Biomedical Engineering Reference
In-Depth Information
8.8 PROCESS PERFORMANCE QUALIFICATION
Data must exist to demonstrate that the commercial-scale manufacturing process
is reproducible, can be maintained within established parameters, and consis-
tently produces products that meet specifications. This could be done by actual
commercial-scale batches or by process knowledge and data from PV studies,
which must be statistically and scientifically sound. Successful PPQ is reflected
by the level of robustness of the manufacturing formula, process recipe and SOPs.
Equipment and supporting systems to be used for the PPQ need to be qualified in
accordance with GMPs [4,6,27]. In most cases, PPQ will have a higher level of
sampling, additional testing, and greater scrutiny of process performance. Consis-
tency beyond the initial qualification batches is demonstrated through continued
monitoring of a subset of the original parameters evaluated during PPQ.
In the past, it has been generally considered acceptable for three consecutive
batches under routine operating conditions to constitute initial validation of the
process or changes to an existing process. This became the norm in the industry
with limited or no inspectional scrutiny from the agencies. Under the new concept
of using a science- and risk-based approach, when selecting the number of batches
in PPQ, appropriate use of scientific data, risk management, and statistical tools
should be considered. Three batches should not be selected without taking these
considerations into account. A FDA colleague has stated that between 2 and 30
would be a range probably used to satisfy the FDA's new paradigm [28]. Note
that international guidances currently maintain an approach that is less risk based
and typically follow a three-batch approach [6,7].
Robustness of contamination controls that prevent bioburden, endotoxin, or
foreign contaminants into a process must be demonstrated. This is accomplished
through a combination of process controls such as raw material specifications and
testing, equipment cleaning and sanitization, operational control, and in-process
monitoring during the production of drug substances and drug products. Clean-
ing, sanitization, sampling, sterilization, and depyrogenation processes should be
qualified or validated to limit the introduction of bioburden into the process.
The manufacture of sterile drug products is subject to specific validation require-
ments, depending on whether the product is terminally sterilized or aseptically
processed, in order to minimize the risk of microbiological and pyrogen contam-
ination. Aseptic processing operations, such as sterile sampling, filtration, filling,
and lyophilization are considered by regulators as higher risk processes. For
mammalian cell culture processes, viral clearance studies must be performed
to assess effectiveness of the process steps in inactivating/removing viruses
and to measure quantitatively the overall level of virus clearance by the pro-
cess.
The scope and extent of validation-related testing of qualification batches may
exceed that of routine commercial manufacturing. In addition to standard speci-
fication tests, comparability studies may include those additional tests needed to
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