All for one, one for all - The Chinese BMV guidance in perspective to other guidelines
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The presentation discusses the evolution and harmonization of bioanalytical method validation guidance documents from various regulatory agencies around the world. It finds that the EMA, MHLW, and CFDA guidelines are very similar in structure and content, and can be considered the "Eurasian standard" for bioanalytical method validation. Several other regions reference or are aligned with this standard. While guidelines from regions like the Americas have some additional local requirements, the overall principles are essentially the same. The presentation concludes that further harmonization on detailed requirements may not be necessary if new or revised guidelines follow the main principles of the "Eurasian standard".
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All for one, one for all - The Chinese BMV guidance in perspective to other guidelines
- 1. Peter van Amsterdam Head Bioanalytics, Abbott Established Pharmaceuticals Division CPSA Shanghai, 17 Apr 2015, Shanghai
- 2. 17-Apr-2015 All for one, one for all 2 The views and conclusions presented in this slide deck are those of the author/presenter and do not necessarily reflect the representative affiliation or company's position on the subject. The focus is on the small molecules / chromatographic assays realm of the bioanalytical world. The works of the Alexandre Dumas are freely used as a metaphor to depict developments and illustrate differences and similarities between guidance documents.
- 3. 1802-1870 1844 17-Apr-2015 All for one, one for all 3
- 4. 17-Apr-2015 All for one, one for all 4 1921 and many many more 2011
- 5. 17-Apr-2015 All for one, one for all 5 The evolution of Regulated Bioanalysis
- 6. 17-Apr-2015 All for one, one for all 6 20201960 1970 1980 1990 2000 2010 TLC, GC (LC-UV) immunoassays Sub μg/mL GC2, GC-MS GC-NPD/ECD HPLC-UV/FL/EC immunoassays ng/mL TLC Immunoassays bioassays μg/mL GC2, GC-MS, GC- NPD/ECD HPLC-UV/FL/EC, LC-MS/MS, Old school Immunoassays Sub ng/mL LC-MS/MS, New generation Binding assays AMS ICP-MS pg/mL New generation LC and MS(/MS) and Binding assays Sub pg/mL? Sensitivity doubles every 2 years (Peter’s law of bioanalysis) Adapted from Philip Timmerman, “Regulated Bioanalysis: A Proposed Global Harmonization Process” ”2nd JBF, Tokyo, 2012
- 7. A tremendous increase of sample analysis power over the last 50 years. Same technology is (more or less) available around the globe and applied with (more or less) the same level of quality and success. But what happened in the regulatory field? 17-Apr-2015 All for one, one for all 7
- 8. 1990s & 2000s: The AAPS / FDA story 17-Apr-2015 All for one, one for all 8
- 9. 17-Apr-2015 All for one, one for all 9 Crystal City I Shah 2001 FDA Guidance CC-I CC-II CC-III Crystal City Conferences Conference papers Additional white papers Regulatory Guidance CC-IV (ISR) CC-IV Fast 1990 2000 2010 CC III Viswanathan CC II Shah (chrom.) Miller (LBA) DeSilva Adapted from Philip Timmerman, “Regulated Bioanalysis: A Proposed Global Harmonization Process” ”2nd JBF, Tokyo, 2012
- 10. US (AAPS / FDA) to lead the way Conference report Crystal City I became THE reference point for many bioanalytical scientists and was basically used as ‘Guidance’ FDA 2001 BMV Guidance substantiated the influence of the CC-I BMV concept in the bioanalytical world Further fine-tuning of the BMV concept and interpretation of the FDA guidance in CC-III and CC-IV 17-Apr-2015 All for one, one for all 10
- 11. 2008 EMA concept paper on BMV 2009 EMA draft BMV guideline 2011 EMA final BMV guideline 2010 GBC founded 17-Apr-2015 All for one, one for all 11
