Change Control

Change Control
Luisa Stoppa
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Nanjing, the People’s Republic of China – 16-20 November 2009
Objectives of the presentation
To answer to the following questions:
⚫ What is the purpose of change control?
⚫ What must be taken into consideration when introducing change control

programs?
⚫ How can changes be graded?
⚫ What should be regulated in a “change control” operating instruction?
⚫ What is the function of the change control committee?
⚫ How shall the implementation of changes be recorded?

⚫ What has an inspector to inspect and to check?

2 | Nanjing, the People’s Republic of China, 16-20 November 2009
Programme
⚫ To introduce the general elements on change control
⚫ To train you in the guidelines (WHO-GMP, PIC/S

guidelines, EU-GMP)
⚫ To become confident with SOP, forms and records of

Change Control System
⚫ To develop your inspection plan on change control

Principles of change control
Before a medicinal product can be released, we need:
⚫ the manufacture and quality control procedure should be

documented in the form of instructions;
⚫ The materials to be used must be specified;
⚫ The basic conditions required for a reproducible quality,

efficacy and safety must be defined (i.e. suitable rooms,
qualified facilities, trained personnel, validated
procedures, established specifications)

⚫ Before the requirements can be implemented, the suitability of

equipments/facilities and procedures must be proven with
qualification / validation
⚫ This principle is not only valid the first time a medicinal product is
manufactured or the first time a facility is used or a procedure
comes into effect
⚫ The principle applies to the whole history of a medicinal product, a

procedure or a facility and it is to be guaranteed
⚫ As each requirement is stated in a document, it is clear that each

change control for the requirements must also always involve a
documentation control

⚫ Each change to previously approved requirements

requires a review and authorization to keep the system in
its original state of “proven suitability” The task
of
⚫ Formal change control guarantees that all changes are
evaluated for their effect on product quality or validation change
status control
⚫ Change control minimizes the risk that changes can have
on the quality or process characteristics
⚫ Change control programs have become recognized as

essential element of the pharmaceutical quality assurance
system

⚫ In the WHO-GMP guideline glossary there is definition of

the term “change control”
⚫ However, the GMP guideline basically contains only few

notes about the handling of changes

⚫ In the American Code of Federal Regulation CFR, the responsibility

for the verification and authorization of changes is task of the
quality control unit
⚫ In the EU regulations, the responsibility is assigned to Quality Unit
⚫ As the change control is considered an essential element of the

pharmaceutical quality assurance system, it is logical the person
responsible is quality assurance (QA representative, QA head)

⚫ Change control is not department-specific, rather the task

of the whole company
⚫ The change control monitors all types of changes which

can influence the process or product quality and states
the measures necessary for implementing the change or
decides that a change should not be implemented

Change control programs
⚫ Change control program is a managerial task
⚫ We expect a quality structure of change control
QM change
statement policy
standard operating operating instruction

procedure / instructions for change control
records / forms change requests
and other relevant documents and other relevant documents

⚫ Many types of changes affect several areas at the same

time:
GMP requirements Regulatory requirements
Process security (validation)
Product quality (specifications, approval)
Effectiveness / safety (approval)
Suitable rooms and equipment (qualification)
Suitable personnel (training, experience)

⚫ A central processing of change procedures, coordinated

by the quality assurance department, has several
advantages:
– there is a common understanding of what a change represents;
– the classification schemes used by the staff involved to rate
changes are congruent;
– the risk connected with the change can be evaluated in a multi-
disciplinary manner;
– there is uniform documentation and authorization procedure

⚫ The type and scope of a change control program must

comply with the requirements:
1. In the classical GMP-relevant areas the change control

helps to maintain the validated and established status.
Validated processes, qualified facilities, material
specifications can be influenced by changes and
medicinal products no longer comply with specifications

2. Holder of marketing authorization must guarantee that

necessary regulatory pre-requisites are met. Contract
manufacturers that do not have their own authorization
must guarantee that the contract giver is informed of
internal changes that could have an influence on their
application documentation (this requires that the contract
giver is included in the change control program of the
contract manufacturer)

3. In areas where medicinal products are developed,

processes are optimized or clinical research takes place,
changes should also evaluated and documented so that
the development of medicinal product or process must
be consistently proved

⚫ Many companies rate the changes requiring control
EU-GMP
Major change Minor change Not requiring
control
⚫ The example is one
Significance Influences product Influences a unit No relevance to
way to rate them: of change quality or process requiring control GMP or
reliability authorization
Possible ⚫ Official license ⚫ Amendment ⚫No relevance to
measures GMP or
(selection) ⚫ New approval ⚫ Review authorization
⚫ revalidation ⚫ documentation
examples ⚫Change of ⚫Replacement of ⚫Change to
manufacturer: other apparatus part of the working times
synthesis route of a same design
starting material (other ⚫Installation of air
impurities) ⚫Change of cleaning conditioner in
agent for floors administrative
⚫Removal of processes area
to another site ⚫Change of laundry for
work clothes (non- ⚫Change in
⚫Change in the product sterile or antibiotics purchase
composition area) procedure
⚫Change to the process

parameters

⚫ Other
classifications are
possible

⚫ It is not decisive which and how many change-

classes a company has rated, but how it is
guaranteed that changes requiring control are
recognized as such and implemented according
to a defined procedure

