Change Control / Change Management
A Q10 Perspective
Presented by
Karen Ginsbury
PCI Pharmaceutical Consulting Israel Ltd.
for IFF
February 2009
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Course Content
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Change Control: What companies are used to doing
ICH Q10 and the Change Management System
Use of Risk Assessment to evaluate proposed changes
Change Management and the Product Lifecycle:
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Managing changes for investigational products
Changes during technology transfer
Changes in commercial product
Product discontinuation
• Change of product ownership and change in the
context of the current fiscal whirlwind
• Evaluation of change effectiveness and reversal of
ineffective changes
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What is change?
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INTRODUCTION
Alteration
Modification
Variation
Transformation
Revolution
Conversion
Adjustment
Amendment
Difference
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FDA Warning Letter
21 cfr 211.100a
• Written procedures for production and
process CONTROL to assure that the
drug product has the strength, quality,
identity, purity they are purported to have.
• Procedures including any CHANGES
reviewed and approved by appropriate
functions and QA
European Directive
• “When any new manufacturing formula or
method of preparation adopted…demonstrate
suitability for routine processing.”
• “Significant amendments to the
manufacturing process, including any change
in equipment or materials, which may affect
product quality and / or process
reproducibility should be validated”
GMP Regulations
• 21 CFR part 210, 211
• EU directive / orange guide
• Neither one specifically mentions change
control and even process validation was
an after thought
• This is presently being addressed
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ICH Q10: Pharmaceutical Quality Systems
The change management system ensures
continual improvement is undertaken in a
timely and effective manner while
providing a high degree of assurance
there are no unintended consequences
of the change
Quality System Lifecycle
• The concept of Q8, 9 and 10 is an all
embracing concept that addresses
– Product
– Process
Lifecycle
• The lifecycle of a product / process
involves constant change
• Change is INEVITABLE and is a part of
continuous improvement
ICH Q9
QUALITY RISK MANAGEMENT
• Managing Change is Managing Risk
• Provides a detailed description including
tools for risk management including risk
assessment and how to perform it
• Provides flow diagrams that define the
process (see next slide)
Q9 - Overview of Quality Risk Management Process
Q10 – Pharmaceutical Quality System
Q10 - Enablers
• Knowledge management
(a systematic approach to acquiring, analyzing, storing and disseminating
information related to products, processes and components)
• Quality risk management
(Quality risk management can provide a proactive approach to identifying
and controlling potential risks to quality throughout the lifecycle)
enable a consistent scientific approach to achieve the Q10 objectives
• (Some) Sources of knowledge:
– prior knowledge (public domain or internally documented),
pharmaceutical development studies, technology transfer activities,
process validation studies over the product lifecycle, manufacturing
experience, continual improvement and
change management activities
Preventing Unintended Consequences
• Identify risks associated with the change
– Consider the change itself
– It’s impact on product and process
• DON’T forget potential impact on OTHER
systems, products, processes
• We are compliant when all runs smoothly
• Change (and deviations) are dangerous
because of the potential for loss of control
Preventing Unintended Consequences
• Analyze risks and see how you can reduce
the likelihood of something going wrong
• What CONTROLS can be introduced to help
reduce consequences
• What MONITORING methods can be used
to see if you have achieved the intended
result
• How will you COMMUNICATE the CHANGE
PLAN to stakeholders = TRAINING
Preventing Unintended Consequences
• What documentation is to accompany
implementation of the change
• Who is going to be responsible for follow-up
on test results and measuring the
effectiveness (Success or Failure) of the
change
• Where will that be documented and how will
this person be notified about ACTUAL date
of implementation
Product Impact
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Small scale off-line study / studies?
First batch manufactured?
First three batches manufactured?
Additional testing of the batch?
Process validation? (lifecycle concept)
Stability testing?
Environmental monitoring increased?
Other...
Question
• Are there any current
GMP requirements / quality
requirements pertaining
to R&D?
• In particular to change
management in R&D i.e investigational
products ?
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Answers
• 21 CFR part 211.100a – currently applies
when manufacturing for human use
(except for phase 1)
• Annex 13 of EU GMPs refers to all EU
GMP + additional requirements for IMPs
so….YES
• ICH Q10 addresses:
– Product development
– Technology transfer
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Additional Answer for APIs
• “Changes are expected during
development, as knowledge is gained and
the production is scaled up. Every change
in the production, specifications, or test
procedures should be adequately
recorded”(ICHQ7A, §19.70)
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The stated purpose of Q10
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Who is responsible to…
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And…
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Understanding Product and Process
• We can’t manage change
• Without managing the development
process
• Q10 Enablers
– Knowledge Management
• Q9 tools:
– Risk Management
– DOE
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No more magic #3!
