“5th Japan Bioanalysis Forum (JBF) Symposium – 2014” March 06‐07, 2014 Organized by JBF, at Tower Hall, Finabori, Tokyo, Japan
“Current Status of Regulated Bioanalysis and Contribution of Indian Bioanalytical Community to Global Harmonization Efforts”
Manish S. Yadav [AVP & Head – CRO, Alkem Labs Ltd., Mumbai] [Chair Elect – Regulated Bioanalysis, APA‐India] 1
Outline – Understanding – Regulated bioanalysis (RegBio) – Progress – Regulated Bioanalysis – Reg.bio. and Indian bioanalytical community – Global harmonization efforts – contribution of Indian bioanalytical community
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Understanding – Regulated Bioanalysis • Regulated bioanalysis (RegBio) comprises off two vital components – Basic Science – Regulatory considerations “Quality” is the focal point on both the fronts
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Progress – Regulated bioanalysis • Rapid progress and Dynamism predominately witnessed by last 2 decades • Scientific Advancement – on the go – Better scientific clarity (published literature) – Extended Experimentation for Quality & Reliability – Understanding of allied sciences e.g. clinical & Formulation
• Regulatory Advancement – Findings/Observations – 483s, Warning letters (e.g. Failures, ISR) – Leads to Transformation in regulations – Issue of New BMV Guidance – EMEA, 2011; ANVISA, 2012 & USFDA, 2013
• Good Quality Practices – GxP (GCP, GLP, GMP & GDP etc.) 4
Progress – Regulated Bioanalysis • From Regulatory front: Advancement and Progress of Bioanalysis can be divided in to 3 Era: (predominately witnessed by last two decades)
– Pre‐regulations Era – Post regulations Era – Dynamic Era
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Progress – Regulated Bioanalysis • Pre‐regulations Era – Distinguished by developments prior to 1990s i.e. AAPS/FDA workshops & reports – No mandatory guidelines available for the conduct of bioanalysis – Often sponsors used to enforce their own set of acceptance criteria for BMV (the basic BMV parameters e.g. sensitivity, accuracy and precision as required by US 21 CFR 320.29)
• Post‐regulations Era – Distinguished with series of CC Workshops organized by AAPS & FDA (1990 to 2000) – Created base for the release of first regulatory guidance‐US FDA guidance, May 2001 – The bioanalytical community equipped with industry standard for BMV
• Dynamic Era – Distinguished with series of workshops/Conferences e.g. CC Workshops, AAPS‐UFDA; WRIB, CVG‐Canada and EBF‐EU; after 2000 – Created base to release Various White papers – Release of the revised‐latest guidance: ANVISA‐2011; EMEA‐2012 & US FDA‐2013 6
Era of Bioanalysis – at a glance Parameters
Pre-regulations Era (prior 2000)
Post-Regulations Era (2000-2006)
Dynamic Era (2006 onwards)
Knowledge of Bioanalysis
Good
Very Good
Excellent
Evaluation of BMV
Based on Scientific Common Based on USFDA BMV Sense & Sponsor driven Guidance, in a robotic way
Learning phase Bioanalytical Science Almost, No understanding Allied Sciences Dominated by HPLC-UV Instrumentation Automation (Softwares, e-data, None (integraters, char recorders etc.) extractions, Reports) Extremely high Sponsor's Interventions Not available Bioanalytical research articles Not available White Papers Not available BMV Guidance Few Regulatory inspections Regulatory Focus
BMV & Bioanalysis. Documentation.
Bioanalytical Experts
Rare
Good Understanding Learning phase Dominated by HPLC-MS/MS Introduced and used vastly Low Available (JCB, RCM, AAPS) Few available USFDA, ANVISA, Canada Good no. of inspections BMV & Bioanalysis. Documentation. Doer’s Approach, Latest conceptsME, System suit. analytical batch, Failures, Outliers etc. Available
Based on USFDA guidance, white papers and science. Excellent Understanding understood, and still learning Dominated by HPLC-MS/MS Integrated part of Bioanalysis i.e. Sample-prep., Data-transfer & Reports
very low in science & regulations Plenty (AAPS, JPBA, Bioanalysis) Plenty (AAPS, CVG, APA, EBF) EMEA,USFDA,ANVISA, Regional High no. of inspections BMD, BMV & Bioanalysis & Postbioanalysis phase. Documentation. Doer’s Approach. Latest conceptsME, ISR, IS-variation, PK Repeats, investigations & Outliers etc. Plenty 7
Reg.Bio. and Indian Bioanalytical Community • Pre‐regulations Era (prior to 2000) Learnt best industry practices Followed ‘Gold Standard’ and international practices for bioanalysis Keenly understand and followed White papers of CC workshop & Shah et al Devised ‘Quality Systems’ and ‘SOPs’ based on best bioanalytical practices and sponsor’s scientifically sound and practically applicable recommendations – Religiously, implemented best practices to practical acquired through white papers, Literature and western colleagues – Generated more than the required data, but not less – – – –
• e.g. Long‐term stability data generated by comparing against freshly‐prepared and 1st day QC samples
– Learning of Era: Scientific Common sense to understand, select and implement best bioanalytical practices
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Reg.Bio. and Indian Bioanalytical Community • Post‐regulations Era (2000‐2006) – Era was distinguished with series of: • • •
CC Workshops, AAPS‐US FDA and subsequent White papers Excellent research articles – Matrix effect , simultaneous estimations e.g. inter‐conversion etc. Good technological advancement – instrumentation, chemistry and automation (Security & IT)
– Focal point of Bioanalytical science: • •
Understanding of Matrix Effect and Post column infusion for HPLC‐MS/MS based assays Extent of experimentation and proof for BMV
– Regulatory outcomes: • •
Dominated by 483s and critical findings. Repeated observations on scientific and regulatory understanding Precision & Accuracy (P&A) batches, Analytical batches, outliers and analytical batch failures and Repeat Analysis (analytical & PK) etc.
