Management of Change
Control
Overview
• Changes – Good or bad? Forced or voluntary?
• The Importance of Change Control
• Major Changes to both legacy company documents
• Scope and Responsibilities according to our new
Directive
• General Requirements
• The Process with the detailed Requirements
Changes - Good or Bad?
• A pharmaceutical company is built on both Quality and
Consistency
 To always get the right product quality
 To follow the established process
• But a successful firm has also to perform changes
 To make continuous improvements and implement innovations
 To remain competitive and ultimately stay in business
Changes - Forced or Voluntary?
• Some items must be changed – where you have no option
 Supplier cannot deliver the material
 Raw material no longer available
• Other items can be changed – where we do have an option
 Change of site, scale, or equipment
 Change of QC test method
• We need to consider the risk versus benefit of each change
• But the biggest risk by far is an uncontrolled change
• Even the smallest changes can cause very high risk if not properly
controlled
The Importance of Change
Control
• Changes must be controlled, managed and
followed up to ensure that they are processed
according to GMP requirements and Health
Authority regulations
• This includes changes initiated by site or other
company internal decisions as well as changes
resulting from regulatory requests
• The change control process must ensure quality,
efficacy and safety of the product throughout its
life cycle and updated regulatory files.
In other words : Change Control
Process has
• To evaluate the impact of proposed changes on the quality, efficacy
and safety of the final product
• To evaluate the equivalence of changes of facilities, equipment,
manufacturing process, and technical transfer
• To assess the impact on changing specifications and/or analysis
methods of all materials used
• To determine appropriate actions before the change is implemented
Scope
• This scope applies to all manufacturing sites, affiliates and
subcontractors
• It applies to all modifications of a product or a process covering the
following not limited to :
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Raw materials (Change of suppliers, process, specs….)
Formula of drug products
Manufacturing process
Specifications and control procedures of components, bulk and
finished product
Primary packaging, storage and labelling
Medical devices
Equipment (incl. computerized automated systems)
Facilities, utilities and environment
GMP documentation (e.g., SOPs, MBR, batch records)
Responsibilities (1)
• Site Management is responsible for ensuring that
any modification to their operations is documented,
evaluated and approved from a technical, scientific,
quality and regulatory point of view
• Site Quality Management along with other appropriate
functions are responsible for coordinating change control
activities in their respective areas to ensure that there is
an assessment of all proposed changes and that
approved changes are communicated to all affected
parties.
Responsibilities (2)
• The site Quality Head is responsible for
ensuring that there are systems and
procedures to comply with applicable
Directives
• The site Quality Head is responsible for
approving or rejecting a proposed change
at site level following an assessment by
the site Change Control Committee.
Responsibilities (3)
• It is the responsibility of site Quality Management (QM) to ensure
that the regulatory evaluation assesses any potential impact the
change may have on the registration file
• If the change has a potential regulatory impact, it is the
responsibility of the Regulatory Site Officer (RSO) to involve the
appropriate functions for further activities
• If the change has a no regulatory impact, the implementation
/closing is handled by the site QM/RSO
• For non-local products (i.e. products under the responsibility of
Corporate), the RSO is responsible to initiate the assessment of the
proposed change via the Corporate Change Control Committee
QM Responsibilities for Change
Control
• QM is responsible for ensuring a robust and easy
to handle Change Control system
 Defining clear roles and responsibilities (initiator,
reviewer, approver)
 Creating a simple procedure with flow-charts
 Defining the needed activities (internally and
externally)
 Ensuring that all needed functions are involved
 Training and education of all employees involved
Change Control Management
needs Training
• QM is responsible for managing the site Change Control system
• Change control is a topic in which every employee involved in the
manufacturing process needs to be trained
• Good change control will be as good as the training and education
received
• Focus the training on the serious potential for negative impact of
any uncontrolled change
• We do not want anyone making unauthorised changes to any
activity that has Quality and/or Compliance impact
A Strong Reminder
• Change made and intended to improve can result in a
worse situation or even in a disaster. Therefore, all
consequences must be considered
• With a “good” change you can create other related
problems and also high amount of costs
• Even minor changes or those that are considered to
be minor, can have a big impact to product quality and
regulatory compliance
• And finally, all changes need to be closed-out.
General Requirements (1)
• Any change, which can affect a product with respect to
its qualitative and/or quantitative composition, quality
(including bioavailability, tolerance), purity, appearance,
functionality and/or stability must be assessed for its
potential impact prior to its implementation and
processed according the result of the assessment
• There must be a procedure in place at the site for
periodic assessment that incremental changes have not
altered the overall process.
