PROCESS VALIDATION STRATEGIES

For a product to be considered for retrospective validation, it must have a stable
process; that is, one in which the method of manufacture has remained essentially
unchanged for a period of time.
The first step in the product selection process is therefore to obtain a
summary of changes in the method of manufacture. In most companies such
information is part of the master batch record file. Then a time interval is selected
that represents the last 20 to 30 batches. Products for which there is no
record of a change in the method of manufacture or control during this period
can be regarded as candidates for validation. The 20-to-30-batch rule originates
from control chart principals, which consider 20 to 30 points that plot within
the limits as evidence of a stable process [4]. Once this criterion is met, the
number selected is actually somewhat arbitrary, as there is no one number that
is correct for every product. The ideal number of batches required to study a
product is theoretically the number that permits all process variables to come
into play. By process variables, we mean raw materials from different but approved
vendors, introduction of similar but different pieces of equipment, personnel
and seasonal changes, and the like. This academic approach may present
a rather unwieldy situation, especially for a high-volume product, for which
change in process variables occurs infrequently. The influence of seasonal
changes is such an example. In such instances, compromise will need to be
reached between process variables included for study and the number of batches
that can be examined for data. This decision making is best handled by a validation
committee, the organization and makeup of which is covered in detail later
in this chapter.
The second step in the product selection process addresses the situation in
which a change in the method of manufacture or control was implemented during
the last 20 or so production batches. The fact that a change has occurred
does not automatically disqualify the product for retrospective validation. One
must first know whether the particular modification has caused an expected
result to be different to the extent that it is no longer comparable to previous
batches. An example may be helpful. Suppose the method of granulating was
changed midway through the series of 20 batches selected for the validation
study. The number of batches representing the new process would be significantly
reduced and could be insufficient to capture some of the interactions that
can affect process reproducibility. In general, a history of any one of the follow-
Copyright © 2003 Marcel Dekker, Inc.
ing changes to the method of manufacture and control should be fully investigated
before any decision is made to validate retrospectively:
1. Formulation changes involving one or more of the active ingredients
or key excipients
2. Introduction of new equipment not equivalent in every respect to that
previously in use
3. Changes in the method of manufacture that may affect the product’s
characteristics
4. Changes to the manufacturing facility
A product found to be unsuitable for retrospective validation because of a
revised manufacturing process is a likely candidate for prospective validation,
which is beyond the scope of this chapter [1]. Such a discovery, however, should
be brought to the attention of the appropriate authority. In today’s regulatory
environment ignoring the matter would be imprudent.
The third and last step in our selection process is to identify which products
are likely to be discontinued because of a lack of marketing interest or
regulatory consideration, to be sold, or to be reformulated. The timing of these
events will dictate whether the product in question remains a viable candidate
for retrospective validation.