Change Control – Strategies for Successful Company-Wide Implementation
Good Manufacturing Practices (GMP), manufacturers must comply with numerous requirements. Industry must document instructions for manufacture and quality control procedures. They must specify materials needed and define the basic conditions required for a reproducible quality, such as suitable rooms, qualified facilities, trained personnel and type of documentation. Before a company can implement these requirements, it needs a regulatory body to review their suitability for the intended purpose.
Pharmaceutical manufacturing companies must prove the suitability of apparatus/facilities and procedures with qualification/validation. In these cases, someone responsible must sign the qualification/validation report confirming suitability and authorization for use.
The procedure must adhere to suitable requirements is not only first time a drug is manufactured or the first time a facility follows a procedure. They must follow and adhere to these requirements throughout the whole history of a drug or procedure.
Shall be documented requirements, such as written specifications for materials or directions for procedures. Firms must also document each change control for the requirements. As a result of scientific/technical development, changes to the legal basic conditions, or business restraints, manufacturers typically have to redefine, modify, enhance, or cancel requirements again and again in practice.
Change to previously approved requirements requires a review and authorization procedure to keep the system in its original state of proven suitability.
Change control programs are essential elements of pharmaceutical quality assurance systems.
Definition as per Annex 15 of the EU GMP Guidelines
“A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state.”
EU GMP Guidelines – the handling of changes
“Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process should be validated.”
Change control (21 CFR, 211.100)
(a) “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.”
Change control” (21 CFR, 211.160)
“The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit. The requirements in this subpart shall be followed and shall be documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified.”
“Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications. “(Annex 15, no. 43, PI 006-2).
“Change control is an important element in any Quality Assurance system. Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or support system operation.” (PIC/S document PI 006, section 6.7.1)
The change control monitors all types of changes which can influence the process reliability or product quality, evaluates them in reference to the relevant established requirements, and determines the measures necessary for implementing the change or decides that a change should not be implemented.
Many types of changes affect several regulation areas simultaneously (e.g., GMP requirements, authorization requirements, and employment protection requirements). Quality-relevant changes can affect several areas of a company (e.g., research/development, regulatory affairs, manufacture, quality control, engineering, and marketing); therefore, the control must be a task for the whole company.
The central processing of change procedures, coordinated by the quality assurance department, has several advantages compared to the handling of change control within various departments:
- There is a common understanding of what a change represents.
- The classification schemes used by the staff involved to grade changes are consistent.
- The risks connected with the change can be evaluated in a multi-disciplinary manner.
- There is a uniform documentation and authorization procedure.
Grading the Changes
According to the area of consideration (e.g., approval conformity or validation status), it may be necessary to use different change procedures as a base.
Changes to printed packaging material (information for use, folding cartons, and labels) in accordance with a special change control procedure, because these changes occur relatively frequently in practice and the process sequences can be standardized easily. In these cases, the sequences and the criteria used are not independent, but are carefully matched to suit and coordinate with each other.
The examples (lists, flow charts) for grading the changes, as used in many companies, can and should not replace the individual evaluation of a change, in particular the linked consideration of risk.
Some companies use different and extensive grading categories. After the introduction phase, most companies find that changes do not always fit into a prefabricated chart and instead it’s important to rely on experience and know-how for particular cases.
|Grading of Changes|
|Changes requiring control.||Changes not requiring control.|
|(Major Change)||(Minor Change)|
|Significance of change||Influences product quality or process reliability.||Influences a unit requiring control.||No relevance to GMP or authorization|
|Possible measures (selection)||• Official license|
• New approval
|• No relevance to GMP or authorization|
|Examples||• 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
|• Replacement of apparatus part of the same design|
• Change of cleansing agent for floors
• Change of laundry for work clothing (nonsterile or antibiotics area)
• Introduction of co-sales right
|Change to working times • Renovations in administration area.|
• Installation of air conditioner in staff room • Introduction of electronically readable plant ID cards
Other classifications not included in table are possible.
There is a list of changes that may make a revalidation necessary, including:
- Physical characteristics of the raw material.
- Origin of the starting material (change of supplier).
- Packaging material (e.g. replacement of plastic with glass).
- Process changes (e.g. mixing times, drying temperatures).
- Equipment (e.g. introduction of an automatic detection system).
- Production area and supply systems (e.g. new water plant).
- Moving manufacturing into a new building.
Deviations should not be treated as changes, not even when deviations become changes after the company clarifies the failure. A deviation is an unplanned and undesirable variation from a requirement. It does not correspond with the aim and procedure of change control and should be dealt with according to a special procedure about handling deviations.
Change Control Committee
An important function as part of the change control program is fulfilled by the change control committee (also known as: change control team, change control panel)
Change control committee generally consists of:-
- Head of quality assurance, who frequently also chairs.
- Heads of manufacturing,
- Heads of quality control,
- Heads of sales,
- Heads of regulatory affairs
- Heads of information representative.
If necessary, further departments (e.g. research/development, EDP, and engineering) also become involved.
Main Role of Change Control Committee
To evaluate changes, determine the measures required, coordinate measures for the departments affected by the change, and provide final authorization.
Change Control Committee should process only changes requiring control. These are changes relevant for the regulatory status and involve reporting or authorization procedures. They are also changes that could have an influence on the attributes of a GMP-relevant system, facility, apparatus, material/product, or a procedure/process and also deal with all changes whose grade or implementation is unclear or questionable.
