Current Trends in GLP-like Analysis

Transcription

1 Current Trends in GLP-like Analysis CORESTA Biomarker Sub-Group Kirk Newland - Celerion

2 Sources of Insight into Regulatory Requirements Guidance Harmonization Recent published discussions between the FDA, EMEA and other regulatory bodies have provided an opportunity to better understand newer requirements for bioanalytical submissions White Papers A rapid expansion of discussion groups have given regulators an opportunity to make suggestions regarding best practices and to hear industry feedback on concerns Trends in Bioanalytical 483 Documents Companies such as Pharmaceutical Outsource Solutions data mine regulatory observations from redacted 483 documents giving the opportunity to observe trends

3 Topics of Discussion Reference Standard Characterization Identity and Purity Bridging Experiments Method Selectivity / Matrix Effect Testing Metabolites 5,000 Concomitant Analytes in Tobacco? Hemolytic and Lipemic Samples Incurred Sample Analysis How many are enough and how should they be selected? ISR analysis as a part of method validation What are ISR investigations uncovering?

4 Reference Standards The FDA has clearly stated that it is the responsibility of the CRO to scientifically justify the applicability for use of each reference material. Best practices, as seen with Cerilliant and Chemtos, include proton NMR and MS for identification, HPLC chromatographic purity, and micro-kf for water content. While less concern has been given to the characterization of stable-isotope labelled standards, short-term stability concerns have been noted in 483 documents.

5 Method Selectivity / Matrix Effect Testing Metabolite analysis primarily a concern with Nicotine and TSNAs As pharmacokinetic evaluations are observed with nicotine in blood matrix, it is expected that plasma assay validation data demonstrate sufficient selectivity in the presence of high concentration metabolites. In the presence of low concentration target analytes, high concentration metabolite concentrations should be supplemented to ensure conversion during collection, sample extraction, and detection does not occur.

6 Method Selectivity / Matrix Effect Testing cont. Recently additional requirements regarding medications allowed during studies has been noted. Stability testing in the presence of con-meds should be evaluated. While this is clearly not possible for all tobacco constituents, it is common practice to include selectivity testing of an OTC cocktail when evaluating assay selectivity Evaluation of the impact of sample hemolysis and lipemia is now expected for assays of blood matrices.

7 Incurred Sample Analysis How many ISRs? It is the practice of Celerion to analyze 10% for the first 1000 samples of a study and 5% thereafter. Evaluation of this practice by the FDA has met acceptance. The FDA has recently cited a laboratory for the analysis of insufficient ISR samples, indicating that only 7.8% had been analyzed. It is assumed the study had less than 1000 samples. Incurred Sample Analysis is considered the final step in method validation. As test samples from tobacco users are readily available, some ISR analysis should occur within method validation. The inclusion of incurred sample analysis, and the evaluation of incurred sample pools of higher and lower concentrations during stability evaluations provides great strength to the initial method validation data as many of the concomitant medication concerns may be addressed at an earlier time.

8 Incurred Sample Analysis cont. Investigation of failed ISR testing has found the following common root causes Analyte stability Failure to bridge reference standard materials / stocks / standards Metabolite conversion or selectivity concerns Analytical technique failure in the laboratory (i.e. dilution error or performance variability) While the original intent was to demonstrate consistent method performance, failure due to assay variability has infrequently been observed.

9 References Guidance for Industry Bioanalytical Method Validation, 2001 EMA Draft Guideline 2009 Quarterly reports on 483 documents Pharmaceutical Outsource Solutions, Inc White Paper on Recent Issues in Bioanalysis The Calibration and Validation Group, Bioanalysis (2010) 2(1), Workshop/Conference Report Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays, The AAPS Journal 2007 Critical topics in ensuring data quality in bioanalytical LC-MS method development, Bioanalysis (2010) 2(6),

10 Thank you for your time! Questions or Thoughts?