The USP has issued USP <1037> Process Analytical Technology – Theory and Practice, which is open for comments until the end of July 2025. This draft chapter is comprehensive and discusses the relationship between QbD and PAT, the fundamental requirements of PAT, PAT applications, and chemometrics, along with lifecycle management of PAT methods.
The chapter espouses the virtues of PAT whereby it demonstrates the relationship of PAT to manufacturing processes’ CPPs and the associated CQA where, through risk management, PAT can be applied to those critical processing risks that are most impactful to product quality. USP <1037> states:
PAT provides the means to monitor these risks closely and mitigate them as they arise, thereby improving the robustness and reliability of the manufacturing process, which is crucial for maintaining high-quality standards in pharmaceutical production.
In addition, the chapter refers to a potential regulatory benefit for those submissions that incorporate PAT:
This knowledge not only enhances regulatory compliance and efficiency but also potentially accelerates the review process, leading to faster market approval for pharmaceutical products.
PAT has been available to the industry for over twenty years. The FDA’s Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance was originally released in October 2004; however, traditional “off-line” in-processing testing is still commonplace and companies have been slow to integrate PAT even with the potential benefit of real-time release. So, the natural question is, why? As well as referencing the benefits of PAT, USP <1037> also illustrates the complexity and investment that PAT requires in terms of cost, time, technical know-how (training), and the required cross-department support/involvement (engineering, production, validation, regulatory, and design). The last item is critical as, once the PAT system is installed, it must be considered an integral component of the manufacturing process’ monitoring system and not as a standalone, offline instrument and, therefore, must be commissioned and qualified as a comprehensive system (with an understanding of system criticality/potential impact).
However, when considering the significant upfront investment with PAT implementation, one needs to consider the return on investment as it relates to a more thorough understanding of the firm’s manufacturing processes’ CPPs, the enhanced control strategy, reduced time loss from offline analysis, fewer costly investigations, regulatory benefits from enhanced process understanding, etc.
USP <1037> has a section dedicated to the application of chemometrics for establishing the PAT model. This is the heart of the PAT method and, as such, this is where the greatest risk lies (in terms of generating accurate/reliable data); therefore, this needs to be reflected with the lifecycle management of the PAT method. From the outset, the firm needs to be clear on the objective of the PAT model. USP <1037> states (in relation to the PAT model):
This is the most important consideration, as it influences all subsequent model-building and optimization activities. One must first provide a clear definition of the use case and performance requirements for the model, which is often linked to the analytical target profile (ATP) of the overall analytical method that the model supports. For models that are to be used for high-impact applications, it is also recommended to conduct a formal risk assessment to address factors that could impact the model performance.
The chapter then discusses those critical model performance factors, such as data filtration/preprocessing for the training data (that is used to build the model), sample selection, the span of the sample population (the data from which is the basis for the model), and instrument variable selection, all of which should be considered as part of development.
Ongoing performance verification for PAT methods is critical as the firm will want to confirm the continued accuracy/precision/robustness of the model where the analysis of various control samples/reference standards can prove to be beneficial. This should also be considered in the context of change management as it relates to changes in the process that the PAT method monitors, but any change to the PAT method or the PAT system/technology should be considered. The change control will need to assess the risk/impact and the need for redevelopment, recalibration, or revalidation.
If you have any questions related to PAT methods, then please reach out to Lachman Consultant Services at LCS@lachmanconsultants.com.
