C. T. Viswanathan

Bioanalytical Method Validation—A Revisit with a Decade of Progress

This report is a synthesis of (1) the earlier conference on Analytical Methods Validation−Bioavailability, Bioequivalence and Pharmacokinetic Studies (Conference held in Arlington, VA, December 3–5, 1990 and the report published in Pharmaceutical Research, 9: 588-592, 1992) and (2) the workshop on “Bioanalytical Methods Validation—A Revisit with a Decade of Progress,” (Workshop held in Arlington, VA, January 12–14, 2000), sponsored by the American Association of Pharmaceutical Scientists and the U. S. Food and Drug Administration. The bioanalytical method validation workshop of January 12–14, 2000 was directed towards small molecules. A separate workshop was held in March 1–3, 2000 to discuss validation principles for macromolecules. The purpose of this report is to represent the progress in analytical methodologies over the last decade and assessment of the major agreements and issues discussed with regard to small molecules at both the conference and the workshop. The report is also intended to provide guiding principles for validation of bioanalytical methods employed in support of bioavailability, bioequivalence, and pharmacokinetic studies in man and in animals.

Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays

AbstractThe Third AAPS/FDA Bioanalytical Workshop, entitled “Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays” was held on May 1–3, 2006 in Arlington, VA. The format of this workshop consisted of presentations on bioanalytical topics, followed by discussion sessions where these topics could be debated, with the goal of reaching consensus, or identifying subjects where addition input or clarification was required. The discussion also addressed bioanalytical validation requirements of regulatory agencies, with the purpose of clarifying expectations for regulatory submissions. The proceedings from each day were reviewed and summarized in the evening sessions among the speakers and moderators of the day. The consensus summary was presented back to the workshop on the last day and was further debated. This communication represents the distillate of the workshop proceedings and provides the summary of consensus reached and also contains the validation topics where no consensus was reached.ConclusionFor quantitative bioanalytical method validation procedure and requirements, there was a relatively good agreement between chromatographic assays and ligand-binding assays. It was realized that the quantitative and qualitative aspects of bioanalytical method validation should be reviewed and applied appropriately.1.Some of the major concerns between the 2 methodologies related to the acceptable total error for precision and accuracy determination and acceptance criteria for an analytical run. The acceptable total error for precision and accuracy for both the methodologies is less than 30. The 4–6–15 rule for accepting an analytical run by a chromatographic method remained acceptable while a 4–6–20 rule was recommended for ligand-binding methodology.2.The 3rd AAPS/FDA Bioanalytical Workshop clarified the issues related to placement of QC samples, determination of matrix effect, stability considerations, use of internal standards, and system suitability tests.3.There was a major concern and issues raised with respect to stability and reproducibility of incurred samples. This should be addressed for all analytical methods employed. It was left to the investigators to use their scientific judgment to address the issue.4.In general, the 3rd AAPS/FDA Bioanalytical Workshop provided a forum to discuss and clarify regulatory concerns regarding bioanalytical method validation issues.

Analytical methods validation: Bioavailability, bioequivalence and pharmacokinetic studies: Sponsored by the American Association of Pharmaceutical Chemists, U.S. Food and Drug Administration, Fédération Internationale Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists

Abstract This is a summary report of the conference on ‘Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies.’ The conference was held from December 3 to 5, 1990, in the Washington, DC area and was sponsored by the American Association of Pharmaceutical Scientists, U.S. Food and Drug Administration, Federation Internationale Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists. The purpose of the report is to represent our assessment of the major agreements and issues discussed at the conference. This report is also intended to provide guiding principles for validation of analytical methods employed in bioavailability, bioequivalence and pharmacokinetic studies in man and animals. The objectives of the conference were: (1) to reach a consensus on what should be required in analytical methods validation and the procedures to establish validation; (2) to determine processes of application of the validation procedures in the bioavailability, bioequivalence and pharmacokinetic studies; and (3) to develop a report on analytical methods validation (which may be referred to in developing future formal guidelines). Acceptable standards for documenting and validating analytical methods with regard to processes, parameters or data treatments were discussed because of their importance in assessment of pharmacokinetic. bioavailability, and bioequivalence studies. Other topics which were considered essential in the conduct of pharmacokinetic studies or in establishing bioequivalency criteria, including measurement of drug metabolites and stereoselectivc determinations, were also deliberated.

Opportunities for Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development

Carl C. Peck, MD, William H. Barr, PharmD, PhD, Leslie Z. Benet, PhD, Jerry Collins, PhD, Robert E. Desjardins, MD, Daniel E. Furst, MD, John G. Harter, MD, Gerhard Levy, PharmD, Thomas Ludden, PhD, John H. Rodman, PharmD, Lilly Sanathanan, PhD, Jerome J. Schentag, Pharmfl, Vinod P. Shah, PhD, Lewis B. Sheiner, MD, Jerome P. Skelly, PhD, Donald R. Stanski, MD, Robert J. Temple, MD, C. T. Viswanathan, PhD, Judi Weissinger, PhD, and Avraham Yacobi, PhD

Opportunities for integration of pharmacokinetics, pharmacodynamics and toxicokinetics in rational drug development: Sponsored by the American Association of Pharmaceutical Scientists, U.S. Food and Drug Administration and American Society for Clinical Pharmacology and Therapeutics

Abstract This report derives from the conference on ‘The Integration of Pharmacokinetic, Pharmacodynamic and Toxicokinetic Principles in Rational Drug Development,’ held on April 24–26, 1991 in Arlington, VA. The conference was sponsored by the American Association of Pharmaceutical Scientists, U.S. Food and Drug Administration and American Society for Clinical Pharmacology and Therapeutics. The objectives of the conference were: (1) To identify the roles and the interrelationships between pharmacokinetics (PK), pharmacodynamics (PD) and toxicokinetics (TK) in the drug development process. (2) To evolve strategies for the effective application of the principles of pharmacokinetics, pharmacodynamics and toxicokinetics in drug development, including early clinical trials. (3) To prepare a report on the use of pharmacokinetics and pharmacodynamics in rational drug development as a basis for the development of future regulatory guidelines.