Transcript
Supplementary Training Modules on Good Manufacturing Practice
Validation
WHO Technical Report Series, No. 937, 937, 2006. 2006. Annex 4.
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Validation
Part 1. General overview on qualification and validation
Part 2. Qualification of HVAC and water w ater systems
Part 3. Cleaning validation 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
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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
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HVAC Objectives
To understand key issues in – commissioning, – qualification and – maintenance of HVAC and Water systems 8.
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HVAC Documentation requirements to assist in commissioning, qualification and maintenance q
Description of design, installation and functions
q
Specifications, Specification s, requirements
q
Manuals
q
Operating procedures
q
Instructions for performance control, monitoring and records
q
Maintenance instructions and records
q
Training of personnel ―
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programme and records Slide 5 of 48
HVAC Commissioning
Precursor to qualificatio qualification n
Includes setting up, balancing, adjustment and testing of entire HVAC system to ensure it meets m eets requirements in URS and capacity
Acceptable tolerances for parameters
Training of personnel
8.1.1, 8.1.4, 8.1.5
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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
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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
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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
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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
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HVAC
Design conditions and normal operating ranges set to achievable limits
A C T I O N L IM IM I T
A C T I O N L IM IM I T A L E R T LIL I M I T
A L E R T LIL I M I T
D e s i g n C o n d i tit i o n
OOS results recorded
N o r m a l O p e r a tit i n g R a n g e
O p e r a t ini n g R a n g e - V a l idi d a t e d A c c e p t a n c e C r it e rir i a
8.2.12 – 8.2.15
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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
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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 differential differentials) s) 8.2.17
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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
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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 Requalification 8.2.18 – 8.2.20, 8.2.9
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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 st andards used, calibration records; and conditions specified
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HVAC Schedule of tests to t o demonstrate continuing compliance Test Parameter
Objective
Maximum time interval
Test procedure* and key aspects
Particle count test
Verifies cleanliness
6 months or 12 months depending on Class
Particle counter. Readings and positions
Air pressure difference
Absence of crosscontamination
12 months
Measure pressure difference
Airflow volume
Verify air change rates
12 months
Measure supply and return air, calculate air change rate
Airflow velocity
Verify unidirectional 12 months airflow and or containment condition
Velocity measurement 8. Table 3
*Test procedure as per ISO 14644 Validation
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HVAC Recommended Recommende d optional strategic tests Test Parameter
Objective
Maximum time interval
Test procedure* and key aspects
Filter leakage
Verify filter integrity
12 months
Filter media and filter seal integrity
Containmentt leakage Containmen
Verify absence of cross-contamination
12 months
Airflow direction and pressure differential
Recovery (time)
Verify clean-up time
12 months
Time taken maximum 15 minutes
Airflow visualization
Verify required airflow patterns
12 months
Airflow direction, documented evidence
*Test procedure as per ISO 14644
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8. Table 3
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
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HVAC Cleanroom monitoring programme (2) Particles and Microbiological contaminants q
Number of points/locations for monitoring determined, specified, documented in procedure and or protocol
q
Sufficient time for exposure, and suitable sample size
q
Identification and marking of sampling points
q
Definition of transport, storage, and incubation conditions
q
Results to reflect the procedure/protocol followed followed
q
Define alert and action limits as a function of cleanliness zone/class See also ISO 14644
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HVAC Cleanroom monitoring programme (3) Cleanrooms should be monitored for microorganisms and particles air
Example of a sampling point Validation
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HVAC Definition of Conditions as built
at rest
in operation
air
air
air
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HVAC Qualification – examples of aspects to consider in qualification (OQ, PQ) Uni-directional airflow / LAF
Test
Turbulent / mixed airflow
Differential pressure on filters
2
2
Room differential pressure
N/A
2, 3
Airflow velocity / uniformity
2, 3
Optional
Description
1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to to perform OQ) OQ) 3 = Operational (ideally (ideally used to perform perform PQ)
Airflow volume / rate
2
2
Parallelism
2
N/A
Airflow pattern
2
3
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HVAC Qualification – examples of aspects to consider in qualification (OQ, PQ)
Uni-directional airflow / LAF
Test
Turbulent / mixed airflow
Description
Recovery time
N/A
2
1 := As built (ideally used to perform IQ)
Room classification (airborne particle)
2
2,3
