1. Basic Principles of GMP
Validation
This module deals with the subject of validation.
It is an important one that will form a major part of your inspections in the future.
This module lasts half a day, divided into 2 sessions.
Each session will take the usual format of 30 minutes presentation, 45–60 minutes group discussion and 30 minutes feedback.
There will be a short test of 30 minutes at the end to confirm your understanding of the topic.

2. Validation Objectives To review the definition and types of validation
To understand the requirements for documentation and key stages in the process of validation
To consider models for process validation
There are three objectives to this module:
Firstly, we are going to start by looking at the definition of validation and the different types that are used.
Secondly, we will discuss documents associated with validation, and review the key stages of the validation process.
Thirdly, we shall look at a model approach for process validation in the context of the WHO documentation.
Finally, we are going to look at where validation has got to in your country and talk about the barriers that need to be overcome.
This module will deal with the very fundamentals of validation but it will only provide an overview. It will not be an in-depth review of the subject. The subject is very important and requires a lot of careful thought. It will be a major topic of discussion with companies that you inspect and also within the inspectorate.
It is important to remember that validation does not improve bad processes.

3. Validation Definition
Validation is the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected result
There are a number of definitions of validation - all of which say the same thing in different ways. The definition on this slide is the one given in the WHO GMP texts. There is a more expanded version in the WHO text on the validation of manufacturing processes:
The collection and evaluation of data, beginning at the process development stage and continuing through the production phase, which ensure that the manufacturing processes – including equipment, buildings, personnel and materials – are capable of achieving the intended results on a consistent and continuous basis.
Validation is the establishment of documented evidence that a system does what it is supposed to do.
There are three key points to take from these definitions:
1. The evidence must be documented. (The results of the validation must be recorded).
2. Validation applies to several aspects of manufacturing, including e.g. process development, materials, personnel and equipment).
3. It should demonstrate that the system does what is expected of it.
Validation is carried out against a set of criteria that are defined in advance. These criteria are detailed in predefined protocol documents.

4. Validation Essential Part of GMP Predetermined protocols
Written reports
Processes and procedures
Periodic revalidation
Specific attention:
processing
testing
cleaning
Validation is an essential part of GMP. There are two main reference sources in the WHO documentation relating to validation. Firstly, the WHO GMP text covers validation in Part One, section 5. It emphasizes that validation should be conducted in accordance with predefined protocols. Written reports summarizing recorded results and conclusions should be prepared and stored.
Processes and procedures should be established on the basis of a validation study. Periodic revalidation should be performed to ensure that processes and procedures remain capable of achieving the intended results.
Particular attention should be given to the validation of processing, testing and cleaning procedures.
Process validation requires the identification of critical elements of the production process. It also includes qualification of supporting systems such as water production, air supply systems and equipment qualification.
Test procedures must be validated (or verified) by the manufacturer or laboratory, before they are used for routine testing. Compendial methods need to be verified. This means that the method is demonstrated to give correct results in the laboratory facilities available. Non-compendial methods must be validated (e.g. proving accuracy, precision, linearity, range and sensitivity).
Cleaning validation is needed in particular where different products can be manufactured on the same piece of equipment. There are specific requirements and guidelines for performing cleaning validation.

5. Validation WHO References
Good manufacturing practices: guidelines on the validation of manufacturing processes
Validation of analytical procedures used in the examination of pharmaceutical materials
The main reference text that the WHO has produced relating to validation is published as Annex 6 of the thirty-fourth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations, published in 1996 (WHO Technical Report Series NO. 863). The Annex is titled “Good Manufacturing Practices: Guidelines on the validation of manufacturing processes”.
This document covers the subject in some detail. It provides a glossary of terms, discussions of the topic in general, types of validation, the different approaches that can be taken and recommendations on how to organize a validation program. It also presents an outline for a validation protocol and report.
The focus is mainly on the validation of manufacturing processes, but many of the points also relate to other operations, such as cleaning.
However, for guidance on the validation of analytical techniques, you should refer to Annex 5 of the WHO Expert Committee’s thirty-second report entitled “Validation of analytical procedures used in the examination of pharmaceutical materials” (WHO Technical Report Series No 863 and Quality assurance of pharmaceutical, A compendium of guidelines and related materials, volume I, pp WHO, Geneva, 1997).
Annex 6

