1Vilayat A. Sayeed, Ph.D.Division Director, Chem III, OGDLane V. Christensen, Ph.D.Chemist, Immediate Office, OGDAlbinus D’Sa, Ph.D.Deputy Country Director, India OfficeOpinions expressed in this presentation are those of the speaker and donot necessarily reflect the views or policies of the FDA
2Workshop OverviewSession 1• OGD Overview/QbD Overview• The Quality Target Product ProfileSession 2• Product Design and UnderstandingSession 3• Process Design and UnderstandingSession 4• Control Strategy, Risk Assessment, Design ofExperimentsSession 5• Generic Drug User Fees
3Workshop OverviewSession 1• OGD Overview/QbD Overview• The Quality Target Product ProfileSession 2• Product Design and UnderstandingSession 3• Process Design and Understanding and ControlStrategySession 4• Generic Drug User Fees
4Understanding Generic ApprovalProcessVilayat A. Sayeed, Ph.D.Director, Division of Chemistry IIIOffice of Generic DrugsOpinions expressed in this presentation are those of the speakerand do not necessarily reflect the views or policies of the FDAFDA, DIA India and Pharmexcil WorkshopApril – May 2012
5Outline• ANDA/Generic Product Requirement• Filing and Quality Review Process• Anticipated Time Line for QbDImplementation• Overview of recent changes• OGD Outreach to Generic Industry• Compliance• United States Pharmacopeial Convention(USP)
6Generic Product Requirement in USfor 505(j) Application• Must have an approved reference product in US• Must be bioequivalent (where applicable) andPharmaceutical equivalent to a brand name drug(Therapeutic equivalent)• And meet the quality standards• All related facilities have acceptable CGMPcompliance
7ANDA Review Process ChartANDA ApplicationAcceptable And FiledRefuse to ReceiveNoYescGMP CMC Review Micro ReviewBA/BE/Clinical Labeling ReviewDeficiency CommentsCommunicated toANDA ApplicantNot Acceptable AcceptableANDA ApprovedDMF Review
8Office of Generic Drugs
9Filing and Quality Review Process• Submission is checked by the regulatory branch forcompleteness against a publically available check list• Failing to meet either regulatory or technical datarequirement, a Refuse to Receive letter is issued• In 2011, 148 ANDAs were RTR (RTR may havefinancial implication starting 10/2012)• Check list is updated every quarterhttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/default.htm• Upon filing it is assigned to appropriate quality reviewdivisions
10Office of Generic Drugs
11The Timeline for QbDImplementationMay2010May2011Fall2011Winter2012Spring2012Spring-Fall2012Jan2013= QbD Implementation for Generic Drugs
12QbD Implementation Benefits• Enhance Knowledge Sharing• Improve Time to Market (potentially compressingapproval time)• Reduce cost associated with poor quality (recalls andrejects)• Improve Consumer Generic Skepticism• Minimize Post-approval Changes
13Overview of Recent ChangesBA/BE Requirement• Submit all failed bio-studies and related CMC informationrequired under 21 CFR 320.1(g)• For certain therapeutic class drugs 90% confidenceinterval range may change to 90-111% for AUC – Underdiscussion• Significance of Tmax in BA/BE assessmentCMC Expectations for Generic Drugs• Office of Generic Drugs is planning to fully adopt Q1stability guidances for generic drug applications including• Q1A (R2) Stability Testing of New Drug Substances andProducts• Q1B Photostabiltiy Testing of New Drug Substances andProducts
14Overview of Recent ChangesCMC Expectations for Generic Drugs• Q1C Stability Testing for New Dosage Forms• Q1D Bracketing and Matrixing Designs for StabilityTesting of New Drug Substances and Products• Q1E Evaluation of Stability Data- statistical analysis• OGD is requesting sponsor to include• Quality target product profile (QTPP)• Critical quality attributes (CQAs) of the drug product• Product design and understanding including identification ofcritical excipient and drug substance attributes• Process design and understanding including identification ofcritical process parameters• Control strategy and justification
15Overview of Recent ChangesAgency Guidance (Review Related)• Residual Drug in Transdermal and Related DrugDelivery Systems (Final – 8/2011)• Size of Beads in Drug Products Labeled for Sprinkle(Final – 2/2012)• Tablet Scoring: Nomenclature, Labeling, and Data forEvaluation (Draft – 8/2011)• Limiting the Use of Certain Phthalates as Excipientsin CDER-Regulated Products (Draft – 3/2012)http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064979.htm
16Overview of Recent ChangesAgency Guidance (CGMP/Compliance)• Dosage Delivery Devices for Orally Ingested OTCLiquid Drug Products (Final – 5/2011)• Process Validation: General Principles and Practices(Final – 1/2011)• Non-Penicillin Beta-Lactam Risk Assessment: ACGMP Framework (Draft - 3/2011)http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htm
17OGD Outreach to Generic Industry• Control Correspondence (use only when theinformation is not available on Website)• Quality by design (QbD) for a modified releasedosage form• Model Bioequivalence data summary table andmore infohttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm142112.htm
18cGMP/Compliance• All facilities used must be in compliance• Inspection program is also design to check data integrity– If data integrity is in question all review will stop• Post-approval – validation activities is the responsibilityof compliance– Compliance may use the new PV guidance for validation• Pre-approval inspection
19United States Pharmacopeial Convention (USP)• Compendia articles have to meet or exceed USPstandards (legal requirement)– Failing to meet can potentially delay the approval process• Pharmacopeial Forum (PF) - not official but can changethe status and impact the approvability– Be proactive in this process with USP• Pending Monographs (Draft and Authorize)– Refer to USP website for its intent for this process• Pending monographs not official until the Agencyapproves application supporting pending monograph• Meeting the pending monograph requirement does notmake the product USP
20GDUFA Negotiations• GDUFA Goals Letter• Draft Legislation• Agreement on a 5-year program• $299M/year
21GDUFA Goals• Backlog file review• ANDA review• Type 2 DMF assessment• Facility Inspections• Communications• Regulatory Research• Hiring
22ANDA Review Goals• 90% of ANDAs reviewed in 10 months• Ramp-up over next 5 years of program• In year 3 on words– 60% in 15 months– 75% in 15 months– 90% in 10 months
23Backlog Review Goals• 90% of ANDAs, Amendments, and PASs by end of5th year.• Applies to files pending review on 10/1/12.
