World Health Organization

World Health Organization
24 April, 2019 Supplementary Training Modules on Good Manufacturing Practice Validation In this supplementary training module, we will be looking at the recommendations by WHO, on Validation and qualification. The module consists of 7 parts: Part 1. General overview on qualification and validation Part 2. Qualification of HVAC and water systems Part 3. Cleaning validation Part 4. Analytical method validation Part 5. Computerized system validation Part 6. Qualification of systems and equipment Part 7. Non sterile product process validation Each part deals with a specific topic, and each part can be presented in about one to one and a half hours time. Presenters should know the topics and add practical examples to the texts taken from the WHO guideline. WHO Technical Report Series, No. 961, Annex 5

Validation 24 April, 2019 Part 1. General overview on qualification and validation Part 2. Qualification of HVAC and water systems Part 3. Cleaning validation Part 4. Analytical method validation Part 5. Computerized system validation Part 6. Qualification of systems and equipment Part 7. Non sterile product process validation

24 April, 2019 Supplementary Training Modules on Good Manufacturing Practice Qualification of HVAC and water systems Part 2 WHO Technical Report Series, No. 961, Annex 5

HVAC 24 April, 2019 Objectives To understand key issues in commissioning, qualification and maintenance of HVAC and Water systems First number of slides dealing with HVAC, followed by water systems 8.

24 April, 2019 HVAC Documentation requirements to assist in commissioning, qualification and maintenance Description of design, installation and functions Specifications, requirements Manuals Operating procedures Instructions for performance control, monitoring and records Maintenance instructions and records Training of personnel programme and records

HVAC 24 April, 2019 Commissioning Precursor to qualification Includes setting up, balancing, adjustment and testing of entire HVAC system to ensure it meets requirements in URS and capacity Acceptable tolerances for parameters Training of personnel 8. Commissioning, qualification and maintenance 8.1 Commissioning 8.1.1 Commissioning should include the setting up, balancing, adjustment and testing of the entire HVAC system, to ensure that it meets all the requirements, as specifi ed in the user requirement specifi cation (URS), and capacities as specifi ed by the designer or developer. 8.1.2 The installation records of the system should provide documented evidence of all measured capacities of the system. 8.1.3 The data should include items such as the design and measurement fi gures for airfl ows, water fl ows, system pressures and electrical amperages. These should be contained in the operating and maintenance manuals (O & M manuals). 8.1.4 Acceptable tolerances for all system parameters should be specifi ed prior to commencing the physical installation. 8.1.5 Training should be provided to personnel after installation of the system, and should include operation and maintenance. 8.1.1, 8.1.4, 8.1.5

HVAC 24 April, 2019 Commissioning (2) Records and data maintained include: Installation records – documented evidence of measure capacities of the system Data: design and measurement for, e.g. air flow, system pressures O&M manuals, schematic drawings, protocols, reports 8.1.3 The data should include items such as the design and measurement fi gures for airfl ows, water fl ows, system pressures and electrical amperages. These should be contained in the operating and maintenance manuals (O & M manuals). 8.1.4 Acceptable tolerances for all system parameters should be specifi ed prior to commencing the physical installation. 8.1.5 Training should be provided to personnel after installation of the system, and should include operation and maintenance. 8.1.6 O & M manuals, schematic drawings, protocols and reports should be maintained as reference documents for any future changes and upgrades to the system. 8.1.2, 8.1.3, 8.1.6

HVAC 24 April, 2019 Qualification Validation is an extensive exercise Qualification of the HVAC system is one component in the overall approach that covers premises, systems/utilities, equipment, processes, etc. See also full guidelines on "Validation" in WHO TRS, No. 937, 2005, Annex 4 Risk based approach for HVAC qualification 8.2 Qualifi cation 8.2.1 Validation is a many-faceted and extensive activity and is beyond the scope of these guidelines. Qualifi cation and validation guidelines are included in: Expert Committee on Specifi cations for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2005 (WHO Technical Report Series, No. 937), Annex 4 (see also Fig. 28). 8.2.1

HVAC 24 April, 2019 Qualification (2) Described in a Validation Master Plan (VMP) VMP to include the nature and extent of tests, and protocols DQ, IQ, OQ, and PQ Risk analysis to determine critical and non-critical parameters, components, subsystems and controls 8.2.2 The qualifi cation of the HVAC system should be described in a validation master plan (VMP). 8.2.3 It should defi ne the nature and extent of testing and the test procedures and protocols to be followed. 8.2.4 Stages of the qualifi cation of the HVAC system should include DQ, IQ, OQ and PQ. 8.2.5 Critical and non-critical parameters should be determined by means of a risk analysis for all HVAC installation components, subsystems and controls. 8.2.2 – 8.2.5

