1. Purpose
The purpose of this guideline is to provide guidance on the preparation of Validation Master Plans (VMP).
2. Scope and Applicability
All functions, departments and manufacturing sites within the sponsor or its contractors operating under GMP regulations or guidelines. This guideline applies to all existing and new drug compounds.
It covers the planning of validation activities related to the manufacturing and control of the registered stages of Drug Product or Active Pharmaceutical Ingredient(API) for clinical use, validation or sale.
All manufacturing activities concerned with:
– The receipt and establishment of new Drug Products or API’s.
– Major processing changes to existing Drug Products or API’s.
– The construction of new manufacturing or related facilities.
– Major alterations to existing manufacturing or related activities. Should be carried out in accordance with approved procedures for validation.
Where a project consists of a range of different validation activities then a Validation Master Plan (VMP) should be prepared. Different major projects carried out in one facility may each have its own VMP. Activities should be planned and prepared for by local management who should approve essential documentation prior to starting validation activities.
3. Definitions
3.1 Active Pharmaceutical Ingredient, (API)
Any substance or mixture of substances intended to be used in the manufacture ofa drug (medicinal) product that when used in the production of a drug becomes anactive ingredient of the drug product. Such substances are intended to furnishpharmacological activity or other direct effect in the diagnosis, cure, mitigation,treatment or prevention of disease or to affect the structure and function of thebody.Note: Also known as Bulk drug or Drug Substance.
3.2 Drug Product
The dosage form in the final intermediate packaging intended for marketing.
3.3 Validation
Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.
3.4 Validation Master Plan (VMP)
Is a strategic document which identifies the elements to be validated, the approach tobe taken for validation of each element, the organizational responsibilities and thedocumentation to be produced in order to ensure full consideration is given to productquality aspects. It will show how the separate validation activities are organized andinter-linked. Overall it provides the details and relative timescales for the validationwork to be performed.
3.5 Validation Master Report (VMR)
A summary of the activities actually performed in fulfillment of the Validation Master Plan.
3.6 User Requirement Specification (URS)
Describes what the equipment or system is supposed to do, thus containing at least a set of criteria or conditions that have to be met
3.7 Functional Specification (FS)
A document which records and approves the proposed solution to the User Requirement Specification prior to detailed design.
3.8 Installation Qualification (IQ)
Documented verification that all physical aspects of a facility or system, which affect product quality, adhere to the approved specification and are correctly installed.
3.9 Operational Qualification (OQ)
Documented verification that all functional aspects of a facility or system, which affect product quality, perform as intended throughout all anticipated operating ranges.
3.10 Performance Qualification (PQ)
A process which ensures /verifies that the facilities, utilities and equipment, as connected together, function as intended and produce intended results repeatedly and reliably.
3.11 Computerized System
A group of hardware components assembled to perform in conjunction with a setof software programs which are collectively designed to perform a specificfunction or group of functions in a defined environment (and including peripheraldevices, personnel and documentation, e.g. manuals, SOPs).Computerized Systems can be automated systems or purely information management systems. For GMP they concern systems which can affect product quality, either directly or indirectly.
3.12 Automated System
Includes (but is not limited to) automated manufacturing equipment, processcontrol systems, automated laboratory systems, manufacturing execution systems and, manufacturing and laboratory database systems. The automated system consists of the hardware, software, and if applicable, network components, together with the controlled functions and associated documentation.
Note: Automated systems are a type of computerized system.
3.13 Computerized System Validation
Establishing documented evidence which provides a high degree of assurance that a computerized system will consistently function in accordance with its pre-determined specifications and quality attributes throughout it’s lifecycle. (It applies to systems which can affect product quality.)
3.14 Process Validation
Establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.
3.15 Prospective Validation
Establishing documented evidence that systems do what they purport to do prior to the commercial distribution of a new product or an existing product made by a new or modified process.
3.16 Concurrent Validation
The validation carried out during routine production of products for sale. (In exceptional circumstances it may not be acceptable to complete a validation program before routine production starts.)
3.17 Sterile Process Validation
Establishing documented evidence that a sterilization or aseptic manufacturing process will produce a product that is sterile.
3.18 Analytical Method Validation
The process by which it is established, by laboratory studies, that the performance characteristics of the analytical methods meet the requirements for the intended application.
3.19 Cleaning Validation
Establishing documented evidence that a specified cleaning procedure will provide a high degree of assurance that it can be used to consistently clean a piece of equipment or a facility to a predetermined acceptable level of cleanliness.
3.20 Materials Validation
Provides documented evidence that all the necessary qualification associated with materials used during manufacture have been generated and approved as appropriate.
It includes specifications, vendor audits/ vendor rating, purchase standards for Raw Materials and Excipients, Primary Packaging Materials, Processing Aids.
