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
Developing a comprehensive process validation strategy early in clinical development is critical to the execution of a successful
validation program, and should also be consistent with the FDA's Quality by Design initiative.1 Development and process support activities leading to process validation require the allocation of internal and external
resources. Because of the nature of validation requirements, partnering with external experts in this area can prove to be
an important decision to complete the program successfully. Time and budgetary constraints do not allow for repeating required
activities, so all external resources need to be proven in their experience. Development of the validation strategy, mainly
by defining the process to be validated, will help define the development path, focus the resources to execute the key studies,
and drive the validation exercise.
The validation strategy is captured in a document that defines the process and activities related to each stage of process
validation.2 The requirements of the strategy are defined in the following sections.
The key to executing a successful validation is defining the exact process to be validated. Each parameter included in the
manufacturing instructions must have a documented control space that has been established based on experimental or manufacturing
data, as well as the quality of the starting materials and the capability of the operators, facility, equipment, and utilities.
This requires an evaluation of historical data, deviations, and planned experiments during clinical batches. Figure 1 depicts
the flow of the process definition and validation activities.
Figure 1. Process definition and validation flow
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.