Validation Master Plans

Module Outcomes

On completion of this module the participant should be able to:

Define what should be in a Validation Master Plan

Interpret Regulatory Guidelines for VMPs

List the required schedules

Organise Validation Documents (protocols, guides and reports)

Effectively present validation documents and plans to regulatory bodies

Prepare a Validation Master Plan

Background and Definitions

(VMP)
It is a requirement of GMP that each pharmaceutical company
identifies what qualification and validation work is required to prove
control of the critical aspects of their particular operation.
Common sense and an understanding of pharmaceutical
processing go a long way towards determining what aspects of
an operation are critical.
The key elements of a qualification and validation programme of a
company should be clearly defined and documented in a Validation
Master Plan.
PIC &EC VMP Draft -1999

Validation Master Plans (VMP)

What is a VMP ?
a) A document that summarises the firms overall philosophy,
intentions and approach to be used for establishing performance
adequacy.
b) A document providing information on the companys validation
work programme. It should define details of and timescales for the
validation work to be performed. Responsibilities relating to the
plan should be stated.
PIC &EC VMP Definition -1999

Responsibilities
Standards

Content/Guidance

Schedules of Work

Why Prepare a VMP?

Helps management to:
know scope of validation and resources needed
understand the need for the programme
Helps members of the validation team to know their tasks
and responsibilities
Helps GMP Inspectors to:
Understand the firms approach to validation and the
set up and organisation of all validation activities

Validation Master Plans

Two Types
Prospective Specific major project (new facility or
project)
Retrospective - Overall facility (including existing facility
and operations

VMP Scope - EC (Draft Annex 15) 1999

1.3. Scope
All validation activities relating to critical technical operations,
relevant to product and process controls within a firm should be
included in a VMP.
This includes qualification of critical manufacturing and control
equipment.

The VMP should comprise all Prospective, Concurrent,

Retrospective Validations as well as Re-validations.

VMP Coverage
Facility and Rooms Finishes
Utilities, HVAC and Services
Equipment
Cleaning and Sanitation Programs
Computers
Processes
Laboratory
Schedules and Resources
Example Protocol
Control Documents

Different Validation Master Plans for:

Manufacturing

Production/Engineering

CleaningPrograms

Technical/Production

ComputerisedSystems

ComputerServices

LaboratoryMethods

LaboratoryManagement

VMP Industry and Regulatory Standards

(referenced when preparing protocols)

FDA Guideline on General Principles of Process Validation (1987)

Computer Systems Guides - (GAMP and GALP etc)
PICs Recommendations on Validation - 1999
EC cGMP (Draft) Annex 15 - Validation Master Plans 10/99
ISPE Guides for New Facilities - Bulk Pharmaceutical Chemicals
ISPE Baseline Guide Pharmaceutical Water and Steam Guide - Draft
FDA Guidelines - (water, process, cleaning )
FDA Validation Documentation Inspection Guide - (unpublished)
PDA Technical Monograph No1. Validation of Steam Sterilisation Cycles.
Australian cGMP - Appendix D Laboratory Instrumentation (1991)
Pharmacopoeias (BP/EP and USP)
ICH Technical Guidelines
AS1386 -1989: Cleanrooms and Clean Workstations
Codes of GMP (TGA/EU and FDA)
Company SOPs and Standards

Example Table of Contents - VMP

PART A - ORGANISATION and SCOPE
1
2

INTRODUCTION
SCOPE OF THE VALIDATION MASTER PLAN

REGULATORY STANDARDS INDUSTRY GUIDE

GLOSSARY OF TERMS
4.1 General Definitions
4.2 Validation Definitions
4.3 Documentation Definitions

MANAGERIAL RESPONSIBILITIES
5.1. Quality Assurance Manager
5.2. Operations Manager
5.3. Validation Document Preparation and
Authorisation

VALIDATION PHASES
6.1 Design Qualification
6.2 Installation Qualification
6.3 Operation Qualification
6.4 Performance Qualification

7. REQUALIFICATION OF CRITICAL GMP SYSTEMS

8. VALIDATION PLANS (NEW PROJECTS)
9 DOCUMENTATION STRUCTURE
9.1 Document Flow
9.2 Validation Support Documents
9.3. Qualification (IQ and OQ) Commissioning
Protocols
10. STRUCTURE OF SUPPORT DATA FILES
11. DOCUMENTATION CONTROL AND ARCHIVING
12 CHANGE CONTROL

