Change Control: Luisa Stoppa

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

Nanjing, the Peoples 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 Peoples 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
Formal change control guarantees that all changes are
evaluated for their effect on product quality or validation
status
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
The task
of
change
control

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
statement
change
policy
standard operating
procedure / instructions
operating instruction
for change control
records / forms
and other relevant documents
change requests
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 multidisciplinary 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
The example is one

way to rate them:
Significance
of change
Possible
measures
(selection)
examples
Major change
Minor change
Not requiring
control
Influences product
quality or process
reliability
Influences a unit
requiring control
No relevance to
GMP or
authorization
Official license
Amendment
New approval
Review
revalidation
documentation
Change of
manufacturer: other
synthesis route of a
starting material (other
impurities)
Removal of processes
to another site
Replacement of
apparatus part of the
same design
Change in the product

composition
Change to the process
parameters

Change to
working times
Installation of air
conditioner in
administrative
area
Change of cleaning
agent for floors
No relevance to
GMP or
authorization
Change of laundry for

work clothes (nonsterile or antibiotics
area)
Change in
purchase
procedure

Other
classifications are
possible


It is not decisive which and how many changeclasses 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
(planned changes)
Submission of request
- description of change
- rationale
Evaluation
- effect on validation status

- definition of revalidation measures
Approval
Implementation of change
Closing
Deviations
(unplanned changes)
Notification
- description of deviation
Evaluation
- effect on product quality
- definition of corrective actions
- effect on validation status
- definition of revalidation measures
Implementation of deviation
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
More
information
required
Change Request
Submission
Evaluation of
Change Impact
Validation
Change Request
Change Activities
Change Activities
Approval
Approval
Activities
Completion
Activities
Completion
Change Closed

Documentation

Documentation
Change control
procedure: flow
chart (example 4)

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
date
Requester /
department
Item
Description
QA Manager signature _________ Date_______

Approval
date
Actions and
time limit
Closing
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
62 |
Workshop on WHO prequalification requirements for reproductive health medicines,

Jakarta, October 2009

Change Control: Luisa Stoppa

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Change Control

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Objectives of the presentation

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

To become confident with SOP, forms and records of

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Principles of change control

The materials to be used must be specified;

Principles of change control

Principles of change control

Principles of change control

However, the GMP guideline basically contains only few

Principles of change control

As the change control is considered an essential element of the

Principles of change control

The change control monitors all types of changes which

Change control programs

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

Process security (validation)

Effectiveness / safety (approval)

Suitable rooms and equipment (qualification)

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

Change control programs

The example is one

Change in the product

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change of laundry for

Change control programs

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

Change control programs

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

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

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

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

PIC/S document PI006

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

The so called trials cause a problem in change control program.

Trials are preliminary, temporary changes which can permanently

With trials, there is a risk that these intended temporary changes

How long a trial is retained and whether it is withdrawn after a trial

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Change control programs

Change control programs

- effect on validation status

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

QA Manager signature ___ Date_