Implement a Change Control Program
in Your Operation
Gamal Amer, Ph. D.
Principal
Premier Compliance Services, Inc.
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1
What is a Change Control System?
It is a formal system which is designed not to prevent
change, but rather document and control it. Its main
purpose is to ensure that a system/process/operation
is always in a GMP compliant and in a validated state
of control, regardless of changes made to it. It is
usually implemented using a procedure.
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2
Regulations
• 21 CFR 211.100
– (a) There shall be written procedures for production and process control designed to
assure that the drug products have the identity, strength, quality, and purity they
purport or are represented to possess. Such procedures shall include all requirements in
this subpart. These written procedures, including any changes, shall be drafted,
reviewed, and approved by the appropriate organizational units and reviewed and
approved by the quality control unit.
• 21 CFR 211.160
– (a) The establishment of any specifications, standards, sampling plans, test procedures,
or other laboratory control mechanisms required by this subpart, including any change
in such specifications, standards, sampling plans, test procedures, or other laboratory
control mechanisms, shall be drafted by the appropriate organizational unit and
reviewed and approved by the quality control unit.
Regulatory Guidance
• ICH Q7
– Responsibility of the quality unit includes:
• Approving changes that potentially affect intermediate or API quality
• Evaluating proposed changes in product, process or equipment
– Changes to computerized systems should be made according to a change
procedure and should be formally authorized, documented, and tested.
– Changing the source of supply of critical raw materials should be treated
according to Section 13, Change Control
– Specifications, sampling plans, and test procedures, including changes to
them, should be drafted by the appropriate organizational unit and reviewed
and approved by the quality unit(s).
– Section 13
• A formal change control system should be established to evaluate all changes that could affect
the production and control of the intermediate or API.
Regulatory Guidance
• ICH Q7
– Section 13 (cont.)
• Written procedures should provide for the identification, documentation, appropriate review,
and approval of changes in raw materials, specifications, analytical methods, facilities, support
systems, equipment (including computer hardware), processing steps, labeling and packaging
materials, and computer software.
• Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the
appropriate organizational units and reviewed and approved by the quality unit(s).
• The potential impact of the proposed change on the quality of the intermediate or API should
be evaluated. A classification procedure may help in determining the level of testing, validation,
and documentation needed to justify changes to a validated process. Changes can be
classified(e.g., as minor or major) depending on the nature and extent of the changes, and the
effects these changes may impart on the process. Scientific judgment should determine what
additional testing and validation studies are appropriate to justify a change in a validated
process.
• When implementing approved changes, measures should be taken to ensure that all
documents affected by the changes are revised.
• After the change has been implemented, there should be an evaluation of the first batches
produced or tested under the change.
Regulatory Guidance
• ICH Q8
–
Changes in formulation and manufacturing processes during development and lifecycle management
should be looked upon as opportunities to gain additional knowledge and further support
establishment of the design space.
• ICH Q9
– Auditing/Inspection of Process- frequency and scope based on …. Major changes of building,
equipment, processes, key personnel
– Change management/change control
•
•
To manage changes based on knowledge and information accumulated in pharmaceutical development and
during manufacturing
To determine appropriate actions preceding the implementation of a change, e.g., additional testing,
(re)qualification, (re)validation, or communication with regulators
– Periodic review - To evaluate the impact of the changes on the availability of the final product and
–
evaluate the impact on product quality of changes to the facility, equipment, material,
manufacturing process, or technical transfers.
Change as a tool to mitigate risk
Regulatory Guidance
• ICH Q10
– Change Management is a systematic approach to proposing, evaluating, approving,
implementing, and reviewing changes. Change management as a knowledge
management tool
– The pharmaceutical quality system should include the following elements, as described
in section IV (3): process performance and product quality monitoring, corrective and
preventive action, change management, and management review of process
performance and product quality
– Innovation, continual improvement, the outputs of process performance and product
quality monitoring, and CAPA drive change. To evaluate, approve, and implement these
changes properly, a company should have an effective change management system.
– There is generally a difference in formality of change management processes prior to the
initial regulatory submission and post submission, where changes to the regulatory filing
might be required under regional requirements.
– Change management insures continual improvement and should provide a high degree
of assurance there are no unintended consequences of the change.