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Change is not much Liked!
• Common reasons that people fear change:
– I won’t understand / be incompetent
– Risk of change is greater than risk of leaving
things as is
– Fear of hidden agenda: this is the start of a
bigger change that will be bad for me
– Emotional: I set up the process as is
– Genuine belief that the idea is bad
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Overcoming Resistance to Change
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Education and communication
Participation and involvement
Facilitation and support
Negotiation and agreement
Manipulation and co-optation
Explicit and implicit coercion
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Overcoming Resistance
• The proponent of a change may perceive
as resistance what his or her audience
considers careful assessment and scrutiny
• Almost every change requires the
cooperation, collaboration, and coownership of others
• Only by giving the assessment and
scrutiny of these people full consideration
will the change be accepted and succeed
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Causes of Resistance
Questions
Objectives
Layers of Resistance
Situation assessment, description of
“current reality,” identification of core
problem and assumptions that
1) Lack of agreement on the
What to change?
sustain it.
problem
Diagnosis, systemic root cause
analysis.
2) Don’t agree on direction
Describe solution, describe strategy for a solution
to attain the desired state, and avoid 3) Don’t think solution will
truly address the problem
What to change to? undesirable side effects.
Plan, decision-making, and solution 4) The solution will lead to
development.
new, undesirable side
effects (“Yes, but…”)
5) Lack of a clear path
Develop detailed plans and tactics
around obstacles blocking
that will clarify what needs to happen the solution
How to make the
Synchronize efforts of the group in
6) Lack of follow-through
implementation of the strategy.
even after agreement to
change happen?
Planning, team-building, and
proceed with the solution
leadership
(unverbalized fear or
concerns)
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The Vitamin B12 Story
• “It wasn’t a change….
It was an improvement”
• All changes are intended as improvements
• We mess up because we failed to
consider the associated RISKS !
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Q10 Objectives
(every one involves change)
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Achieve Product Realisation: Establish, implement and
maintain a set of processes that provides a product with appropriate
quality attributes for the needs of patients, health care professionals,
regulatory authorities (includes compliance with marketing
authorisations) and internal customers
Establish and Maintain a State of Control: Develop and
use effective monitoring and control systems for process
performance and product quality to provide assurance of continued
process suitability and capability. Quality risk management can be
useful in establishing the monitoring and control system
Facilitate Continual Improvement: Identify and implement
appropriate product quality improvements, process improvements,
variability reduction, innovations, and pharmaceutical quality system
enhancements, thereby increasing the ability to consistently fulfil
quality needs. Quality risk management can be useful to identify and
prioritise areas for improvement
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Q10 – Continual Improvement and
Change Management
• Reduce variability through process
understanding (application of knowledge
throughout the product life cycle)
• Use data that your company has collected
to evaluate the risks associated with
changes or the failure to make those
changes
Q10 – Continual Improvement
PREVENT
DETECT
CORRECT
ANALYZE
Quality of Drug Products
• Efficacy:
It does what it is meant to do
(gets rid of your headache, lowers blood
pressure etc.)
• Safety:
Without harming the user / Patient
(liver toxicity, nausea, hallucinations)
• FIT FOR USE
(not: meets customer’s requirements)
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Product Registration File
Manufacturer’s declaration of:
• Product composition
• Equipment / systems participating in the
manufacturing process
• Raw material / component manufacturers
• Critical production / process parameters
e.g. mixing time, temperature, pressure
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Quality Systems Approach to
CGMP Regulation
• Risk-based pharmaceutical quality
assessment to replace CMC review
process
• Reduce need for manufacturing
supplements
• Encourage implementation of new
technologies (e.g. PAT) and facilitate
continuous manufacturing improvements
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Desired State
 Product quality and performance achieved and
assured by design of effective and efficient
manufacturing processes
 Product specifications based on mechanistic
understanding of how formulation and process
factors impact product performance
 Continuous "real time" assurance of quality
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Desired State
 Regulatory policies tailored to recognize the
level of scientific knowledge supporting product
applications, process validation, and process
capability
 Risk based regulatory scrutiny relate to the:
 level of scientific understanding of how formulation
and manufacturing process factors affect product
quality and performance, and
 the capability of process control strategies to prevent
or mitigate risk of producing a poor quality product
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Product Control Strategy
• A planned set of controls, derived from
current product and process
understanding that assures process
performance and product quality
ICH Q8: Integrating QbD and Risk Mitigation Dimensions
Tests & Controls -Risk Mitigation
Illustrative Examples of points to
Development Objectives
consider
Risks to Quality
Intended Use
Risk of incorrect identity
Route of administration
Poor product & process
Patient population
Changes in clinical trial product
…..
