Bioanalytical method validation - Global regulatory chalenges

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Detailed comparison of the bioanalytcial method validation guidelines of Europe, Japan, Brazil and the United States

Text of Bioanalytical method validation - Global regulatory chalenges

  • Evaluating EMA and FDA guidance on bioanalytical method validation Peter van Amsterdam (Abbott/EBF/GBC) 10th Bioavailability / Bioequivalence, Dissolution and Biowaivers 14 May 2014, Budapest
  • Evaluating EMA and FDA guidance on bioanalytical method validation Contents 1. Guidance 2. Method validation 3. Sample analysis 4. Quality systems --------------------- Further reading 14 May 2014 2
  • Guidance 14 May 2014 Evaluating EMA and FDA guidance on bioanalytical method validation 3
  • What to look for Global OECD ICH WHO Regional FDA EMA ASEAN National HPFB MHLW CFDA etc. Evaluating EMA and FDA guidance on bioanalytical method validation 414 May 2014 Where to look .. Bioanalytical method validation guidelines BA/BE specific guidelines PK / phase I specific guidelines TK guidelines Analytical chemistry guidance documents GLP GC(L)P G-other-P
  • BMVs International: ICH (2005) Q2(R1): Validation of Analytical Procedures: Text and Methodology USA: FDA (2001) Guidance for Industry: Bioanalytical Method Validation Europe: EMA (2011) Guideline on Bioanalytical Method Validation Brazil: ANVISA (2012) RESOLUO - RDC N 27, DE 17 DE MAIO DE 2012 Dispe sobre os requisitos mnimos para a validao de mtodos bioanalticos empregados em estudos com fins de registro e ps-registro de medicamentos. Japan: MHLW (2013) Guideline on Bioanalytical Method Validation in Pharmaceutical Development USA: FDA (2013) DRAFT Guidance for Industry: Bioanalytical Method Validation Evaluating EMA and FDA guidance on bioanalytical method validation 514 May 2014
  • BABEs USA: FDA (2003) Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations China: CFDA (2005) Technical guideline for human bioavailability and bioequivalence studies on chemical drug products India (2005) Guidelines for Bioavailability & Bioequivalence Studies Europe: EMA (2010) Guideline on the Investigation of Bioequivalence China: CFDA (2011) Guidance on Management of Laboratory for Drug Clinical Trial Biological Sample Analysis (interim) Canada: HPFB (2012) Conduct and Analysis of Comparative BA Studies and many more Evaluating EMA and FDA guidance on bioanalytical method validation 614 May 2014
  • GLPs USA: FDA (1978) 21CFR Part 58 Good Laboratory Practice for Nonclinical Laboratory Studies International: OECD (current) Principles of Good Laboratory Practice and Compliance Monitoring International: WHO (2009) Good Clinical Laboratory Practice (GCLP) Europe: EMA (2012) Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples USA: FDA (1997) 21CFR Part 11 Electronic Records; Electronic Signatures Europe: Eudralex (2010) Good Manufacturing Practice - Medicinal Products for Human and Veterinary Use - Annex 11: Computerised Systems and many more Evaluating EMA and FDA guidance on bioanalytical method validation 714 May 2014
  • 14 May 2014 Evaluating EMA and FDA guidance on bioanalytical method validation 8
  • let us try to simplify the matter Evaluating EMA and FDA guidance on bioanalytical method validation 914 May 2014
  • and concentrate on EMA BMV (2011) Evaluating EMA and FDA guidance on bioanalytical method validation14 May 2014 10 Guideline on the validation of bioanalytical methods http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf Well written with a clear structure Clear distinction between method validation and sample analysis First BMV guideline addressing all the specifics for LBA/macromolecules Defines applicable quality systems: GLP (pre-clinical) and GCP (clinical) Good match with current thinking in BA community Good fit with EMA Bioequivalence guideline Fits with developing concepts on GCP for bioanalytical laboratories Well accepted within the global BA community Final & Current FDA is from 2001 + a challenged 2013 draft (not taking updates of CC-III & CC-IV into account) ANVISA is specific for Brazil MHLW is quite similar to EMA
  • Table of contents EMA BMV 1. Introduction 2. Scope 3. Legal basis 4. Method validation 4.1. Full validation of an analytical method o 4.1.1. Selectivity o 4.1.2. Carry-over o 4.1.3. Lower limit of quantification o 4.1.4. Calibration curve o 4.1.5. Accuracy o 4.1.6. Precision o 4.1.7. Dilution integrity o 4.1.8. Matrix effect o 4.1.9. Stability 4.2. Partial validation 4.3. Cross validation Evaluating EMA and FDA guidance on bioanalytical method validation14 May 2014 11
