Supplementary Training Modules on Good Manufacturing PracticeValidation WHO Technical Report Series, No. 937, 2006. Annex 4. Validation August 2006 | Slide 1 of 48 Validation 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 Validation August 2006 | Slide 2 of 48 Supplementary Training Modules on Good Manufacturing Practice Qualification of HVAC and water systems Part 2 WHO Technical Report Series, No. 937, 2006. Annex 4. Appendix 1 and 2 Validation August 2006 | Slide 3 of 48 HVAC Objectives To understand key issues in – commissioning, – qualification and – maintenance of HVAC and Water systems 8. Validation August 2006 | Slide 4 of 48 HVAC Documentation requirements to assist in commissioning, qualification and maintenance q q q q q q q 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 Slide 5 of 48 Validation August 2006 | HVAC 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 8.1.1, 8.1.4, 8.1.5 Validation August 2006 | Slide 6 of 48 HVAC 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 8.1.2, 8.1.3, 8.1.6 Validation August 2006 | Slide 7 of 48 HVAC 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 8.2.1 Validation August 2006 | Slide 8 of 48 HVAC 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 – 8.2.5 Validation August 2006 | Slide 9 of 48 HVAC 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 – 8.2.11 Validation August 2006 | Slide 10 of 48 HVAC Design conditions and normal operating ranges set to achievable limits OOS results recorded A C TIO N LIM IT A LE R T L IM IT A L E R T LIM IT A C TIO N L IM IT D e s ig n C o n d itio n N o r m a l O p e r a tin g R a n g e 8.2.12 – 8.2.15 O p e r a tin g R a n g e - V a lid a te d A c c e p ta n c e C r ite r ia Validation August 2006 | Slide 11 of 48 HVAC 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 Validation August 2006 | Slide 12 of 48 HVAC 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) 8.2.17 Validation August 2006 | Slide 13 of 48 HVAC 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 Validation August 2006 | Slide 14 of 48 HVAC 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 14644 for methods of testing Requalification, and change control 8.2.18 – 8.2.20, 8.2.9 Validation August 2006 | Slide 15 of 48 HVAC 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 Validation August 2006 | Slide 16 of 48 HVAC Schedule of tests to demonstrate continuing compliance Test Parameter Particle count test Objective Verifies cleanliness Maximum time interval 6 months or 12 months depending on Class 12 months 12 months Test procedure* and key aspects Particle counter. Readings and positions Measure pressure difference Measure supply and return air, calculate air change rate Velocity measurement 8. Table 3 Air pressure difference Airflow volume Absence of crosscontamination Verify air change rates Airflow velocity Verify unidirectional 12 months airflow and or containment condition *Test procedure as per ISO 14644 Validation August 2006 | Slide 17 of 48 HVAC Recommended optional strategic tests Test Parameter Filter leakage Containment leakage Recovery (time) Objective Verify filter integrity Verify absence of cross-contamination Verify clean-up time Maximum time interval 12 months 12 months 12 months Test procedure* and key aspects Filter media and filter seal integrity Airflow direction and pressure differential Time taken maximum 15 minutes Airflow direction, documented evidence Airflow visualization Verify required airflow 12 months patterns *Test procedure as per ISO 14644 8. Table 3 Validation August 2006 | Slide 18 of 48 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 Validation August 2006 | Slide 19 of 48 HVAC Cleanroom monitoring programme (2) Particles and Microbiological contaminants q Number of points/locations for monitoring determined, q q q q q 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 | Slide 20 of 48 Validation August 2006 HVAC Cleanroom monitoring programme (3) Cleanrooms should be monitored for microorganisms and particles air Example of a sampling point Validation August 2006 | Slide 21 of 48 HVAC Definition of Conditions as built air at rest air in operation air Validation August 2006 | Slide 22 of 48 HVAC Qualification – examples of aspects to consider in qualification (OQ, PQ) Test Uni-directional airflow / LAF 2 N/A 2, 3 2 2 2 Turbulent / mixed airflow 2 2, 3 Optional 2 N/A 3 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) Airflow volume / rate Parallelism Airflow pattern Description Differential pressure on filters Room differential pressure Airflow velocity / uniformity Validation August 2006 | Slide 23 of 48 HVAC Qualification – examples of aspects to consider in qualification (OQ, PQ) Test Recovery time Room classification (airborne particle) Temperature, humidity Uni-directional airflow / LAF N/A 2 N/A 2 Turbulent / mixed airflow Description 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) 2,3 2,3 Validation August 2006 | Slide 24 of 48 HVAC 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 Validation August 2006 | Slide 25 of 48 8.3.1 – 8.3.5 