gmp validation

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SUPPLEMENTARY GUIDELINES ON

GOOD MANUFACTURING PRACTICES (GMP):

VALIDATION 1. INTRODUCTION Validation is an essential and integral part of Good Manufacturing Practice (GMP). It is, therefore, an element of the quality assurance programme associated with a particular product or process. It is accepted that the basic principles of quality assurance have as their goal the production of products that are fit for their intended use. These principles may be stated as:

(1) quality, safety and efficacy must be designed and built into the product; (2) quality cannot be inspected or tested into the finished product; and (3) 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. It is by design and validation of both process and process controls that a manufacturer can establish confidence that all manufactured products from successive lots will be acceptable. The documentation associated with validation includes:

- a quality manual - Standard Operating Procedures (SOPs) - specifications - Validation Master Plan (VMP) - validation and qualification protocols - validation and qualification reports

The implementation of validation work requires considerable resources in terms of:

- time: generally validation work is submitted to rigorous time schedules; - finance: validation studies require time of highly specialized personnel and expensive

technology; and - personnel: collaboration of experts of various disciplines. A good validation team is

a multidisciplinary team, comprising quality assurance, engineering, manufacturing, and other disciplines, depending on product and process.

This guideline aims to give guidance to inspectors of pharmaceutical manufacturing facilities on the requirements for validation, the design of a validation protocol, recording of validation data and implementation of a system based on the outcome of the validation report.

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2. GLOSSARY The definitions given below apply to the terms used in this guideline. They may have different meanings in other contexts. Calibration The performance of tests and retests to ensure that measuring equipment (e.g. for temperature, weight, pH) used in a manufacturing process or analytical procedure (in production or quality control) gives measurements that are correct within established limits. Computer validation Documented evidence which provides a high degree of assurance that a computerized system records data correctly and that data processing complies with predetermined specifications. Concurrent validation Validation carried out during routine production of products intended for sale. Cleaning validation Documented evidence to ensure that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration i.e. batch size, dosing, toxicology, equipment size, etc. Design qualification (DQ) Documented evidence that the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements of GMP. Installation qualification (IQ) IQ is the documentary evidence to verify that the equipment has been built and installed in compliance with design specifications. Operational qualification (OQ) OQ is the documentary evidence to verify that the equipment operates in accordance with its design specifications in its normal operating range and performs as intended throughout all anticipated operating ranges. Performance qualification (PQ) PQ is the documentary evidence which verifies that the equipment or system operates consistently and gives reproducibility within defined specifications and parameters for prolonged periods. (The term “process validation” may also be used.) Process validation Documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics.



Prospective validation Validation carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on the basis of past experience to determine whether they may lead to critical situations. Qualification Qualification is the planning, carrying out and recording of tests on equipment and systems, which form part of the validated process, to demonstrate that it will perform as intended. Retrospective validation Involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged. Re-validation Involves the repeat of the initial process validation to provide assurance that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality. Validation Documented series of actions that prove that any procedure, process, equipment, material, activity or system performs its intended functions adequately and consistently, and lead to the expected results of uniform batches that meet the required specifications and quality attributes. Validation Protocol (VP) The VP is a written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment and decision points on what constitutes acceptable test results. Validation Report (VR) The VR is a written report on the validation activities, the validation data and the conclusions drawn. Validation Master Plan (VMP) VMP is a high level document that establishes an umbrella validation plan for the entire project and summarizes the manufacturer’s overall philosophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturer’s validation work programme and defines details of and time-scales for the validation work to be performed, including stating the responsibilities relating to the plan. Worst case A condition or set of conditions encompassing upper and lower processing limits and circumstances, within SOPs, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily include product or process failure.



3. SCOPE OF DOCUMENT The guideline focuses mainly on the overall concept of validation and is intended as a basic guide for use by GMP inspectors. It is not very prescriptive in specific validation requirements. There are many parameters affecting the different types of validation and it is, therefore, difficult to define and address all aspects related to one particular type of validation. Manufacturers should realistically set their validation parameters for each project, with the view to create a cost-effective process, yet still complying with all the regulatory standards and ensuring that product quality, safety and uniformity are not compromised. The aspects addressed in this guideline include the validation team, validation master plan, types of validation and change control associated with validation. 4. VALIDATION 4.1 Approaches to validation There are two basic approaches to validation - the experimental approach and an approach based on the analysis of historical data. The experimental approach, which is applicable to both prospective and concurrent validation, may involve:

- extensive product testing, which may involve extensive sample testing, with the estimation of confidence limits for individual results and batch homogeneity;

- simulation process trials, which involve mainly aseptic sterilization with the target contamination level of microbial growth not exceeding 0.1%;

- challenge/worst case tests, which determine the robustness of the process; and - controls of process parameters being monitored during normal production runs to obtain

additional information on the reliability of the process. The approach based on the analysis of historical data, which is applicable to retrospective validation, combines all available historical data of a number of batches with the outcome of the results, indicating whether the process is under control. No experiments are performed. Retrospective validation is not applicable to the manufacturing of sterile products. 4.2. Scope of validation Validation is not considered to be a one-off process.



Validation requires meticulous preparation and careful planning of the various steps in the process. All work involved should be carried out in a structured way according to the documented procedures to ensure that the set objectives are met. The accumulation of documentary evidence relating to a process, item of equipment, or facility is achieved by means of a validation protocol which should exist for every product and which details the tests to be carried out, and the accumulation and review of data against agreed acceptance criteria. Validation should be performed for new processes and new equipment, and when major changes have been made or implemented to premises, systems, equipment, materials and/or processes. When any new manufacturing formula or method of preparation is adopted steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality. In this phase the extent to which deviations from the chosen processing parameters can influence product quality should also be evaluated. In general the final batch size should not be more than 10 times the batch size of the representative development batches. Validation in the production unit mainly comprises the determination and evaluation of the process parameters applied for the scale-up to final batch size. The control of all critical process parameters, results of the in-process controls, final controls and stability tests should prove the suitability of the important individual steps of a procedure. At least three batches (including at least two production batches in the final batch size) should be validated, to show consistency. Worst case situations should be considered. When certain processes or products have been validated during the development stage it is not always necessary to re-validate the whole process or product if similar equipment is used or similar products have been produced, provided that the final product conforms to the in-process control and final product specifications. There should be a clear distinction between in-process controls and validation. In-process tests are performed each time on a batch-to-batch basis, using specifications and methods devised during the development phase. The objective is to monitor the process continuously. Validation can be prospective, concurrent, or retrospective, depending on when validation is performed. A written report should be available after completion of the validation. The results should be evaluated, analysed and compared with acceptance criteria. All results should meet the criteria of acceptance and satisfy the stated objective. If necessary further studies should be performed. If found acceptable the report should be approved and authorized (signed and dated). Levels where validation and qualification must be performed should be established, with the type of product to be validated, determining the intensity of the validation. Normally it should be least for liquid preparations (solutions) and most for parenteral preparations, and for solid dosage forms it should depend on the criticality of the product to the patient.



4.3 Benefits of validation Processes consistently under control require less process support, will have less down time, fewer batch failures, and may operate more efficiently, with greater output. In addition timely and appropriate validation studies will transmit a commitment to product quality, which may facilitate pre-approval inspections and expedite the granting of marketing authorizations. Successfully validating a process may reduce the dependence upon intensive in-process and finished product testing. 5. QUALIFICATION Validation and qualification are essentially the same concept. Qualification is considered to be the act of planning, carrying out and recording the results of tests on equipment to demonstrate that it will perform as intended. Qualification should be completed before process validation is performed. The process of qualification is a logical, systematic process and should start from the design phase of buildings, equipment and instruments. There should be a specific programme for qualification of equipment

For systems and equipment performance qualification (PQ) is often synonymous with validation. Depending on the function and operation of some equipment, only installation qualification (IQ) and operational qualification (OQ) would be required, as the correct operation of the equipment could be considered to be a sufficient indicator of its function (refer to Section 12 for IQ, OQ and PQ). (The functions should then be monitored and calibrated according to a regular schedule.)