HVAC 24 April, 2019 Qualification (3) Direct impact components and critical parameters should be included Non-critical systems and components are subjected to Good Engineering Practices (GEP) Acceptance criteria and limits defined in design stage Design conditions, normal operating ranges, operating ranges, alert and action limits 8.2.5 Critical and non-critical parameters should be determined by means of a risk analysis for all HVAC installation components, subsystems and controls. 8.2.6 Any parameter that may affect the quality of the pharmaceutical product, or a direct impact component, should be considered a critical parameter. 8.2.7 All critical parameters should be included in the qualifi cation process. Note: A realistic approach to differentiating between critical and noncritical parameters is required, to avoid making the validation process unnecessarily complex. Example: • The humidity of the room where the product is exposed should be considered a critical parameter when a humidity-sensitive product is being manufactured. The humidity sensors and the humidity monitoring system should, therefore, be qualifi ed. The heat transfer system, chemical drier or steam humidifi er, which is producing the humidity controlled air, is further removed from the product and may not require operational qualifi cation. Figure 28 Qualifi cation is a part of validation Equip 1 Equip 2 Equip 3 Equip 4 Equip 5 Equip 6 QUALIFICATION VALIDATION Equip 7 System 2 System 1 Process Equip, equipment. 80 Figure 29 System operating ranges • A room cleanliness classifi cation is a critical parameter and, therefore, the room air change rates and HEPA fi lters should be critical parameters and require qualifi cation. Items such as the fan generating the airfl ow and the primary and secondary fi lters are non-critical parameters, and may not require operational qualifi cation. 8.2.8 Non-critical systems and components should be subject to GEP and may not necessarily require qualifi cation. 8.2.9 A change control procedure should be followed when changes are planned to the direct impact HVAC system, its components and controls that may affect critical parameters. Acceptance criteria and limits should be defi ned during the design stage. The manufacturer should defi ne design conditions, normal operating ranges, operating ranges, and alert and action limits. 8.2.5 –

HVAC Design conditions and normal operating ranges set to achievable limits OOS results recorded –

HVAC 24 April, 2019 Qualification – examples of aspects to consider DQ – Design of the system, URS (e.g. components, type of air treatment needed, materials of construction) IQ – Verify installation E.g. relevant components, ducting, filters, controls, monitors, sensors, etc. Includes calibration where relevant

HVAC 24 April, 2019 Qualification (4) Typical parameters to be included in qualification (based on risk assessment): Temperature Relative humidity Supply, return and exhaust air quantities Room air change rates Room pressures (pressure differentials) For a pharmaceutical facility, based on a risk assessment, some of the typical HVAC system parameters that should be qualifi ed may include: — temperature — relative humidity — supply air quantities for all diffusers — return air or exhaust air quantities — room air change rates — room pressures (pressure differentials) — room airfl ow patterns — unidirectional fl ow velocities — containment system velocities — HEPA fi lter penetration tests — room particle counts — room clean-up rates — microbiological air and surface counts where appropriate — operation of de-dusting — warning/alarm systems where applicable. 8.2.17

HVAC 24 April, 2019 Qualification (5) Typical parameters to be included in qualification (based on risk assessment) (2): Room clean-up rate Particulate matter, microbial matter (viable and non-viable) HEPA filter penetration tests Containment system velocity Warning/alarm systems 8.2.17

HVAC 24 April, 2019 Qualification (6) Conduct of the tests: Time intervals and procedure to be defined by the manufacturer Influenced by the type of facility and level of protection See also ISO for methods of testing Requalification, and change control The maximum time interval between tests should be defi ned by the manufacturer. The type of facility under test and the product level of protection should be considered. Note: Table 3 gives intervals for reference purposes only. The actual test periods may be more frequent or less frequent, depending on the product and process. Periodic requalifi cation of parameters should be done at regular intervals, e.g. annually. Requalifi cation should also be done when any change, which could affect system performance, takes place. – , 8.2.9

HVAC 24 April, 2019 Qualification (7) Tests performed according to protocols and procedures for the tests Results recorded and presented in report (source data kept) Traceability, e.g. devices and standards used, calibration records; and conditions specified