Regulatory Guidance
•
ICH Q10
– The change management system should include the following, as appropriate
for the stage of the lifecycle:
(a)
(b)
(c)
(d)
Quality risk management should be utilized to evaluate proposed changes. The level
of effort and formality of the evaluation should be commensurate with the level of
risk.
Proposed changes should be evaluated relative to the marketing authorization,
including design space, where established, and/or current product and process
understanding. There should be an assessment to determine whether a change to the
regulatory filing is required under regional requirements. As stated in ICH Q8, working
within the design space is not considered a change (from a regulatory filing
perspective). However, from a pharmaceutical quality system standpoint, all changes
should be evaluated by a company’s change management system.
Proposed changes should be evaluated by expert teams contributing the appropriate
expertise and knowledge from relevant areas (e.g., Pharmaceutical Development,
Manufacturing, Quality, Regulatory Affairs, and Medical) to ensure the change is
technically justified. Prospective evaluation criteria for a proposed change should be
set.
After implementation, an evaluation of the change should be undertaken to confirm
the change objectives were achieved and that there was no deleterious impact on
product quality.
Regulatory Guidance
• FDA Guidance Process Validation: General
Principles and Practices-January 2011
– After establishing and confirming the process, manufacturers must maintain
the process in a state of control over the life of the process, even as materials,
equipment, production environment, personnel, and manufacturing
procedures change.
– The validation project plan should also include the firm’s requirements for the
evaluation of changes.
– A description of the planned change, a well-justified rationale for the change,
an implementation plan, and quality unit approval before implementation
must be documented.
The Regulatory Imperatives
• You must have a procedure for change control.
• You must invoke the procedure each time a change is
contemplated.
• You must follow the procedure.
• You must use SME and scientific reasoning and risk analysis to
define the changes and the actions to be taken for
implementation.
• Changes and all studies associated with them must be
documented (with appropriate rational), reviewed and
approved.
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10
The Regulatory Imperatives
• Changes in process, procedures, laboratory methods must be
reviewed and approved by the appropriate organization and
the Quality Unit.
• Prior to implementing the change define the actions you must
take to make the change permanent.
• Review and monitor changes once implemented to ensure no
problems arise.
• Evaluate the impact of the change on the product.
• The formality of change management differs between pre and
post submission.
• Change management should be implemented throughout the
product life cycle.
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11
Need For Change
• Better knowledge and understanding of product quality
issues
• Improved understanding of the technology
• Increased capacity
• Process Improvement
• Improved technology and science
• Improved equipment
• Equipment maintenance issues
• Correct/Prevent deviations & non-conformances (CAPA)
• Improved raw materials and intermediates
• Better or alternative suppliers
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12
Where Do Changes Happen
Changes Happen in:
– Facility, Utilities and Process
Configuration/Equipment
– Material/Services and Suppliers
– Procedures and Training
– Could be anywhere or to any component of the
operation, Etc.
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Types of Changes Encountered
Changes Can Be:
– Planned – Are well defined and studied
– Emergency – Usually unexpected with many
unknowns
– Major – Present high risk and compliance
challenges
– Minor – Easy to implement and of lesser risk
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Defining the need for change
• The need for change is determined based on:
– Changes to improve the process
– Changes as corrective or preventive actions
• Trends towards failure
• Deviations
• Non conformance
– Changes to accommodate increased production
– Changes for product quality improvement
– Profit improvement
Importance of Change Control
•
•
•
•
Not to prevent change.
To control and document change.
Required by the regulations.
Identify potential risks associated with the
change
• Identify GMP and validation implications.
• Ascertain process remains in a state of control.
• Must be implemented using a procedure.
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Change as Tool for Mitigating Risk
• Process and environmental monitoring can
identify risky trends.
• CAPA is used to define actions to mitigate risks
resulting from process/environmental trends,
deviations, or non-conformities
• CAPA actions normally result in changes to the
process or the way it is conducted
• Change management will define requirements
associated with implementing the change that
would insure the process remains in a state of
control.
Maintaining GMP Compliance Status
• The GMP Compliant State
– Updated quality system
– Up-to-date documentation
•
•
•
•
Drawings and process documentation
Product specifications
Analytical techniques
Procedures
– Proper training of personnel
– Validated State for the process
Maintaining GMP Compliance Status
Post Change
• Possible actions to maintain GMP compliant state
– Update quality system to reflect most recent
developments and needed modification resulting from
the change
– Update drawings to reflect changes
– Update specifications
– Update procedures to reflect changes
• Analytical
• Processing
• Training, etc.
