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
2
|
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?
3
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
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

4
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
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)
5
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Principles of change control
 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
6
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Principles of change 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
7
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Principles 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
8
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Principles of change control
 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)
9
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Principles of change control
 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
10
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
records / forms
and other relevant documents
standard operating
procedure / instructions
QM
statement
change requests
and other relevant documents
operating instruction
for change control
change
policy
Change control programs
 Change control program is a managerial task
 We expect a quality structure of change control
11
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Change control programs
 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)
12
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
Change control programs
13
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
Change control programs
14
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
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)
Change control programs
15
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
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
Change control programs
16
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Change control programs
 Many companies rate the changes requiring control



EU-GMP
17
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Change control programs
 The example is one
way to rate them:



Not requiring
control
Minor change Major change
No relevance to
GMP or
authorization
Influences a unit
requiring control
Influences product
quality or process
reliability
Significance
of change
No relevance to
GMP or
authorization
Amendment
Review
documentation
Official license
New approval
revalidation
Possible
measures
(selection)
Change to
working times
Installation of air
conditioner in
administrative
area
Change in
purchase
procedure
Replacement of
apparatus part of the
same design
Change of cleaning
agent for floors
Change of laundry for
work clothes (non-
sterile or antibiotics
area)
Change of
manufacturer: other
synthesis route of a
starting material (other
impurities)
Removal of processes
to another site
Change in the product
composition
Change to the process
parameters
examples
18
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Change control programs
 Other
classifications are
possible
19
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
Change control programs
20
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Not all changes require a revalidation
Change control programs
WHO-GMP
21
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 In the PIC/S document PI 006 (chapter 6.7.4) there is a list of
changes that may require a re-validation:
Change control programs
22
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Also in the WHO-GMP guidelines there is a list of changes that
may require a re-validation
Change control programs
23
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 WHO-GMP guidelines
Change control programs
24
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 PIC/S document PI006
Change control programs
25
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
Change control programs
26
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 “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
Change control programs
27
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Changes
(planned changes)
Deviations
(unplanned changes)
Submission of request
- description of change
- rationale
Evaluation


- effect on validation status
- definition of revalidation measures
Approval
Implementation of change
Closing
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
Change control programs
28
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
Change control programs
29
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Change control programs
PIC/S guideline
30
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
Change control programs
31
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
Change control programs
32
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
Change control programs
33
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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


Change control programs
34
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009



Change control programs
EU-GMP
35
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
36
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Documentation
 Change control requires a written procedure to establish at least
the following steps:


37
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Documentation
 Change control requires a written procedure to establish at least
the following steps:


38
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
39
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
40
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Documentation
WHO-GMP
41
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Change control
procedure
(example 1)
Documentation
42
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Change control procedure (example 2, 1/2)
Documentation
43
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Change control
procedure (example
2, 2/2)
Documentation
44
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 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
45
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Change control procedure: flow chart (example 1)
Documentation
46
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Documentation
 Change control procedure: flow chart (example 2)
Change Request
Submission
Evaluation of
Change Impact
Validation
Change Request
More
information
required
Change Activities
Change Closed
Approval
Activities
Completion
Change Activities
Approval
Activities
Completion
47
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Documentation
 Change control procedure: flow chart (example 3)
48
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Change control
procedure: flow
chart (example 4)
Documentation
CCB = change control board
49
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Documentation
 Change control
procedure: flow
chart for change
master documents
(example 1)
50
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Change request
form (example 1,
1/2)
Documentation
51
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Change request
form (example 1,
2/2)
Documentation
52
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Change request
form (example 2,
1/2)
Documentation
53
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Change request
form (example 2,
2/2)
Documentation
54
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
 Change request
form (example 3)
Documentation
55
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Documentation
 Change database:
electronic copy
56
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Documentation
 Change control logbook
Change control logbook (year:________)
Closing
date
Actions and
time limit
Approval
date
Description Item Requester /
department
Request
date
Nb.
Page:__ of ____
QA Manager signature _________ Date_______
57
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
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
58
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
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)
59
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
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)
60
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
Conclusion
The old adage says: the only thing constant is change!
61
|
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China, 16-20 November 2009
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
62
|
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 2009
l.stoppa@aifa.gov.it