6. Types of Process Validation
Experimental approach
Prospective validation
Concurrent validation
Analysis of historical data
Retrospective validation
Revalidation
Periodic revalidation
Revalidation after change
Critical processes should be validated. Different types of process validation are shown on this slide. Let’s look at the definitions and then relate them to real examples that you are likely to come across during your inspections.
Prospective validation is carried out during the development stage. It includes the division of the production process into separate steps, and the analysis of potentially critical points in the manufacturing process e.g. mixing times, or temperature. Trials are carried out in which these steps and critical points are simulated and the effect on the process is assessed.
Concurrent validation is carried out during normal production. It requires a full understanding of the process based on prospective work. It involves very close and intensified monitoring of the steps and critical points in at least the first three production-scale batches.
Retrospective validation 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 10 to 25 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 is divided into two categories:
Revalidation after change.
Periodic revalidation.
In the former category, typical changes that require revalidation include changes in a raw material or packaging material, changes in the process parameters, changes to equipment, including major repairs, and changes to the premises.
Periodic revalidation offers the opportunity to check that the systems are still operating as originally validated and that no unintended changes have effected the process, system or piece of equipment and end result.
Each manufacturer should have a program of validation that covers the installation, commissioning, start-up and other phases of manufacture. This can be a combination of prospective and concurrent validation. However, for most facilities that have been established since before validation was introduced, there will be a gradual process of performing validation. Retrospective validation may be performed in such cases. The program is based on an assessment of the critical processes and allocation of priorities. For example, a sterile product is more critical than a tablet and the sterilization step will be the one that should take priority in the validation program. Even in these older facilities, the introduction of new products should be accompanied by prospective and/or concurrent validation.

7. Validation Stages of Validation Design qualification (DQ)
Installation qualification (IQ)
Operational qualification (OQ)
Performance qualification (PQ)
Qualification is part of validation. There are different stages of qualification. These stages are generally applied to projects such as premises, equipment and supporting systems such as water supply systems, Heating, Ventilation and Air Conditioning (HVAC) and other systems.
You should be familiar with these terms as you will have to evaluate the qualification of equipment and related systems during your inspections.
Design qualification (DQ) is the process of completing and documenting design reviews to illustrate that all quality aspects have been fully considered at the design stage. The purpose is to ensure that all the requirements for the final systems have been clearly defined at the start. In other words, has it been designed and selected correctly?
Installation qualification (IQ) is the process of checking the installation, to ensure that the components meet the approved specification and are installed correctly, and to see how that information is recorded. The purpose is to ensure that all aspects (static attributes) of the facility or equipment are installed correctly and comply with the original design. In other words, has it been built or installed correctly?
Operational qualification (OQ) is the process of testing to ensure that the individual and combined systems function to meet agreed performance criteria and to check how the result of testing is recorded. The purpose is to ensure that all the dynamic attributes comply with the original design. In other words, does it work correctly?
Performance qualification (PQ), also called process qualification, is the process of testing to ensure that the individual and combined systems function to meet agreed performance criteria on a consistent basis and to check how the result of testing is recorded. The purpose is to ensure that the criteria specified can be achieved on a reliable basis over a period of time. In other words, does it produce the product correctly?

8. Priorities for Process Validation
Type of process Requirement
New Every new process before approval for routine
Existing:
Sterile products All processes affecting the sterility, and manufacturing environment including sterilization stage
Non-sterile Low dose tablets and capsules: mixing and granulation; content uniformity (and other parameters)
Other tablets and capsules: uniformity of mass (and other parameters)
These are examples of requirements for process validation.
(See Quality Assurance of Pharmaceuticals, A compendium of guidelines and related materials (Volume 2), Good Manufacturing Practices and inspection, WHO, 1999)

9. Types of Documentation
Validation
Types of Documentation
Validation Master Plan (VMP)
Validation protocols (VP)
Validation reports (VR)
Standard Operating Procedures (SOPs)
There are different types of documents related to validation:
Master plans, protocols, reports and SOPs.
Each manufacturer should have a validation master plan (VMP). It describes the overall philosophy, intention and approach to establishing performance adequacy (validation policy).
It also identifies which items are subject to qualification and validation and the nature and extent of such validation. It defines the applicable validation and qualification protocols and procedures.
During the inspection, you should evaluate the VMP to assess whether it covers the overall policy that defines validation and what should be subjected to validation. It should cover the responsible persons, what should be validated, where should the validation be done, when validation should be performed, why and how the validation should be performed. It should include a breakdown of the process, plant or equipment into separate parts. It should also determine which are critical to the quality of the product and therefore require validation, and at which stages. For example, in a project to commission a sterile manufacturing suite, the operation of the sterilizers is critical and will require IQ, OQ and PQ; and the operation of the ventilation system is critical and will require IQ, OQ and PQ.
The VMP should be a concise and easy-to-read document which will serve as a guide to the validation committee and personnel who are responsible for performing validation. The VMP is also a source document for use by regulatory inspectors.