Major equipment and critical systems, however, require IQ, OQ and PQ. 6. CALIBRATION AND VERIFICATION Regular calibration, validation and verification of all equipment, instruments and other devices used to measure the physical properties of substances, must be performed at regular intervals according to the SOPs (having regard to the extent to which they are used). The following are some examples:

- balances; - infrared spectrophotometers; and - HPLC. A calibration programme should be available. Equipment should be listed, together with the following information for each piece of equipment: calibration standards and limits, responsibilities for performing calibration, intervals



between calibration, record-keeping requirements and logs, and actions to be taken when problems are identified.

After calibration each piece of equipment, instruments and other devices under the control of the laboratory, and requiring calibration, should be labelled, coded or otherwise identified to indicate the status of calibration and the date when re-calibration is due. When the equipment, instruments and other devices are outside the direct control of the laboratory for a certain period of time, the laboratory should ensure that their function and calibration status are verified and shown to be satisfactory before they are taken into service again. There is a link between equipment calibration and preventative maintenance. Preventative maintenance assures that the equipment is in good working condition within calibration intervals. Personnel who provide calibration and preventative maintenance should have appropriate training. 7. VALIDATION TEAM In compliance with Good Validation Practice requirements, a validation team and validation steering committee should be appointed which will be responsible for the policy and performance of all validation respectively. The validation team should consist of a representative from at least the following sections of the company: - Regulatory Affairs; - Quality Assurance; and - Finance, The validation team should meet regularly, in accordance with a defined schedule, to discuss issues relating to validation and to assess progress and compliance with the validation plan and schedule. The validation team should maintain records of the meetings and should inform management of progress in terms of the validation plan and schedule. The validation team should be responsible for liaison with any third party contract acceptors and for approving or rejecting all validation protocols and reports. The team should make the final recommendation regarding the performance of validation, the type of validation, and the acceptance of the reports and recommendations by the validation steering committee. The validation steering committee should consist of members of staff who are responsible for the act of performing the validation in the different sections on site. The steering committee should,



at regular intervals, report to the validation team on progress made regarding the performance of the validation. 8. VALIDATION MASTER PLAN (VMP) 8.1 General requirements The Validation Master Plan (VMP) complements the manufacturer’s site master file and should be the first document to be reviewed during inspection by a regulatory authority. The VMP reinforces the commitment of the company to GMP. It is a formal policy document which describes the overall philosophy of the company towards validation and which also describes the key elements of the validation programme, organizational structure of validation, schedules and responsibilities. It should describe: “Why, what, where, by whom, how and when?”. The VMP should direct to the more specific, detailed documents such as protocols, reports and documentation preparation and their control, SOPs, and personnel training records. The VMP should identify which systems, facilities, equipment and processes are subject to validation, the nature and extent of such testing and the applicable validation and qualification protocols and procedures. It should outline the test procedures and protocols to be followed to accomplish validation. It should serve as a guide to the validation team, steering committee and personnel who are responsible for implementing the validation protocols, and should be a source document to identify tasks and responsibilities and should assist regulatory inspectors to understand the manufacturer's approach to validation and how the validation activities are organized and managed. It should help management to know what the validation programme involves with respect to time, people and money, and to understand the necessity for the programme. 8.2 Specific requirements The VMP should be concise and should typically include the following: - table of contents; - introduction, policy and objectives; - description of facilities, including plans; - constitution of the validation committee; - glossary of terms; - description and history of equipment; - description and listing of protocols; - preventative maintenance programme; - personnel training programme; - process and cleaning validation;



- laboratory instrument qualification; - analytical method validation; - facility/utility qualification; - computer system validation; - re-validation intervals; - new process cycles validation; - reasonable unexpected events (worst case), e.g. power failure, computer crash and recovery,

filter integrity test failure; - key acceptance criteria; - documentation format to ensure a systematic approach to the layout and format of these

documents, e.g. training record, raw data retention record, calibration record, validation protocol, validation report, etc.;

- list of relevant SOPs (how?); - planning and scheduling (when?); - location where the validation activity is to be performed (where?); - estimate of staffing requirements to complete the validation effort described in the plan

(who?); - time plan for the project, showing detailed planning of sub-projects (when?); - change control identifying the company’s commitment to controlling critical changes; and - approvals. 9. VALIDATION PROTOCOL The Validation Protocol (VP) should clearly describe the procedure to be followed for performing validation. The VP should include at least significant background information, the objectives of the validation and qualification study, site of the study, the responsible personnel, description of SOPs to be followed, equipment (including calibration before and after validation), standards and criteria for the relevant products and processes, the type of validation, and frequency. 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. Pre-determined acceptance criteria for drawing conclusions should be provided, as well as a description on how the results will be analysed.



10. VALIDATION REPORT A written report (VR) should be available after completion of the validation. The report should include the title and objective of the study, and should refer to the protocol, details of material, equipment, programmes and cycles used, procedures and test methods. Recommendations on the limits and criteria to be applied to all future production batches, which should form part of the basis of the future batch manufacturing document, should be included. The results should be evaluated, analysed and compared with the acceptance criteria. All results should meet the criteria of acceptance and satisfy the stated objective. If necessary further studies should be performed. If found acceptable the report should be approved and authorized (signed and dated). 11. RELATIONSHIP BETWEEN VALIDATION AND QUALIFICATION Validation and qualification are essentially the same concept. Validation is the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results. Qualification is the act of planning, carrying out and recording of tests on equipment and systems, that form part of the validation process, in order to demonstrate that it will perform as intended. Validation, therefore, refers to the overall concept of validation, including process validation, while qualification refers to the validation part of equipment and systems. In this sense, qualification is part of validation. The scheduling of validation should only be done once qualification is complete. Validation is, therefore, a multifaceted activity that relates to various aspects, of which some are summarized below. 11.1 Premises Manufacturing and packing facility premises should be subjected to qualification as part of validation, where relevant. In areas where required, such as sampling and dispensing rooms, room qualification should be performed. Some of the basic criteria to be considered during room qualification should include:



- building finish and structure; - air filtration; - air change rate or flushing rate; - room pressure; - location of air terminals and directional airflow; - temperature and humidity; - material and personnel flow; and - equipment movement. 11.2 Systems The prevention of contamination and cross-contamination is an essential design consideration of the architectural components of the manufacturer and should be considered at the design stage of the facility. Supporting facilities should be subjected to the different stages of qualification (e.g. Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ)) and should be recorded. Supporting facilities/systems include waste systems, e.g. process drain systems, hazardous waste, solid waste disposal systems, air handling systems such as Heating Ventilation and Air Conditioning (HVAC), air filtration, laminar flow hoods, water systems such as RO water; gas systems such as compressed air, gas supply (nitrogen, oxygen and other gases), and electrical systems such as electrical emergency power and back-up power. All supporting systems should have been validated before a specific system is subjected to PQ, e.g. the steam system should be validated before the autoclave is validated. A realistic approach to differentiating between critical and non-critical parameters should be followed. Systems and components, which are non-critical components, should be subject to Good Engineering Practice (GEP) reviews in lieu of OQ and PQ. There should be a relationship between the design conditions, operating range and validated acceptance criteria (action limits and alert limits). During system OQ all parameters should fall within the design condition range. However, during normal operating procedures it is acceptable for the conditions to fall out of the design conditions range, but they should remain within the operating range. Re-qualification of parameters should be done at regular intervals, e.g. at least annually.



