11

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

22

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

33

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

44

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

55

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?

1010

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

1111

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

?

1212

Quality by DesignQuality by Design

Unit OperationsMixing

CompressionCoating…

Drug Substance

Excipients

AssayUniformity

PurityDiss

“Always” Meet Spec

PAT

Clinical Relevance

1313

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

1414

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

1515

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

1616

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

1717

Diagram of the ICH Common Technical Document

QOSSummary of Critical CMC Elements

Body of DataCMC SubmissionPackage

1818

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

1919

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

2020

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””

2121

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””

2222

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

2323

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

2424

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

2525

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

2626

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

2727

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