Change Control / Change Management A Q10 Perspective

1
Change Control / Change ManagementA Q10
Perspective

• Presented by Karen Ginsbury
• PCI Pharmaceutical Consulting Israel Ltd.
• for IFF
• February 2009

2
Course Content

• 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
• 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?

• INTRODUCTION
• Alteration
• Modification
• Variation
• Transformation
• Revolution
• Conversion
• Adjustment
• Amendment
• Difference

4
FDA Warning Letter
5
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

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European Directive

• When any new manufacturing formula or method of
  preparation adopteddemonstrate 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

7
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

8
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

9
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

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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)

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Q9 - Overview of Quality Risk Management Process
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Q10 Pharmaceutical Quality System
13
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
  andchange management activities

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Preventing Unintended Consequences

• Identify risks associated with the change
• Consider the change itself
• Its impact on product and process
• DONT 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

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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

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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

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Product Impact

• 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...

18
Question

• Are there any currentGMP requirements /
  qualityrequirements pertainingto RD?
• In particular to changemanagement in RD i.e
  investigational products ?

19
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 IMPsso.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
22
Who is responsible to
23
And
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Understanding Product and Process

• We cant 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 wont 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

27
Overcoming Resistance to Change

• 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 co-ownership 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
What to change? Situation assessment, description of current reality, identification of core problem and assumptions that sustain it. Diagnosis, systemic root cause analysis. 1) Lack of agreement on the problem
What to change to? Describe solution, describe strategy to attain the desired state, and avoid undesirable side effects. Plan, decision-making, and solution development. 2) Dont agree on direction for a solution 3) Dont think solution will truly address the problem 4) The solution will lead to new, undesirable side effects (Yes, but)
How to make the change happen? Develop detailed plans and tactics that will clarify what needs to happen Synchronize efforts of the group in implementation of the strategy. Planning, team-building, and leadership 5) Lack of a clear path around obstacles blocking the solution 6) Lack of follow-through even after agreement to proceed with the solution (unverbalized fear or concerns)
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The Vitamin B12 Story

• It wasnt 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)

• 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

PCI Pharmaceutical Consulting Israel Ltd
31
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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

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Q10 Continual Improvement
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Quality of Drug Products

• EfficacyIt does what it is meant to do(gets
  rid of your headache, lowers blood pressure etc.)
• SafetyWithout harming the user / Patient(liver
  toxicity, nausea, hallucinations)
• FIT FOR USE(not meets customers requirements)

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Product Registration File

• Manufacturers declaration of
• Product composition
• Equipment / systems participating in the
  manufacturing process
• Raw material / component manufacturers
• Critical production / process parameterse.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

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ICH Q8 Integrating QbD and Risk Mitigation
Dimensions
Illustrative Examples of points to consider
Development Objectives
Risks to Quality Risk of incorrect identity Poor
product process Changes in clinical trial
product (Bridging studies) Inadequate Design
Specifications Critical to quality and
performance? Risk of unqualified impurities Risk
of poor bioavailability Risk of incorrect expiry
date Risk of inadequate controls Risks After
Approval Risk of SUPAC,.. unrepresentative
test samples Inadequate Facility and QS
Tests Controls -Risk Mitigation
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 processThis
  allows
• Steps taken to implement the change
• Effects of the change on the processto 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

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The Decision Making Chain
50
The Decision Making Chain - Influences
regulatory
quality
time
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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 re-organizing
  human resources so that people, the greatest
  resource, use their time to the greatest effect

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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 implementedscientific management
  and assembly line

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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

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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

• 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 wont 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 aint broken - dont fix it ? Who decides?

63
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
• RD

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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 anothere.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 cant
  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 changei.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)

74
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?

75
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

77
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...

78
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?

79
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)

80
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

81
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

83
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
  isntwhat tests will demonstrate thishave
  the test results been reviewed before production
  is renewed?has product been quarantined?

84
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.
PCI Pharmaceutical Consulting Israel Ltd
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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 havent 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

86
Detect, Analyze, Correct, Prevent

• Perform the change and
• Do increased IPC testing
• Increased finished product testing
• Stability testing
• Process validation (one batch)

87
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

88
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?

89
Detect, Analyze, Correct, Prevent

• May need to involve
• RD 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?

90
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)

91
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

92
MA 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
• The ongoing responsibilities are defined for each
  company involved
• The necessary information is transferred

93
Change is reversed

• After making the change you decide that it didnt
  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
  cant but cant put back original either)

94
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