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Introduction
Pharmaceutical change control is the most critical and vital part of compliance with
regulatory requirements for Quality Systems. It is also the central component of
each of the six-systems of GMPs which the FDA employs for facility inspections.
Any change in the elements of the six-systems of GMPs would warrant a proper
review and execution.
The six systems of GMPs include:
§ Quality system,
§ Facility and Equipment system,
§ Materials system,
§ Laboratory system,
§ Production, and
§ Packaging and labeling.
Change Management is not a singular concept; rather it includes a set of best
practices and experiences, which are used to handle both internal as well as
external changes.
Change Management includes effective management of current as well as new
methods and systems in an ongoing organization. Change from an existing setup to
a new environment has its own set of inherent problems and the problems become
multifold when applied in a service institution. The other side, we have
introduction of new methods or systems which never existed in the organization
before, either because they were not required or were deficient and are now
recognized necessary based on the internal or external audit reviews.
Change is a continuous, often contradictory process, which brings difficult challenges as
well as opportunities. Change is no longer a choice.
So organizations cannot avoid change – as it is inevitable! It has to be done – when
the need is recognized.
Managers, leaders have to be aware of change and must therefore, take active role
in anticipating, planning, facilitating and implementing organizational change
through effective change management strategies. Competencies in managing
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changes can help them to be more effective in moving the compliance to a higher
level.
Change Management
is "the process of Management when
managing changes defined simply is
that occur because of nothing but making
an event" wise choices at the
correct time.
Change management is not a stand-alone process for designing a business solution.
These are the processes, tools and techniques for managing the people-side of
change. It is not a process improvement method. Change management is a method
for reducing and managing resistance to change when implementing process,
technology or organizational change. Change management is not a stand-alone
technique for improving organizational performance.
Change management is a necessary component for any organizational performance
improvement process to succeed, including programs like:
§ Six Sigma,
§ Business Process Reengineering, Change management is about
§ Total Quality Management, managing desired change to realize
§ Organizational Development, business results.
§ Restructuring and
§ Continuous process improvement.
Earlier the Quality
Assurance function used
to say a blatant NO to
any change proposal.
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Change control within Quality Management System (QMS) is a
formal process used to ensure that:
· Changes to a product or system are introduced in a controlled and
coordinated manner.
· Reduces the possibility that unnecessary changes will be introduced to a system
without forethought, introducing faults into the system or undoing changes made by
other users of software.
· Minimal disruption to services, reduction in back-out activities, and cost-effective
utilization of resources involved in implementing.
The Pharmaceutical industry is in a dynamic situation, ever
evolving and improving the standards of quality, safety, efficacy
and cost. This necessitates changes in the manufacturing
process/procedures, specifications, equipment, packaging etc. It
evolves mechanisms to manage such changes through proper
review, evaluation, implementation and follow-up. This
Management to control and document a change is termed Change
Control System.
Objectives of Change Control Management:
· To prevent unauthorized modifications to a validated system;
· To identify changes and to evaluate proposed changes to assess their potential effects
on the manufacturing process;
· To determine the impact of changes on the critical chemical and physical attributes of
the drug product (such as impurity profile, stability and particle size);
· To ensure that all documents affected by changes are promptly revised, and
· To determine if, and to what extent, revalidation is needed.
Six-Step Process for Managing Changes:
Changes can be managed only through a systematic methodology. Therefore, it is
necessary to have SOP in place, which can provide general as well as specific
guidelines on the following points:
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· Record / Classify /Critical review
• Proposing a change through consultation,
• Initiates change by making a formal request for something to
be changed.
• Request for a meeting to discuss the change proposal.
• Initiating a change control document,
• Evaluation of the need and justification for the change.
• Study objective, scope, justification, advantages, regulatory & GMP implications
and follow-up.
• Categorization would include estimates of importance, impact, and complexity.
· Change - Risk Assessment
• Assessment for impact on qualification, on validation, on
process performance, on product quality.
• Risk analysis both to the business and to the process;
• Who will approve the change proposal? Competent?
• Who will carry out changes? Experience?
• Who will collect data and document the changes?
• Consolidate if more than one type of assessment;
• Common consent to determine whether there is a business or technical justification
for the change.
· Change Management Plan
• Approval to administer the change,
• Management will assign the change to a specific delivery team, usually one with the
specific role of carrying out this particular type of change,
• The team's first job is to plan the change in detail as well as construct a regression
plan in case the change needs to be backed out.
• Implementation,
• Documentation, and
• Follow-up & closure.
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· Build / Test
• If all stakeholders agree with the plan, the delivery team will build the solution,
which will then be tested,
• They will then seek approval and request a time and date to execute the
implementation phase.
