The success of process analytical technology (PAT), a recent initiative by the United States Food and Drug Administration (FDA), depends to a large extent on efficient control of manufacturing processes to achieve predefined quality of the final product. In this column, we review the various analytical methods that can enable use of PAT. A critical evaluation of suitability of each analytical method as a PAT tool in terms of sampling (in-line, at-line, or on-line), sample preparation, duration of analysis, and its industrial application is performed.
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Process analytical technology (PAT) is a system for designing, analyzing, and controlling manufacturing through timely measurement (that is, during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality (1–3). Although the term analytical in PAT is broadly defined to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner (see Table I), the emphasis in this article is on analytical techniques that enable the monitoring of critical performance attributes of raw and in-process materials and processes during biotechnology manufacturing. However, it is important to understand that the goal of PAT is not only the use of these analytical techniques for monitoring, but also to control the manufacturing process to consistently yield the desired product quality.
Table I: Examples of the various combinations of analyzers and statistical tools that together form a PAT application
Successful implementation of PAT requires the appropriate selection of a process analyzer. The selection of technique depends on the application and molecule, as well as the capability of the analytical method under consideration. In the biotechnology industry, drug products are manufactured using a series of unit operations. These products have to meet high expectations with respect to product quality, as documented in the pharmacopoeias and other regulatory documents. This is important to ensure the safety and efficacy of the manufactured drug substance and drug product. These requirements may be with respect to identity, content, quality, purity profile, moisture content, particle size, polymorphic form, and other such characteristics of the product. Traditional manufacturing involves the use of extensive analytical testing, most of which is retrospective as the data from analysis is received after the product lot has already advanced to the next process step. This approach results in a waste of manufacturing plant time, product rejects, scraps, and reprocessing (4). In contrast, PAT relies on enhanced process understanding to create controls that can result in continuous verification of product quality through all stages of manufacturing, reducing the chances of product loss.
Process analyzers play a key role in successful implementation of PAT and hence, are the focus of this paper. The analyzers may be used for monitoring of the critical quality attributes of the product, performance attributes of the process, and key characteristics of the various raw and in-process materials used in the process.