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Life Cycle Management of AnalyticalMethods for Biotechnology Products:A Regulatory PerspectiveRashmi Rawat, Ph.D.Acting Team Leader, Product QualityDivision of Monoclonal AntibodiesOBP/ OPS/CDERWCBP 2014: 18th Symposium on the Interface of Regulatory and AnalyticalSciences for Biotechnology Health Products, Jan. 28-30, 2014, WashingtonDC1

Presentation Outline Life cycle of analytical methods Analytical method development and validationthrough the product life cycle Regulatory considerations for changes inanalytical methods Case Studies: replacement and transfer ofanalytical methodsDisclaimerSome of the views expressed during this presentation are my ownand may not necessarily reflect the official opinion of FDA2

Major Stages in a Method’s Life CycleSelection/DevelopmentQualificationValidation3

Selection and Design of Analytical MethodsThe selection and design of analytical method shouldbe based on a systematic approach: Intended use of the assay– Purity, impurities, potency, identification, safety– Release test, stability test, characterization, in-processtesting Identify sources of analytical variation– Method variability, risk from analyst, reagents, andinstruments Define reportable results– Independent tests, mean of replicates etc.4

Rational Assay Development/Qualification Investigate and identify the assay’s critical characteristicsand parameters. Method robustness studies are performed to evaluate itsreliability during conditions of use. Detailed assay SOP, with system suitability requirements,that incorporates the assay’s characteristics and parametersinto a clear, concise procedural plan. Use this information as a basis from which to develop ascientifically sound validation plan that will demonstrate thatthe assay does what it is intended to do on a routinebasis.5

Qualification Vs. Validation Assay Qualification:Determining whether an assay is suitable for itsintended purpose Limited pre-determined performance criteriaAssay Validation:Assuring the assay is suitable for its intendedpurpose on a routine basis Pre-defined assay performance criteria 6

Analytical Method Validation Validation trials are run according to an establishedvalidation protocol. Method performance specifications are pre-established,documented and confirmed during validation trial. These specifications must be met by every validation trial. A method can fail validation; if it does, assignable cause forthe failure must be investigated, resolved, and the assayre-validated.7

Why Validate an Assay?21 CFR 211.165“The accuracy, sensitivity, specificity, andreproducibility of test methods employed by the firm shall beestablished and documented in accordance with 21 CFR211.194(a)(2).”21 CFR 211.194(a)(2)“[The firm] shall indicate the location of data thatestablish that the methods used in the testing of the samplemeet proper standards of accuracy and reliability as appliedto the product tested . The suitability of all testing methodsused shall be verified under actual conditions of use.”8

Analytical Method ValidationNon-Compendial Method: Non-compendial methods arevalidated according to the principles described under ICH Q2(R1) document. Typical validation characteristics are: SpecificityLinearityAccuracyPrecision (repeatability, intermediate precision and reproducibility)RangeQuantitation LimitDetection LimitCompendial Method: Procedures used to evaluate a definedcharacteristic of the drug substance or drug product that arelegally recognized under 21 USC 501(b) (USP/NF). Generally,will need only partial validation i.e., need to be verified underactual conditions of use ( USP chapter 1225 and 1226 ). 9

Analytical Method ValidationAnalytical methods that need to be validated are: Lot release assays Stability methods for defining expirationdates/holding times Assays for significant process relatedimpurities (e.g., host cell proteins, residualDNA, protein A, etc.) Analytical in-process tests Excipient and raw material testing (generallycompendial)10

Expectations For Methods DuringProduct Development Ensure safety of the product Assay is providing meaningful results Assurance that analytical information gained indevelopment can be reliably related to commercialmanufacturing Determine method performance capabilities includingspecificity, linearity, accuracy, precision, robustness,and stability11

Expectations For Methods During Product Development FDA Process Validation Guidance (2011)– “Validated analytical methods are not necessarilyrequired during product- and process-developmentactivities or when used in characterization studies.”– “ analytical methods should be scientifically sound(e.g., specific, sensitive, and accurate) and provideresults that are reliable.”– Clinical supply production should follow the CGMPsappropriate for the particular phase of clinicalstudies. Interpretation:Review staff focus on the adequacy of non-compendialsafety tests for early phase clinical supply material12

