Basic Principles of GMP

Basic Principles of GMP
3. Validation (and Qualification) 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.

Validation, Qualification
Two phylosophies: Validation, qualification (and calibration) are different, although interrelated activities (e.g. EU GMP) Qualification and also calibration belong to validation activities (e.g. WHO GMP)

Qualification or validation?
Terms Qualification or validation? A system/equipment 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 the autoclave, while you validate the whole sterilization process (and calibrate a measuring instrument!) 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?

Three basic principles of Quality Assurance:
Validation Introduction Three basic principles of Quality Assurance: Quality, safety, efficacy Cannot inspect quality into a product Processes must be under control (for this, they should be validated, whether they can 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.

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.

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.

A Validation Master Plan helps the manufacturer and inspectorate
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.

Validation Essential Part of GMP Predetermined protocols
Written reports Processes and procedures Periodic revalidation Specific attention: processing process validation testing analytical method validation cleaning cleaning validation 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.

Types of Manufacturing 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.

Prospective validation
Before starting a new manufacturing process (or after its significant change), or revalidation: Manufacturing 3 batches only for validation purposes, all data documented. Reason: to see that the process is under control As a rule, these batches are not marketed later, except special decision to do that

Concurrent validation
In case of rarely produced medicines (e.g. 2 batches per year: no reason to produce 3 „validation” batches) Concurrent validation: during the manufacture of „normal” batches to be marketed Strict documentation!

Retrospective validation
This validation means the assessment of data generated during previous batch manufacturing Only for established technologies, the GMP is strictly applied, defects are rare Assessment of data of batches, including defective ones (their data are very valuable to see how the process can run out of control!)

Types (Stages) of Qualification
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?

Design qualification DQ
E.g. of a manufacturing equipment Before purchasing! Collection of data about the similar equipments available on the market, assessing our needs, resources to buy and to operate, space and maintenance they would need, etc. Making the decision

Installation Qualification IQ
E.g. of a manufacturing equipment After purchasing (or critical repair) Put it on its intended place, connect with other equipments, electric power, material flow devices Collect its documents incl. Operation Manual, etc. Its formal „release”: it is ready for working with

Operational Qualification OP
E.g. of a manufacturing equipment „Model manufacturing” experiments with model materials, similar to those to be used in the real manufacture E.g. qualifying an autoclave we use culture-media Permit the acceptable fluctuations of parameters, even set the „worst conditions”

„Worst conditions” say, an equipment must be operated within the limits of temperature: 20 and 35 oC pressure: 0.9 and 1.2 atm The worst cases, when it operates at 20 oC and 0.9 atm 35 oC and 1.2 atm 20 oC 0.9 and 1.2 atm 35 oC and 0.9 atm

Performance Qualification PQ
Similar to the Operational Qualification, but the real manufacture is running Permit accepted fluctuations up to their limits (incl. worse conditions, if occur)

Qualification DQ IQ OQ PQ relationships and considerations:
DQ (Design Qualification) should relate to Process: what needs to be done? DQ can be user requirements. IQ (Installation Qualification) considerations include: Equipment design features (i.e. materials of construction cleanability, etc.) Installation conditions (functionality, utilities, wiring, etc.) Calibration, preventative maintenance, cleaning schedules; safety features Supplier documentation, prints, drawings and manuals, software documentation Environmental conditions (such as clean room requirements, temperature, humidity) Spare parts list OQ (Operational Qualification) considerations include: Process control limits (e.g. time, temperature, pressure, line speed, setup conditions) Software parameters; starting material specifications Process operating procedures; material handling requirements Process change control; training; short term stability and capability of the process, (latitude studies or control charts) Risk analysis and potential failure modes, action levels and worst-case conditions (Failure Mode and Effects Analysis, Fault Tree Analysis) PQ (Performance Qualification) includes: Actual product and process parameters and procedures established in OQ Assurance of process capability as established in OQ Acceptability of the product Process repeatability, long term process stability

Validation Priorities for Process Validation
Type of process New Existing Sterile products  Non-sterile Requirement Every new process before approval for routine All processes affecting the sterility, and manufacturing environment including sterilization stage Low dose tablets and capsules: mixing and granulation, content uniformity (possible other parameters) Other tablets and capsules: uniformity of mass(possible 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)

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.

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.

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.

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.

Let us spend some time on the Validation Master Plan now

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. .

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?

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.

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.

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.

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

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.

The “Introduction” to the VMP
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.

VMP should state who is responsible for:
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

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

Validation VMP should contain, 2: Descriptions of Personnel attributes
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.

Validation VMP should contain, 3:
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.

VMP should contain change control
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.

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).

In summary, a VMP should contain at least:
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).

Finishing Validation Master Plan, something about the Validation Protocol and Report

Validation Protocol and Report, 1
WHO Model for Validation Protocol and Report, 1 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.

WHO Model for Validation Protocol and Report, 2 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.

WHO Model for Validation Protocol and Report, 3 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.

Special validation types
Validation of cleaning manuf. process QC related processes

Cleaning validation

Cleaning validation Objectives To review: General requirements
Validation protocol requirements How to check limits Analytical requirements Sampling methods The objectives of Part 2 of Module 1 are to review in detail: General requirements on cleaning validation, excluding specialized cleaning or inactivation that for example may be required for viral or mycoplasma removal in the biological manufacturing industry. Validation protocol requirements: what needs to go in the protocol, and how it should be written. How to check limits; the acceptance criteria need to be established before the experimental section. Analytical requirements for cleaning; residues at lower levels and analytes can be many. Sample methods; because the sampling efficiency is fundamental to cleaning validation.

Why cleaning validation is so important (1)
Pharmaceuticals can be contaminated by potentially dangerous substances Essential to establish adequate cleaning procedures Why cleaning validation is so important: Cleaning is like any other critical process that requires validation. However, it is not generally well understood or studied. The greater the risk of the product, the greater the drug potency or toxicity, the more effort on the validation of cleaning methods is required. Once established and validated, the cleaning process must be followed, adhered to, documented, recorded and maintained. Pharmaceutical products can be contaminated by a variety of substances (some of them potentially dangerous) left over from previous batches by poor cleaning methods. They can also be contaminated by cleaning agents, micro-organisms and materials such as airborne particles, dust, lubricants and raw materials. It is essential that adequate cleaning procedures be established and validated.

Why cleaning validation is so important (2)
“Particular attention should be accorded to the validation of … cleaning procedures” (WHO) “Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure” (PIC/S) “The data should support a conclusion that residues have been reduced to an ‘acceptable’ level” (FDA) Why cleaning validation is so important: (Contd.) Three quotations are worth remembering: “Particular attention should be accorded to the validation of … cleaning procedures” “Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure.” “The data should support a conclusion that residues have been reduced to an ‘acceptable’ level.” WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992 (WHO Technical Report Series, No. 823). Annex 1, 5.1. PIC/S GMP Guide, Annex 15 (cl.36) FDA Guide to Inspections of Validation of Cleaning Processes July 1993

Possible contaminants
Cleaning validation Possible contaminants Product residues Cleaning agent residues and breakdown Airborne matter Lubricants, ancillary material Decomposition residues Bacteria, mould and pyrogens All contaminants need to be assessed as part of cleaning validation. It was once believed that the presence or absence of active materials was all that was needed to be tested for; but there are many other objectionable contaminants, as follows: Product residues, both active and excipient Cleaning agent residues Airborne matter, such as dust and particulate Lubricants, and ancillary material, such as disinfectants Decomposition residues which include: product residue breakdown products occasioned by e.g. use of strong acids and alkalis during the cleaning process, and breakdown products of the detergents, acids and alkalis that may be part of the cleaning process. Bacteria, mould and pyrogens. If the equipment is left wet for long periods before being cleaned it will encourage the growth of microorganisms. Conversely, if left to dry out, residues become extremely difficult to remove.

Strategy on cleaning validation
Product contact surfaces After product changeover Between batches in campaigns Bracketing products for cleaning validation Periodic re-evaluation and revalidation The Manufacturer should have a strategy on cleaning validation covering: Product contact surfaces. Cleaning after product changeover, when one pharmaceutical formulation is being changed for another, completely different formulation. Between batches in campaigns, when the same formula is being manufactured over a period of time, and on different days. (Some participants may come from agencies where there must be extensive cleaning between all batches, even of the same formula. Be prepared to discuss the length of time for a campaign. It seems accepted that a campaign can last a working week but anything longer becomes difficult to control and define.) Bracketing products for cleaning validation. This often arises where there are products containing substances with similar properties (such as solubility) or the same substance in different strengths. An acceptable strategy is to manufacture the more dilute form (not necessarily the lowest dose!) and then the most concentrated form. There are sometimes “families” of products which differ slightly as to actives or excipients. (Be prepared to discuss this point with the participants.) Periodic evaluation and revalidation. (The trainer could ask: “How many batches are required to be assessed for cleaning validation, and for periodic revalidation”. “How often should a validated cleaning process be revalidated?”)

