How to make use of Post approval change management protocol in

How to make use of Post
approval change
management protocol in
life cycle management of
pharmaceuticals
Mats Welin
Senior expert
Medical Products Agency
Uppsala, Sweden
26th Annual
EuroMeeting
25-27 March 2014
ACV, Vienna
Austria
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Life cycle managment
• Managing all phases in the life of a product from
the initial development through marketing until
the product´s discontinuation.
• This talk will concentrate on actions post
approval- how to improve the process/ product
with a sufficient regulatory oversight but still
allowing for flexibility.
– basics
– variations
– Post approval change management protocols
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Regulatory oversight
• What is in the filed dossier
– Descriptions of processes and monitoring
thereof, validation, testing of starting material,
intermediates, drug substance, drug product
etc.- Basis for approval of application
• GMP related issues
– quality systems, knowledge managment,
adherence to GMP requirements, trending,
change control etc. Basis for approval of site
4
Regulatory oversight (cont.)
• To reach a preferred state in accordance with
Q8-11, these two parts need to work togethere.g. certain residual risks identified in an
assessment could be cleared through
appropriate GMP related systems assuring that
the process is in control.
• This calls for an enhanced collaboration
between inspectors and assessors and possibly
more product related inspections
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Variations
• Requested for changes to the MA post approval
• Classification of variations depending on level of
risk to public or animal health & impact on the
quality, safety and efficacy of medicinal product
concerned
• Variation regulation handled by the Commission.
Classification group at EMA-recommendations
may or may not be followed.
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Types of Variations
Changes not requiring
prior approval
Design
space
Type IA
Do and tell
Changes requiring
prior approval
Type IB
Type II
Extension
Variations
Assessment adapted to the level of risk
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Introd
uction
to
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Post Approval Change Management
Protocols (PACMPs)
• Introduced in the EU legislation 2010 (2010/C
17/01 )
• Option for a faster and more predictable
implementation of changes post-approval.
• Uses a step-wise procedure
– starting with an evaluation of the strategy for
the change
– followed by a separate evaluation of the data
produced based on the agreed strategy.
PACMP
Strategy
•Planned
studies
•Acceptance
criteria
•Methods
+ Results
Strategy
•Planned
studies
•Acceptance
criteria
•Methods
Early Step 1:
“Traditional” approach
Evaluation of a
proposed variation as a
‘whole’ (Strategy +
Results)
Submission of
a Protocol
MAA / Type II
Variation
+ Results
Quick Step 2:
Implementation of
the change
Type IB Variation for
biologics/IA or IB for
small molecules
Post Approval Change Management
Protocol (PACMP)
• Apply to all medicinal products for human
and veterinary use including
biotechnological or biological products.
– Irrespective of whether a traditional or
enhanced Quality by Design (QbD) approach
has been used for product development.
Post Approval Change Management
Protocol (PACMP)
• May be included in an original marketing
authorisation application or (line) extension
application, or be submitted as a stand alone
variation.
• Not feasible for biological medicinal products
where non-clinical/clinical data are needed as
part of the comparability exercise.
• A PACMP should not include changes that
would result in a line extension.
Post Approval Change Management
Protocol (PACMP)
• Protocols should be specific to a product
although the same management strategies may
be applicable to other products and processes.
• Companies are recommended to submit
PACMPs only for those changes that they are
highly likely to implement and whose feasibility
has already been investigated and is supported
by relevant data.
– Inclusion of several PACMPs for a given process may
cause problems as the prechange “starting point” may
differ depending on the number introduced.
Post Approval Change Management
Protocol (PAMPC) - Content of the protocol
EU guideline on Quality:
Questions and Answers Post approval change
management protocols
(EMA/CHMP/CVMP/QWP/586330/2010)
Post Approval Change Management
Protocol (PAMPC) - Content of the protocol
•
•
•
•
•
•
Justification for the need for a specific change(s) within a reasonable
timeframe.
Commitment to update the approved protocol, due to significant changes to
test methods/acceptance criteria or new knowledge or regulatory
requirements.
A detailed description of the change.
Data from development or pilot scale studies supporting that proposed
approach is feasible.
Risk assessment of the impact of the change on product quality.
Identification for potential risks and details on the strategy of how the risks
will mitigated or managed.
Appropriateness of the approved control strategy and additional tests
needed
Post Approval Change Management
Protocol (PAMPC) - Content of the protocol,
continued
•
•
•
•
•
Description of the studies to be performed, and the test methods and
acceptance criteria that will be used
For biologics, the approach to be used to demonstrate the comparability of
the pre- and post- change product (IPC test, spec’s and extended
characterisation studies).
A plan for stability studies should be included, if appropriate;
For chemical medicinal products, a proposal of how the implementation of
the change will be reported, as a Type IA / IAIN variation or Type IB
variation
For biological medicinal products the reporting shall always be made as a
Type IB variation
Post Approval Change Management
Protocol (PAMPC) - Content of the protocol
• A prerequisite for the implementation of a change
described in an approved protocol is that all studies
described in the protocol have been performed, and the
results of the studies comply with the predefined criteria
set out in the protocol.
• The variation procedures used for reporting of data
cannot include e.g. justifications for deviations to an
established protocol or the pre-defined acceptance
criteria → revision or submission as a standard
variation.
• Worthwhile to discuss with rapporteurs though
PACMPs- whats the benefit?
• Predictability !!!
– If the protocol is approved and the results as
expected, a quick approval can be foreseen
with no requests for further data- validation
batches can be commercialised
• Delays due to questions at initial stage not
end of the world
• Faster approval once the variation is ready
for implementation
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PACMPs – experience so far
• Primarily used for biotechnological/biological products
– 36 applications for biotech products in the centralized
procedure
• 6 in MAA ( 2 withdrawn during assessment) the
rest as type IIs
– < 10 applications for chemical products in the
centralized procedure
No official figures available on national/MRP applications
but according to SE experience the number is low with a
similar overweight seen for biotech products.
Why is this?
• Many variations which are classified as
type IIs for biologicals are IB´s for small
molecules- less incentive to use a
procedure starting with a type II variation
by default.
– But if put in the initial application and
approved, the reporting category will likely be
lower. Therefore also likely to be of interest
for small molecules
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PACMPs – experience so far
• Most applications have referred to process
transfers to new manufacturing sites.
• Some for changes of the manufacturing
process such as
– Reorganisation of the process
– Change of column matricides/filters
– Change of other raw materials
– Up-scale of production
PACMPs – experience so far
Problems seen so far:
• Primarily linked to the timing of the
application of the PACMP
– Changes not described in sufficient detail
– Too limited data to support that the change
is feasible
– Too limited data to support the proposed
strategy for definition of acceptance criteria
– Content of the follow-up variation
PACMPs- future opportunities
• Combination of PACMPs and worksharing
to handle many products undergoing the
same change (e.g. change in filling,
change of rubber stopper)
– One application to cover the work to be done
can serve for all. Product specific
implementation when data is available
• Possibility of a reporting IA opportunity for
biologicals as well in the future?
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Life cycle managment -Conclusion
• Holistic approach which needs more extensive
interaction assessors/ inspectors
• Regulation of variations incl PACMPs are living
documents- forward your proposals for better fit
with need
• Make use of PACMPs as this will smoothen
introduction of variations both for small
molecules and biotech- we are happy to discuss
your proposals. F2F or written advice
• Acknowledge the complexity if several PACMPs
deals e.g. with the manufacturing process
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Thank you
Questions?
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