11.2.1 Heating, Ventilation and Air Conditioning (HVAC) system The HVAC system plays an important role in product protection, personnel protection and environmental protection. For all HVAC installation components, sub-systems or parameters, critical parameters and non-critical parameters should be determined. If the component comes into direct contact with the product, or if the parameter affects the quality of the drug product, it should then be classified as a critical parameter. Some of the typical HVAC system parameters that should be qualified include: - room temperature and humidity; - supply air and return air quantities; - room pressure, air change rate, flow patterns, particle count and clean-up rates; and - laminar flow velocities and HEPA filter penetration tests 11.2.2 Water system All water-treatment systems should be subject to planned maintenance, validation and monitoring. Validation of water systems should consist of at least three phases: • Phase 1: Investigational phaseDuring the first 2-4 weeks of the commissioning of the plant the DQ, IQ and OQ should be performed. Operational parameters should be established and the cleaning and sanitization procedures, including frequencies for cleaning and sanitization, should be determined. Daily sampling should be performed at each point of use. On completion of the phase the SOP for the water system should be developed. • Phase 2:Short-term control

During the following 4-5 weeks the control of the system should be verified. Sampling should be performed as during Phase 1. • Phase 3: Long-term controlDuring the following year the objective should be to demonstrate that the system is in control over a long period of time. Sampling may be reduced to weekly.The validation performed and re-validation requirements should be included in the Water Quality Manual.



11.3 Equipment Requirement for qualification should be applied to equipment used in production as well as in quality control laboratories. The Design Qualification (DQ) should define the functional and operational specifications of the instrument and should detail the conscious decisions in the selection of the supplier. Prior to use and to ensure that the equipment is fit for its intended use the different stages of qualification should be performed, e.g. IQ, OQ, and PQ (refer to Section 12 for detail). In addition, the equipment should be well maintained and routinely calibrated. Certain stages of the equipment qualification may be done by the supplier or a third party. Each major piece of equipment should have a logbook which should detail at least, the supplier’s name, module, model and serial number, date of installation, all qualification performed, maintenance performed and reference to records, and routine use. 11.4 Processes Production processes should be validated. Process validation should only begin when qualification is complete. Process validation should be organized and administered in the same way as qualification. It should be associated with the writing and issuing of process validation protocols, and the accumulation and review of data against agreed acceptance criteria. The level of validation should reflect the complexity of the process. The critical process parameters should be defined during the course of pre-formulation, pharmaceutical development and scale-up studies, and the validation protocol should challenge and explore them. Prospective, concurrent or retrospective validation may be applied. Re-validation should be performed as identified per schedule and product (refer to Section 13 for detail). In some cases process validation may be conducted concurrently with performance qualification, for example, where an item of equipment is dedicated to one process producing one product. 11.5 Procedures 11.5.1 Analytical method Analytical results should be accurate and reproducible. Critical factors that should be validated include:



- specificity; - accuracy; - precision; - recovery; - linearity; - system suitability for chromatographic determination (refer to Section 15 for detail); and - robustness. The method may or may not be stability indicating. The validated analytical method from development should be transferred to quality control. Additional validation or re-validation studies may be required if equipment differs. 11.5.2 Packaging component Packaging material should be evaluated and selected for drug products to provide the required properties of compatibility, stability, security and sterility. Their validation should be considered as part of the process validation of the product. 11.5.3 Cleaning validation Validation of cleaning methods is an important element of qualification and process validation for drug substances and drug product manufacture (refer to Section 16 for detail). The establishment of acceptance criteria for contaminant levels in the sample should be practical and achievable. Each situation should require individual assessment. However, it is often considered that a cleaning procedure, that consistently reduces the contaminants to a level not exceeding one-thousandth of its lowest daily therapeutic dose in the highest daily therapeutic dose of the product, can be regarded as validated. Worst case situations should be investigated. Cleaning validation should be documented either as part of an OQ or process validation protocol, or separately if appropriate. 11.6 Computer systems validation Computerized systems should be considered as equipment. A written validation plan should be available. Specifications should be identified and design review should be performed. The system should be tested (IQ, OQ and PQ should be performed and documented). Results should be reviewed, and validation outcome concluded (refer to Section 14 for detail). 12. QUALIFICATION STAGES



There are different stages in the performance of qualification. These include: - Design Qualification (DQ); - Room Qualification (RQ); - Installation Qualification (IQ); - Operational Qualification (OQ); - Performance Qualification (PQ); and - Re-Qualification (RQ). The qualification protocol should provide the specific procedure to be followed, the acceptance criteria, list of materials, equipment and documentation needed to perform the validation. 12.1 Design Qualification Design Qualification (DQ) constitutes the assurance that the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements of GMP. 12.2 Installation Qualification Installation Qualification (IQ) is associated with the performance of tests to ensure that the installation of machines, measuring devices, utilities and manufacturing areas used in the manufacturing processes are: - appropriately selected; - correctly installed; and - will be operating in accordance with the established specifications. An IQ protocol should be used to document the specific (static) attributes of a facility or item of equipment, in order to prove that the installation of the unit has been correctly performed and that the installation specifications of the manufacturer have been met. The IQ protocol should be numbered, dated, and approved for issue by appropriately authorized personnel. The IQ protocol should contain at least an introduction and objectives, plant inventory number, standard operating procedure number, purpose of the facility or equipment, design and construction details, details of services required and provided, addenda such as chart recorder traces, technical drawings, and acceptance criteria. The protocol should be written for all critical processing equipment and systems used within a manufacturing/packing/testing facility. It should list all the identification information, location, utility requirements and safety features of the equipment.

During the IQ process it should be verified that the item matches the purchase specification and that all the drawings, manuals, spare parts list, vendor address and contract numbers, and other important documentation are available.

The IQ data should be reviewed and approved before operational qualification commences.



12.3 Operational Qualification Operational Qualification (OQ) is associated with the performance of the equipment to ensure that the function of machines, measuring devices, utilities and manufacturing areas operate according to its operational specification in the selected environment. An OQ protocol is used to document specific (dynamic) attributes of a facility or item of equipment to prove that it operates as expected throughout its operating range. As with the IQ protocol, the OQ protocol should be numbered, dated and formally approved. Tests should be designed to demonstrate that the unit performs properly at the limits of its operating conditions, as well as within its normal operating range. Measurements made on a statistical basis should be fully described in the protocol. The OQ protocol should outline the information required to provide evidence that all the components of the system or equipment operate as specified. It should include verification of all the operation controls, alarm points, switches and displays. The protocol should reflect all SOPs for operation, maintenance and calibration, and training of operators. The OQ protocol should include an introduction and objective, identification information, visual inspection parameters, functioning of switches and indicator lights, check and calibration of sensors, probes, gauges, recorders, air flow rates, direction, pressures, temperatures, filter integrity and efficiency tests, cleaning procedures, details of qualification instrumentation used, acceptance criteria, actions resulting from the OQ (what to do when out-of-specification results are obtained), re-qualification time scales and triggering factors. The OQ data should be formally reviewed and approved before process validation can commence.

12.4 Performance Qualification

Performance Qualification (PQ) is done after both IQ and OQ have been completed, reviewed and approved. The PQ protocol describes the procedure to be followed for demonstrating that a system or equipment can consistently perform and meet required specifications under routine operation (or worst case conditions).

The PQ protocol may be used in cases where performance data are gathered over a long period of time. Under these circumstances, it may be difficult to “sign off” the operational qualification (OQ) as complete. One solution is to define and approve the OQ at a single point in time, and to create a PQ protocol which is then used as the vehicle for amassing the ongoing data.