Cleaning validation protocol (1)
Should include : Objective of the validation Responsibility for performing and approving validation study Description of equipment to be used Cleaning validation protocol: The protocol should be written before the experimental section of the work commences. It should be seen as the written description of the experiment, as is often taught in the first year of high school chemistry (Aim, Method, Equipment, Results, Conclusions). It should include: Objective of the validation. What is the experiment trying to do? Responsibility for performing the validation study: Who are the people and what are their responsibilities? It is extremely important that the person signing off the work, for example, has adequate qualifications and experience. In some situations, some inspection agencies have found the person to be not adequately qualified, trained or experienced and so all of the work was invalidated and the process deemed to be out of control. Description of equipment to be used. This is where the list of equipment is needed which should include make, model and serial number or some other unique code.

Cleaning validation protocol (2)
Should include: Interval between end of production and cleaning, and commencement of cleaning procedure Cleaning procedures to be used Any routine monitoring equipment used Number of cleaning cycles performed consecutively Sampling procedures used and rationale Sampling locations (clearly defined) Cleaning validation protocol: (Contd.) Should include: Interval between end of production and cleaning, and commencement of cleaning procedure. To take into account the maximum period that equipment will be left dirty before being cleaned. There may also be a need for the manufacturer to establish the time after cleaning and before use. This may be especially important for control of micro-organisms. Cleaning procedures to be used for each product, each manufacturing system or each piece of equipment. Reference to the standard operating procedure is required here. Cleaning process must already be documented in an SOP. Note that some cleaning agents are incompatible with the drug. For example, removal of chlorhexidine residues (cationic) with an anionic surfactant will result in intractable, sticky residues. Any routine monitoring equipment used. This includes conductivity meters, pH meters, and Total Organic Carbon analyzers. The number of cleaning cycles to be performed consecutively. Sampling procedures used and rationale for why a certain sampling method is used. A review of the two most commonly used methods, the swab or swatch sample, and the rinse fluid sample is given later in this module. The sample procedure should describe where the samples should be taken based upon a previous analysis of the equipment to identify the most difficult to clean places. Clearly defined sampling locations.

Record of cleaning validation
Should include : Data on recovery studies Analytical methods including Limit of Detection and Limit of Quantitation Acceptance criteria and rationale When revalidation will be required Must have management and QA involvement Management commitment and QA involvement Cleaning validation protocol: (Contd.) Should include: Data on recovery studies. The efficiency of the recovery of the sampling technique needs to be established. Analytical methods, including Limit of Detection and Limit of Quantitation. Analytical methods should be referred to by a unique number, code or unique reference. Acceptance criteria and rationale for setting the specific limits. The acceptance criteria should include a margin for error and for sampling efficiency. When revalidation will be required. The cleaning validation protocol must have management commitment, in order that money, time and resources are allocated to the validation work, as well as QA involvement.

Cleaning validation Results and reports
Cleaning record signed by operator, checked by production and reviewed by QA Final Validation Reports, including conclusions Results and reports: The record of cleaning validation should be the raw data of the test results together with, for example, the cleaning record, which must signed by the operator, checked by production and reviewed by QA. There must be a Final Validation Report including conclusions reached. The final outcome must be stated, such as: “All the acceptance criteria were met”.

Cleaning validation Personnel
Manual cleaning methods are difficult to validate Cannot validate people; can measure proficiency Must have good training Must have effective supervision Personnel: Manual cleaning methods are difficult to validate. You cannot validate people but you can measure proficiency. People are not machines (they sometimes are much better than machines!). To compensate for any human weaknesses they should have good training (with appropriate records archived and which can be cross-referenced in the cleaning validation report) and they must have effective supervision.

Microbiological aspects
Cleaning validation Microbiological aspects Include in validation strategy Analyse risks of contamination Consider equipment storage time Equipment should be stored dry Sterilization and pyrogen contamination The microbiological review of cleaning is as important as the chemical cleaning since the equipment may appear to be clean but could be contaminated with micro-organisms, including pathogenic bacteria, during the cleaning process. Consequently the manufacturer must arrange to include the microbiological risk analysis in the validation strategy. This should mean advice from a competent, qualified person experienced in microbiology. He or she should consider unclean equipment storage time. Time frames and conditions for the storage of cleaned equipment should be established. There should be some documented evidence that routine cleaning and storage of equipment does not allow microbial proliferation. Equipment should be stored dry and this should be reflected in the protocol and in the cleaning SOPs. Under no circumstances should stagnant water be allowed to remain in equipment after cleaning operations. The control of the bioburden through adequate cleaning and storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve adequate sterility assurance. This is also important for the control of pyrogens in sterile processing since equipment sterilisation processes may not achieve significant inactivation or removal of pyrogens.

Cleaning validation How to take samples Swab/swatch Rinse fluid
Placebo The sample transport and storage conditions should be defined The dirty item is cleaned according to the SOP and then it has to be checked for cleanliness according to the cleaning validation protocol. This means taking a sample of the surface and analysing it. How? Two common methods are the swab and the rinse sample. A less common method is the placebo batch. None is ideal, all have advantages and disadvantages. Check to see if the manufacturer uses them in combination. The sample transport and storage conditions should be defined. The swab and rinse methods are discussed on the following slides.

Cleaning validation Swab samples Direct sampling method
Reproducibility Extraction efficiency Document swab locations Disadvantages inability to access some areas assumes uniformity of contamination surface must extrapolate sample area to whole surface Swab samples: This is a direct method of sampling, rather than indirect such as rinse sampling. The swab is perhaps the most common method of checking. It involves taking an inert (usually cotton wool or similar) material on the end of a probe and rubbing it methodically across a surface. A “swatch” (a big piece of material) can sample a larger surface area. Advantages are that residues that are "dried out" or are insoluble can be sampled by physical removal, and areas that are hardest to clean and which are reasonably accessible can be evaluated. It is expected the swab will pick up all the residues on the surface which can then be assayed. The reproducibility is suspect because of the human involvement. There must be a proper SOP and training on the technique. Sampling spiked surfaces is often used as a training method. Where possible, a template is used to ensure the same surface area is being swabbed. Similarly, the extraction efficiency must be checked because the swab may pick up the contaminant but may not necessarily release it to the extraction solution in the laboratory. The swab locations must be documented in the experimental section of the protocol. There are a number of disadvantages of using swabs including: Inability to access some areas; these are usually the most difficult to clean areas. Assumes uniformity of contamination surface; invariably, contamination is not uniform. Must extrapolate sample area to whole surface; it can be difficult to estimate the total surface area of the equipment and the calculation also requires that the swab location be carefully measured and recorded. (Use flip chart and draw equipment and points to illustrate the above)

Cleaning validation Rinse samples Indirect method Combine with swabs
Useful for cleaning agent residues pH, conductivity Insufficient evidence of cleaning Sample very large surface areas Rinse samples: This is an “indirect” sampling method. The solvent (usually water) used for the final rinsing of equipment has much useful information. It should not be discarded before all of the information can be gleaned from it. The rinse sample should be used in combination with swabs; together they balance out the disadvantages each has on its own. The rinse sample is also useful for checking cleaning agent residues, e.g. detergents. Sometimes this can be with non-specific, simple tests such as pH, conductivity and, increasingly, Total Organic Carbon (TOC); which can also be put “on line” to measure routinely the cleaning endpoint. However, consideration should be given to the fact that the residue or contaminant may be insoluble or may be physically occluded in the equipment. Rinse samples on their own are insufficient evidence of cleaning and should be used in combination with other sampling methods, such as swabs. The manufacturer should be aware of the “dirty pot” syndrome. That is, the container may appear to rinse clean but it could still be contaminated. However, rinse samples allow sampling of a large surface area, of otherwise inaccessible systems or those that cannot be routinely disassembled.

Cleaning validation Analytical method (1) Validate analytical method
Must be sensitive assay procedure: HPLC, GC, HPTLC pH conductivity UV ELISA Analytical method: The method must be a sensitive analytical procedure. Analytes of the order of parts per billion will be examined. A non-specific assay method is not a disadvantage for cleaning validation where total contaminants are being studied as opposed to just specific analytes. Examples of suitable methods are: Chromatographic: HPLC, GC, High Performance Thin Layer Chromatography (HPTLC) are all very sensitive and also very specific. TLC may not be sensitive enough. TOC: total organic carbon analysers are increasingly popular because they are very sensitive, but not specific. However, if the manufacturer puts a total residues limit of say 500ppb (parts per billion) then TOC is a very useful analytical tool. It should be used with pH and conductivity to be of value. pH; very sensitive to hydrogen ions, so very good at checking even trace levels of acids and alkalis that may be used as part of the cleaning process. Conductivity: a very sensitive method for total ions. (These last three, TOC, pH and conductivity, when used in combination, are proving very powerful cleaning validation assay methods.) UV spectroscopy: Moderate specificity but not quantitative. Can have high sensitivity depending on analyte. ELISA (Enzyme-linked immunosorbent assay): very sensitive and specific for biopharmaceuticals but very expensive, and labour intensive, with a long sample turn- around.

