Change Management

Liam C. Feely, Ph.D.

Vice President,
Manufacturing Science & Technology
AbbVie
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Change Management| August 2015 | Company Confidential © 2015 2

Context
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

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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.

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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.

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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.”

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Change Management Process
Implement and
conduct post
implementation
Stimuli for verification
change
Gain
Regulatory
approval

Confirm
Impact acceptability of
assessments outcome and
document

Risk assessment &

information/data
need to support
the change

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Stimuli For Change (not exhaustive)
Commercial Manufacturing Experience
(Continual knowledge gain &
improvement)
Enhancement of
Control Strategy Trending of CQA
Data
Desire to increase
batch size,
Desire to utilize throughput, etc. for Elimination
new technologies Assurance of Supply of Suppliers

Inspection Pharmacopeial
Observations/ Changes
cGMPs

Desire to increase
number of
Additional Change of
manufacturing sites
development studies Shelf Life
or suppliers for
or knowledge gained Assurance of Supply
from other products

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Impact Assessment

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?

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Risk Assessment and data needed to support the change
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?

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Confirm acceptability of outcome and document
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

Continue to implement
YES change
Experimental
Criteria Achieved?
NO
Do not
implement
Conduct experiments with change
additional controls

• 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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Gain Regulatory Approval

• Update Regulatory Dossier

and submit to Regulatory
Authorities

• Wait…

• Once Regulatory Approval

received, proceed to
implementation

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Implement and conduct post implementation verification

• 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

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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

Source comparability Potential product impact

12 Literature and internal
10
New Source
Original Source
experience:
8
Primary particle size a key variable
in wet granulation
Volume %

4
Development experience:
Product dissolution sensitive to
2 extent of granulation
0
0.1 1.0 10.0
Particle size, um
100.0 Production Experience:
Particle size distribution of new Dissolution not sensitive to normal
source is outside of development variation in lactose particle size
and production experience

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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

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Trend Monitoring: Apply Common Sense

FLI -Assay
1
Prior to Validation 2
Validation and Launch Build
110 Upper Limit

105
Individual Value

+3
_ Std Dev
100 X=100.63
-3 Std Dev

95

90 Lower Limit

010 006 011 016 0 21 057 062 067 076 083 088
-0 -0 31
0
31
0
31
0
31
0
31
0
31
0
31
0
31
0
31
0
- 07 - 08
RD RD
Tab Batch Number

Not all statistical variations require action and adjustment:

Resources should focus on patient impact

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Additional Complications

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

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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 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?

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Concluding Remarks
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

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