12.4 Re-qualification



Equipment should be subject to re-qualification in accordance with a defined schedule. The frequency of re-qualification is dependent on the analysis of results relating to calibration, verification, and maintenance. Re-qualification is subdivided into periodic re-qualification, and re-qualification after change. These changes include adaptation of equipment, maintenance, movement and repairs (refer to Section 17 for detail). 12.5 Qualification report A written report should be available after completion of the validation/qualification. The results should be evaluated, analysed and compared with acceptance criteria. All results should meet the criteria of acceptance and satisfy the stated objective. If necessary further studies should be performed. The report should include the title and objective of the study, reference to the protocol, details of material and equipment, programmes and cycles used, details of procedures and test methods. The report should include a conclusion and recommendation as to the suitability of the equipment and whether the qualification was considered to be satisfactory. If found acceptable the report should be approved and authorized (signed and dated). 13. PROCESS VALIDATION By definition process validation requires the accumulation of documentary evidence relating to a process. Types of process validation include: - prospective validation; - concurrent validation; and - retrospective validation. 13.1 Prospective validation Prospective validation is carried out during the development stage of a product. If the validation programme is designed and the protocol issued before the equipment or facility comes on stream, or before the product manufactured by the process being validated is distributed, then it constitutes prospective validation. It should be performed by means of a risk analysis of the production process which is broken down into individual steps. It should involve the establishment of 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.



Prospective validation is required for new manufacturing formulae or methods of preparation where the latter are adopted. Steps should be taken to demonstrate their suitability for routine processing. The purpose is to ensure that the defined process, using the materials and equipment specified, should be shown to yield a product that is consistently of the required quality. In this phase the extent to which deviations from the chosen processing parameters can influence product quality should also be evaluated. In general the final batch size should not be more than 10 times the batch size of the representative development batches. The process should include the identification and evaluation of individual steps, the identification of critical situations, design of trial plans and set of priorities, performance of trials and recording of results, and finally assessment and evaluation of results. If the results are unsatisfactory then the processes are modified and improved until acceptable results are obtained. This is essential to limit the risk and errors that may occur on production scale. 11.2 Concurrent validation Concurrent validation is carried out during normal production. This method of validation can only be successful if the development stage has resulted in a proper understanding of the fundamentals of the process. It is carried out during normal production of products intended for sale. It should involve close and intensive monitoring of the steps and critical points in at least the first three production scale batches. The results of in-process controls can be used to provide some of the evidence required for validation but these are no substitute for validation. Validation in the production unit mainly comprises of the determination and evaluation of the process parameters of the facilities applied for the scale-up to final batch size. The control of all critical process parameters, the results of the in-process controls, final controls and stability tests should prove the suitability of the important individual steps of a procedure.



11.3 Retrospective validation Retrospective validation is based on a review of historical manufacturing and testing data, and is the analysis of accumulated results from past production to assess the consistency of a process. It is assumed that the composition, procedures and equipment remained unchanged. During retrospective validation results of in-process and final control tests are evaluated. It should include trend analysis of test results and a close examination of all recorded process deviations. Quality control charts could be used when performing retrospective validation. A total of 10-25 batches (or more), manufactured over a period of 12 months, should be used when reviewing the results, to provide a statistically significant picture. Trend analysis should be conducted. Rejected batches should not be included in the analysis. Failure investigations should however, be performed separately. All difficulties and failures recorded should be analysed to determine limits of process parameters. Product-related problems should be analysed. These should include rejections, complaints, returns and unaccountable ADR. As retrospective validation is not considered to be a quality assurance measure it should not be applied to new processes or products. It is not the preferred method of validation and should be used in exceptional cases only. When the results of retrospective validation are positive it is considered to be an indication that the process is not in need of immediate attention, and may be validated later in accordance with the normal schedule. Steps during retrospective validation include: - choosing a critical quality parameter (e.g. assay value, unit dose uniformity, disintegration

time, dissolution); - extracting the analytical results from each batch (the results of a batch are grouped as

subgroups); - pooling the results from the batches; - calculating the grand average (process average) and control limits; and - plotting the results on graphs or charts. The process may be considered reliable if the plotted data are within the control limits and the variability of individual results is stable (or tends to decrease). Where the existing data are inadequate additional tests should be performed.



Acceptance criteria must be set before validation, and 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. 14. COMPUTER VALIDATION 14.1 General Computer systems should be validated in accordance with the level appropriate for their use and application. This is of importance in production as well as in quality control. The utilization of a computer system includes different stages. These are planning, specification, programming, testing, commissioning, document operation, monitoring and modifying. The purpose of computer system validation is to ensure a degree of evidence (documented, raw data), confidence (dependability and thorough, rigorous achievement of predetermined specifications), intended use, accuracy, consistency and reliability. Aspects to be validated include both the system specifications and functional specifications. Periodic (or ongoing) evaluation should be performed after the initial validation. There should be written procedures for performance monitoring, change control, programme and data security, calibration and maintenance, personnel training, emergency recovery and periodic re-evaluation. Aspects of computerized operations that should be considered include: - networks; - manual back-ups; - input/output checks; - process documentation; - monitoring; - alarms; and - shutdown recovery. 14.2 System specification There should be a control document or system specification. The control document should contain the objectives of a proposed computer system, the data to be entered and stored, the flow of data, how it interacts with other systems and procedures, the information to be produced, the limits of any variable and the operating programme and test programme. [Examples of each document produced by the programme should be included.]



System elements in computer validation that need to be considered include hardware (equipment), software (procedures) and people (users). 14.3 Functional specification A functional or performance specification should provide instructions for testing, operating, and maintaining the system, as well as names of the person(s) responsible for its development and operation. The following general aspects should be kept in mind when using computer systems: location, power supply, temperature, and magnetic disturbances. Fluctuations in the electrical supply can influence computer systems and power supply failure can result in loss of memory. The following general GMP requirements are applicable to computer systems: - Verification and re-validation. (After a suitable period of running a new system it should be

independently reviewed and compared with the system specification and functional specification.)

- Change control. (Alterations should only be made in accordance with a defined procedure

which should include provision for checking, approving and implementing the change.) - Checks. (Data should be checked periodically to confirm that they have been accurately and

reliably transferred.) 14.4 Security This is of importance in production as well as in quality control. Data should only be entered or amended by persons authorized to do so. Suitable security systems should be in place to prevent unauthorized entry or manipulation of data. The activity of entering data, changing or amending incorrect entries and back-ups should all be done in accordance with written, approved SOPs. The security procedures should be in writing. Security should also extend to devices used to store programmes, such as tapes, disks and magnetic strip cards. Access should be controlled. Traceability is of particular importance and it should be able to identify the persons who made entries/changes, released material, or performed other critical steps in manufacture or control. The entry of critical data into a computer by an authorized person (e.g. entering a master processing formula) requires an independent verification and release of use by a second authorized person. SOPs should be validated for certain systems or processes, e.g. the procedures to be followed if the system fails or breaks down should be defined and tested. Alternative arrangements should



be developed by the validation team, and a disaster recovery procedure should be available for systems which need to be operated in the event of a breakdown. 14.5 Back-ups Regular back-ups of all files and data should be made and stored in a secure location to prevent intentional or accidental damage. 14.6 Validation Planning, which should include the validation policy, project plan and SOPs, is one of the steps in the validation process. The computer-related systems and vendors should be defined and the vendor and product should be evaluated. The system should be designed and constructed, taking into consideration the types, testing and quality assurance of the software. After installation of the system it should be qualified. The extent of the qualification should depend on the complexity of the system. The system should be evaluated and performance qualification, change control, maintenance and calibration, security, contingency planning, SOPs, training, performance monitoring and periodic re-evaluation should be addressed. 14.7 Validation of hardware and software The following summary indicates aspects of computer systems that should be subjected to validation:



Table 14.1. Summary of validation requirements for computer systems

HARDWARE SOFTWARE 1. Types

1.1 Input device 1.2 Output device 1.3 Signal converter 1.4 Central Processing Unit (CPU) 1.5 Distribution system 1.6 Peripheral devices

1. Level

1.1 Machine language 1.2 Assembly language 1.3 High level language 1.4 Application language

2. Key aspects

2.1 Location environment distance input devices

2.2 Signal conversion 2.3 I/O operation 2.4 Command overrides 2.5 Maintenance

2. Software Identification

2.1 Language 2.2 Name 2.3 Function 2.4 Input 2.5 Output 2.6 Fixed set point 2.7 Variable set point 2.8 Edits 2.9 Input manipulation 2.10 Programme overrides

3. Validation

3.1 Function 3.2 Limits 3.3 Worst case 3.4 Reproducibility/consistency 3.5 Documentation 3.6 Re-validation

3. Key aspects

3.1 Software development 3.2 Software security

4. Validation

4.1 Function 4.2 Worst case 4.3 Repeats 4.4 Documentation 4.5 Re-validation

14.7.1 Hardware As part of the validation process appropriate tests and challenges to the hardware should be performed. Static, dust, power feed voltage and electromagnetic interference could influence the system. The depth of validation should depend on the complexity of the system. Hardware is considered to be equipment, and focus should be placed on location, maintenance and calibration of hardware, as well as on validation/qualification.



The validation/qualification of the hardware should prove : - the capacity of the hardware matches its assigned function (e.g. foreign language); - that it operates within the operational limits (e.g. memory, connector ports, input ports); - that it performs under worst case conditions (e.g. long hours); and - reproducibility/consistency (e.g. at least three runs covering different conditions). The validation should be done in accordance with written qualification protocols and the results should be recorded in the qualification reports. Re-validation should be performed when significant changes are made. Much of the hardware validation may be performed by the computer vendor. However, the ultimate responsibility for suitability of equipment used remains with the company. Hardware validation data and protocols should be kept by the company. When validation information is produced by an outside firm, e.g. computer vendor, the records maintained by the company need not be all inclusive of voluminous test data; however, such records should be reasonably complete (including general results and protocols) so as to allow the company to assess the adequacy of the validation. A mere certification of suitability from the vendor, for example, will be inadequate. 14.7.2 Software Software is the term used to describe the total set of programmes used by a computer which should be listed in the menu or main menu. Records are considered as software with focus placed on accuracy, security, access, retention of records, review, double checks, documentation and reproduction accuracy. Identification The company should identify the following key computer programmes: language, name, function (purpose of the programme), input (determine inputs), output (determine outputs), fixed set point (process variable that cannot be changed by the operator), variable set point (entered by the operator), edits (reject input/output that does not conform to limits and minimize errors, e.g. four- or five-character number entry), input manipulation (and equations) and programme overrides (e.g. stop a mixer before time). Persons should be identified who have the ability and/or are authorized to write, alter or have access to programmes. Software validation should provide assurance that computer programmes (especially those that control manufacturing/processing) will consistently perform as they are supposed to, within pre-established limits. When planning the validation, the following points should be considered:



- function: does the programme match the assigned operational function (e.g. generate batch documentation, different batches of material used in a batch listed, etc.)?

- worst case: perform validation under different conditions (e.g. speed, data volume, frequency);

- repeats: enough times (replicate data entries); - documentation: protocols and reports; and - re-validation: when significant changes are made. 15. ANALYTICAL VALIDATION 15.1 General During manufacturing of any product it is a requirement that specifications be available for the materials, components and in-process material as well as the finished product. Test methods should be available to enable the quality control section to perform tests. Pharmacopoeias provide specifications for the materials in the monographs, as well as official test methods. It is not compulsory or mandatory to follow the test methods described in the pharmacopoeia. Suitable alternative methods may be used if these give results of equivalent significance. Only methods as approved for use in registration dossiers may be used for registered products. Before material or products are released or rejected the results obtained should be checked to make sure that they are consistent with all other information and specifications. 15.2 Pharmacopoeia methods When pharmacopoeia methods for starting materials (APIs and excipients) are chosen as the method of choice in the registration dossier, authorities normally only require laboratories to verify the method, with the laboratory proving that the method can be performed in the laboratory environment. Validation is not required. The verification of pharmacopoeia methods used for determination of content or impurities in pharmaceutical products should demonstrate that the methods are specific with respect to the product (no placebo interference). 15.3 Non-pharmacopoeia methods Non-pharmacopoeia methods can be used once approved by the authorities. These methods are normally developed during the developmental phase of the product. Validation is required.



15.4 Method validation Methods used in routine analysis should be simple to use, give results quickly and inexpensively, but they should be accurate, precise and robust. When an in-house method is to be developed and used - as opposed to using a pharmacopoeia method - justification of the proposed test procedure in comparison with other possible methods must be given (including comparative data), a description of the procedure should be given with as much detail as is deemed necessary to allow properly trained workers to carry it out in a reliable manner (reagents needed, reference standards, formula for calculation of results), and validation data need to be submitted to the authorities. Re-validation may be required when there have been any changes, including transfer of methods from site to site, from laboratory to laboratory, or changes to materials, etc. Tests that could be subjected to validation are identity tests, tests for related substances, and assay. Validation should be performed in accordance with the validation protocol. The results should be documented in the validation report. 15.5 Validation report A written report should be available after completion of the validation. The results should be evaluated, analysed and compared with acceptance criteria. All results should meet the criteria of acceptance and satisfy the stated objective. If necessary further studies should be performed. If found acceptable the report should be approved and authorized (signed and dated). The report should include the title and objective of the study, reference to the protocol, details of materials used, description of the equipment, programmes and cycles used where applicable, details of procedures, including description of the test conditions, precautions, reagents, reference materials, verification (e.g. system suitability), formulae for calculations of results and statistical routines. The data generated and recorded or documented in log books or worksheets should be maintained, as these may be used during inspections for verification purposes. 15.6 Characteristics of analytical procedures Critical parameters that should be included as part of the analytical procedure validation include accuracy, precision, repeatability, reproducibility, robustness, linearity and range, specificity, limit of detection, and limit of quantitation.



Accuracy is the degree of agreement of test results with the true value, or the closeness of the results obtained by the procedure to the true value. Sometimes referred to as the difference between the experimental and true values. It is the comparison with the established reference method (e.g. pharmacopoeia method), or alternatively the procedure can be applied to samples of the material to be examined that have been prepared to quantitative accuracy. [It is acceptable that “spiked” placebo be used where known quantities or concentration of a reference material is used.] Precision (repeatability) is the degree of agreement among individual results. The complete procedure is applied repeatedly to separate, identical samples drawn from the same homogeneous batch of material. It is measured by the scatter of individual results from the mean (good grouping) and usually expressed as the standard deviation (RSD). The minimum number of repeats used to assess precision should be at least five (single or multiple samples). Repeatability (within laboratory variation) is the precision of the procedure when repeated by the same operator under the same conditions (reagents, equipment, settings and laboratory) within a short interval of time. It is normally a measure of consistency. Reproducibility is the precision of the procedure when it is carried out under different conditions (usually a different laboratory, analysts, equipment or at different times). Robustness (or ruggedness) is the ability of the procedure to provide analytical results of acceptable accuracy and precision under a variety of conditions. Results from separate samples are influenced by changes in the operational or environmental conditions. Factors that can have an effect:

- variation in analyst experience, - humidity, - temperature, - stability of test and standard samples, - reagents (e.g. different suppliers), - columns (different batches).

