The Goldilocks Challenge—Controlling Uncertainty When Setting Product Specifications

Abstract

Product specifications are ideally based on knowledge of patient needs or requirements of subsequent manufacturing steps. However, in most applications, knowledge of patient needs is neither precise nor comprehensive enough to fully define specifications. The prevailing practice is to base specifications on process experience, setting limits to assure consistency of future results with initial results representative of clinical material. Developers of new medicines are often required to set initial product specifications and other limits when only small amounts of process experience have been accumulated. Product developers and health authority reviewers share the mandate to protect patients from harm and assure the effectiveness of medical products, which motivates a tendency to set limits very tight. But although tighter limits give the impression of tighter control, limits alone accomplish no reduction in the variation that exists in established processes and test methods. Limits that are too tight do not represent the natural variability of the process and test methods. Unnaturally tight limits will result in a high number of excursions beyond the limits, potentially causing discards, supply disruptions, and higher cost of goods sold. In this article, we demonstrate how to deliberately control the probability of having intervals that are too tight during the early manufacturing process.