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Best Practices for OINDP Pharmaceutical DevelopmentPrograms Leachables and ExtractablesVIII. Quality Control and Specification SettingPQRI Leachables & Extractables Working GroupPQRI Training CourseApril 12-13, 2007Chicago, IL

Definition Review A Leachables Study is a laboratory investigation into thequalitative and quantitative nature of a particular OINDPleachables profile(s) over the proposed shelf-life of theproduct. Supports:§ Developing an extractables/leachables correlation§ Establishment of drug product leachables acceptance criteria. Routine Extractables Testing is the testing by which OINDPcontainer closure system critical components arequalitatively and quantitatively profiled for extractables,for:§ Establishing extractables acceptance criteria§ Release by established acceptance criteria.April 2007PQRI Training Course2

Control of Leachables ThroughControl of Extractables Specificationsand acceptance criteria are requiredfor leachables profiles in OINDP. Implementation of routine leachables testing andspecifications/acceptance criteria is a policymatter. If extractables/leachables correlations can beestablished, then leachablesspecifications/acceptance criteria may beestablished as “if tested will comply”. Therefore, in the ideal situation leachables can becontrolled through routine testing of extractables.April 2007PQRI Training Course3

Routine Extractables TestingPerformed on all critical components of OINDP containerclosure systems with following general goals: To establish extractables acceptance criteria for OINDPcritical container closure system components.To help ensure that the leachables profile in the drugproduct is maintained within appropriate limits.To release OINDP container closure system criticalcomponents according to established acceptance criteria,which are designed to:§ Confirm the identities and levels of known extractables;§ Detect “unspecified” extractables which could be present as theresult of component ingredient changes, manufacturing changes,external contamination, or other causes.April 2007PQRI Training Course4

Recommendations for RoutineExtractables Testing Analyticalmethods for Routine ExtractablesTesting should be based on the analyticaltechnique(s)/method(s) used in the ControlledExtraction Studies. Consider the following:§§§§April 2007Simplicity relative to R&D methodsRuggedness and robustnessTransferabilityCost effectivenessPQRI Training Course5

Transition from Extractables StudiesMethod to Routine QC Extrables TestingRoutine Extractables Method – GC/FIDpA400350300GC/MS Extractables Profile of an Elastomer250200A bundanc e150TIC: 0240000052200000101520253035 min20000001800000Routine Extractables Method – HPLC/UV16000001400000DAD1 A, Sig 200,4 Ref 550,100 00010000001758000006000001502-propanol .00Tim e-- 35.001007550Development Method250024681012141618minQuality Control Method(s)April 2007PQRI Training Course6

Routine Extractables Testing- MethodDevelopment and Validation-References1.2.3.4.5.April 2007ICH Harominzed Tripartite Guideline, “Text on Validation ofAnalytical Procedures Q2A”, International Conference onHarmonization of Technical Requirements for Registration ofPharmaceuticals for Human Use.ICH Harominzed Tripartite Guideline, “Validation of AnalyticalProcedures: Methodology Q2B”, International Conference onHarmonization of Technical Requirements for Registration ofPharmaceuticals for Human Use.“Reviewer Guidance – Validation of Chromatographic Methods”,Center for Drug Evaluation and Research (CDER), United StatesFood and Drug Administration, November, 1994.“Guidance for Industry – Analytical Procedures and MethodsValidation – Chemistry, Manufacturing, and ControlsDocumentation”, Draft Guidance, Center for Drug Evaluation andResearch (CDER), United States Food and Drug Administration,August, 2000.Michael E. Swartz and Ira S. Krull, Analytical Method Developmentand Validation, Marcel Dekker, Inc., New York, 1997.PQRI Training Course7

Routine Extractables Testing- Method Developmentand Validation Extraction procedures for critical componentsshould be based on the optimized procedures fromthe quantitative Controlled Extraction Studies§ Demonstrate asymptotic levels of extractables. Thelinear dynamic range of the analytical methodshould be established based on levels ofextractables anticipated from quantitativeControlled Extraction Studies The Limit-of-Quantitation of the method should beestablished with consideration of the appropriateAET.April 2007PQRI Training Course8

Routine Extractables Testing- MethodDevelopment and Validation (cont.) Method validated according to the ICH validationcharacteristics of a quantitative impurity test,§ Include: Accuracy, Precision (Repeatability, IntermediatePrecision), Specificity, Limit-of-Quantitation (LOQ), Linearity, andRange.§ System Suitability parameters should be established§ Robustness should be evaluated§ Note that in certain cases it may be appropriate to validate routineextractables methods as “Limit Tests”, in which case onlySpecificity and Limit-of-Detection (LOD) need be considered. Accuracy can be determined through the analysis of spikedsamples.§ Spiking matrix could be an extract taken through the extractionprocedure minus the component sample.§ Spiking levels should be chosen so as to be representative ofanticipated extractables levels based on results from quantitativeApril 2007 Controlled Extraction Studies.PQRI Training Course9

Specifications and AcceptanceCriteria for Leachables Leachablesspecifications should include a fullyvalidated analytical test method. Acceptance criteria for leachables should applyover the proposed shelf-life of the drug product,and should include:§ Quantitative limits for known drug product leachablesmonitored during product registration stability studies.§ A quantitative limit for “new” or “unspecified” leachablesnot detected or monitored during product registrationstability studies.April 2007PQRI Training Course10

