11

Advisory Committee for Pharmaceutical Advisory Committee for Pharmaceutical Science October 26, 2005Science October 26, 2005

Advisory Committee for Pharmaceutical Advisory Committee for Pharmaceutical Science October 26, 2005Science October 26, 2005

Implementation of Quality-by-Design Implementation of Quality-by-Design (QbD) Principles in CMC Review of (QbD) Principles in CMC Review of

Generic DrugsGeneric Drugs

Lawrence X. Yu, Ph. D.Lawrence X. Yu, Ph. D.Director for ScienceDirector for Science

Office of Generic DrugsOffice of Generic DrugsFood and Drug AdministrationFood and Drug Administration

22

OGD Question-based Review OGD Question-based Review SystemSystem

Why?Why?

How?How?

And What?And What?

33

Receipts of ANDAsReceipts of ANDAs

0

200

400

600

800

1000

2001 2002 2003 2004 2005

ANDAs

Employees

44

Receipts of SupplementsReceipts of Supplements

2000

2500

3000

3500

4000

2001 2002 2003 2004

55

cGMP Initiative “Desired State”: cGMP Initiative “Desired State”: RegulatoryRegulatory

““Regulatory policies and procedures are Regulatory policies and procedures are tailored to recognize the level of scientific tailored to recognize the level of scientific knowledge…” knowledge…”

““Risk based regulatory scrutiny is Risk based regulatory scrutiny is associated with the level of scientific associated with the level of scientific understanding...”understanding...”

66

Current OGD CMC ReviewCurrent OGD CMC Review

One size fits all – Risk is not One size fits all – Risk is not systematically considered systematically considered

Does not adjust review to the level of Does not adjust review to the level of scientific understandingscientific understanding– All products (simple and complex) use the All products (simple and complex) use the

same approachsame approach– All products are subject to the same post-All products are subject to the same post-

approval supplementsapproval supplements

77

Why Question-based Review?Why Question-based Review?

WorkloadWorkload

QualityQuality– cGMP for 21cGMP for 21stst Century; Quality by Design Century; Quality by Design– Continuous improvement of our review Continuous improvement of our review

processprocess

88

OGD Question-based Review OGD Question-based Review SystemSystem

Why?Why?

How?How?

And What?And What?

99

cGMP Initiative “Desired State”: cGMP Initiative “Desired State”: Manufacturing Manufacturing

Product quality and performance achieved and Product quality and performance achieved and assured by design of effective and efficient assured by design of effective and efficient manufacturing processesmanufacturing processes

Product specifications based on mechanistic Product specifications based on mechanistic understanding of how formulation and process understanding of how formulation and process factors impact product performancefactors impact product performance

An ability to effect continuous improvementAn ability to effect continuous improvement and and continuous "real time" assurance of quality continuous "real time" assurance of quality

1010

Discussions InternallyDiscussions Internally

Question-based ReviewQuestion-based Review: Timetable: Timetable– 1/2005 – 2/2005: 1/2005 – 2/2005: Question-based Review Question-based Review DraftedDrafted– 3/2005 – 4/2005: Division Directors Discussion3/2005 – 4/2005: Division Directors Discussion– 5/2005 – 6/2005: 5/2005 – 6/2005: Team Leaders DiscussionTeam Leaders Discussion

– 7/2005 – 8/2005: Reviewers Discussion7/2005 – 8/2005: Reviewers Discussion– 2/2005 – 12/2005: Discussions with Stakeholders and 2/2005 – 12/2005: Discussions with Stakeholders and

Upper ManagementUpper Management– 9/2005 – 12/2006: Trial Period and Gradual 9/2005 – 12/2006: Trial Period and Gradual

ImplementationImplementation– 1/2007: Full Implementation1/2007: Full Implementation

1111

Discussions ExternallyDiscussions Externally

February 24, 2005: GPhA Technical Committee February 24, 2005: GPhA Technical Committee meetingmeeting

June 8, 2005: GPhA Technical Steering June 8, 2005: GPhA Technical Steering Committee meetingCommittee meeting

June 29, 2005: GPhA Technical MeetingJune 29, 2005: GPhA Technical Meeting

October 5, 2005, AAPS WorkshopOctober 5, 2005, AAPS Workshop

October 21, 2005: GPhA QbR WG MeetingOctober 21, 2005: GPhA QbR WG Meeting

October 25, 2005: OGD QbR ReportOctober 25, 2005: OGD QbR Report

More…More…

12

Question-Based Review for CMC Evaluations of ANDAs

The Office of Generic Drugs (OGD) is developing a question-based review (QbR) for the Chemistry, Manufacturing, and Controls (CMC) evaluation of an Abbreviated New Drug Application (ANDA) that is focused on critical pharmaceutical quality attributes. The QbR initiative began in early 2005 with the development of a revised review template and is approaching the early implementation phase as we gain feedback through wide internal and external discussions.