10. Validation The Validation Master Plan could consist of:
Approval page and table of contents
Introduction and objectives
Facility and process description
Personnel, planning and scheduling
Responsibilities of committee members
Process control aspects
Equipment, apparatus, processes and systems to be validated
Acceptance criteria
Documentation e.g.validation protocols and reports
SOPs
Training requirements
The VMP should typically include at least the following sections:
Approval page and table of contents.
Introduction and objectives.
Facility and process description.
Personnel, planning and scheduling.
Responsibilities of committee members.
Process control aspects.
Equipment, apparatus, processes and systems to be validated.
Acceptance criteria.
Documentation e.g. validation protocols and reports.
SOPs.
Training requirements.

11. Validation
Protocol
Objectives of the validation and qualification study
Site of the study
Responsible personnel
Description of the equipment
SOPs
Standards
Criteria for the relevant products and processes
A validation protocol is a detailed document relating to a specific part of the validation process e.g. the OQ for a manufacturing vessel. It outlines the tests that are to be carried out, the acceptance criteria and the information that must be recorded. It also defines the approval process for the validation.
The protocol should clearly describe the procedure to be followed for performing validation. It should include at least the objectives of the validation and qualification study, the site of the study, the responsible personnel, a description of the equipment to be used (including calibration before and after validation), SOPs to be followed (e.g. the operation and cleaning of the equipment) and the standards and criteria for the relevant products and processes.
The type of validation and time/frequency should also be stipulated. The processes and/or parameters to be validated (e.g. mixing times, drying temperatures, particle size, drying times, physical characteristics, content uniformity, etc.) should be clearly identified.

12. Validation Report Title Objective of the study Refer to the protocol
Details of material
Equipment
Programmes and cycles use
Details of procedure and test methods
The results obtained during the performance of the validation, must be recorded.
The validation report reflects the final test results and other documents such as instrument calibration certificates. It is on the basis of this report that the decision is taken on whether a particular process is judged to be validated. During the inspection, you must assess whether there is a written report reflecting the results after completion of the validation. The results should have been evaluated, analyzed and compared with acceptance criteria by the responsible personnel. All results should meet the criteria of acceptance and satisfy the stated objective. If necessary, further studies should have been performed. If the results were found to be acceptable, the report should been approved and authorized (signed and dated).
The report should include the title and objective of the study, and refer to the protocol, details of material, equipment, programs and cycles used, together with details of procedures and test methods. It should provide a comparison of the results with the acceptance criteria.
In addition, it should include recommendations on the limits and criteria to be applied to all future production batches. It is common practice in many companies for the protocol and the report to be combined into a single set of documents. The protocol is approved as a form on which the test results are recorded as they become available. This reduces the amount of paperwork that needs to be stored and makes an overall assessment of the validation results easier to carry out.

13. Validation Group Session 1: Option 1
From your experience of factory inspections, what progress has been made in introducing validation in your country?
What are the major obstacles and how can they be overcome?
First option:
We are now going to move into the first group session.
Using your experience from inspections that you have carried out, what is your assessment of the progress that has been made in establishing validation in your country?
List the major obstacles that exist and suggest how they might be overcome.

14. Validation Group Session 1: Option 2
List some documents related to validation, that you expect to find at a manufacturing site.
Identify aspects in each document that you would evaluate or assess.
What problems do you anticipate the company to have faced when the company drafted these documents?
Second option:
We are now going to move into the first group session.
From the point of view of validation, which documents would you expect to find in a manufacturing site?
What are the major problems you would expect the company to have faced in drafting these documents? How would you expect them to have overcome these obstacles?
(The trainer could request the group to focus on a specific dosage form, e.g. a tablet or capsule. The critical steps or points in the manufacturing process should thus be covered in the validation protocol).

15. Validation Possible Issues Lack of time Lack of personnel
Lack of experience and knowledge
Changes to the process
Prospective versus retrospective validation
Lack of documentation infrastructure
Lack of implementation of validation
Poorly designed documents
Possible Issues
Lack of time
Lack of personnel
Lack of experience and knowledge
Changes to the process
Prospective versus retrospective validation
Lack of documentation infrastructure
Lack of implementation of validation
Poorly designed documents

