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This article
presents an
innovative
approach to the
completion of
Performance
Qualification
(PQ).
Continuous Verification
Introduction
Continuous Verification
Stage 1, Process Design the stage at which product
and process understanding is developed. At its basic level,
this delivers a list of Critical Quality Attributes (CQAs)
and Critical Process Parameters (CPPs) that form the basis
of ongoing process control.
It is proposed in this article that from the time a draft control
strategy is identified, typically for Phase III Clinical Trial
batch manufacture, then verification of process control may be
commenced. This will initiate the process validation activity
providing the assurance that product of the requisite quality
is being produced.
Stage 2, Process Qualification a multi-component
activity concerned with the qualification of facilities and
equipment, the validation of analytical methods and taking
the process to a point where it may be commercialized.
Stage 3, Continued Process Verification ongoing
verification that ensures the production process remains
in control and continual improvement is facilitated.
The end of Stage 2 is the point at which the manufacturer
is able to document that the process is capable of producing
material of the requisite quality to be commercialized.
Traditionally, this Performance Qualification (PQ) has
involved the production of three consecutive, commercial
scale batches, which have been documented as meeting acceptance criteria. The successful completion of these three
batches indicates that the process is controlled and supports
the release and supply of commercial product.
While this approach remains as a viable option, there is
now the opportunity to investigate improved strategies for
achieving the point of commercialization. These have the
potential to offer significant benefit to manufacturers and
regulators alike.
A comparison of traditional and Continuous Verification
(CV) approaches to performance qualification is shown in
Table A.
Traditional Approach
For a recently launched product, a CV approach, incorporating data and knowledge from manufacture of development, clinical, and commercial material, has been used as
an alternative to the traditional approach of verifying three
commercial scale batches. For this product, this approach
enabled the provision of a comprehensive package of data
supporting process validation based mainly on clinical production, and requiring only one batch of commercial material
to be manufactured.
The validation approach was reviewed during PreApproval Inspection of the drug product manufacturing
site, conducted by representatives of FDA, EMA, and
MHRA. The agencies were fully supportive of the approach.
Additionally, details of the validation approach have been provided with the submission in many international territories.
Although some questions for clarification have been asked,
there have so far been no adverse comments about the CV
approach with no agencies asking for traditional validation
to be undertaken.
The product has recently received approval in the US, EU,
and a number of other markets.
Continuous Verification
for clinical batches may be different from commercial batches)
presents no risk to the control of the commercial product and
that no additional data are required. These differences may
be discussed at pre-submission meetings (e.g., pre-NDA or
equivalent meetings) and are transparent to regulators at
Pre-Approval Inspection (PAI).
This approach to validation enables continual improvement
of the control strategy during development to be included in
validation of the product and provides high confidence that
the product will be well controlled. This philosophy of enabling
continual improvement of the control strategy through a riskbased scientific approach continues throughout the lifecycle
of the product.
To achieve the inclusion of development data in PQ, the
Validation Master Plan is issued before Phase III Clinical
Trial batches are made and when the draft control strategy
is identified.
Protocols containing acceptance criteria with supporting
rationale are written for each campaign of clinical and commercial batches included in the PQ for commercial launch.
Data are reviewed and trended for each batch and for each
campaign to show compliance with the PQ criteria. Prior to
commercialization, a validation summary report is written,
drawing on previous PQ campaign reports to show compliance
with criteria and completion of the validation plan.
From launch onward, data are reviewed on a batch and
campaign basis. An essential part of CV is that relevant attributes of the input, intermediate and drug product materials, and manufacturing process parameters are monitored
and evaluated, both within and between batches, as part
of routine operation. While some elements of a traditional
periodic product review are carried out under CV on a batchby-batch basis, other elements of the review process, e.g.,
reviews of CAPAs and customer complaints continue to be
required on a periodic basis. These formal periodic reviews
are undertaken to determine the need for any changes in
manufacturing, control procedures, and/or product specifications, including any changes to the design space, control
strategy, and models for the product. The frequency of the
periodic review will depend on the number of batches produced within a specific timeframe and may vary during the
product lifecycle.
CV approaches to process validation provide greater assurance of product quality at the point of commercialization
and through the lifecycle by:
enabling ongoing assessment and knowledge to be built into
the validation exercise, providing a lower risk approach to
the point of commercialization
trending of critical aspects through clinical, development,
and commercial manufacture
verifying that any multivariate relationships between
attributes and parameters found in development are
maintained in commercial production
enabling verification of the design space
using a data set from a larger number of batches
potentially influencing the development plan and the way
Practical Application of CV
for a New Product
Introduction
Continuous Verification
This included the generation of a specific PQ1 validation
rationale detailing the reasons behind the strategy adopted
and a PQ1 validation protocol detailing the number of batches
and acceptance criteria which were to be applied to the PQ
exercise.
