A risk-based proposal
What is to be done with respect to the extent of the initial validation under FDA's new guidance? FDA's Risk-Based Compliance
initiative of 2004 incorporates some general precepts about how firms should use risk in defining and controlling their operations
(3). Risk-based thinking has perhaps the greatest potential influence on validation. Performance-qualification protocols,
especially as they relate to sampling size, sample location, and acceptance criteria, incorporate risk decisions throughout.
The number of lots required for validation should be established through a risk-based approach to determining the number of
trials required. Table I includes an example of a risk-based methodology applied to production processes for the completion
of FDA's Stage II validation evaluation.
Although three or more batches are preferred for initial release, the distribution of products is permitted for any product
after the successful production of a single batch. For processes that are new to the producer or heavily modified, extensive
design of experiments (DOE) support is required in preparation for concurrent release.
The numbers listed in Table I are based on the following assumptions:
- These numbers are minimum requirements that could be increased when production demands and inventory charges permit.
- Relevant analytical methods are validated for all raw materials, solvents, excipients, in-process tests, and finished goods
before process validation.
- Critical parameters for each process are predefined and controllable at scale-up.
- Phase I DOE experiments have been completed successfully for all critical parameters.
- Specifications and key characteristics are established and in compliance for all materials.
- All equipment is in a state of current qualification.
- Interim reports should be prepared for all materials released concurrently during the overall validation exercise.
- A single batch can be concurrently released with adequate prior development.
- In-process and finished-goods specifications are established based on documented experience rather than preconceived or arbitrary
The choices of specific numbers in Table I are arbitrary and based on the author's nearly 40 years of pharmaceutical-industry
experience, which embraced all of these processes. In selecting the number of studies to perform in each instance, the author
drew upon diverse sources for basic direction.
First, the process (i.e., process validation) and product are inseparably linked (4, 5). The process consists of the equipment
chosen, the sequence of activities, the choice of materials, and the operating parameters. These items can be chosen independently
to obtain the desired result. The result of the process is a product with unique characteristics (e.g., potency, uniformity,
impurities, and moisture content). The product attributes depend on the process parameters used to make the product. The products'
characteristics are the result of the process. If the process is altered in a meaningful way, the product key attributes also
will be changed. Thus, the better defined the process, the more reproducible the result.
When a firm uses a process repeatedly, a substantial amount of useful data can be gathered for use when that same process
is applied to different materials to produce a different product. For example, experience with tablet coating can be used
for multiple products because the operating principles will remain constant, though the exact process parameters will differ.
The amount of experience that a firm has with a particular process should be a factor in determining the number of Stage II
validation batches necessary to demonstrate their capabilities.
Second, as is evident throughout the draft revision of the process-validation guideline, FDA expects manufacturers to acquire
knowledge regarding the interaction between the independent process variables and the dependent product-quality attributes.
The expectations for quality by design (QbD) are for the acquisition of knowledge regarding these relationships. The goal
of the knowledge building is a minimization of risk in the commercial production that follows the developmental effort. Although
this goal was stated explicitly in the guidance, an even clearer picture was provided in FDA's first presentations about process
analytical technologies, and later in presentations about the QbD initiative (see Figure 1) (6).
Figure 1: Process understanding and risk. (FIGURE IS COURTESY OF THE AUTHOR)
Third, the draft guidance appropriately emphasizes the importance of sound development during Phase I as the basis for a validated
commercial process. Although QbD has become increasingly common, it would be safe to say that the majority of current products
and processes have not been developed in a rigorous manner. When Stage I is performed as described, the scale-up and commercial
demonstration exercise that follows in Stage II of the guidance entails an expectation that the exercise is more likely to
be successful because of the increased process understanding and product knowledge the firm has gleaned from its developmental
efforts. Under those circumstances, an extended Stage II demonstration with numerous lots might be of less benefit than it
would when the development effort was weaker. Under the draft guidance, fewer Stage II batches are required because the process
is more fully defined.