General Requirements (2)
• The Corporate Change Control Committees must address all
changes with regulatory impact, evaluate all technical, quality and
regulatory aspects and decide
• The Corporate Change Control Committees must decide on the :
 Worldwide strategy based on the technical and/or scientific, quality and
regulatory information available at the Corporate Change Control
Committee level
 Identification of Department/Person in charge of writing the dossier
 Action plan including timelines until submission
More details later !
Initiation of the Change Control
Request at the Site Level (1)
• For an effective primary technical, scientific, quality
and regulatory evaluation, the following systems and
processes must be implemented :
• An evaluation system which allows the assessment of
all changes proposed by the site on a regular basis.
This must include the creation of a change control
committee at site level involving appropriate site
functions/experts
• Use of a Change Control Request Form (CCRF) and
follow-up tool (e.g. via electronic mails) as described
in the company procedure on change control.
Initiation of the Change Control
Request at the Site Level (2)
• The CCRF must be submitted to the site’s change
control committee
• Proposed changes must be justified by adequate and
sufficient supporting data and documentation must
allow complete understanding and the implications of
the planned change to ensure adequate assessment
• The technical and/or scientific evaluation of the
change is under the responsibility of the concerned
departments (Technical, Production and/or
Development departments) at the site level.
Initiation of the Change Control
Request at the Site Level (3)
• The quality and regulatory evaluation is under the responsibility of
the Head of Quality and the site regulatory officer. Advice provided
by experts such as the regulatory representative responsible for the
product may be requested
• If the proposed change has a regulatory impact and is approved by
the Head of Quality, the completed CCRF must be routed by Quality
Management and site regulatory officer to other appropriate
functions outside the site for coordination of a complete assessment
of the technical and/or scientific, quality and regulatory actions
required to enact the change, including timing of implementation.
Processing of the Change Control
Request after Site Approval (1)
• Changes approved by the Head of Quality must be
supported by a detailed time and events schedule
that has been agreed upon by the Change Control
Committee or directly with affiliate RAs
• The Change Control Committee (CCC) addresses
all changes with regulatory impact for all active
pharmaceutical ingredients and all quality changes
that may have an impact for the pharmaceutical
product (ex: crystallography)
Processing of the Change Control
Request after Site Approval (2)
• In all cases, the Committee must involve representatives of
appropriate functions competent to assess the proposed
change request with regards to technical and/or scientific,
quality and/or regulatory aspects in order to approve or to
reject the proposed change or to put the proposed change on
hold until supplementary information is made available
• The Corporate Change Control Committees must decide on
the
 Worldwide strategy based on the technical and/or scientific,
quality and regulatory information available at Corporate Change
Control Committee level.
 Identification of Department/Person in charge of the writing of
the dossier
 Action plan including timelines until submission
Processing of the Change Control
Request after Site Approval (3)
• Any modification of the change must be
reported to the Committee through an
addendum of the initial CCRF for new
assessment
• The Corporate Change Control Committees’
decision should have a validity period of typically
6 months. If a change is not processed during
this period, a new CCRF must be initiated for reassessment
Compilation of Documentation Supporting
Changes with Regulatory Impact
• On receipt of filled-in and signed-off CCRF from either Corporate
Change Control Committees or local Change Control Committees ,
the Affiliate Regulatory Affairs or regulatory site officer must prepare
or support the preparation of submission ready documents based on
the agreed regulatory assessment of the change and must provide
them to the appropriate regulatory function for review and approval
for file ability
• The appropriate regulatory function must submit the provided
documentation to the appropriate Health Authorities
• The Affiliate Regulatory Affairs or the site regulatory officer must
inform the change control committee, as applicable, of the receipt of
regulatory notification or approval or rejection of submitted
changes.
Implementation of Changes
at Site Level (1)
• For changes without regulatory impact, the site
Change Control Committee must decide about the
prerequisites and implementation timelines as well as
informing the respective unit in which the change will
occur. A change must only be implemented after
receipt of the written approval documented on the
CCRF
• For changes with regulatory impact, the release of the
batch after implementation of the change must only
be made after notification or approval of the
submitted file by the respective Health Authorities
(except in case of an annual reportable change for the
US).
Implementation of Changes
at Site Level (2)
• The regulatory site officer must inform
affiliate regulatory affairs of the date of
implementation of such a change with the
specific batch number reference
• The change request form must be
archived by site Quality Management.
Conclusion and Summary
• Changes need to be traceable
 Who changed, What, Where, When, Why, and How
 What are the consequences with respect to risks and costs, to
validation status and submission to Authorities
• Changes need to be planned in advance, evaluated, approved,
implemented and followed-up
• The required experts need to be involved. Don´t forget engineers
and IS people!
• Documentation should be clear, accurate and complete
• Keep you manufacturing process in the validated state/ state of
control when you perform changes !
Thank You
Any Questions