WHO: Supplementary Training Modules on Good Manufacturing Practice

1. Supplementary Training Modules on
Good Manufacturing Practice
Validation
WHO Technical Report Series,
No. 937, 2006. Annex 4.
Validation | Slide 1 of 48 August 2006

2. 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 | Slide 2 of 48 August 2006

3. 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 | Slide 3 of 48 August 2006

4. HVAC
Objectives
To understand key issues in
– commissioning,
– qualification and
– maintenance of
HVAC and Water systems
8.
Validation | Slide 4 of 48 August 2006

5. 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
Validation | Slide 5 of 48 August 2006

6. 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 | Slide 6 of 48 August 2006

7. 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 | Slide 7 of 48 August 2006

8. 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 | Slide 8 of 48 August 2006

9. 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 | Slide 9 of 48 August 2006

10. 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 | Slide 10 of 48 August 2006

11. HVAC
 Design A C T IO N L IM IT A C T IO N L IM IT
conditions A L E R T L IM IT A L E R T L IM IT
and normal
operating
ranges set to
achievable
limits
 OOS results D e s ig n C o n d itio n
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
Validation | Slide 11 of 48 August 2006

12. 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 | Slide 12 of 48 August 2006

13. 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 | Slide 13 of 48 August 2006

14. 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 | Slide 14 of 48 August 2006

15. 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 | Slide 15 of 48 August 2006

16. 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 | Slide 16 of 48 August 2006

17. HVAC
Schedule of tests to demonstrate continuing compliance
Test Parameter Objective Maximum time Test procedure*
interval and key aspects
Particle count test Verifies cleanliness 6 months or 12 Particle counter.
months depending on Readings and
Class positions
Air pressure Absence of cross- 12 months Measure pressure
difference contamination difference
Airflow volume Verify air change 12 months Measure supply and
rates return air, calculate
air change rate
Airflow velocity Verify unidirectional 12 months Velocity
airflow and or measurement
containment condition
8. Table 3
*Test procedure as per ISO 14644
Validation | Slide 17 of 48 August 2006

18. HVAC
Recommended optional strategic tests
Test Parameter Objective Maximum time Test procedure*
interval and key aspects
Filter leakage Verify filter integrity 12 months Filter media and filter
seal integrity
Containment leakage Verify absence of 12 months Airflow direction and
cross-contamination pressure differential
Recovery (time) Verify clean-up time 12 months Time taken maximum
15 minutes
Airflow visualization Verify required airflow 12 months Airflow direction,
patterns documented evidence
*Test procedure as per ISO 14644
8. Table 3
Validation | Slide 18 of 48 August 2006

19. 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 | Slide 19 of 48 August 2006

20. 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
Validation | Slide 20 of 48 August 2006

21. HVAC
Cleanroom monitoring programme (3)
Cleanrooms should be monitored for microorganisms and
particles
air
Example of a sampling point
Validation | Slide 21 of 48 August 2006

22. HVAC
Definition of Conditions
as built at rest in operation
air air air
Validation | Slide 22 of 48 August 2006

23. 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
Validation | Slide 23 of 48 August 2006

24. 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)
Validation | Slide 24 of 48 August 2006

25. 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
Validation | Slide 25 of 48 August 2006

26. 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)
Validation | Slide 26 of 48 August 2006

27. 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
Validation | Slide 27 of 48 August 2006

28. HVAC
Further proceedings
This series of explanations will now be followed by:
Group discussion, with a simple exercise
Short test
Validation | Slide 28 of 48 August 2006

29. HVAC
Group Session
S a m p lin g
Rooom 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 )
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 ri m 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 tin 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 ic e R o o m
Validation | Slide 29 of 48 August 2006

30. HVAC
Group Session – modified layout
20P a S a m p lin g
Rooom 0P a S e rv ic 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 A L1
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 ril e e y e d ro p s P a c kin g P a c kin g
40P a 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 ti n 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 ic e R o o m 0P a
0P a
0P a
MAL = Material Air Lock
PAL = Personnel Air Lock
Validation | Slide 30 of 48 August 2006

31. Supplementary Training Modules on
Good Manufacturing Practice
Commissioning,
Qualification and
validation of Water
systems
WHO Technical Report Series
No 929, 2005. Annex 3
Validation | Slide 31 of 48 August 2006

32. HVAC
Objectives
 To understand key issues in
– commissioning,
– qualification and
– maintenance of
HVAC and Water systems
7.
Validation | Slide 32 of 48 August 2006

33. 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 | Slide 33 of 48 August 2006

34. 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 | Slide 34 of 48 August 2006

35. 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 | Slide 35 of 48 August 2006

36. 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 | Slide 36 of 48 August 2006

37. 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 | Slide 37 of 48 August 2006

38. 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 | Slide 38 of 48 August 2006

39. 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 | Slide 39 of 48 August 2006

40. 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 | Slide 40 of 48 August 2006

41. 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 | Slide 41 of 48 August 2006

42. 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 | Slide 42 of 48 August 2006

43. 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 off-
line sample testing
 Data analysed for trends
7.3
Validation | Slide 43 of 48 August 2006

44. 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 | Slide 44 of 48 August 2006

45. 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 | Slide 45 of 48 August 2006

46. 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 | Slide 46 of 48 August 2006

47. 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 7.5
Validation | Slide 47 of 48 August 2006

48. Validation
 Group session
Validation | Slide 48 of 48 August 2006