Implementing New USP Chapters for Analytical Method Validation

Implementing New USP Chapters for Analytical Method Validation March 2010 Ludwig Huber Fax.: +49 7243 602 501 E-mail: Ludwig_Huber@labcompliance.com Today s Agenda Handling Method Changes vs. Adjustments EU, ICH; FDA, Enforcement Practices (Recent) Recommendations from USP and EP Changing HPLC column particle size and ID Verification of Compendial methods according to USP <1226> Transferring methods: New USP proposal Interactive Exercises Copyright Ludwig Huber - LabCompliance Slide 2 1

Reference Material Master Plan: Transfer of Analytical Methods SOP Validation of Analytical Methods Transfer of Analytical Methods Method Changes vs. Adjustments USP Stimuli Paper: Transfer of Analytical Procedures: A Proposal for a New General Chapter (Link) References www.labcompliance.com/misc/conferences/dublin-aiq.aspx (available until April 10, 2010) Copyright Ludwig Huber - LabCompliance Slide 3 FDA CGMP Regulation - 21 CFR Part 211.194 (a) (2) Laboratory records shall include a statement of each method used in the testing of the sample. The statement shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested If the method employed is in the current revision of the United States Pharmacopoeia, or in other recognized standard references, or is detailed in an approved new drug application and the referenced method is not modified, a statement indicating the method and reference will suffice. The suitability of all testing methods used shall be verified under actual condition of use. Copyright Ludwig Huber - LabCompliance Slide 4 2

FDA Guidelines For Method Validation Analytical Procedures and Methods Validation (Draft) FDA - Industry Guidance Bioanalytical Method Validation Methods Validation for Abbreviated New Drug Applications Guideline for Submitting Samples and Analytical Data for Methods Validation Validation of Chromatographic Methods Copyright Ludwig Huber - LabCompliance Slide 5 Other Guidelines For Method Validation ICH - Guidance for Industry - Q2(R1) Validation of Analytical Procedures - Terminology and Methodology- United States Pharmacopeia 32, <1225> : Validation of Compendial Methods, United States Pharmacopeia 32, <1226> : Verification of Compendial Methods United States Pharmacopeia 32, <621> Recommendations for Accepted Adjustments to Validated Methods : ICH = International Conference for Harmonization Copyright Ludwig Huber - LabCompliance Slide 6 3

Change vs. Adjustment of Methods Receiving Laboratory can not get performance as specified by transferring Laboratory Transferring to New Technology 1. Check USP <621> and EP 5, Section 2.2.4 for allowed variables, e.g., flow rate, col. Temperature 2. If modifications are in the allowed range, perform system suitability testing. 3. If SST pass, continue with analyses. If not make further modifications. If total modifications are in allowed ranges, go back to 2. Otherwise revalidate Copyright Ludwig Huber - LabCompliance Slide 7 USP 30 - Supplement 2 <621>: Method Variations Adjustments of operating conditions to meet system suitability requirements may be necessary The user should verify the suitability of the method under the new conditions by assessing the relevant analytical performance characteristics potentially affected by the change Copyright Ludwig Huber - LabCompliance Slide 8 4

Allowed Variations USP/EP HPLC Column USP EP Length ±70% ±70% Internal diameter ±25% ±25% Particle size Reduction of 50%, no increase Reduction of 50%, no increase Copyright Ludwig Huber - LabCompliance Slide 9 Allowed Variations USP/EPs HPLC USP EP Flow rate ±50% ±50% Column Temperature ±10 Deg C ±10% Max 60 C Injection volume Change allowed as long as SST criteria are met May be decreased (if LOD and repeatability ok..) Copyright Ludwig Huber - LabCompliance Slide 10 5

Allowed Variations USP/EP HPLC USP EP ph ±0.2 ±0.2 (+-1% for neutral substances) UV wavelength Conc. of salts in buffer No change outside No adjustment manufacturer specs permitted ±10% ±10% Copyright Ludwig Huber - LabCompliance Slide 11 Allowed Variations USP/EP HPLC Mobile Phase Composition USP EP Composition of mobile phase Minor components (<50%) ±30% or ±10% absolute whichever is smaller Minor components ±30% or ±2% absolute whichever is larger Copyright Ludwig Huber - LabCompliance Slide 12 6

Allowed Variations USP/EP Gas Chromatography - Column USP EP Length ±70% ±70% Internal diameter ±50% ±25% Particle size Changes allowed SST must pass -50%, no increase Film Thickness -10 to +100% -10 to +100% Copyright Ludwig Huber - LabCompliance Slide 13 Allowed Variations USP/EP Gas Chromatography USP EP Flow rate ±50% ±50% Oven. Temperature ±10% ±10% Injection volume Change allowed as May be decreased long as SST criteria (if LOD and are met repeatability ok..) Copyright Ludwig Huber - LabCompliance Slide 14 7