Part B

- General Validation Standards and

Guidelines - List of Guidelines

Part C Schedule of Validation Activities 1999

Technical Standards and Validation Guidelines

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

Design Qualification GMP Design Review and Qualification of Specifications

Construction Documentation and Quality Assurance New Facilities
Installation Qualification and GMP Room Finishes New Facilities
Qualification of Unclassified GMP Manufacturing Rooms
GMP Cleanroom Environment - Qualification of Class 3500/350/3.5 Cleanrooms
Critical Utilities - Heating, Ventilation and Air Conditioning (HVAC)
Critical Utilities - Electricals and Lighting in Manufacturing Areas
Critical Utilities - Drains, Plant Water and Waste Discharge
Qualification of Process and Purified Water Systems
Qualification of Water for Injection (WFI/PFW) Water Systems
Qualification of Compressed Gases Systems (Air, Nitrogen and CO2)
Qualification of New Manufacturing Equipment General Approach
(Re) Qualification of Existing Manufacturing Equipment General Approach
Qualification of Sterilisation Equipment and Processes - Autoclaves
Qualification of Sterilisation Equipment and Processes - Hot Air Ovens & Tunnels

Technical Standards and Validation Guidelines

16
17
18
19
20
21
22
23
24
25
26
27
28

Process Validation - Paramaters to be Monitored for Critical Process Steps

Retrospective Process/Product Review and Verifications
Guidelines for the Content of Process Validation Protocols
Guidelines for the Content of Process Validation Reports/Executive Summaries
Support Systems - Calibration and Preventative Maintenance Programs
Guidelines for Equipment Cleaning Programs - CIP and Manual
Guidelines for Validating Equipment Steam - in - Place (SIP) Systems
Validation of Quality Control Testing Procedures
Validation of Sterilising Filtration of Liquids (Bacterial Retention)
Validation of Pasteurisation Processes
Validation of the Clean Steam Supply
Validation of Freeze Dryers
Validation of Aseptic Processing

Project Specific Validation Plans

Provides overview of Validation

philosophy for major projects
(multi system or process line)

Allows for informed pre-approval

of Validation work

Provides opportunity for team

input into refining and focussing
validation work

Provides a clear understanding of

the scope, timing and resource
requirement for validation
Is the primary document presented
to a regulatory authority

VMPforSiteOrganisation
andPrograms

ValidationPlan
forSpecificProject
ProjectPlan
forCommissioning

Define
Responsibilities and Authorities
Top Management
Line Management (production, development, engineering)
Department Management/supervision
Operators and Supervision
Quality Assurance

Validation Authorisation Matrix

Category
Mechanical Services
Qualification
Process Equipment
Qualification
Laboratory Equipment
Qualification
Computer Systems
Cleaning & Sanitation
Programs
Technology Transfer/Scale Up
Process Validation of Existing
Products and Processes
Test Method Validation

Protocol &
Document
Preparation
Contractors &
Enginee ring
Cross
Functional
Team
Quality Control
Laboratory
Cross
Functional
Team
Cross
Functional
Team
Quality
Assurance
Cross
Functional
Team
Quality Control
Laboratory

Protocol &
Document
Approval

Execution of
the Work and
Documentation

Enginee r M gr
Contractors &
Operations M gr
Engineering
Technical M gr
Enginee r M gr
Cross
Operations M gr
Functional
Technical M gr
Team
QC M gr
Quality Control
Technical M gr
Laboratory
Operations M gr
Technical M gr
IS De partme nt
Enginee r M gr
Operations M gr
Technical M gr
Prod Dev t M gr
Operations M gr
Technical M gr
Operations M gr
Technical M gr
QC M gr
Prod Dev t M gr
Technical M gr

Cross
Functional
Team
Cross
Functional
Team
Cross
Functional
Team
Cross
Functional
Team
Quality Control
Laboratory

Certification of Validation Programs

(example)
Technical
Manager

Enginr
Mgr

Process and Ancillary

Equipment

Laboratory Test
Methods

Computer Systems

Facility, Utility and

Services

Operatio n

Processes/Products
- New Products
- Existing Products
Equipment Cleaning
SOPs

_
_
_

R&D
Mgr

Operation
Mgr

GMP
Mgr

_
_

Lab. QC
Mgr

Co-ordination/Management
of Validation Programmes
Validation Working Party representatives:
Validation/QA
Engineering
Production

Responsibilities
Execution of Validation (Master) Plan
Validation time line

Execution of Protocols
IQ/OQ - Engineering responsibility
PQ - QA (Validation) responsibility
Co-opt Line supervision and operators

TRAINING

Typical VMP Schedules

(Equipment)

