As we scale up manufacturing processes, increase production rates, and strive to minimize batch failures in an increasingly stringent regulatory environment, it is valuable to characterize processes at the levels appropriate for each product development stage (preclinical through phase 3 and commercial manufacturing). Amgen currently characterizes several aspects of the manufacturing process comparable to that performed by other biotech companies. The increased understanding of each process that results from these characterizations can vary - from minimal knowledge, during development and non-GMP runs, to detailed knowledge of each unit operation or group of unit operations in late clinical development. Predictably, in-depth process characterization requires a significant commitment of resources and time.
The overall goal of adequate process characterization for commercial manufacturing processes is to ensure efficient and successful validation and the assurance of consistent process performance. More specifically, the characterization should provide:
Compliance and Business Drivers Process characterization has often been viewed as a "check the box" activity or something that was completed but which required little scientific rigor. This was most likely a result of cost cutting. Thorough process characterization requires a significant resource from process development and analytical departments. Many companies now recognize the benefits of sound process characterization - and, unfortunately, the cost of incompletely understood processes (1).
For compliance, process characterization needs to identify key operating and performance parameters, justify operating ranges and acceptance criteria, recognize interactions between key variables, and ensure that the process delivers a product with reproducible yields and purity. This is the complete and rational approach to process validation. Costly registration delays resulting from poorly understood processes and failed validation batches can cost a company tens of millions of dollars.
From a business standpoint, process characterization can improve run success rates and lead to incremental, but significant, yield improvements. Better process understanding can also minimize - and aid in the investigation of - process deviations.
Timing of the Studies To conserve resources, waiting until after phase 2 is the best time to start "intensive" process characterization work. At that point, the commercial process should be developed, and you know whether or not the product is likely to make it to market. Unfortunately, the driver for process characterization timing is the start of conformance or validation lots. Therefore the work should be completed by that point so that information gained from it can be used to support operating ranges and acceptance criteria for validation protocols.
Precharacterization Work Three steps are involved in precharacterization:
Once data mining is complete, risk should be assessed for each unit operation on the effect and likelihood of an excursion from operating ranges. Hazard analysis and critical control points (HACCP) (3), failure mode and effects analysis (FMEA) (4-7), cause-and-effect diagrams (8), and other risk assessment tools can be used for risk analyses. FMEA assigns a numerical rating (typically 1 to 10) to the severity of an excursion from operating parameter ranges, the probability of an excursion, and the likelihood of detecting an excursion before it has an effect on the product (4-7). The combined risk factor - the risk priority number (RPN) - is a multiple of the three variables, rating each parameter from 1 to 1,000 (4-7).