Handling Instrumental Changes (USP only, HPLC only) Going from 4.6 to 2.1 or 1.0 mm columns to save mobile phase Reducing particle size to reduce analysis time 1. Colum diameter; As of Dec 1, 2009 (USP 32-2), column diameter can be reduced as long as flow rate is also reduced (performance based approach) 2. Particle size A USP discussion paper also suggests a performance based approach, but not yet official USP Stimuli Paper: Transfer of HPLC Procedures to suitable Columns of Reduced Dimensions and Particle Sizes Copyright Ludwig Huber - LabCompliance Slide 15 Flow Diagram: Change vs. Adjustment System Suitability Test Pass? no Adjust method parameters no yes Continue with sample analysis yes Pass? Changes in permitted range? no Partial or full Revalidation yes Document Run System Suitability Test Copyright Ludwig Huber - LabCompliance Slide 16 8

Validation of Compendial Methods? FDA GMPs refer to USP or other standards Typically no need for validation, if the method has not been modified Suitability must be verified under conditions of actual use No further guideline from FDA and equivalent international agencies USP has developed drafts on Verification of Compendial Procedures USP <1226>: Verification of Compendial Procedures) Copyright Ludwig Huber - LabCompliance Slide 17 USP <1226> - Goal and Scope Clarify on how to verify the suitability of compendial methods Provide consistency between laboratories and regulatory agencies Present a high level view of the verification process Provide guidelines on how to apply performance characteristics while allowing free flexibility to determine which performance characteristics are most appropriate For new methods, not retroactive application to already existing methods Copyright Ludwig Huber - LabCompliance Slide 18 9

USP <1226> Statements Users of compendial analytical procedures are not required to validate these procedures when first used in their laboratories, But documented evidence of suitability should be established under actual conditions of use. Copyright Ludwig Huber - LabCompliance Slide 19 USP <1226> Verification Process Laboratory personal should be qualified to understand and perform the compendial methods as written Acceptance criteria for verification should be established If the verification of the compendial procedure is no successful, it may be concluded that the procedure may not be suitable for use with the article being tested It may be necessary to develop and validate an alternate procedure Copyright Ludwig Huber - LabCompliance Slide 20 10

USP <1226> Verification Requirements (I) Verification requirements should be based on an assessment of the complexity of both the procedure and the material to which the procedure is applied Only those characteristics that are considered to be appropriate for the verification of the particular method need to be evaluated Some of the analytical performance characteristics as listed in USP <1225> may be used Copyright Ludwig Huber - LabCompliance Slide 21 USP <1226> Verification Requirements (II) The degree and extent of the verification process will depend on the verification process will depend on The level of training and experience of the user Associated equipment or instrumentation The specific procedural steps The material to be tested Copyright Ludwig Huber - LabCompliance Slide 22 11

Performance Characteristics to be Considered for Testing Chromatographic method: specificity to evaluate impurity profiles of drugs from different suppliers, that are not addressed in the compendial procedure Assessment of the limit of detection for an impurities procedure Precision of an assay procedure To demonstrate suitability of the compendial method under actual use Copyright Ludwig Huber - LabCompliance Slide 23 Examples where Verification is NOT Required For common compendial test procedures that are routinely performed in a laboratory Loss on drying Residue on ignition Various wet chemical procedures, e.g., acid value Simple instrumental methods, e.g., ph measurements Unless there is an indication that the compendial procedure is not appropriate for the article under test Copyright Ludwig Huber - LabCompliance Slide 24 12

Recommendations for Planning and Execution 1. Develop a verification plan 2. Describe test procedure, performance characteristics and acceptance criteria 3. Define and perform critical tests using USP procedure 4. Compare tests results with acceptance criteria 5. Perform and document assessment 6. Write a statement that the compendial procedure can be used Copyright Ludwig Huber - LabCompliance Slide 25 Recommendations for HPLC Performance Testing Application 1: Quantitation of major compounds of drug substances in finished drugs or APIs Tests: precision, ii specificity, ifiit linearityit Application 2: Quantitative determination of impurities in drug substances or degradation products in finished drugs Tests: Precision, specificity, quantitation limit Application 3: Limit tests of impurities in drug substances or degradation products in finished drugs Tests: Specificity, limit of detection Tests are application and instrument specific Copyright Ludwig Huber - LabCompliance Slide 26 13

Recommendations for Deviations If the tests don t pass acceptance criteria, identify the source of the problem Develop corrective action plan Provide additional training Use other equipment Update verification document Repeat the tests If successful, document initial results, corrective actions and final results If not successful, develop alternative procedure Copyright Ludwig Huber - LabCompliance Slide 27 Verification of Compendial Methods - Steps Change or Develop and Validate (full/partial) Document no Define Scope Match Compendial method? yes Corrective Action? Test for suitability yes no Root Cause? no Acceptable? yes Document Copyright Ludwig Huber - LabCompliance Slide 28 14