Specifications and Acceptance Criteria forLeachables Quantitativeacceptance criteria should be basedon safety considerations as outlined in the ‘L&EBest Practices‘§ Actual leachables levels, and trends in leachables levels,observed over time and across various storageconditions and drug product orientations during productregistration stability studies should be considered. Abilityto consistently meet should be establishedwith appropriate statistical analysis.April 2007PQRI Training Course11

Specifications and Acceptance Criteria forLeachables Comprehensivecorrelation should obviate the need forroutine implementation of drug product leachablesspecifications and acceptance criteria, assuming:§ Adequate information from critical component suppliers§ Understanding and control of critical componentfabrication§ Controlled Extraction Studies on critical components.§ Validated leachables methods and a Leachables Study.§ Validated Routine Extractables Testing methods anddatabase of critical component extractables profiles.§ Appropriate specifications and acceptance criteria forextractablesApril 2007PQRI Training Course12

Specifications and Acceptance Criteria forExtractables RoutineExtractables Testing should be performedon OINDP critical components prior to drugproduct manufacture. Critical components should be released to drugproduct manufacture based on definedspecifications and acceptance criteria establishedthrough:§ Understanding of critical component composition(s),ingredients, and compounding/fabrication processes.§ Comprehensive Controlled Extraction Studies.§ A significant database of extractables profiles obtainedwith validated Routine Extractables Testing methods.§ A complete leachables/extractables correlation.April 2007PQRI Training Course13

Specifications and Acceptance Criteria forExtractables Acceptancecriteria for OINDP criticalcomponent extractables can include thefollowing:§ Confirmation of extractables identified inControlled Extraction Studies.§ Quantitative limits for extractables identified inControlled Extraction Studies.§ A quantitative limit for ”new” or “ unspecified”extractables not detected during ControlledExtraction Studies.April 2007PQRI Training Course14

Establishing Specifications:Widgets vs. Pills Rest Pharmaceuticalsof World (Planes,Trains & Automobiles )§ Known requirementsthat must be met toinsure productperformance§ Establish that process iscapable of meetingrequirementsApril 2007PQRI Training Course§ Vaguely knownrequirements (vsproduct performance)§ Establish requirementsfrom vaguely knownprocess capabilities15

Statistical Tools Related toSpecifications ProcessCapability & Performance Analysis§ Statistical evaluation of process variability with respectto limits§ Typically includes both process and measurementvariability OperatingCharacteristic Curves§ Statistical evaluation of decision making process relatedto an individual test§ Considers influence of different test structures: numbersof samples, average vs. individuals, tiered testing April 2007PQRI Training Course16

Types of Quality Inspections Inspectionby Attributes§ Defect testing (pass/fail by unit)Visual inspection of containers for foreign material or defectsSpray test of MDIs Inspectionby Variables§ Estimation of Batch Parameters (centraltendency, variability)HPLC Assay of tablets for active ingredientDelivered Dose Uniformity of an MDIContent Uniformity of a tabletLeachable/extractable testingApril 2007PQRI Training Course17

What we would like to have toestablish/verify acceptance criteria:April 2007PQRI Training Course18

What we typically have toestablish acceptance criteria:Impurity X0.240.070.15NDApril 2007PQRI Training Course19

Performance of Limits Established withSmall DatasetsRobustness of Establishing Acceptance Criteria with Small Datasets(limits established via /- 3 standard deviations)Variablen 3n 4n 5n 6n 7n 8n 9n 10n 20Risk of obtaining limits worsethan the associated compliance rate1008060402000.0April 20070.20.40.60.8Fraction of Results Complying with LimitsPQRI Training Course1.020

Comparison of DifferentApproaches to Setting LimitsComparison of Different Approaches to Establishing Limitsn 7Risk of obtaining limits worsethan the associated compliance )3 stdmin/max95/9599/998060402000.1April 20070.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0Fraction of Results Complying with LimitsPQRI Training Course21

Process Capability & Performance ProcessCapability: Statistical comparison ofinherent process variability (common causevariability only) to some limits. Generally,represents the best possible performance. Process Performance: Statistical comparisonof the total observed variability to somelimits. May include special cause variability.April 2007PQRI Training Course22

Process Capability Several different ‘Capability Indices’ existDesigned to show whether process measurement arecapable of meeting limitsCp (USL-LSL)/6σwCpk Min{[(USL-Avg)/3σw],[(Avg-LSL)/ 3σw]} Minimum Cpk of 1.33 expected for new processCp Cpk when process is ‘centered’Above is for two-sided limit, for a one-sided limit Cp ismeaningless and Cpk considers only the range to thespecified limitApril 2007PQRI Training Course23

Process Performance Several different ‘Performance Indices’ existDesigned to show process measurement performancerelative to limitsPp (USL-LSL)/6σPpk Min{[(USL-Avg)/3σ],[(Avg-LSL)/ 3σ]} Minimum Ppk of 1.33 expected for new processPpk Cpk when no ‘special cause’ source of errorAbove is for two-sided limit, for a one-sided limit Pp ismeaningless and Ppk considers only the range to thespecified limitApril 2007PQRI Training Course24