HVAC Inspecting the air-handling system q Verification of design documentation, including ® description of installation and functions ® specification of the requirements q Operating procedures q Maintenance instructions q Maintenance records q Training logs q Environmental records q Discussion on actions if OOS values q On site verification (walking around the site) Validation August 2006 | Slide 26 of 48 HVAC Conclusion Air-handling systems: q q q Play a major role in the quality of pharmaceuticals Should be designed properly, by professionals Should be treated as a critical system Validation August 2006 | Slide 27 of 48 HVAC Further proceedings This series of explanations will now be followed by: q q Group discussion, with a simple exercise Short test Validation August 2006 | Slide 28 of 48 HVAC Group Session S a m p lin g Rooom A ir S h o w e r S e rv i c e C o rrid o r ( c o n t a in s V a c u u m & R O w a t e r s u p p ly ) W a re h o u se A ir L o c k 2 W e ig h in g T a b le t 1 T a b le t 2 L iq u id s M ix S o ftg e l C a p su le P a c kin g A / Lock 1 C le a n C o rrid o r E m ergenc y E x it A ir L o c k 3 S te rile e y e d ro p s d isp e n sin g & a c e p tic fillin g 2 S ta g e p e rso n n e l e n try fo r e y e d ro p s M a le Change 2 F e m a le Change 2 P a c ke d G oods Q u a ra n tin e P rim a ry & S e c o n d a ry P a c kin g E q u ip m e n t W a sh M a le Change 1 F e m a le Change 1 A ir L o c k 4 S e rv ic e R o o m Validation August 2006 | Slide 29 of 48 HVAC Group Session – modified layout 20P a S a m p lin g Rooom 30P a 0P a S e rv ic e C o rrid o r ( c o n t a in s V a c u u m & R O w a t e r s u p p ly ) A ir S h o w e r 20P a 10P a W a re h o u se M AL 2 0P a W e ig h B o o th 20P a P o st S ta g in g 30P a 30P a T a b le t 1 15P a T a b le t 2 15P a L iq u id s M ix 30P a S o ftg e l C a p su le P a c kin g M A L1 A ir L o c k 15P a 30P a C le a n C o rrid o r E m ergenc y E x it 20P a 40P a 20P a PAL M AL 3 40P a S te ril e e y e d ro p s d isp e n sin g & a sc e p tic fillin g 60P a M a le Change 2 F e m a le Change 2 10P a 10P a 15P a 10P a P a c ke d G oods Q u a ra n ti n e S e c o n d a ry P a c kin g 20P a P rim a ry P a c kin g 30P a M AL 4 50P a Change 50P a E q u ip m e n t W a sh M a le Change 1 F e m a le Change 1 A ir L o c k 4 0P a S e rv ic e R o o m 0P a MAL = Material Air Lock PAL = Personnel Air Lock Validation August 2006 | Slide 30 of 48 0P a Supplementary Training Modules on Good Manufacturing Practice Commissioning, Qualification and validation of Water systems WHO Technical Report Series No 929, 2005. Annex 3 Validation August 2006 | Slide 31 of 48 HVAC Objectives To understand key issues in – commissioning, – qualification and – maintenance of HVAC and Water systems 7. Validation August 2006 | Slide 32 of 48 Water for Pharmaceutical Use Objectives To discuss the operational considerations of water systems including: q Start up, commissioning and qualification q Monitoring q Maintenance q System reviews 7. Validation August 2006 | Slide 33 of 48 Water for Pharmaceutical Use 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 7.1 Validation August 2006 | Slide 34 of 48 Water for Pharmaceutical Use 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 Validation August 2006 | Slide 35 of 48 Water for Pharmaceutical Use 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 Validation August 2006 | Slide 36 of 48 Water for Pharmaceutical Use 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 Validation August 2006 | Slide 37 of 48 Water for Pharmaceutical Use 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 7.2 Validation August 2006 | Slide 38 of 48 Water for Pharmaceutical Use 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 Validation August 2006 | Slide 39 of 48 Water for Pharmaceutical Use 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 7.2 Validation August 2006 | Slide 40 of 48 Water for Pharmaceutical Use 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 Validation August 2006 | Slide 41 of 48 Water for Pharmaceutical Use 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 7.2 Validation August 2006 | Slide 42 of 48 Water for Pharmaceutical Use 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 offline sample testing Data analysed for trends 7.3 Validation August 2006 | Slide 43 of 48 Water for Pharmaceutical Use 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 Validation August 2006 | Slide 44 of 48 Water for Pharmaceutical Use Maintenance A controlled, documented maintenance programme covering: Defined frequency with plan and instructions Calibration programme SOPs for tasks Control of approved spares 7.4 Record and review of problems and faults during maintenance Validation August 2006 | Slide 45 of 48 Water for Pharmaceutical Use 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 Validation August 2006 | Slide 46 of 48 Water for Pharmaceutical Use 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 Validation August 2006 | Slide 47 of 48 7.5 Validation Group session Validation August 2006 | Slide 48 of 48