What is a Validation Master Plan?

-A validation master plan (VMP) is a detailed, structured plan of work providing

information for controlling all the validation work on a project.

-It should define the validation philosophy and organisation for the project.

-Additionally, clients may decide this is a useful place for documenting some of
the pre-qualification activities.

-The master validation plan is a living document, not a one-time exercise. It

should be modified in response to changing needs

How Detailed Should a Validation Master Plan Be?

*This section gives an overview of the sections of a validation master plan and
what should be included in these sections.

-Introduction

-Aim

-Responsibilities

-Descriptions - Facility, Equipment, Utilities, Products and Manufacturing

Process, Computer Systems, Validation Strategy (Including Matrix), Validation
Systems (SOPs, Maintenance, Training etc.)

The Introduction - explains what the project is, where it occurs and the reason it
is required. It should clearly state the central aim in the project and focus on a
commitment to cGMP and validation.

The Aim -should include notification of the project team and regulatory
authorities about the project, facility layout, utilities, equipment, systems and the
processes that the facility is designed to house. Also, the aims should state the
approach that's to be taken on the project and lay out the assorted roles and
responsibilities involved.
The Responsibilities- this section should introduce the project team members
(by job title) and will define the role each member will play in the project.

The Description - this section should avoid details, especially engineering detail
and it should focus on highlighting cGMP related aspects. Some of the elements
contained in the Description section are described below:

1. Facility

 This is a key component of the VMP. It should explain the rationale for:

-Layout

-Personnel Flow

-Product/ Components Flow

-Equipment Flow

-Area Classifications

-Finishes

 It should also include a description of how the facility will be used.

 The author should use simple bubble diagrams to indicate the corridors,
rooms etc. This will help readers to have a basic understanding of the
facility.
 The facility description should highlight how equipment is moved around
the facility, and how it will be cleaned and stored.
 It should describe personnel access (operators, administrators,
maintenance personnel etc.) and describe security measures and a
method for changing regimes.
 It should give a plan for component and product storage and
transportation. This should highlight the measures that will be taken to
minimize risks of cross contamination.
 It should briefly describe the room finishes.
  It should give different area classifications and the reasons for these
classifications. It should use bubble diagrams to indicate air pressure
regimes.

2. Utilities

 Utilities must be broken into two categories: critical and non-critical. An

explanation should be provided explaining each items classification.
 There should be schematic diagrams to enhance the readers
understanding.
 This section should explain what each utility is used for and how and
where it is generated and stored. It should also describe where the utility
serves and how it is transferred. It should describe the level of refinement
that is introduced along the way. A Utility Matrix is an extremely helpful
element that can be added as an attachment for a complete overview.
 This section must emphasize the suitability of the materials and finishes of
all product contact parts.
 It should also explain critical parameters and indicate the quality required
at every point of use.

3. Equipment

 This section should list only the KEY equipment to be used in the facility. It
should label each piece of equipment as critical and non-critical and
explain the difference between these labels. **Critical equipment is
equipment that plays a direct role in manufacturing the product.
 It should identify which equipment is new and which is pre-existing
(legendry).
 It should explain the role of the equipment, cycles, critical parameters and
other pertinent information.
 It should address the suitability of the materials of construction/ finishes of
any product contact parts.

4. Products and Manufacturing Processes

  This section provides concise but complete descriptions of each step in
the process and the overall process. This section includes flow diagrams
to assist in reader interpretation
 This section also describes process control systems in sufficient detail to
explain their impact on the safety and value of the product
 It includes the details of test requirements for in-process goods and
finished goods

5. Computer Systems

 This section describes possible cGMP implications for each system

 It introduces all the computers that will be employed in the facility and the
role each one will play
 It indicates which computer systems are stand-alone and which are used
as equipment or utility control systems
 It explains the different levels of validation that will be applied and the
reason, for example GMP v non-GMP systems

6. Validation Strategy

 This section explains the rationale for the approach to validate the facility
 It also introduces any specific company policies and procedures
 It explains every qualification process and describes the activities required
for each one
 This section explains the difference between critical and non-critical
systems
 It compiles a matrix of systems to identify the qualifications that need to be
applied to each
 This section also describes the methods of documenting various validation
activities. It includes flow charts, when appropriate, to assist the reader
 It explains the format and content. It gives instructions for the preparation
of documents including who is responsible, when they will be drawn up
and gives instructions for their review and approval
 It describes a method for numbering documents
 This section explains how various document types are controlled and how
changes will be managed
Validation Assurance Systems