Cleaning validation Analytical method (2) Check:
Precision, linearity, selectivity Limit of Detection (LOD) Limit of Quantitation (LOQ) Recovery, by spiking Consistency of recovery The laboratory must validate the analytical method before validation is started. Alternatively, there needs to be evidence that the analytical method is suitable for use. The laboratory should check: Precision, linearity, selectivity (the latter if specific analytes are being targeted). However, note that interference by another analyte will make the validation fail, rather than pass. Limit of Detection (LOD). Limit of Quantitation (LOQ). Recovery, by spiking with the analyte; below 50% is considered unacceptable by some authorities, above 80% is good. The result is multiplied by the recovery factor to give the actual level of residue. Consistency of recovery, or reproducibility of the method should be checked. The last two measure the sensitivity of the procedure and are critical features of a good analytical method.

Cleaning validation Setting limits (1)
Regulatory authorities do not set limits for specific products Logically based Limits must be practical, achievable and verifiable Allergenic and potent substances Limit setting approach needed Setting Limits: It should be noted at the outset: “Regulatory authorities do not set limits for specific products”. It is up to the manufacturer to determine the level of carry over of any contaminant. (The US FDA says each manufacturer is responsible for setting its own limits.) Setting limits must be logically based. The limits must be practical, achievable and verifiable. The limit setting approach can be: Product specific Grouped into product families: for example all those products containing multiple ingredients and one common, low-level ingredient, and choosing a worst case product. Collected into similar risk groups (e.g. very soluble products, similar potency, highly toxic, or difficult to detect products). Different safety factors for different dosage forms based on physiological response. This method is essential for potent materials. Setting limits on carryover. Certain allergenic ingredients, (e.g. penicillins, cephalosporins) and highly potent material (e.g. anovulent steroids, potent steroids and cytotoxics) should not be detectable by best available analytical methods. In practice this may mean that dedicated manufacturing facilities are used for these products. The methods of limit setting are discussed on the next slides.

Cleaning validation Setting limits (2)
Uniform distribution of contaminants not guaranteed Decomposition products to be checked Setting limits; cleaning criteria: visually clean 10 ppm in another product 0.1% of therapeutic dose Setting limits: (Contd.) Some points to note when setting limits: As noted on a previous slide, uniform distribution of contaminants is not guaranteed. Decomposition products should be checked. These can arise from interaction with the washing or cleaning procedures. If used, check reactions with alkalis, acids, lights, heat (polymerization of substances can make them extremely difficult to remove). The three most common methods of setting cleaning criteria are: visually clean 10ppm in another product 0.1% of therapeutic dose Note that the PIC/S Guidelines on Validation calls for use of the most stringent of three options: dose-based, 10 ppm default or the visually clean standard. (Clause of PIC/S Recommendations on VMP, IQ, OQ, Non-sterile process validation and Cleaning validation, August 2001.)

Setting limits: “Visually clean”
Cleaning validation Setting limits: “Visually clean” Always first criteria Can be very sensitive but needs verification Use between same product batches of same formulation Illuminate surface Spiking studies Setting limits: (Contd.) The human eye meets the criteria of a non-specific, sensitive analytical procedure. Of course, surfaces have to be visible! It is not a method for closed systems. “Visually clean”, on its own, is not an option for high potency, low dosage drugs. “Visually clean” is always the first criterion. It can be very sensitive, and may allow detection of gross contamination concentrated in small areas that are not detected by other analytical methods. There are reports of consistent results of 4 micrograms per cm2. (G.L. Fourman and M.V. Mullen, "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations," Pharm.Technol. 17 (4), (1993)) A simple "visually clean" may be an appropriate acceptance criteria in some cases. Verification that the limit is acceptable is needed e.g. by spiking, and observing model surfaces, in a "blinded" manner. Some inspection agencies accept 'visually clean' between batches of the same product of the same formulation. For example; the USA FDA's guidelines specify that when cleaning between lots of the same product, visually clean is sufficient and validation is not required. The checker must use a proper light source (white light, black light) oblique to the surface. Checking cleaned equipment using less than 400 lux is unsatisfactory. The “visually clean” method is also useful for checking “non-product contact surfaces” such as walls, floors, doorknobs, ceilings, etc. Spiking studies should determine the concentration at which most active ingredients or contaminants are visible.

Cleaning validation Setting limits: “10 ppm” Historical
In some poisons regulations Pharmacopoeias limit test Assumes residue to be harmful as heavy metal Useful for materials for which no available toxicological data Not for pharmacologically potent material Setting limits: (Contd.) The limit of 10ppm was used historically in some early food standards, as a limit for heavy metals, etc. Consequently it is still a standard in some poisons regulations and is used in most pharmacopoeias as the basis for limits on, for example: As, Pb, heavy metals for starting materials. It: assumes residue to be harmful as heavy metal; is useful for materials for which no toxicological data is available such as detergents; may be too generous for pharmacologically potent material. Example: Maximum allowable amount of contaminant (MC) (10 ppm) Product A Product B (following product) MC = R x S x U T R: 10 ppm = 10 mg/Kg S: Batch size of Product B (Kg) T: Total surface area (inch2) where product A and B contact U: Area of swab (usually 4 inch2) e.g. Batch size of Product B = 13 Kg Total surface area = inch2 MC = 10 mg/Kg x 13 Kg x 4 inch2/swab = 116 mg/swab 4 500 inch2 (Tutor should use flip chart to illustrate the above.)

Setting limits: not more than 0.1%
Cleaning validation Setting limits: not more than 0.1% Proportion of MINIMUM daily dose of current product carried over into MAXIMUM daily dose of subsequent product Need to identify worst case Setting limits: (Contd.) Toxicologists suggest that an acceptable level of a toxic material may be not more than 1/1000 of a toxic dose or 1/ /1000 of an amount which is not known to show any harmful biological effect in the most sensitive animal system known, e.g. no effect; the assumption that the proportion of the MINIMUM daily dose of the current product carried over into the MAXIMUM daily dose of a subsequent product should be not more than 0.1%. Minimum daily dose = maximum daily dose x 1 1000 The manufacturer needs to identify worst case. (Trainer should use flip chart to illustrate the above.)

Cleaning validation Other issues Clean-In-Place (CIP) systems
Placebo studies Detergent residues; composition should be known Scrubbing by hand Other issues: Clean-In-Place (CIP) systems: Critical areas i.e. those hardest to clean should be identified, particularly in large systems that employ semi-automatic or fully automatic CIP systems. Placebo studies: A placebo method relies on the manufacture of a placebo batch and then checking it for carry over of the previous product. It is an expensive and laborious process. It should be used in conjunction with rinse and/or swab samples. It is difficult to provide assurance that the contaminants will be dislodged from the equipment surface uniformly. Additionally, if the contaminant or residue is of large enough particle size, it may not be uniformly dispersed in the placebo. Lastly, the sensitivity of the assay may be greatly reduced by dilution of the contaminant. Detergents residues: detergents should facilitate the cleaning process but are sometimes found to have the most persistent residues. For example, cationic detergents adhere very strongly to glass and are difficult to remove. Detergent composition should be known and removal demonstrated. Acceptable limits should be defined for detergent residues after cleaning. The possibility of detergent breakdown should also be considered when validating cleaning procedures. Detergents should be acceptable to QA/QC departments, and preferably be able to meet local food industry standards. Scrubbing by hand: Note that manual cleaning methods are difficult to replicate.

Questions for the GMP Inspector to ask
Cleaning validation Questions for the GMP Inspector to ask How is equipment cleaned? Are different cleaning processes required? How many times is a cleaning process repeated before acceptable results are obtained? What is most appropriate solvent or detergent? At what point does system become clean? What does visually clean mean? Questions for the GMP Inspector to ask: How is equipment cleaned? Manual cleaning may be more difficult to validate than automated or Clean-In-Place procedures. Are different cleaning processes required? How many times is a cleaning process applied before an acceptable result is obtained? That is, will an inspection determine if the cleaning process meets specifications? What is the most appropriate solvent or detergent? At what point does the system become clean? With very good analytical procedures now available, it is possible to pick up insignificant amounts of residues. The regulators do not set limits but the manufacturer must. There is an extensive section on setting limits of contaminants earlier in this Part. What does visually clean mean? “Visually Clean” can actually mean very clean indeed, provided the human eye has assistance e.g. from black and white light.

Cleaning validation Conclusion
The manufacturer needs a cleaning validation strategy Assess each situation on its merits Scientific rationale must be developed equipment selection contamination distribution significance of the contaminant “Visually clean” may be all that is required Conclusion: The cleaning validation programme should be based on detailed cleaning procedures, a good training programme, a validation protocol, validated chemical and microbiological methods, a change control programme, a final report and any auditing required to ensure compliance. Assess each situation on its merits. Scientific rationale must be developed equipment selection contamination distribution significance of the contaminant In some situations “visually clean” may be all that is required.

