Abstract
Nonclinical safety studies are required to follow applicable Good Laboratory Practice (GLP) regulations. Nonclinical dose formulations are required to be analyzed to confirm the analyte concentration, homogeneity, and stability. Analytical samples that fall outside of the acceptance criteria are considered out of specification (OOS), and an investigation should be conducted. The US FDA has issued a guidance document for GMP studies on conducting OOS investigations. However, no regulatory guidance has been issued regarding nonclinical safety study (GLP) OOS investigations, which often vary in regard to content, assessment, and impact statements. There is opportunity to improve the quality of OOS investigations by defining expectations and providing guidance in several areas including root cause assessment, impact statements, and acceptable paths forward. This paper will provide recommendations of best practices for nonclinical dose formulation OOS investigations.
Highlights
Nonclinical studies intended to support applications for research or marketing permits are required to follow applicable federal regulations as specified in 21 CFR, Part 58
Recommended specifications according to the AAPS white paper for “Nonclinical dose formulation analysis method validation and sample analysis” are 100±10 % recovery with ≤10 % relative standard deviation (RSD) for solutions, 100± 15 % recovery with ≤10 % RSD for suspensions, and 100±20 % recovery with ≤20 % RSD for solids [4]
This article is published with open access at Springerlink.com including the responsibility of the analyst and the laboratory supervisor, as well as the investigation of out of specification (OOS) test results, including review of production, additional laboratory testing, reporting testing results, and concluding the investigation. This Good Manufacturing Practices (GMP) guidance is sometimes used as a basis for performing NCDFA-OOS investigations; it is not specific to nonclinical dose formulation sample test results
Summary
Nonclinical studies intended to support applications for research or marketing permits are required to follow applicable federal regulations as specified in 21 CFR, Part 58 Including the responsibility of the analyst and the laboratory supervisor, as well as the investigation of OOS test results, including review of production, additional laboratory testing, reporting testing results, and concluding the investigation This GMP guidance is sometimes used as a basis for performing NCDFA-OOS investigations; it is not specific to nonclinical dose formulation sample test results. A standard process for conducting an NCDFA-OOS investigation for nonclinical studies is proposed This includes the following steps: review of data and methods (analytical and formulation), assessment of OOS root cause, assessment of the impact to the study, and determination of the path forward. This may vary among companies in terms of specific responsibilities as defined by Standard Operating Procedures (SOPs); the process should be similar among companies This should include the analytical lab, the formulation lab, quality assurance, and the Study Director [7]. The Study Director is responsible for approving the conclusions of the investigation
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