Linearity and range indicate the ability to produce results that are directly proportional to the concentration of the analyte in samples. A series of samples are prepared having analyte concentrations spanning the claimed range of the procedure. Range is an expression of the lowest and highest levels of analyte that have been demonstrated to be determinable for the product.



Specificity (selectivity) is the ability to measure the analyte in a manner that is free from other components in the sample being examined (e.g. impurities and excipients). Sensitivity is the capacity of the test procedure to record small variations in concentration. Limit of detection is the lowest level of an analyte that can be detected, and not necessarily determined, in a quantitative fashion. Limit of quantitation is the lowest level of an analyte in a sample that may be determined with acceptable accuracy and precision. Characteristics that should be considered for different types of analytical procedures are summarized in Table 15.1.

Table 15.1. Characteristics to consider during analytical validation

Class A

Class B

Class B

Class C

Class D

Quantitative tests

Limit tests

Accuracy

X

X

X

Precision

X

X

X

Robustness

X

X

X

X

X

Linearity and range

X

X

X

Selectivity

X

X

X

X

Limit of detection

X

Limit of Quantitation

X

X

Whereas tests can be classified as summarized in Table 15.2.



Table 15.2. Classification of tests

Class

Tests

A

To establish identity

B

To detect and quantitate impurities

C

To determine quantitatively the concentration of a substance in a finished dosage form

D

To assess characteristics of finished dosage forms

16. CLEANING VALIDATION 16.1 General Cleaning, like any other critical process, should be validated. The objective of cleaning validation is to prove that the equipment is consistently cleaned from product, detergent and microbial residues to an acceptable level, to prevent contamination and cross-contamination. These guidelines address the general requirements on cleaning validation, excluding specialized cleaning or inactivation that may, e.g. be required for viral or mycoplasma removal in the biological manufacturing industry. There should be written SOPs detailing the cleaning process for equipment and apparatus. The SOP for cleaning a piece of equipment should only be written once the cleaning process has been validated. The validated procedure should thus be followed consistently, adhered to, appropriately documented and recorded in cleaning logs and maintained to ensure that the equipment is always cleaned as required. Before the cleaning procedure is validated a written SOP should be available, detailing how the cleaning processes will be validated, and referring to accountabilities, acceptance criteria, microbiological aspects (bio-burden control) and re-validation requirements. The complexity and design of the equipment, training of operators, size of the system and time delay between end of processing and cleaning should be kept in mind when designing the cleaning SOP. The greater the risk of the product, or the greater the drug potency or toxicity, the more effort is required on the validation of cleaning methods. Pharmaceutical products can be contaminated by a variety of substances such as contaminants associated with previous products (both API and excipient residues), residues of cleaning agents,



airborne matter such as dust and particulate, lubricants and ancillary material, such as disinfectants, and decomposition residues which include: - product residue breakdown 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. Detergents residues

Detergents are not part of the manufacturing process and are only added to facilitate cleaning during the cleaning process. Detergents should facilitate the cleaning process and should be easily removable. If not, a different detergent should be used. Detergents found to have persistent residues are, e.g. cationic detergents, which 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 the QA/QC departments and should preferably be able to meet local food industry standards. 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). It seems acceptable 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; and

- periodic evaluation and re-validation of the number of batches required should be included. At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. The practice of re-sampling should not be utilized and is acceptable only in rare cases. Constant re-testing and re-sampling can show that the cleaning process is not validated since these re-tests actually document the presence of unacceptable residue and contaminants from an ineffectual cleaning process. The cleaning validation protocol should be formally approved by the Quality Unit and other appropriate management.



Records of the cleaning validation, which include all raw data of the test results together with, e.g. the cleaning record (signed by the operator, checked by production and reviewed by QA), should be kept and a final validation report should be prepared. The final outcome should be stated, e.g. “all the acceptance criteria were met”. Personnel/operators who perform cleaning routinely should be trained and should have effective supervision. Equipment

Normally only cleaning procedures for product-contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts into which product or any process material may migrate. Critical areas should be identified (independently from method of cleaning), particularly in large systems employing semi-automatic or fully automatic clean-in-place systems. Dedicated equipment should be used for products which are difficult to clean, equipment which is difficult to clean, or for products with a high safety risk where it is not possible to achieve the required cleaning acceptance limits via a validated cleaning procedure. 16.2 Sampling There are two methods of sampling that are considered to be acceptable. A combination of the two methods is generally the most desirable. (a) Surface sampling This direct method of sampling is the most commonly used and involves taking an inert material (usually cotton wool or similar) on the end of a probe and rubbing it methodically across a surface. The type of sampling material used and its impact on the test data is important. It is known that the sampling material may interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of samples. Factors that should be considered include the supplier of the swab, area swabbed, number of swabs used, wet or dry swabs, swab handling and swabbing technique. The swab location is important, taking into consideration the material of the equipment (e.g. glass, steel) and the location (e.g. blades, tank walls, fittings). Worst case locations should be considered. The protocol should identify the swab locations. Therefore, the validation programme should ensure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.



Advantages of direct sampling include: - areas hardest to clean and which are reasonably accessible can be evaluated (leading to

establishing a level of contamination or residue per given surface area); and - residues that are “dried out” or are insoluble can be sampled by physical removal. Some disadvantages of using swabs include: - inability to access some areas; - presumes uniformity of contamination surface; - must extrapolate sample area to whole surface; and - reproducibility is suspect due to the human involvement and extraction efficiency. (b) Rinse samples This indirect method allows sampling of a large surface, of inaccessible areas or those that cannot be routinely disassembled and provides an overall picture. Rinse samples give sufficient evidence of cleaning where accessibility of equipment parts can preclude direct surface sampling. However, as a norm, rinse sample should be used in combination with other sampling methods such as swabs. Rinse samples are also useful for checking cleaning agent residues, e.g. detergents. Disadvantage of rinse samples: - residue or contaminant may not be soluble or may be physically occluded in the equipment. (c) Other methods

Batch placebo method

A less frequent sampling method, due to its high cost. The 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. Samples should be taken throughout manufacture. Traces of the preceding products are sought in these samples. The sensitivity of the assay may be greatly reduced by dilution of the contaminant. Scrubbing by hand

Manual cleaning methods are difficult to replicate.



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. 16.3 Analytical methods Validated analytical methods, having sensitivity to detect residues or contaminants, should be used. The analytical method should be validated before the cleaning validation is started. Aspects that should be checked are:

� precision, linearity, selectivity (the latter if specific analytes are targeted). 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; and � reproducibility.

The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminants. A non-specific assay method is not a disadvantage where total contaminants are being studied as opposed to just specific analytes. Suitable methods could include:

� 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 very sensitive, but not specific. Should be used with pH and conductivity.

� pH: very sensitive to hydrogen ions. Used for trace levels of acids and alkalis that may be used as part of the cleaning process.

� Conductivity: sensitive for total ions. (TOC, pH and conductivity, when used in combination, are proving very powerful cleaning validation assay methods.)

� UV spectroscopy: moderate specificity, not quantitative. � ELISA (Enzyme-linked immuno sorbent assay): very sensitive and specific for

biopharmaceuticals; expensive, labour-intensive, long sample turn-around. Establishment of limits

The validation team should set limits. The rationale for the residue limits established should be logical, based on the knowledge of the materials involved. They should be practical, achievable, and verifiable.