24Type 2 DMF Goals• Applies to all DMFs (eCTD format submission highlyrecommended)• Completeness “Filing” assessment• Posting on FDA external website“Available for reference by ANDA”• DMF list will be updated every week• Letter to DMF-holder will be issued in support of an ANDAapproval• Any updates in agency’s opinion that have an adverseeffect on quality and safety of the DS may make itdeficient
25Inspectional Goals• Risk-adjusted, biennial, cGMP inspections• API sites• Finished-Dosage Form sites• Parity between foreign & domestic sites
27Regulatory Science Goals• FDA – Industry Working Group• Annual list of projects• Examples:– BE of locally-acting products– Excipient effects on permeability & absorption– Post-marketing surveillance– Phyisicochemical characterization of complex drugsubstances
28Hiring Goals• Hiring for:– CDER– Office of Regulatory Affairs– Office of the Commissioner• Goals:– 25% in FY-13– 50% in FY-14– 25% in FY-15
30AcknowledgementFDA International Office, New Delhi IndiaDIA India and PharmexcilOPS, OGD ManagementQuestions?
31Overview of QbD for GenericDrugsLane V. Christensen, Ph.D.Chemist, Immediate OfficeOffice of Generic DrugsOpinions expressed in this presentation are those of the speakerand do not necessarily reflect the views or policies of the FDAFDA, DIA India and Pharmexcil WorkshopApril – May 2012
32Patients* Benefit *Regulators BenefitManufacturers BenefitQbD enhances the quality of generic drugsPharmaceutical Quality in the 21stCentury“We will implement QbD together”-- Lawrence Yu, PhDOGD Deputy Director for Science andChemistry
33FDA’s Strategic Plan Priority Areas:1. Modernize Toxicology to Enhance ProductSafety2. Stimulate Innovation in Clinical Evaluationsand Personalized Medicine to ImproveProduct Development and Patient Outcomes3. Support New Approaches to Improve ProductManufacturing and Quality4. Ensure FDA Readiness to EvaluateInnovative Emerging Technologies5. Harness Diverse Data through InformationSciences to Improve Health Outcomes6. Implement a New Prevention-Focused FoodSafety System to Protect Public Health7. Facilitate Development of MedicalCountermeasures to Protect Against Threatsto U.S. and Global Health and Security8. Strengthen Social and Behavioral Science toHelp Consumers and Professionals MakeInformed Decisions about Regulated Products
34Importance of Generic Drug Availability
35• Differences in product quality is notacceptable• The responsibility of OGD/generic industryis to support public confidence in genericdrug product qualityImportance of Generic Drug ProductAvailability
36What is Pharmaceutical Quality?• Janet Woodcock– Free of contamination and reproduciblydelivering the therapeutic benefitpromised in the labelPharmaceutical Quality= f(Drug substance, excipients,manufacturing, and packaging)• ICH Q8 R(2)– The suitability of either a drug substance or a drugproduct for its intended use• Quality cannot be tested into products; qualitycan only be built into products
37What is a Generic Drug?• A generic drug is therapeutically equivalent tothe brand name drug.• Therapeutic Equivalence– “have the same clinical effect and safetyprofile when administered to patients underthe conditions specified in the labeling”• FDA Practice– Pharmaceutical Equivalence +Bioequivalence= Therapeutic Equivalence
38Pharmaceutical Equivalence• Same active ingredient(s)• Same dosage form• Same route of administration• Identical in strength or concentration• Meet compendial or other applicablestandards of strength, quality, purity, andidentity• May differ in shape, excipients,packaging...
39Bioequivalence• Absence of a statistically significantdifference in the rate and extent to whichthe active ingredient in pharmaceuticallyequivalent products becomes available atthe site of action, when administered tosubjects at the same molar dose undersimilar conditions.
40NDA Requirements ANDA Requirements1. Chemistry 1. Chemistry2. Manufacturing 2. Manufacturing3. Testing 3. Testing4. Labeling 4. Labeling5. Inspections 5. Inspections6. Animal Studies7. Clinical Studies 6. Bioequivalence8. BioavailabilityNDA vs. ANDA RequirementsPE
41Claimed to be Acceptable Based Upona Passing BE study to the RLD“Equivalence by Testing”Past/Present Paradigm QbD ParadigmAsks Sponsors How They SystemicallyArrived at a Bioequivalent Drug Product“Equivalence by Design”ANDA Formulation/ProcessSubmitted Without ContextSystematic approachQTPP/CQA: predefined target.Product & process design andunderstanding: pharmaceuticalequivalence to the RLD.Control strategy: to ensureintended performance beconsistently delivered.Paradigm Shift
42OPS View on Modern ManufacturingScience• Moving toward a common view on QbD• OPS MaPP 5016.1: “Applying ICH Q8(R2), Q9,and Q10 Principles to CMC Review”• Focusing on better understanding through QbDconcepts to reducepostmarketing issues• QbD examples for thegeneric industry and FDA– Industry’s contributionHelen Winkle, OPS Director, CDER, FDA
43New Drug QbD Submissions0123456789102005 2006 2007 2008 2009 2010 2011 2012Fiscal YearNumberofSubmissions010203040506070CummulativeNumber# of QbD NDAs# of QbD SupplementsCummulativeQbD pilot program initiated in 2005
44ANDA QbD Submissions• Submissions containing QbD elements arebeing tracked• >60 ANDAs containing QbD elementsreviewed or under review• Submissions currently being filed forreview?• 100% by January 1, 2013
45Quality by Design (QbD) andQuestion-based Review (QbR)Generic Applicant:ImplementingQbD in development,manufacturing, and controlFDA OGD:Developed a QbR Systemthat assesses applicant’sQbD ANDAsFDA’s Pharmaceutical cGMPfor the 21st CenturyQbD Initiative, ICH Q8, Q9, and Q10
46Question-based Review (QbR)• Implemented for generic drugs in 2007• QbR is a general framework for a science and risk-basedassessment of product quality• QbR contains the important scientific and regulatoryreview questions to– Comprehensively assess critical formulation and manufacturingprocess variables– Set regulatory specifications relevant to quality– Determine the level of risk associated with the manufacture anddesign of the productGeneric Drugs Information for Industry>Question based Review webpage:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm120971.htm
47Reviewer Perspective of QbR• Allows more focused Scientific Reviewless typing and documentation time• Guides firms to provide more pertinent andfocused information better submissions• Facilitates a consistent review process• Facilitates applicant’s product and processunderstanding• Promotes consistency in the informationprovided
48Changes coming for QbR• Revision of QbR to be presented at theupcoming GPhA meeting in May.– Refer to DMF??– Contain QbD elements– More focus on understanding of the drugproduct, development process and how it iscontrolled• FAQ document and model QOS examplesunder development
49QbD for Generic DrugsOGD will use the “enhanced” QbD approach as defined inICH Q8(R2). It should include the following:• Quality target product profile (QTPP)– Including critical quality attributes (CQAs) of the drug product• Product design and understanding (through, e.g., priorknowledge, experimentation and risk assessment)– Critical material attributes (CMAs) of the drug substance and excipients• Process design and understanding (through, e.g., priorknowledge, experimentation and risk assessment)– Critical process parameters (CPPs)• Control strategy, including justification
