The Validation Master Plan

This article
describes the
elemental
requirements of
a Validation
Master Plan
(VMP), what it
should look like,
what level of
detail should be
included, and
FDA
expectations.

Reprinted from

PHARMACEUTICAL ENGINEERING

Reasons, Regulations, and Rules:

A Guide to the Validation Master
Plan (VMP)
by Brian W. Saxton

he US Food and Drug Administration

(FDA) has been explicit in the need for
validation, but implicit on the elements
of that program. The chanting of the thou shalt
validate mantra is heard throughout the Drug,
Biologics, and Medical Devices sections of the
Code of Federal Regulations (CFR), but, alas,
there is no boilerplate template to follow. Organizations are thus left to interpret the regulatory requirements and craft individual programs
to comply. Is there a guiding principle that can
be applied here, to help companies distill reams
of mind-numbing regulations into elemental
validation requirements?
An adage about public speaking says there
are three keys to a successful presentation:
1. Tell them what youre going to say.
2. Say it.
3. Tell them what you said.
This adage, in a slightly modified form, can be
used to describe the major elements of a Validation Program:
1. Tell them what youre going to do.
2. Do it.
3. Tell them what you did.
This three-step outline is a greatly simplified
model of the multitude of tasks associated with
a validation program, but is an accurate summary of the goals of each step of the process. The
role of the Validation Master Plan is to help an
organization get its arms around a projectspecific validation effort by setting the scope by
which all subsequent documents shall be
bounded.
To see how the parts of the validation program fit into this modified adage, lets briefly
review the elements. Validation Program is

18

PHARMACEUTICAL ENGINEERING MAY/JUNE 2001

Copyright ISPE 2001

The Official Journal of ISPE

May/June, 2001 Vol. 21 No. 3

an umbrella term, encompassing all of the components below - Table A.

Validation Master Plan (VMP)

The VMP serves as the validation roadmap,
setting the course, justifying the strategy, outlining the preliminary test and acceptance criteria, and documenting the necessary programs
that ensure a continuing state of validation.

Qualification
The Qualification phase provides documentation that equipment and utility systems were
installed properly through an Installation Qualification (IQ), operate correctly through an Operational Qualification (OQ), and perform effectively through a Performance Qualification (PQ).
Qualification assures that the criteria set forth
in the Basis of Design documents generated at
project inception have been met in the field
installation.

Process Validation
Building on the data generated from the Qualification phase, the Process Validation (PV) phase
focuses on the reproducibility of the systems
used and the resulting product quality. This
program challenges the ability of the systems
used (methods, equipment, and operators) to
meet the pre-approved design intent.

Final Reports
Final Reports (FR) compare the conclusions of
data gathered to the acceptance criteria outlined in the Qualification and Validation phases.
They determine the pass/fail status and address the resolution of any deviations. They also
can be referred to as Summary Reports.

Compliance Programs
The Validation program must ensure policies
and procedures comply with current Good Manufacturing Practices (cGMP). Systems such as
calibration, preventative maintenance, change
control, and revalidation contribute to a continuous state of validation.

The Validation Master Plan

Validation Program
 Validation Master Plan (VMP)
 Documents Intent and Pathway
 Qualification (IQ/OQ/PQ)
 Confirms Design Intent
 Process Validation (PV)
 Assures Process Consistency
 Final Reports (FR)
 Summarizes Test Results vs. Acceptance Criteria
 Compliance Programs
 Ensures Continuing State of Validation
Table A. Validation program.

Considering the above, we can now complete the Validation

Program adage:
1. Tell them what youre going to do (VMP).

VMP is often underutilized: serving as a vehicle to open up

dialogue between the regional District Office of the FDA and
the organization. Initiating a pre-submission meeting with the
FDA to review the VMP will save time to market by addressing
any concerns about the validation philosophy or methodology
up front, when the correction of those issues is not on a critical
path for time to market. This allows companies to work with
the FDA in an advisory versus an enforcement mode, which
will help take some of the anxiety out of the validation process
and improves its chances of success. The FDAs Center for
Biologics Evaluation and Research (CBER) has published a
document through its Manual of Standard Operating Procedures and Policies that discusses this. It suggests that a brief
description of the validation procedures including the validation master plan1 be submitted for review prior to the preNDA (New Drug Application) meeting. Although this procedure was written for Biologics, the benefits of such meetings
for Drug and Medical Device products is obvious, particularly
if there are unique processing steps and/or equipment that the
average FDA compliance officer may not be familiar with.