Limits may be expressed as a concentration in a subsequent product (ppm), limit per surface area (mcg/cm2), or in rinse water as ppm . (It is important to define the sensitivity of the analytical methods in order to set reasonable limits.) The manner in which limits are established should be carefully considered. In establishing residual limits it may not be adequate to focus only on the principal reactant, since other chemical variations may be more difficult to remove. There are circumstances where TLC screening, in addition to chemical analyses, may be needed. Looking only for evidence of the absence of the previous compound during cleaning validation would be considered inadequate. Evidence (from TLC tests on the rinse water) of the presence of residues of reaction by-products and degradants from the previous process is considered unacceptable. Any residues from the cleaning process itself (detergents, solvents, etc.) also have to be removed from the equipment. It should be noted at the outset that regulatory authorities do not set limits for specific products. The limits must be practical, achievable and verifiable. The limit setting approach can be: - product specific; - grouped into product families, e.g. 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; and - Different safety factors for different dosage forms based on physiological response (method is

essential for potent materials). Setting limits on carry-over

The rationale for selecting limits of carry-over of product residues, cleaning agents and microbial contamination should be scientifically justified, based on the materials involved. 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. It should be kept in mind that uniform distribution of contaminants is not guaranteed and that decomposition products should be checked. The three most common methods of setting cleaning criteria are: - visually clean (first criterion) [not suitable for high potency, low dosage drugs]. Reports of

consistent results of 4 micrograms per cm2 are available; - 10ppm in another product [basis for heavy metals in starting materials]; and



- 0.1% of therapeutic dose [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%] with the most stringent of three options: dose-based, 10 ppm default or the visually clean standard to be used.

Grouping

Grouping may be allowed under certain conditions. Strategies that could be followed include grouping by product or grouping by equipment. The grouping by product may be allowed when the products are similar in nature or property and will be processed in the same equipment. Identical cleaning processes should then be used for these products (cleaning agent, cleaning method, process parameters). When a representative product is chosen it should be the most difficult to clean. Grouping by equipment may be allowed if it is similar equipment, or the same equipment in different sizes (e.g. 300l, 500l and 1000l tanks). An alternative is validating separately by using the smallest and the largest size. Cleaning validation protocol

There should be a cleaning validation protocol for each product and for each piece of equipment. In drafting the protocol, the following should be considered: - disassembly of system; - pre-cleaning; - cleaning agent, concentration, solution volume, water quality; - time and temperature; - flow rate, pressure, and rinsing; - complexity and design of the equipment; - training of operators; and - size of the system.

The cleaning validation protocol, which should be written before the experimental section of the work commences, laying down the procedure on how the cleaning process will be validated, should include: (a) the objectives of the validation process; (b) the responsibilities for performing and approving the validation study; (c) the description of the equipment to be used, including the list of equipment, make, model,

serial number or other unique code; (d) the interval between the end of production and cleaning and the commencement of the

cleaning procedures (interval may be part of the validation challenge study itself)

– the manufacturer is to take into account the maximum period that equipment will be



left dirty before being cleaned as well as the establishment of the time after cleaning and before use;

(e) microbiological levels (bio-burden); (f) the cleaning procedures (documented in an existing SOP, including definition of any

automated process) to be used for each product, each manufacturing system or each piece of equipment;

(g) all routine monitoring equipment used, e.g. conductivity meters, pH meters, total organic carbon analysers;

(h) number of cleaning cycles to be performed consecutively; (i) the sampling procedures used (direct sampling, rinse sampling, in-process monitoring,

sampling locations) and the rationale; (j) data on recovery studies (efficiency of the recovery of the sampling technique should be

established); (k) analytical methods (specificity and sensitivity) including the limit of detection and the

limit of quantification; (l) the acceptance criteria (with rationale for setting the specific limits) including a margin

for error and for sampling efficiency; (m) choice of the cleaning agent should be documented and approved by the Quality Unit and

should be scientifically justified based on, e.g.: • solubility of the materials to be removed • the design and construction of the equipment and surface materials to be cleaned • safety of the cleaning agent • ease of removal and detection • product attributes • knowledge gained through experience • the minimum temperature and volume of cleaning agent and rinse solution • manufacturer's recommendations; and

(n) re-validation requirements. Cleaning validation report

A validation report should be available, approved by the validation team, and stating whether or not the cleaning process is valid. The data should support a conclusion that residues have been reduced to an “acceptable level”. As with validation of other processes there may be more than one way to validate a cleaning process. In the end the test of any validation process is whether scientific data show that the system consistently does as expected and produces a result that consistently meets predetermined specifications.



16.4 Evaluation When evaluating the validation data focus should be upon the objective of the validation process, as specified in the Validation Protocol. Ideally a piece of equipment or system should have one process for cleaning. This will depend on the products being produced, whether the clean-up occurs between batches of the same product (as in a large campaign) or whether the clean-up occurs between batches of different products. Normally cleaning validation would be applicable for critical cleaning such as cleaning between products, product-contact surfaces, drug products and active pharmaceutical ingredients (API). Cleaning validation is not necessarily required for non-critical cleaning such as between batches of the same product (or different lots of the same intermediate in a bulk process), floors, walls, outside of vessels, and some intermediate steps. The company need only meet a criteria of “visibly clean” for the equipment. Such between-batch cleaning processes do not require validation. However, validation is an important part in facilities of high flexibility. It will be required for at least the equipment, sanitization, garment laundering and general cleaning. The design of equipment may influence the effectiveness of the cleaning process. Consideration should be given to the design of the equipment in drafting a validation protocol for cleaning, e.g. V blenders, transfer pumps, filling lines, etc. Operators responsible for performing cleaning operations should be aware of problems and have special training in cleaning these systems and equipment. The cleaning operators should have knowledge of these systems and the appropriate level of training and experience in cleaning them. Drying of residues

A critical element in the documentation of the cleaning processes is the identification and controlling of the length of time between the end of processing and each cleaning step. This is especially important for topical, suspensions, and bulk drug operations. In such operations the drying of residues will directly affect the efficiency of a cleaning process. Microbiological aspects of equipment cleaning

Microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred. There should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation.



Control of the bio-burden through adequate cleaning and storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility, and the control of pyrogens in sterile processing. Equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens. The period and conditions of storage of unclean equipment before cleaning, and the time between cleaning and equipment re-use, should form part of the validation of cleaning procedures. Documented evidence should indicate that routine cleaning and storage of equipment does not allow microbial proliferation. Equipment should be stored dry and under no circumstances should stagnant water be allowed to remain in equipment after cleaning operations. Recovery studies

Validation of recovery: swabs and rinse sampling A plate should be spiked with a known amount of substance. This should be removed by means of a swab or rinse procedure. The sample should be analysed. This should be performed at and below the acceptance limit in the test solution. Acceptable recovery:

> 80%

good

>50%

reasonable

<50%

questionable

17. RE-VALIDATION Processes and procedures should undergo periodic critical re-validation to ensure that they remain capable of achieving the intended results. It is necessary to ensure that changes in the process (whether intentional or unintentional) do not adversely affect product quality or process characteristics. The nature of the changes that require re-validation should be stated in the VMP. Re-validation involves a repeat of the process validation. If any of the following are changed the process becomes invalid and the process could be viewed out of control, even if the finished product meets the marketing authorization specifications for finished products: - changes of starting materials (physical properties, such as density, viscosity or particle size

distribution may affect the process or product); - transfer of processes to another site (change of facilities and installations which influence the

process);



- 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, installation of new

equipment, major revisions to machinery or apparatus and breakdowns); - changes of equipment which involve the replacement of equipment on a “like-for-like” basis

would not normally require a re-validation. For example, a new centrifugal pump replacing an older model would not necessarily mean re-validation;

- production area and support system changes (e.g. rearrangement of areas, new water treatment method);