Process validation

Process validation Objectives To review: Finalization of validation
Validation, risk analysis, and critical steps of processing Points to consider in process validation of: solid dose mixing tablet compression sterilization Finalization of validation The objectives of Part 3, Module 1 will review the following: Validation, risk analysis, and critical steps of processing: The participants will be introduced to risk analysis as a means of identifying critical steps of manufacture and critical products. Solid dose and sterile product process validation: Specific requirements for some pharmaceutical forms will be reviewed. Validation of other pharmaceutical dosage forms is not covered in this module. Finalization of validation will be reviewed, including the preparation of the final report

Reliable, repeatable, under control
Process validation Reliable, repeatable, under control At least first 3 consecutive batches - repeatable Must investigate failures The rationale should be documented if experimental method is changed document deviations, decisions and reasoning Does not improve processes Should not validate bad processes Reliable, repeatable, under control: The manufacturer must demonstrate that the process is reliable, repeatable, and under control by validating, typically, at least the first three consecutive production batches. There must be no failed batch without a “failure investigation” with root cause analysis and corrective action. If there is a change to the experimental method required, the rationale must be documented. All deviations, decisions and reasoning must be documented. Validation does not improve processes. It can only confirm or deny that the process has been properly developed and is under control. Bad processes should not be validated; for example, containers cannot be sterilized by immersion in isopropyl alcohol. Similarly, validation of badly formulated products should not be attempted.

Process validation DQ, IQ, OQ and PQ
Design user or process requirements Install installation qualification Operate operational qualification Perform performance qualification and process validation Review periodically (+ change control) We were briefly introduced to DQ, IQ , OQ and PQ in Module 4 of the WHO Basic Training series. Validation starts in development and continues until the stage of full-scale production. In the course of development, critical processes, steps or unit operations are identified. The GMP Inspector should determine that the manufacturer has appropriately identified the following: Check that the premises, the supporting utilities, the equipment and the processes have been designed in accordance with the requirements of GMP. This normally constitutes Design Qualification or DQ. Check that the premises, supporting utilities and the equipment have been built and installed in compliance with their design specifications. This constitutes Installation Qualification or IQ. Check that the premises, supporting utilities and the equipment operate in accordance with their design specifications. This constitutes Operational Qualification or OQ. Performance qualification and process validation: Check performance qualification protocols and reports and that process validation has been done. Validation will ensure that a product will meet its predetermined specifications and quality attributes. The whole process then cycles in a review and change phase, since each process has a finite life cycle: Design – user or process requirements Install - installation qualification Operate - operational qualification Validate - process qualification and process validation Review - periodically - change control

Critical factors or parameters
Process validation Critical factors or parameters Need to be determined Need to be monitored during validation May affect the quality of the product Critical factors or parameters: Need to be determined Need to be monitored during validation May affect the quality of the product

Marketing authorisation limits based on stability specifications
Process validation Setting Limits Marketing authorization limits stability specifications Release specification Validation limits Setting limits: Marketing authorization limits: usually the national compendia limits or those agreed at the time of product registration. The product must meet these at any time that it is on the market and within its expiry date. Stability specifications: The specification minimally needed to maintain required potency over the shelf life of the product, based on stability study data. Release specification: the product must meet at the time of release and in order to allow for any changes (super-potency, sub-potency, dissolution, disintegration, etc) over shelf life of product. This is the simplest criteria for setting validation acceptance testing, but will not necessarily include process capability. In the development of acceptance criteria, all three of the above specification areas must be taken into consideration, including an analysis of data gathered during the initial development and stability work. In most cases, this data will be limited but will give enough information on test and process variability to allow for some guidance. The most important thing to remember is to keep the statistics simple. Validation acceptance criteria may be tighter than, or equal to the release limits, which may be tighter than, or equal to the compendial limits. Marketing authorisation limits based on stability specifications Batch release limits Validation limits

Process validation Determining critical control point: example of a tablet granulation process Particle size distribution of the active(s) Blending time for the powder Granulating time and speed, Amount of granulating fluid-binder concentration Drying time - final moisture content, granule particle size distribution Granule active content and homogeneity, blending time of external phase Determination of critical control points is a way of ensuring validation effort is not wasted and to identify quality control points. For tablets manufactured by granulation and compression, the critical mixing parameters may include: particle size distribution of the active pharmaceutical ingredient(s) blending time for the powder granulating time and speed amount of granulating fluid-binder concentration drying time - final moisture content, granule particle size distribution granule active content and homogeneity, blending time of external phase In the production of higher risk prescription tablets, especially those containing low dose of active(s), compressed tablet uniformity should be checked more intensively than uniformity of bulk blend study. The next slide shows how to “flow chart” a process to determine critical control points.

Determining critical control points
Process validation Determining critical control points A useful strategy to determine which steps to study intensively, is to “flow chart” the process and conduct a hazard analysis of critical control points. Critical control points indicate critical processing steps. It is necessary to note how often critical control points come at the end stages as the value-adding process proceeds. The flow chart above shows a tablet granulation process where Step XVI and XVIII have been identified as a critical control point. Blend uniformity and cleaning validation has to be performed at step XVI, and during actual manufacture, a reconciliation of the actual yield against the expected yield must be performed before the tablet compression step. (The trainer should explain that this diagram is incomplete, as there are other IQ, OQ, PQ requirements, steps, etc. to be included The slide provides an example only.)

Process validation Solid dose mixing (1)
Homogeneity in blending – the key to quality! Sampling strategy Sample site, label, container Storage Transport Sample thief Solid dose mixing: Homogeneity in blending - the key to quality In pharmaceutical production, the blending step (whether for solid - or liquid - dose forms) is one of the most critical in the process. Type of blender, load, time and speed are the most critical parameters. Additionally, the density, particle size and moisture or solvent content of the powders all affect the time to achieve a homogeneous blend. Minor changes (within specification), are present in the starting materials for any mixture. Sampling strategy: the number of samples to be drawn and the sample sites must be specified. Samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the tablet or capsule “content uniformity” test. The samples to be properly labeled with date, time, location, batch details, sampler. Sample container needs to be appropriate: air tight, inert, etc. The samples need to be carefully handled, stored, and transported to the laboratory to avoid de-mixing or fracturing the granulate. Analysis should commence promptly to avoid sample deterioration. Sampling probe: samples of the mixture are withdrawn by a “thief”, which takes samples from several depths throughout the blender. The volume taken must be in proportion to the mass of the unit dose. This method of grabbing a sample, extracting and performing a wet chemical analysis is potentially inaccurate and is certainly time-consuming.

Process validation Solid dose mixing (2) In situ analysis
Methods of analysis Statistical analysis inter-batch intra-batch within-sample-site Solid dose mixing: (Contd) There are now manyin situ spectroscopic approaches, such as infrared (IR), near-infrared (NIR), and Raman spectroscopy, which are fast, accurate and easily performed. Probes may be placed directly into the mixing vessel or be positioned at windows along the walls of the vessels, allowing for real-time, uninterrupted homogeneity measurements. Remember uniformity or homogeneity are being considered, not a determination of the active. Although the best marker is the active (must be the active for low dose and potent product), the marker can be chosen if it is representative of the blend. The methods of analysis for these samples of the blend are extracted and assayed by UV or HPLC, or similar validated test method. Note that non-specific methods are satisfactory – which is a big difference from e.g. stability studies. The actual spectra (from, for example, near-Infrared) and methods of calculating the homogeneity of the actives should be subject to statistical analysis. The within-sample-site variability must also be acceptable for low dilution powders, such as micro-dose tablets or capsules. This can usually be demonstrated on just the first batch, not for each of the three batches. It is a “minivalidation” of the sampling thief and sampling method used.

Tablet compression variables
Process validation Tablet compression variables Fill volume Pre-compression force, compression force Turntable speed Dwell time Granule size and feed Ejection force, lubrication The tablet compression variables include: Fill volume: tableting and capsulation use a volumetric fill. A tableting press equipped with a pressure-transducer will help in collecting statistical data on the uniformity of die-fill and, therefore, on mass uniformity. Pre-compression force; compression force Turntable speed Dwell time Granule feed and uniformity. Granules made by the wet granulation method are less prone to de-mixing than dry granulation. This is critically important for microdose tablets (or capsules). Ejection force - lubrication (e.g. magnesium stearate) During validation studies, the testing of the solid dose form to a greater extent than the normal routine quality control is required, e.g. several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then treated statistically to verify normal distribution and standard deviation. Confidence limits for individual results and for batch homogeneity are also estimated.

Process validation Tablet compression parameters Tablet coating
Mass Hardness Moisture Friability Disintegration Dissolution Thickness Tablet coating variables Spray rate Inlet and outlet air temp Coating weight The critical tablet parameters may include: Tablet mass Tablet hardness Moisture Friability Disintegration Dissolution Thickness - if it affects packaging performance If the tablet is film coated, the following additional parameters may require validation: Spray rate of coating solution Inlet and outlet air temperatures Coating weight with respect to tablet appearance, friability, disintegration, and dissolution

Sterilization validation (1)
Process validation Sterilization validation (1) Sterility test Physical measurements Chemical and biological indicators Loading patterns Sterilization validation: One of the reasons for the intensity required of sterilization validation is that there are many basic problems with the sterility test (which must still be used to check the validation batches) as follows: Cannot test every type of microbial contamination, ie lack of sensitivity. Subject to an unreasonable rate of error. Repeat testing (if permitted) increases the possibility of passing a contaminated batch. Small number of containers tested with a chance (increasing as the number of tests is repeated) of passing a batch . It will not detect pyrogens or foreign particles. Time, temperature and pressure should be used to monitor the process. The sterilizing conditions in all parts of each type of load to be processed should be demonstrated by physical measurements: calibrated thermocouples, and pressure monitor, position used for controlling and recording should be determined during the validation. Control instrumentation should be independent of monitoring instrumentation and recording charts. Chemical and biological indicators should be used, distributed throughout the load with a focus on the coolest parts determined during OQ studies by thermal mapping. They should not take the place of physical measurements. Loading patterns should be established for all sterilization processes.