Occurrence of Method Transfer Sponsor company to contract lab Analytical development to QC labs Across different sites The same lab conditions Different lab conditions Existing to new instrumentation With different specifications With different technology Supplier of material to client Transfer to new instruments with different instrument characteristics Copyright Ludwig Huber - LabCompliance Slide 29 FDA 483 There is no assurance that analytical methods transferred from other laboratories are adequate for use in that the current SOP Does not require predetermined acceptance criteria for the transfer from the technical services laboratory to the Quality control laboratory Does not provide provisions for technical transfer from an external Quality Control laboratory Solely requires a ruggedness test if a validation protocol has been established for the test procedure Ref: GMP trends Copyright Ludwig Huber - LabCompliance Slide 30 15

Warning Letter Failure to establish and document the accuracy and reproducibility of test methods employed. (W-186) For example, methods that were validated at one facility and transferred to xxx site are being used without a methods transfer or revalidation protocol. (W-186) Ref: www.fdawarningletter.com Copyright Ludwig Huber - LabCompliance Slide 31 FDA Warning Letter The firm does not have sufficient data to support analytical method transfer Method transfer protocol, which was prepared to transfer the analytical testing method, did not require testing of the XX (100 mg and 400 mg), and only require testing of one lot of the 200 mg tablets The method transfer protocol and the method transfer report were not signed nor dated There was no formal analytical methods transfer facilities Ref: APV Education Course, Dr. Scheidegger Copyright Ludwig Huber - LabCompliance Slide 32 16

FDA Warning Letter The firm failed to perform finished product test method transfers for 34 products (W-187) The firm has failed to perform method validations, method verifications, or method transfers for any of the laboratory test methods used to test active pharmaceutical ingredients (W-187) Ref: www.fdawarningletter.com Copyright Ludwig Huber - LabCompliance Slide 33 Definition of Method Transfer Process that qualifies a laboratory to use an analytical test procedure Process of establishing documented evidence that the analytical test procedure works in the receiving laboratory as well as it does in the transferring laboratory Ref: Margareth Marques, Ph.D., US Pharmacopeia Copyright Ludwig Huber - LabCompliance Slide 34 17

Why Controlled Method Transfer Expected by agencies The suitability of all testing methods used shall be verified under actual condition of use Reduces failure rate Improves the quality of the testing at the new place Problems can come up due to different equipment, different analysts and lab environment Copyright Ludwig Huber - LabCompliance Slide 35 FDA Guidance on Method Transfer We recommend that you hold a training session at which personnel from your reference laboratory demonstrate the method for representatives from the participating laboratories, to highlight or clarify practical details of the assay method. During the training session, you should also discuss all aspects of the protocol(s) to ensure everyone understands the procedures and objectives This can help you identify key points that may cause difficulties in the transfer study Ref: FDA Industry Guidance: Protocol for the Conduct of Method Transfer for Type C Medicated Feed Assay Methods Copyright Ludwig Huber - LabCompliance Slide 36 18

USP Stimuli Paper: Transfer of Analytical Procedures: A Proposal for a New General Information Chapter Published in Pharmacopeial Forum, Nov 2009 Provides the basis for a new USP chapter: Analytical Method Transfer Content Discussion of 4 types of analytical transfer Elements recommended for transfer of analytical procedures The importance transfer protocol The analytical procedure and report Copyright Ludwig Huber - LabCompliance Slide 37 Options for Method Transfer Comparative Testing Co-validation Complete or partial validation or revalidation Omission of formal transfer Criteria: type of method (simple, complex), experience and capabilities of receiving lab Copyright Ludwig Huber - LabCompliance Slide 38 19

Comparative Testing Most frequently used The same tests are carried out by both labs Should only be performed with validated methods Used with complex methods Requires pre-approved protocol 2-5 lots analyzed by both labs Well defined test procedures and acceptance criteria Results are compared with a set of pre-determined acceptance criteria Copyright Ludwig Huber - LabCompliance Slide 39 Co-validation Received lab is part of original method validation Transferring and receiving lab conduct the same validation experiments Useful for methods not (fully) validated Should challenge all USP or ICH validation parameters Include receiving lab in validation inter-laboratory tests. Ensures harmonization of method at both sites A site that performs validation studies is qualified to run the method Copyright Ludwig Huber - LabCompliance Slide 40 20

Method Validation on/or Revalidation Received lab repeats some or all of the validation experiment Done after initial method validation Validation parameters depend on the method e.g., Limit selectivity and limit quantitation for impurities Precision for content uniformity assays Similar process as verification of compendial methods Copyright Ludwig Huber - LabCompliance Slide 41 Transfer Waivers Method is used without special revalidation or testing Reasons should be well justified and documented Receiving lab already testing the product and is familiar with the method Receiving lab already testing a similar method Method developer moves from transferring to receiving ii lb lab Waiver should be well justified and documented Copyright Ludwig Huber - LabCompliance Slide 42 21

