first October 20, 2006Training; first October 20, 2006
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ChallengesChallenges
Knowledge of formulation and manufacturing Knowledge of formulation and manufacturing sciencescience– ChemistsChemists
OGD’s ActionsOGD’s Actions– RecruitingRecruiting
Formulation scientists and process engineersFormulation scientists and process engineers– Internal trainingInternal training
QbR seminars and workshopsQbR seminars and workshopsReview papers or commentaryReview papers or commentary
– External trainingExternal trainingPurdue NIPTE; 12 review chemists attended Purdue NIPTE Purdue NIPTE; 12 review chemists attended Purdue NIPTE liquid and solid dosage form trainingliquid and solid dosage form training
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Next StepNext Step
Risk Assessment and Supplement Risk Assessment and Supplement ReductionReduction– Two opportunities for supplement reductionTwo opportunities for supplement reduction
For QbR ANDAs: at the time of approvalFor QbR ANDAs: at the time of approval
For all ANDAs: after sufficient product commercial For all ANDAs: after sufficient product commercial manufacturing historymanufacturing history
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ConclusionsConclusions
OGD is implementing a new OGD is implementing a new pharmaceutical quality assessment pharmaceutical quality assessment system thatsystem that– Enhances quality of generic drugsEnhances quality of generic drugs– Improves review quality and consistencyImproves review quality and consistency– Reduces review timeReduces review time– Reduces supplementsReduces supplements
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OGD QbR InitiativeOGD QbR InitiativeAndre Raw Andre Raw Robert Lionberger Robert Lionberger Radhika RajagopalanRadhika RajagopalanLai Ming LeeLai Ming Lee Frank Holcombe Frank Holcombe Rashmikant Patel Rashmikant Patel Florence FangFlorence Fang Vilayat SayeedVilayat Sayeed Paul SchwartzPaul SchwartzRichard AdamsRichard Adams Lawrence Yu (Chair)Lawrence Yu (Chair)
, Brenda Arnwine, Gururaj Bykadi, James Fan, Scott Furness, Dave Gill, Hossein Khorshidi, Shing Hou Liu, Albert Mueller, , Brenda Arnwine, Gururaj Bykadi, James Fan, Scott Furness, Dave Gill, Hossein Khorshidi, Shing Hou Liu, Albert Mueller, Susan Rosencrance, Michael Smela, Glen Smith, Ubrani Venkataram, Naiqi Ya, Susan Zuk Susan Rosencrance, Michael Smela, Glen Smith, Ubrani Venkataram, Naiqi Ya, Susan Zuk
Karen Bernard, Christina Bina, Barbara Davit, Tom Hinchliffe, Robert Iser, Andrew Langowski, Koung Lee, MaryJane Mathews, Karen Bernard, Christina Bina, Barbara Davit, Tom Hinchliffe, Robert Iser, Andrew Langowski, Koung Lee, MaryJane Mathews, Yanping Pan, Susan Pittinger, Roslyn Powers, Ramnarayan Randad, Shanaz Read, Dominick Roselle, Xiumei Ruan, Barbara Yanping Pan, Susan Pittinger, Roslyn Powers, Ramnarayan Randad, Shanaz Read, Dominick Roselle, Xiumei Ruan, Barbara
Scott, Mouna Selvam, Aloka Srinivasan, Guoping Sun, Neeru Takiar, Ruth Warzala, Quan Zhang, Susan ZukScott, Mouna Selvam, Aloka Srinivasan, Guoping Sun, Neeru Takiar, Ruth Warzala, Quan Zhang, Susan Zuk
Gary Buehler, Robert West, Rita Hassall, Helen Winkle, Keith Webber, Mansoor Khan, Joseph Famulare, Nicholas Buhay, Gary Buehler, Robert West, Rita Hassall, Helen Winkle, Keith Webber, Mansoor Khan, Joseph Famulare, Nicholas Buhay, Albinus D Sa, Rick Friedman, Albinus D Sa, Rick Friedman,
Brian HasselbalchBrian Hasselbalch