Sterilization validation (2)
Process validation Sterilization validation (2) Cooling fluid or gas Automated process Leak tests Control instrumentation Steam quality Heat distribution Sterilization validation: (Contd.) Any cooling fluid or gas which may come in contact with the product should be sterilized. Where automated control and monitoring systems are used they should be validated. There should be leak tests on the chamber when a vacuum phase is part of the cycle. Automated control systems or software which controls processes are also required to be validated. Computer validation is not covered by this module. Steam used for sterilization should be of suitable quality (usually Pure Steam of WFI standards) and should not contain contaminating additives. Heat distribution studies should be performed at OQ. Suggested Reading: ISO Sterilization of health care products - Requirements for validation and routine control of industrial moist heat sterilization ISO Medical devices - Validation and routine control of ethylene oxide sterilization ISO Sterilization of health care products -Requirements for validation and routine control - Radiation sterilization ISO/TR Sterilization of health care products - Dose setting methods for radiation sterilization - Part 1 : Substantiation of 25 kGy for sterilization of small or infrequent production batches ISO/DIS Aseptic processing of health care products - Part 1 : General requirements

Dry heat sterilization
Process validation Dry heat sterilization Parameters Air circulation, positive air pressure, HEPA filter Advantages microorganisms destroyed depyrogenation possible Disadvantages poor heat transfer higher temperatures for long periods Dry heat sterilization: Dry heat sterilization has many features in common with moist heat sterilization with respect to IQ, OQ, loading patterns, sterility testing and so forth. The required parameters are: minimum recommended time/temperature cycles: 160° C for not less than 120 min 170° C for not less than 60 min 180° C for not less than 30 min For depyrogenation - 250°C for not less than 30 minutes Air circulation, positive air pressure, HEPA filter: Air should be passed through a HEPA filter. There should be air circulation within the chamber and positive air pressure to prevent the entry of non-sterile air. Advantages: microorganisms are destroyed. depyrogenation is possible; challenge tests using endotoxins should be used as part of the validation. Disadvantages: poor heat transfer higher temperatures, for long time periods.

Process validation Process variation Temperature, humidity
Controllable causes of variation may include: Temperature, humidity Variations in electrical supply Vibration Environmental contaminants Light Human factors Variability of materials Wear and tear of equipment Process variation: The process variations are due to many controlled and uncontrolled events. The uncontrolled are due to the natural variation of e.g. machines. One of the outputs of OQ and PQ is the development of attributes for continuous monitoring and maintenance. Process and product data should also be analysed to identify any variation due to controllable causes. Depending on the nature of the process and its sensitivity, controllable causes of variation may include: Temperature, Humidity : may be important for tablets, critically important for sterilization Variations in electrical supply: can impact on sterilization processes. Vibration Environmental contaminants Light Human factors (ergonomic factors, stress, etc.). Support with good documentation supervision and training. Variability of materials: starting materials should be subject to a change control procedure after the process is validated. Wear and tear of equipment; revalidation is necessary to check that the equipment is still functioning properly. Appropriate measures should be taken to eliminate controllable causes of variation. Eliminating them will reduce variation and make the process more consistent, resulting in a higher degree of assurance that the product will consistently meet specifications.

Process validation Change control
Must be a review procedure for validated processes From time to time changes may be necessary Documented change control procedure needed “Like for like" changes do not require re-validation Change control: There must be a review procedure for validated processes. Sometimes this is during an annual product review as equipment is repaired, renewed or replaced; or as new technology emerges. Changes may be necessary to any process as it goes through a life cycle; as new equipment or technology comes into being, or improvements are introduced. Documented change control procedures are needed but “Like for Like" changes do not require re-validation UNLESS they impact on GMP or change the state of validation (IQ, OQ, calibration or PQ). Examples of changes that are likely to require re-validation are given in Part 1 of this module (at slide 21).

Mixing validation liquid and solid dose change control and scale up
Process validation Mixing validation liquid and solid dose change control and scale up Mixer type and size Batch size Pilot study scale up Limit on the proportion of the scale up Mixing validation – liquid and solid dose: The mixer type and size must be considered when changes are made. The same technology mixer can be used for pilot studies and then for scale up. Usually one pilot scale study may be permitted as counting towards the three batches requirement. (Note there must still be at least three consecutive batches produced and validated to demonstrate reliability of the process.) The batch size may be increased or decreased as long as it is within the mixer supplier’s specifications and if the batches have been subject to the extremes during validation. Note the scale up must use the same mixing technology; there cannot be a shift from say, a propeller stirrer to a helical stirrer, or from a ribbon mixer to a cube mixer. There may need to be a limit on the proportion of the scale up, say at 10 x the pilot size batch.

Finalization of validation process
Process validation Finalization of validation process Final report required Summarize and reference protocols and results Conclusion required: “Is the process valid” Final report should be reviewed and approved by the validation team “authorized person” Finalization of the validation process: A validation report must be prepared at the conclusion of validation activities. It should summarize and reference all protocols and results. Obviously, a conclusion is required: “Is the process valid”, but strangely often omitted. The conclusions of the report are sometimes accompanied by a certificate of validity, with an expiry date to ensure revalidation is carried out on time. Good validation practice requires the close collaboration of departments such as those concerned with development, production, engineering, quality assurance and control. This is most important when processes go into routine full-scale production following pharmaceutical development and pilot-plant operations. Consequently, the final report should be reviewed and approved by the validation team. The authorized person, as the overall quality controller, will be a member of the validation team and he or she should have the final decision on whether or not the process is valid and under control.

Tablet manufacturing flow chart
In this group session, (see handout ) 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.

Quality Control related validation

QC related validation Introduction
Why is analytical monitoring necessary? What is the purpose of analytical validation? Introduction: Analytical monitoring of a pharmaceutical product, or of specific ingredients within the product, is necessary to ensure its safety and efficacy throughout all phases of its shelf-life, including storage, distribution, and use. This monitoring should be conducted in accordance with specifications validated during product development. The principal purpose of analytical validation is to ensure that a selected analytical procedure will give reproducible and reliable results that are adequate for the intended purpose. It is necessary to define properly both the conditions in which the procedure is to be used and the purpose for which it is intended. These principles apply to all procedures described in a pharmacopoeia and to non-pharmacopoeia procedures used by a manufacturing company. These guidelines apply to procedures used to examine chemical and physicochemical attributes, but many are equally applicable to microbiological and biological procedures.

QC related validation Objectives To introduce the concepts of :
Protocol development Instrument qualification Analytical procedure Extent of validation Method transfer Chemical and physical, biological, and microbiological test validation The objectives of Part 4, Module 1 are to introduce the concepts of analytical validation: Protocol development Instrument qualification Analytical procedure, with some illustrated examples of some specific characteristics, such as linearity and precision Extent of validation Method transfer and Chemical and physical, biological and microbiological test validation.

QC related validation Validation of analytical procedures requires:
Qualified and calibrated instruments Documented methods Reliable reference standards Qualified analysts Sample integrity Validation of analytical procedures requires: Qualified and calibrated instruments; the qualification is identical to that previously discussed for production equipment. Documented methods: the test must be documented for the laboratory itself and it should not just be a photocopy of a method, such as pharmacopoeial methods, which sometimes do not spell out exact details. Reliable reference standards: these should preferably be primary reference materials sourced from the pharmacopoeia commission or a National Control Laboratory, or secondary standards that have been qualified against the primary reference material and have been fully characterized. Qualified analysts: experience and qualifications as detailed in a previous module within the WHO Basic Training Modules on GMP, on Personnel (Module 8). There should be training and proficiency testing records cross-referenced in the validation report. Sample integrity: the sample must be beyond reproach – see also the slide for microbiological testing validation.

QC related validation Validation protocol for analytical method
Statement of purpose and scope Responsibilities Documented test method List of materials and equipment Procedure for the experiments for each parameter Statistical analysis Acceptance criteria for each performance parameter Validation protocol for analytical method: The validation protocol for an analytical method is very similar to that required for any process validation. It should include: Statement of purpose and scope Responsibilities for approval, execution and review The documented test method which should have a unique reference number List of materials and equipment: the instruments, columns, reagents, test kits and so on Procedure - details of the experiments for each performance parameter Statistical analysis. These are usually standard deviation, linear regression, and Analysis of Variants or ANOVA. Acceptance criteria for each performance parameter which should be settled before the experimental phase of the work commences.

QC related validation Qualification of the instrument
Make, model and maker’s manual Modifications Installation and operational qualification Calibration programs Maintenance schedules Instrument qualification: Critical instruments in the QC laboratory have similar qualification requirements to equipment used in the factory. There should be available: Make, model and maker’s manual. Any modifications that have been made to the instrument since it was purchased. This is very important because the servicing of the instrument could result in upgrades, e.g. to software, that are not revealed by the service person to the QC supervisor. Installation and operational qualification. Calibration programs. Maintenance schedules.