The QbR will transform the CMC review into a modern, science and risk-based pharmaceutical quality assessment that incorporates and implements the concepts and principles of the FDA’s Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach and Process Analytical Technology initiatives ……..……..

  August, 2005

1313

How is Question-based Review How is Question-based Review Developed?Developed?

Quality built in by design, development, Quality built in by design, development, and manufacture and confirmed by testingand manufacture and confirmed by testingRisk-based approach to maximize Risk-based approach to maximize economy of time, effort, and resources economy of time, effort, and resources Preserve the best practices of current Preserve the best practices of current review system and organizationreview system and organizationBest available science and wide Best available science and wide consultation to ensure high quality consultation to ensure high quality questionsquestions

1414

OGD Question-based Review OGD Question-based Review SystemSystem

Why?Why?How?How?

And What?And What?

1515

Question-based ReviewQuestion-based Review

Question-based Review is a general Question-based Review is a general framework for a science and risk-based framework for a science and risk-based assessment of product qualityassessment of product qualityQuestion-based Review contains the Question-based Review contains the important scientific and regulatory review important scientific and regulatory review questions toquestions to– Comprehensively assess critical formulation Comprehensively assess critical formulation

manufacturing process variablesmanufacturing process variables– 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

1616

What Does a CMC Reviewer do?What Does a CMC Reviewer do?

Evaluates identity, strength, stability, purity, and Evaluates identity, strength, stability, purity, and qualityquality– Definition of Quality: the drug product is free from Definition of Quality: the drug product is free from

contamination and will reproducibly deliver the contamination and will reproducibly deliver the therapeutic benefit promised in the label to the therapeutic benefit promised in the label to the consumer (Janet Woodcock)consumer (Janet Woodcock)

Determines that the generic drug product Determines that the generic drug product – is appropriately designed (a pharmaceutical is appropriately designed (a pharmaceutical

equivalent to the brand name product)equivalent to the brand name product)– can be reproducibly manufacturedcan be reproducibly manufactured

1717

Questions to Whom?Questions to Whom?

CMC ReviewerCMC Reviewer– Questions guide reviewers to provide a Questions guide reviewers to provide a

consistent and comprehensive evaluation of consistent and comprehensive evaluation of the applicationthe application

IndustryIndustry– Questions also alert the industry to what Questions also alert the industry to what

issues we generally consider critical in the issues we generally consider critical in the evaluation of their applicationsevaluation of their applications

1818

CMC Review Under CMC Review Under QbR QbR

Questions guide reviewers to provide a Questions guide reviewers to provide a high quality and comprehensive evaluation high quality and comprehensive evaluation of the applicationof the application– Some CMC deficiencies under the current Some CMC deficiencies under the current

system are related to reviewer chemists’ system are related to reviewer chemists’ education and experienceeducation and experience

Allow reviewers to derive bioequivalence Allow reviewers to derive bioequivalence inferences inferences – Pharmaceutical development/quality by Pharmaceutical development/quality by

design information and prior knowledgedesign information and prior knowledge

1919

CMC Review Under CMC Review Under QbR QbR

The risk and science-based regulatory The risk and science-based regulatory assessment assessment – Level of assessment is associated with Level of assessment is associated with

complexity of drug productscomplexity of drug products– Post-approval change supplements are Post-approval change supplements are

related to scientific understandingrelated to scientific understanding

2020

CMC Review Under CMC Review Under Question-Question-based Review (Continued) based Review (Continued)