HVAC 24 April, 2019 Schedule of tests to demonstrate continuing compliance *Test procedure as per ISO 14644 Test procedure* and key aspects Maximum time interval Objective Test Parameter Particle counter. Readings and positions 6 months or 12 months depending on Class Verifies cleanliness Particle count test Measure pressure difference 12 months Absence of cross- contamination Air pressure difference Measure supply and return air, calculate air change rate Verify air change rates Airflow volume Velocity measurement Verify unidirectional airflow and or containment condition Airflow velocity 8. Table 3

HVAC 24 April, 2019 Recommended optional strategic tests *Test procedure as per ISO 14644 Test procedure* and key aspects Maximum time interval Objective Test Parameter Filter media and filter seal integrity 12 months Verify filter integrity Filter leakage Airflow direction and pressure differential Verify absence of cross-contamination Containment leakage Time taken maximum 15 minutes Verify clean-up time Recovery (time) Airflow direction, documented evidence Verify required airflow patterns Airflow visualization 8. Table 3

Cleanroom monitoring programme (1)
World Health Organization 24 April, 2019 HVAC Cleanroom monitoring programme (1) Routine monitoring programme as part of quality assurance Additional monitoring and triggers, e.g. 1. Shutdown 2. Replacement of filter elements 3. Maintenance of air-handling systems 4. Exceeding of established limits

24 April, 2019 HVAC Cleanroom monitoring programme (2) Particles and Microbiological contaminants Number of points/locations for monitoring determined, specified, documented in procedure and or protocol Sufficient time for exposure, and suitable sample size Identification and marking of sampling points Definition of transport, storage, and incubation conditions Results to reflect the procedure/protocol followed Define alert and action limits as a function of cleanliness zone/class See also ISO 14644

24 April, 2019 HVAC Cleanroom monitoring programme (3) Cleanrooms should be monitored for microorganisms and particles air Example of a sampling point

Definition of Conditions
World Health Organization 24 April, 2019 HVAC Definition of Conditions air as built at rest in operation

24 April, 2019 HVAC Qualification – examples of aspects to consider in qualification (OQ, PQ) Test Differential pressure on filters Turbulent / mixed airflow Description Uni-directional airflow / LAF Room differential pressure Airflow velocity / uniformity Airflow volume / rate Parallelism Airflow pattern 2 N/A 2, 3 Optional 3 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) This slide shows a series of tests to be carried out during qualification. There are different tests for the turbulent and for the uni-directional air flows. The differential pressure on filters is an indication of the clogging of the filters: with the charging of dust on the filters, the differential pressure will increase. In order to keep the volume of air constant, the fan speed may increase, with the following consequences: Damage to filters, and passage of unfiltered air Particles and micro-organismes will be “pushed” through the filter units. (Inspectors should check whether pressure differential manometers are installed on the AHUs. Without this means of monitoring the filters, the system could go out of control causing contamination problems.) Airflow patterns are interesting to visualize (smoke tests), as zones without proper flushing can be easily identified. It is also important to monitor air flow velocities for each HEPA filter according to a program of established intervals because significant reductions in velocity can increase the possibility of contamination, and changes in velocity can affect the laminarity of the airflow. Airflow patterns should be tested for turbulence, as these can interfere with the flushing action of the air.

24 April, 2019 HVAC Qualification – examples of aspects to consider in qualification (OQ, PQ) Test Turbulent / mixed airflow Description Uni-directional airflow / LAF Recovery time Room classification (airborne particle) Temperature, humidity N/A 2 2,3 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) The recovery time (clean-up time) is also an important parameter to be determined. Once doors have been opened and people have been entering a room, the original conditions have been disturbed and, for a short while, before recovering, the room does not always correspond to the laid down parameters. It is important to know how long this period is. There are no regulations laid down as to how long this clean-up time should be. However, the generally accepted time to clean-up from one cleanroom classification to the next higher classification, should be less than 15 minutes. It should also be remembered that a room is to be qualified “in operation” when it has a certain number of people in it. After qualification, the number of people in that room, as challenged during qualification, cannot be exceeded. Temperature and humidity can also be important (comfort in clean areas, stability of effervescent products, etc.)