QC related validation Characteristics of analytical procedures (1)
Accuracy Precision Repeatability Reproducibility Characteristics of analytical procedures: Accuracy The accuracy of the procedure is the closeness of the results obtained by the procedure to the true value. Accuracy may be determined by applying the procedure to samples of the material to be examined that have been prepared with quantitative accuracy. Wherever possible, these samples should contain all the components of the material, including the analyte. Possibly three methods: 1. Spike into placebo matrix: active component is added to (“spiked”) in known amounts usually ranging from 25% to 150% of dose strength; 2. Standard addition technique; and 3. Comparison of two methods for equivalence. Precision The precision of the procedure is the degree of agreement among individual test results. It is measured by the scatter of individual results from the mean and it is usually expressed as the standard deviation or as the coefficient of variation . (The relationship between Accuracy and Precision is shown on the next slide.) Repeatability (within-laboratory Variation) This is the precision of the procedure when repeated by the same analyst under the same set of conditions (same reagents, equipment, settings, and laboratory) and within a short interval of time. Reproducibility This is the precision of the procedure when it is carried out under different conditions—usually in different laboratories—on separate, putatively identical samples taken from the same homogeneous batch of material.

Relationship between accuracy and precision
QC related validation Relationship between accuracy and precision The relationship between accuracy and precision can be represented by arrows being shot at a target. The first small target at the top shows the arrows have landed indiscriminately. This is neither accurate nor precise. The second target on the left shows the arrows have grouped together nicely but are not on the bullseye. This is precise but inaccurate. This is sometimes called analytical bias and sometimes a correction factor can be applied. The third, small target shows the arrows AVERAGE is on the bullseye, but the precision is unacceptable. The fourth, large target shows the arrows are all clustered on or in the bullseye; this shows accuracy and precision. Accurate AND Precise

Ruggedness Robustness Variability caused by: Day-to-day variations Analyst-to-analyst Laboratory-to-laboratory Instrument-to-instrument Chromatographic column-to-column Reagent kit-to-kit Instability of analytical reagents Characteristics of analaytical procedures: (Contd) Ruggedness and Robustness Robustness, and ruggedness, of an analytical procedures is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters, and thus provides an indication of the reliability of the method during normal usage, under various conditions. Ruggedness is due to factors external to the method; robustness is due to factors internal to the method. Things that may cause variability include: Day-to-day variations in e.g. temperature, relative humidity, etc. Analyst-to-analyst Laboratory-to-laboratory Instrument-to-instrument Chromatographic column-to-column Reagent kit-to-kit or lot-to-lot variation Time from sample preparation to assay Instability of analytical reagents

Linearity and range Specificity Sensitivity Limit of detection Limit of quantitation Characteristics of analytical procedures: (Contd.) Linearity and range The linearity of an analytical procedure is its ability to produce results that are directly proportional to the concentration of analyte in the samples. The range of the procedure is an expression of the lowest and highest levels of analyte that have been demonstrated to be determinable with acceptable precision, accuracy, and linearity. Specificity The specificity or selectivity of a procedure is its ability to measure the analyte in a manner that is free from interference from other components in the sample being examined (for example, impurities arising from manufacture or degradation or ingredients other than the analyte). Sensitivity The specificity or sensitivity is the capacity of the test procedure to record small deviations in concentration. It is the slope of the calibration curve. A more general use of the term to encompass limit of detection and or limit of quantitation should be avoided. Limit of detection The limit of detection is the lowest level of analyte that can be detected, but not necessarily determined in a quantitative fashion. Limit of quantitation The limit of quantitation is the lowest concentration of analyte in a sample that may be determined with acceptable accuracy and precision when the required procedure is applied.

Reference material mg/ml
QC related validation Table of values (x,y) x y # Reference material mg/ml Calculated mg/ml 1 0.0100 0.0101 2 0.0150 0.0145 3 0.0200 0.0210 4 0.0250 0.0260 5 0.0300 0.0294 6 0.0400 0.0410 This is a typical plot of raw data to check for linearity and range. The table of raw data on the right hand side has been plotted using linear regression to obtain a line of best fit. The x axis is the reference material that was weighed out and the y axis the calculated values from the instrument readings. These are plotted (the blue line with the points as a yellow box and error bars) and a linear regression analysis is performed. The two yellow lines are the 2-sided 95% confidence limits.

QC related validation Linearity Statistics Intercept -0.0002
Limit of Linearity and Range 0.005 – mg/mL Slope Correlation coefficient Pearson Olkin and Pratt Relative procedure standard deviation 3.4% Determination of linearity: The data from the chart on the previous slide is analysed to obtain: The Intercept value It is important not to force the line through zero as the xy intercept should be known in order to also check slope. Determination of Limit of Linearity and Range The assay should only be used within the range and linearity validated. The working range if the slope is linear should be 75% to 125% of the predicted content of the analyte. Slope “Slope” checks the ability to measure accurately small increments of analyte. This method shows a nearly one-to-one relationship. Correlation coefficient (r2) The correlation coefficient is calculated. Better than 0.99 is required but better than should be routinely obtained for example, in case of HPLC assays. Standard deviation The standard deviation should be calculated. This generally should be below 2%. However, some manual methods, such as volumetric methods can be as high as 3%. Although linearity is acceptable, the value of 3.4% is unsatisfactory and could give arbitrarily high or low results resulting in possible release of sub- or super-potent material, or rejection of acceptable material.

QC related validation LOQ, LOD and SNR Limit of Quantitation
Limit of Detection Signal to Noise Ratio Peak B LOQ There are no specific criteria set for the Limit of Quantitation (LOQ) and Limit of Detection (LOD) but guidance is available from specifications and pharmacopeias. The noise is measured by running the instrument at maximum gain with no test being processed. The ripple generated is noise due to the instrument’s electronics, etc. The peak is measured relative to this noise and the ratio is calculated. This is known as the Signal to Noise Ratio (SNR). Generally: LOD SNR should be greater than 2:1. Peak A is acceptable for LOD but not for quantitation; The LOD can be calculated if the standard deviation (SD) of the response (which is standard deviation of the blank) and the slope is determined: LOD = 3.3 x SD slope Similarly LOQ = 10 x SD The LOQ SNR should generally be above 10:1. Peak B is suitable for quantitation; Precision as a percentage relative standard deviation should be % at the limit for LOQ. Peak A LOD noise Baseline

Different classes of analytical tests
QC related validation Different classes of analytical tests Class A: To establish identity Class B: To detect and quantitate impurities Class C: To determine quantitatively the concentration Class D: To assess the characteristics What analytical characteristics are applicable in particular cases? Not all of the characteristics previously discussed will need to be considered in all validation cases; those applicable should be identified on a case-by-case basis. As a guide, however, the following generalizations may assist. Methods used for the examination of pharmaceutical materials may be broadly classified as follows: • Class A: Tests designed to establish identity, whether of bulk drug substances or of a particular ingredient in a finished dosage form. • Class B: Methods designed to detect and quantitate impurities in a bulk drug substance or finished dosage form. The detection of impurities, without quantitation, is referred to as a limit test. • Class C: Methods used to determine quantitatively the concentration of a bulk drug substance or of a major ingredient in a finished dosage form; referred to as assay. • Class D: Methods used to assess the characteristics of finished dosage forms, such as dissolution profiles and content uniformity.

QC related validation Characteristic A B quant. B Limit test C D
QC related validation Characteristic A B quant. B Limit test C D Accuracy X X* Precision Robustness Linearity and range Specificity Limit of detection Limit of quantitation This table offers guidelines to the characteristics that are relevant in each case. There will clearly be occasions when certain characteristics marked as not being required may be necessary and vice versa. The purpose for which the testing is being made may have a bearing on the choice of characteristics and the extent to which they are specified. For example, although Classes B, C, and D are all referred to in Table 1 as requiring consideration of precision, the stringency applied may be different. For estimation of an impurity it may not be necessary to be as precise as for quantitative assessment of a bulk drug substance. By the same token, a degree of bias may be acceptable in determining the accuracy of a test for uniformity of content (Class D) that would not be permissible for a quantitative assessment of the concentration of an ingredient in a finished dosage form (Class C). Similarly, a test designed to establish the identity of a new drug entity, for which no previous data have been lodged, may need to be considerably more searching than tests designed to verify the identity of a long-established drug substance to be included in a pharmacopoeia. A different emphasis may be required for pharmacopoeial as opposed to registration purposes. For example, robustness is a critical characteristic for pharmacopoeial methodology but may be less significant for a manufacturer’s release specification. Suggested Reading: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992 (WHO Technical Report Series No. 823). Annex 5: Validation of analytical procedures used in the examination of pharmaceutical materials. ICH Harmonised Tripartite Guidelines. Text on validation of analytical procedures and validation of analytical procedures: Methodology. October and November 1996 respectively. * A degree of bias may be allowed

QC related validation Extent of validation
New methods require complete validation Pharmacopoeial methods require partial validation (or verification) Significant changes mean partial revalidation equipment changes formula changed changed suppliers of critical reagents Extent of validation required: New (from manufacturer/literature) methods require complete validation. Methods in pharmacopoeias require partial validation, if the method has not been previously validated for that specific drug product. Manufacturers should validate pharmacopoeial methods to ensure they work with their own products - as a minimum accuracy and specificity. The USP monograph states: “Already established general assays and tests - should also be validated to verify their accuracy (and absence of possible interference) when used for a new product or starting materials.” At least partial revalidation is required whenever significant changes are made which could reasonably be expected to affect the results obtained, e.g. in case of instrument change, product formula change, changed suppliers of critical reagents, method.

