The amount of development and supporting activities leading to process validation requires the allocation of an enormous amount of both internal and external resources. Consequently, time and budgetary constraints rarely allow for repeating any portion of the required activities. Development of a sound process validation strategy, a major portion of which involves defining the process to be validated, will help define the path, focus the resources, and drive the prevalidation exercise to meet every milestone.
To ensure that validation activities do not need to be repeated, the areas listed in Figure 1 should be defined and qualified by a parallel path.
The facility should be qualified for manufacturing the intended product and appropriate for the respective phase of development.3 Before implementation of a process in any developmental phase, it should be verified that procedures are in place for quality systems management such as facility cleaning; gowning; the flow of personnel, equipment, and material; environmental monitoring; calibration; change control; and preventive maintenance. A strategy for open versus closed processing steps should be developed so that appropriate environmental and process controls can be established. More stringent environmental requirements are implemented as the product moves from the fermentation and cell culture area through isolation and purification. For example, whole cells and viruses are typically manipulated in the upstream areas and completely removed from the product stream before entering the purification area. Often, this is ensured by adding a filtration step between the isolation and purification suites. Additionally, controls are increased throughout the course of purification. For example, during a final chromatography step, additional environmental monitoring can be performed, and all connections, fraction collection, sampling, and container closure can be performed under a laminar flow hood.
These facility prevalidation activities are documented in reports and outlined in facility flow diagrams that can be used to show control of the environment, product, personnel, material, and contamination. A comprehensive list of supporting information related to facility control can be used for regulatory submissions and as references during pre-approval inspection (PAI) readiness activities and the PAI.