HVAC 24 April, 2019 Maintenance Procedure, programme and records for planned, preventative maintenance e.g. Cleaning of filters, calibration of devices Appropriate training for personnel Change of HEPA filters by suitably trained persons Impact of maintenance on: Product quality Qualification 8.3 Maintenance 8.3.1 There should be a planned preventive maintenance programme, procedures and records for the HVAC system. Records should be kept. 8.3.2 Maintenance personnel should receive appropriate training. 82 8.3.3 HEPA fi lters should be changed either by a specialist or a trained person. 8.3.4 Any maintenance activity should be assessed critically to determine any impact on product quality including possible contamination. 8.3.5 Maintenance activities should normally be scheduled to take place outside production hours, and any system stoppage should be assessed with a view to the possible need for requalifi cation of an area as a result of an interruption of the service. 8.3.1 – 8.3.5

24 April, 2019 HVAC Inspecting the air-handling system Verification of design documentation, including description of installation and functions specification of the requirements Operating procedures Maintenance instructions Maintenance records Training logs Environmental records Discussion on actions if OOS values On site verification (walking around the site)

24 April, 2019 HVAC Conclusion Air-handling systems: Play a major role in the quality of pharmaceuticals Should be designed properly, by professionals Should be treated as a critical system

24 April, 2019 HVAC Further proceedings This series of explanations will now be followed by: Group discussion, with a simple exercise Short test

24 April, 2019 HVAC Group Session The diagram, which is given in handout , shows a layout of a small pharmaceutical plant for non-sterile tablets, liquids and soft-gel capsules, as well as aseptically filled eye-drops. The group session participants should indicate on the diagram the required cleanroom classes, room pressures (in Pa), as well as any architectural changes which they think necessary. (This layout is not ideal, but as many different types of operations have been incorporated in the facility as possible, so that different concepts can be addressed.) (Note to trainer: The next handout, , giving suggested modifications, should not be distributed until after the group discussion has taken place.)

24 April, 2019 HVAC Group Session – modified layout This slide indicates the proposed additions, and can be displayed after the group session discussions have taken place. See handout MAL = Material Air Lock PAL = Personnel Air Lock

24 April, 2019 Supplementary Training Modules on Good Manufacturing Practice Commissioning, Qualification and validation of Water systems WHO Technical Report Series No 970, Annex 2

HVAC 24 April, 2019 Objectives To understand key issues in commissioning, qualification and maintenance of HVAC and Water systems First 30 odd slides dealing with HVAC, followed by water systems 7.

Water for Pharmaceutical Use
World Health Organization Water for Pharmaceutical Use 24 April, 2019 Objectives To discuss the operational considerations of water systems including: Start up, commissioning and qualification Monitoring Maintenance System reviews 7.

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Start up and commissioning Precursor to qualification and validation Should be planned, well defined, well documented Includes setting to work Includes system set-up Includes recording of system performance parameters Controls loop tuning 7. Operational considerations 7.1 Start-up and commissioning of water systems Planned, well-de.ned, successful and well-documented commissioning is an essential precursor to successful validation of water systems. The commissioning work should include setting to work, system setup, controls loop tuning and recording of all system performance parameters. If it is intended to use or refer to commissioning data within the validation work then the quality of the commissioning work and associated data and documentation must be commensurate with the validation plan requirements. 7.1

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Qualification WPU systems are "direct impact systems" Therefore stages to be considered in qualification should include DQ, IQ, OQ, PQ DQ: Design review influenced by source water and required water quality IQ: Installation verification of the system 7.2 Qualification WPU, PW, HPW and WFI systems are all considered to be direct impact, quality critical systems that should be quali.ed. The quali.cation should follow the validation convention of design review or design quali.cation (DQ), installation quali.cation (IQ), operational quali.cation (OQ) and performance quali.cation (PQ). This guidance does not de.ne the standard requirements for the conventional validation stages DQ, IQ and OQ, but concentrates on the particular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period. Phase 1. A test period of 2–4 weeks should be spent monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation. The following should be included in the testing approach. • Undertake chemical and microbiological testing in accordance with a de.ned plan. • Sample the incoming feed-water daily to verify its quality. • Sample after each step in the puri.cation process daily. • Sample at each point of use and at other de.ned sample points daily. • Develop appropriate operating ranges. • Develop and .nalize operating, cleaning, sanitizing and maintenance procedures. • Demonstrate production and delivery of product water of the required quality and quantity. • Use and re.ne the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting. • Verify provisional alert and action levels. • Develop and re.ne test-failure procedure. Phase 2. A further test period of 2–4 weeks should be spent carrying out further intensive monitoring while deploying all the re.ned SOPs after the satisfactory completion of phase 1. The sampling scheme should be generally the same as in phase 1. Water can be used for manufacturing purposes during this phase. The approach should also: — demonstrate consistent operation within established ranges; and — demonstrate consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs. Phase 3. Phase 3 typically runs for 1 year after the satisfactory completion of phase 2. Water can be used for manufacturing purposes during this phase which has the following objectives and features. • Demonstrate extended reliable performance. • Ensure that seasonal variations are evaluated. • The sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2. 7.2