50QbD Examples• Intended to illustrate the types of developmentstudies ANDA applicants may use as theyimplement QbD• Provide a concrete illustration of the QbDprinciples from ICH Q8, Q9 and Q10– Both IR and MR illustrate QbD principles• Development of a real product may differ fromthe examples• Number of experiments may depend on theexperience of the applicant– This should be explained in the submission
51QbD IR Example• IR tablet– Low solubility drug substance: Acetriptan– Manufactured by roller compaction– Uses common excipients in similar amounts to theRLDIngredient Function Weight/tablet (mg) % (w/w)Acetriptan, USP Active 20.00 10Intragranular ExcipientsLactose Monohydrate, NF Filler 81.5 40.75Microcrystalline Cellulose, NF Filler 81.5 40.75Croscarmellose Sodium, NF Disintegrant 6 3Talc, NF Glidant/Lubricant 5 2.5Extragranular ExcipientsMagnesium Stearate, NF Lubricant 1 0.5Talc, NF Glidant/Lubricant 5 2.5Total Weight 200.0 100
52QbD MR Example• MR Tablet with IR and ER components– High solubility drug substance: Z– Biphasic release to achieve particular clinical profile– ER beads coated with release controlling polymer– IR granules and ER beads compressed into a tablet– Discussion of scale up issues
53Quality Target Product Profile(QTPP)• A prospective summary of the qualitycharacteristics of a drug product that willideally be achieved to ensure the desiredquality (performance)• Guide to establish formulation strategyand keep the product development effortfocused and efficient
54Basis for Establishing QTPPfor ANDA• Pharmaceutical equivalence andbioequivalence• Analysis of the reference listed drugproduct– Clinical use– Pharmacokinetics– Drug release– Physicochemical characterization• Product labeling/administration
55What Does QTPP Include?• Intended use in clinical setting– Route of administration, dosage form (deliverysystems), and container closure system• Quality attributes of drug product– Appearance, Identity, Strength, Assay, Uniformity,Purity/Impurity, Stability, and others• Active pharmaceutical ingredient release ordelivery and attributes affectingpharmacokinetic characteristics (Safety andefficacy)– Dissolution, aerodynamic performance
56Common QTPP Format• Include Standard Elements in the First Table– Dosage form– Dosage design– Route of administration– Dosage strength– Container closure system– Pharmacokinetics– Drug product quality attributes• Criticality and justification in a separate table (CQA table)– Stability– Administration/concurrence with labeling• Include Target• Include Justification for Target
57QbD MR Example: QTPP
58QbD IR Example: QTPP
59Critical Quality Attributes (CQA)s• ICH Q8 (R2) definition:– CQA is a physical, chemical, biological, or microbiological property orcharacteristic that should be within an appropriate limit, range, ordistribution to ensure the desired product quality.• OGD recognizes the ICH Q8 (R2) definition and identifies CQAbased on the severity of harm to a patient (safety and efficacy)resulting from failure to meet that quality attribute.• In the context of product development, only the subset of CQAs thathave a high potential to be impacted by the formulation or processvariables will be investigated and discussed in detail in subsequentformulation and process development.– Not all CQAs are impacted by formulation and process development(i.e. identity) not discussed further in detail– All quality attributes are target elements of the drug product and shouldbe achieved through a good quality management system, appropriateformulation/process design and development.
60QbD MR Example: CQAs
61QbD MR Example: CQAs (2)
62Steps for Product Understanding1. Identify all possible drug substance and excipient attributes thatcould impact the performance of the product as per label claim2. Use risk assessment and scientific knowledge to identify potentiallyhigh risk drug substance and excipient attributes3. Determine levels or ranges of these attributes to be investigated4. Design experiments, using DOE when appropriate5. Conduct actual experiments6. Analyze experimental data to determine if an input material attributeis critical.– An input material attribute is critical when a realistic change inthat material attribute can significantly impact the quality of theoutput materials.7. Establish the control strategy– For critical attributes, define acceptable ranges. For non criticalattributes, the acceptable range is the range investigated.
65Steps for Process Understanding1. Identify all possible material attributes and process parameters thatcould impact the performance of the process2. Use risk assessment and scientific knowledge to identify potentiallyhigh risk attributes and/or parameters3. Determine levels or ranges of these variables to be investigated4. Design experiments, using DOE when appropriate5. Conduct actual experiments6. Analyze experimental data to determine if an input material attributeor process parameter is critical.– A material attribute or process parameter is critical when arealistic change in that material attribute or process parametercan significantly impact the quality of the output materials.7. Establish the control strategy– For critical material attributes or process parameters, defineacceptable ranges. For non critical attributes, the acceptablerange is the range investigated.
66MR QbD Example: Risk AssessmentProcessVariablesRiskAssessmentJustification and Initial StrategyProducttemperatureHighProduct temperature is a function of inlet airtemperature, air volume, and spray rate.If product temperature is too high, spray dryingmay occur and results in large amount of fines.If product temperature is too low, agglomerationmay occur.Process efficiency and dissolution profile may beimpacted.Investigate with DOEAir volume HighIf air volume is too high, spray drying may occur.If air volume is too low, agglomeration may occur.Process efficiency and dissolution profile may beimpacted.Investigate with DOESpray rateper nozzleHighIf spray rate is too high, agglomeration may occur.If spray rate is too low, spraying time may be toolong and spray drying may occur.Process efficiency and dissolution profile may beimpacted.Investigate with DOEAtomizationair pressureHighIf atomization air pressure is too high, attrition tothe beads may occur.If atomization air pressure is too low,agglomeration may occur.Process efficiency and dissolution profile may beimpacted.Investigate with DOEProcessVariablesRiskAssessmentJustification for the Mitigated RisksProducttemperatureLowProduct temperature range is identified.Product temperature is a scaleindependent parameter, and can beapplied to other scales.Air volume MediumAir volume range is identified at 40 kgscale. Air volume is a scale dependentparameter. Further adjustment may benecessary.Spray rate MediumSpray rate range is identified at 40 kgscale.Spray rate is a scale dependentparameter. Further adjustment may benecessary.Atomizationair pressureLowAtomization air pressure is identified at 40kg scale. Atomization air pressure is ascale dependent parameter. However, theatomization air pressure for each nozzle iskept the same.Mitigated risks after process developmentInitial risk assessment for the coating process of ER beads
67Scale Effect on Design Space10 Fold=?Lab/Pilot Scale Design Space Commercial ScaleDesign SpaceGenerationConfirmationTo be verified
68Design Space of What?• Lab scale design space• Pilot scale design space• Commercial scale design space• Only commercial scale design space canhave meaningful regulatory flexibility asdefined in ICH Q8(R2)Are sources of variabilitydefined at this point?