– Bioanalytical practices were devised out of learning through • • •
Conference/Workshop Reports or White Papers Research Articles – BMV, Matrix Effect, Biotransformation and stability issues & investigations etc. Regulatory outcomes
– Learning of Era: Scientific and Regulatory common sense to understand, select and implement best bioanalytical practices 9
Reg.bio. and Indian Bioanalytical Community • Dynamic Era (2006 onwards) – Era was distinguished with series of: • • •
CC Workshops, AAPS‐US FDA; WRIB, CVG‐Canada; and EBF, EU etc. and Subsequent White papers Excellent research articles – ME, Simultaneous estimations, LTS & whole blood stability issues, Carryover issues, Failure investigations and ISR issues etc. Great technological advancement – instrumentation, chemistry and automation (Security & IT)
– Focal point of Bioanalytical science: • • •
Understanding of impact of endogenous (plasma components) and exogenous (formulation excipients) components on the performance of HPLC‐MS/MS based assays Controlling analytical variations – elimination of ME, use of SIL‐IS and appropriate training levels Extent of experimentation and proof for BMV and BMD as well
– Regulatory outcomes: • •
Dominated by 483s and critical findings via for cause audits Repeated observations on scientific and regulatory understanding of ISR, Analytical batch design & failures, incomplete investigations, stability issues, IS variations and selective PK & analytical repeats etc.
– Bioanalytical practices were devised out of learning through • • •
Various Conference/Workshop Reports/White Papers. AAPS, JCB, RCM, JPBA and Bioanalysis papers Research Articles on Biotransformation, stability issues, ISTD variations, investigations , analytical batch & ISR failures, Repeat analysis and understanding of allied sciences & bioanalytical method standardization Regulatory outcomes
– Learning of Era: Scientific , Quality and Regulatory common sense to understand, select and implement best bioanalytical practices while taking care of efficiency of bioanalytical assays 10
Global Harmonization Efforts – Contribution of INDIA •
Dr. Srinivas Savale, Torrent Research, Ahmedabad – Organizing Committee Member, RegBio, APA‐INDIA – Steering Committee Member, GBC
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Mr. Puran Singhal, Alkem Labs, Mumbai – GBC Representative, India – HT Member – A2 and A7
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Manish S. Yadav, Alkem Labs, Mumbai – Chair Elect & Organizing Committee Member, RegBio, APA‐INDIA. – Harmonization Team (HT) Member – A1, A6 & A9
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Other GBC contributing bioanalytical scientists – Jignesh Kotecha (A10), Jignesh Bhatt (A7), Srinivas Reddy (A8), Ravi Sankar (S1, S3), Mahesh Kumar (A3, L3), Ravi K Trivedi (L1, S2, S3), Subramanium Ramchandran (A5), Arumugam Muruganandam (L2) and Madhan Kumar Rose (L6)
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APA‐INDIA – Chair, Chair‐Elect and Organizing Committee Members – 20+ Bioanalytical experts
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ACKNOWLEDGEMENT My Sincere Gratitude to; Organizers – Dr. Shinobu Kudoh, JBF, Japan APA-INDIA Management & Scientists – CRO, Alkem Labs Bioanalytical Scientists, India My Well Wishers, Known & Unknown as well!
Thanks Manish S. Yadav [AVP & Head – CRO, Alkem Labs Ltd., Mumbai] [Chair Elect – Regulated Bioanalysis, APA‐India]
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References •
Buick AR, Doig MV, Jeal SC, Land GS, McDowall RD. Method validation in the bioanalytical laboratory. J Pharm Biomed Anal. 8, 629‐37 (1990).
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Shah VP, Midha KK, Dighe S, McGilveray IJ, Skelly JP, Yacobi A, Layloff T, Vishwanathan CT, Cook CE, McDowall RD, Pittman KA, Spector S. Analytical methods validation: bioavailability, bioequivalence, and pharmacokinetic studies. Pharm. Res. 9, 588‐592 (1992).
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Shah VP, Midha KK, Findlay JW, Hill HM, Hulse JD, McGilveray IJ, McKay G, Miller KJ, Patnaik RN, Powell ML, Tonelli A, Viswanathan CT, Yacobi A. Bioanalytical method validation‐ a revisit with a decade of progress. Pharm. Res. 17, 1551‐1557 (2000).
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US FDA. Guidance for industry bioanalytical method validation. US Department of Health and Human Services, FDA Centre for Drug Evaluation and Research, MD, USA (2001).
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European Medicines Agency, Committee for Medicinal Products for Human Use, Guidelines on Validation of Bioanalytical Methods (draft), EMA/CMP/EWP/ 192217/ 2011. www.ema.europa.eu/ema
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ANVISA, Brazilian Health Surveillance Agency, Brazil, 2012. portal.anvisa.gov.br
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US FDA. Draft guidance for industry bioanalytical method validation. US Department of Health and Human Services, FDA Centre for Drug Evaluation and Research, MD, USA, 2013. www.fda.gov 13
