Analytical method validation clinical need

The majority of 21 CFR 211.160 (laboratory controls) and subsections can be applied in the same manner for clinical supplies as for commercial products. An exception, in many cases, is the time by which analytical methods validation is required. For new chemical entities or significant formulation changes, new analytical methods may need to be developed. As with manufacturing processes, until such methods are robust it is difficult (or impossible) to validate them to the full extent that is expected for commercial products. 

During clinical phases of a development project, there will be few batches that will need a clinical release status, so they can be utilized in clinical trials in humans. For a clinical release, all test methods need to be written by an analytical chemist and approved by a quality assurance group. All test methods that are utilized to test a clinical batch needs method validation as described in Chapter 9. Everything at this stage is performed by following cGMPs. 

This chapter will discuss the role of the analytical chemist in the preformulation process and highlight the methods that will need to be developed, validated and utilized to support these studies. An assortment of analytical techniques is needed to measure a number of critical quality attributes of the new molecular entity such as solubility, purity, and crystalline habit. The methods will be used to make important decisions such as the choice of salt form, or which sohd oral dosage form has the best probability of providing adequate exposure in an early phase clinical study. These analytical tools are critical to the decision that a pharmaceutical development organization uses to evaluate the first round of solid dosage form development prior to the availability of clinical data. 

Whether the monitoring of endoxifen plasma concentrations in breast cancer patients would constitute a valid approach to optimize individual dosage and improve treatment efficacy is under scrutiny and remains to be demonstrated. In that purpose large prospective studies relating endoxifen plasma levels to clinical outcomes are as yet needed. In this perspective, it is critical to settle analytical and selectivity discrepancies between methods and laboratories and to ensure reproducible quantification results between laboratories. These concerted harmonization efforts can be carried out within the frame of an international external quality control program, which as yet, remains to be organized. 

This should be determined using validation samples, and it is ideal if these are the same samples that will be used as quality control samples in the sample analysis phases of the studies. Choice of the concentrations will be determined by the use of the assay and, as previously mentioned, assay kit components will usually need to be supplemented by additional QC samples, either due to different concentrations or specific matrix requirements. The concentrations may be driven by the analytical range of the method, or the clinically relevant range expected to be important when analyzing test samples, or both. 

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