1. Supplementary Training Modules on Good Manufacturing Practices
Validation
Module 1 of the Supplementary Training Modules on GMP expands on the subject of VALIDATION that was introduced to you in WHO Basic Training Module 4. It is, perhaps, one of the least understood aspects of GMP but is fundamental to the production of quality pharmaceuticals.

2. Validation Part I: Introduction and The Validation Master Plan (VMP)
Part 2: Cleaning validation
Part 3: Process validation
Part 4: QC-related validation
Part 5: Review and summary
Divided into five parts, this module can be modified to fit a one to one-and- a- half day programme.
Part 1 covers an Introduction, after which we will review the Validation Master Plan (VMP). Part 2 focuses on Cleaning validation, and Part 3 on Process validation, which includes aspects of non-sterile liquid and solid dosage forms, sterile manufacturing, and an introduction to steam, and dry heat validation. Part 4 covers QC-related validation including test method validation relating to microbiological, chemical and physical testing validation requirements, followed by Part 5, Review and summary.
Suggested times are:
Presentation: Part –60 minutes
Presentation: Part –60 minutes
Presentation: Part –60 minutes
Group session 60 minutes (optional)
Presentation: Part – 90 minutes
Presentation: Part minutes
Test paper 45 minutes
(Note for the Trainer: the times noted are very approximate. As part of the preparation phase, the trainer will need to get an understanding of the audience and any special issues involved such as language ability. The times for the different sections may then have to be altered accordingly. Allow for breaks of minutes about every one-and-a-half hours.)

3. Validation Objectives of Part 1
To provide an introduction to the subject of Validation
To provide information on the Validation Master Plan
The objectives of Part 1 are:
To provide an introduction to the subject of Validation
To provide information on the Validation Master Plan

4. Three basic principles of Quality Assurance:
Validation
Introduction
Three basic principles of Quality Assurance:
Quality, safety, effectiveness
Cannot inspect quality into a product
Processes must be under control
These are the three basic principles of quality assurance:
Quality, safety and effectiveness must be designed and built into the product.
Quality cannot be inspected or tested into the finished product.
Each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications.
Validation of processes and systems is fundamental to achieving these goals.

5. Validation WHO validation definition
The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results. 
The WHO Validation definition is:
“The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results.”
From: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992; (WHO Technical Report Series No. 823). Annex 1: Good manufacturing practices for pharmaceutical products.

6. Qualification or validation?
A system must be qualified to operate in a validated process
Qualify a system and/or equipment
Validate a process
Qualification versus validation, e.g. you
qualify an autoclave, whereas you validate
a sterilization process
Qualification or validation?
The “system” is the complete set of equipment needed to carry out a specific process.
A system must be qualified to operate in a validated process. Qualification is part of validation. You qualify a system (systems include autoclave, freeze dryer, cleanroom and water treatment).
You validate a process (processes include sterilisation, freeze drying, mixing, cleaning, filling).
From: Dr C A Kemper, Kemper-Masterton Inc, PIC Sep 96) Validation or Qualification?

7. Validation Qualification and validation work require:
Collaboration of experts
Budget
Meticulous and careful planning
A Validation Master Plan helps the manufacturer and inspectorate
Qualification and validation work requires:
Collaboration of experts and a multidisciplinary approach: A specific characteristic of validation work is that it requires the collaboration of experts of various disciplines such as pharmacists, technologists, metrologists, chemical analysts, microbiologists, engineers, experts on Q.A. validation etc. The manufacturer may need to engage specialists e.g. for computer software development, check that the manufacturer keeps records of qualifications, experience and training.
Budget: the manufacturer must allow enough money, time and human resources to carry out proper validation studies. Costs: Validation studies are costly as they require time of highly specialized personnel and expensive technology. Time constraints: Generally, validation work is subject to rigorous time schedules. These studies are always the last stage prior to taking new processes, and facilities into routine operation.
Validation requires a meticulous preparation and careful planning of the various steps in the process. All work should be carried out in a structured way according to documented procedures.
The above factors require a well-organized and structured approach that
should be adequately described in a Validation Master Plan (VMP), which helps
both the manufacture and the inspector understand the company’s strategy and
approach to validation.

8. The Validation Master Plan
(VMP)
Philosophy
Content
Strategy
A Validation Master Plan (VMP) is a document that summarizes the manufacturer’s overall philosophy, intentions and approach to be used for establishing performance adequacy. The following slides review the nature and extent of the contents of the VMP and what the manufacturer’s strategy should be.
The VMP should present an overview of the entire validation operation, its organizational structure, its content and planning, the core of the VMP being the list/inventory of the items to be validated and the planning schedule. .

