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Change Management
Liam C. Feely, Ph.D.Vice President,Manufacturing Science & TechnologyAbbVie
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Disclosures
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employed or affiliated.
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Changes are extremely common in relation to the production andsupply of a pharmaceutical product over its lifecycle. Example changesinclude:
• Manufacturing process parameters and scale
• Analytical methods
• In-process controls
• Suppliers of Active Pharmaceutical Ingredients (APIs) regulatorystarting materials, reagents, excipients and packaging materials
• Specifications related to ingredients and packaging materials
• Material and Product Shelf Life
• Sites of intermediate, API & product manufacturing /packaging
Change Management, therefore, needs to be an integral andimportant part of any company’s Pharmaceutical Quality System
Context
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Q10 on Change Management (1)
“3. Change Management System (3.2.3)
Innovation, continual improvement, the outputs of processperformance and product quality monitoring, and CAPA drive change.To evaluate, approve, and implement these changes properly, acompany should have an effective change management system. Thereis generally a difference in formality of change management processes
prior to the initial regulatory submission and after submission, wherechanges to the regulatory filing might be required under regionalrequirements.
The change management system ensures continual improvement isundertaken in a timely and effective manner. It should provide a highdegree of assurance there are no unintended consequences of thechange.
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Q10 on Change Management (2)
The change management system should include the following, asappropriate for the stage of the lifecycle:
(a) Quality risk management should be utilized to evaluate proposedchanges. The level of effort and formality of the evaluation shouldbe commensurate with the level of risk.
(b) Proposed changes should be evaluated relative to the marketingauthorization, including design space, where established, and/orcurrent product and process understanding. There should be anassessment to determine whether a change to the regulatory filingis required under regional requirements. As stated in ICH Q8,working within the design space is not considered a change (from
a regulatory filing perspective). However, from a pharmaceuticalquality system standpoint, all changes should be evaluated by acompany’s change management system.
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Q10 on Change Management (3)
The change management system should include the following, asappropriate for the stage of the lifecycle:
(c) Proposed changes should be evaluated by expert teamscontributing the appropriate expertise and knowledge fromrelevant areas (e.g., Pharmaceutical Development, Manufacturing,Quality, Regulatory Affairs, and Medical) to ensure the change is
technically justified. Prospective evaluation criteria for a proposedchange should be set.
(d) After implementation, an evaluation of the change should beundertaken to confirm the change objectives were achieved andthat there was no deleterious impact on product quality.”
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Change Management Process
Stimuli forchange
Impactassessments
Risk assessment &information/dataneed to support
the change
Confirmacceptability ofoutcome and
document
GainRegulatoryapproval
Implement and
conduct postimplementation
verification
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Stimuli For Change (not exhaustive)
Commercial Manufacturing Experience
(Continual knowledge gain &improvement)
Trending of CQAData
Enhancement ofControl Strategy
Change ofShelf Life
Desire to utilizenew technologies
Eliminationof Suppliers
Desire to increasebatch size,
throughput, etc. forAssurance of Supply
InspectionObservations/
cGMPs
Desire to increasenumber of
manufacturing sitesor suppliers for
Assurance of Supply
Additionaldevelopment studiesor knowledge gainedfrom other products
PharmacopeialChanges
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Clear definition of scope• Relevance to other sites?
• Relevance to other products?
Impact on other aspects of the manufacturing process or controlstrategy
Regulatory Impact
• Within or beyond established conditions?• Relevant to an approved post approval change protocol?
Impact Assessment
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Objective is to ensure no unintended consequences of
implementing the change
Risk Identification, Analysis & Evaluation
• Consider input from CMC Scientists, Manufacturing, QA,
Regulatory, Supply Chain, Medical Affairs, etc.
Identify additional experimentation/data needed (risk control/reduction)
• At what scale this should be conducted?
• What existing knowledge informs the level of risk?
• What outcomes would be considered acceptable?
Risk Assessment and data needed to support the change
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If experimental criteria are not met, revert back to risk assessment and
either do not implement change or conduct additional experimentation withadditional controls to ensure no unintended consequences of change
Confirm acceptability of outcome and document
ExperimentalCriteria Achieved?