Lifecycle Management of Analytical Methods13

Lifecycle Management of Analytical MethodsPost-licensure activities for the method lifecyclemanagement1. Revalidation2. Analytical Method Comparability Change in method (Method Replacement andmodification)Analytical Method TransferPost marketing changes to analytical proceduresmust be reported to the FDA in compliance with 21CFR 314.70 or 21 CFR 601.12.14

Lifecycle Management of Analytical MethodsPost-LicensureRevalidation of analytical procedure should beconsidered: When an analytical method can only meet theestablished system suitability criteria with repeatedadjustment to operating conditions stated in theanalytical procedure When a change is made to an analytical procedure(e.g. change in reagent, equipment, formulation, ormanufacturing process)15

Lifecycle Management of Analytical MethodsConsiderations for Revalidation Ensure that the analytical method maintainsits critical performance characteristics,e.g., specificity, sensitivity, precision, etc. The degree of revalidation depends on the natureof the change16

Lifecycle Management of Analytical MethodsAnalytical Method Comparability shoulddemonstrate The new method, coupled with any additionalcontrol measures, is equal or superior than theoriginal method for the intended purpose The new procedure is not more susceptible tomatrix effect than the original procedure17

Considerations for Method Comparability Studies To demonstrate that changes in the analytical proceduresimprove or do not significantly change analytical procedurecharacteristics that are relevant to the type of analyticalprocedure, its validation, and its intended use. Homogenous samples from the same batches should beincluded in the studies. Statistical analyses should be performed to demonstrate thecomparability or equivalency of the new method with theexisting method.18

Considerations for Analytical Method ComparabilityIf an assay has stability indicating properties: The stability indicating properties of the new assay shouldbe the same or better than the existing assay. Appropriate samples from multiple lots should be includedthat allow the comparison of the new and original method todetect relevant product variants and degradation species If new product related variants or process relatedimpurities are seen with the new assay, information fromretained samples should be provided demonstrating thatthe variants/impurities are not new.19

Considerations for Analytical Method ComparabilityIf an assay has stability indicating properties (contd.): Number of batches analyzed for comparisonshould be statistically relevant The statistical analyses performed to compareproduct testing should be identified. All biasesseen with comparative results should bediscussed with an explanation20

Case StudiesChange in Analytical Methods21

Changes in Analytical Methods ForPurity and Charge Assays New methods to detect purity and charge (cSDS, cIEF,CEX, etc.) are used to replace old methods such as SDSPAGE or IEF method. The new assays have higher sensitivity detectingproduct-related impurities, at release or during stabilitystudies, that were not detected by the original method. Use of these new methods raises the question whetherthe impurities are new or the new assay is better than theold assay at detecting product degradants.22

Case Study #1:Change from IEF to cIEF Sponsor seeks to replace a qualitative (IEF) assay with aquantitative (cIEF) assay. The IEF assay had acceptance criteria of “compares toreference” while the cIEF assay had quantitative acceptancecriteria for the major peaks. Using these acceptance criteria, stability samples were failingby the IEF assay at earlier time points than by the cIEF assay. It appeared that the new assay was not as stability indicatingas the old assay. The stability failures by IEF appear to be due to theappearance of a particular isoform compared to the referencestandard. In case of cIEF same isoform is consistently presentat very low levels and is detected by the cIEF, even in the 23reference standard.

Case Study #1:Replacing IEF to cIEFRecommendationThe cIEF was allowed for use in stability testing based on thedata and risk assessment provided by the sponsor that showed: Detection by the IEF was the result of a less than 0.5 %change in its level. Because this was considered a ‘change’from reference, it was considered a stability failure by IEF, butdid not actually represent a significant change in productquality. Impurity was identified and justified not to impact productefficacy or safety.24

Case Study #2: Replacing IEF with cIEFAt the time of licensure, a sponsor seeks to replace an IEFassay with a cIEF assay. The new cIEF method was shown to have comparable orbetter performance compared to the old IEF method. There was, however, limited data from drug product lots usingthe new cIEF method upon which to base quantitative releaseand/or stability acceptance criteria.RecommendationNew method run concurrently with old method until sufficientdata accumulated with which to establish relevant acceptancecriteria.25

Case Study#3 : Host cell protein (HCP) assaysHCP assay was updated from a third-party anti-HCP assayto a product specific assay. Third party assay: The anti-HCP antiserum is raisedagainst a ‘generic’ cell line (e.g., CHO , NS0, E. coli). Specific assay: The anti-HCP antiserum is raised againsta cell line that is the same as that used for transfection.Generally a vector transfected cell line.26