9. Validation Validation Master Plan Recommendation only
Cover manufacturer’s validation policy and needs
Provides information on validation organization
It should describe:
why?
what?
where?
A Validation Master Plan is a recommendation only, contained within the WHO guidelines, Annex 6. There is no regulatory requirement but the inspector should encourage its development as explained in the following slides
The VMP should cover the pharmaceutical manufacturer's validation policy and needs, including qualification and validation, such as:
Prospective validation
Concurrent validation
Retrospective validation
Revalidation
Change control (See next slide for explanation of these terms.)
The VMP provides information on the way a firm organizes validation work
It should describe: Why, what where, by whom, how and when?
by whom?
how?
when?

10. Validation Validation Master Plan Prospective validation
Concurrent validation
Retrospective validation
Revalidation
Change control
Prospective validation: This is carried out during the development stage. It involves establishing documented evidence that a process, procedure, system, equipment or mechanism used in manufacture does what it purports to do, based on a pre-planned validation protocol.
Concurrent validation: This is carried out during normal production of products intended for sale. It requires a full understanding of the process, based on prospective work. It involves very close and intensive monitoring of the steps and critical points in at least the first three production-scale batches.
Retrospective validation: This is the analysis of accumulated results from past production to assess the consistency of a process. It includes trend analysis on test results and a close examination of all recorded process deviations. It is important to analyse batches manufactured over a period of 12 months, to provide a statistically significant picture. It is not the preferred method of validation and should be used in exceptional cases only.
Revalidation: This involves a repeat of the process validation, to provide an assurance that changes in the process/equipment introduced in accordance with change control procedures do not adversely affect process characteristics and product quality.
Change control: This is a formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state.

11. Validation The VMP helps: Management Validation team members
Project leaders
GMP inspectors
A VMP helps management: to know what the validation programme involves with respect to time, people and money, and to understand the necessity for the programme.
A VMP helps leaders and members of the validation team: to know their tasks and responsibilities.
A VMP helps GMP inspectors to understand the manufacturer's approach to validation and how the validation activities are organized and managed.

12. Validation
The VMP
Identifies validation items (products, processes, systems)
Defines nature and extent of testing expected
Outlines test procedures and protocols
Summary document
Management agreement
The VMP identifies which items (products, processes, systems) are subject to validation. It defines the nature and extent of the testing expected and it outlines the test procedures and protocols to be followed to accomplish validation.
The VMP should be a summary document. It should be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as policy documents, SOP's and validation protocols/reports. It should include validation of analytical techniques which are to be used in determining the validation status of other processes or systems. All validation activities included in the VMP should be summarized and compiled in a matrix format. Such a matrix should provide an overview and contain all items covered by the VMP that are subject to validation describing the extent of validation required [i.e. IQ, OQ and/or PQ].
The contents of the VMP should be agreed by top management. Management should thus be aware of the nature and extent of the work required and the resources that may be needed.

13. Validation Validation Activities in VMP
Every validation activity included
Revalidation
Validation of new process cycles
Large validation projects have separate VMPs
Include reasonable unexpected events
The VMP should include every validation activity, e.g. validation of analytical techniques which are to be used in determining the validation status of other processes or systems.
Revalidation provides the evidence that changes in a process and/or the process environment that have been introduced either intentionally or unintentionally, do not adversely affect process characteristics and product quality.
There are two basic categories of revalidation : (a) Revalidation in cases of known change (including transfer of processes from one pharmaceutical manufacturer to another or from one site to another), (b) Periodic revalidation carried out at scheduled intervals. The VMP should include the revalidation intervals.
The VMP should define how new process cycles will be validated.
Large validation projects, such as water systems, HVAC systems, should have separate VMPs.
Reasonable unexpected events (worse case) are required to be covered in the VMP e.g:
power failure
computer crash and recovery
filter integrity test failure

14. Validation The VMP: Enables overview of entire validation project
Lists items to be validated with the planning schedule as its heart
Is like a map
The VMP should present an overview of the entire validation operation,
its organizational structure, its content and planning. The heart of the
VMP is the the list or inventory of the items to be validated and the
planning schedule.
The VMP is like a map – to show you how to get from one place to another.

15. Validation The “Introduction” to the VMP Validation policy
Project scope
Location and timing (including priorities)
Validation procedures
Standards
The Introduction should state: validation policy, project scope (general description of the scope of those operations covered by the VMP), location and timing (including priorities), validation procedures, and standards.
The individual validation projects should be described with reference to national and international standards as required.

