World Health Organization

World Health Organization
21 April, 2017 Basic Principles of GMP Qualification and 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, and is divided into 2 sessions. Each session will take the usual format of 30 minutes presentation, 45–60 minutes group discussion and 30 minutes feedback. Please note that this is a basic introduction to validation. There is a separate module on validation in the supplementary training modules. There will be a short test of 30 minutes at the end to confirm your understanding of the topic. Section 4

Qualification and Validation
World Health Organization 21 April, 2017 Objectives To review basic aspects of qualification and validation To understand the scope of qualification and validation Introduction to documentation associated with validation (See also Supplementary Training Module on 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.

World Health Organization Qualification and Validation 21 April, 2017 Definitions Validation Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results Qualification Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results (Validation usually incorporates the concept of qualification) Glossary 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.

World Health Organization Qualification and Validation 21 April, 2017 Principle Qualification and Validation: Essential part of GMP Manufacturer has to identify what qualification and validation work is required. Provides proof that critical aspects of work are controlled and provide documented evidence Key elements of qualification and validation defined and documented: Policy and approach: VMP 4.1, 4.2, 4.8 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 section 4 of the general GMP text. Then there is a second document on Validation that describes recommended practices for validation and qualification (40th Report of the Expert Committee). Manufacturers should identify what validation and qualification work should be done. All systems, equipment, processes, procedures should be reviewed and the manufacturer should decide what qualification and validation work needs to be performed. The intention is to prove that all critical aspects of the work are controlled, and perform as required. Validation and qualification work must be documented.

World Health Organization Qualification and Validation 21 April, 2017 Scope Documented evidence to prove that, e.g. Premises Supporting utilities Equipment have been designed in accordance with GMP Also referred to as Design Qualification (DQ) where appropriate 4.3(a) Documented evidence should be provided that prove that e.g. Premises Supporting utilities such as water systems, air handling systems, gas supply, compressed air (where these are relevant) Equipment have been designed in accordance with GMP and meet their user requirements/design specification needs. Also referred to as Design Qualification (DQ) where appropriate.

World Health Organization Qualification and Validation 21 April, 2017 Scope Documented evidence to prove that, e.g. Premises Supporting utilities Equipment have been built and installed in accordance with their design specifications Also referred to as Installation Qualification (IQ) Documented evidence should be provided that prove that e.g. Premises (area or room verification proves that the design conditions are met) Supporting utilities such as water systems, air handling systems, gas supply, compressed air (where these are relevant) Equipment have been built and installed in accordance with GMP and meet their specifications. Also referred to as Installation Qualification (IQ) where appropriate. 4.3(b)

World Health Organization Qualification and Validation 21 April, 2017 Scope Documented evidence to prove that, e.g. Supporting utilities Equipment operate in accordance with their design specifications Also referred to as Operational Qualification (OQ) Documented evidence should be provided that prove that e.g. Premises (area or room verification proves that the design conditions are met) Supporting utilities such as water systems, air handling systems, gas supply, compressed air (where these are relevant) Equipment are operating in accordance with GMP and meet their operational specifications. Also referred to as Operation Qualification (OQ) where appropriate. 4.3(c)

World Health Organization Qualification and Validation 21 April, 2017 Scope Documented evidence to prove that, e.g. Supporting utilities Equipment perform consistently in accordance with their design specifications – see also next slide on PV Also referred to as Performance Qualification (PQ) Documented evidence should be provided that prove that e.g. Supporting utilities such as water systems, air handling systems, gas supply, compressed air (where these are relevant) Equipment are consistently performing in accordance with GMP and their specifications, usually over a period of time. Also referred to as Performance Qualification (PQ) where appropriate. 4.3(d)

World Health Organization Qualification and Validation 21 April, 2017 Scope Documented evidence to prove that: A specific process will consistently produce a product meeting its predetermined specifications and quality attributes Also referred to as Process Validation (PV) 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. 4.3(d)

World Health Organization Qualification and Validation 21 April, 2017 Scope Qualification and validation: Applicable to any aspect of operation which may affect the quality of the product Directly or indirectly Cover e.g. premises, facilities (utilities), equipment, processes In case of significant changes – consider the need for requalification or re-validation But, what should be qualified and validated? Explain the use of risk assessment in determining the extent of qualification / validation Qualification and validation should be applicable to aspects of operation which may affect the quality of the product. It therefore may include premises (environment conditions, space, contamination levels), supporting utilities (e.g. water), processing equipment performance and the actual process. Any significant change (e.g. adaptation of equipment or systems, major repairs etc) may require re-qualification or re-validation. 4.4

World Health Organization Qualification and Validation 21 April, 2017 Principle Qualification and validation should be done in accordance with an ongoing programme Initial qualification and validation Annual review (determine the need for re-validation) Ensure continued validation status is maintained Policy described in relevant documentation, e.g. quality manual, or Validation Master Plan 4.5, 4.6 Qualification and validation should be done in accordance with an ongoing programme Initial qualification and validation is normally required (DQ, IQ, OQ and PQ). Then there should be an evaluation or review e.g. annually, to determine whether validation or qualification is required again (Requalification and revalidation). This is to ensure that the company maintains a continued validation status The company policy on validation should be described in relevant documentation e.g. quality manual, or Validation Master Plan

World Health Organization 21 April, 2017 Types of Documentation Validation Master Plan (VMP) Validation protocols Validation reports 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.

