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Chen M.-L.,U.S. Food and Drug Administration | Shah V.P.,International Pharmaceutical Federation FIP | Crommelin D.J.,Utrecht Institute for Pharmaceutical science | Shargel L.,Applied Biopharmaceutics LLC | And 14 more authors.
AAPS Journal | Year: 2011

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products. © 2011 American Association of Pharmaceutical Scientists.


Chen M.-L.,U.S. Food and Drug Administration | Shah V.P.,International Pharmaceutical Federation FIP | Crommelin D.J.,Utrecht Institute for Pharmaceutical science | Shargel L.,Applied Biopharmaceutics LLC | And 12 more authors.
European Journal of Pharmaceutical Sciences | Year: 2011

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products. © 2011 Elsevier B.V. All rights reserved.


Musuku A.,Pharmascience Inc. | Tan A.,BioPharma Services Inc. | Awaiye K.,BioPharma Services Inc. | Trabelsi F.,BioPharma Services Inc.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2013

Linear calibration is usually performed using eight to ten calibration concentration levels in regulated LC-MS bioanalysis because a minimum of six are specified in regulatory guidelines. However, we have previously reported that two-concentration linear calibration is as reliable as or even better than using multiple concentrations. The purpose of this research is to compare two-concentration with multiple-concentration linear calibration through retrospective data analysis of multiple bioanalytical projects that were conducted in an independent regulated bioanalytical laboratory. A total of 12 bioanalytical projects were randomly selected: two validations and two studies for each of the three most commonly used types of sample extraction methods (protein precipitation, liquid-liquid extraction, solid-phase extraction). When the existing data were retrospectively linearly regressed using only the lowest and the highest concentration levels, no extra batch failure/QC rejection was observed and the differences in accuracy and precision between the original multi-concentration regression and the new two-concentration linear regression are negligible. Specifically, the differences in overall mean apparent bias (square root of mean individual bias squares) are within the ranges of -0.3% to 0.7% and 0.1-0.7% for the validations and studies, respectively. The differences in mean QC concentrations are within the ranges of -0.6% to 1.8% and -0.8% to 2.5% for the validations and studies, respectively. The differences in %CV are within the ranges of -0.7% to 0.9% and -0.3% to 0.6% for the validations and studies, respectively. The average differences in study sample concentrations are within the range of -0.8% to 2.3%. With two-concentration linear regression, an average of 13% of time and cost could have been saved for each batch together with 53% of saving in the lead-in for each project (the preparation of working standard solutions, spiking, and aliquoting). Furthermore, examples are given as how to evaluate the linearity over the entire concentration range when only two concentration levels are used for linear regression. To conclude, two-concentration linear regression is accurate and robust enough for routine use in regulated LC-MS bioanalysis and it significantly saves time and cost as well. © 2013 Elsevier B.V.


Tan A.,BioPharma Services Inc. | Saffaj T.,University Sidi Mohammed Ben Abdellah | Musuku A.,Pharmascience Inc. | Awaiye K.,BioPharma Services Inc. | And 4 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2015

The current approach in regulated LC-MS bioanalysis, which evaluates the precision and trueness of an assay separately, has long been criticized for inadequate balancing of lab-customer risks. Accordingly, different total error approaches have been proposed. The aims of this research were to evaluate the aforementioned risks in reality and the difference among four common total error approaches (β-expectation, β-content, uncertainty, and risk profile) through retrospective analysis of regulated LC-MS projects. Twenty-eight projects (14 validations and 14 productions) were randomly selected from two GLP bioanalytical laboratories, which represent a wide variety of assays. The results show that the risk of accepting unacceptable batches did exist with the current approach (9% and 4% of the evaluated QC levels failed for validation and production, respectively). The fact that the risk was not wide-spread was only because the precision and bias of modern LC-MS assays are usually much better than the minimum regulatory requirements. Despite minor differences in magnitude, very similar accuracy profiles and/or conclusions were obtained from the four different total error approaches. High correlation was even observed in the width of bias intervals. For example, the mean width of SFSTP's β-expectation is 1.10-fold (CV. = 7.6%) of that of Saffaj-Ihssane's uncertainty approach, while the latter is 1.13-fold (CV. = 6.0%) of that of Hoffman-Kringle's β-content approach. To conclude, the risk of accepting unacceptable batches was real with the current approach, suggesting that total error approaches should be used instead. Moreover, any of the four total error approaches may be used because of their overall similarity. Lastly, the difficulties/obstacles associated with the application of total error approaches in routine analysis and their desirable future improvements are discussed. © 2015 Elsevier B.V.


Tan A.,BioPharma Services Inc. | Awaiye K.,BioPharma Services Inc. | Trabelsi F.,BioPharma Services Inc.
Bioanalysis | Year: 2014

The global bioanalytical community increasingly craves scientifically sound practices and guidance where the rationale is given for each requirement. To this end, it is critical to first evaluate all the existing practices and requirements based on scientific findings and critical thinking. Here we are challenging several important common practices in regulated LC-MS bioanalysis, from the requirement of at least six different calibration concentrations, no extrapolation, use of blank and zero standard in each batch, selection of quality controls, to the way matrix effect and dilution integrity are being validated. Both the reasons why these common practices are unnecessary or inadequate and the potential solutions are presented. © 2014 Future Science Ltd.

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