2 = At rest (ideally used to to perform OQ) OQ)
Temperature, humidity
N/A
2,3
3 = Operational (ideally (ideally used to perform perform PQ)
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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
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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 requirem requirements ents
q
Operating procedures
q
Maintenance instructions
q
Maintenance records
q
Training logs
q
Environmentall records Environmenta
q
Discussion on actions if OOS O OS values
q
On site verification (walking around the site)
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HVAC Conclusion Air-handling systems: q
Play a major role in the quality of pharmaceuticals
q
Should be designed properly, by professionals
q
Should be treated as a critical system s ystem
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HVAC Further proceedings This series of explanations will now be followed by: q
Group discussion, with a simple exercise
q
Short test
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HVAC Group Session S a m p li n g Rooom
S e r v i c e C o r rir i d 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 )
AirShow er
W a re h o u s e
W e ig h in g
2 k c o L
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
r i A 1 k c o L / A
C l e a n C o rr i d o r Emergency Exit
A ir Lo ck 3
S t e r il e e y e d ro p s dispensing & a c e p t i c fi ll i n g
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M a le Change 2
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F e m a le Change 2 Packed Goods Q u a r a n t ini n e
M a le Change 1
E q u i p m e n t W a sh
Validation
2 Stage personnel e n t ryr y f o r eyedrops
F e m a le Change 1
A ir Lo ck 4
P r im a r y & S e c o n d a r y Packing
S e rv ic e R o o m
HVAC Group Session – modified layout S a m p l ini n g Rooom
20Pa
0Pa
S e rv i c e C o rri d 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 )
30Pa
AirShow er 20Pa 10Pa
W a re h o u s e 2
W e ig h Booth 20Pa
30Pa
Post Staging T ablet 1
30Pa
T ablet 2
S o f tgt g e l C a p s u l e P a c kin g
Liquids M ix
L A
15Pa
M
0Pa
15Pa
30Pa
Air Lo ck
1 L
15Pa
A M
30Pa
C l e a n C o r ri d o r Emergency Exit 20Pa
PA L 40Pa
M A L 3 40Pa
S t e r il e e y e d ro p s dispensing & a s c e p t ic f i ll in g
20Pa
M a le Change 2
F e m a le Change 2
10P a 60Pa
M A L 4
15Pa
E q u i p m e n t W a sh
50Pa
Change 50Pa
10P a
M a le Change 1
F e m a le Change 1
10Pa
Packed Goods Q u a r a n ti n e
Air Lock 4 0Pa
MAL = Material Air Lock PAL = Personnel Air Lock Validation
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0Pa
Secondary P a c ki n g
20P a
P r im a r y Packing 30P a
S e rv ic e R o o m
0Pa
Supplementary Training Modules on Supplementary Good Manufacturing Practice Commissioning, Qualification and validation of Water systems
WHO Technical Report Series No 929, 2005. Annex 3
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HVAC Objectives
To understand key issues in – commissioning, – qualification and – maintenance of HVAC and Water Water systems systems 7.
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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.
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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
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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
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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
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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
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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
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Water for Pharmaceutical Use Phase 1 (3)
Demonstrate production and delivery of product water of the t he required quality and quantity
Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooti troubleshooting ng
Verify provisional alert and action levels
Develop and refine test-failure procedure
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Water for Pharmaceutical Use Phase 2 (1)
A further test period of 2–4 weeks – further intensive monitoring monitoring the system
Deploying all the refined SOPs after the satisfactory completion of phase 1
Sampling scheme generally generally the same as in phase 1
Water can be used for manufacturing purposes during this phase 7.2
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Water for Pharmaceutical Use Phase 2 (2) Demonstrate:
Consistent operation within established ranges
Consistent production and delivery delivery of water w ater of the required quantity and quality when the system is operated in accordance with the SOPs.
7.2
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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
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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
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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 c hemical and microbial attributes 7.3
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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
Record and review of problems and faults during maintenance
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7.4
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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
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Water for Pharmaceutical Use System review (2)
The review to cover, e.g. – changes made since the last review; – system performance performance;; – reliability; – quality trends; – failure events; – investigations; – out-of-specification out-of-specifications s results from monitori monitoring; ng; – changes to the installation; – updated installation documentation; – log books; and – the status of the current SOP lists
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7.5
Validation
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Group session
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