2. Do it (IQ/OQ/PQ/PV).
3. Tell them what you did (FR).
This article will focus on the Tell them what youre going to do
part of the Validation Program, otherwise know as the Validation Master Plan.

Planning Overview
The purpose of the VMP, in a prospective or concurrent validation effort, is to explain the validation rationale associated
with the installation, start-up, and use of a new production
line. This rationale should review manufacturing systems and
assess the potential of each to affect end-product quality. The
new process may be as simple as an accessory change on
existing product equipment, or as complex as a new building
with all new utilities and equipment. The size and scope of the
project determines the size and scope of the resulting VMP. For
a retrospective validation effort, the VMP documents the
existing production line and outlines the anticipated test and
analytical methodologies to be employed.
The VMP should be authored for its audience, including the
organizations quality, engineering, and regulatory departments, the FDA, and potential outside contractors. Each group
looks for different elements. Outside contractors want a
Deliverables List on which to base quotes and define the scope
of work; the FDA looks for the pre-approved intention to
comply with Federal regulations; while in-house quality, engineering, and regulatory departments look for an accurate
representation of systems and corporate policies. The VMP
should address all of these concerns.
The VMP serves the purpose of documenting the intent of
the validation program, and therefore needs to be pre-approved by the same departments that will ultimately be
responsible for reviewing and approving the subsequent protocols. At a minimum, this includes Regulatory Affairs, Quality,
and Engineering.

Regulatory References to Validation

and Planning
The FDA can determine prohibited acts and penalize drug and
device manufacturers who market adulterated product.2 An
adulterated product is one whose quality characteristics can
not be satisfactorily assured due to nonconformity with current Good Manufacturing Practices (cGMPs)3. The definition
of adulterated product is straightforward, but preventing its
occurrence can be complex. In essence, a Validation Program
ensures that systems, policies, and procedures exist to prevent
the manufacturing of adulterated products. Its in the cGMPs
for Drugs (21CFR 210 & 211), Biologics (21CFR 600) and
Devices (21CFR 800) where the need for validation is specified.

Drug Products
For drug products, Parts 210 and 211 of the cGMPs refer
loosely to maintaining appropriate validation data. However, the practice of validation is implied more strongly in
211.68 (a): Automatic, mechanical, or electronic equipment or
other types of equipment, including computers, or related
Typical VMP Contents
1.

Introduction

2.

Scope

3.

Facility Description

4.

Commissioning

5.

Qualification

6.

Process Validation

7.

Computer System Validation

8.

List of Required Protocols and Procedures

9.

List of Required Standard Operating Procedures

10. Equipment and Utility System Descriptions

11. Computer System Description

Opening a Dialogue with the FDA

There are a number of good reasons to create a VMP: the FDAs
expectation that one be created, determining resource scheduling and loading, and defining the necessity to create or
amend corporate procedures. However, one function of the

12. Other cGMP Programs

13. References

Table B. Typical VMP contents.

MAY/JUNE 2001 PHARMACEUTICAL ENGINEERING

19

Copyright ISPE 2001

The Validation Master Plan

Process Equipment/Other Systems
EQUIPMENT

Comm.

IQ

OQ

PQ

PV

Reactor System Series 100

Centrifuge

Catch Tank

Solvent Storage and Distribution

Glass Lined Mix Tank and TCU

UTILITY SYSTEM

Comm.

