Other Considerations

Comprehensive records of complaints received either directly from the customer
or through a drug problem reporting program should be reviewed. Furthermore,
a record of any follow-up investigation of such complaints is mandatory [6] and
should be part of this file. Review of customer complaint records can furnish a
useful overview of process performance and possibly hint at product problems.
Complaint analysis should therefore be viewed as a meaningful adjunct to the
critical process step and control test selection process.
Batch yield reflects efficiency of the operation. Because yield figures are
the sum of numerous interactions, they fail in most cases to provide specific
information about process performance and therefore must be used with caution
in retrospective validation. In any event, this information should be collected,
as it can contribute to further refinement of the yield limits that appear in the
batch record.
Lot-to-lot differences in the purity of the therapeutic agent must be considered
when evaluating in-process and finished-product test results. In addition to
potency such qualities as particle size distribution, bulk density, and source of
the material will be of interest. Such information should be available from the
raw material test reports prepared by the quality control laboratory for each lot
of material received. The physical characteristics of the excipients should not
be overlooked, especially for those materials with inherent variability. Metallic
stearates is a classic example. In such instances, the source of supply is desirable
information to have available.
There is value in examining logs of equipment and physical plant maintenance.
These documents can provide a chronological profile of the operating
environment and reveal recent alterations to the process equipment that may
have enough impact to disqualify the product from retrospective validation consideration.
For this reason, it is always prudent to contemplate equipment status
early in the information-gathering stage. The availability of such information
should be ascertained for yet another reason: rarely is equipment dedicated to
Copyright © 2003 Marcel Dekker, Inc.
one product. More often than not, each blender, comminutor, tablet press, and
so forth is used for several operations. Information gathered initially can therefore
be incorporated into subsequent studies.
Retrospective validation is directed primarily toward examining the records
of past performance, but what if one of these documents is not a true
reflection of the operation performed? Suppose that changes have crept into the
processing operation over time and have gone unreported. This condition would
result in the validation of a process that in reality does not exist. It is therefore
essential to audit the existing operation against the written instructions. There is
obvious advantage to undertaking this audit before commencing data acquisition.
Ideally, the manufacture of more than one batch should be witnessed, especially
where multiple-shift operations are involved. The same logic would apply
to the testing performed in process and at the finished stage. If any deviation
from the written directions is noted, an effort must be made to measure its
impact. In this regard, the previously described validation organization is a logical
forum for discussion and evaluation.
As a rule, batches that are rejected or reworked are not suitable for inclusion
in a retrospective validation study [7]. Indeed, a processing failure that is
not fully explainable should be cause to rethink the application of retrospective
validation. Nonconformance to specification that is attributable to a unique
event–operator error, for example, may be justifiably disregarded. In such cases,
the batch is not considered when the historical data are assembled.
Raw materials, both actives and excipients, can be a source of product
variability. To limit this risk, there should be meaningful acceptance specifications
and periodic confirmation of test results reported on the supplier’s certificate
of analysis. Also, purchases must be limited to previously qualified suppliers.
A determination that such controls are in place should be part of any
retrospective validation effort.