Analytical method transfer
QC related validation Analytical method transfer Method transfer protocol and procedure precision accuracy ruggedness Written and approved specific test method Proficiency check Formal acceptance by new laboratory Analytical method transfer: An analytical method may need to be transferred from, say Research and Development laboratory, to the QC laboratory. This should: require documented evidence of method transfer require a method transfer protocol and procedure The protocol should address performance parameters: - precision - accuracy - ruggedness Documentation must be written and approved for the specific test method before the transfer is verified. Proficiency: The method must be followed by the new laboratory without input (or coaching - since any training must already have been given) from the originator laboratory. There should be three assays in the new laboratory which are compared to originator’s results. Formal acceptance is then required by the new laboratory’s management.

Chemical laboratory validation requirements (1)
QC related validation Chemical laboratory validation requirements (1) Balances Chromatography HPLC, HPTLC, GC, TLC Dissolution or disintegration apparatus Karl Fischer moisture determination Melting, softening or freezing point apparatus Ovens, refrigerators, incubators Chemical laboratory validation requirements: (Note to trainer: The trainer should discuss the PQ requirements of laboratory instruments, including calibration. When should it be done? And how? The list below should be checked in the laboratory and the requirements listed should be used by the trainer to stimulate discussion.) Balances: IQ and OQ, linearity, range, precision, accuracy. Chromatography: HPLC, HPTLC, GC, TLC: IQ and OQ plus - e.g. pump for solvent delivery – ripple, pressure, leaks; injector sample delivery precision; detector checks (eg variable UV, Refractive Index (RI) or diode array); and computer validation. Dissolution or disintegration apparatus: IQ, OQ and calibration. Computer validation if relevant. Karl Fischer: IQ, OQ. Computer validation if relevant. Melting, softening or freezing point apparatus: IQ, OQ. Check against calibrators. computer validation if relevant. Ovens, refrigerators, incubators, furnaces: IQ, OQ, heating time, cooling, thermal mapping. Data loggers may need computer validation.

Chemical laboratory validation requirements (2)
QC related validation Chemical laboratory validation requirements (2) pH meter Polarimeter - optical rotation Refractometer Spectrophotometer UV/Vis, IR, FTIR, Raman, AA Timers Viscometer Volumetric equipment Chemical laboratory validation requirements: (Contd.) (Note to trainer: The list below should be checked in the laboratory and the requirements below should be used by the trainer to stimulate discussion.) pH meter: IQ, OQ, linearity, stability, slope, temperature. Polarimeter: Optical rotation - IQ, OQ and calibration against quartz discs or sucrose, computer validation if required. Refractometer: IQ, OQ. Temperature stability, water bath IQ and OQ if relevant, precision and accuracy. Spectrophotometer: UV/Vis, IR, FTIR, Raman, Atomic Absorption (AA): IQ, OQ and calibration. Computer validation if required. Timers: IQ, OQ and calibration against National Time Standard. Viscometer: IQ, OQ and calibration. Volumetric equipment: Autotitrators, nonaqueous titration equipment: IQ, OQ and linearity, precision, accuracy. Computer validation if required. Volumetric Glassware: pipettes, burettes, volumetric flasks: IQ.

Typical validation of HPCL assay (1)
QC related validation Typical validation of HPCL assay (1) System suitability (performance check) system precision column efficiency symmetry factor capacity factor The system suitability tests are carried out during the method development phase, prior to method validation. These tests are designed to evaluate the performance of the entire system. It is done by analysing a “system suitability” sample, which consists of the main components, including impurities. This may also contain excipients, which may interfere with peaks of interest. The system suitability is evaluated in terms of the following parameters: - system precision - column efficiency (usually >2000) - symmetry factor (acceptance criteria 0.9 to 2.5) - capacity factor (acceptance criteria NLT 1.5)

Typical validation of HPLC assay (2)
QC related validation Typical validation of HPLC assay (2) Method validation specificity accuracy precision linearity robustness Following a system suitability test, the actual analytical method is then validated by checking: Specificity: by checking that the method is free of interference from excipients, impurities, etc. Accuracy: by checking that the method gives closeness to true results. Precision: by checking that the method is precise. Linearity: by checking that the method will produce results that are directly proportional to the concentration of analyte in the samples. Robustness: by checking that the method will withstand deliverate changes.

QC related validation Biological assays Can be difficult to "validate"
"Validity" on a case by case basis Strictly adhere to the Biological Testing monographs in pharmacopoeias Biological assays: Biological Method Validation: Examples are rabbit pyrogen testing. The principles and performance parameters listed in the general monograph in the various pharmacopoeias for method validation can be applied to biological assays systems. However, it can be difficult to "validate" a biological assay using the characteristics previously described. Biological systems contain a larger variability than a chemical or physical test system. It is not realistic to apply the same acceptance criteria to biological systems since it is not possible to totally define all the key factors that affect the assays let alone control them. Validation is still a critical issue with biological systems. Consequently, there must be good assay design, elimination of systematic bias and “built-in” validity. "Validity" is assessed on a case-by-case basis: validation design should include the following: The assay is performed in triplicate; The assay includes three different dilutions of the standard preparation and three dilutions of sample preparations of activity similar to that of the standard preparation; The assay layout is randomised; ideally the analyst should be “blinded” to sample and location on the matrix; If the test sample is presented in serum or formulated with other components, the standard is likewise prepared. Lastly, the biological testing monographs in pharmacopoeias must be strictly adhered to with no deviations permitted.

Microbiological testing requiring validation
QC related validation Microbiological testing requiring validation Microbial limit testing Microbial count Sterility testing Preservative effectiveness testing Environmental monitoring program Biological testing Microbiological methods also need validation. In each microbiological testing laboratory, the types of methods which must be validated or verified include: Microbial limit testing - such as limit tests for indicator organisms, nominated in pharmacopoeias (BP/EP and USP specify strains of Escherichia coli, Staphylococcus aurens, Pseudomonas aeruginosa and Salmonella typhimurium). Microbial count - such as total viable aerobic counts of starting materials and finished products. Sterility testing Preservative effectiveness testing Environmental monitoring program - such as water, air and surface monitoring Biological testing - such as large plate assays for vitamins or antibiotics.

Validation of microbial test procedures (1)
QC related validation Validation of microbial test procedures (1) Virtually impossible to completely validate test procedures for every microorganism Neutralize /inactivate inhibitory substances, or dilute Periodic media challenge Media QC Reliable methods Validation of microbial test procedures: According to some people it is conceded that it is virtually impossible to completely validate test procedures for every microorganism that may be objectionable. Methods are, however, generally validated for recovery of specified indicator organisms nominated by pharmacopoeias and which generally are required to be absent from the product. Test method validation demonstrates that any inhibitory substances present in the sample have been neutralized/inactivated or diluted to a sub-inhibitory level. It involved inoculation of culture media with low levels of specified indicator organisms, in the presence and absence of the product/material to be tested. The capability of the media to promote the growth of organisms may be affected by the media preparation process, sterilization and storage procedures. The age of the culture media may affect growth promotion and selective properties of the media. For this reason, the shelf-life of culture media should be validated, and media not used beyond its expiry. All batches of prepared culture media should be subject to QC to ensure media is suitable for its intended purpose. Methods that the manufacturer selects must be able to reliably detect the presence of objectionable organisms such as Pseudomonas species, fungi, Escherichia coli, etc.

Validation of microbial test procedures (2)
QC related validation Validation of microbial test procedures (2) Incubation temperature and time Media may not grow all microorganisms Variations in media may affect recovery Inhibitory disinfectants or preservatives Sample procedures handling, storage, transport Validation of microbial test procedures: (Contd.) The following parameters and reasons to validate microbiological methods include the facts that: Incubation temperature and time may not support the growth of all organisms. A classic example is demonstrated by water where the natural flora grow better at temperatures below 30oC, and for a longer period than is normally given other samples - up to or greater than 5 days. Media may not support the growth of all organisms. The use of Tryptic Soya Agar for water analysis may underestimate the microflora by up to 3 logs depending on time and temperature compared to say R2A or Plate Count Agar. Variations in media may affect recovery. For example, a recall of a product containing pseudomonas was necessary when media beyond its shelf life was used to screen for the objectionable microorganism. Disinfectants or preservatives may inhibit growth. Water with chlorine (even low levels) should have sodium thiosulphate added to the sample container to immediately neutralize the free chlorine. Sampling procedures, sample handling and transport may affect test results. If the sample is contaminated when the sample is drawn, or very long storage and very hot or cold storage temperatures are used, then the sample will be affected. A cold chain may need to be demonstrated if the laboratory is a long way from where the sample is drawn.