- appearance of negative quality trends; and - appearance of new findings based on current knowledge, e.g. sterilization where the

frequency of checking is dependent on sophistication of in-process methodology. NOTE: The extent of re-validation will depend on the nature and significance of the changes. There are two basic categories of re-validation: (a) re-validation in cases of known change (change having a bearing on product quality), including transfer of processes from one pharmaceutical manufacturer to another, or from one site to another; and (b) periodic re-validation carried out at scheduled intervals. 17.1 Periodic re-validation Periodic re-validation is required as process changes may occur gradually over a period of time or because of wear of equipment. The decision on the time interval for re-validation is based on the results following review of historical data. The following points should be considered when periodic re-validation is performed: - review the master formula and specifications; - check the calibration records; - review the SOP; - review the cleaning records; - review the analytical methods; and - review the records regarding planned preventative maintenance. 17.2 Re-validation after changes Re-validation after changes should be performed when these changes could have an effect on the quality of the product, or the product characteristics. These include changes in:



- raw material; - packaging material; - manufacturing process; - equipment; - manufacturing areas; and - support system changes. The extent of re-validation could be the same as the initial validation. This will be decided by the validation team. 18. CHANGE CONTROL The manufacturer should have a “change control” procedure. Change control 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.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 aspect 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 extent of re-validation discussed. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorized.Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the responsible staff. Failure to properly document changes to the system means invalidation. 19. PERSONNEL Validation of personnel is not always considered in the pharmaceutical industry. Where relevant personnel should be subjected to validation. Personnel should undergo health checks before employment and at regular intervals thereafter. The manufacturer must demonstrate that personnel possess the necessary levels of competence. The signatories of the validation work must have appropriate training, experience, education and qualifications. Microbiologists should sign microbiological work, engineers, engineering, etc. The final report should be co-signed by the person responsible for the project. Training requirements need to be identified for personnel who will maintain or carry out the processes that have been validated. Personnel should be trained in GMP and procedural activities in accordance with an SOP.



Examples of validation of personnel applicable to the manufacture and control of sterile products, analysis and related activities that may have a direct impact on the quality of a product include: - aseptic technique: media fills; - validation of analysts in laboratories for performing certain analyses; - validation of personnel performing activities in accordance with SOPs; - performing visual inspection of sterile injectable products ; and - personnel working on computerized systems.



REFERENCES

Fourman, G. L., Mullen, M.V. Determining cleaning validation acceptance limits for

pharmaceutical manufacturing operations. Pharmaceutical Technology, 1993, 54:1-6.

1. Hwang, R. Process design and data analysis for cleaning validation. Pharmaceutical

Technology, 1997, 62-68.

2. Pharmaceutical Inspection Convention Scheme. Guide to Good Manufacturing Practice for Medicinal Products. PH 1/97 (rev. 3), 15 January 2002..

3. Pharmaceutical Inspection Convention Scheme. In: The Inspection of Quality

Control Laboratories Seminar. Training provided on GMP Guidelines for the inspection of Pharmaceutical Quality Control Laboratories. Lecturers provided at the GMP Training Seminar, Bratislava, 3-6 June 2003.

4. Proprietary Association of South Africa.. Guide to Good Manufacturing Practice.

Pharmaceutical Manufacturers Association of South Africa (Scientific Advisory Subcommittee) and Proprietary association of South Africa (Legislative Subcommittee Medicines), Johannesburg, 1996.

5. 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 Practices: guidelines on the validation of manufacturing processes.

6. Quality Assurance of Pharmaceuticals: A Compendium of Guidelines and Related

Materials. Volume 1. Geneva, World Health Organization, 1997, pp. 119-124.

7. Quality Assurance of Pharmaceuticals: A Compendium of Guidelines and Related Materials. Good Manufacturing Practices and Inspection. Volume 2. Geneva, World Health Organization, 1999, pp. 53-70.



ANNEX

Format for an Installation Qualification Protocol and Report The following format outlines the requirements for an Installation Qualification protocol.

Name and address of site:___________________________ Page __of __ Validation Protocol # ________________________________IQ Protocol number: ___ Title: ________________________________________________________________ Protocol written by: _______________________ Protocol approved by: _______________________ Date: _______________________QA Approval: _______________________ Date: _______________________ Objective To ensure that __________ (system/equipment) installed conforms to the purchase specifications and the manufacturer details and literature, and to document the information that ___________ (system/equipment) meets its specifications. Equipment inventory number: ____________________ Scope To perform installation qualification as described in this IQ protocol at the time of installation, modification and relocation. Responsibility ___________ (post/person) overseeing the installation will perform the qualification and records results. ___________ (post/person) will verify results and write the report. Quality Assurance will review and approve the IQ protocol and report.



Annex

Validation Protocol ___________Installation Qualification Page __of __ Title: ___________ Name and address of site:___________________________ System/Equipment _____________________________ Code no.: ___________________ a. Description of the system/equipment being installed: general description of the

function and the main components. _____________________________________________________________________________________________________________________________________________________________________________

b. List of the main components: 1. ___________________________ Code no.: ____________________________ 2. ___________________________ Code no.: ____________________________ 3. ___________________________ Code no.: ____________________________ 4. ___________________________ Code no.: ____________________________ c. Description of supporting utilities (e.g. piping, connections, water supply) 1. ___________________________ Code no.: ____________________________ 2. ___________________________ Code no.: ____________________________ 3. ___________________________ Code no.: ____________________________ 4. ___________________________ Code no.: ____________________________ Procedure 1. Prepare a checklist of all components and parts, including spare parts according to the purchase order and manufacturer’s specifications. 2. Record the information for each actual part, component, auxiliary equipment, supporting facilities, and compare to the manufacturer’s specifications. 3. Record any deviations to the system/equipment. 4. Prepare a deviation report including justification of acceptance and impact on the function. 5. Prepare a IQ report.* 6. Submit the report to QA for review and approval.

* IQ report should at least include the date of the study initiation, date completed, observations

made, problems encountered, completeness of information collected, summary of deviation report, results of any tests, sample data if appropriate, location of original data, other information relevant to the study, and conclusion on the validity of the installation.



Annex

Validation Protocol ________Installation Qualification __________ Page __of __ Title: _______ Name and address of site___________________________

Checklist for component no. _________ Name: _______________ Code no.: __________ Component function: _______________________________________________________

Require/Order Actual Deviations

1 Model/serial no.

2 Specification

3 Manual

4 Drawing

5 Wiring/cabling

6 Power, fusing

7 SOP (operation) SOP (maintenance) SOP (calibration)

8 Input/output control

9 Environment

10 Test equipment or instruments

11 Utilities and service

12 Spare parts list, part number and supplier

13 Other

Performed by: _____________________________ Date: _________________ Deviations: _____________________________ Date: _________________ Verified by: _____________________________ Date: _________________



Annex

Validation Protocol ___________Installation Qualification ______page __of __ Title: ___________ Name and address of site:___________________________ Deviation report Deviations: ______________________________________________________________ __________________________________________________________________________________________________________________________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________________________________________________________________________________________________________________________ Justification for acceptance __________________________________________________________________________ __________________________________________________________________________________________________________________________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________________________________________________________________________________________________________________________ Impact on operation: __________________________________________________________________________ __________________________________________________________________________________________________________________________________________________________________________________________________________________________________ Report written by: __________________________________ Date: _________________



Annex

Validation Protocol ___________Installation Qualification ______page __of __ Title: ___________ Name and address of site:__________________________ Installation Qualification Report Results: ______________________________________________________________ __________________________________________________________________________________________________________________________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________________________________________________________________________________________________________________________ Conclusions: __________________________________________________________________________ __________________________________________________________________________________________________________________________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________________________________________________________________________________________________________________________ __________________________________________________________________________ _____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ Report written by: __________________________________ Date: ________________ QA approved by: __________________________________ Date: ________________

* * *

gmp validation

Documents

validation data

validation of processes

cleaning validation

initial process validation

term process validation

validation studies

validation protocol

introduction validation