1. Purpose
To define the principles for management of change within Operations.
2. Scope and Applicability
This document may applies to the Change Management, MCM process, to Regulatory Affairs CMC and to all cGMP activities performed by an Operation sites. It applies to all facilities, processes, systems and procedures used during manufacture, testing and distribution that may directly or indirectly affect the quality of pharmaceuticals products. The principles contained in this document apply to contractors. The teams/sites managing contractors has the responsibility to serve as the link between the contractor local change system and the company’s Change Control system.
3. Definitions
3.1 Change Control
A formal process by which qualified representatives of appropriate disciplines review (including technical and operational impact assessment), authorize, approve and close proposed or actual changes to facilities, systems, equipment and processes to ensure that they are maintained in a controlled manner.
3.2 MCM (Manufacturing Change Management)
Manufacturing Change Management. This is the process that facilitates the tracking, review and approval/rejection of changes that may impact on the registered data and on the international supply of products.
3.3 CMT (Change Management Team)
Teams with members from Operations and Regulatory CMC (Chemistry Manufacturing & Control) for monitoring and follow-up of manufacturing/control changes administered in the MCM system. (Manufacturing Change Management). There are several teams per therapy area.
3.4 RA (Regulatory Affairs)
An organizational function responsible for company regulatory activities.
3.5 CMC (Chemistry, Manufacturing and Controls)
FDA term to describe the section of the NDA which details the pharmaceutical development and the stability as well as the manufacturing processes and the analytical controls used in the production of a drug substance and a drug product.
3.6 DMG (Dossier Management Group)
Function within Supply chain in Operations responsible for maintaining Chemistry, Manufacturing & Control (CMC) dossiers post approval throughout the product life cycle. The function is also responsible for communicating regulatory commitments to manufacturing sites.
3.7 Abbreviations
IRM –Integrated Risk Management
MC — Marketing Company
QP — Qualified Person
QAJD — QA Justification Document
RPS — Regulatory Position Statement
SCM — Site Change Manager
3.8 Regulatory Position Statement (RPS)
The RPS describes the regulatory implications and evaluates risks and potential compliance issues of implementing a change prior to full market approval. It is compiled by company’s RA CMC.
3.9 QA Justification Document (QAJD)
The QAJD describes the justification for implementing a manufacturing change and for batch release decision, for materials/products affected by a change, prior to full market approval or prior to submission. The local site QA department compiles the QAJD.
4. Responsibilities
4.1 Supply Teams (ST)
A ST is lead by a Head of Supply. The team is amongst many things responsible for: Creating a product supply plan. Monitoring and ensuring implementation of manufacturing changes within the agreed timelines. These responsibilities are key in the change management process in order to give the right business input to the change management process.
4.2 Change Management Team (CMT)
The CMT is responsible for management of changes with international supply chain or regulatory compliance impact. All registered products shall be covered by a CMT or CMT principles shall be applied. The head of Supply team is accountable for setting up and running the CMT. The responsibility of running the CMT can be delegated.
The CMT shall have participants from at least the following functions:
– Supply Chain
– RA- CMC
– Operations
The CMT is the forum to discuss all changes, the implications of the changes and the implementation plans.
4.3 Site Change Manager (SCM) or responsible person at site
For Operations which consist of multiple sites, the SCM is responsible for the management of the change control procedure that is operated locally, for interaction with the other site or process and the MCM system. The SCM is accountable for highlighting the need for a Regulatory Position Statement when required from an Operations point of view and communicating this to the RA Regulatory CMC.
4.4 QP (or QA manager at non EU site)
Is responsible for batch release for products affected by a change and where all regulatory approvals have not yet been obtained. The justification for such decision shall be documented using a QA Justification Document according to this procedure.
4.5 Regulatory Affairs (RA) – CMC
Is responsible for providing a Regulatory Position Statement (RPS), which may include consultation with company’s RA group and MCs and as appropriate. The need for a RPS may also be identified in the regulatory strategy for the change. The RA CMC Manager is also responsible for archiving the document and for making it available in the MCM system (preferably at the high level plan stage or regulatory submit & approve stage).
5. Procedure
5.1 Local Change Control
All manufacturing sites shall establish a formal, documented system that evaluates the effectiveness of all changes proposed. The impact of the change on the validation and registration status must be assessed. Risk management must be a part of this process. The local QA unit must be involved in reviewing and approving all changes proposed. The implementation procedure for all changes must ensure that regulatory and GMP compliance is maintained. The operation of the system shall ensure adequate control and monitoring of change projects. The system shall be designed to ensure the complete and accurate recording of the decisions to approve or reject a change and the history of the change from inception to implementation. The system shall ensure that relevant documentation is updated accordingly. All sites shall appoint a Site Change Manager with clearly defined roles and responsibilities. All site should appoint a lead team which is responsible for the contractors are ensuring that appropriate links are established and maintained between the contractor and coordinated MCM process.
5.2 Changes with International or regulatory impact
The changes that have an impact on the registered data and/or on international supply must be handled in the global change management process. This process is supported by the MCM data system. This global process and system facilitates the tracking, review and approval/rejection of changes that may impact on the registered data and on the international supply of products. Decisions for Products affected by a manufacturing change require a QAJD and a RPS, if requested. The risk assessment may be done during different stages of a change in accordance with the IRM framework. For example, at the high level planning phase (in MCM), when a change has to be implemented on a tight schedule according to the regulatory submission strategy or from a supply point of view. During regulatory approval from the markets or from a supply point of view. The RPS document describes the regulatory implications of a change (i.e. parts of the dossier affected and type of regulatory procedures to be used in the different regions), the regulatory strategy (i.e. for the different regions, planned submission timelines and expected approval times) and a regulatory risk assessment. The RPS document should also include or refer to a list of markets where the change has already been approved or where submission is not needed. The regulatory position statement must include as a minimum:
– Scope of change
– Products affected
– Markets affected
– Type of regulatory procedure
– Regulatory strategy
– Status of change (including expected approval times for the remaining submissions)
– Regulatory risk assessment
– MCM reference (number and title)
– Date and signature
The RPS must be available in the MCM system. The RPS can be used as a supporting document in the batch disposition process; the batch release must then be justified by means of a QAJD. The QAJD allows provision for reviewing and approving documented quality risk assessments and ensures appropriate records are visible and retained. The QAJD must include as a minimum:
– Description of the change
– Reference to the relevant RPS if available
– Products affected
– Justification for release to the markets affected
– Date and signature
– A final decision to implement a change is always the responsibility of the
– QP/the QA-manager.
The RPS and QAJD should be traceable e.g. by referring to the MCM number in the documentation for the first batch released to the affected market/markets. A copy of RPS and QAJD should be archived at the site. The decision to implement the change must be captured in the MCM system. If during implementation of the change, the release of the first batch is done to a market where the final batch release to the market has to be done locally e.g. the US, information of the implementation of the change has to be put forward to the affected QA department. Some changes are initiated by regulatory initiatives such as scheduled updates of the registered documentation, other drivers are external initiatives e.g. pharmacopoeia changes that might impact the registered data. Also these types of shall be handled in MCM.
5.3 Pharmacopoeia changes
A Pharmacopoeial Committee should handle changes in the different pharmacopoeias, some of these changes might affect the submitted documentation. If that is the case the implementation of the change is a subject of the MCM process and the secretary of Pharmacopoeial Committee is responsible for raising a MCM errand.