IQ

OQ

PQ

PV

Fire Water System

Breathing Air System

Cold Glycol System

USP Water System

HVAC

Utility Systems

Legend
Comm.:
IQ:
OQ:
PQ:
PV:

Commissioning
Installation Qualification
Operational Qualification
Performance Qualification
Process Validation
Not Applicable

Table C. List of required protocols and procedures.

systems that will perform a function satisfactorily, may be

used in the manufacture, processing, packing, and holding of
a drug product. The burden of proof lies with the manufacturer to show equipment will perform a function satisfactorily, and that proof should take the form of in-process testing
or alternately, Process Validation.
To clarify the validation requirements implicit in this
regulation, the Agency issued a Federal Register Notice proposing changes to Parts 210 and 211.4 One change would offer
this definition: Validation protocol means a written plan
describing the process to be validated, including production
equipment, and how validation will be conducted.5 Another
proposed section states: The manufacturers determination of
equipment suitability shall include testing to verify that the
equipment is capable of operating satisfactorily within the
operating limits required by the process.6 In both of these
cases, a well-crafted VMP will show the Agency the preapproved intent to comply with the expectations of cGMP
regulations.

Biologics
For Biologics, Part 600 addresses unique considerations associated with biological products and blood components. Biological-derived drug products must adhere to Parts 210 & 211.
Also, cGMP section 601.12 requires validation for changes to
an approved application. Before distributing a product made
using a change, an applicant shall demonstrate through appropriate validation the lack of adverse effect of the change on
the identity, strength, quality, purity, or potency of the product.7 This requirement governs changes in product, production process, quality controls, equipment, facilities, responsible personnel, or labeling.8 Whether the change is
20

PHARMACEUTICAL ENGINEERING MAY/JUNE 2001

Copyright ISPE 2001

major or minor, a VMP will provide the Agency the basic

components of the organizational validation philosophy and
intentions to comply with applicable regulations.

Medical Devices
For Medical Devices, 21 CFR 820 serves as the cGMP requirements section. Section 820.75 deals with Process Validation
and states that the validation activities and results, and
where appropriate the major equipment validated, shall be
documented.9 This outlines the need for a validation program,
and the VMP can help comply with this requirement by
documenting which major equipment systems will be validated.

Part 11
All regulated industries are struggling to understand and
comply with the requirements of 21CFR 11, which addresses
Electronic Records and Electronic Signatures, and requires
Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or
altered records.10 Based on the number and complexity of the
computer systems utilized, a separate Computer System Validation Master Plan may need to be written and referenced in
the VMP. Here again, this can serve as a vehicle for a preexecution meeting with the FDA in order to gain guidance.
These specific instances do not explicitly detail the requirement for a Validation Master Plan; however, a properly crafted
VMP will document the pathway to compliance.

VMP References
Increasingly, the FDA is showing it agrees. Recently, the
Agency issued a Guidance for Industry document, meant to

The Validation Master Plan

address the selection criteria governing

what equipment and utility systems need to
undergo Process Validation.

reflect the Agencys current thinking, that explicitly calls out

for a VMP. In Guidance on Quality System Regulation Information for Various Pre-Market Submissions, a requirement
of the Quality System Manufacturing Dossier is a copy of the
Validation Master Plan or a description of which manufacturing processes have been or will be validated. A Validation
Master Pan is a convenient method of quality planning for
process validations required in the manufacturing of the
Clearly the expectation of the
device ( 820.20(d)).11
Agency is that organizations have a validation strategy as part
of product and process development, and translate that strategy into a plan that will lead to an installation compliant with
regulatory requirements.

The Validation Master Plan

Listed below are the headings for the major sections of a VMP
followed by a description of the purpose and the suggested
content - Table B.

1. Introduction
This section should include the company name, location, division or subsidiary name (if applicable) and business sector
served. A short overview of the project provides the reader with
the necessary background from a macro standpoint. A crossreference to the relevant company Quality Assurance Policy is
appropriate here.

2. Scope
This section defines the breadth and reach of the validation
effort covered by the VMP. A brief description of the installation, whether single- or multi-product, and a breakdown of
installed equipment as new or existing should be included
here.

3. Facility Description
Whether the project is a new building, extension, or remodeling of a current building, the facility characteristics are listed
here. The number of floors, the inter-connectivity of process
and utility systems, isolation means, and the design product
and personnel flow used to minimize cross-contamination are
identified. Be sure to note any room classification (cleanroom
certification levels) and specialty surfaces and finishes integral to achieving the required product quality. Process Flow
Diagrams (PFDs) are useful here, depicting the anticipated
personnel, raw material, process, and waste material flow. The
emphasis here is on design considerations to eliminate crosscontamination of material.

validated while another is. The VMP needs to answer that

question, identifying support utilities that do not need to be
validated because they do not directly affect product quality. It
also demonstrates thoroughness, showing the FDA that all
systems have been examined for product quality impact. To
maximize the usefulness of commissioning, the system should
be tested within the anticipated operating range of the respective OQ.