Three-tiered assessment of manufacturingThree-tiered assessment of manufacturing– Tier 1 applies to all dosage formsTier 1 applies to all dosage forms– Tier 2 applies to dosage forms that are not Tier 2 applies to dosage forms that are not

solutions (equivalent to current practice)solutions (equivalent to current practice)– Tier 3 applies to dosage forms that are not Tier 3 applies to dosage forms that are not

solutions, IR tablets, or IR capsulessolutions, IR tablets, or IR capsules

2121

CMC Review Under CMC Review Under Question-Question-based Review (Continued)based Review (Continued)

Proposed Risk-based Scoring SystemProposed Risk-based Scoring System

ANDA drugs: ANDA drugs: Risk scoreRisk score

NTI Drugs NTI Drugs +1+1

Complex dosage form Complex dosage form +1+1

Insufficient or missing PD reports Insufficient or missing PD reports +1+1

Application of poor quality (>Application of poor quality (> 2 CMC cycles) 2 CMC cycles) +1+1

2222

CMC Review Under CMC Review Under Question-Question-based Review (Continued)based Review (Continued)

Post-approval Change RecommendationPost-approval Change Recommendation– Total risk score of 1 or less Total risk score of 1 or less

Many CBE-0 and CBE-30 changes shifted to annual reportMany CBE-0 and CBE-30 changes shifted to annual report

Possible to downgrade certain PAS changes to CBE/annual Possible to downgrade certain PAS changes to CBE/annual reportreport

– Total risk score of >1Total risk score of >1No change in supplement submission and reviewNo change in supplement submission and review

– At the time of ANDA approval the review team At the time of ANDA approval the review team will propose a risk assessment score for the will propose a risk assessment score for the applicationapplication

2323

CMC Review Under CMC Review Under Question-Question-based Review (Continued)based Review (Continued)

Risk-based Conclusion and Post-approval Risk-based Conclusion and Post-approval Supplements ReductionSupplements Reduction– Should the application be approved?– What post-approval waivers/commitments are

appropriate for this product?Eliminate/ downgrade up to 80% of CMC Eliminate/ downgrade up to 80% of CMC supplements, and thus free up scarce review supplements, and thus free up scarce review resourcesresourcesAllow sponsors freedom to execute changes in Allow sponsors freedom to execute changes in manufacturing processes for which they have manufacturing processes for which they have demonstrated process understandingdemonstrated process understanding

2424

Generic Drug Applications Under Generic Drug Applications Under Question-based Review Question-based Review

Common Technical Document FormatCommon Technical Document Format

Quality Overall Summary that willQuality Overall Summary that will– directly address the directly address the reviewers’reviewers’ questions questions

and guide reviewers through the applicationand guide reviewers through the application

– eliminate unnecessary copying of information eliminate unnecessary copying of information such as composition, specification, and such as composition, specification, and manufacturing process, etc., resulting in manufacturing process, etc., resulting in shorter review timeshorter review time

2525

Generic Drug Applications Under Generic Drug Applications Under Question-based ReviewQuestion-based Review (Continued) (Continued)

Product Development Report (Quality by Product Development Report (Quality by Design) that will explainDesign) that will explain– how drug substance and formulation variables how drug substance and formulation variables

affect the performance of the drug productaffect the performance of the drug product– how the sponsor identifies the critical how the sponsor identifies the critical

manufacturing steps, determines operating manufacturing steps, determines operating parameters, selects in-process tests to control parameters, selects in-process tests to control the process, and scales up the manufacturing the process, and scales up the manufacturing processprocess

2626

Generic Drug Applications Under Generic Drug Applications Under Question-based ReviewQuestion-based Review (Continued) (Continued)

The 1999 Guidance for Industry The 1999 Guidance for Industry “Organization of an ANDA” “Organization of an ANDA” – Does not include Quality by Design principlesDoes not include Quality by Design principles– Does not provide for a QoSDoes not provide for a QoS– Is no longer current for the OGD Is no longer current for the OGD Question-Question-

based Reviewbased Review

2727

Generic Drug Applications Under Generic Drug Applications Under Question-based ReviewQuestion-based Review (Continued) (Continued)

Future Generic ApplicationsFuture Generic Applications – We strongly recommend that generic sponsors submit We strongly recommend that generic sponsors submit

generic applications generic applications based on the format of ICH CTD, based on the format of ICH CTD, preferably, electronicallypreferably, electronically

Module 1: Administrative InformationModule 1: Administrative Information

Module 2: Quality Overall Summary and Clinical SummaryModule 2: Quality Overall Summary and Clinical Summary