69Where we are. . .• IR and MR examples are for illustrative purposes andhave been completed to be used to understand concepts• Training• OGD has received >60 submissions containing QbDelements and receiving meeting requests by applicantsfor further clarification.• Meetings with the Generic Industry/GPhA– 3 QbD Workshops – June 2009, May 2010, May 2011, Oct 2011– 4 QbD Roundtable Discussions – Jun 2009, Oct 2009, Feb 2011,Apr 2011Prior knowledge, risk analysis• Other professional meetings, workshops, . . .
70Publications• A. Srinivasan, R. Iser. Common Deficiencies in Abbreviated New DrugApplications (Part 4). Pharm Tech. 35:62-68 (2011).• A. Srinivasan, R. Iser and D. Gill, Common Deficiencies in Abbreviated NewDrug Applications (Part 3) Pharm. Tech. 35 (2), 58–67 (2011).• A. Raw, R. Lionberger, and L. X. Yu. Therapeutic equivalence by design forgeneric drugs: Modified release products. Pharm. Res. 28, 1445-1453(2011).• A. Srinivasan and R. Iser, Pharm. Tech. 34 (1), 50–59, (2010).• A. Srinivasan, R. Iser and D. Gill, Pharm. Tech. 34 (8), 45–51 (2010).• D. Skanchy. Question-Based Review: An FDA Reviewer’s Perspective.Pharm Tech. 33 (10) 2009.• L. X. Yu, R. Lionberger, M. C. Olson, G. Johnston, G. Buehler, and H.Winkle. Quality by Design for Generic Drugs. October Issue, pp. 122-127(2009).• A. Srinivasan and R. Iser. FDA Office of Generic Drugs QbR Initiative: AnUpdate. J. Valid. Tech., 15 (2), 2009.
71Publications (continued)• W. L. Jiang and L. X. Yu. Quality evaluation of generic drugs. J. PrescriptionDrugs. 79:39-42. (2008).• W. Jiang and L. X. Yu. Modern pharmaceutical quality standard: Question-based review. In Y. Qiu et al. (Ed.). Pharmaceutical Theory and Practice inDeveloping Solid Oral Dosage Forms. 2008.• R. Lionberger, L. X. Yu et al. Quality by design: Concepts for ANDAs. TheAAPS Journal. 10:268-276 (2008).• L. X. Yu. Pharmaceutical quality by design: Product and processdevelopment, understanding, and control. Pharm. Res. 25:781-791 (2008).• L. X. Yu et al. FDA Office of Generic Drugs’ pharmaceutical quality initiative:progress and feedback on Question-based Review. Pharm. Eng. 27,Nov/Dec, 52-61 (2007).• L. X. Yu et al. U.S. FDA Question-based review for generic drugs: A newpharmaceutical quality assessment system. J. of Generic Medicines. 4:239-248 (2007).• S. L. Lee, A. S. Raw, and L. X. Yu. Significance of drug substancephysicochemical properties in Quality by Design. In M. C. Adeyeye and H.G. Brittain (Eds.). Preformulation in Solid Dosage Form Development. 2007.
72Communication with OGDWe encourage you to apply Quality by Design (QbD) principles to thepharmaceutical development of your future original ANDA productsubmissions. A risk-based, scientifically sound submission would beexpected to include the following:– Quality target product profile (QTPP)– Critical quality attributes (CQAs) of the drug product– Product design and understanding including identification of critical attributes ofexcipients, drug substance(s), and/or container closure systems– Process design and understanding including identification of critical processparameters and in-process material attributes– Control strategy and justificationAn example illustrating QbD concepts can be found online at FDAs GenericDrugs: Information for Industry webpage:http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM286595.pdf
73The Timeline for QbDImplementationMay2010May2011Sep/Oct2011Fall2011Winter2012Spring2012Spring-Fall2012Jan2013= QbD Implementation for Generic Drugs
75Vilayat A. Sayeed, Ph.D.Director, Division of Chemistry IIIOffice of Generic DrugsOpinions expressed in this presentation are those of the speakerand do not necessarily reflect the views or policies of the FDAQuality Target Product Profile (QTPP) inGeneric Drug QbD DevelopmentFDA, DIA India and Pharmexcil WorkshopApril – May 2012
76Outline• QTPP as it relates to Generic Product• Essential and Dynamic Components• Pre-formulation Studies• Formulation Optimization• Stability Studies• Container/Closure System• BA/BE pilot study/ies• Process optimization and Exhibit Batch
77What is Quality Target Product Profile(QTPP)?• QTPP - A prospective summary of thequality characteristics of a drug productthat ideally will be achieved to ensure thedesired quality, taking into account safetyand efficacy of the drug product.– ICH Q8R(2)
78What is Quality Target Product Profile(QTPP) for Generic Products?QTPP for generics can be divided in twocomponents• Essential Components - Generic application hasto be same as reference to meet 505(j)requirement• Dynamic Components – These are qualitycomponents where flexibility is allowed withjustification
79Product Design Objective• “In a QbD approach the product is designed tomeet patient needs and performancerequirements; the process is designed toconsistently meet product critical qualityattributes; the impact of starting and rawmaterials and process parameters on productquality is understood; and critical sources ofprocess variability are identified and controlled.”ICH, Q8
80Generic Product Design ObjectiveEssential Components• DS (e.g., same salt, ester etc)• Dosage form (tablets, capsules, creams etc)• Strength (single or multiple)• Route of administration (oral, topical,transdermal, IM, IV, IT etc)• Condition of use/labeling*– *Exceptions as allowed by regulation
81Generic Product Design ObjectiveDynamic Components• Quality (Dissolution, appearance, dégradation,pH, microbial control etc.)• Dosage form Design (Can be different butshould meet the label recommendation andproduct performance)• Excipients• DP manufacturing process and controls
82Generic Product Design ObjectiveDynamic Components• DS manufacturing process and controls• DS solid state• Stability• Container Closure System• Risk assessment and mitigation
83Dosage Form and DesignDosage form provided in RLD Label• RLD Product labeled as IR - do not chew or breakrecommendation (needs close scrutiny of the entirelabel)Dosage Design• In product description, Dose and Administration orSystem Components and Performance• RLD is multi-layer and test is single layer (needs closescrutiny)– provide justification if test different,• RLD is DR with a laser hole– test is just DR – provide justification
84Dosage Form and DesignDosage Design• RLD is single-composition osmotic technology (SCOT™)– check test design prior to using same claim in the label• RLD label as un-scored but allows to split for use– Pay attention when the RLD is MR– Provide supportive data, follow draft guidance• RLD is multi beads (IR, DR & MR), test single MR bead– provide justification if test different• RLD capsule label for sprinkle– Use sprinkle guidance and pay close attention to targetpopulation
85Dosage Form and DesignRLD Performance Attributes• Find out if IVIVC is done on RLD – Information availablepublicly• Analyze the RLD using different dissolution medium andapparatus• Choice of medium and apparatus is product and dosagefrom dependent• Method may be available from OGD, published literature• Method can be developed in-house• Have a dissolution profile on the RLD
86Pharmaceutical Quality• Deliver clinical performance per label claimoutcome• Does not introduce additional risks due tounexpected contaminants• Janet Woodcock, M.D. American PharmaceuticalReview
87Quality• Identification (controls on API susceptible for isomerization)• Assay (90-110% may not be acceptable in all cases – certaintherapeutics)• CU (USP <905> may not be acceptable in all cases – product withvery low drug load and closely spaced strength)• Appearance (look for DP with same size, shape and color, informyour division)• Impurities & Degradation (Understand the path of degradation, makesure this meets ICH and OGD guidance requirements)• Unknown impurities in compendia item must meet ICH• Genotox impurities must meet Agency draft guidance requirements