- 12. 17-Apr-2015 All for one, one for all 12 2001 FDA Guidance for Industry: Bioanalytical Method Validation 2002 ANVISA Manual for Good Bioavailability and Bioequivalence Practices. Module 2: Analytical Step 2003 ANVISA Resolução - RDC Nº 899: Guide for Validation of Analytical and Bioanalytical Methods 2004 ANMAT Normativa Aplicable a la Etapa Analítica Para la Realizacion de Estudios de Biodisponibilidad - Bioequivalencia 2011 EMA Guideline on Bioanalytical Method Validation 2012 ANVISA Resolução - RDC Nº 27: Dispõe sobre os requisitos mínimos para a validação de métodos bioanalíticos empregados em estudos com fins de registro e pós-registro de medicamentos. 2013 ANMAT Normativa de Buenas Practicas de Laboratorio Aplicable a Los Centros Bioanalíticos Para Estudios de Biodisponibilidad I Bioequivalencia MHLW Guideline on Bioanalytical Method Validation in Pharmaceutical Development FDA DRAFT Guidance for Industry: Bioanalytical Method Validation 2014 MHLW Guideline on Bioanalytical Method (Ligand Binding Assay) Validation in Pharmaceutical Development CFDA (PhC) DRAFT Guidance on Bioanalytical Method Validation
- 13. Can we get the genie back in the bottle? What can e.g. GBC do? Is there benefit in having a guidance document from an international organization (ICH, WHO, OECD, …) Is there really a problem? What do we want to achieve? o Harmonization on a detailed level? o Alignment on main principles? 17-Apr-2015 All for one, one for all 13
- 14. Global Guidance on Bioanalytical Method Validation 17-Apr-2015 All for one, one for all 14
- 15. 17-Apr-2015 All for one, one for all 15 Selectivity Matrix effect EMA 6 sources, no pools < 20% at LLOQ, < 5% for IS Attention to: co-medications and metabolites 6 sources, no pools Calc. MF and IS norm MF, CV IS norm MF < 15% Attention to excipients and special populations In addition: hemolyzed & lipemic FDA, Draft 2013 Same principle as EMA, but no specifics given Open (=judgment of scientists) ANVISA 6 sources, no pools < 20% at LLOQ, < 5% for IS NO Attention to: co-med and metabolites Required: hemolyzed & lipemic 8 sources: 4 normal, 2 lipemic, 2 hemolyzed, no pools Calc. MF CV MF < 15% NO Attention to excipients and special populations MHLW 6 sources, no pools < 20% at LLOQ, < 5% for IS NO Attention to: co-medications and metabolites 6 sources, no pools Calc. MF CV MF < 15% NO Attention to excipients and special populations NO: hemolyzed & lipemic CFDA 6 sources, no pools < 20% at LLOQ, < 5% for IS NO Attention to: co-medications and metabolites 6 sources, no pools Calc. MF and IS norm MF, CV IS norm MF < 15% NO Attention to excipients and special populations In addition: hemolyzed & lipemic
- 16. Aspect Overlaps … but … Full validation ANVISA, CFDA, FDA*), MHLW Reference standards CFDA, MHLW ANVISA: CoA information FDA*): extra requirements Selectivity CFDA, MHLW, FDA*) ANVISA: Lipemic & hemolyzed Carry-over CFDA, FDA*), MHLW ANVISA: experimental set-up LLOQ All Note: BE requirement EMA Calibration curve CFDA, MHLW ANVISA: weighting and non-linear models FDA*): exclusion of calibrators Accuracy & Precision CFDA, MHLW ANVISA: add 5th QC = dilution QC FDA*): outliers & QCs match sample conc. Dilution integrity ANVISA, CFDA, FDA*), MHLW Note: ANVISA: dilution is part of A & P Matrix effect CFDA, FDA*), MHLW ANVISA: 2x lipemic & hemolyzed MHLW: CV_MF < 15% All for one, one for all 16 17-Apr-2015 Taking EMA as reference……
- 17. Aspect Overlaps … but … Stability CFDA ANVISA & MHLW: triplicate FDA*) also IS stock stab & injection repro. Recovery ANVISA, CFDA FDA*) & MHLW: recovery chapter Endogenous analyte CFDA, MHLW ANVISA & FDA*): endogenous analytes chapter Partial validation All Note: species change within a matrix or matrix change within a species may require a full validation (EMA) Cross validation All Note: MHLW accepts 20% difference Reporting ANVISA, CFDA, MHLW FDA*) recommendations All for one, one for all 17 17-Apr-2015 Taking EMA as reference…… *) 2013 draft