16. Validation VMP should state who is responsible for: Preparing the VMP
The protocols and SOPs
Validation work
Report and document preparation and control
Approval/authorisation of validation protocols and reports in all stages of validation process
Tracking system
Training needs in support of validation
The VMP should state the organizational structure and who is responsible for:
Preparing the VMP
The protocols
SOPs (which are the execution of protocols)
Report and document preparation, and their control
Approval/authorization of validation protocols and reports in all stages of the validation process
Tracking changes
Training needs in support of validation

17. Validation VMP should contain: Cross references to documents
Specific process considerations
Specific characteristics briefly outlined
Validation list (What to validate)
premises, systems and equipment
processes
products
The VMP should contain:
Cross references to other documents, such as standards, SOPs, work instructions, calibration procedures, pharmacopoeias.
Specific process considerations; such as dry heat sterilization or gamma-irradiation.
Specific characteristics or requirements of the factory or process etc. that may be briefly outlined.
Validation list
Premises, systems and equipment
Processes (for example, aseptic filling)
Products

18. Validation VMP should contain: Descriptions of
plant (where to validate)
processes
products
Personnel attributes
expertise and training
Key acceptance criteria
The VMP should contain:
Descriptions of
Plant
Processes
Products
These should be brief.
Personnel attributes. This is the requirement for expertize and training of the engineers, pharmacists, chemists, microbiologists who need to undertake and review the validation work. The manufacturer must demonstrate that personnel possess the necessary levels of competency. The signatories of the validation work must have appropriate training, experience, education and qualifications. Microbiologists should sign microbiological work; engineers the engineering, etc. The final report should be co-signed by the person responsible for the project. The training requirements need to be identified for personnel who will maintain or carry out the processes that have been validated.
Key acceptance criteria. The acceptance criteria must be set before validation, NOT after the experimental phase of the work has been completed. This is another reason why retrospective validation is not encouraged since the acceptance criteria are set after all the analytical work has already been performed.

19. Validation VMP should contain:
Format for protocols and other documentation
List of relevant SOPs (How)
Planning and scheduling (When)
Location (Where)
Estimate of staffing requirements (Who)
A time plan of the project (When)
Annexes
The VMP should contain:
Protocol and documentation format; it is important that there be a systematic approach to the layout and format of the documents.
List of relevant SOPs. (How)
Planning and scheduling. (When)
The location where the validation activity is to be performed. (Where)
Estimate of staffing requirements to complete the validation effort described in the plan. (Who)
A time plan of the project showing detail planning of sub-projects. (When)
Annexes: for training record format, raw data retention, calibration record retention, etc.

20. Validation VMP should contain change control Policy and procedure
Risk assessment
Authorization
Failure to properly document changes to the system means invalidation of the process
The manufacturer must have a “change control” procedure.
Change control is an important element in any Quality Assurance system. Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or support system operation. All changes should be formally requested, documented and accepted by representatives of Production, QC/QA, R&D, Engineering and Regulatory Affairs, as appropriate.
The likely impact (risk assessment) of the change on the product should be evaluated and the need for, and the extent of revalidation discussed. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorised.
Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by responsible staff, including (where appropriate) the Qualified Person.
Failure to properly document changes to the system means invalidation.

21. Validation Changes that require revalidation
Software changes; Controllers
Site changes; Operational changes
Change of source of material
Change in the process
Significant equipment change
Production area changes
Support system changes
The nature of the changes that require revalidation should be stated in the VMP. If any of the following are changed the process becomes invalid and in some agencies’ view, the process is out of control, even if the finished product meets the marketing authorization specifications for finished products:
Software changes, changes in controllers (eg temperature controllers), site changes, operational changes.
Changes that are likely to require revalidation are:
Changes of starting materials (physical properties such as density, viscosity, particle size distribution may affect the process or product).
Transfer of processes to another site.
Change of starting material manufacturer.
Changes of packaging material (e.g. substituting plastic for glass).
Changes in the process (e.g. mixing times, drying temperatures).
Changes in the equipment (e.g. addition of automatic detection systems). Changes of equipment which involve the replacement of equipment on a 'like for like' basis would not normally require a revalidation. For example, a new centrifugal pump replacing an older model would not necessarily mean revalidation.
Production area and support system changes (e.g. rearrangement of areas, new water treatment method).

22. Validation In summary, a VMP should contain at least:
Validation policy
Organizational structure
Summary of facilities, systems, equipment, processes to be validated
Documentation format for protocols and reports
Planning and scheduling
Change control
Training requirements
In summary, a VMP should contain at least:
Validation policy
Organizational structure of validation and responsibilities
Summary of facilities, systems, equipment and processes to be validated
Documentation format for protocols and reports
Planning and scheduling
Change control
Training requirements
Suggested reading:
WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth Report. Geneva, World Health Organization, 1996 (WHO Technical Report Series, No. 863). Annex 6: Good manufacturing practice: Guidelines on the validation of manufacturing processes.
Pharmaceutical Inspection Cooperation Scheme (PIC/S). Recommendations on Validation Master Plan, installation and operational qualification, non-sterile process validation, cleaning validation. 3 August (Refer to for copy).