88Quality Attributes• pH (may meet the USP and/or RLD range)– pH target must be establish based on API stability in PD• Preservative (If not present in RLD needs justification for use,should provide preservative effectiveness data in PD)• Antioxidants (If not present in RLD needs justification for use)• Disintegration (compendia article must meet the requirementor need a disclaimer on label – inform labeling)• Dissolution (compendia article must meet the requirement orneed a disclaimer on label – inform labeling)• Dissolution (dose dumping study is needed in sometherapeutics)• Fill volume vs. draw volume
90Workshop OverviewSession 1• OGD Overview/QbD Overview• The Quality Target Product ProfileSession 2• Product Design and UnderstandingSession 3• Process Design and Understanding and ControlStrategySession 4• Generic Drug User Fees
91Vilayat A. Sayeed, Ph.D.Director, Division of Chemistry IIIOffice of Generic DrugsOpinions expressed in this presentation are those of the speakerand do not necessarily reflect the views or policies of the FDAProduct Design and UnderstandingFDA, DIA India and Pharmexcil WorkshopApril – May 2012
92Generic Product Design andDevelopmentProduct Development• Quality Target Product Profile– Product Quality attributes relevant to in-vivoperformance• Pre-formulation Studies– Drug substance properties (physical andchemical)– Drug substance, excipient compatibility– Product Design Selection– Formulation and Process selection (APIattributes and drug load)
93Generic Product Design andDevelopment• Formulation and Process Screening– Identify the CMAs and CQAs based on DOEor Prior knowledge• Formulation and Process Optimization– Component supply chain variability and itsimpact on product performance based onDOE or Prior knowledge– Explore operating ranges• Scale up
94Drug SubstanceDS properties that can affect DPdevelopment, manufacture, or performanceThe physicochemical and biological properties ofthe drug substance that can influence theperformance of the drug product and itsmanufacturability, or the properties specificallydesigned into the drug substance (e.g., solid stateproperties), should be identified and discussed.– Guidance for Industry Q8(R2) Pharmaceutical Development
95Drug SubstanceUnderstanding API properties critical for DPdevelopment and manufacture• DS characteristics are well established based onpublished literature• DP manufacturer and quality reviewer should have fullunderstanding of DS physicochemical properties andimpact on product quality and performance• API solubility as it relates to PSD• API sensitivity to light, humidity, pH, air/oxygen andtemperature
96Drug SubstanceUnderstanding API properties critical for DPdevelopment and manufacture• API flow properties, compressibility, particle size andshape (for high drug load drugs)• Functional groups in API (amines, acid, alcohol etc)• Is API a recemate or single isomer• Impurities (Follow ICH Q3A, Q3B, Q3C & Q3D-step1)• At the end of the API characterization one should havean idea of the DP process
97Excipients• Study/Analyze excipient/API physical, chemical andperformance compatibility• Justify proposed intended function of excipient• Include IID compliance even for routinely used excipients(where appropriate safety information should beprovided)• Justify use of excipients that requires label warning (notpresent, inform Labeling)• Justify use of excipient that can form adduct, chelate orchange product during processing• Justify/check use of excipients that can modify orenhance penetration (topical drug products)
98Excipients• Buffers and/or preservatives if different from RLD inophthalmic (needs justification, inform clinical)• Buffers and/or preservatives if different from RLD ininjections (needs justification, close scrutiny)• Certain excipients needs Melamine free certification(must be part of PD)• If Dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate(DEHP) are used inform Division (Draft guidance safetyconcern)• Include excipients specification, adequately justified forintended performance (compendia specification may notbe appropriate)
99Generic Product Design andDevelopmentProduct DevelopmentFormulation and Process Selection• At the end of the API characterization one should havean idea for the DP process• At the end of excipient and API study one should havean idea on formulation and the process• Make a prototype product and place on stability• Move to optimization
100Generic Product Design andDevelopment• Describe steps followed in process designselection• Describe tools and reasoning used in choosingan alternative design to reference• Describe product design and explain itsstrategic impact in meeting clinical outcome
101Generic Product Design andDevelopmentFormulation and Process Optimization• Identify CMAs, CQAs and CPPs for each unit operation• Identify process dependent and process in-dependedparameters• Identify risk and mitigation controls• Establish target specifications based on producttherapeutic, intended population and dispensingrecommendations (stability studies may not sufficient)• At this stage one has a lead product for tech transfer(scale up)
102Generic Product Design andDevelopmentStability Studies during Development• API/Excipient compatibility studies includesstability• Studies should be done beyond physical mixture• Perform stability on prototype product• Follow ICH recommendations
103Generic Product Design andDevelopmentContainer Closure System• Provide studies on C/C system suitability on the productstability and performance over shelf life• Devises that are critical for DP performance shouldinclude performance data• May need CDRH consult• Droppers and cups included with the C/C system needscalibration data
104Generic Product Design andDevelopmentContainer Closure System• Including C/C system presentation not in RLD (needsclose scrutiny)• Prefilled syringes, needs performance data and mayneed a CDRH consultRisk Assessment and Mitigation• Should provide risk analysis• Identify risk to quality and/or performance• Provide appropriate mitigation andcommunication plan
105Generic Product Design andDevelopmentBA/BE pilot Study on Prototype Product• Based on comparable dissolution profilesbetween test and reference• Run a pilot bio study to confirm test productperformance• Bio study passes move to next step• Pilot study fails, back to formulation and/orprocess optimization• Justify changes in formulation and/or processaddress to address the failure (Cmax or AUC)
106Generic Product Design andDevelopmentBA/BE pilot Study on Prototype Product• Establish ranking order to understand andjustify by using a discriminating dissolutionmethod• Failed study reporting is required under 21 CFR320.1(g)• Provide a CMC summary report in PD for failedstudies with explanation and justification
107Example Failed Bio-studyFasting Bioequivalence Study, Study No. X12-1111,N=18 (Male=11 and Female=7) Least SquaresGeometric Means, Ratio of Means, and 90%Confidence IntervalsTest Product A vs. Reference Product C, N=18• Parameter (units) Test Reference Ratio90% CI• AUC0-t (hr *ng/ml) 209.24 240.63 0.8778.35 to 98.16• AUC∞ (hr *ng/ml) 230.16 258.10 0.9179.61 to 100.39• Cmax (ng/ml) 35.60 41.06 0.9174.15 to 101.37
108Repeat Bio-study PassedFasting Bioequivalence Study, Study No. S05-1231,N=18 (Male=11 and Female=7) Least SquaresGeometric Means, Ratio of Means, and 90%Confidence IntervalsTest Product B vs. Reference Product C, N=18• Parameter (units) Test Reference Ratio90% CI• AUC0-t (hr *ng/ml) 239.32 240.63 0.9988.10 to 112.28• AUC∞ (hr *ng/ml) 254.10 258.10 0.9887.45 to 100.83• Cmax (ng/ml) 39.04 41.06 0.9581.33 to 111.18
109Generic Product Design andDevelopmentProcess scale-up and process optimization• Explore operating ranges of each unit operation• Component supply chain variability and itsimpact on product performance• Can be based on developed knowledge (DOE)and prior knowledge• Provide basis operating establish ranges andaccepted component variability
110Generic Product Design andDevelopmentDP manufacturing process and controls• Manufacture the exhibit batch following processand controls identified by the development group• Place on stability following ICH conditionsAnalytics• All studies must be based on validated methods• Include justification for each test used and itsrelevance to the measurement
111AcknowledgementFDA International Office, New Delhi IndiaDIA India and PharmexcilOPS, OGD ManagementQuestion?