Commercial versus Specific HCP AssaysThird party HCPAssay AntibodySpecific HCPAssay AntibodySilver stain ofHCP assaystandardsWestern blots27

Non-Specific Vs. Specific HCP AssaysSpecificAssayThird PartyAssayRecommendation: Implement specific assay early in development28

Analytical Method Transfer29

Analytical Method Transfer Method Transfer is managed under an internal transferprotocol that details the parameters to be evaluated inaddition to the predetermined acceptance criteria that willbe applied to the results A statistically relevant number of test articles are used bythe originating and receiving laboratories (e.g., same lots ofDS and/or DP lots). In cases where the transferred analytical method is alsostability indicating; forced degradation samples or samplescontaining pertinent product-related impurities should be30analyzed

Analytical Method TransferThe comparative analytical method transfer studiesare performed to evaluate : Accuracy Precision (repeatability and Intermediateprecision, e.g., equipment, operators, differentdays)31

Case Studies: Analytical Method Transfer32

Case Study #4: Analytical Method TransferFollowing a change in the drug substance (DS)manufacturing process and site change, the SDS-PAGEmethod for purity of the DS was transferred to new site. At the new site a different densitometer was used toquantify protein gels. Result on DS lots from the new site with the newdensitometer showed a decrease in product purity for thenon-reduced SDS-PAGE assay.33

Case Study #4: Analytical Method Transfer To demonstrate that the decrease in product purity was not due tothe process change the sponsor performed side-by-side testing asfollow:- DS batches produced by new manufacturing process weretested at the previous analytical laboratory site and at the newanalytical site.- DS lots from original and new manufacturing process weretested at the new analytical site. Results from these side-by-side comparisons showed that theapparent decrease in purity was due to the use of the newdensitometer and not due to change in product quality.34

Case Study #5: Analytical Method TransferSponsor submitted a PAS for the transfer of multiple analyticalmethods for drug product (DP) testing. The following deficiencieswere noted in the method transfer study: It did not include comparison on percent monomer - a lot releaseand stability specification. The method transfer included only one analyst at the recipientsite. The results of the DP lots used to support the transfer of themethod used to detect impurities were predominantly reported as LOQ. No data was provided to demonstrate that LOQ of thetransferred method at the recipient site is comparable to theoriginal site.35

Case Study #5: Analytical Method TransferRecommendations: To compare monomer results from both facilities Method transfer should include two operators atboth sites or provide data from additional testingsites to demonstrate that assay is not subject tooperator bias. Include analysis of additional lots with detectableimpurities. The analysis of spiked samples withknown amount of impurities could also be used.36

Summary1. The Lifecycle Management of Analytics involves regularperformance trending and evaluation of the capabilities ofthe method; which may trigger the need for analyticalupdates and revalidation.2. If making a major change in how a quality attribute ismeasured: Assess consistency and comparability acrossmultiple lots. Release and stability data from multiple lots will berequired to set commercial specifications.37

Summary3. Comparative method transfer studies shouldinclude: assessments of accuracy and precision, forced degradation samples or samplescontaining relevant product related impurities(for stability indicating assays)4. A statistically relevant number of DS and/or DP samplesshould be analyzed in analytical method comparabilitystudy.5. In anticipation of life cycle changes in analytics appropriatenumber of DS and DP samples representative of pivotaland marketed product should be archived to allow for38comparative studies.

References on Analytical Methods Validation1. ICH Guidelines Q2(R1) [2005]2. FDA draft Guidance on Analytical Procedures and3.4.5.6.Methods Validation [2000]FDA Guidance on Process Validation: General Principlesand Practices [2011]FDA -GFI: Changes to an Approved Application forSpecified Biotechnology and Specified SyntheticBiological Products[1997]FDA guidance on Content and format of IND for Phase 1studies of Drug, including Well-Characterized,Therapeutic, Biotechnology products [2000]FDA-GFI: INDs for phase 2 and phase 3 studies, CMCInformation [2003]39

Lifecycle Management of Analytical Methods Post-licensure activities for the method lifecycle management 1. Revalidation 2. Analytical Method Comparability Change in method (Method Replacement and modification) Analytical Method Transfer Post marketing changes to analytical pro

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