(Bridging studies)
Product Design
Inadequate Design Specifications
Critical to quality and performance?
Risk of unqualified impurities
Design Specifications
Risk of poor bioavailability
(Customer requirements)
Risk of incorrect expiry date
Risk of inadequate controls
Regulatory
Risks After Approval
Specs.
[Risk of SUPAC,..]
Manufacturing Process
[unrepresentative test samples]
and its Control
[Inadequate Facility and QS]
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ICH Q9
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Change Plans
• Comparability Protocol:
– Comprehensive, detailed, written plan that
describes specific tests and studies, analytical
procedures and acceptance criteria to be
achieved to demonstrate lack of adverse
effect for a CMC change that may relate to
safety or efficacy
• Rational Experimental Design
• Ongoing Data Evaluation
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Validation
• Validation provides a snapshot of a
system, an equipment item, a process at
start-up
• i.e. control
• The control can be easily lost
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Quality Systems Approach to Validation
• Process validation provides initial proof,
through commercial batch manufacture
that the design of the process produces
the intended product quality
• Although initial commercial batches
provide supportive evidence, the entire life
cycle should be addressed
• Process validation is not a one time event
but an activity that continues
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Quality Systems Approach to Validation 2
• As experience is gained, opportunities for
process improvement may become
evident
• Change control systems should provide for
dependable mechanism for prompt
implementation of technically sound
manufacturing improvements
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Quality Systems Approach to Change 3
• When implementing a change, determining its
effect should be based on monitoring and
evaluating those elements that may be affected
based on an understanding of the process
This allows:
– Steps taken to implement the change
– Effects of the change on the process
to be considered systematically
• Evaluating the effects may require additional
tests e.g. in-process, stability etc.
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Proposed Rule - Change Control
(Now officially dead)!
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Proposed Rule - Changes
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What is Decision Making?
• Identify and choose alternatives based on the values and
preferences of the decision maker:
– identify as many alternatives as possible
– choose the one that
• (1) has the highest probability of success or effectiveness
• (2) best fits with company goals, desires, values
• Sufficiently reduce uncertainty and doubt about alternatives to
allow a reasonable choice to be made from among them
– This definition stresses the information-gathering function of decision
making
– Uncertainty is reduced rather than eliminated
– Very few decisions are made with absolute certainty because complete
knowledge about all alternatives is seldom possible
– Therefore:
EVERY DECISION INVOLVES A CERTAIN
AMOUNT OF RISK
The Decision Making Chain
EVALUATE
FRAME
DECIDE
IMPLEMENT
COMMUNICATE
The Decision Making Chain Influences
EVALUATE
FRAME
quality
regulatory
DECIDE
IMPLEMENT
cost
COMMUNICATE
time
Deming and Juran on Total Quality
• “Total quality has had a great impact
on...the way corporations manage and
organize their decision-making process”
• Total Quality Management includes reorganizing human resources so that
people, the greatest resource, use their
time to the greatest effect
A rose by another name?
• The Japanese have a decision-making process
that minimizes problems through pre-impact
extensive evaluation
• Feedback is requested up and down and across
the organization and only when consensus is
reached is action taken
• In Western decision making action is taken and
extensive evaluation made after the decision
has already been implemented
“scientific management and assembly line”
Change and Risk Management
• Evaluate first in order to make actions as
risk-free as possible
• Involve as many company members as
possible in the process
• Empower operators in decision-making
processes in their production sphere
Changes to Registration File / MA
• Question # 1 for any change:
• Does it constitute a change in the
registration file?
• If yes: prior approval, notification or annual
update?