112Vilayat A. Sayeed, Ph.D.Director, Division of Chemistry IIIOffice of Generic DrugsOpinions expressed in this presentation are those of the speakerand do not necessarily reflect the views or policies of the FDAProduct Equivalency - ConsiderationsFDA, DIA India and Pharmexcil WorkshopApril – May 2012
113Equivalency ConsiderationsOverview• Contents in capsule shell• Tablet score - Ease of splitting• Tablet size and shape• Summary
114Objective of Generic ProductTherapeutic equivalents (TE):Generic Product has to be PE + BE to be TE to the reference to meet505(j) requirement• 21 CFR 320.1(c) “Pharmaceutical equivalents means drug productsin identical dosage forms that contain identical amounts of theidentical active drug ingredient, ….• Active Ingredient• Dosage form• Strength• Route of administration• Performance characteristics and Intended use• Quality
115QualityAs Defined Currently• Identification• Assay• Content Uniformity• Dissolution• Appearance• Impurities• Degradation• Disintegration• Microbial quality and etc• Patient Compliance not addressed
116Current RequirementReference Test ATest BPatientTE TEConsumer ConcernsEquivalency considerations
117Product EquivalencyTablet size, Shape and Color• Consumer complains• Difficulty in swallowing (over 6 million hits in Google)• Test substantially larger than RLD for same strength• Same size, shape and color for all strengths (medicationerror)• Include this in PD strategy to address consumercompliance
119Product EquivalencyContents in capsule shell• Reference has beads/powder – Test has mini tablet• Final guidance published for capsules label for sprinkle• Recommends target bead size up to 2.5 mm withno more than 10 percent variation over this size, toa maximum size of 2.8 mm• Pay attention to target population• Capsule products with no sprinkle recommendation notcovered by this guidance• Include this in PD strategy to address consumercompliance
120Product EquivalencyTablet Score – Ease of Splitting• In-house work (OTR/DPQR Laboratory)– Volpe et al., Int. J. Pharm., 2008, 350, 65-69– Na Zhao et al., Int. J. Pharm., 2010, 401, 25-31– Rakhi et al., AAPS PharmSciTech, 2010, 11, 1359-1367• Draft developed to address concern and public commentare closed• Addressing the public comments and final guidance willbe issued soon• Include this in PD strategy to address consumercompliance
121Points to consider DP Development• Is the tablet score (bisect, trisect etc)• Is the tablet modified release (DR or ER)• Is the tablet a combination product• Is the tablet a critical dose product• Is the tablet film coated (possible reason)
122Points to consider DP Development• Formulation• Depth of Score (ease of breaking)• Hardness• Loss of mass breaking, crumble (initial and storage)
123Points to consider DP Development• Friability of half tablet• Drug content in each half• Loss of potency due to stability• Change in degradation profile between wholeand split tablet• Dissolution• Guidance introduces the concept of functionalscore
124Product EquivalencyTaste, Odor masking and Tablet dust• Is a concern and we are closely monitoring in our post-marketing surveillance• DP process difference and non- functional coating (dustand taste)• Odor (residual solvents)
125SummaryEquivalency Considerations• Consider these aspects in DP development• Review divisions are paying attention• Failure may result in delay and/or refuse toapprove in some cases
126AcknowledgementFDA International Office, New Delhi IndiaDIA India and PharmexcilOPS, OGD ManagementQuestions?
127Workshop OverviewSession 1• OGD Overview/QbD Overview• The Quality Target Product ProfileSession 2• Product Design and UnderstandingSession 3• Process Design and Understanding and ControlStrategySession 4• Generic Drug User Fees
128Process Design andUnderstanding and ControlStrategyLane V. Christensen, Ph.D.Chemist, Immediate OfficeOffice of Generic DrugsOpinions expressed in this presentation are those of the speakerand do not necessarily reflect the views or policies of the FDAFDA, DIA India and Pharmexcil WorkshopApril – May 2012
129Process development is easy.• It is just like cooking.– Buy the ingredients.– Put the stuff in the mixer,– Mix it– Put it on the stove, or in the oven to cook it, or dry it.– Place a topping on it, if necessary– Package it to protect it.• If we write the process that way, it will be easy.– Just execute the record as stated and we have areproducible product.– But: “Do not over-estimate the intelligence of the staff.”True statement??
130Product & Process design andUnderstanding???
131Potential Problems• Case Study-1: XYZ tablets, the initial formulation was submitted to theAgency, though it was bioequivalent and manufacturable at an exhibit batchscale, it was not manufacturable at full scale due to the poor selection of thefiller used erratic flow and high variability in tablet weight. The applicantchanged to a different grade of excipient, which by virtue of having better flowcharacteristics reduced the variability in tablet weight during commercialproduction.• This required an additional review cycle to evaluate and delayed approval byseveral months. (This certainly would have been averted had the sponsorcarefully considered the material properties (e.g. flow properties) of thisexcipient during development.)• Though the above resolved the weight variability, another problem arose dueto the change in excipient tablet chipping during shipping (Because thesponsor had constraints on its CPP, compression pressure, due to toolingdesign). Outcome: Product WithdrawalLesson learned: Need better understanding not just for material attributes,and process parameters, but also potential interactions.