5. Qualification
The selection criteria governing what equipment and utility
systems will undergo Qualification is discussed here. Individual definitions of IQ, OQ, and PQ, may be included. Company policies, regulatory references, and published guidelines
used in this selection process should be addressed. This discussion may include considerations such as product contacting
surfaces, critical/non-critical instrumentation, direct and indirect systems,12 and downstream processing, among others. A
discussion of protocol and final report formats may be included
here, with either a reference to existing protocol development
procedures, or a description of the format to be utilized. Final
Reports may be generated as attachments to the protocols
themselves, or as separate documents.

6. Process Validation
This section addresses the selection criteria governing what
equipment and utility systems need to undergo Process Validation. Company policies, regulatory references, and published guidelines utilized in the selection process should be
addressed. One such criteria is if the results of a process
cannot be fully verified by subsequent inspection and test, the
process shall be validated.13 Also included is a discussion on
the appropriate Cleaning Validations (CV) required to verify
inter- and intra-campaign cleaning methods. If this is to be a
finished product, Packaging and Sterility validation needs to
be addressed.

7. Computer System Validation

A separate section should be devoted to the discussion of
Computer Validation, whether that is in the form of a Programmable Logic Controller (PLC) or a Distributed Control
System (DCS). Computer Validation criteria also should be
discussed, and whether the installed control system is to be 21
CFR 11 compliant, i.e., secure audit trails, authority checks,
etc.

8. List of Required Protocols and Procedures

Include here a tabular representation of the equipment and
utility systems, and the required protocols and procedures
associated with each - Table C. This is the essence of the VMP
because it defines the validation requirements for the project,
and can be used to determine resource loading. This table can
subsequently be used as a Deliverables List if the validation
effort is contracted outside of the organization.

9. List of Required Standard Operating Procedures (SOPs)

4. Commissioning
Document here the selection criteria governing what equipment and utility systems will undergo Commissioning. As
Commissioning is not part of the Validation Program and is
not regulated by the FDA, people often wonder why they
should include this section at all. The reason is the FDA is just
as interested in the rationale behind why one system is not

This should take the form of a tabular representation of the

installed equipment and utility systems and the required SOP
associated with each, similar to the List of Required Protocols
and Procedures. This will help identify the level of SOP
generation necessary to complete validation activities. These
will generally take the form of Operation, Maintenance, and
Cleaning SOPs.
MAY/JUNE 2001 PHARMACEUTICAL ENGINEERING

21

Copyright ISPE 2001

The Validation Master Plan

An overview of the particular system should be given, aligned

with the Basis of Design documentation. Table D serves as an
example of specific verbiage used in a typical VMP. A listing of
proposed Qualification tests (IQ/OQ/PQ) should be identified
with a brief description of the procedure and how the associated Acceptance Criteria will be determined. As the VMP
should be developed early in the planning stage, many system
specifics will be in the draft phase and subject to change. To
avoid duplication of effort and unnecessary revisions, do not
assign numeric-specific Acceptance Criteria in the VMP. Those
details will be fully delineated in the respective Qualification
Section 10.0: Equipment and Utility System Descriptions
Nitrogen Distribution System
Description
Nitrogen gas is distributed throughout the facility using a network
of carbon steel (from supply to inline filter) and stainless steel
(from inline filter to use point) piping. Nitrogen gas is obtained
from an existing 400-psig nitrogen gas system located in the
facility.
A one-micron filter is utilized to filter high-pressure nitrogen to
be used in the Series 100 Reactor System for pressuring,
purging, and for the agitator gland seal. Nitrogen line pressure
from the header is reduced prior to use-point delivery. Lowpressure header branches service the tank farm and production
areas, and each branch will utilize a one-micron filter, as well as
upstream and downstream pressure indicators to verify filter
cartridge integrity.
Installation Qualification
Installation Qualification will be performed in accordance with the
guidelines specified in SOP #95IQ001. All IQ data will be
documented in an approved Installation Qualification protocol
Protocol preparation, review, and approval will be scheduled to
coincide with the installation of the Nitrogen Distribution System.
Operational Qualification
Operational Qualification of the Nitrogen Distribution System will
be performed in accordance with the guidelines specified in SOP
#95OQ001. Proposed OQ testing and the corresponding
acceptance criteria are described below.