⚫ Not all changes require a revalidation
WHO-GMP

⚫ In the PIC/S document PI 006 (chapter 6.7.4) there is a list of

changes that may require a re-validation:

⚫ Also in the WHO-GMP guidelines there is a list of changes that

may require a re-validation

⚫ WHO-GMP guidelines

⚫ PIC/S document PI006

⚫ The so called “trials” cause a problem in change control program.
⚫ Trials are preliminary, temporary changes which can permanently

established or revoked after a trial period
⚫ With trials, there is a risk that these intended temporary changes

gradually become permanent changes without a formal change
control procedure being carried out
⚫ How long a trial is retained and whether it is withdrawn after a trial

phase or be introduce permanently, should be included in the
same procedure “change control” as all other changes

⚫ “Deviations” should not be treated as changes, not even

when deviations become changes after a failure has
been clarified
⚫ Deviation is an unplanned and undesirable deviation

from a requirement; it occurs spontaneously
⚫ Deviations should be dealt with according a procedure

about “handling deviations”
⚫ All variations implemented in emergency (no planned, no

controlled, no permanent) are included in deviations

Changes Deviations
(planned changes) (unplanned changes)
Submission of request Notification

- description of change - description of deviation
- rationale
Evaluation Evaluation
- effect on product quality
- definition of corrective actions
- effect on validation status - effect on validation status
- definition of revalidation measures - definition of revalidation measures
Approval
Implementation of change Implementation of deviation
Closing Closing

⚫ An important function as part of the change control

program is fulfilled by the “change control committee
CCC” (also known as change control team or change
control board)
⚫ This committee consists of the head of Quality

assurance, the heads of manufacturing, quality control,
regulatory affairs, IT department, engineering, sales
⚫ The task of the committee is to evaluate the changes,

establish and coordinate measures to put in place and
authorize the changes

PIC/S guideline

⚫ A problem is the issue of which changes the change

control team should dealt with
⚫ It is obvious that this team cannot deal with all changes

in the company
⚫ As matter of fact, only changes requiring control should

be processed by this team

⚫ Firstly, these are changes relevant for the regulatory

status
⚫ Secondly, they are changes which could have an

influences on the attributes of a GMP-relevant system,
facility, equipment, material/product, procedure/process
⚫ The team should also deal with all changes whose grade
or implementation is unclear or questionable

⚫ How the team members communicate with each other?
⚫ Not all changes require a meeting
⚫ In cases which are easy to make a decision about, it can

be useful traditional paper-based circulation procedures,
e-mail agreement or access to Intranet-based forms

⚫ When a change control program has been introduced,

the effectiveness of the system can be reviewed using
data which is easy to determine
Total number of changes request /year

Number of completed change requests / year
Change type / department involved
Duration of procedure: from application to closing
Number of deviations/year
Number of internal or external complaints /year
Number of OOS /year

EU-GMP
Documentation
⚫ Change control requires a written procedure to establish at least

the following steps:
What type of changes does change control take into account?

What are the requirements for urgent changes?
For which areas does this operating procedure apply?
Who can suggest changes?
How are changes requested (forms, method of communication)?
How are changes graded and who is responsible for the rating?
How are the measures for carrying out the change established?
Who is responsible for the implementation and monitoring of all measures?
Who is included in the change control team?
What are the duties of the change control team?
How is the change documented (format, content, storage)?
Who is responsible to authorize changes?

Documentation


Documentation


Documentation
⚫ All quality-relevant changes should be documented
⚫ All actions to be taken, including the need for and extent

of qualification or validation, should be described
⚫ The records can be archived in paper form or

electronically
⚫ When storing documents, raw data and other relevant

documents for change should be kept accessible

Documentation
⚫ Changes requiring control are generally documented in

the form of a “change request” in which the applicant for
the change proposes the type of change, suggests the
timeframes and measures for carrying out the change
⚫ The change control team authorizes or not the change
⚫ The documentation for the change procedure should

show that the change was evaluated (risk analysis)

Documentation
WHO-GMP

Documentation
⚫ Change control
procedure
(example 1)

Documentation
⚫ Change control procedure (example 2, 1/2)

Documentation
⚫ Change control
procedure (example
2, 2/2)