132Begin with the End in MindPharmaceuticalDevelopmentExhibit batchCommercialDevelopment Studies- Prior Knowledge- Product Understanding- Process Understanding- Risk Management- PAT?DesignSpaceManufacturingExperienceEnhancedunderstanding(product/process)Continual ImprovementRegulatory FlexibilityChanges within Design SpaceContinuous Process Verification
133Process Development• Selection of a process is dependent on– CQA – How is the CQA affected by the equipment and input materials?– Input Materials – Is there source variability? (i.e., purity, multiple vendorsusing different processes, etc)– Equipment – Is there an equipment specific attribute that could affect theproduct? (shear rate (mixing), heat transfer, mechanical motion leads toattrition)– Stability of the product – Can product stability be affected by the processchosen? (heat labile, moisture sensitive products, polymorphic transistion,etc)– Common cause vs special cause variation
134Process Development (continued)• No one size fits all– Just because you are developing a similar process to one you’ve donebefore, does not mean you’ll have the same CPP to CQA relationship.• In some cases it may be possible to manufacture the product usingdifferent manufacturing processes.– Do any of the potential processes have an added benefit to the desiredproduct? (i.e., better impurity profile, control of polymorphism, etc)• More complex processes are dependent on the specialized form ortechnology platform that offers specific advantages to patient thatcannot be possible by conventional manufacturing processes.
135Control your inputsto reduce variatione.g., CMAsProcess parameters blendthe inputs to produceoutputs e.g., CPPsMeasurePerformancee.g., CQAsInputs PharmaceuticalUnit Operation-Process ParametersOutputsCQAs = f (CPP1, CPP2 , CPP3 …CMA1, CMA2, CMA3…)Establish ranges forCMAsEstablish ranges forCPPsControl StrategyUnderstanding the Relationshipbetween CMAs, CPPs, and CQAs
136Steps for Process Understanding1. Identify all possible material attributes and process parameters thatcould impact the performance of the process2. Use risk assessment and scientific knowledge to identify potentiallyhigh risk attributes and/or parameters3. Determine levels or ranges of these variables to be investigated4. Design experiments, using DOE when appropriate5. Conduct actual experiments6. Analyze experimental data to determine if an input material attributeor process parameter is critical.– A material attribute or process parameter is critical when arealistic change in that material attribute or process parametercan significantly impact the quality of the output materials.7. Establish the control strategy– For critical material attributes or process parameters, defineacceptable ranges. For non critical attributes, the acceptablerange is the range investigated.
137Process Map - Example QbD MRStep 1Who and how?
138Quality Risk Management – ICH Q9“Quality risk management isa systematic process for theassessment, control,communication and reviewof risks to the quality of thedrug (medicinal) productacross the productlifecycle.”PDControl StrategyContinual ImprovementStep 2
139Principles of Quality Risk ManagementTwo primary principles of quality risk managementare:• The evaluation of the risk to quality should bebased on scientific knowledge and ultimately linkto the protection of the patient; and• The level of effort, formality and documentationof the quality risk management process shouldbe commensurate with the levels of risk.
140Risk assessment in manufacturing versus developmentRisk assessment in cGMPmanufacturingRisk assessment in product and processdevelopmentStatus: Established procedureRisk scenario:deviation from pre-defined rangeObjectives:identify root cause and suggestcorrective and preventive actionsCharacteristics:• Mainly reactive, some proactive• Backwards to upper stream operation• Narrow scope• PreventiveStatus: Uncertainty, undefined rangeRisk scenario:potential impact on CQAsObjectives:identify high risk variables anddetermine future actionsCharacteristics:• Mainly proactive, some reactive• Forwards to down stream operation• Leverage of knowledge, can besubjective• Broad scope• Focus on prioritization• Informative
141Risk assessment during development• To identify (not eliminate) relative risk levelsfrom the beginning of product development• To prioritize limited development resources• To document the decision making processthroughout development• To assess the critical attributes of rawmaterials, solvents, drug substances andexcipients
142Risk assessment during development• To identify appropriate specifications, criticalprocess parameters and manufacturing controls• To enhance knowledge of product performanceover a range of material attributes• To decrease variability of quality attributes(product/material and manufacturing defects)• To assess the needs of additional studies forscale up and technology transfer
143Which method can be used in development?• Failure Mode Effects Analysis (FMEA)• Failure Mode, Effects, and Criticality Analysis (FMECA)• Fault Tree Analysis (FTA)• Hazard Analysis and Critical Control Points (HACCP)• Hazard Operability Analysis (HAZOP)• Preliminary Hazard Analysis (PHA)• Risk ranking and filtering• Basic risk management facilitation methods (flowcharts,check sheets, etc.)It is neither always appropriate nor always necessary to use a formal riskmanagement process….. The use of informal risk management processescan also be considered acceptable. -ICH Q9A risk based justification based on experience and data is alwaysnecessary!
144Example of risk assessment: IR Example• QbD IR example: AcetriptanIR tablet– BCS II drug with poorsolubility and highpermeability– Focus on particle sizeflowability, blend uniformity– Manufactured by rollercompaction– Uses common excipients insimilar amounts to the RLD
145IR QbD Example: Risk Assessment
146QTPP:• Intended use in clinical setting• Quality attributes of drug product• Active pharmaceutical ingredientrelease or delivery and attributesaffecting pharmacokinetic characteristics(Safety and efficacy)impacted by formulationor process variableshigh riskquality attributes impactpatient safety and efficacyQuality target product profile (QTPP)CQARisk assessmentDOEControl strategyRiskrankingandfilteringExamples of risk assessment applicationin pharmaceutical product and process development
147Using tools to enhanceunderstandingY = ƒ(X)CQAsYVariability fullyunderstoodMethodMachineMeasurementMother NatureINPUTS(X)ManpowerMaterialOUTPUTS(Y)Steps 3-6
148BBCompare Two ApproachesOFAT ‐ One Factor at A Time • an univariate approach• Estimates of effects at set conditionsof the other factors• Slow and inefficient• Can miss interactionsDOE – Design of Experiments• A statistics‐based multivariate approach • Good coverage of space• A methodology to achieve a predictive knowledge of a complex process with the fewest trials possibleABCA
149Type of DOE• Factorial DOE– Screening through many factors to find the significant few– fractional factorial DOE– Placket-Burman DOE– etc.• Optimization DOE (Response Surface Methods, RSM)– further understanding interactions /curvature (if any) of the few significant factorsand to move towards optimum conditions– Box-Behnken Design– Central Composite Design• central composite face-centered design (CCF)• central composite circumscribed design (CCC)– D-optimal DOE– Three level full factorial DOE– etc.• Mixture DOE– Discover the optimal formulation (1. the components add to a fixed total; 2. theresponse is a function of the proportions of the components)– Simplex-Lattice Design– Simplex-Centroid Design– D-Optimal Mixture Designs– etc.• Combined DOE– Combine process variables, mixture components and categoric factors in onedesign
150Factorial DOE: Fraction &ResolutionMain effect: the average change in the response when a factor is changed from low to high level: M(1)Interactions: the effect of one factor on the response depends on the value of another factor(s): 2FI, 3FI Aliased: confounded, not distinguishableFactorial DOE(e.g. 6 factors)# ofrunsAliasedeffectsResolution ResourceFull factorial (26) 64 No N/A Very HighHalf fraction (26-1) 32 3FI = 3FI VI HighQuarter fraction (26-2) 16M(1) = 3FI2FI = 2FIIV MediumEighth fraction (26-3) 8 M(1) = 2FI III Low
151• Begin with the end in mind: holistic overview (systematicapproach)• Define the responses (QTPP/CQAs)• List all possible process parameters and material attributesthat could impact the responses• Identify potentially high risk parameters and/or materialattributes (prior knowledge + risk assessment)• Decide the range of the experimental factors (prior knowledge+ feasibility study)• Select appropriate type DOE (fit for the purpose)• Conduct actual experiments (product/process understanding)– Use center point for estimation of curvature– Use replicates to estimate the repeatability– Block what you can and randomize what you cannot• Analyze the experimental data– Identify critical process parameter or critical material attribute(CPP/CMA)– Establish relationship between CPP/CMA and CQA: y = f(x)Steps in DOE Study
152Summary• OFAT is an univariate approach: slow, inefficient,assuming no interaction, leads to rigid manufactureprocess with high risk of DP failure.• DOE is a statistically designed multivariateapproach.• DOE is an efficient tool to identify CPPs and CMAsand establish relationship between CPP/CMA andCQA• Different DOEs are appropriate for different phasesof pharmaceutical development.• Use sound science, design space developed at labor pilot scale through DOE studies can beproposed for commercial scale, but it needs to beverified at production scale.• Overall, DOE is a valuable tool to facilitate theimplementation of QbD.
