Transcript GMP Updated Training Modules

Supplementary Training Modules on
Good Manufacturing Practice
Validation
WHO Technical Report Series,
No. 961, 2011. Annex 5
Validation
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Slide 1 of 48
August 2006
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
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Slide 2 of 48
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Supplementary Training Modules on
Good Manufacturing Practice
Qualification of HVAC
and water systems
Part 2
WHO Technical Report Series, No. 961,
2011. Annex 5
Validation
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Slide 3 of 48
August 2006
HVAC
Objectives
 To understand key issues in
– commissioning,
– qualification and
– maintenance of
HVAC and Water systems
8.
Validation
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Slide 4 of 48
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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
―
Validation
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programme and records
Slide 5 of 48
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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
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Slide 6 of 48
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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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Slide 7 of 48
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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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Slide 9 of 48
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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
ACTION LIMIT
ACTION LIMIT
ALERT LIMIT
 OOS results
recorded
ALERT LIMIT
Design Condition
Normal Operating Range
Operating Range - Validated Acceptance Criteria
8.2.12 – 8.2.15
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Slide 11 of 48
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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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Slide 12 of 48
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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 differentials)
8.2.17
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Slide 13 of 48
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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
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 used, calibration
records; and conditions specified
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HVAC
Schedule of tests to demonstrate continuing compliance
Test Parameter
Objective
Maximum time
interval
Particle count test
Verifies cleanliness
6 months or 12
Particle counter.
months depending on Readings and
Class
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
*Test procedure as per ISO 14644
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Test procedure*
and key aspects
Velocity
measurement
8. Table 3
HVAC
Recommended 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
Containment leakage
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
8. Table 3
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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
 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
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HVAC
Cleanroom monitoring programme (3)
Cleanrooms should be monitored for microorganisms and
particles
air
Example of a sampling point
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HVAC
Definition of Conditions
Validation
as built
at rest
in operation
air
air
air
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Slide 22 of 48
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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 perform OQ)
3 = Operational (ideally used to perform PQ)
Airflow volume / rate
2
2
Parallelism
2
N/A
Airflow pattern
2
3
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Slide 23 of 48
August 2006
HVAC
Qualification – examples of aspects to consider in
qualification (OQ, PQ)
Uni-directional
airflow / LAF
Test
Recovery time
Room classification (airborne
particle)
Temperature, humidity
Validation
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Slide 24 of 48
Turbulent /
mixed airflow
Description
N/A
2
1 := As built (ideally used to perform IQ)
2
2,3
2 = At rest (ideally used to perform OQ)
N/A
2,3
3 = Operational (ideally used to perform PQ)
August 2006
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
 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)
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HVAC
Conclusion
Air-handling systems:

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
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Play a major role in the quality of pharmaceuticals
Should be designed properly, by professionals
Should be treated as a critical system
Slide 27 of 48
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HVAC
Further proceedings
This series of explanations will now be followed by:


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Group discussion, with a simple exercise
Short test
Slide 28 of 48
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HVAC
Group Session
Sampling
Rooom
Service Corridor
(contains Vacuum & RO water supply)
Air Shower
A/ Lock1
Air Lock2
Warehouse
Weighing
Tablet 1
Tablet 2
Liquids Mix
Softgel Capsule
Packing
Clean Corridor
Emergency
Exit
Air Lock 3
Sterile eyedrops
dispensing
& aceptic filling
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Slide 29 of 48
Male
Change 2
August 2006
Female
Change 2
Packed
Goods
Quarantine
Male
Change 1
Equipment Wash
Validation
2 Stage
personnel
entry for
eyedrops
Female
Change 1
Air Lock 4
Primary & Secondary
Packing
Service Room
HVAC
Group Session – modified layout
Sampling
Rooom
20Pa
0Pa
Service Corridor
(contains Vacuum & RO water supply)
30Pa
Air Shower
20Pa
10Pa
MAL 2
Warehouse
0Pa
Weigh
Booth
20Pa
30Pa
Post
Staging
Tablet 1
30Pa
Tablet 2
15Pa
Softgel Capsule
Packing
Liquids Mix
15Pa
30Pa
MAL1
Air Lock
15Pa
30Pa
Clean Corridor
Emergency
Exit
PAL
40Pa
MAL 3
40Pa
Sterile eyedrops
dispensing
& asceptic filling
20Pa
20Pa
Male
Change 2
Female
Change 2
10Pa
60Pa
15Pa
Equipment Wash
MAL 4
Change
50Pa
50Pa
10Pa
Male
Change 1
Female
Change 1
10Pa
Packed
Goods
Quarantine
Air Lock 4
0Pa
0Pa
MAL = Material Air Lock
PAL = Personnel Air Lock
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Slide 30 of 48
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Secondary
Packing
20Pa
Primary
Packing
30Pa
Service Room
0Pa
Supplementary Training Modules on
Good Manufacturing Practice
Commissioning,
Qualification and
validation of Water
systems
WHO Technical Report Series
No 970, 2012. Annex 2
Validation
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Slide 31 of 48
August 2006
HVAC
Objectives
 To understand key issues in
– commissioning,
– qualification and
– maintenance of
HVAC and Water systems
7.
Validation
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Slide 32 of 48
August 2006
Water for Pharmaceutical Use
Objectives
To discuss the operational considerations of water systems
including:
 Start up, commissioning and qualification
 Monitoring
 Maintenance
 System reviews
7.
Validation
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Slide 33 of 48
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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
Validation
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Slide 34 of 48
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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
Validation
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Slide 35 of 48
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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
Validation
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Slide 36 of 48
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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
Validation
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Slide 37 of 48
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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
Validation
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Slide 38 of 48
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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
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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
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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
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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
Validation
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Slide 42 of 48
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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
Validation
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Slide 43 of 48
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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 and microbial attributes
7.3
Validation
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Slide 44 of 48
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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
7.4
 Record and review of problems and faults during maintenance
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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
Validation
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Slide 46 of 48
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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;
– 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
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Slide 47 of 48
August 2006
7.5
Validation
 Group session
Validation
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Slide 48 of 48
August 2006