Area Plant Equipment

Weighing Utensils - Dispensary
Dispensary Scales
Packaging Accumulating Tables
Blending Equipment (2X)
Blistering M achine (3X)
Capsule Sorter
Hoist for Bulk Bin
Pump - Liquids / creams
Shrink tunnel
Tablet Compression Press
Bottle Conveyor line
Granulation Mix Drying Oven

Critical

FAT

IQ

OQ

Estimated
PLC
Computer Labour
Control
Val
Hrs*

Yes
Yes
Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes
Yes

Yes

Yes
Yes

Yes
Yes

Yes

Yes

Yes
Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes
8
11

Yes

Yes

Yes
Yes

Yes

Protocols
Executions

Yes
12
15

Total Hours
Total Hours
TOTAL

4
4
8
50
60
12
4
8
8
20
4
60
200
232
432

Support
Services

Calib'n
Vendor
Engineer
Engineer
Vendor
Laboratory
Vendor
Engineer
Vendor
Engineer

Typical VMP Schedules

(Room Qualification)

Process
Zone
Room
No
1
2
3
4
5
Production
6
7
8
9
10
Other
11
12

Room Description
Coating 1
Coating 2
Drying Ovens
Fluid Bed Drier (Future)
Future
Solvent Preparation
Compressing 1
Compressing 2
Encapsulation
Solid Dose Staging
Change Room
Wash Room
No of Protocols
No of Execution
Total

Room
Class
100,000
100,000
100,000
100,000
GMP
100,000
100,000
100,000
100,000
GMP
GMP

Room (at rest) In Op'n

OQ
IQ
PQ
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

1
11

Yes
Yes
Yes
Yes

Yes
Yes
Yes

Yes
Yes
Yes
Yes

Yes
Yes
Yes

1
8

1
6

Labour
Hours
10
10
10
5
2
10
10
10
5
2
2
8
76
84

Support
Services
Contractor
Contractor
Contractor
Laboratory
Laboratory
Contractor
Contractor
Contractor
Laboratory

Protocol
Execution
Total

Other Schedules
Process Validation
Cleaning Validation
Computerised GMP Systems
Laboratory Test Methods
Critical Services and Utilities

How much validation ?

What to validate ?
Relate the validation effort to the risk

Risk Analysis and Validation

Low

RisktoConsumer

Complex
Technology

Sterile
Biotechnology

RiskofFailure

Simple
Technology

High

Listedand
OTCProducts

Validation Priority Strategy

Equipment/Utilities

Critical Services (direct contact)

Contamination Potential

Major Common Services (Water, HVAC)

Performance History

Products

Relative Complexity of
Manufacture (failure modes)

Current Line Control (Security)

Potential Risk to Consumer

(failure effect)

Relative Sales Volume (Exposure)

ProvideaRationaleintheVMP

Documentation Systems
Validation Master Plan - (Part A)
Validation Plans
(per project)

Validation Guidelines for

Critical Systems (Part B)
Commissioning
Process Validation
PV Protocol*
PV Report*

* Review & Audit by:

QA Internal
GMP Auditors
Support Registration

IQ Protocol*
IQ Report*

Validation Summary
Files Critical Systems *
Raw and Support
Data Files

OQ Protocol*
OQ Report*

Validation Documentation System

Store completed validation packages in an orderly
manner to facilitate access and traceability
Keep validation documentation up-to-date as change
occurs

Validation Support Documentation

Validation Cover Page
Protocol Supplement (Variation) Page
Deficiency Report

Validation Cover Page

Register of Protocols
Date Tracking
Responsibility
Approvals

Validation Supplement Report

Record of Changes
Auditable History
File with Protocol
Approvals

Validation Deficiency Report

Record of Deviation
Auditable History
File with Reports
Demonstrate Investigations
Demonstrate Resolution

Validation Reports

IQ

OQ

Report

Report

Define

Calibration Schedules
Training Needs
Maintenance Schedules
Safety Requirements

Define

Operating Procedures
Cleaning Procedures
Staff Training
Control Functions

Specifications

PQ

Report

Define

Update M of M
Update Batch Records
Set Process Limits
Verify Specifications
Revalidation Program

Validation History Files

VALPLAN

DQs

IQs

VALSUMREP

Auditable

OQs

PQs

Support Data Only

SUPPORTDOCUMENTS

Without a Validation Plan

Protocols are developed without a clear focus

Replication/omission occurs between OQ/PQ

Management unable to overview the work

Staff/resource requirements unknown

Final report is the first indication of the full extent of

the work

Final reports too lengthy

Auditors cannot be presented with a clear picture of

the Validation effort.