Submitting Advanced Bioanalytical Test Methods for Regulatory Approval

Sep 15, 2005

FDA and regulatory agencies worldwide have recently approved many advanced bioanalytical technologies. Receiving approval of advanced test methods for new biopharmaceutical products is relatively straightforward, provided clinical and process validation data are generated by the same (or at least similar) test method. However, regulatory approval becomes more difficult and time consuming when compendial test methods or test methods for already licensed biopharmaceuticals are changed. The two most important regulatory submission aspects are the actual analytical method validation (AMV) results and protocol acceptance criteria, and evidence of method comparability of the new method versus the current one. This overview will mostly address the demonstration of method comparability. The critical elements for method development, validation, and transfer activities, including the upcoming regulatory expectations for standard-to-sample curve parallelism for the validation of bioassays were discussed in detail elsewhere. 1-4

Current GMP expectations are that new test methods must bring an overall improvement to measuring process and product quality. From a regulatory perspective, "improved" means that new test methods should perform equal to or better than classical methods (compendial or otherwise officially recognized) or approved methods (licensed) in regards to their critical method performance characteristics. Although an incentive for the firm, many method improvements such as cost-savings in reagents and automation do not necessarily demonstrate a sufficient improvement to the regulatory authorities. An equal or improved performance of the new or candidate test method versus the current one should be demonstrated by method comparability studies concurrent or after completion of the formal AMV studies. The method comparability studies could be included as part of the formal AMV protocol or simply be executed under a separate protocol after the AMV was completed. From a regulatory perspective, both are acceptable as long as all data was generated under a formal protocol with pre-specified acceptance criteria. Performing a separate method comparability study after AMV completion has several advantages. If the AMV results reveal that a method was not optimized, time and effort will be saved by holding off the comparability studies until the new method is ready. Also, the potential differences between results generated by both methods could be estimated and used to support the studies before the formal method comparability is initiated. However, pre-specified method comparability acceptance criteria should not be derived only from this knowledge. The candidate method's acceptability should be compared to the current method with respect to historical process control data in relation to the relevant release specifications. Other sources of method comparability acceptance criteria such as being within an acceptable difference that is/was shown to be clinically insignificant may also be justifiable.