• If no: can proceed through change control
within company
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Change - for better or worse
• “This is going to improve the process
yield”
• “The product is going to be better”
• “We are going to improve the pressure
differential”
• “We are going to sterilize the water system
daily”
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Not all Change is good
• There are inherent dangers in making
changes which are not always readily
apparent
• Therefore it is essential to be prepared for
change and to have the right professionals
assessing the dangers
• Need to be in a situation where you can
forecast effects
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API GMP (ICH Q7A)
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API GMP (ICH Q7A) - 2
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API GMP (ICH Q7A) - 3
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Define Change
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Change IS NOT = to Deviation
A DEVIATION may result in Change
Change may be temporary or permanent
Change may or may not affect product
A planned deviation is actually a
temporary change
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Description of Change
• Sufficiently detailed to allow reviewers to
make relevant decisions and Risk
Assessment
• Usually need to attach diagrams and
verbiage (words)
• Lack of detail results in poor review
• Not sufficient to refer to other documents
because reviewers won’t go to look at
them before approving the change
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Reason for Change
• DO NOT approve change unless there is a
tangible benefit or need which is being
realised
• Many changes are proposed as “nice to
have” e.g. you decide to do up your
apartment because its old - but it was
doing fine
• If it ain’t broken - don’t fix it ? Who
decides?
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Reason for Change
• QA function is to stop non-essential change ?
• QA should see change as a potential show
stopper ?
• QA should be fearful of change
• QA must approve change fast where shown
to be necessary
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Professional Judgement
• What is the basis for decision making?
Ask for help:
– Engineering / Maintenance
(Requires mutual trust)
– Production / Operations
(are likely to benefit)
– BEWARE of production pharmacists
– RA
– R&D
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Professional Judgement - 2
• What is the status of the registration file
• Does the change require:
– Prior approval
– Prior notification
– Annual update
– No notification required
• If any of the first three: how will it be
controlled?
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Implementation
• Temporary / Permanent
– Not sufficient that change has been approved
– What needs to be addressed: documentation
– How is the change to be conveyed to relevant
persons e.g. instructions to Maintenance, to
Production, to QA
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Implementation 2
• Is product likely to be affected?
• How are the first batches to be produced
after the change to be handled?
• Is there a system for flagging batches?
• How are personnel informed?
• Is stability data required?
• Validation ?
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Change Management Plan
• The change control form should constitute
a plan of action which allows
implementation to be controlled throughout
each step
• Relevant personnel must be involved in
the review process at several critical
points
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Types of Changes
• Alteration of pressures in dry production /
sterile / biotech facility
• Modification of motor on tabletting
machine
• Addition of user points to purified water
system
• Change control system in autoclave
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Dangers
• Knock-on effect:
– intend to improve one parameter and cause
trouble with another
e.g. pressures improve but airflow patterns
result in turbulence and failure of media fill,
increased contamination
• Operation successful - Patient dies
– motor replaced, machine operates better but
can’t make tablets which meet specs
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Defining the Change
1. Replacement of a formulation vessel used for
manufacture of a suspension with a new one
of exactly the same kind – same manufacturer,
same URS
2. Adding a user point to the Purified Water
System
3. Raising the pressure differential in the aseptic
gowning room
4. Changing a key excipient in a tablet
formulation (Magnesium stearate?)
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Describe the change to be performed
• Provide sufficient detail to be able to
assess the change
i.e. allow for comparison of old and new
• May want to include diagrams
• May want to attach other information
(relevant and directed – not just huge
amount of paper)
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Reason for the Change
• This can be confusing – bear in mind, you
need to do risk assessment
• Be careful not to focus on the benefits to
the exclusion of dangers / risks
• But the reason should provide a concrete
improvement or be essential (e.g.
manufacturer of excipient going out of
business)
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Identify the Risks
• Think as broadly as you possibly can:
– Risks to the specific product / processes or
system or equipment involved
– Risks to other systems that are validated /
qualified
– Regulatory risk: will the change require:
• Prior approval: in all markets (if global company)
will the approval take the same amount of time or
will you need to manufacture old process and new
process for different countries?
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Mitigate the Risks
• Strategies might include:
– Performing small scale studies including
stability with DOE
– Review of similar changes performed in the
past for other products or processes and how
they were handled
– Other...
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Communicate the Risks
• Hold a stakeholders meeting to discuss
the change
• Discuss risks and proposed control
methods
• Have a brainstorming session (Ishikawa or
fishbone diagram is useful)
• Then assess the outcome and design the
change plan
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Strategies for Monitoring
• What metrics are you going to use:
– Could be intensive testing of parameters that are
normally monitored
– Could be introduction of tests normally reserved for
stability program e.g. impurity profile, or more
complex QC tests
– Could be use of tests that are not usually used for this
product / process (validation of method? Acceptance
criteria)
– Could be additional environmental monitoring
– Other...
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Strategies for Monitoring
• Product impact:
– Stability testing?
– Follow one parameter or all?
– Process validation: three batches or one
batch and compare to initial process
validation...with statistical criteria?
