1. Change Control Luisa Stoppa
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, the People’s Republic of China – November 2009

2. 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. 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. 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. 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. 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. 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. 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. 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. 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

11. 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. Change control programs
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

13. Change control programs
The type and scope of a change control program must comply with the requirements:
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

14. Change control programs
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)

15. Change control programs
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

16. Change control programs
Many companies rate the changes requiring control
EU-GMP

17. Change control programs
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
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
The example is one way to rate them:

18. Change control programs
Other classifications are possible

19. Change control programs
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

20. Change control programs
Not all changes require a revalidation
WHO-GMP

21. Change control programs
In the PIC/S document PI 006 (chapter 6.7.4) there is a list of changes that may require a re-validation:

22. Change control programs
Also in the WHO-GMP guidelines there is a list of changes that may require a re-validation

23. Change control programs
WHO-GMP guidelines

24. Change control programs
PIC/S document PI006

25. Change control programs
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

26. Change control programs
“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

27. Change control programs
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

28. Change control programs
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

29. Change control programs
PIC/S guideline

30. Change control programs
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

31. Change control programs
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

32. Change control programs
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, agreement or access to Intranet-based forms

33. Change control programs
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

34. Change control programs
EU-GMP

35. 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?

36. Documentation
Change control requires a written procedure to establish at least the following steps:

37. Documentation
Change control requires a written procedure to establish at least the following steps:

38. 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

39. 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)

40. Documentation
WHO-GMP

41. Documentation
Change control procedure (example 1)

42. Documentation
Change control procedure (example 2, 1/2)

43. Documentation
Change control procedure (example 2, 2/2)

44. 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

45. Documentation
Change control procedure: flow chart (example 1)

46. Validation Change Request Activities Completion Activities Completion
Documentation
Change control procedure: flow chart (example 2)
Change Request
Submission
More information required
Evaluation of
Change Impact
Validation Change Request
Change Activities
Change Activities
Approval
Approval
Activities Completion
Activities Completion
Change Closed

47. Documentation
Change control procedure: flow chart (example 3)

48. Documentation Change control procedure: flow chart (example 4)
CCB = change control board

49. Documentation
Change control procedure: flow chart for change master documents (example 1)

50. Documentation
Change request form (example 1, 1/2)

51. Documentation
Change request form (example 1, 2/2)

52. Documentation
Change request form (example 2, 1/2)

53. Documentation
Change request form (example 2, 2/2)

54. Documentation
Change request form (example 3)

55. Documentation
Change database: electronic copy

56. Change control logbook (year:________) Requester / department
Documentation
Change control logbook
Page:__ of ____
Change control logbook (year:________)
Closing date
Actions and time limit
Approval date
Description
Item
Requester / department
Request date
Nb.
QA Manager signature _________ Date_______

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

61. 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