System Capacity Testing/Flow Determination

Under maximum use conditions (system design basis),
nitrogen flow rate and system header pressure must remain
acceptable.
Static Pressure Testing
Nitrogen pressure at usepoints must meet system
specifications and end user requirements.
Performance Qualification
Performance Qualification of the Nitrogen Distribution System will
be preformed in accordance with the guidelines specified in SOP
#95PQ001. Proposed PQ testing and the corresponding
acceptance criteria are described below.

Moisture/Dewpoint Determination
The measured dewpoint at selected usepoints must closely
correspond to the dewpoint of the supply.
Particulate
Particulate measurements will be at or below predetermined
levels.
Oxygen Concentration
Oxygen concentration at predetermined usepoints must
closely correspond to the oxygen concentration of the supply.

Table D. Example of an equipment and utility system description.

22

PHARMACEUTICAL ENGINEERING MAY/JUNE 2001

Copyright ISPE 2001

10. Equipment and Utility System Descriptions

With the inclusion of some additional

information the VMP can help serve as a
resource- and task-planning tool

and Validation protocols that will follow. Keep in mind the

intent of the VMP as a scope and guidance document. Systemspecific acceptance criteria fall under the auspices of the
individual protocols.

11. Additional cGMP Programs

The VMP is meant to be a Validation Life Cycle document. It
should cover the activities and requirements from project
inception to testing completion and on through a program of
continuous monitoring and evaluation. Associated with this
effort are Quality Assurance/Quality Control procedures meant
to support and update the validation effort. These programs
include, but are not limited to:

11.1 Document/Change Control

A procedure must be in place to govern and capture documentation creation, revision, and control. This procedure will be
applicable to all validation documentation, and must designate the review and approval responsibilities of various functional groups. Archival guidelines shall include duration of
record retention, and means of storage and retrieval.

11.2 Standard Operating Procedures

SOPs shall exist to address such cGMP issues as facility
sanitation, waste collection and disposal, the use of suitable
rodenticides, insecticides, fungicides and fumigating agents,
and building maintenance.

11.3 Calibration
A system shall exist detailing the methods, frequency, and
documentation of the calibration program including justification for a no calibration required status.

11.4 Preventative Maintenance

This system will be indexed to distinct equipment identifiers,
and outline the maintenance procedures required to ensure
proper system functionality. This procedure will identify the
appropriate documentation and frequency requirements.

11.5 Revalidation
A crucial part of the Validation program is determining when
to revalidate. This determination may be periodic, or triggered
by the replacement of critical instruments. Part of the Change
Control program will be an assessment of the impact of any
proposed change on the validated state of the affected equipment, and if revalidation is required.

11.6 Operator Training

A program must exist to ensure and document that personnel
shall have the appropriate education, training, and/or experience to perform their assigned functions. Personnel shall be
trained on good sanitation practices, as well as the use of
protective apparel to prevent product contamination.

The Validation Master Plan

12. References
All company policies and procedures, as well as any applicable
local, state and federal regulations, and industry standards
referenced should be listed.

Input to the VMP

A certain minimum level of documentation needs to be developed in order to produce a VMP. An equipment list, which
provides basic specifications such as size/capacity, instrumentation and controls, design/operating limits, and capabilities
needs to be available. Additional documentation such as a
Design Basis is important to delineate how equipment and
utility systems should perform, independently and in concert,
to produce the product. For Biologics and Pharmaceuticals,
generally a set of preliminary Piping and Instrumentation
Diagrams (P&IDs) helps define system boundaries. For Medical Devices, the Manufacturing Flow Diagrams required in the
Manufacturing Dossier section of the Pre-Market Submission
also may provide system boundary information.
Approval of the VMP prior to the generation of the associated protocols is as important as approval of protocols prior to
data collection. Just as protocols require QA approval prior to
execution, the VMP requires QA approval prior to protocol
generation. The VMP should be under revision control, as it
documents corporate approval of the scope and intent of the
validation program, and will require QA approval. Any Basis
of Design or validation philosophy changes should be preapproved in the VMP prior to the generation of the affected
protocols. The VMP needs to be updated to document major
project scope changes such as the addition or deletion of
equipment, and project completion (i.e., release to production).
This provides a clean audit trail of pre-approved intent versus
execution.