4. Responsibilities
4.1 Each site should have in place SOPs for the preparation of validation documents that take account of this, or are equivalent to, this guideline. This documentation and the VMP should be approved by the Quality Assurance Function.
4.2 It is the responsibility of each site to appoint an individual responsible for validation, nominally the validation manager for a validation project.
4.3 The validation manager should be responsible for all validation activities including the preparation of a VMP. The validation manager, together with the site management staff, is responsible for ensuring SOPs are in place for the preparation of related validation documentation.
4.4 The VMP should be prepared, commented on and approved by the senior site persons as agreed locally or nominated by a Steering Committee. QA approval is required.
The approval signatures on the VMP would normally be those of the site or manufacturing unit management team.
4.5 VMPs should be prepared and managed by members of the manufacturing site where the exercise is to be carried out and utilize personnel competent for the tasks assigned. Where consultants are used to prepare VMPs, their work should be subject to the same level of scrutiny and approval as in-house documentation
4.6 In the case where third party contractors are used to manufacture an intermediate or API it is the responsibility of the Quality Assurance Agreement Coordination (QAAC) them/ Lead site to ensure that the facilities, equipment and processes at the contractor are qualified/ validated in line with site requirements.
5. Guideline
5.1 When is a VMP required?
5.1.1 Significant changes to the facilities, the equipment and processes which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation.
5.1.2 A new VMP should be prepared for projects involving major change to existing equipment.
5.1.3 A VMP is not required for projects, which involve the installation or alteration of a single item of equipment – these should be documented on separate validation plans and reports.
5.1.4 The VMP should be available prior to starting any of the validation activities.
5.1.5 For some sites, both a site VMP (for the site’s validation requirements) and project specific VMPs may exist. The site validation committee should provide co-ordination as appropriate.
5.2 What should a VMP contain?
5.2.1 Each VMP shall describe the scope of the activities and address relevant key elements of validation affected by the change, indicating the actions and documents that will be needed. The key elements are those factors that can have an effect on product quality.
5.2.2 The VMP shall identify all the components to be included within a validation project.
Flow diagrams or matrixes can be useful to provide an overview and monitoring tool.
A high level process map or flowchart of the manufacturing process should be included.
5.2.3 Following the issue of the VMP, detailed risk assessments (system and component impact assessments) should be carried out to identify items requiring qualification.
5.2.4 The content of the VMP should reflect the complexity of the extent of the validation activities to be undertaken. At minimum the VMP should address the following:
– Title, statement of commitment and approval page.
– Summary description of the project and its scope.
– A statement of validation policy and the objectives of the validation activity
– References to other existing validation documents.
– A description of the organization and responsibilities for validation
– The validation strategy to be adopted opposite Facilities and Systems (process equipment and services including automated systems),
– Materials, Quality Control, Personnel including training.
– The intent in respect of Process Validation and Cleaning Validation foreach of the drug product range.
– The documentation management and control system to be used.
– A description of the validation change management process.
– An indicative relative timescale plan.
– Clear acceptance criteria against which the outcome of the validation exercise will be judged.
5.2.5 The requirements for the above should be reflected in a completed Responsibility Chart for all deliverable documentation.
5.2.6 Appendix 1 illustrates the inter-relationship of validation documents, as an example for a major project.
5.2.7 For large projects involving many materials, a Materials Validation Plan may be used. For smaller projects, a Materials Validation Plan is optional. The VMP (Validation Master Plan) or lower tier documentation alone may cover the qualification of materials.
5.2.8 The headings of the VMP may be based on the above list. A project may be organized in different ways, however, depending on the character of the project.
5.2.9 The VMP should demonstrate that the validation activities have been considered and are being organized in a structured manner.
5.2.10 A VMP should be presented as a formal document which is suitable both as an internal guide and for scrutiny by a member of a regulatory inspectorate. It should therefore be concise, easy to read and not excessively duplicate text from documents held elsewhere in the Quality System.
5.3 Reporting
5.3.1 Each VMP should result in a report confirming that all validation activities have been completed satisfactorily.
5.3.2 It is recommended that a Summary Validation Report (or Validation Master Report, VMR) is prepared which summarizes activities undertaken, presents the overall conclusions and provides cross references to any associated reports or follow up actions.
5.3.3 The VMR may report under the main sub headings of the VMP and also include a reference list of all main GMP documents created for the project.
5.4 Changes to a VMP
5.4.1 VMPs should be prepared and managed by members of the manufacturing site where the exercise is to be carried out and utilize personnel competent for the tasks assigned.
Where consultants are used to prepare VMPs, their work should be subject to the same level of scrutiny and approval as in-house documentation.
5.4.2 Any changes from a VMP after issue, should be agreed with the steering committee for the project.
The VMP should not be revised once the activities it describes have started. The changes should be recorded in the project documents derived from the VMP and be reported in the VMR.
6. Appendices
6.1 Appendix 1: Validation Master Plan