Fourth, the draft guidance has adopted a life-cycle approach to process validation in which the exercise is no longer considered
an isolated activity, but one that is fully integrated into the development and commercial life of the product. This shift
in thinking mandates a changed perspective on how validation is implemented and used in an environment in compliance with
current good manufacturing practice (CGMP). The requirement for an annual review of product performance is a 21 CFR 211 expectation (7). In the author's experience, that activity was rarely linked to process validation in any meaningful
way. Annual reports were largely isolated from the individual release decisions for a particular lot.
One means to address FDA's draft Stage III recommendations for continued process verification is to implement near real-time
evaluation of results for commercial materials. With the increasingly available electronic tools of laboratory information-management
systems, system control and data acquisition, among others, the results of testing for any lot can be rapidly compared with
prior results for evidence of a shift in performance. This capability and expectation can substantially reduce the importance
of the Stage II data. Although Stage II is important as part of the initial scale-up, it merely suggests future performance
rather than predicting it. Release decisions in Stage III are made according to an even larger body of evidence, of which
the Stage II results are only one part.
Fifth, when the 1987 process-validation guidance was issued there was an implied understanding that analytical methods should
be validated. Methods and principles for that validation were not widely accepted, however, and the analysis was often labor-intensive.
The ability to analyze samples in large numbers often was limited by the number of analysts available.* Process automation
first appeared on the manufacturing floor, and is now found throughout the facility, including nearly all laboratories. Present-day
laboratories are increasingly automated, which allows for the accommodation of larger sample sizes, higher throughput, and
more timely and reliable results. Processes and products can be more effectively and expeditiously evaluated than ever before,
and confidence in the results is substantially higher. As a consequence, Stage II lots can be characterized better than ever
before, and added lots to build knowledge of process capability are not needed as much.
*The author has encountered numerous instances where the number of validation exercises that could be performed was limited
by the laboratories' ability to analyze the validation samples in a timely manner. This was complicated by the sample numbers
taken for purposes of validation that were many times the number used for routine release. These situations are far less common
with today's automated analytical laboratories.
Last, and perhaps most importantly, Stage III of the validation life cycle lasts longer than any other, and the number of
batches needed to make the transition from Stage 2 to Stage 3 is really not a significant factor. Maintaining a process in
a validated state over its commercial life requires several supportive controls defined under CGMP regulations. The essential
elements to support a product or process over its life cycle are change control (i.e., materials, procedures, test methods,
and equipment), calibration, preventive maintenance, and personnel training. These mechanisms support the acceptability of
the product or process for the longest period, and the number of successful Stage II batches completed is largely irrelevant.
Recommendations for Stage II
Considering the points that this article has examined, it would be inappropriate for the author not to take a definitive stance
on the number of batches that should be required. The author believes that although cogent arguments for more batches exist
in some instances for complex processes, perhaps equally good reasons indicate that increasing the expected number of batches
across the board would create an unnecessary (and perhaps superfluous) burden in other instances. The author believes that
essentially no change in historical practices is warranted. Three batches have served industry, FDA, and the patient well
for more than 20 years. The suggested approach in Table I provides a risk-based approach that gives adequate consideration
to the technical, commercial, and regulatory risks. The new guidance addresses that approach by requiring that firms develop
a fuller understanding of their product and process and be thus able to support its adequacy without resorting to large numbers
of Stage II studies.
Table I: Phase II validation batch expectations.