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Change Control / Change Management A Q10 Perspective


Change Control / Change Management A Q10 Perspective Presented by Karen Ginsbury PCI Pharmaceutical Consulting Israel Ltd. for IFF February 2009 PCI Pharmaceutical ... – PowerPoint PPT presentation

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Title: Change Control / Change Management A Q10 Perspective

Change Control / Change ManagementA Q10
  • Presented by Karen Ginsbury
  • PCI Pharmaceutical Consulting Israel Ltd.
  • for IFF
  • February 2009

Course Content
  • Change Control What companies are used to doing
  • ICH Q10 and the Change Management System
  • Use of Risk Assessment to evaluate proposed
  • 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

What is change?
  • Alteration
  • Modification
  • Variation
  • Transformation
  • Revolution
  • Conversion
  • Adjustment
  • Amendment
  • Difference

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 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

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

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

  • 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
  • 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

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

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
  • 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

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...

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

  • 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

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)

The stated purpose of Q10
Who is responsible to
Understanding Product and Process
  • We cant manage change
  • Without managing the development process
  • Q10 Enablers
  • Knowledge Management
  • Q9 tools
  • Risk Management
  • DOE

No more magic 3!
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

Overcoming Resistance to Change
  • Education and communication
  • Participation and involvement
  • Facilitation and support
  • Negotiation and agreement
  • Manipulation and co-optation
  • Explicit and implicit coercion

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

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)
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 !

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
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
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)

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

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

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

Desired State
  • Regulatory policies tailored to recognize the
    level of scientific knowledge supporting product
    applications, process validation, and process
  • 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

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
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
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

  • Validation provides a snapshot of a system, an
    equipment item, a process at start-up
  • i.e. control
  • The control can be easily lost

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

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

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
  • 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.

Proposed Rule - Change Control(Now officially
Proposed Rule - Changes
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
  • (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

The Decision Making Chain
The Decision Making Chain - Influences
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

A rose by another name?
  • The Japanese have a decision-making process that
    minimizes problems through pre-impact extensive
  • 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

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
  • If yes prior approval, notification or annual
  • If no can proceed through change control within

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
  • We are going to sterilize the water system daily

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

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

Description of Change
  • Sufficiently detailed to allow reviewers to make
    relevant decisions and Risk Assessment
  • Usually need to attach diagrams and verbiage
  • 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

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?

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

Professional Judgement
  • What is the basis for decision making? Ask for
  • Engineering / Maintenance(Requires mutual trust)
  • Production / Operations(are likely to benefit)
  • BEWARE of production pharmacists
  • RA
  • RD

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

  • 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

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 ?

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

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

  • 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

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
  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?)

Describe the change to be performed
  • Provide sufficient detail to be able to assess
    the changei.e. allow for comparison of old and
  • May want to include diagrams
  • May want to attach other information (relevant
    and directed not just huge amount of paper)

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)

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 /
  • 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?

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
  • Other...

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

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...

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?

  • MUST have clear acceptance criteria or it is not
    possible to monitor post change
  • Who defines the criteria, where and who approves
  • Who will be responsible for taking the additional
  • Who will test they know how and why and
    acceptance criteria? (communication)

  • 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

  • Where are the acceptance criteria documented?
  • Needs to be a controlled document
  • change control protocol?
  • Validation protocol?
  • Stability protocol?
  • All of the above?

  • Should be clearly assigned and communicated
  • Need a documented training session prior to
  • Need to coordinate implementation
  • Need follow-up especially of any regulatory

Product, Product, Product
  • Throughout the change control process the major
    questions to be asked over and 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?

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
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
  • If the latter ALL batches placed on hold until
    effectiveness reviewed and final release provided

Detect, Analyze, Correct, Prevent
  • Perform the change and
  • Do increased IPC testing
  • Increased finished product testing
  • Stability testing
  • Process validation (one batch)

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
  • Product fails to meet all pre-determined
    acceptance criteria

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?

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?

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)

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
  • Prior to making the change
  • During / after the change
  • Prior to product release and including flagging /
    product hold until release or rejection decision

MA Change of Product Ownership
  • No. 1 drugmaker Pfizer to buy Wyeth for 68
  • 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

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)

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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