– Train personnel to ensure their competence in dealing
with changes
Validated/Qualified State
A system is in a validated/Qualified state if:
–
–
–
–
–
–
–
Properly qualified/validated originally.
Same equipment used.
Same procedures followed
Equipment maintained in original state.
Instruments and controls are calibrated.
Process inputs (raw material, etc.) the same.
No significant changes were made.
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20
The Qualification Life Cycle
-
Qualified System
Change Control
System
Implement Change
Modified System
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21
Controlling Change
• How to maintain a validated state after change
(implementing change control):
– Evaluate for impact on GMP compliance.
– Evaluate for impact on validation.
– Knowledgeable assessment of requirements to maintain
compliance and validation (commensurate with risk
level).
– Develop plan to implement requirements.
– Implement requirements and maintain a compliant and
validated system.
– Monitor to ensure change did not introduce unexpected
issues
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22
ASTM E2500 Life Cycle Process
Verification
Good Engineering Practices
Process
Knowledge
Regulatory
Requirements
Company
Quality Req.
Requirements
Product
Knowledge
Operation &
Continuous
Improvement
Risk Management
Design Review
Change Management
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23
Change Control System
Change to be
implemented
GMP
Issues?
YES
YES
Emergency?
NO
NO
Implement as
Maintenance
Obtain
Approvals
Implement
Compliance
Requirements
Document
Change
Review and
define actions
Implement
Change
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24
Change Control Procedure (cont.)
• Define what is needed to make the change
permanent.
• Identify GMP compliance requirements.
• Identify revalidation requirements, if any.
• Implement change and the requirements.
• Change permanent.
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25
Initiating Change
• A short and concise form
• Should have space for comments and
approvals
• Should have all information needed to render
judgment
• Risk assessment for the change itself
• Should have space to define requirements for
implementing change
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26
Change Request Form
Page 1
•
•
•
•
•
•
•
•
Originator’s Information
Date
Short Title
Reason for Requesting Change
Description of Requested Change
Known or suspect risks associated with change
Known or Suspected GMP Implications
Add support documentation and/or drawings
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27
Change Request Form
Page 2
Review, Requirements, and Approval
• Technical review and comments by engineering,
technical services, operation, and QA-recommend
approval/disapproval
– Should include a risk assessment of the proposed change
– Decision to proceed or not based on risk
– Define a risk mitigation strategy if suitable
• Review and approval by Change Control Committee
(needed if disagreements occur above)
• Define requirements to be satisfied for change
implementation; e.g. validation, document or drawing
modification, procedure modification, training,..etc.
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28
Risk/Impact Assessment
• The change is proposed
• Technical aspects for implementing the change
are identified
• The impact of the change itself on the product
quality and public wellbeing is assessed
• A RPN is developed to define the level of risk this
change may posed to the public
• Based on the RPN the change maybe accepted as
is, modified to reduce its risk, or rejected for
presenting an unacceptable risk.
Change Control procedure
Generate
Change Request
Evaluate Change
No
Back to the
drawing board
No
Implement Change
as Maintenance
Proceed?
Change required
Yes
GMP
Implications?
End
Yes
Requalification?
Revalidation?
No
Implement Change
& Insure GMP
Requirements Done
Issue GMP
Report
Obtain
Approvals
Change is
Permanent
Obtain Approval
Yes
Requalify
Revalidate &
Issue Reports
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Change is
Permanent
End
30
Paper vs. Electronic
• Paper based change control
• Too much paper
• Very cumbersome and time consuming
• Limited Access
• Electronic based change control
• Better accessibility
• Quicker and more transparent
• Software must be part 11 compliant
Emergency Changes
• Implement Change
• Fill out paper work and circulate for comments and
approval (within 48 hours)
• Conduct a risk assessment of the change’s impact on
product quality
• Implement GMP required actions immediately
• Release is contingent on a risk assessment exercise,
additional testing, and implementation of GMP
requirements.
• Keep a close eye on the lots released once distributed
and facilitate fast customer feedback.
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32
Monitoring
• Monitoring entails three distinct activities:
– Collecting data about the system,
– Review and analysis of the data collected, and
– Defining reminders and warnings about the
system status (Statistical trends, alert & action
points, etc.).
