PCI Pharmaceutical Consulting Israel Ltd. 1 Change Control / Change Management A Q10 Perspective...

PCIPCI Pharmaceutical Consulting Israel Ltd . 1

Change Control / Change ManagementA Q10 Perspective

Presented by Karen GinsburyPCI 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 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

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


FDA Warning Letter

21 cfr 211.100a

• Written procedures for production and process CONTROLCONTROL to assure that the drug product has the strength, quality, identity, purity they are purported to have.

• Procedures including any CHANGESCHANGES 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

ICH Q10: Pharmaceutical Quality Systems

The change management system ensures continual improvement is undertaken in a timely and effective manner while while providing a high degree of assurance providing a high degree of assurance there are no unintended consequences there are no unintended consequences of the changeof the change

Quality System Lifecycle

• The concept of Q8, 9 and 10 is an all embracing concept that addresses– Product– ProcessLifecycle

• 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 activitieschange 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


• 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


• 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

• 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...

PCI Pharmaceutical Consulting Israel LtdPCI Pharmaceutical Consulting Israel Ltd.. 18

Question

• Are there any currentGMP requirements / qualityrequirements pertainingto R&D?

• In particular to changemanagement in R&D i.e investigational products ?


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


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…


And…


Understanding Product and Process

• We can’t 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 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


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


QuestionsObjectivesLayers 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) Don’t agree on direction for a solution 3) Don’t think solution will truly address the problem4) 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 happenSynchronize 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 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 !RISKS !

PCI Pharmaceutical Consulting Israel Ltd

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

31

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

DETECT

ANALYZECORRECT

PREVENT


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 USEFIT FOR USE(not: meets customer’s requirements)


Product Registration File

Manufacturer’s 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 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

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

Risks to QualityRisk of incorrect identityPoor product & process

Changes in clinical trial product(Bridging studies)

Inadequate Design SpecificationsCritical to quality and performance?

Risk of unqualified impuritiesRisk of poor bioavailability

Risk of incorrect expiry dateRisk of inadequate controls

Risks After Approval[Risk of SUPAC,..]

[unrepresentative test samples][Inadequate Facility and QS]

Intended UseRoute of administration

Patient population…..

Product Design

Design Specifications(Customer requirements)

Manufacturing Processand its Control

RegulatorySpecs.

Tests

& C

on

trols

-R

isk M

itig

ati

on

ICH Q9

Illustrative Examples of points to consider

Development Objectives


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

• 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 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.

PCIPCI Pharmaceutical Consulting Israel Ltd .46

Proposed Rule - Change Control(Now officially dead)!


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 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

FRAME

DECIDE

COMMUNICATE

IMPLEMENT

EVALUATE

The Decision Making Chain - Influences

FRAME

DECIDE

COMMUNICATE

IMPLEMENT

EVALUATE

cost

regulatoryquality

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 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 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


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”


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


API GMP (ICH Q7A)


API GMP (ICH Q7A) - 2


API GMP (ICH Q7A) - 3


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 (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


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?


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


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


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?


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


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


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

can’t 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 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?)


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)


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 /

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?


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...


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?


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 responsibleWho will be responsible for taking the additional samples?

• Who will test them...do they know how and why and acceptance criteria? (communication)


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


Metrics

• Where are the acceptance criteria documented?

• Needs to be a controlled document:– change control protocol?– Validation protocol?– Stability protocol?– All of the above?


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


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?”

PCI Pharmaceutical Consulting Israel Ltd

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.

84


Detect, Analyze, Correct, Prevent

• You are all set to perform the changeReview 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



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



• 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



• 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?



• 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?



• 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 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

M&A: Change of Product Ownership

No. 1 drugmaker Pfizer to buy Wyeth for $68 billion

COMBINED WIRE SERVICES January 27, 2009 Q10 section 2.8Management 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



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)


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

PCI Pharmaceutical Consulting Israel Ltd. 1 Change Control / Change Management A Q10 Perspective...

Documents

Transcript of PCI Pharmaceutical Consulting Israel Ltd. 1 Change Control / Change Management A Q10 Perspective...