153Design Space• Design Space– The multidimensional combination and interaction ofinput variables (e.g. Material attributes) and processparameters that have been demonstrated to provideassurance of quality– Use sound science, design space developed at lab orpilot scale can be proposed for commercial scale, butit needs to be verified at production scale,• Regulatory Implication– Movement out of the design space is considered tobe a change and would normally initiate a regulatorypost-approval change process. Design space isproposed by the applicant and is subject to regulatoryassessment and approval
154Scale Effect on Design Space10 Fold=?Lab/Pilot Scale Design Space Commercial ScaleDesign SpaceGenerationConfirmationTo be verified
155Design Space of What?• Lab scale design space• Pilot scale design space• Commercial scale design space• Only commercial scale design space canhave meaningful regulatory flexibility asdefined in ICH Q8(R2)
156Availability of Various ToolsIncreasing more sophisticated tools !– Terahertz spectroscopy– Solid State NMR– PAT– Chemometrics– Real Time Release (RTR)
157Use of PAT• Ideally PAT principles and tools should beintroduced during the development phase• Increased level of inquiries submitted to OGD• Use of in-line NIRS method in the IR and MRexamples to determine endpoint for BU
158Define Specifications with Justification• Specifications Required– Drug Substance/Intermediates- (Requirementfrom DMF holder and applicant)– Drug Product– Container Closure System (Nasal, Injectables)– Device Components (MDI & DPI)– Stability• Specifications in support of the above– In Process Testing– Raw Material TestingStep 7
159***The control strategy ensures CQAs aremet consistently. . . a regulatory commitment***Control Strategy• Control Strategy - A planned set of controls, derived fromcurrent product and process understanding that ensuresprocess performance and product quality.• Controls can include the following:– Input material control (e.g., drug substance, excipients, primarypackaging materials)– Product control (specification)– Manufacturing process (unit operation) control– In-process or real-time release testing in lieu of end-producttesting– A monitoring program (e.g., full product testing at regularintervals) for verifying multivariate prediction models
161IR Example – Control Strategy
162IR Example – Control Strategy
163Why this MattersBy enhancing the process knowledge/understandingand principles we will achieve:– Rigorous Science– More robust manufacturing processes– Reduce variability– Ensure safety– Increase efficiency at all unit operations– Increased productivity, less failure– Increased knowledge transfer– Enhanced communication & collaboration
164References• Quality by Design for ANDAs: An Example for Modified ReleaseDosage Forms• Quality by Design for ANDAs: An Example for Immediate ReleaseDosage Forms• Guidance for Industry: Q8(R2) Pharmaceutical Development• Guidance for Industry: Q9 Quality Risk Management• Guidance for Industry: Q10 Pharmaceutical Quality System• Guidance for Industry: Q11 Development and Manufacture of DrugSubstances• Guidance for Industry PAT: A Framework for Innovative PharmaceuticalDevelopment, Manufacturing, and Quality Assurance• 2012 EMEA Guideline on the Use of Near Infrared Spectroscopy(NIRS) by the Pharmaceutical Industry and the Data Requirements forNew Submissions and Variations.
165Further questions• What are your concerns with implementingQbD?• What are the limitations?• What is the “end” in your target(submission, approval, commercial scale-up/to the market, discontinuation)?• What about the rest of ICH Q9, Q10?
167Inactive Ingredients DatabaseOGD is working with IPEC to update IID to meet customerneeds– Posting of historical IID files by quarter for the past 3 years (2009-2012)– Acceptance of summary sheet of pharm/tox data with reference to thespecific location of the data as a justification in lieu of completepharm/tox submission at time of filing– Further meetings with IPEC to discuss IID improvements and excipientissuesMinutes posted on Generic Drugs: Information for Industry webpagehttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm142112.htm
168Control Correspondencehttp://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm120610.htmAlso linked from the Generic Drugs: Information for Industry webpage
169Control Correspondence• Target response time: 60 days• Notification– The Office of Generic Drugs is reviewing yourquery but is unable to respond at this timedue to the nature of the inquiry. We willprovide a response once a determination hasbeen reached. Please refer to Control#_____ when referencing this inquiry in anyfuture related correspondence.
170Controls on Batch SizeRegarding batch size, the following are conditions where batch sizes<100,000 units are acceptable:1. The reference product has an orphan drug exemption2. The reference product is a controlled substance3. Indication that the batch size is the same as the commercial batchsize with a commitment there will be no scale up post approval withoutan approved prior approval supplement (PAS).In general, applicants should provide a commitment that thecommercial batch will be the same as the exhibit batch and there willbe no scale up post approval. Any subsequent batch scale up wouldbe subject to review and approval of a PAS.Cost of the drug alone should not be a factor in allowing a smallerbatch size.
172Workshop OverviewSession 1• OGD Overview/QbD Overview• The Quality Target Product ProfileSession 2• Product Design and UnderstandingSession 3• Process Design and Understanding and ControlStrategySession 4• Generic Drug User Fees