The Food and Drug Administration (FDA) is tasked with protecting the public health by ensuring the safety, efficacy, and security of the nation’s food supply, human and veterinary drugs, biological products, medical devices, vaccines, and other products. In order to fulfill its mission, the FDA requires that all products under its domain meet guidelines outlined in current Good Manufacturing Practice (GMP) regulations.  These guidelines serve to ensure that end products are free from contamination and consistent in manufacture, that the manufacturing process has been well documented, that personnel are well trained, and that the product has been checked for quality throughout the manufacturing process.

In order to establish documentary evidence that a system, procedure, process or activity carried out during product production and testing meets guidelines outlined in GMP regulations, the FDA expects manufacturers to carry out validation activities. Since there are a wide variety of systems, procedures, processes, and activities that need to be validated, industry-leading organizations typically create a Validation Master Plan (VMP) at each manufacturing facility to track, coordinate and standardize validation efforts. While a VMP is not a requirement for an organization, it has become standard practice and FDA inspectors will often want to see a VMP to determine whether a facility has a well thought out validation strategy. Towards this end, let’s discuss best practices for creating an effective Validation Master Plan.

What is a Validation Master Plan?

FDA regulations set the expectation that all aspects of a production process are well defined and controlled in order to ensure that the products produced are consistent in their safety and efficacy. A VMP is a foundational document that helps to achieve this goal by documenting compliance requirements and detailing necessary validation activities across a site or facility.

In this regard, the VMP is different than validation plans written for a single validation project. The VMP is a top layer document that establishes a disciplined and structured approach to all validation projects and describes the overall risk-based strategy for achieving and maintaining a qualified facility with validated processes.

A comprehensive VMP will assign clear responsibilities for authoring, reviewing, approving and executing all validation documentation and tasks. As such, the VMP allows manufacturers to demonstrate that they are focused on quality and in control of their quality system. This document is often one of the first that FDA inspectors will ask to review, as it will provide a concise overview of how the company has

• delegated responsibilities
• justified its validation efforts
• designed production processes
• planned resource usage
• established a trained and competent workforce
• integrated cGMP regulations into every aspect of its operations

The VMP is ultimately a unifying document which helps to create a common understanding of the company’s approach towards validation in all team members to enable effective organizing and execution of validation activities. It also serves to help management understand what the validation program involves and why it is important.

Components of a Good VMP

Best practice for creating a VMP document is to involve a team that includes key stakeholders from each part of the facility that the plan will touch. A team-writing approach will bring together the comprehensive knowledge and differing perspectives necessary to ensure all relevant processes, equipment, utilities and systems are addressed in the VMP. While the document should be written in a concise and to the point manner, it should also be comprehensive and as lengthy as needed to convey the necessary information, as an incomplete VMP sets the facility up for compliance challenges.

The VMP should address all quality supporting systems (e.g., equipment, instruments, processes, procedures, computer systems, utilities, etc.) used for manufacturing, processing, testing, labelling or packaging of products. A comprehensive VMP for a manufacturing facility will address validation in the following areas:

• Equipment/instrument validation/qualification
• Utilities validation
• Cleaning validation
• Process Validation
• Analytical method validation
• Computer system validation

In order to create a VMP that will serve as an effective document for company stakeholders and satisfy the expectations of regulatory inspectors, the following elements should be included:

Title Page. Includes title, document number and version.

Authorization. Contains signatures of management at the facility that have initiated, checked, approved and authorized the MVP. Management from all functional areas that the MVP touches should be represented (e.g., production, engineering, IT, QA, QC, GM, etc.).

Table of Contents. Documents the page numbers for each section of the VMP for easy reference.

Introduction. Provides a brief overview of both the facility (company name, location, any applicable division/subsidiary name, the sector/industry it serves) and the MVP document, along with references to the company’s Quality Assurance Policy.

Facility Description and Design. Provides a general description of the facility utilizing reference drawings detailing the areas included in the validation plan (e.g., material storage, manufacturing areas, GMP vs. non-GMP areas, etc.), with a particular focus on anything that can affect product quality. Describes all relevant products produced, equipment, and processes utilized at the facility – this information can be provided in the Appendix of the VMP.

Objectives. Describes how the VMP serves company personnel. Also describes how the VMP helps to ensure validation activities are carried out following company protocols, which are designed to evaluate whether equipment, systems, processes and methods:

• Meet design specifications
• Are suitable for intended use
• Satisfy cGMP regulations
• Meet applicable safety requirements
• Effectively ensure that products produced are safe and fit for use

Validation Policy. Describes the organization’s commitment to satisfying regulations by conducting appropriate qualification and validation activities on all applicable areas. Also describes any mandated company policies that serve as guidelines for validation activities.

Validation Approach. Describes the risk management strategy, risk-based assessment criteria,  and methodology used to execute the validation program at the facility.

Scope of Validation. The VMP applies to all critical equipment, systems, instruments, procedures, utilities and other quality supporting systems that are used for manufacturing, labelling, packaging, testing, and processing which may affect product quality either directly or indirectly. Describes the areas which require validation and qualification at the facility, along with the justification for each.

Validation Program. Provides important details, protocols, guidelines (i.e., Validation Plans) for the validation team on the different validation projects which will be conducted at the facility.

Roles and Responsibilities. Lists the members of the validation team, along with their roles and responsibilities in the validation process. Also details any anticipated resource needs to carry out the VMP.

Acceptance Criteria. Defines the requirements that need to be satisfied (i.e., expected results of validation testing) before the equipment, system, instrument, procedure or utility is considered suitable for use in regulated activities.

Validation Deviations. Discusses the procedure for documenting and investigating any deviations encountered during the validation process.

Validation Matrix. Lists the required validations throughout the facility in order of criticality.

Validation Schedule. Provides a schedule and timeline for completion of required validations based on information in the Validation Matrix.

Change Control. Documents the change control system that must be followed when changing the validation protocol, test reporting formats, or other related documents.

Outsourced Services. Describes selection, management (i.e., vendor validation) and services provided by outside vendors.

Training. Lists competence expectations for validation activities and any planned validation training events.

Ongoing Activities. Outlines details of the ongoing activities which will need to be implemented to maintain validation compliance going forward.

Appendix. Contains a variety of documents referenced in the CSV – product list, process flows, equipment list. Also lists any relevant documents impacting or providing guidance for the execution of validation and qualifications (e.g., SOPs, specifications, etc.).

Abbreviations and Glossary. Defines technical terms, or terms specific to the organization, that may be unfamiliar to readers.

Conclusion

Validation of systems, processes, equipment, utilities and methods is an important part of a company’s Quality Management System. This is especially the case for the Life Sciences industry. A comprehensive VMP is critical to an organization’s success in both producing quality products and regulatory compliance.

Lack of a VMP, or a poorly developed one, have been the source of many form 483 observations and warning letters from the FDA. A comprehensive VMP will force the implementation of a structured and standardized approach to validation across the organization, ultimately helping to better serve the public by ensuring the safety and efficacy of the products your company produces.