05 Feely Change Management ISPE Oct 15 v4

Change Management
Liam C. Feely, Ph.D.

Vice President,
Manufacturing Science & Technology
AbbVie
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Change Management| August 2015 | Company Confidential 2015
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 companys Pharmaceutical Quality System
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.

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
companys change management system.

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 Process

Implement and
conduct post
implementation
verification
Stimuli for
change
Gain
Regulatory
approval
Confirm
acceptability of
outcome and
document
Impact
assessments
Risk assessment &

information/data
need to support
the change
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,
throughput, etc. for
Assurance of Supply
Desire to utilize
new technologies
Pharmacopeial
Changes
Inspection
Observations/
cGMPs
Additional
development studies
or knowledge gained
from other products
Elimination
of Suppliers
Change of
Shelf Life
Desire to increase
number of
manufacturing sites
or suppliers for
Assurance of Supply
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?
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?
10
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
Experimental
Criteria Achieved?
Continue to implement
change
YES
NO
Do not
implement
change
Conduct experiments with

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
11
Gain Regulatory Approval

Update Regulatory Dossier
and submit to Regulatory
Authorities
Wait
Once Regulatory Approval
received, proceed to
implementation
12
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
13
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
14
Risk Assessment
Source comparability
Literature and internal

experience:
12
Volume %
10
New Source
Original Source
Primary particle size a key variable

in wet granulation
8
6
Development experience:
Product dissolution sensitive to

extent of granulation
2
0
0.1
Potential product impact
1.0
10.0
Particle size, um
100.0
Particle size distribution of new

source is outside of development
and production experience
Production Experience:
Dissolution not sensitive to normal
variation in lactose particle size
15
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
16
Trend Monitoring: Apply Common Sense

FLI -Assay
1
Prior to Validation 2
Validation and Launch Build
Upper Limit
Individual Value
110
105
+3
_ Std Dev
X=100.63
-3 Std Dev
100
95
90
Lower Limit
16
10
88
57
11
21
06
83
67
76
62
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
-0
-0
31
31
31
31
31
31
31
31
31
07
08
RD
RD
Tab Batch Number
Not all statistical variations require action and adjustment:

Resources should focus on patient impact
17
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
Dont 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
18
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 shouldnt be done under a Do
and Tell and how might ICH Q12 address this?
19
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 companys 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 companys PQS rather than additionally requiring regulatory
approval prior to implementation
20

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Change Management

Liam C. Feely, Ph.D.

Change Management| August 2015 | Company Confidential 2015

Change Management| August 2015 | Company Confidential 2015

Q10 on Change Management (1)

Change Management| August 2015 | Company Confidential 2015

Q10 on Change Management (2)

Change Management| August 2015 | Company Confidential 2015

Q10 on Change Management (3)

Change Management| August 2015 | Company Confidential 2015

Change Management Process

Risk assessment &

Stimuli For Change (not exhaustive)

Change Management| August 2015 | Company Confidential 2015

Change Management| August 2015 | Company Confidential 2015

Risk Assessment and data needed to support the change

Change Management| August 2015 | Company Confidential 2015

Confirm acceptability of outcome and document

Conduct experiments with

Update Risk Assessment

Gain Regulatory Approval

Change Management| August 2015 | Company Confidential 2015

Implement and conduct post implementation verification

Change Management| August 2015 | Company Confidential 2015

Example: Adding a new supplier for an excipient

Change Management| August 2015 | Company Confidential 2015

Literature and internal

Primary particle size a key variable

Product dissolution sensitive to

Potential product impact

Particle size distribution of new

Change Management| August 2015 | Company Confidential 2015

Implement source change under normal change control

Monitor routine production:

Trending of dissolution results reinforces no impact of change

Change Management| August 2015 | Company Confidential 2015

Trend Monitoring: Apply Common Sense

Not all statistical variations require action and adjustment:

Control of supply chain when approvals come through gradually

Change Management| August 2015 | Company Confidential 2015

Change Management| August 2015 | Company Confidential 2015

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