Conclusion
In its simplest form, the VMP is meant to document the major
equipment and utility systems associated with the production
process, assess the impact on the quality of the resulting
product, and determine the validation requirements. With the
inclusion of some additional information; however, the VMP
can help serve as a resource- and task-planning tool. For
instance, a Deliverables List can be developed from the List of
Protocols, which can be used to gauge the man-hour requirements of the job, for either internal budgeting or comparing
outside contractor quotes. The Additional cGMP Programs
section can isolate the need for policies or procedures to be
created and/or updated.
The creation of a VMP at the beginning of the project serves
many purposes: to identify the timing and level of anticipated
resource needs, to document the corporations validation philosophy and individual elements, and to show the FDA the preapproved intent to bring on a new product line in full compliance. It is well worth the extra time spent to write this
document at project inception, and to get early regulatory
feedback via a pre-submission meeting with the FDA, than to
answer Agency questions during the approval cycle and pay
with a delayed product launch date.

2. Federal Food, Drug and Cosmetic Act, Chapter III, Sections 301, 303, 304, as amended by the FDA Modernization
Act of 1997.
3. Federal Food, Drug and Cosmetic Act, Chapter V, Section
501 (a)(2)(B), as amended by the FDA Modernization Act of
1997.
4. U.S. Food and Drug Administration, 21 CFR parts 210 &
211, Proposed Rule, Federal Register, Friday May 3 1996
Docket No. 95N-0362.
5. U.S. Food and Drug Administration, 21 CFR parts 210 &
211, Proposed Rule, Federal Register, Friday May 3, 1996
Docket No. 95N-0362, page 20113, proposed 210.3 (b)
(23).
6. U.S. Food and Drug Administration, 21 CFR parts 210 &
211, Proposed Rule, Federal Register, Friday May 3, 1996
Docket No. 95N-0362, page 20115, proposed 211.220 (c).
7. U.S. Food and Drug Administration, 21 CFR 601.12 (a),
April 1, 2000.
8. IBID
9. U.S. Food and Drug Administration, 21 CFR 820.75 (a),
April 1, 2000.
10. U.S. Food and Drug Administration, 21 CFR 11.10 (a),
April 1, 2000.
11. U.S. Food and Drug Administration, Guidance for Industry and/or for FDA Staff: Guidance on Quality System
Regulation Information for Various PreMarket Submissions, Draft Guidance-Not for Implementation, Draft released for comment on August 3, 1999, Section 19. Design
History File (DHF).
12. ISPE Baseline Pharmaceutical Engineering Guide: Pharmaceutical Engineering Guides for New and Renovated
Facilities; Volume 3, Sterile Manufacturing Facilities,
First Edition, January 1999, pages 119-120.
13. U.S. Food and Drug Administration, 21 CFR 820.75 (a),
April 1, 2000.

About the Author

Brian W. Saxton is the Manager of Validation Services at
Process Facilities Inc. in Boston, MA. He is responsible for
client-based validation programs including master planning,
protocol generation and execution, and final reporting. He has
been involved in developing and executing validation programs for the past 12 years for various regulated industries.
He has a BS in chemical engineering from Manhattan College,
Bronx, New York, and an MBA from Boston University, Boston, MA.
Process Facilities Inc., 160 Federal St., Boston MA 02110.
[email protected].

References
1. U.S. Food and Drug Administration, Manual of Standard
Operating Procedures and Policies, Communication, SOPP
8101.1, Version 1, Effectivity date February 11, 1999.
MAY/JUNE 2001 PHARMACEUTICAL ENGINEERING

23

Copyright ISPE 2001