Do notimplement
change
YES
NO
Conduct experiments withadditional controls
Continue to implementchange
•
Update Risk Assessment
• Update Manufacturing documents and Control Strategy as needed.
• Update any mathematical model as needed
•
Complete re-validation (PPQ) as appropriate
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• Update Regulatory Dossierand submit to RegulatoryAuthorities
• Wait…
• Once Regulatory Approval
received, proceed toimplementation
Gain Regulatory Approval
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• Formally approve commercialbatches and release to market
• Conduct any defined postvalidation monitoring
• Ongoing trending of batch to
batch CQA data to confirm noprocess drift
Implement and conduct post implementation verification
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Example: Adding a new supplier for an excipient
Additional source of supply of lactose• Standard high-shear
wet-granulation process
• Conventional lactose/microcrystalline cellulose
formulation
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Risk Assessment
Literature and internalexperience:
Primary particle size a key variable
in wet granulation
Development experience:
Product dissolution sensitive toextent of granulation
Production Experience:
Dissolution not sensitive to normalvariation in lactose particle size
0
2
4
6
8
10
12
0.1 1.0 10.0 100.0 Particle size, um
V o l u m e
%
New Source
Original Source
Particle size distribution of newsource is outside of developmentand production experience
Potential product impactSource comparability
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Risk Mitigation
Conduct small-scale study:
• Head-to-head process comparison at 2L scale showed no differencebetween original and new source
Verify:
• Extended dissolution testing (profiles) of full scale demonstration batchshowed F2 comparability
Implement source change under normal change controlprocedures:
•
Monitor routine production:• Trending of dissolution results reinforces no impact of change
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Trend Monitoring: Apply Common Sense
3 1 0 0
8 8
3 1 0 0 8 3
3 1 0 0
7 6
3 1 0 0
6 7
3 1 0 0
6 2
3 1 0 0
5 7
3 1 0 0
2 1
3 1 0 0
1 6
3 1 0 0 1 1
R
D - 0 8
- 0 0 0
6
R
D - 0 7
- 0 0 1
0
110
105
100
95
90
Tab Batch Number
I n d i v i d u a l V a l u e
_ X=100.63
+3 Std Dev
Prior to Validation Validation and Launch Build1 2
Lower Limit
Upper Limit
1 2
-3 Std Dev
FLI -Assay
Not all statistical variations require action and adjustment:Resources should focus on patient impact
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Changes relevant to Suppliers and Third Parties
• Additional oversight provided through:
• Quality/Technical Agreements
• Trending of data from Certificates of Analysis
• Audits
Control of supply chain when approvals come through graduallyover a number of years
• Don’t implement until final approval received or
• Implement as approvals come in and make some of version A and
some of version B• Issue becomes even more complicated if a second change is
needed before all approvals received for first change
Additional Complications
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Questions to Consider
Is there a need to standardize best practices?
–Understand stimuli for change?
– Understand scope of change and its implications for other
aspects of the process/control strategy?
– Perform a science and risk-based assessment of the change?
What would need to be articulated in Q12 to encourage best practicesimplementation?
How would these practices be assessed by regulators during aninspection?
How would changes involving third parties, with different qualitysystems, be handled?
Are there specific types of changes that shouldn’t be done under a ‘Doand Tell’ and how might ICH Q12 address this?
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Changes to the manufacture and supply of pharmaceutical products is
common over the product lifecycleChange Management is and integral part of a company’s PharmaceuticalQuality System
The scientific rigor used to confirm that a change will not adversely affectproduct performance is risk based and should be exclusive of whether a prior
regulatory authority approval is needed or not
The variability in timing of regulatory approvals worldwide complicate thesupply chain in relation to making changes in production
Trend monitoring is a valuable tool to ensure product manufacturing remainsin control and also to confirm implemented changes have no adverse effect on
overall product safety and efficacy
The opportunity for ICH Q12 is to enable more changes to be handled purelywithin within a company’s PQS rather than additionally requiring regulatoryapproval prior to implementation
Concluding Remarks
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