Validation: WHO Technical Report Series, No. 937, 2006. Annex 4

Supplementary Training Modules on
Good Manufacturing Practice
Validation
WHO Technical Report Series,

No. 937, 2006. Annex 4.
Validation | 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

Qualification of HVAC
and water systems
Part 2
WHO Technical Report Series, No. 937,
2006. Annex 4. Appendix 1 and 2

HVAC
Objectives
 To understand key issues in

– commissioning,
– qualification and
– maintenance of
HVAC and Water systems

8.

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
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

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

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

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

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

HVAC
 Design A C TIO N LIM IT A C TIO N LIM IT
conditions A LE R T LIM IT A LE R T LIM IT
and normal
operating
ranges set to
achievable
limits
D e s ig n C o n d itio n
 OOS results
recorded
N o r m a l O p e r a tin g R a n g e
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

8.2.12 – 8.2.15

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

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

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

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

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

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

HVAC
Recommended optional strategic tests
Test procedure* Maximum time Objective Test Parameter
and key aspects interval
Filter media and filter 12 months Verify filter integrity Filter leakage
seal integrity
Airflow direction and 12 months Verify absence of Containment leakage
pressure differential cross-contamination
Time taken maximum 12 months Verify clean-up time Recovery (time)
15 minutes
Airflow direction, 12 months Verify required airflow Airflow visualization

documented evidence patterns
*Test procedure as per ISO 14644

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

HVAC
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

HVAC

Cleanrooms should be monitored for microorganisms and
particles
air
Example of a sampling point

HVAC
Definition of Conditions
as built at rest in operation

air air air

HVAC
Qualification – examples of aspects to consider in
qualification (OQ, PQ)
Uni-directional Turbulent / mixed
Test Description
airflow / LAF airflow
Differential pressure on filters 2 2
Room differential pressure N/A 2, 3 1 := As built (ideally used to perform IQ)

2 = At rest (ideally used to perform OQ)
Airflow velocity / uniformity 2, 3 Optional
3 = Operational (ideally used to perform PQ)
Airflow volume / rate 2 2
Parallelism 2 N/A
Airflow pattern 2 3

HVAC
Qualification – examples of aspects to consider in

qualification (OQ, PQ)
Uni-directional Turbulent /
Test Description
airflow / LAF mixed airflow
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 perform OQ)
Temperature, humidity N/A 2,3 3 = Operational (ideally used to perform PQ)

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
8.3.1 – 8.3.5
– Qualification

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)

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

HVAC
Further proceedings
This series of explanations will now be followed by:

 Group discussion, with a simple exercise
 Short test

HVAC
Group Session
S a m p lin g
Rooom 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
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
M a le F e m a le
2 S ta g e Change 2 Change 2
S te ril e e y e d ro p s p e rso n n e l P rim a ry & S e c o n d a ry
d isp e n sin g e n try fo r P a c ke d
P a c kin g
& a c e p tic fillin g e y e d ro p s G oods
A ir L o c k 3
Q u a ra n ti n e
M a le F e m a le
Change 1 Change 1
E q u ip m e n t W a sh A ir L o c k 4
S e rv i c e R o o m

HVAC
Group Session – modified layout
20P a S a m p lin g
Rooom 0P a S e rv i c e C o rrid o r
30P a ( 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 30P a
10P a
W e ig h P o st
B o o th S ta g in g S o ftg e l C a p su le
W a re h o u se
20P a 30P a T a b le t 1 T a b le t 2 L iq u id s M ix P a c kin g
M AL 2 15P a 15P a 30P a
0P a
A ir L o c k
M AL1
15P a
30P a
C l e a n C o rri d o r
E m ergenc y
E x it
20P a 20P a
PAL
40P a M a le F e m a le 10P a
M AL 3 Change 2 Change 2 S e c o n d a ry P rim a ry
S te rile e y e d ro p s P a c kin g
40P a
P a c kin g
d isp e n sin g P a c ke d
& a sc e p tic fillin g G oods
Q u a ra n tin e 20P a 30P a
10P a 10P a
60P a
Change M a le F e m a le
15P a M AL 4
50P a Change 1 Change 1
E q u ip m e n t W a sh 50P a A ir L o c k 4
S e rv i c e R o o m 0P a
0P a
0P a
MAL = Material Air Lock
PAL = Personnel Air Lock
Commissioning,
Qualification and
validation of Water
systems
WHO Technical Report Series

No 929, 2005. Annex 3

HVAC
Objectives
 To understand key issues in

– commissioning,
– qualification and
– maintenance of
HVAC and Water systems

7.

Water for Pharmaceutical Use
Objectives
To discuss the operational considerations of water systems
including:
 Start up, commissioning and qualification
 Monitoring
 Maintenance
 System reviews
7.

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

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
 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

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

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

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

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

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

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

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

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

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

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 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
 Group session

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Supplementary Training Modules on

Good Manufacturing Practice

WHO Technical Report Series,

Validation | Slide 1 of 48 August 2006

 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 | Slide 2 of 48 August 2006

Validation | Slide 3 of 48 August 2006

 To understand key issues in

HVAC and Water systems

Validation | Slide 4 of 48 August 2006

Validation | Slide 5 of 48 August 2006

 Includes setting up, balancing, adjustment and testing of entire

 Acceptable tolerances for parameters

8.1.1, 8.1.4, 8.1.5

Validation | Slide 6 of 48 August 2006

 Installation records – documented evidence of measure

 Data: design and measurement for, e.g. air flow, system

 O&M manuals, schematic drawings, protocols, reports

8.1.2, 8.1.3, 8.1.6

Validation | Slide 7 of 48 August 2006

 Qualification of the HVAC system is one component in the

 See also full guidelines on "Validation" in WHO TRS, No. 937,

 Risk based approach for HVAC qualification

Validation | Slide 8 of 48 August 2006

 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,

Validation | Slide 9 of 48 August 2006

 Non-critical systems and components are subjected to Good

 Acceptance criteria and limits defined in design stage

 Design conditions, normal operating ranges, operating

Validation | Slide 10 of 48 August 2006

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 | Slide 11 of 48 August 2006

Validation | Slide 12 of 48 August 2006

Validation | Slide 13 of 48 August 2006

Validation | Slide 14 of 48 August 2006

 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 | Slide 15 of 48 August 2006

 Tests performed according to protocols and procedures for

 Results recorded and presented in report (source data kept)

 Traceability, e.g. devices and standards used, calibration

Validation | Slide 16 of 48 August 2006

Validation | Slide 17 of 48 August 2006

Airflow direction, 12 months Verify required airflow Airflow visualization

*Test procedure as per ISO 14644

Validation | Slide 18 of 48 August 2006

Validation | Slide 19 of 48 August 2006

Validation | Slide 20 of 48 August 2006

Cleanroom monitoring programme (3)

Example of a sampling point

Validation | Slide 21 of 48 August 2006

as built at rest in operation