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Qualification OQ: operational qualification Presentation focusing on PQ PQ demonstrates consistent and reliable performance of the system Three phase approach recommended over extended period – proves reliability and robustness 7.2 Qualification WPU, PW, HPW and WFI systems are all considered to be direct impact, quality critical systems that should be quali.ed. The quali.cation should follow the validation convention of design review or design quali.cation (DQ), installation quali.cation (IQ), operational quali.cation (OQ) and performance quali.cation (PQ). This guidance does not de.ne the standard requirements for the conventional validation stages DQ, IQ and OQ, but concentrates on the particular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period. Phase 1. A test period of 2–4 weeks should be spent monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation. The following should be included in the testing approach. • Undertake chemical and microbiological testing in accordance with a de.ned plan. • Sample the incoming feed-water daily to verify its quality. • Sample after each step in the puri.cation process daily. • Sample at each point of use and at other de.ned sample points daily. • Develop appropriate operating ranges. • Develop and .nalize operating, cleaning, sanitizing and maintenance procedures. • Demonstrate production and delivery of product water of the required quality and quantity. • Use and re.ne the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting. • Verify provisional alert and action levels. • Develop and re.ne test-failure procedure. Phase 2. A further test period of 2–4 weeks should be spent carrying out further intensive monitoring while deploying all the re.ned SOPs after the satisfactory completion of phase 1. The sampling scheme should be generally the same as in phase 1. Water can be used for manufacturing purposes during this phase. The approach should also: — demonstrate consistent operation within established ranges; and — demonstrate consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs. Phase 3. Phase 3 typically runs for 1 year after the satisfactory completion of phase 2. Water can be used for manufacturing purposes during this phase which has the following objectives and features. • Demonstrate extended reliable performance. • Ensure that seasonal variations are evaluated. • The sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2. 7.2

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Phase 1 (1) A test period of 2–4 weeks - monitoring the system intensively System to operate continuously without failure or performance deviation The following should be included in the testing approach: Undertake chemical and microbiological testing in accordance with a defined plan 7.2 Qualification WPU, PW, HPW and WFI systems are all considered to be direct impact, quality critical systems that should be quali.ed. The quali.cation should follow the validation convention of design review or design quali.cation (DQ), installation quali.cation (IQ), operational quali.cation (OQ) and performance quali.cation (PQ). This guidance does not de.ne the standard requirements for the conventional validation stages DQ, IQ and OQ, but concentrates on the particular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period. Phase 1. A test period of 2–4 weeks should be spent monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation. The following should be included in the testing approach. • Undertake chemical and microbiological testing in accordance with a de.ned plan. • Sample the incoming feed-water daily to verify its quality. • Sample after each step in the puri.cation process daily. • Sample at each point of use and at other de.ned sample points daily. • Develop appropriate operating ranges. • Develop and .nalize operating, cleaning, sanitizing and maintenance procedures. • Demonstrate production and delivery of product water of the required quality and quantity. • Use and re.ne the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting. • Verify provisional alert and action levels. • Develop and re.ne test-failure procedure. 7.2

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Phase 1 (2) Sample daily: incoming feed-water after each step in the purification process each point of use and at other defined sample points Develop: appropriate operating ranges and finalize operating, cleaning, sanitizing and maintenance procedures Phase 1. A test period of 2–4 weeks should be spent monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation. The following should be included in the testing approach. • Undertake chemical and microbiological testing in accordance with a de.ned plan. • Sample the incoming feed-water daily to verify its quality. • Sample after each step in the puri.cation process daily. • Sample at each point of use and at other de.ned sample points daily. • Develop appropriate operating ranges. • Develop and .nalize operating, cleaning, sanitizing and maintenance procedures. • Demonstrate production and delivery of product water of the required quality and quantity. • Use and re.ne the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting. • Verify provisional alert and action levels. • Develop and re.ne test-failure procedure. 7.2