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Metrics
• MUST have clear acceptance criteria or it
is not possible to monitor post change
• Who defines the criteria, where and who
approves them
• Who will be responsible for taking the
additional samples?
• Who will test them...do they know how and
why and acceptance criteria?
(communication)
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Metrics
• Who is the Change Manager?
• No use defining acceptance criteria for
monitoring the effectiveness of the change
if:
– It is not clear on what day, at what time and
for which batch of which product, the change
was first implemented
– Maintenance have not finished the
implementation but production restarts
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Metrics
• Where are the acceptance criteria
documented?
• Needs to be a controlled document:
– change control protocol?
– Validation protocol?
– Stability protocol?
– All of the above?
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Responsibilities
• Should be clearly assigned and
communicated
• Need a documented training session prior
to implementation
• Need to coordinate implementation
• Need follow-up especially of any
regulatory commitments
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Product, Product, Product
• Throughout the change control process
the major questions to be asked over and
over….
“is product going to be affected?”
“how can I prove that it isn’t”
“what tests will demonstrate this”
“have the test results been reviewed
before production is renewed?”
“has product been quarantined?”
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Change Management Through Lifecycle
Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuation
Change is an
inherent part of the
development process
and should be
documented; the
formality of the
change management
process should be
consistent with the
stage of
pharmaceutical
development.
The change
management system
should provide
management and
documentation of
adjustments made to
the process during
technology transfer
activities.
A formal change
management system
should be in place
for commercial
manufacturing.
Oversight by the
quality unit should
provide assurance of
appropriate science
and risk based
assessments.
Any changes after
product
discontinuation
should go through an
appropriate change
management system.
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Detect, Analyze, Correct, Prevent
• You are all set to perform the change
Review your checklist before final green light:
• The date of implementation is known to:
– QA, Department Manager, RA, other?
• The regulatory authorities have been notified (CBE) and
haven’t come back with a refusal
• Training has been performed and
• FIRST batch is to be placed on hold...what about
subsequent batches: do you go back to the original
formula / equipment or stay with the new
• If the latter – ALL batches placed on hold until
effectiveness reviewed and final release provided
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Detect, Analyze, Correct, Prevent
• Perform the change and:
– Do increased IPC testing
– Increased finished product testing
– Stability testing
– Process validation (one batch)
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Detect, Analyze, Correct, Prevent
• Collect data (who does this)
• Analyze the data - two possibilities:
– Product meets all pre-determined acceptance
criteria, collected sufficient data and can
release (prior notification of regulators if so
agreed)
– Product fails to meet all pre-determined
acceptance criteria
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Detect, Analyze, Correct, Prevent
• Product fails to meet all pre-determined
acceptance criteria:
– Analyze: why
– Can corrections be made (and are these
changes and how do they need to be
handled)
– Does the change need to be rejected and go
back to previous situation
– If the latter how will you address the fact that
there was a need for change?
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Detect, Analyze, Correct, Prevent
• May need to involve:
– R&D for small scale experimentation to
trouble-shoot off line
– Engineering for redesign of equipment
– QA for product impact assessment: batch
rejection? And what happens in the
meantime?
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Detect, Analyze, Correct, Prevent
• Change may be initially successful but
subsequently problems arise
• Perform assessment at pre-agreed
intervals – might be:
– Management review
– Product Quality Review / Annual review
– Annual report to regulatory authorities (USA)
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CAPA and Post Change Monitoring
• Your CAPA system is the ideal tool for
post-implementation monitoring of change
• Develop a checklist of items that need to
be completed:
– Prior to making the change
– During / after the change
– Prior to product release and including flagging
/ product hold until release or rejection
decision made
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M&A: Change of Product Ownership
No. 1 drugmaker Pfizer to buy Wyeth for
$68 billion
COMBINED WIRE SERVICES January 27, 2009
Q10 section 2.8
Management of Change in Product Ownership
When product ownership changes, (e.g., through
acquisitions) management should consider the
complexity of this and ensure:
(a) The ongoing responsibilities are defined for each
company involved
(b) The necessary information is transferred
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Change is reversed
• After making the change you decide that it
didn’t help and want to go back to the
original set-up
• Needs to be documented as precisely as
the change because may not be able to
achieve this
(happens at home - try to insert a
replacement part and can’t but can’t put
back original either)
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In conclusion...
• Change = risk
• Risk requires risk management
• Risk management requires:
– Detection / identification of the risk
– Risk mitigation measures
– Communication with stakeholders
– Metrics for success
– Follow-up (CAPA system) on metrics: did I
succeed or not
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