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This article
presents an Continuous Verification – Providing
innovative
approach to the an Alternative Approach to Process
completion of
Performance Validation
Qualification
(PQ).
by Richard Kettlewell, John Upfield, Rosemary Leak,
and Andrew Harris
Introduction
R
This change in emphasis has driven a change
egulatory authorities around the globe in thinking about what constitutes validation,
recognize the need for process validation leading to many papers and conferences on
to assure that the production of medici- what validation is and how it may be conducted.
nal products is capable of consistently Recent articles in Pharmaceutical Engineering
delivering the required quality. indicate that regulators, consensus standard
Recent developments in the pharmaceuti- organizations and manufacturers are embracing
cal industry driven by ICH guidelines Q8, Q9 the opportunity to promote and use alternative,
and Q10, FDA and EMA draft documents on science and risk-based approaches to valida-
process validation and an ASTM Standard on tion.5,6
Continuous Quality Verification, have created Fundamentally, the actual process of “vali-
an environment where scientific and techni- dating” a product and getting it to market has
cal understanding of products and processes not changed. It is still expected that 1. validation
permits innovative, science and risk-based ap- exercises are governed by a plan, 2. pre-approved
proach to the process validation lifecycle.1,2,3,4 protocols define the scope of work to be under-
Process understanding, together with con- taken and acceptance criteria, 3. approaches
trol of critical quality attributes and critical are justified, 4. aspects of qualification are
process parameters, provides the basis for this reported, and 5. the overall validation exercise
approach. This provides greater confidence to is concluded by a summary report.
the company and regulatory authorities that However, while the basic deliverables may
products and processes are controlled, while remain the same, the opportunity to utilize
providing greater flexibility to the manufacturer greater scientific understanding in the design
in the way processes are validated. Continuous of validation programs is welcomed and should
verification is initiated before the manufacture be embraced for those products and processes
of Phase III Clinical Trial batches and continues developed following a Quality by Design ap-
throughout the product lifecycle, facilitating proach. An increase in the scientific and
continual improvement of the manufacturing technical content of the overall process
process. validation provides better opportunities
This has enabled the development of a to justify “what is,” and sometimes more
comprehensive and innovative validation and importantly, “what is not” validated, and
regulatory package supporting the recent the scope and extent of validation work
launch of VotrientTM Tablets, based on the use of undertaken.
development, clinical, and commercial batches There is much made of changes of termi-
to verify the performance of the control strategy. nology, but fundamentally the validation of a
The validation approach was reviewed during product/process should be viewed as a lifecycle
Pre-Approval Inspection of the drug product – the Process Validation Lifecycle. The recent
manufacturing site, conducted by FDA, EMA, draft guidance issued by FDA illustrates this
and MHRA. The agencies were fully supportive as a three stage process:
of the approach.
What Were the Pre-Requisites for PQ1? How Were the Pre-Requisites for PQ1 Achieved?
Before commencing PQ1, sufficient knowledge and under- Early development work using commercial scale equipment
standing of the commercial product and process were required. at the proposed commercial manufacturing site allowed the
The following were identified as pre-requisites: identification of process parameters and material attributes
relevant to drug product performance and enabled the descrip-
• qualification of all related facilities, equipment, and process tion of the process for the commercial scale manufacture of
measurement technology VotrientTM Tablets.
• identification of potential CQAs and CPPs Further commercial scale work provided an understand-
• identification of a control strategy and associated design ing of the relationships between attributes of API, attributes
space of in-process materials produced from unit operations (e.g.,
• More efficient and effective change control – changes 5. Calnan, N., Redmond, A., and O’Neill, S., “The FDA’s Draft
proposed can be assessed against the available process Process Validation Guidance – A Perspective from Industry,”
understanding, minimizing the level of additional verifica- Pharmaceutical Engineering, May/June 2009, Vol. 29, No.3,
tion required to support the change. pp. 8-16, www.ispe.org.
A future aim will be to incorporate additional knowledge 6. McNally, G., “The Draft Process Validation Guidance – A
in regulatory filings to facilitate certain lifecycle changes Perspective from the FDA,” Pharmaceutical Engineering,
post-approval, effectively reducing the number of regulatory May/June 2009, Vol. 29 , No.3, pp. 18-22, www.ispe.org.
post-approval changes.