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Phase 1 (3) Demonstrate production and delivery of product water of the required quality and quantity Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting Verify provisional alert and action levels Develop and refine test-failure procedure 7.2

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Phase 2 (1) A further test period of 2–4 weeks – further intensive monitoring the system Deploying all the refined SOPs after the satisfactory completion of phase 1 Sampling scheme generally the same as in phase 1 Water can be used for manufacturing purposes during this phase Phase 2. A further test period of 2–4 weeks should be spent carrying out further intensive monitoring while deploying all the re.ned SOPs after the satisfactory completion of phase 1. The sampling scheme should be generally the same as in phase 1. Water can be used for manufacturing purposes during this phase. The approach should also: — demonstrate consistent operation within established ranges; and — demonstrate consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs. 7.2

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Phase 2 (2) Demonstrate: Consistent operation within established ranges Consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs. 7.2

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Phase 3 Over one year after the satisfactory completion of phase 2 Water can be used for manufacturing purposes during this phase Demonstrate: extended reliable performance that seasonal variations are evaluated Sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2 Phase 3. Phase 3 typically runs for 1 year after the satisfactory completion of phase 2. Water can be used for manufacturing purposes during this phase which has the following objectives and features. • Demonstrate extended reliable performance. • Ensure that seasonal variations are evaluated. • The sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2. 7.2

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Ongoing system monitoring After Phase 3 – system review needed Based on review including results, establish a routine monitoring plan Monitoring to include a combination of on-line monitoring and off- line sample testing Data analysed for trends 7.3 Continuous system monitoring After completion of phase 3 of the quali.cation programme for the WPU system, a system review should be undertaken. Following this review, a routine monitoring plan should be established based on the results of phase 3. Monitoring should include a combination of online instrument monitoring of parameters such as .ow, pressure, temperature, conductivity and total organic carbon, and of.ine sample testing for physical, chemical and microbiological attributes. Of.ine samples should be taken from points of use and speci.c sample points. Samples from points of use should be taken in a similar way to that adopted when the water is being used in service. Tests should be carried out to ensure that the selected pharmacopoeia speci.cation has been satis.ed, and should include, as appropriate, determination of conductivity, pH, heavy metals, nitrates, total organic carbon, total viable count, presence of speci.c pathogens and endotoxins. Monitoring data should be subject to trend analysis. 7.3

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Ongoing system monitoring (2) Monitoring parameters to include: flow, pressure, temperature, conductivity, TOC Samples taken: From points of use, and specific sample points In a similar way how water is used in service Tests to include physical, chemical and microbial attributes 7.3

World Health Organization Water for Pharmaceutical Use 24 April, 2019 Maintenance A controlled, documented maintenance programme covering: Defined frequency with plan and instructions Calibration programme SOPs for tasks Control of approved spares Record and review of problems and faults during maintenance 7.4 Maintenance of water systems WPU systems should be maintained in accordance with a controlled, documented maintenance programme that takes into account the following: — de.ned frequency for system elements; — the calibration programme; — SOPs for speci.c tasks; — control of approved spares; — issue of clear maintenance plan and instructions; — review and approval of systems for use upon completion of work; and — record and review of problems and faults during maintenance. 7.4

World Health Organization Water for Pharmaceutical Use 24 April, 2019 System review WPU (PW, HPW and WFI) systems to be reviewed at appropriate regular intervals Review team includes engineering, QA, operations and maintenance 7.5 System reviews WPU (PW, HPW and WFI) systems should be reviewed at appropriate regular intervals. The review team should comprise representatives from engineering, QA, operations and maintenance. The review should consider matters such as: — changes made since the last review; — system performance; — reliability; — quality trends; — failure events; — investigations; — out-of-speci.cations results from monitoring; — changes to the installation; — updated installation documentation; — log books; and — the status of the current SOP list. 7.5

World Health Organization Water for Pharmaceutical Use 24 April, 2019 System review (2) The review to cover, e.g. changes made since the last review; system performance; reliability; quality trends; failure events; investigations; out-of-specifications results from monitoring; changes to the installation; updated installation documentation; log books; and the status of the current SOP lists 7.5

Validation World Health Organization 24 April, 2019 Group session The trainer should give the participants a case study, based on experience

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