World Health Organization Qualification and Validation 21 April, 2017 Documentation Clearly defines responsibility of performing validation Conducted in accordance with predefined, approved validation protocols Recorded results and conclusions presented in written validation reports – prepared and stored Processes and procedures should be established on the basis of these results The documents should clearly define who is responsible for performing validation. Qualification and validation should be conducted in accordance with predefined, approved validation protocols, and the results and conclusions presented in written validation reports. These should be in a recommended format, ensure a proper audit trail, traceability –and stored for a defined period of time. Processes and procedures should be established on the basis of these results 4.7 – 4.10

World Health Organization Qualification and Validation 21 April, 2017 Importance: Premises, utilities, equipment and processes Critical importance and particular attention paid to validation of: Analytical test methods Automated systems Cleaning procedures We already mentioned what should be validated. Of particular importance is the qualification and validation of premises, utilities, equipment and processes. Of critical importance, with particular attention, is the validation of: Analytical test methods Automated systems and Cleaning procedures 4.11

Basic Principles of GMP
World Health Organization 21 April, 2017 1. List qualification requirements for this piece of equipment. 2. Discuss aspects to be considered in validation during this processing stage. Ask the participants to list some requirements in terms of qualification and validation for the FBD, and the drying process. (DQ, IQ, OQ, PQ – expand on the components of each of these stages). Then discuss the critical elements of the drying step.

World Health Organization 21 April, 2017 The Validation Master Plan may contain elements (and policy) such as: Approval page and table of contents Introduction and objectives Facility and process description Personnel, planning and scheduling Responsibilities of validation team members Process control aspects Equipment, apparatus, processes and systems qualified, validated – and to be qualified or validated Acceptance criteria Documentation, e.g.validation protocols and reports SOPs Training requirements and other elements… 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.

World Health Organization 21 April, 2017 A qualification or validation protocol may contain: 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 (See WHO formats (handouts) as part of training material) 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.

World Health Organization 21 April, 2017 A qualification or validation report should reflect the elements of the protocol, and may contain elements such as: Title Objective of the study Reference to the protocol Details of materials, equipment, instruments, personnel Programmes and cycles used Details of procedure and test methods … etc. 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.

World Health Organization 21 April, 2017 New approaches recommend that manufacturers should perform a risk assessment as part of their approach to validation Risk assessment can be useful in: Identifying the need for qualification, or the extent and or scope of qualification (e.g. utilities and equipment) areas of focus in process validation Cleaning validation Explain how risk assessment can be used in determining the scope and extent of the validation or qualification exercise. Use FMEA as a tool. Use a flow chart of e.g. an oral solid dosage form.

World Health Organization 21 April, 2017 There is currently a move to change the approach to qualification and validation. The principles remain however the same. US and EU guidance now focus on “Process qualification” which covers the complete lifecycle of a products with additional focus on product design Three Phases are identified that cover “process design, process qualification” and “continued process verification” The trainer may wish to briefly discuss here the new US FDA guideline, and the proposed EU guideline.

World Health Organization 21 April, 2017 Phase I Process design Process qualification Phase II Continued Process verification Phase III

World Health Organization Qualification and Validation 21 April, 2017 WHO References Supplementary guidelines on good manufacturing practices: validation … including details about Validation of heating, ventilation and air-conditioning systems Validation of water systems for pharmaceutical use Cleaning validation Analytical method validation Validation of computerized systems Qualification of systems and equipment Non-sterile process validation The main reference text that the WHO has produced relating to validation is published as Annex 4 of the fortieth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations, published in 2006 (WHO Technical Report Series NO. 937). The Annex is titled “Supplementary Guidelines on Good Manufacturing Practices: Validation ” and includes details about: - Validation of heating, ventilation and air-conditioning systems - Validation of water systems for pharmaceutical use - Cleaning validation - Analytical method validation - Validation of computerized systems - Qualification of systems and equipment - Non-sterile process validation Annex 4

World Health Organization 21 April, 2017 Example of 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)

World Health Organization 21 April, 2017 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.

World Health Organization 21 April, 2017 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 faced when it prepared 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).

World Health Organization 21 April, 2017 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

World Health Organization 21 April, 2017 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.

World Health Organization 21 April, 2017 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

World Health Organization 21 April, 2017 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

World Health Organization 21 April, 2017 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

World Health Organization 21 April, 2017 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

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