PROCESS VALIDATION AND FILING

The impact of design space on process validation is an active topic of discussion among manufacturers of biological products. At a minimum, an enhanced understanding of the manufacturing process and an expanded design space should provide more manufacturing flexibility during process validation. Since the design space "assures quality" of the drug product, these limits also should provide the basis of the validation acceptance criteria. This can be observed in Figure 2, where the limits that establish the acceptable variability in product quality and process performance attributes would also serve as the process validation acceptance criteria. Once the design space has been created, process validation becomes an exercise to demonstrate (1) that the process will deliver a product of acceptable quality if operated within the design space and (2) that the small- and pilot-scale systems used to establish the design space accurately model the performance of the manufacturing scale process. Thus, unanticipated manufacturing excursions that remain within the design space should not jeopardize the success of the validation exercise.

Once the design space has been established and validated, the regulatory filing would include the acceptable ranges for all key and critical operating parameters (i.e., design space) in addition to a more restricted operating space typically described for biotech products.

Figure 2. Application of the design space concept on process characterization, validation, monitoring, and regulatory filing.

The primary benefit of an expanded design space would be a more flexible approach by regulatory agencies. Process changes within the design space will not require review or approval. Therefore, process improvements during the product lifecycle with regard to process consistency and throughput could take place with reduced post-approval submissions. The burden, however, lies with the applicant to provide sufficient rationale for this, as stated in ICH Q8: "The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided." In addition to regulatory flexibility, the enhanced understanding of the manufacturing process would allow a more informed risk assessment, as per ICH Q9, of the effects of process changes and manufacturing deviations (excursions) on product quality.³

Design space and regulatory flexibility should not be confused with relaxed process control or increased process variability. Regardless of how wide the design space is, process consistency is still the goal and it is expected that the manufacturing process will be performed in a reasonably narrow operating space. Excursions outside the operating space would indicate unexpected process drift, and would initiate both an investigation into the cause of the deviation and a subsequent corrective action. As long as operating parameters remain within the design space, however, product release would not be in jeopardy. As manufacturing experience grows and opportunities for process improvement are identified, the operating space could be revised within the design space without the need for postapproval submission.

ICH Q8 points out that design space can also be derived from manufacturing experience. Although first produced for the original marketing application, process knowledge and design space can be updated as understanding is gained over the lifecycle of a product. For example and as illustrated in Figure 2, process understanding gained from process monitoring can be used in future changes to the design space. Such changes should be evaluated against the need for further characterization or revalidation.

LINKAGE BETWEEN DESIGN SPACE AND PROCESS ANALYTICAL TECHNOLOGY

Process Analytical Technology (PAT) has been defined as "a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality." As such, the goal of PAT is to "enhance understanding and control of the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design."⁴