Module 3: QualityModule 3: Quality– Pharmaceutical Development; Quality by DesignPharmaceutical Development; Quality by Design

Module 4: NonclinicalModule 4: Nonclinical

Module 5: Clinical (Bioequivalence)Module 5: Clinical (Bioequivalence)

2828

Benefits of Benefits of Question-based ReviewQuestion-based Review

Risk based reduction of supplementsRisk based reduction of supplements

Science based specificationsScience based specifications

Consistency and transparency of reviewConsistency and transparency of review

Efficient and timely review processEfficient and timely review process

2929

Reviewer EducationReviewer Education

Regulatory Science Training SeriesRegulatory Science Training Series– Past training workshopsPast training workshops

Polymorphism, Controlled Release, Injectable Polymorphism, Controlled Release, Injectable Drug Products, Aerosols and Sprays, Drug Products, Aerosols and Sprays, Impurities, Excipients, and ManufacturingImpurities, Excipients, and Manufacturing

– Future training workshopsFuture training workshopsQuality by Design (OPS)Quality by Design (OPS)

Preformulation, Biopharmaceutics, DissolutionPreformulation, Biopharmaceutics, Dissolution

Process Identification, Simulation, Monitoring, Process Identification, Simulation, Monitoring, and Controland Control

3030

ExpectationsExpectations

Office of Generic DrugsOffice of Generic Drugs – Ask the right questionsAsk the right questions– Produce a concise, consistent, and Produce a concise, consistent, and

comprehensive reviewcomprehensive review

IndustryIndustry– Consistent, science and risk-based Consistent, science and risk-based

assessmentassessment– Accelerated approval of applicationsAccelerated approval of applications– Reduced supplementsReduced supplements

3131

OGD Question-based Review OGD Question-based Review SystemSystem

Why?Why?– Workload, cGPM initiative, and current review Workload, cGPM initiative, and current review

processprocess

How?How?– Quality by design, risk and science-based Quality by design, risk and science-based

approach, and wide consultationapproach, and wide consultation

What?What?– A modern, science and risk-based A modern, science and risk-based

pharmaceutical quality assessment systempharmaceutical quality assessment system

More Information on Question-based ReviewMore Information on Question-based Reviewwww.fda.gov/cder/ogd/QbR.htmwww.fda.gov/cder/ogd/QbR.htm

3232

AcknowledgementAcknowledgementAndre Raw Andre Raw Robert LionbergerRobert LionbergerRadhika RajagopalanRadhika Rajagopalan Lai Ming LeeLai Ming LeeFrank Holcombe Frank Holcombe Rashmikant Patel Rashmikant Patel Florence FangFlorence Fang Vilayat SayeedVilayat SayeedPaul SchwartzPaul Schwartz Richard AdamsRichard AdamsLawrence Yu (Chair)Lawrence Yu (Chair)

Gary Buehler, Robert West, Rita Hassall, Brenda Arnwine, Gururaj Bykadi, Gary Buehler, Robert West, Rita Hassall, Brenda Arnwine, Gururaj Bykadi,

James Fan, Scott Furness, Dave Gill, Shing Hou Liu, Albert Mueller, Michael James Fan, Scott Furness, Dave Gill, Shing Hou Liu, Albert Mueller, Michael Smela, Glen Smith, Ubrani Venkataram, Karen Bernard, Neeru Takiar, Roslyn Smela, Glen Smith, Ubrani Venkataram, Karen Bernard, Neeru Takiar, Roslyn Powers, Mouna Selvam, Ramnarayan Randad, Shanaz Read, Quan Zhang, Powers, Mouna Selvam, Ramnarayan Randad, Shanaz Read, Quan Zhang,

Andrew Langowski, Susan Rosencrance, Barbara Scott, Robert Iser, Guoping Andrew Langowski, Susan Rosencrance, Barbara Scott, Robert Iser, Guoping Sun, Yanping Pan, Raman Murali, Aloka Srinivasan, Ruth Warzala, Barbara Sun, Yanping Pan, Raman Murali, Aloka Srinivasan, Ruth Warzala, Barbara

Davit, Christina Bina, Koung Lee, and Tom HinchliffeDavit, Christina Bina, Koung Lee, and Tom Hinchliffe