Prerequisites for Successful Method Transfer Analytical methods validated Includes ruggedness testing Includes robustness testing Scope well defined Sample, matrix Performance characteristics, acceptance criteria Equipment, Copyright Ludwig Huber - LabCompliance Slide 43 Required Documents Transfer Master Plan (TMP) used as frame work Transfer project plan or method transfer protocol (MTP) Approach for controlled transfer and justification SOPS for step-by-step implementation Templates and forms for efficiency i and consistency Copyright Ludwig Huber - LabCompliance Slide 44 22

Transfer Plan or MT Protocol Reason and purpose of the transfer Scope of the plan and method transfer The approach Description of transfer process Responsibilities Transferring, receiving labs, project owners, QA Assumptions E.g., Analysts in the receiving i lab not familiar with the method Training details Test Plan MTP = Method Transfer Protocol Copyright Ludwig Huber - LabCompliance Slide 45 Test Plan Tests to be performed and test parameters Rational behind tests Description of materials and samples Description of equipment Number of lots, batches replicates, injections Pitfalls that may be encountered Test schedule Acceptance criteria Documentation, approvals Copyright Ludwig Huber - LabCompliance Slide 46 23

Two Step Process Step 1: Analysts in receiving familiar with the method Ensures that the receiving lab understand the method and have the equipment and expertise to perform the analysis Receiving lab performs complete analysis according to the protocol Step 2 Comparative tests with the complete transfer study set Ref: FDA Industry Guidance: Protocol for the Conduct of Method Transfer for Type C Medicated Feed Assay Methods Copyright Ludwig Huber - LabCompliance Slide 47 Steps for Comparative Testing Develop and approve a test plan Order missing equipment and materials Training Concurrent execution of the protocol Evaluation of test results Compare with acceptance criteria Resolution of deviations, if there are any Gather all required documents Write method transfer report (MTR) Copyright Ludwig Huber - LabCompliance Slide 48 24

Experiments - Example Five replicates of the study samples Five replicates of the study samples fortified at 0.5x the lowest expected concentration Five replicates of the study samples fortified at 1.5x the highest expected concentration Analyze the study sample set over several days Ref: FDA Industry Guidance: Protocol for the Conduct of Method Transfer for Type C Medicated Feed Assay Methods Copyright Ludwig Huber - LabCompliance Slide 49 Considerations for Testing Number of samples, lots, batches (2-5) One or more concentrations (1-3) Number of repetitive analysis / sample (4-6) One or more analysts? (1-2) One or more days? (2-5) Equipment from one or more manufacturers? (1 -all) Copyright Ludwig Huber - LabCompliance Slide 50 25

Possible Pitfalls Scope of the method not defined equipment Method not fully validated Methods are not robust Resources not well planned Equipment, people, time Analysts not trained Acceptance criteria not well defined Copyright Ludwig Huber - LabCompliance Slide 51 Recommendations for Deviations If the tests don t pass acceptance criteria, identify the source of the problem Develop corrective action plan Provide additional training Use other equipment Update the procedure Repeat the tests If successful, document initial results, corrective actions and final results If not successful, develop alternative procedure Copyright Ludwig Huber - LabCompliance Slide 52 26

Method Transfer Report Report items and format to be specified in the study transfer plan Summary of method familiarization results Detailed results of transfer study Description of any deviations and from expected results and how they have been resolved Signatures of individuals responsible for transfer studies Copies of supporting material, e.g., chromatograms and spectra Assessment of the transfer study results Copyright Ludwig Huber - LabCompliance Slide 53 Thank You I would like to thank All attendees for your attention IVT for organization and invitation to the conference Give feedback and choose any two from over 150 documents (value: $138) for free: SOPS and/or Validation examples. GOTO: www.labcompliance.com/misc/conferences/feedback.aspx Check topics and details of 100+ audio/video seminars Audio: www.labcompliance.com/seminars/audio Video: www.labcompliance.com/seminars/video Copyright Ludwig Huber - LabCompliance Slide 54 27

Laboratory Compliance Package With 30 SOPs and Laboratory Master Plan Primer and Interactive audio seminar on laboratory compliance: requirements and strategies for implementation 30 SOPs for fast implementation Multiple forms, templates and examples for consistent and effective implementation Three gap analyses and master plan 10+ reference papers FDA presentations Analysts, IT and QA learn all about requirements and strategies And get SOPs and examples for easy implementation. More info: www.labcompliance.com/books/lab-compliance Copyright Ludwig Huber - LabCompliance Slide 55 28