Authored By: Mo Heidaran, Robert Iser, Changting Haudenschild, Mark Levi, PAREXEL® Consulting
Making changes to the process/product is an evitable part of making a better product. However, introducing major manufacturing changes late in development, during clinical trials, could potentially markedly change the product’s critical characteristics. For this reason, manufacturers are encouraged 1) to introduce major manufacturing changes early on during the product development life cycle, 2) to demonstrate that the product pre and post change are similar.
However, in reality and for a variety of reasons, manufacturers are opting to introduce major manufacturing changes very late in the product’s development life cycle. Some of the more common changes include scale up and automation. Although regulatory authorities have established somewhat-defined expectations on how to demonstrate comparability, the real risk is one that manufacturers bear if changes to the critical attributes of the product, which correlate with clinical outcomes, could go undetected. Thus, failure to detect the potential impact of these changes during late phase or post-approval could potentially affect product quality, effectiveness and ultimately commercial success of the product. To address these potential pitfalls, manufacturers are strongly encouraged by FDA and other health authorities to implement a plan of action to understand the critical quality attributes(CQA) which could potentially correlate with product quality and the clinical outcomes. Accomplishing this goal is not trivial and requires not only an in depth understanding of the product and its associated analytics but also a systematic approach to correlate these key attributes to various clinical outcomes.
In the context of existing FDA regulation, CQAs can be measured in vitro using a potency assay which is a regulatory requirement for the final drug product approval. Although potency is not very well defined per 21 CFR 600.3(s), the potency test is arguably the most important measure of the biological activity of a given product. FDA encourages manufacturers to consider establishing multiple potential potency assays, as early as possible, in order to select and qualify the best potency test(s) for late stage trials, such as Phase III, pivotal or licensing trials, where the product efficacy is being evaluated. During early and late stage of trial, manufacturers are encouraged to collect data measuring product potency and if permissible correlate this data with various clinical outcomes. A comprehensive and systematic approach in data collection and analysis should be used in identifying and prioritizing CQAs which could correlate with clinical outcome using well-defined degrees of statistical certainty. This knowledge is an invaluable part of making a better product, more consistently by readily implementing major manufacturing changes pre and even post approval to improve the final drug product quality and to establish more manufacturing control and consistency.
We at PAREXEL Consulting can help you develop these strategies early on by following a well-defined process that uniquely merges your understanding of product attributes with the clinical outcome(s).