16. Validation Protocol and Report - I
WHO Model for
Validation Protocol and Report - I
Part 1 – Purpose and prerequisites
Part 2 – Presentation of the process
Part 3 – Validation protocol
Manufacturers can approach the implementation of validation in different ways. There are different models for performing validation. During inspections, you will have to assess the model used by the manufacturer.
We are now going to look at the WHO model for process validation. It is divided into 9 parts (Annex 6, WHO Technical Report Series No. 863). We will review each of these in turn.
Part 1 should contain the definition of the purpose of the validation. It outlines the scope of the project. For example, if a project relates to a complete facility with a new purified water system, the water system will be included in the scope of the validation. However, if the project relates to refurbishment of part of a factory and the purified water system is already in use in other parts of the factory, it will probably be excluded from the validation.
Part 2 should contain a review of the entire process being covered by the validation It could be divided into sub-processes or constituent parts that can be validated separately. At this point it is useful to see if the manufacturer had included such things as flow diagrams. This assists in understanding some of the processes. The critical steps in the process should be identified.
Part 3 normally completes the planning process. It fills in any of the gaps in the “who, what, where, when, why and how”. It is the point at which approval of the programme is obtained from the validation team and technical managers.

17. Validation Protocol and Report - II
WHO Model for
Validation Protocol and Report - II
Part 4 – Installation qualification
Part 5 – Qualification protocol/report
Part 6 – Product characteristics
Part 4 should cover the Installation Qualification stage of validation. It is the point at which the project or process is reviewed against the original design to ensure that it has been built or installed correctly. For example, for a new building and/or equipment, it will include a review of all the drawings (mechanical, electrical, process, etc.) to ensure that they are accurate. If there are points of divergence, a decision has to be taken on whether the drawing is amended to provide an accurate “as-built” record or whether the physical item should be amended to match the drawing.
Part 5 is the main part of the validation and in terms of the stages outlined previously, constitutes the Operational Qualification and part of the Performance Qualification. Each sub-process outlined in part 1 is covered in turn and a series of steps are completed:
the purpose of the sub-process is stated;
the method of carrying out the sub-process is listed, including manufacturing and packaging instructions and SOPs;
the sampling and testing procedures are listed, together with acceptable criteria for each one;
results for each test are recorded, including calibration of test equipment, raw test data and a summary of results;
on the basis of these test results, a decision is taken as to whether the sub-process is acceptable or requires amendment and revalidation.
Part 6 is the completion of Performance Qualification, with the review of product characteristics arising from the three test batches that have been produced. All data and results should have been recorded in the validation reports.

18. Validation Protocol and Report - III
WHO Model for
Validation Protocol and Report - III
Part 7 – Evaluation
Part 8 – Certification
Part 9 – Summary
Part 7 is the evaluation of all the test data for the whole validation programme, including listing any recommendations that have arisen. These will include comments on the suggested frequency for revalidation of the process.
Part 8 is the process of approving the validation of the project or process. It involves each of the team members reviewing the evaluation produced in Part 7 and deciding whether he/she will sign off on the programme.
Part 9 is the part that will be most useful to you as inspectors. The amount of material produced as a result of a validation programme is very large. It is therefore advisable for companies to prepare a summary report that can be used by inspectors who wish to gain an overview of the programme without going through the entire validation file.

19. Validation Group Session 2
List the aspects that you will evaluate when assessing the validation for the project that your group has been given.
Identify the critical parameters that should have been evaluated by the manufacturer.
List the tests to be carried out and comment on the acceptance criteria to be set.
In this group session, you should list the aspects that you will evaluate when assessing the validation for the project that your group had been given.
Identify the critical parameters that should have been evaluated by the manufacturer.
List the tests to be carried out and comment on the acceptance criteria to be set.

20. Validation Possible situation – I
Refurbishment of a liquids department, producing a single product on an established site with an existing purified water system.
Ventilation system
Equipment and process
Training
Types and stages of validation for the refurbishment of a liquids department, producing a single product on an established site with an existing purified water system.
Ventilation system
Equipment and process
Training

21. Possible situation – II
Validation
Possible situation – II
New product introduced into an existing tablet manufacturing site, with 20 products already being produced
Process Cleaning
Training
Validation of a new product introduced into an existing tablet manufacturing site, with 20 products already being produced
Manufacturing process, critical parameters of the manufacturing process
Cleaning validation
Training of operators

22. Possible situation – III
Validation
Possible situation – III
A new liquids manufacturing building on an existing site which will produce 2 products.
Ventilation
Equipment and process
Cleaning
Training
A new liquids manufacturing building on an existing site which will produce 2 products. Consider the validation requirements for:
Ventilation systems
Equipment and manufacturing process
Cleaning validation
Training

23. Possible situation– IV
Validation
Possible situation– IV
An existing sterile suite producing 5 products that are terminally sterilized
Sterilizers
Ventilation and other environmental aspects
Equipment and process
Cleaning
Training
An existing sterile suite producing 5 products that are terminally sterilized
Sterilizers
Ventilation and other environmental aspects
Equipment and process
Cleaning
Training