33
Monitoring
• Need to know the right Critical Quality
Attributes (CQAs) of the product and those
which maybe affected by the change
• Need to know the Critical Processing
Parameters (CPPs) which affect those CQAs
• Monitor those CPPs and CQAs
• Insure you take actions when you see a
deviation beyond reminders and warnings, or
observe trends.
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34
Post Change Monitoring and its
Importance
• Once change is implemented and becomes
permanent you must continue to monitor the
changed part to ensure
– The change gave the intended result
– No unintended issues arise.
• Do a lot of monitoring in the beginning to establish
background information, then scale back to a
statistically appropriate level.
• Look at variation for a batch and also for batch to
batch variations.
• Always be quantitative and use statistical methods
when ever possible.
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35
Requirements
• You must detect variations and trends (do not
overreact to individual events).
• Once variation is detected it must be
characterized from a risk management point
of view.
• Determine the root cause of variation (FMEA,
HACCP, Fault Tree Analysis, etc.).
36
What and Where to Monitor?
• WHAT:
– Critical Processing Parameters (CPP) such as temperature, pressure,
flow, yields, impurities, etc.
– Critical Utilities output such as water, HVAC, compressed air, etc.
– Cleanliness and Sanitization conditions.
– Process, Laboratory, and people performance (deviations, adverse
events, OOS, number of human errors, Etc.).
• WHERE:
–
–
–
–
Points where product is at maximum vulnerability
At the critical process points
At the end of critical steps
Within the facility where the product maybe affected by prevailing
conditions.
37
Data from variable being monitored should conform to a
random pattern around the target value, and should be within the
action limits to indicate that the system/process/condition is
under control.
Failure
Action Level
*
Function
Being
Monitored
*
*
*
* * *
*
*
*
*
*
Alert Level
*
*
*
*
*
*
*
*
Target Value
Alert Level
Action Level
Time
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38
Monitoring ensures trends towards failure are identified in time
Trend begins
Action Level
*
Function
Being
Monitored
*
*
*
* * *
*
*
*
*
Alert Level*
*
* *
*
*
*
*
*
*
Alert Level
*
Action Level
Change
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39
Correct the negative trend by manipulating the proper CPP
Begin Manipulating CPP(s)
and/or
Implement Corrective Action(s)
Action Level
* *
* * **
Alert Level
*
*
*
*
* *
***
* **
*
Function
Being
Monitored
*
*
*
* * *
*
*
*
*
*
*
*
Alert Level
Action Level
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40
ASTM E2500 View of Change Control
Copied with permission D. Petko, Presentation to ISPE
Delaware Valley Chapter, April 2008
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41
Interactive
Define Issues associated with the
following proposed change
• The issue
– Background
• Supplier of carbon source for a fermentation used to
produce a therapeutic agent goes out of business
– Proposed Chang
• Use a different supplier who claims they can provide a
similar material
Issues
• Regulatory
– Do we need to inform regulators of change of supplier?
• Technical issues
– Is material the same from a chemical point of view?
– Does material give the same growth characteristics?
– Does the titer of active match the old titer for same conditions?
• Quality issues
– Does the fermentation using new carbon source result in similar
quality product?
– Is the impurity profile the same?
– Are their other process or processing changes that are needed to
ensure a quality product is produced?
• Risk to the patient
– What are the risks of a different quality product?
– What are the risks of different impurity profile?
– Severity, Frequency, detectability and RPN determination
Issues
• Yes-No decision
– Risk too high, reconsider the new supplier or find an alternate one
– Can the new supplier do something in order to provide a material that
will not result in such high risk?
• What are the requirements?
– Documents (yours and the supplier’s)
– Additional modifications to the process or processing in order to reduce
the risk associated with the new material
– Revalidation
– Retraining
• What to do? How to proceed?
–
–
–
–
Laboratory testing of the new material
Conduct pilot fermentation and/or Plant trails with the new material
Laboratory analysis of the resulting product
Possibly conduct some clinical trials
Issues
• What else?
– Further processing of the material at your site?
• Larger change than originally anticipated
– Modify the process at your site (e.g. longer
fermentation cycle, higher fermentation temperature,
etc.)
• Process change thus going beyond raw material change
– Require supplier to use some additional processing?
• Supplier may need to implement changes
– Identify other suppliers and test their materials?
– Need to inform regulators?
– What else can you think of?