· Implement
• All stakeholders must agree to a time, date and cost of implementation of proposed
change.
• Following implementation, it is usual to carry out a post-implementation.
· Close / Gain Acceptance
• When the client agrees that the change was implemented correctly, the change can be
closed!
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SOP on Change Controls
Firms are expected to write adequate SOP for the same and be in total compliance with
proper documentation. Each change needs to be reported. However, it is
mysterious how even after several decades of GMP inspections we still encounter
several deficiencies with respect to management of changes in the pharmaceutical
industry – right from development stages to manufacturing, processing, packaging
and distribution.
Such deficiencies include:
· Inadequate SOP,
· Inadequate documentation,
· Improper evaluation of change,
· Inadequate impact assessment,
· Incorrect execution of change,
· Deviation from the intent,
· Re-validation not covered,
· Communication not sent to clients, regulatory agencies, and
· Closure of the change control procedure.
Quality Management Systems are often inspected by the agency and FDA
expects all change records to be readily available for inspection.
In order to have a consistent and reliable compliance to the change controls the
development of SOP on Change Controls is the foremost thing.
SOP on Change Controls should:
· Define Scope;
· Define responsibilities;
· List types of changes;
· Categorize changes with examples;
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· Describe Initiation process;
· Define Change Control Team and responsibilities;
· Describe process to be followed for review of the proposal;
· Describe process of impact analysis;
· Include Regulatory, GMP & Validation status;
· Explain Reporting to management, customers/clients and Regulatory Agency; and
· Describe documentation.
Change control is an important principle in the pharmaceutical industry.
There are several types of changes: for example: change of system, change of
analytical methods or change of processes. Change controls take on a regulatory
meaning in the pharmaceutical industry.
Common to these different types of change controls is the need to monitor the
status of the system, method, process, equipment, facility or material, with respect
to the initial qualification/validation and to put measures in place to verify that the
changes do not affect the GMP status of the system and the validity of the
assumptions under which the system, method, process, equipment, facility or
material was operated prior to the change.
FDA is clear what it expects in a change control process. The process must control
any changes that will impact the SQIPP (strength, quality, identity, potency and purity)
of the drug product. That is itself the scope of what must be under change control.
It has also been stated by FDA that all changes must be submitted, reviewed for
impact assessment and approved by the Quality Unit. The most important part of
this process is to ensure that, there is a clear audit trail to the changes which impact
the product.
It should be remembered that documents are only a part of what is included in
Change Control; process as well as documentation are also a part of it. The
important areas - front end to the system - are: impact assessment, approval and
submission of change related supplement(s) to the agency that have an impact on
the filing of documents.
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Reference: The FDA’s Guidance for the Industry: Changes to an Approved NDA or
ANDA (April 2004 – Revision-1)
Change control is the “Center stage” of any regulatory inspection. The auditors will definitely
review the SOP and the associated records of changes made to any of the important relevant
processes or systems or equipment. It is the firm’s approach to reporting of changes, evaluation,
impact assessment, communication, and documentation that can satisfy the tough auditors.
It is recommended that the following change request be handled through a formal
change control system:
· New facility validation,
· Equipment qualification changes,
· Changes in existing processes,
· Changes in laboratory test methods and procedures,
· Changes associated with product rework,
· Changes in labeling,
· Introduction of new procedures,
· Introduction of new processes,
· Changes to approved applications,
· Changes related to new drug approvals,
· Document changes,
· Changes associated with product specifications,
· Changes related to the CAPA system (from corrective action),
· New process validation,
· Changes related with the quality management system, and
· Introduction of new products.
A thumb rule for the pharmaceutical industry is that any change that
affects the five inputs of a process: man, material, method, machine,
and Mother Nature should be processed through a formal change
control.
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The guidance documents that have been provided by FDA are SUPAC/BACPAC
and Changes to and Approved NDA and an ANDA. Change control process must
support not only modification to NDA or ANDA, but also Annual Product Quality
Reviews. An Annual Product Quality Review must start with a review of Change
Control to determine what alternatives were made to what products during the
past year. Change Control applicable modifications also should be documented in
Incident Reports, Exception/Deviation Reports and through CAPA (Corrective
Action and Preventive Action).
Where the regulations are not very clear about inputs for a pharmaceutical
change control system, changes with the highest potential for increased variation
in the final product ought to be looked at through a formal change control system.
How to Categorize Changes?
Impact assessment of changes is extremely important to the agency and changes are
outlined as Major, Moderate and Minor. A compliance of Regulatory group within
the company determines the filing impact and submits it to FDA, a Prior-Approval
Supplement (PAS) for Major Changes, a CBE-30 or CBE-0 for Moderate Changes or
an Annual Report for Minor Changes.