The CV approach is equally applicable to drug substance
and drug product, but in the case of VotrientTM drug substance,
a more traditional approach to process validation using three
conformance batches was adopted based on previously agreed
project schedules.
Although different validation strategies were adopted to
achieve the point of commercialization for the drug substance
and drug product, the same underlying levels of product and
process understanding were available. This facilitated the
adoption of CV concepts for the drug substance post commercialization.
Before commencing PQ1, sufficient knowledge and understanding of the commercial product and process were required.
The following were identified as pre-requisites:
Continuous Verification
granule properties), processing parameters and critical quality attributes of the drug product. It indicated those process
parameters, and material attributes which were critical to
control to achieve the drug product CQAs, and enabled the
definition of the process and the draft control strategy for the
commercial scale manufacture of VotrientTM Tablets.
Following risk assessment to prioritize activities, further
development work to establish the design space and final
control strategy for the commercial manufacture of VotrientTM
Tablets was undertaken. This work used a Design of Experiments with extremes of processing parameters and stretching
of excipient attributes to demonstrate areas of acceptable
process performance at commercial scale and confirm earlier
development conclusions. This completed the pre-requisites
for PQ1.
Batch process data and end product testing data were assessed
against the process performance criteria to demonstrate that
the process provided product of acceptable quality. Data from
the exercise were added to univariate and multivariate statistical charts for comparison purposes. Control charts with
action limits were developed once sufficient data had been
produced.
The PQ1 batches provided evidence that the process performed reliably and delivered product of the desired quality
and in accordance with the process performance criteria. The
PQ1 batches were reported, making reference to conformance
with batch release methods, supporting development history,
and supporting facility and equipment validation status. This
report is the first version of the Validation Summary Report
(VSRv1), and its issue marked the completion of PQ1.
In order to use data from the clinical trial batches, the precampaign protocol was introduced for each manufacturing
campaign. This pre-approved document detailed the batches
to be manufactured, the formulation, the control strategy, the
process performance criteria, the specification to be applied,
the status of analytical method validation and details of any
development work to be undertaken. The output of each campaign was formally reported against the pre-campaign protocol
ensuring knowledge was available to support the process
validation. This approach to the collation of information was
cited as a good practice during the Pre-Approval Inspection.
As this product had a high demand for clinical material,
a total of 31 clinical-image batches (1 200 mg and 30 400
mg) and one commercial image 200 mg batch, all at commercial scale, were manufactured prior to launch using the
defined control strategy, within the design space intended for
commercial production. A comparison of clinical and commercial tablet images is given in Table B. Part of the validation
rationale included a scientific and technical appraisal of 200
mg and 400 mg tablet production in both clinical and commercial images. An understanding of the relationships
between tablet strength, shape, porosity, thickness,
disintegration time, and dissolution rate provided the
rationale for using data from one strength/image to
support other variants.
These 32 batches comprised the PQ1 validation batches and
were documented within the PQ rationale and PQ protocol.
In order to approve the start of commercial supply, the following were in place and documented for VotrientTM Tablets:
Clinical
Commercial
Strength
(mg as free base)
200
200
400
Tablet Core
Formulation
Commercial Formulation
Tablet Shape
Oval
Oval
Shaped
Shaped
Modified
Capsule
Shaped
Modified
Capsule
Shaped
Gray
Yellow
Debossed
on one face
Debossed
on one face
White
400
White
Debossing
None
None
Continuous Verification
verification that the control strategy enables consistent
manufacture of product complying with its CQAs
Batch data from PQ2 batches showing compliance with
the process control strategy, process performance criteria,
end product specifications, and GMP
review and verification of models used in the control strategy (e.g., NIR)
risk assessment and risk management plan
an approved report of the work undertaken at PQ2
At this point, a final validation summary report (VSRv2) will
be produced, marking the end of PQ2 and completion of the
work described in the Validation Master Plan.
Periodic Review
The periodic product review process has been modified to
ensure that the design space, control strategy, and models
are included in the review.
Batch Release
Existing batch release procedures were modified to include
verification that a batch has been produced within the design
space and in accordance with the control strategy, and that
the process performance criteria have been met.
Change Management
All planned changes which have the potential to impact
the quality of a material or product will be prospectively
assessed in order to ensure that the risks associated with
the implementation of the change are identified, quantified,
and managed.