- 18. Aspect Overlaps … but … Analytical run All Acceptance criteria All Calibration range All Reanalysis of study samples All Note: EMA requirement with respect to patient safety FDA*): specific no. of replicates Reintegration All FDA*): original & reintegration data Incurred sample reanalysis ANVISA, CFDA, MHLW FDA*): 7% System suitability ANVISA, CFDA FDA*) & MHLW requirements Reporting ‘All’ Note: some detailed req. All for one, one for all 18 17-Apr-2015 Taking EMA as reference…… *) 2013 draft
- 19. INTERIM CONCLUSIONS EMA and CFDA (PhC) are very similar MHLW is quite similar to EMA & CFDA, but some differences on detailed level exist US FDA draft, although essentially similar, has a number of requirements different to ANVISA, CFDA, EMA, MHLW ANVISA, although essentially similar, has a number of requirements different to CFDA, EMA, FDA draft, MHLW AND THUS ….. 17-Apr-2015 All for one, one for all 19
- 20. 17-Apr-2015 All for one, one for all 20 EMA, MHLW and CFDA (PhC) are very similar in set-up and content
- 21. ‘Yes’ Australia: refers to EMA BE & BMV and FDA BMV Canada: specifically refers to EMA BMV ‘Maybe’ India: general chapter in BE guideline. ASEAN: chapter in BE guideline, refers to OECD GLP Gulf States: chapter in BE guideline, clearly inspired by EMA ‘Not yet’ Brazil: same principles as others BMVs, but a lot of specific requirements Argentina: general ‘Good Analytical Procedures’ + general principles of BMV 17-Apr-2015 All for one, one for all 21
- 22. Can we get the genie back in the bottle? No What can e.g. GBC do? o Add main BMV principles to existing/new ‘global’ quality documents? o Prepare/publish the ‘global BMV white paper’? Is their benefit in having a guidance document from an international organization (ICH, WHO, OECD, …) o Yes, but may take long and added value is perhaps limited Is there really a problem? o Maybe not. Not if new or revised guidelines follow the ‘Eurasian standard’ What do we want to achieve? o Harmonization on a detailed level? Would be nice, but not an issue if there is mutual acceptance for global studies/filings o Alignment on main principles? This we already have 17-Apr-2015 All for one, one for all 22
- 23. CONCLUSIONS CFDA (PhC), EMA and MHLW guidelines show great similarity in set-up and contents. (each of) These three guidelines can be considered as the ‘Eurasian Standard’ for BMV A number of other countries/regions are already or may likely follow this standard Guidelines of ‘The Americas’, although essentially similar, have a number of local requirements different to the ‘Eurasian Standard’ 17-Apr-2015 All for one, one for all 23
- 24. CPSA-Shanghai for giving me the opportunity to present at their meeting. EBF members and Steering Committee for the learning experiences. The GBC Founding & Steering Committee members and Harmonization Team leads for the learning experiences The regulators and inspectors for stimulating us to continuously improve our work You, for your attention and Alexandre Dumas for his inspiring novels All for one, one for all 17-Apr-201524
- 25. 17-Apr-2015 All for one, one for all 25
- 26. 17-Apr-2015All for one, one for all 26
- 27. 1963 FDA drafting the GMP concept 1964 Declaration of Helsinki 1973 New Zealand draft GLP concept 1978 FDA GLP final 1978 FDA GMP final 1981 OECD GLP 1982 MHLW GLP 1983 EPA GLP 1989 Revised EPA GLP 1989 ICH global standards for Clinical Research 1997 21 CFR 11 1997 Revised OECD GLP 1997 ICH GCP 2001 EU Clinical Trials directive 2005 EU GCP directive 2009 MHRA GCP for laboratories 2009 WHO GCLP 2012 EMA 'GCLP' reflection paper 17-Apr-2015 All for one, one for all 27 Hmmm…. GCP some 20 yrs later than GLP and GCLP 30 yrs later ?