Why Validation?

细履平沙

INTRODUCTION
The origins of validation in the global healthcare industry
can be traced to terminal sterilization process failures in
the early 1970s. Individuals in the United States point to
the LVP sterilization problems of Abbott and Baxter,
while those in the U.K. cite the Davenport incident (1).
Each incident was a result of a non-obvious fault coupled
with the inherent limitations of the end-product sterility
test. As a consequence of these events, non-sterile
materials were released to the market, deaths occurred,
and regulatory investigations were launched. The
outcome of this was the introduction by the regulators
of the concept of “Validation”:
Documented evidence which provides a high degree
of assurance that a specific process will consistently
produce a product meeting its predetermined specifications
and quality attributes (2).
The initial reaction to this regulatory initiative was
one of puzzlement; after all, only a limited number of
firms had encountered difficulties, and all of the problems
were seemingly associated with the sterilization of LVP
containers. It took several years for firms across the
industry to understand that the concerns related to
process effectiveness were not limited to LVP solutions,
and even longer to recognize that those concerns were
not restricted to sterile products. Perhaps most unfortunate
of all was the lack of enthusiasm on the part of
industry in adopting this concept. From its earliest days,
validation was identified as a new regulatory requirement
to be added to the list of things that firms must
do, with little consideration of its real implications. The
first efforts reflected what can be termed the “scientific
method” of observation of an activity, hypothesis/prediction
of cause/effect relationship, and experimentation
followed by new observations in the form of the experimental
report. In the pharmaceutical validation model
this has evolved into the validation protocol (hypothesis
and prediction), field execution (experimentation), and
summary report preparation (documented observations).
By 1980 when it was evident to all that validation
was here to stay, pharmaceutical firms began to organize
their activities more formally. Ad hoc teams and task
forces that had started the efforts were replaced by
permanent Validation Departments whose responsibilities
and scope varied with the organization but whose
purpose was to provide the necessary validation for a
firm’s products and processes. The individuals in these
departments were the first to grapple with validation as
their primary responsibility, and their methods, concepts,
and practices have served to define validation ever since:
Validation: Establishing documented evidence which
provides a high degree of assurance that a specific
process will consistently produce a product meeting its
pre-determined specifications and quality attributes (3).
The first efforts at validation were rather crude and
limited in their understanding of the full implications.
For example, the first sterilization validations at most
firms were performed without prior qualification of the
equipment. Once validation had been established as a
discipline and something more than a passing fad,
methods for its execution became substantially more
formalized and rigorous.
The validation community made significant strides
in clarifying the various components of a sound validation
program. Perhaps most important of all was the
separation of activities into two major categories: Equipment
Qualification and Process Qualification. The former
(sometimes sub-divided into Installation and Operational
Qualification) focused on the equipment in which the
product was being processed. It is predominantly a
documentation exercise in which details of the physical
components of the system are recorded as definition of
the equipment. Equipment operational capabilities are
also established. Process Qualification (also known as
Process Validation or Performance Qualification)
confirms the acceptability of the product manufactured
via the equipment, and relies heavily on the results of
physical, chemical, and microbial tests of samples.
It was soon apparent that validation had to be
more closely integrated into the mainstream of cGMP
operations in order to maximize its effectiveness in larger
organizations. A number of areas can be identified as
pre-requisites for process or system validation. The
origins of these elements can be identified in the cGMP
requirements for drugs and devices (Table 1) (4).
With this understanding of its dependencies,
validation is more easily assimilated into the overall
cGMP environment rather than something apart from
it. While a firm will likely continue to have a validation
department, it must be supported by the activities in
other parts of the organization. For example, a poorly
developed process performed using uncalibrated equipment
to make a product that has no standard test
methods could never be considered validated. All of the
supportive elements must be properly operated in order
to result in a compliant product, and one that can be
validated. A later definition that addresses the larger
scope of validation within the overall organization is:
Validation is a defined program which, in combination
with routine production methods and quality control
techniques, provides documented assurance that a
system is performing as intended and/or that a
product conforms to its predetermined specifications (5).

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