MAJOR Change
· Is likely to have a detectable impact on the critical attributes of the product,
significantly.
· Could shift the process in a discernible manner (such as: quality, yield, stability,
impurity profile, crystal form, particle size, bulk density).
· Warrants definite additional/major testing and suitable revalidation studies to justify
changes.
· Reviewed by QA at the facility level and approved by Corporate Groups.
· Requires prior FDA approval.
Few examples of Major Changes
• Change in type of solvent used for final crystallization (affects impurity profile,
physical attributes and other Critical Quality Attributes of API),
• Change in equipment type (Dryer configuration, Blender type, crystallizer type,
tablet compression machine, coating equipment),
• Change in Critical Process Parameter(s),
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• Revision of critical quality attribute(s) (specification), such as Assay limit,
Dissolution profile, Related substances test,
• Related Substances limit,
• Revision of Standard Test Procedure for Assay (potentiometric to HPLC), for
Related Substances (TLC to HPLC), for Residual Solvents (GC to Head Space).
• Change in facility (site of manufacturing),
• Change in batch size by more than 10%,
• Change in route of synthesis,
• Change in Isolators, RABS or C-RABS systems,
• Change of API source,
• Change in validated sterilization process,
• Change in sequence of operations.
MODERATE Change
· Is usually for Improvements to process, materials, product or procedure;
· Therefore, no reason to wait for approval.
· Does not require prior approval by the Regulatory/FDA before implementation,
· The Agency will want to review it,
· Can go in Annual Reports to FDA,
· Can be evaluated by QA at the facility and then approved by Corporate Groups.
· These are called "Changes Being Effected",
· Categories are CBE-30 and CBE-0.
Few examples of Moderate Changes
• Improvements in yield,
• Improvements in Critical Quality Attributes,
• Improvements in Process capability/efficiency,
• Cost-effectiveness.
MINOR Change
· Is unlikely to have a detectable impact on the critical attributes of the product.
· Does not shift the process in any discernible manner.
· Can be implemented with minimal testing and revalidation.
· Can be reviewed and approved by QA at the facility level.
· Is reported in Annual Reports to FDA and does not require FDA approval.
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Few examples of Minor Changes
• Like-for-Like equipment replacements,
• Non-critical process parameters,
• Revision of specifications (such as: non-critical parameters) as per process
capability,
• Revised Quantity of components & reagents, marginally in case of API
intermediates,
• Revised operating procedure to add safety,
• Revised cleaning procedure to enhance GMPs,
• Editorial changes.
Scientific judgment should determine what additional testing and validation
studies are needed to justify a change in a validated process.
In the future, the Comparability Protocols will be required to support and justify
the changes. This will improve the approval timing for the agency and also will
reduce the risk of having an adverse affect on the SQIPP of the product. This
requirement will also ensure that no adulterated product ever gets released.
Comparability Protocols will be a submission to the agency and, as such, any
changes to the protocols must go through the Change Control process.
When developing a Change Control procedure, following points must be
considered:
· Developing a robust change control system,
· Educate users of the change control system, and
· Enforce change control system policies and procedures.
A Change Control Policy must be in place with supporting SOPs and a Process Map
that will guide users through the process so as not to deviate or work outside of the
process. Stakeholder Matrix is also important so that it will provide guidance on
what changes impact what stakeholders. It will provide guidance on the
distribution for assessment of impact. The process must be user-friendly and
efficient or it will be unacceptable to the users. After a robust manual process has
been developed and implemented it must be owned by the Quality Organization as
it is a part of compliance requirements.
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All the documents should be complete, accurate, detailed, unambiguous, credible,
verifiable, and defendable and supported by scientific evidence, as they will be
assessed by Federal Regulators. It is also important to make sure a tracking
system is in place so that documents can be located and retrieved at any time.
It is important to understand not only the types of changes that will be a part of
Change control process, but also the priority of those changes. Changes should
never be expedited, but should be either planned or unplanned. Almost all changes
can be planned; only those that are emergencies occurring after hours, on weekends
or are safety-related should be considered as unplanned. In all cases they should be
submitted through Change Control and any required validation/re-validation must
be completed before the change is fully implemented.
Levels of Approval:
The Change Control proposals are formal documents and must be initiated by the
affected group. For example: Production Unit is the affected group for changes to
equipment and facility expansion. In this example, Production unit will initiate the
change proposal. This proposal could be reviewed and discussed by other
responsible persons from departments, such as R&D, QA, Regulatory and affected
client. However, the final approval is granted by Quality Unit.
It is important to assign levels of approval within departments. For changes
categorized as Major, the review and approvals must be dealt with by senior
experts from stakeholder departments and Quality Unit. In contrast, for the
changes categorized as Minor, the review and approvals can be delegated to trained
personnel who are not necessarily from senior management.