When a company has introduced a change control program, the committee can review the effectiveness of the system using data, which is easy to determine. It includes:
- Number of completed change procedures/year
- Number of prematurely terminated procedures of procedure deviations
- Work expenditure/change type
- Duration of procedure: from application to completion
- Number of grading problems/total number of change procedures
- Number of OOS results/year
- Number of internal or external complaints/year
- Stability problems/batch reviews/recalls
The effectiveness of a change control program depends on the knowledge and experiences of the staff involved. The regular training about change control procedures is therefore extremely important. Committees should structure documentation procedures and communication sequences as simply as possible to enable rapid implementation.
Deviations are unplanned and generally unwanted changes. They are expressed in the form of internal and external complaints, stability problems, or batch recalls. If they occur, this can be an indication that the change control program has failed. It is possible that the change to a critical process parameter or material specification has been overlooked or a negative trend in the development of process data has not been noticed in time.
“All changes should be formally requested, documented and accepted by representatives of Production, QC/QA, R&D, Engineering and Regulatory Affairs as appropriate. The likely impact (risk assessment) of the change on the product should be evaluated and the need for, and the extent of Re-validation discussed. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorized.” (PIC/S document PI 006, section 6.7.2)
“All changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted. The likely impact of the change of facilities, systems and equipment on the product should be evaluated, including risk analysis. The need for, and the extent of, re-qualification and re-validation should be determined.” (Annex 15, no. 44)
Change control requires a written procedure (change control program) to regulate at least the following points:
- What types of changes does change control take into account for which areas does this operating instruction apply?
- Who can suggest/initiate changes?
- How changes are requested (forms, methods of communication)?
- How changes are graded, who is responsible for the grading?
- How the measures are necessary for carrying out the change determined, who compiles the directions required?
- Who is responsible for the execution and monitoring of all necessary measures?
- How the change control committee is assembled, what are the duties of the committee?
- How the change is documented (format, content, storage)?
- Who is responsible for authorizing changes?
- What are the special regulations for urgent changes?
If the change affects a manufacturing or testing process, then the qualified person must take this into consideration when releasing the batch (cf. PIC/S document PI 006, chapter 6.7.3).
The records can be archived in paper form or electronically. Keep in mind that when storing these records, you need to have raw data and other relevant documents accessible.
Changes requiring control are generally documented in the form of a change request, in which the applicant for the change proposes the type of grade/evaluation of the change, specifies the time frames and measures for carrying out the change, and requests that the change is authorized or declined by the change control committee. The documentation for the change procedure should prove that the change was evaluated (risk analysis) and the subsequently defined measures were implemented as predetermined. When implementing the change, you will need to coordinate several measures regarding timing and contents. A clear display of the individual measures for a project plan is useful for the coordination of complex changes.
The “change control” operating instruction describes the procedure of change control and contains an application form for documenting the change procedure.
Implementation of change control procedures
Forms for change control procedure are issued by the QA department. If a new form is issued, a change number is automatically allocated to the change procedure by the change database and is entered on the form.
The applicant should specify the object of the change and the significant reasons and circumstances of the change in the change request. He should then sign and date it.
The heads of area affected by the change should have the opportunity to give their opinion on the intended change, to identify any risks and to suggest necessary measures and schedules. In any case, they should be acquainted with the planned change. This is documented in the change control Forms.
The QA representative transfers the data required to identify the procedure into the change control database.
The members of the CCC jointly carry out a risk analysis of the change request, classify the change and give their decision to authorize or reject the change application. Authorization may be associated with a time scale. The applicant and his head of area are informed of the decision via a copy of the completed change request.
A decision by the change control committee may only be made if all the information and documents relevant to the decision are submitted. If necessary, the request may be returned to the applicant for completion.
If the change is authorized, the CCC can establish a measures plan in the change control Forms (tasks, responsibilities, schedule). This must be completed and authorized for the change procedure to be completed.
Those responsible in accordance with the measures plan shall each receive a copy and shall inform the QA representative when the established measures have been completed.
The QA representative shall collect all the completed measures plans, check them for successful completion of each task and include them with the original change request. The completed change request is archived and the result and date of the completion is entered in the change database.
In simple cases, in which the applicant can implement the change himself without requiring any scheduling, an electronic copy of the request may be distributed to the CCC via the internal e-mail system instead of at a meeting (circulation procedure). Each CCC member then gives his written consent regarding the change request via e-mail with electronic signature. The change request and electronic consent from the CCC member are to be archived. If there is no unanimous decision, the QA representative calls a meeting about the request.
Deviation from the procedure
It is permissible to deviate from the regulations only if an immediate change is urgently required for operational or staff safety or an immediate change has considerable significance for the unit, the need for it was not foreseeable and it was not possible to comply with the formal procedure in the time available.
In the cases, the consent of the responsible head of area or his representative should be sought before the change is implemented.
Once the change has been implemented, the procedure must be followed at the earliest opportunity.
Summary of Change Control Procedure
Change Control systems should be an integral part of the quality management system (QMS) of each company. Their task and aim is to ensure that all announced or requested changes are carefully checked and completely documented and authorized.
Before starting to implement the change, questions need to be answered like:
- How is the change classified?
- Is it a variation or a change?
- Who needs to be informed?
- What are the regulatory consequences?
A sound Change Control system is used to manage changes of all types. The Change Control process is necessary to prevent inappropriate changes from occurring. All GMP-relevant changes should only be made with a complete review and approval of a quality function and any other department that might be impacted by the change.
Only if all functions involved in the process are working together and know what needs to be considered, the Change Control process will run smoothly and fast enough to benefit from the change.
It is of high importance to know all relevant aspects of the whole Change Control process and the consequences a change might have.
A change control process can be summarized in the following steps:
- Review and Approval.