Revision of QbR for QbD SubmissionsJennifer A. Maguire, Ph.DKaren A. Bernard, Ph.DCMC ReviewersOffice of Generic DrugsFood and Drug AdministrationGPhA/FDA CMC WorkshopMay 22-23, 2012This presentation reflects the views of the author and should not beconstrued to represent FDA’s views or policies.
2Outline• What is QbR?• Why is QbR necessary?• What are the advantages of QbR?• Why are the QbR questions being revised?• What do the revised QbR questions look like?
3Question-based Review (QbR)• Question-based review (QbR) for the CMC evaluation of ANDAswas implemented in 2007• QbR is a general framework for a science and risk-basedassessment of product quality• QbR contains the important scientific and regulatory reviewquestions to– Comprehensively assess critical formulation and manufacturing processvariables– Set regulatory specifications relevant to quality and productperformance– Determine the level of risk associated with the design and manufactureof the productGeneric Drugs Information for Industry>Question based Review webpage:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm120971.htm
4Quality by Design (QbD) andQuestion-based Review (QbR)Generic Applicant:ImplementingQbD in development,manufacturing, and controlFDA OGD:Developed a QbR SystemTo assess applicant’sQbD ANDAsFDA’s Pharmaceutical cGMPsfor the 21st CenturyQbD Initiative, ICH Q8, Q9, and Q10
5Advantages of the QbR SystemTheQbRSystemFacilitates ascience and risk-based review offormulation andmanufacturingvariablesHelps applicantsrecognize whatOGD considerscriticalEnables aconsistent,comprehensiveapproach to theevaluationDirects industrytoward QbDApplicants FDA Reviewers
6Did QbR do what it was supposed to do?• Resulted in better connectivity between allparts of the submission• Improved submission quality• Encouraged better product and processunderstanding• Allowed reviewers to spend more time onassessment and less time on documentation• Created a pathway for implementing QbD
7• Review questions were revised to fully incorporateQbD elements.• QTPP and CQAs• Product design and understanding• Process design and understanding• Control strategy• Questions were improved based on the lessonslearned over the past five years.• Questions answered with ‘refer to DMF’ were removed.• Questions answered with ‘yes/no’ were revised.Key Points for Revision
8Before we begin…• The current QbR questions are included as a.pdf file for reference.• The new questions are presented using thefollowing color scheme:Black: The question has not changed.Orange: The question has been relocated, reworded,combined with another question or in some waytweaked.Purple: The question is new.
92.3 Introduction to the Quality Overall SummaryProprietary Name of Drug ProductNon-Proprietary Name of Drug ProductNon-Proprietary Name of Drug SubstanceDMF (Type II) Number(s) if any and Holder(s)Dosage FormStrength(s)Route of AdministrationProposed Indication(s)Maximum Daily Dose of the Drug Product
102.3.S DRUG SUBSTANCE2.3.S.1 General Information• What are the nomenclature, molecular structure,molecular formula, and molecular weight?2.3.S.2 Manufacture• Who manufactures the drug substance? List theparticipants and facilities, including their clearlystated function, involved in drug substancemanufacturing/testing activities.2.3.S.3 Characterization• What are the potential impurities of the drugsubstance? For each impurity, what is the structure,IUPAC name and origin (process or degradation)?
112.3.S DRUG SUBSTANCE2.3.S.4 Control of Drug Substance• What is the drug substance specification? For eachtest in the specification, what is the justification forthe acceptance criterion?• For each test in the specification, provide a summaryof analytical method(s) and, if applicable, summaryof validation or verification report(s).
122.3.S DRUG SUBSTANCE2.3.S.5 Reference Standards• How were the drug substance and impurityreference standards certified or qualified?2.3.S.6 Container Closure• What container closure system is used for packagingthe drug substance?2.3.S.7 Stability• What are the storage conditions and theretest/expiry period for the drug substance?
132.3.P DRUG PRODUCT2.3.P.1 Description and Composition• What are the components and composition of thefinal drug product on both a per unit dose and %w/wbasis? What is the function(s) of each excipient?• Does any excipient exceed the FDA inactiveingredient database limit for this route ofadministration calculated based on maximum dailydose? If so, please justify.• What are the differences between this formulationand the Reference Listed Drug (RLD) formulation?
142.3.P DRUG PRODUCT2.3.P.2 Pharmaceutical Development• What are the characteristics of the RLD Product?• What are the elements, targets and justifications ofthe Quality Target Product Profile (QTPP)?• For each quality attribute of the drug product, whatis the target and how is it justified? How were thecritical quality attributes (CQAs) selected?• If applicable, what in vitro bioperformanceevaluations (i.e., dissolution method, flux assay, etc.)were used during pharmaceutical development andhow were they developed?
