Drug formulations and manufacturing processes

Design and optimization of drug formulations and manufacturing processes within the PAT framework can include the following steps (the sequence of steps can vary):

• Identify and measure critical material and process attributes relating to product quality
• Design a process measurement system to allow real time or near-real time (e.g., on-, in-, or at-line) monitoring of all critical attributes
• Design process controls that provide adjustments to ensure control of all critical attributes
• Develop mathematical relationships between product quality attributes and measurements of critical material and process attributes
Therefore, it is important to emphasize that a strong link between product design and process development is essential to ensure effective control of all critical quality attributes. Process monitoring and control strategies are intended to monitor the state of a process and actively manipulate it to maintain a desired state. Strategies should accommodate the attributes of input materials, the ability and reliability of process analyzers to measure critical attributes, and the achievement of pre-established process endpoints to ensure consistent quality of the output materials and the final product.

Within the PAT framework, a process endpoint need not be a fixed time, but can be the achievement of the desired material attribute. This, however, does not mean that process time is not considered. A range of acceptable process times (process window) is likely to be achieved during the manufacturing phase and should be evaluated, and considerations for addressing significant deviations from acceptable process times should be developed. Process end points intended for use in real time release should be considered more critical than those that are only used for in-process control.

Where PAT spans the entire manufacturing process, the fraction of in-process materials and final product evaluated during production could be substantially greater than what is currently achieved using laboratory testing. Thus, an opportunity to use more rigorous statistical principles for a quality decision is provided. Multivariate Statistical Process Control can be feasible and valuable to realizing the full benefit of real time measurements. Similarly, rigorous statistical principles should be used for defining acceptance criteria for end product attributes (e.g., content uniformity) that take into consideration differences in the nature of the test (e.g., continuous monitoring) and sample size between an on-line test and a current laboratory test.

Real time or near real time measurement tools typically generate large volumes of data. Certain data are likely to be relevant for routine quality assurance and regulatory decisions. In a PAT environment, batch records should include scientific and procedural information indicative of high product and process quality. For example, batch records could include a series of charts depicting acceptance ranges, confidence intervals, and distribution plots (inter- and intrabatch) showing measurement results. Ease of secure access to these data is important for real time manufacturing control and quality assurance. Installed information technology systems should accommodate such functions.

Technologies that incorporate greater product and process understanding can provide a high assurance of quality on every batch and provide alternative, effective mechanisms to achieve validation. In a PAT framework, process validation can be enhanced and possibly consist of continuous quality assurance where a process is continually monitored, evaluated, and adjusted using validated in-process measurements, tests, controls, and process endpoints.
Installation of process analyzers on existing process equipment in production should be done after risk-analysis to ensure this installation does not adversely affect the process or product quality (i.e. qualified equipment and validated process). Based on this assessment, it should be decided if the existing process should be revalidated or not.

Risk-based approaches are suggested for validation of PAT software systems. The recommendations provided by other FDA guidances such as General Principles of Software Validation should be considered. Other useful information can be obtained from consensus standards, such as ASTM and Good Automated Manufacturing Practices (GAMP) listed in the bibliography section.