Microbiological viable count method validation (1)
QC related validation Microbiological viable count method validation (1) Methods pour plate / spread plate membrane filtration Most Probable Number Sample size Test dilution Inoculation size Microbial viable count method validation: Methods commonly used - Pour plate or spread plate method at optimum dilution. Dilutions allowed to determine optimum 1:10 but generally no more than 1:100. - Membrane filtration method – is prefered for filterable products. - Most Probable Number – MPN, is generally the least accurate method for microbial counts. However, for certain product groups with very low bioburden where membrane filtration is not an option, it may be the most appropriate method. Sample size and dilutions The sample size should be of the order of 10g or 10mL although 1 – 5 g may be used for smaller lots. Test solution and dilutions must be specified. Use within a certain maximum period of time from preparation must be part of the validation. Challenge organisms for validation Use the organisms from a recognized type culture collection recommended by pharmacopoeias. Staphylococcus aureus Bacillus subtilis Escherichia coli Candida albicans Aspergillus niger Challenge inoculum 10 –100 cfu total inoculated at 0.1ml to 100mL test solution. Organisms to be separately challenged and not mixed in one test

Microbiological viable count method validation (2)
QC related validation Microbiological viable count method validation (2) Membrane filtration conditions Incubation conditions Acceptance criteria Microbial viable count method validation: (Contd.) Membrane filtration (MF) conditions Filter must be sterile with a hydrophobic edge if substances with antimicrobial agents are present. The mean pore size should be 0.45 micrometer not 0.2 micrometer because 0.2 causes inhibitory effects called mean pore diameter paradox. Solutions are also much slower to filter through a 0. 2 micrometer filter and can cause problems if filtering viscous liquids. The number of washes must be validated especially for solutions with inhibitory substances present. Incubation conditions During test method validation, visible evidence of growth of the bacterial challenge organisms should be evident within 48 hours after incubation at 30°-35°C. Visible evidence of growth of fungal challenge organisms should be evident within 3-5 days after incubation at 20°-25°C. During performance of the actual viable aerobic count test, the incubation conditions for the aerobic bacterial count should generally be 30°-35°C for 5 days and for the fungal count, 20°-25°C for 5 days. Acceptance criteria Recovery compared to positive control. For satisfactory validation of the total viable aerobic count method the BP/EP require challenge organism recovery counts to differ by not more than a factor of 5 from the control counts; the USP requires at least a 70% recovery rate.

Sterility testing validation requirements
QC related validation Sterility testing validation requirements Media growth promotion, sterility, pH Product validation Stasis testing Environmental monitoring Negative controls Challenge organisms Sterility test validation requirements: The official sterility test must be validated against each product since inhibitory substances, even when present at very low levels, may stop a contaminant growing within the prescribed time. Sterility testing validation requirements include: The media must be competent before use. That is, each batch of sterilized media should be tested for growth promotion (fertility test), sterility and pH. Product validation; by spiking a low level of challenge organisms and demonstrating clear, visible evidence of growth within 3 days for bacteria and 5 days for fungi. “Stasis testing” at the end of the incubation period to demonstrate that culture media supports growth for the full period. Note that this is not a mandated requirement, but is recommended as part of Good Laboratory Practice (GLP). Environmental monitoring of sterility test environment must be satisfactory; settle plates and operator checks should be performed. Negative controls are required to demonstrate that the analyst has the necessary dexterity to carry out the test manipulations properly. Usually the negative control is double sterilized product but its choice should also reflect the manipulations required for the test sample. Negative controls are usually conducted before and after a testing session. The challenge test organisms are: Staphylococcus aureus, Bacillus subtilis, Pseudomonas aerugihosa, Aspergillus niger, Clostridium sporogenes, and Candida albicans. For each challenge organism, the inoculum level is CFU. Validation tests using live microorganisms must not be undertaken in the sterility testing area.

Personnel - Validation team members
Quality Assurance Engineering Manufacturing Other disciplines may be involved depending on the product and process: laboratory, technical services research and development, regulatory affairs clinical chemical engineering purchasing/planning Personnel - Validation team members: A competent validation team is a multi-disciplinary team comprising: Quality Assurance Mechanical engineering Manufacturing Other disciplines may be involved depending on the product and process, eg: - Laboratory - Technical services (calibration, electrical, plumbing) - Research and development - Regulatory affairs - Clinical - Chemical engineering - Purchasing/planning

Protocol development (1)
Validation Protocol development (1) Identification of process Objective and measurable criteria Length and duration of the validation Shifts, equipment Identification and quality of utilities Identification of operators and operator training and qualification Protocol development: Detailed protocols for performing validations are essential to ensure that the process, whether solid dose, liquid or sterile, is adequately validated. Process validation protocols should include: Identification of process: Objective and measurable criteria for a successful validation - Determine WHAT to verify and measure - Determine HOW to verify and measure - Determine HOW MANY to verify and measure, i.e. what statistical test of significance will be applied and what will be the confidence in the result? - Determine WHEN to verify and measure - Define acceptance AND rejection criteria - Define the required level of documentation Length and duration of the validation: Challenges to the process should simulate conditions encountered during actual manufacturing. Challenges should include the range of conditions as defined by the various action levels. Shifts, equipment to be used in the process: This is most important for sterile manufacturing especially aseptic filling and lyophilization. Identification of utilities (air, water, gas, nitrogen, vacuum, etc.) for the process equipment and quality of the utilities Identification of operators and required operator training and qualification

Validation Protocol development (2) Complete description of the process Relevant specifications and tests Samples and sampling methods Special controls or conditions Process parameters to be monitored Methods for controlling and monitoring Protocol development: (Contd.) This continues the protocol development which is common for liquids, solid dosage forms such as tablets and capsules, and sterile products being manufactured using moist or dry heat: Complete description of the process Relevant specifications that relate to the product, ingredients, manufacturing methods, etc. Utilization of standard test methods such as those contained in international or national standards will provide guidance on how to measure specific parameters. Samples and sampling methods Any special controls or conditions to be placed on preceding processes during the validation Process parameters to be monitored, and methods for controlling and monitoring

Validation Protocol development (3) Objective and subjective criteria used to evaluate the product Definition of non-conformance Statistical methods Maintenance and repairs Criteria for revalidation Criteria for change control Protocol development: (Contd.) This continues the protocol development which is common for liquids, solid dosage forms such as tablets and capsules, and sterile products being manufactured using moist or dry heat: Any objective or subjective criteria used to evaluate the product Definition of what constitutes non-conformance for both measurable and subjective criteria (such as odour, appearance, taste) Statistical methods for data collection and analysis Consideration of maintenance and repairs of manufacturing equipment Criteria for revalidation Criteria for change control

GMP Inspector’s check list for validation (1)
Check that the manufacturer has: A VMP and multi-functional team for validation Planned approach, defined requirements Identified and described processes Analyse the amount of validation work to perform Check list for validation: This is a list of activities which may be used as a checklist to review validation activity. The manufacturer should: Create a master validation plan: as described in Part 1. Form a multi-functional team for validation: as described in Part 1. Plan the approach, and define the validation requirements. Identify and then describe the processes. Specify the process parameters and desired output. Analyse the amount of validation work to perform. It is most important that the inspectorate and the manufacturer agree on the risk involved and the extent of validation. High risk products, such as biologicals derived from human blood must be at one end of the scale (requiring considerable validation effort), while at the other end may be very simple, low risk, over- the-counter medicines requiring less validation.

Validation GMP Inspector’s check list for validation (2)
Check that the manufacturer has: Selected methods and tools for validation Created protocols Performed DQ, IQ, OQ, PQ and documented results Exerted change control, set revalidation time Check list for validation: (Contd.) This is a continuation of the list of activities which may be used as a checklist to review validation activity. The manufacturer should: Select methods and tools for validation Create validation protocols Perform DQ, IQ, OQ, PQ and document results Exert change control and set revalidation time or frequencies

Validation: summary Validation A quality tool that makes sense
A prevention-based activity Expensive In danger of becoming overwhelming Risk-based assessment of what needs to be validated or verified The process must be under control Summary Validation is a quality tool to ensure that quality is designed into a process. Validation is a requirement that has always made sense from both a regulatory and quality perspective. Validation is regarded as a prevention-based activity: if more effort is placed on development and validation at the beginning, then there will be less chance of failure during the product’s life. Validation is expensive, a growth industry and in danger of becoming overwhelming for many pharmaceutical manufacturers, particularly those in developing nations. The result may be not to complete any validation work at all. However, the risk-based assessment and determination of critical steps of manufacture should be used to identify what needs to be validated, and what can be simply verified, by testing if needs be. A key statement is: “The process must be under control”; that is, by quality terms, it must be a capable process. Juran defines process capability as "the measured, inherent reproducibility of the product turned out by a process.” In validation the manufacturer is trying to measure reproducibility and establish that the variability falls within pre-established confidence limits. Suggested Reading: J. M. Juran and Frank M. Gryna, eds., Juran's Quality Control Handbook, 4th Edition, McGraw-Hill, Inc, 1988.

We are now validated!

Exam topics

Validation and Qualification in GMP
Definitions. What is their difference? Their importance Describe the 3 process validation types Describe the 4 qualification types Validation documentation (special emphasis to VMP) What is change control, why to do it?

Validation of clening processes and analytical procedures in GMP
Cleaning validation Its 2 targets How to perform it (examples) Analytical method validation List the main method characteristics Classes of testing for validation Analytical instrument validation (examples) Microbiology

Basic Principles of GMP

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