15Resources for Answering These QuestionsLink to MR Example:http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM286595.pdfLink to IR Example:http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf• 1.2 Analysis of the Reference Listed Drug Product• 1.3 Quality Target Product Profile for the ANDA Product• 1.4 Dissolution Method Development
162.3.P DRUG PRODUCT2.3.P.2.1 Components of the Product2.3.P.2.1.1 Drug Substance• What are the physical, chemical, biological and, ifapplicable, mechanical properties including physicaldescription, pKa, chirality, polymorphism, aqueoussolubility (as a function of pH), hygroscopicity,melting point(s), and partition coefficient and, whenavailable, BCS classification?2.3.P.2.1.2 Excipients• What evidence supports compatibility between theexcipients and the drug substance?
172.3.P DRUG PRODUCT2.3.P.2.2 Drug Product• How was the drug product designed to meet thedrug product QTPP and CQAs?• How were the excipient types and grades selected?What formulation development studies, includingscreening, characterization, optimization, andverification (robustness), if any, were conducted?• What attributes of the drug substance, excipients,and in-process materials were identified as criticalvia risk assessment and Design of Experiments whenappropriate and how are they related to the drugproduct CQAs?
182.3.P DRUG PRODUCT2.3.P.2.3 Manufacturing Process Development• What is the rationale for selecting thismanufacturing process for the drug product?• What process development studies, includingscreening, characterization, optimization, andverification (robustness), if any, were conductedand at what scale?• What is the process map listing input materialattributes, process parameters, and outputmaterial quality attributes for all of the unitoperations in the manufacturing process?
192.3.P DRUG PRODUCT2.3.P.2.3 Manufacturing Process Development• For each unit operation, what process parameters andmaterial attributes (drug substance, excipients and in-process materials) were identified as critical via riskassessment and Design of Experiments when appropriateand how are they related to the drug product CQAs?• What is the Control Strategy for CMAs of input materials,CPPs of manufacturing process, and CQAs of outputmaterials for each unit operation?• How was scale dependence for each process stepevaluated during pharmaceutical development? How didthe critical process parameters change across scale?
202.3.P DRUG PRODUCT2.3.P.2.4 Container Closure System• What specific container closure system attributes arenecessary to ensure drug product integrity andperformance through the intended shelf life? Whatare the differences between this product and theReference Listed Drug (RLD) container closuresystem(s)?• How was the container closure system qualified assuitable for use with this dosage form?
212.3.P DRUG PRODUCT2.3.P.2.5 Microbiological Attributes• If applicable, how are the microbiological attributesof the drug product controlled?2.3.P.2.6 Compatibility• If applicable, how is the compatibility of the drugproduct with delivery device, additives and/ordiluents addressed? What is the supportive data?
222.3.P DRUG PRODUCT2.3.P.3 Manufacture• Who manufactures the drug product? List allparticipants and facilities, including their clearlystated function, involved in drug productmanufacturing/testing activities.• What are the exhibit batch and commercial batchformulas and are they proportional? If not, what arethe differences and justifications?• What is the manufacturing and packagingreconciliation of the exhibit batch, with yield limit ateach stage?
232.3.P DRUG PRODUCT2.3.P.3 Manufacture• What are the differences in batch size, equipmentcapacity and estimated use of capacity betweenthe exhibit and commercial scale? What evidenceincluding equipment design and operatingprinciple supports the plan to scale up the processto commercial scale?• What are the in-process controls and test resultsfor each unit operation? What are the differencesin the in-process controls for the exhibit batch andthe intended commercial batches? What are thejustifications for any differences?
242.3.P DRUG PRODUCT2.3.P.4 Control of Excipients• How are the excipients qualified? What ensures theexcipients are suitable for their intended function?2.3.P.5 Control of Drug Product• What is the drug product specification? Does itinclude all the critical drug product qualityattributes? For each test in the specification, what isthe justification for the acceptance criterion?• For each test in the specification, provide a summaryof analytical method(s) and, if applicable, summaryof validation or verification report(s).
252.3.P DRUG PRODUCT2.3.P.6 Reference Standards and Materials• How were the drug substance and impurityreference standards certified or qualified?2.3.P.7 Container Closure System• What container closure system(s) is proposed forpackaging and storage of the drug product?
262.3.P DRUG PRODUCT2.3.P.8 Stability• What is the stability specification? What is thejustification for acceptance criteria that differ fromthe drug product release specification?• What is the proposed tentative expiration date forthe drug product? What drug product stabilitystudies support the proposed shelf life and storageconditions? Are there any trends in the stability datathat warrant further investigation?• What are the post-approval stability protocol andother stability commitments for the drug product?
27Stay Tuned• FDA is working on a FAQ companiondocument and mock QOS-QbR using therevised questions.• FDA welcomes feedback on the revisedquestions.• Finalized questions will be posted in Fall 2012.
28Acknowledgments• QbR Revision Working Group• Lawrence Yu• Bob Iser• Lane Christensen• Daniel Peng• Susan Zuk
29Questions and CommentsGenericDrugs@fda.hhs.gov