APR Sept/Oct 2023 - 72

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MANUFACTURING
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are working toward new approaches to bringing new manufacturing
sites online more swiftly, without cutting corners and potentially
introducing quality or safety concerns.
Specific new measures under International Council for Harmonization
(of Technical Requirements
for Pharmaceuticals for Human Use)
guideline Q12 include the Post-Approval Change Management
Protocol (PACMP). This aims to simplify the process of registering
site changes under certain criteria, through an emphasis on gaining
accelerated upfront feedback from the Regulator before detailed
submissions are compiled. Already, to date, this has been seen to
reduce the approval cycle by up to six months.
So, what's involved under this protocol, and in using the new
framework for post-approvals change management linked to finished
product manufacturing sites?
Current Challenges with
Traditional CMC Variations
Management Protocols
The established approach to site-related changes can become mired
in complexity, especially if there is a cluster of inter-related changes
which, ideally, would be handled simultaneously with the Regulator -
e.g., changes that go beyond the addition of a new manufacturing site.
This take on CMC variations management sets out various pathways
for the different types of change-related submissions, each with its
own set of expectations and expected timelines.
That the likelihood of and timeframes for approvals is difficult to
predict can prevent MAHs from moving as nimbly as they might like
with finished product manufacturing site transfer. This, in turn, can
present a risk to sustainable product supply - and indeed the rollout
of important and innovative new therapies and treatments. Because
the outcome of the approvals process isn't ultimately known until the
end, which could be many months down the line, there is a temptation
for MAHs to be overly thorough in their submissions, to maximize their
chances of a good outcome.
ICH Q12 PACMP: Streamlining Site
Transfer Approvals
The ICH Q12 guideline provides a globally harmonized framework to
facilitate the management of post-approval CMC changes in a more
transparent, predictable and efficient manner across the product
lifecycle.
It introduces regulatory mechanisms such as established
conditions (ECs), product lifecycle management (PLCM), and the
post-approval change management protocol (PACMP) to simplify and
speed up post-approval change implementation and to encourage
continuous product improvement.
The main aim is to provide greater opportunities for an increased
science- and risk-based approach for assessing changes, with a view
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to greater flexibility in managing post-approval changes. This in
turn is designed to promote manufacturing innovation and ongoing
incremental improvements, while allowing regulatory authorities to
better understand companies' pharmaceutical quality systems (PQSs).
Specifically, PACMP allows MAHs to first have their variation strategy
approved, and then the agreed supportive data evaluated. In practice,
this can cut approval timescales by around six months, because
Applicants can confidently collate the information needed, knowing
that their site change submission strategy is on the right track.
The Evolution of PACMP
As a concept, the PACMP is more than a decade old, used for postapproval
filings in the US and EU, having been first introduced as a
means for MAHs to keep a running record describing all changes
planned during the lifecycle of the medicinal product. Under ICH Q12,
the harmonized international protocol presents a comprehensive plan
for assessing the effect of a proposed change, or multiple (related and
consequential) CMC-only post-approval changes, on the quality of a
product - e.g., its identity, strength, purity, potency, performance, and/
or stability.
The protocol describes specific quality change(s) that the Applicant
would like to implement during the lifecycle of a product and how the
impact can be verified. Based on product process understanding, and
a risk assessment of the potential impact of the change on the quality
of the product, a PACMP would include studies, specific tests, and the
acceptance criteria that demonstrate the lack of negative impact of
the proposed CMC changes on the factors mentioned above.
The main parameters of PACMP are as follows:
* CMC changes only: PACMP-based submissions are not
supported where non-CMC data including non-clinical, clinical
and/or immunogenicity data would be required to support the
change.
* Type of products: PACMPs can be applied to all product types,
i.e., small and large molecules, including vaccines.
* A clear, two-step approach to the regulator's assessment of
any changes:
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Early step 1: evaluation of the strategy for
the change(s).
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Step 2: separate evaluation of the data produced,
based on the agreed strategy.
Geographical Applicability
Although relatively new in its current format, the PACMP tool
presented in the ICH Q12 guideline is aligned with FDA Comparability
Protocols, as used in the US from 2003. The European Medicines
Agency (EMA) was the first global Health Authority to employ ICH Q12
in January 2020, with implementation guidance authorized in March
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