The Validation Master Plan


The first question you may ask is: Is a validation master plan required to be compliant with the cGMPs?

The literal answer is no, in fact no regulation specifically calls for a VMP and the only guidance in which the concept shows up is PIC/S’ document PI-006-03, although ISPE has been using the term as early as 1998 (see ISPE Baseline Guide volume 2, first edition, 1998). Euralex Volume 4, Annex 15, published in 2001 references the PIC/S guidance and formalizes the VMP as an integral part of “planning for validation.”

However, I’ve never seen an FDA warning letter that cites the lack of a validation master plan, but there are warning letters dealing with issues in a company’s VMP or failure to follow their own VMP.

Does that mean you shouldn’t waste your time?

Again, the answer is no. The Validation Master Plan can impart huge benefits to the validation effort in general, especially in getting everyone on this same page in terms of purpose, scope, vocabulary, roles and responsibilities, general approach, general requirements, and acceptance criteria. And even if they don’t explicitly require it, regulatory agencies will ask for a VMP, and if you don’t have one, you better have some documentation that covers the considerations typically covered in a VMP (outlined below):

  1. Purpose
  2. Scope
  3. References
  4. Definitions and Acronyms
  5. Roles and Responsibilities
  6. Commercial Products Overview
  7. Plant Description
  8. Validation Approach
  9. General Requirements
  10. Acceptance Criteria
  11. Deviations
  12. Change Control/Change Management
  13. Document Review and Revision Policy
  14. Appendices
  15. Document History

In detail:

  1. Purpose – a couple sentences about what the document is. State the company name, address, and maybe drug products if not too many. The purpose should be short and concise.
  2. Scope – the scope section really details what the document does. Typically a validation plan will:
    1. Document a plan for producing documented evidence of a controlled, validated state for all existing facilities, systems, equipment, and processes, including control systems, utilities, lab equipment, and process equipment, and associated warehouse space, used in GMP operations at [YOUR LOCATION].
    2. Provide a framework for producing documented evidence of
      a controlled, validated state for any new facility, system, equipment, or process, or any modification to an existing facility, system, equipment, or process used in GMP operations at [YOUR LOCATION].
    3. Define the general acceptance criteria for validation and assignment of responsibilities related to validation activities.
  3. References – you may want to include some references in your VMP. Some good/universal ones:
    1. FDA CFR Title 21 Part 210, “Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs, General”
    2. FDA CFR Title 21 Part 211, “Current Good Manufacturing Practice for Finished Pharmaceuticals”
    3. FDA Guidance for Industry, Process Validation: General Principles and Practices, Revision 1
    4. ICH Q7A, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
    5. ISPE Guide, Science and Risk-Based Approach for the Delivery of Facilities, Systems, and Equipment
    6. [YOUR COMPANY’S] Quality Manual/Policy
  4. Definitions and Acronyms – this is where you define your terms and acronyms. Some good ones to include:
    1. Acceptance Criteria: The pre-determined condition or characteristic included in a protocol or test plan that the facility, system, equipment (FSE), or process must meet to pass verification.
    2. Commissioning: A well planned, documented, and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the end-user, that results in a safe and functional environment that meets established design requirements and stakeholder expectations.
    3. Concurrent Qualification/Validation: A qualification or validation that occurs concurrent with manufacture of product for the marketplace, as opposed to a prospective qualification or validation which occurs prior to manufacture of saleable product, or retrospective qualification or validation, which occurs after sale of a product.
    4. Critical Process Parameter (CPP): a process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.
    5. Critical Quality Attribute (CQA): a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
  5. Roles and Responsibilities – this section is critical and is something many auditors will be looking for. That’s because if you have the right approvers on your VMP, and clearly defined roles and responsibilities within, an auditor sees that as commitment to the validation program. This section should clarify things like:
    1. Who contributes to the generation of User Requirements Specifications and other controlled specification documents?
    2. Who maintains and controls the inventory of approved validation packages?
    3. Who informs Regulatory Affairs of new validation project plans to ensure regulatory submissions are updated as appropriate?
    4. Who initiates Change Control documents for modifications to manufacturing FSEs and processes?
  6. Commercial Products Overview – this section should include a description of all drug products made at the facility in the scope of the VMP. Including a high-level process-flow diagram in this section is recommended.
  7. Plant Description – this section includes a high level description of the layout of your facilities, processes, utilities, control systems, etc. The idea is to provide an understanding of things that might come into play in the execution of the validation program. I recommend listing types of equipment, what utilities are in use, and what computer systems are in use (e.g. BMS, SCADA, DCS, electronic document management software, CAPA management software, Calibration/PM management software, inventory control software, etc.)
  8. Validation Approach – this section should detail what deliverables the validation program will generate and the relationship between them. It should speak to inputs (i.e. design documents such as QTPP, URS, etc.) and outputs (approved validation packages, requalification schedules, continuous monitoring plans, etc.)
  9. General Requirements – this section lays out requirements of the validation program, in order to get everyone on the same page, and may cover such things as what GEP means to the site, what are the requirements for documentation used in the validation program, and if the site allows concurrent and/or retrospective validation.
  10. Acceptance Criteria – this section covers the requirements for acceptance criteria, something like:
    1. Acceptance criteria will be pre-approved in specific qualification and validation protocols.
    2. Where possible, acceptance criteria will be derived from approved specifications (URS, FS, etc.) and/or validation plans.
    3. Data collected during validation protocol execution will be analyzed using standard statistical methods, as appropriate, or as described in the protocol instruction.
  11. Deviations – this section should introduce the concept of validation deviations, differential them form manufacturing deviations (typically called “IRs = incident reports”), and reference an SOP that goes into the specifics
  12. Change Control/Change Management – provide details in this section on how changes will be managed at each stage of the lifecycle, especially during commissioning when things are a bit more out of control, state when formal change control is instituted (e.g. after OQ report approval and prior to PQ protocol execution), and reference the change control SOP.
  13. Document Review and Revision Policy – this section includes information on how the VMP will be periodically reviewed and revised
  14. Appendices – includes a list of all appendices, e.g.
    1. General Arrangement Diagram
    2. Validation Process Flow Diagram (example: Example Validation Process Flow Diagram)
    3. List of Validation Requirements by Area
  15. Document History – include a table or document revision history (applies to all controlled documents)

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