Documentation
⚫ Change control procedure includes flow chart of the

change control process and the change request form
(or change form)
⚫ Change request form records a request for change so

that each change is documented before it is approved
⚫ The change request form includes the description of

the change, the benefits, costs, urgency of the
change, change impact

Documentation
⚫ Change control procedure: flow chart (example 1)

Documentation

Change Request
More
Submission
information
required
Evaluation of
Change Impact
Change Activities Validation

Change Request
Change Activities
Approval Approval
Activities Activities
Completion Completion
Change Closed

Documentation

Documentation
⚫ Change control
procedure: flow
chart (example 4)

48 | Nanjing, the People’s Republic of China, 16-20 November 2009 CCB = change control board
Documentation
⚫ Change control
procedure: flow
chart for change
master documents
(example 1)

Documentation
⚫ Change request
form (example 1,
1/2)

Documentation
⚫ Change request
form (example 1,
2/2)

Documentation
⚫ Change request
form (example 2,
1/2)

Documentation
⚫ Change request
form (example 2,
2/2)

Documentation
⚫ Change request
form (example 3)

Documentation
⚫ Change database:
electronic copy

Documentation
⚫ Change control logbook

Page:__ of ____
Change control logbook (year:________)

Nb. Request Requester / Item Description Approval Actions and Closing
date department date time limit date
QA Manager signature _________ Date_______

Examples of changes
⚫ Changes to the cleaning procedure

- use of a new cleaning agent
- change in concentration / volumes of cleaning agent
- change in volumes of rinsing water
- change of cleaning process parameters
⚫ Changes to the production equipment

- changes to the CIP equipment
- changes to / replacement of equipment parts (difficult to give
detailed examples as these changes are too diverse)
- change of process parameters

Examples of changes
⚫ Changes to the product

- changes to composition (reformulation with different excipients)
- changes to the manufacturing process (i.e. transfer of a product)
⚫ Changes to HVAC system / unidirectional flow
⚫ Changes in lay-out (i.e. implementation of a pass-box)

Inspection plan
⚫ To ask for the Change Control standard operating

procedure
⚫ To check that all relevant steps for change control

implementation are detailed
⚫ To choose some applications (from the list in the logbook)
⚫ To verify the applications and all requested documents

(change request form, investigation, request and closing
date)

Conclusion
The old adage says: the only thing constant is change!

Reference documents
⚫ WHO GMP guidelines – Technical Report series n. 937
⚫ EU GMP guidelines, Part I annex 15
⚫ ICH Q7A or EU GMP Part II chapter 13
⚫ PIC/S Recommendations PI 006-3

l.stoppa@aifa.gov.it
Workshop on WHO prequalification requirements for reproductive health medicines,

62 | Jakarta, October 2009

Change Control

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Change Control

Uploaded by

Copyright:

Available Formats

Change Control

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ What must be taken into consideration when introducing change control

⚫ How can changes be graded?

⚫ What should be regulated in a “change control” operating instruction?

⚫ What is the function of the change control committee?

⚫ How shall the implementation of changes be recorded?

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ To introduce the general elements on change control

⚫ To train you in the guidelines (WHO-GMP, PIC/S

⚫ To become confident with SOP, forms and records of

⚫ To develop your inspection plan on change control

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Before a medicinal product can be released, we need:

⚫ the manufacture and quality control procedure should be

⚫ The materials to be used must be specified;

⚫ The basic conditions required for a reproducible quality,

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ Before the requirements can be implemented, the suitability of

⚫ The principle applies to the whole history of a medicinal product, a

⚫ As each requirement is stated in a document, it is clear that each

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ Each change to previously approved requirements

⚫ Change control programs have become recognized as

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ In the WHO-GMP guideline glossary there is definition of

⚫ However, the GMP guideline basically contains only few

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ In the American Code of Federal Regulation CFR, the responsibility

⚫ In the EU regulations, the responsibility is assigned to Quality Unit

⚫ As the change control is considered an essential element of the

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ Change control is not department-specific, rather the task

⚫ The change control monitors all types of changes which

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ Change control program is a managerial task

⚫ We expect a quality structure of change control

standard operating operating instruction

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ Many types of changes affect several areas at the same

Process security (validation)

Product quality (specifications, approval)

Effectiveness / safety (approval)

Suitable rooms and equipment (qualification)

Suitable personnel (training, experience)

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ A central processing of change procedures, coordinated

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ The type and scope of a change control program must

1. In the classical GMP-relevant areas the change control

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

2. Holder of marketing authorization must guarantee that

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

3. In areas where medicinal products are developed,

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ Many companies rate the changes requiring control

⚫Change to the process

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ It is not decisive which and how many change-

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ Not all changes require a revalidation

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

⚫ In the PIC/S document PI 006 (chapter 6.7.4) there is a list of