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Change Management| August 2015 | Company Confidential © 2015 2
Disclosures
The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to the organization with which the presenter is employed or affiliated.
These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved
Change Management| August 2015 | Company Confidential © 2015 3
Changes are extremely common in relation to the production and supply of a pharmaceutical product over its lifecycle. Example changes include: • Manufacturing process parameters and scale • Analytical methods • In-process controls • Suppliers of Active Pharmaceutical Ingredients (APIs) regulatory
starting 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 and important part of any company’s Pharmaceutical Quality System
Context
Change Management| August 2015 | Company Confidential © 2015 4
Q10 on Change Management (1)
“3. Change Management System (3.2.3)
Innovation, continual improvement, the outputs of process performance and product quality monitoring, and CAPA drive change. To evaluate, approve, and implement these changes properly, a company should have an effective change management system. There is generally a difference in formality of change management processes prior to the initial regulatory submission and after submission, where changes to the regulatory filing might be required under regional requirements.
The change management system ensures continual improvement is undertaken in a timely and effective manner. It should provide a high degree of assurance there are no unintended consequences of the change.
Change Management| August 2015 | Company Confidential © 2015 5
Q10 on Change Management (2)
The change management system should include the following, as appropriate for the stage of the lifecycle:
(a) Quality risk management should be utilized to evaluate proposed changes. The level of effort and formality of the evaluation should be commensurate with the level of risk.
(b) Proposed changes should be evaluated relative to the marketing authorization, including design space, where established, and/or current product and process understanding. There should be an assessment to determine whether a change to the regulatory filing is 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 pharmaceutical quality system standpoint, all changes should be evaluated by a company’s change management system.
Change Management| August 2015 | Company Confidential © 2015 6
Q10 on Change Management (3)
The change management system should include the following, as appropriate for the stage of the lifecycle:
(c) Proposed changes should be evaluated by expert teams contributing the appropriate expertise and knowledge from relevant areas (e.g., Pharmaceutical Development, Manufacturing, Quality, Regulatory Affairs, and Medical) to ensure the change is technically justified. Prospective evaluation criteria for a proposed change should be set.
(d) After implementation, an evaluation of the change should be undertaken to confirm the change objectives were achieved and that there was no deleterious impact on product quality.”
Change Management| August 2015 | Company Confidential © 2015 7
Change Management Process
Stimuli for change
Impact assessments
Risk assessment & information/data need to support
the change
Confirm acceptability of outcome and
document
Gain Regulatory approval
Implement and conduct post
implementation verification
Change Management| August 2015 | Company Confidential © 2015 8
Stimuli For Change (not exhaustive)
Commercial Manufacturing Experience (Continual knowledge gain &
improvement)
Trending of CQA Data
Enhancement of Control Strategy
Change of Shelf Life
Desire to utilize new technologies
Elimination of Suppliers
Desire to increase batch size,
throughput, etc. for Assurance of Supply
Inspection Observations/
cGMPs
Desire to increase number of
manufacturing sites or suppliers for
Assurance of Supply
Additional development studies or knowledge gained from other products
Pharmacopeial Changes
Change Management| August 2015 | Company Confidential © 2015 9
Clear definition of scope • Relevance to other sites? • Relevance to other products?
Impact on other aspects of the manufacturing process or control strategy
Regulatory Impact • Within or beyond established conditions? • Relevant to an approved post approval change protocol?
Impact Assessment
Change Management| August 2015 | Company Confidential © 2015 10
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
Change Management| August 2015 | Company Confidential © 2015 11
If experimental criteria are not met, revert back to risk assessment and either do not implement change or conduct additional experimentation with additional controls to ensure no unintended consequences of change
Confirm acceptability of outcome and document
Experimental Criteria Achieved?
Do not implement
change
YES
NO
Conduct experiments with additional controls
Continue to implement change
• Update Risk Assessment
• Update Manufacturing documents and Control Strategy as needed.
• Update any mathematical model as needed
• Complete re-validation (PPQ) as appropriate
Change Management| August 2015 | Company Confidential © 2015 12
• Update Regulatory Dossier and submit to Regulatory Authorities
• Wait…
• Once Regulatory Approval received, proceed to implementation
Gain Regulatory Approval
Change Management| August 2015 | Company Confidential © 2015 13
• Formally approve commercial batches and release to market
• Conduct any defined post validation monitoring
• Ongoing trending of batch to batch CQA data to confirm no process drift
Implement and conduct post implementation verification
Change Management| August 2015 | Company Confidential © 2015 14
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
Change Management| August 2015 | Company Confidential © 2015 15
Risk Assessment
Literature and internal experience: Primary particle size a key variable in wet granulation
Development experience: Product dissolution sensitive to extent of granulation
Production Experience: Dissolution not sensitive to normal variation in lactose particle size
0
2
4
6
8
10
12
0.1 1.0 10.0 100.0 Particle size, um
Volu
me
%
New Source Original Source
Particle size distribution of new source is outside of development and production experience
Potential product impact Source comparability
Change Management| August 2015 | Company Confidential © 2015 16
Risk Mitigation
Conduct small-scale study: • Head-to-head process comparison at 2L scale showed no difference
between original and new source
Verify: • Extended dissolution testing (profiles) of full scale demonstration batch
showed F2 comparability
Implement source change under normal change control procedures: • Monitor routine production:
• Trending of dissolution results reinforces no impact of change
Change Management| August 2015 | Company Confidential © 2015 17
Trend Monitoring: Apply Common Sense
3100
88
3100
83
3100
76
3100
67
3100
62
3100
57
3100
21
3100
16
3100
11
RD-0
8-000
6
RD-0
7-001
0
110
105
100
95
90
Tab Batch Number
Indi
vidu
al V
alue
_X=100.63+3 Std Dev
Prior to Validation Validation and Launch Build1 2
Lower Limit
Upper Limit1 2
-3 Std Dev
FLI -Assay
Not all statistical variations require action and adjustment: Resources should focus on patient impact
Change Management| August 2015 | Company Confidential © 2015 18
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 gradually over 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
Change Management| August 2015 | Company Confidential © 2015 19
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 practices implementation?
How would these practices be assessed by regulators during an inspection?
How would changes involving third parties, with different quality systems, be handled?
Are there specific types of changes that shouldn’t be done under a ‘Do and Tell’ and how might ICH Q12 address this?
Change Management| August 2015 | Company Confidential © 2015 20
Changes to the manufacture and supply of pharmaceutical products is common over the product lifecycle
Change Management is and integral part of a company’s Pharmaceutical Quality System
The scientific rigor used to confirm that a change will not adversely affect product 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 the supply chain in relation to making changes in production
Trend monitoring is a valuable tool to ensure product manufacturing remains in 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 purely within within a company’s PQS rather than additionally requiring regulatory approval prior to implementation
Concluding Remarks