A risk assessment will be carried out to determine the
level of re-qualification required. If the changes proposed are
within the design space, the changes will be managed through
internal quality systems, as it has already been shown that
there will be no impact to the CQAs.
If the changes proposed are beyond the boundaries of the
known design space, then after technical justification and
internal approval, appropriate regulatory action will be taken
prior to making this change.
Existing product and process knowledge and ongoing
verification will be used to support all changes.
Deviation Management
The implementation of a CV approach meant that a number
of potential failure modes needed to be considered in detail;
for example, failure of PAT equipment. A number of decision
6
Continuous Verification
Flexibility in the Validation Approach Taken to
Achieve Commercialization
By issuing a validation plan earlier in the development process
and stating the intention to use data from development and
clinical campaigns to support the point of commercialization, greater flexibility in the final approach to validation is
introduced. In the VotrientTM Tablet example, the CV approach
supported the manufacture of only one commercial image
batch of tablets to achieve commercialization. For a low offtake product, this avoided the risk of material write-off (due
to limited shelf life) and all associated costs.
Conclusion
This article describes our first application of CV to the process
validation of a pharmaceutical drug product. While much
can be taken from the experience of developing and filing
VotrientTM Tablets, it is intended to further investigate and
develop these concepts.
Future efforts will be aimed at making greater use of small
scale batches, and incorporation of other variables within the
Design of Experiments to provide greater manufacturing and
regulatory filing flexibility, e.g., influence of differing site of
manufacture, and changes in equipment type.
Clearly, each product will require different approaches to the
number and scale of development/clinical batches required, so
no single approach to the use of CV can be described. However,
the principle of using late stage development and clinical data
to support the commercialization of products is flexible and
this flexibility is being used in a number of pipeline products.
What is clear though is that validation is no longer about a
number of batches, but more about the accumulated product
and process understanding.
References
1. International Conference on Harmonisation (ICH) guidance for industry, www.ich.org:
a. Q8 Pharmaceutical Development
2. Guidance for Industry Process Validation: General Principles and Practices, Nov 2008.
3. Committee for Medicinal Products for Human Use (CHMP)
and Committee for Medicinal Products for Veterinary Use
(CVMP), EMA/CHMP/CVMP/QWP/809114/2009, Concept
Paper on the Revision of the Guideline on Process Validation, 25 February 2010.
4. ASTM Standard E2537, 2008, Standard Guide for Application of Continuous Verification to Pharmaceutical and
Biopharmaceutical Manufacturing, ASTM International,
West Conshohocken, PA, 2003, 10.1520/E2537-08, www.
astm.org.
5. Calnan, N., Redmond, A., and ONeill, S., The FDAs Draft
Process Validation Guidance A Perspective from Industry,
Pharmaceutical Engineering, May/June 2009, Vol. 29, No.3,
pp. 8-16, www.ispe.org.
Continuous Verification
About the Authors
Richard Kettlewell is the Director of
Validation in the GlaxoSmithKline Global
Manufacturing and Supply organization. He
has an MSc in pharmaceutical sciences from
the University of Manchester, England. He
has worked in the pharmaceutical industry
for 24 years in product development, technical,
and validation. Responsibilities include the
development, implementation and maintenance of company
validation standards, the implementation of Quality by Design
into the validation lifecycle and the introduction/utilization of
continuous verification into new product introduction activities. He is a member of ISPE, the Parenteral Drug Association,
and the Pharmaceutical Healthcare Sciences Society. He may
be contacted by telephone at: +44-1833-692025 or by e-mail
at: richard.e.kettlewell@gsk.com.
GlaxoSmithKline Global Manufacturing and Supply,
Harmire Road, Barnard Castle, County Durham DL12 8DT,
United Kingdom.
John Upfield is Head of Product Quality in
the GlaxoSmithKline Global Manufacturing
and Supply organization. He holds a BSc in
chemistry from the University of London and
an MSc in Spectroscopy from the University
of Surrey. He has worked in the pharmaceutical industry for more than 25 years. Recent
responsibilities have included auditing
of manufacturing and supply activities, development and
implementation of global quality systems, and implementation of Quality by Design into a commercial manufacturing
environment. He has been involved in the implementation
of real time release and continuous verification concepts. He
may be contacted by telephone: +44-1920-864188 or by e-mail:
john.a.upfield@gsk.com.
GlaxoSmithKline Global Manufacturing and Supply, Priory
Street, Ware, Hertfordshire SG12 0DJ, United Kingdom.