 This section will introduce the reader to routine documentation systems in

order to ensure the ongoing validated state of the facility
 It sets up control systems as the key to maintaining validation (software,
documentation, equipment, etc)
 It provides a list of SOP's, or types of SOP's, that need to be prepared for
the facility and indicates when these will be available. SOP's pertaining to
equipment and utility operation should reflect validation work that has
been undertaken and specify the vital role of control parameter ranges
that have already been validated. There is no shortage of these SOPs and
writing them is a considerable task
 There will be a lot of SOPs in place, covering the existing process
however, most of these will require modification to reflect the any
alterations carried out. These SOPs may cover operation of individual
pieces of equipment, maintenance, calibration, cleaning, gowning, change
control, environmental monitoring, chemical testing, sterility testing, waste
disposal, investigations of alarms, microbial sampling of air, surfaces or
other topics
 Personnel must be assigned to write the SOPs. This requires planning
and resourcing
 A complete program of maintenance activities must be written,
coordinated and resourced. If the necessary details are unknown at this
stage it is acceptable to give an indication of what the general philosophy
will be in the VMP. There should also be a timeline for when these issues
will be tackled
 The previous stipulations can also be applied to calibration of work
 Maintenance personnel and operators should be trained by vendors
before the project is completed. This should de done prior to their overall
training programme
 Periodic revalidation of the systems is important. Give details explaining
the revalidation policy that will be adopted

8. Validation: Matrix of Work

  A matrix should be compiled to cross reference the equipment and utilities
for each specified protocol, for example the IQ, OQ etc

Validation Report

The validation master plan clearly states that the OVERALL VALIDATION
REPORT is to be written at the completion of the project. This overall
validation report will summarize all of the DQ, IQ, OQ, PQ Computer
Systems Validation work and other important information.

Validation Risk Assessment - What's Involved

Validation risk assessment is a structured & documented approach to assessing
risks in a validation system. It can be used to identify testing/ information gaps in
development and hence determines if further work is required.

For example, when executing process validation (PV) batches, executing

extremes of all process parameter ranges may lead to escalation of permutations
and hence an impractical number of full scale production runs. A centre-line
approach (run three batches at centre of all ranges) may be used once risk
assessment determines there is already adequate data available to safely
determine effects on process of running process at extremes of ranges. This data
may be available from studies in lab or in manufacturing facility e.g. mixing and
hold studies.

Failure Mode Effects and Criticality Analysis (FMECA)

A FMECA is central to the risk assessment and is carried out on each individual
part of the process. This will list the following for each activity:

 Function - what is this specific activity aiming to achieve

 Failure analysis - what signifies a failure and how it happens
 Effects of failure - list effects of failure listed above on product/ process
 Causes of failure - specify, with as much detail as is available, which
process parameter caused failure
  Risk analysis - read section below
 Potential risk mitigations - if risk priority is high this requires mitigations
that will result in revised risk priority of low
 Revised risk priority - level risk priority will become post completion of
risk mitigations

A separate mitigation tracker document is then generated. This will remain in

draft form until mitigations are closed out and no further amendments are
required to this document.

Risk Analysis

Risk analysis should be conducted via cross functional team meetings covering
the following four criteria:

 Probability - the likelihood that a failure will occur in the process. This
parameter is rated on a scale as follows:

1. Low - unlikely to occur during the lifetime of the system

2. Medium - likely to occur sometime during the lifetime of the system

3. High - will occur several times during the lifetime of the system

 Severity - severity of the effect of each failure on the process. This

parameter is rated on a scale as follows:

1. Low - expected to have a minor impact

2. Medium - expected to have a moderate impact

3. High - expected to have a very significant negative impact

 Risk Class - the risk class is estimated on the likelihood of occurrence

and the impact of the event
 Likelihood of Detection - likelihood of detecting the failure before impact
to the process
1. Low - detection of fault is unlikely

2. Medium - detection of fault is perceived to be reasonably likely

3. High - detection of fault is perceived to be highly likely

Risk Priority

The risk priority is estimated on the likelihood of detection in conjunction with the
risk class and can be used to define the priority for further mitigating risks.
Following implementation of mitigations, the revised risk priority should be low in
order to proceed with that activity in the process.

Most important in this assessment are risk priority at medium. Since it is not low
potential risk mitigations are required. Execution of this agreed risk mitigation
results in a revised risk priority of Low. This means no further work is required on
this parameter prior to actual validation runs.