  • Table of contents (continued) 5. Analysis of study samples 5.1. Analytical run 5.2. Acceptance criteria of an analytical run 5.3. Calibration range 5.4. Reanalysis of study samples 5.5. Integration 6. Incurred samples reanalysis 7. Ligand binding assays 7.1. Method validation o 7.1.1. Full validation (multiple subchapters) 7.2. Partial validation and cross-validation 7.3. Analysis of study samples o 7.3.1. Analytical run o 7.3.2. Acceptance criteria for study sample analysis o 7.3.3. Incurred samples reanalysis 8. Reports 8.1. Validation report 8.2. Analytical report Definitions Evaluating EMA and FDA guidance on bioanalytical method validation14 May 2014 12
  • Method Validation Evaluating EMA and FDA guidance on bioanalytical method validation 1314 May 2014
  • Full Validation Evaluating EMA and FDA guidance on bioanalytical method validation 1414 May 2014 EMA: A full method validation should be performed for any analytical method whether new or based upon literature. Generally a full validation should be performed for each species and matrix concerned Validation should be performed using the same anticoagulant as for the study samples If problematic for validation purposes to obtain an identical matrix compared to the matrix of the study samples, a suitable alternative matrix may be used. The main characteristics of a bioanalytical method that are essential to ensure the acceptability of the performance and the reliability of analytical results are: selectivity, LLOQ, the response function and calibration curve performance, accuracy, precision, matrix effects, stability of the analyte(s) in the biological matrix and stability of the analyte(s) and of the IS in the stock and working solutions and in extracts under the entire period of storage and processing conditions. The principles of validation and analysis apply to all analytes of interest. Draft FDA: Less defined and seems to be more lenient, leaving judgment to scientists ANVISA: Less defined, but follows same principles. Requires chromatographic method for chromatographable analytes MHLW: Quite similar to EMA
  • Reference standards Evaluating EMA and FDA guidance on bioanalytical method validation 1514 May 2014 EMA: Suitable reference standards, include certified standards such as compendial standards (EPCRS, USP, WHO), commercially available standards, or sufficiently characterised standards prepared in-house or by an external non-commercial organisation. A certificate of analysis is required to ensure purity and provide information on storage conditions, expiration date and batch number. The use of certified standards is not needed for IS, as long as the suitability for use is demonstrated, e.g. lack of analytical interference is shown for the substance itself or any impurities thereof. A certificate of analysis is not required. Recommended to use stable isotope labeled IS for MS based assays However, it is essential that the labeled standard is of the highest isotope purity and that no isotope exchange reaction occurs. The presence of any unlabeled analyte should be checked and if relative amounts of unlabeled analyte are detected the potential influence has to be evaluated during method validation. Draft FDA: Similar to EMA, but requires expiration date and purity for IS. Stock solutions should not be used after powder expires. SILIS not mentioned ANVISA: Prefers pharmacopeia reference standards, recommends SILIS and has detailed requirements on CoA information MHLW: Similar to EMA, but less explicit
  • Selectivity Evaluating EMA and FDA guidance on bioanalytical method validation 1614 May 2014 EMA: Selectivity should be proved using at least 6 individual sources of the appropriate blank matrix Normally, absence of interfering components is accepted where the response is less than 20% of the LLOQ for the analyte and 5% for the IS. It may also be necessary to investigate the extent of any interference caused by metabolites of the drug(s), degradation products and possible co-administered medications. Co-medications normally used in the subject population studied which may potentially interfere should be taken into account at the stage of method validation, or on a study specific and compound specific base. The possibility of back-conversion of a metabolite into parent analyte during the successive steps of the analysis should also be evaluated, when relevant (i.e. potentially unstable met