Once a manual process has been implemented, one of the Stakeholder Groups, such
as Regulatory, needs to conduct an internal audit once a year. Based upon business
needs, it may be necessary to automate the process with validated software. If the
process is not working well, this software should not be purchased to fix the
problems. It will only waste the time and will make the situation worse. In order to
find the software that will fit the process; a Functional Requirement Specification
outlining what is expected of the program should be written. From there, a matrix
is used to evaluate the right software for the correct environment.
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When all of the pieces are in place, Change Control process/program will provide
the ability to submit, evaluate, approve, communicate, correctively implement and
document all changes that impact SQIPP.
Handling and Controlling Changes
Handling and Controlling Change Initiator calls for a meeting of Change Control
Team and puts the proposal for change with the problems & consequences and
advantages.
Team reviews through brainstorming session:
· Should the change be allowed?
· Partly or wholly?
· Regulatory impact?
· GMP and Safety impact?
· Need for Re-qualification or Re-validation?
· Customer / Agency to be informed?
· Category of the change? Reporting category?
· Documentation requires and documents affected?
If the team has decided on above points, the CCIF (Change Control Initiation Form)
is processed by the team members for a sign-off and each member understands
her/his responsibilities. The Initiator coordinates the change process at all levels.
QA checks the adequacy of the process data, impact and follow-up for closure and
communicates to the customers / clients and management. Regulatory prepares the
Reporting document for the Agency.
The Pharmaceutical industry - worldwide - has experienced deviations to
the requirements of Change Control! There are some changes which occur
un-reported with the assumption that this is a trivial change. In other
cases, the evaluation is incomplete and in some others inadequacy of
records and closure reports are common.
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Regulatory perspective of change controls:
Considering the regulatory perspective of change control procedures, it is
important to note that there are many guidelines which describe the control of
changes in manufacturing. Few references include:
21 CFR Parts 211: Sec. 211.100
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.
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 Part 211.194 Laboratory records
Complete records shall be maintained of any modification of an
established method employed in testing. Such records shall include the
reason for the modification and data to verify that the modification
produced results that are at least as accurate and reliable for the material
being tested as the established method.
ICH Q7A:
A formal change control system should be established to evaluate all
changes that could affect the production and control of the intermediate or
API. Written procedures should provide for the identification,
documentation, appropriate review, and approval of changes in raw
materials, specifications, analytical methods, facilities, support systems,
equipment, processing steps, labeling and packaging materials, and
computer software.
USFDA Guidance for Industry: Changes to an Approved NDA or ANDA (April
2004-Revision 1)
This guidance provides recommendations to holders of new drug
applications (NDAs) and abbreviated new drug applications (ANDAs)
who intend to make post-approval changes in accordance with section 506
A of the Federal Food, Drug, and Cosmetic Act (the Act) and § 314.70 (21
CFR 314.70).
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The guidance covers recommended reporting categories for post-approval changes
for drugs other than specified biotechnology and specified synthetic biological
products.
Glossary
Corrective and preventive action (CAPA)
Corrective and preventive action abbreviated as CAPA, and also called corrective
action / preventive action, is a concept within good manufacturing practice (GMP).
CAPA focuses on the systematic investigation of discrepancies (failures and/or
deviations) in an attempt to prevent their recurrence (for corrective action) or to
prevent occurrence (for preventive action). To ensure that corrective and preventive
actions are effective, the systematic investigation of the failure incidence is pivotal
in identifying the corrective and preventive actions to be undertaken. CAPA is part
of the overall quality management system (QMS).
New Drug Application (NDA)
The New Drug Application (NDA) is the vehicle in the United States through
which drug sponsors formally propose that the FDA approve a new
pharmaceutical for sale and marketing. The goals of the NDA are to provide
enough information to permit FDA reviewers to establish the following:
· Is the drug safe and effective in its proposed use(s) when used as directed, and do the
benefits of the drug outweigh the risks?
· Is the drug’s proposed labeling (package insert) appropriate, and what should it
contain?
· Are the methods used in manufacturing (Good Manufacturing Practice, GMP) the
drug and the controls used to maintain the drug’s quality adequate to preserve the
drug’s identity, strength, quality, and purity?
Abbreviated New Drug Application (ANDA)
An Abbreviated New Drug Application (ANDA) is an application for a U.S. generic
drug approval for an existing licensed medication or approved drug. The ANDA is
submitted to FDA's Center for Drug Evaluation and Research, Office of Generic
Drugs, which provides for the review and ultimate approval of a generic drug
product. Once approved, an applicant may manufacture and market the generic
drug product to provide a safe, effective, low cost alternative to the public.
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