1. Department of Quality Assurance Maliba Pharmacy College
A Seminar On Validation of Heating, Ventilation and Air conditioning System
Department of Quality Assurance
Maliba Pharmacy College

2. Content Introduction Validation of HVAC HVAC Qualification
Validation master plan
Design Qualification(DQ)
Installation Qualification(IQ)
Operational Qualification(OQ)
Performance Qualification(PQ)
Validation parameter
References

3. Introduction Heating Ventilation and Air Conditioning system(HVAC)
HVAC systems can have an impact on product quality
It can provide comfortable conditions for operators
The impact on premises and prevention of contamination and cross-contamination to be considered at the design stage
Temperature, relative humidity control where appropriate
Supplement to basic GMP

4. What is contamination? Contaminants are :-
It is "the undesired introduction of impurities (chemical/ microbial/ foreign matter) into or on to starting material or intermediate – during sampling, production, packaging or repackaging“.
Contaminants are :-
Products or substances other than the product being manufactured
Foreign matter
Particulate matter
Micro-organisms
Endotoxins (degraded micro-organisms)

5. What is cross-contamination?
“Contamination of a starting material, intermediate product, or finished product with another starting material or product during production”.
Cross-contamination originates from:-
Poorly designed air handling systems and dust extraction systems
Poorly operated and maintained air handling systems and dust extraction systems
Inadequate procedures for personnel and equipment
Insufficiently cleaned equipment

6. Cross-contamination can be minimized by:
Personnel procedures
Adequate premises
Use of closed production systems
Adequate, validated cleaning procedures
Appropriate levels of protection of product
Correct air pressure cascade

7. HVACsystem consists of:-
Air conditioner
AHUs
Dehumidifier / Heater
Filters (Pre & HEPA)
Dust Extractors
Ducting (For delivery of controlled air)
Supply Fans
Smoke Detector
Dampers
Humidity / Temperature / Pressure sensors
Bag Filters
Heating / Cooling Coils

8. Area 1 HVAC Area 2 I M P U R E A Pure air Area 3 Area 4 10% Return Air
Impure air
Pure air
Area 3
Area 4
10% Return Air
Exhaust air

9. with droplet separator
HVAC
Filter
Silencer
Terminal filter
Weather louvre
Control damper
Fan
Flow rate controller
Humidifier
Heating
coil
Cooling coil
with droplet separator
Production Room
components +
Prefilter
Exhaust Air Grille
Heater
Secondary Filter
Recirculated air

10. Validation of HVAC systems
It includes:-
Commissioning
Qualification
Maintenance

11. Commissioning - Precursor to qualification
Includes setting up, balancing, adjustment and testing of entire HVAC system to ensure it meets requirements in URS.
Acceptable tolerances for parameters
Training of personnel

12. Conti… 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

13. Qualification
To ensure that equipment is designed as per requirement, installed properly.
Action of proving that any equipment works correctly and leads to the expected results.

14. HVAC Qualification Validation Master Plan QUALIFICATION
User Requirement Specification
Design Qualification
Installation Qualification
Operation Qualification
Performance Qualification
Re- Qualification.

15. Conti…
Manufacturers should qualify HVAC systems using a risk- based approach.
The qualification of the HVAC system should be described in a validation master plan (VMP).
The validation master plan should define the nature and extent of testing and the test procedures and protocols to be followed.
A change control procedure should be followed

16. Conti…
Risk analysis to determine critical and non-critical parameters, components, subsystems and controls
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

17. Validation master plan
This document should contain :
Validation policy
Organizational structure of validation activities
Summary of facilities, systems, equipment and processes to be validated
Documentation format to be used for protocols and reports
Planning and scheduling
Change control
References to documents

18. Qualification Temperature Relative humidity
Typical parameters to be included in qualification:
Temperature
Relative humidity
Supply, return and exhaust air quantities
Room air change rates
Room pressures (pressure differentials)
Room clean-up rate
Particulate matter, microbial matter (viable and non- viable)
HEPA filter penetration test

19. Conduct of test :
Time intervals and procedure to be defined by the manufacturer
Influenced by the type of facility and level of protection
Requalification, and change control Tests performed according to protocols and procedures for the tests
Results recorded and presented in report

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

21. Design Qualification(DQ)
First step in the qualification of new HVAC systems.
It documents the design of the system and will include:
1. Functional Specification.
2. Technical / Performance specification for equipment.
3. Detailed Air Flow Schematics.
4. Detailed layout drawing of the system.
Compliance with GMPs and other regulatory requirements.

22. Conti… Ensures that design - 1. Meets the user requirements.
2. Details facility airflow and pressure cascade philosophy.
3. Takes into account process and personnel flow (cross- contamination issues)
4. Details materials of construction.
5. Details safety requirements.
6. Full details of the intended construction prior to implementation.
7. Details all equipment that must be ordered.

23. Installation Qualification(IQ)
IQ Should include:-
Instrumentation checked against current engineering drawings and specifications
Properly served by the required utilities
Verification of materials of construction
Installation of equipment and with piping
Calibration of measuring instruments
Operation manuals and spare parts lists to assure the proper and continuous operation of the system
Components are installed at specified location

24. Conti…. IQ Document should contain-
Instrument name, model, I.D. No., Personnel responsible for activities and Date.
A fully verified installation that complies with the documented design. (all deviations will have been recorded and assessed.)
All equipment documentation and maintenance
requirements would be documented.
Completed calibration of measuring instruments.

25. Conti…. Calibration verification:
To provide a list of critical instrumentation and control panel and to document that they have been identified and calibrated in accordance with the approved procedure
SOP verification :
To verify that required SOPs exist in either draft or final form and must be current and approved for use.
Utilities Connection Verification:
Utilities supported to HVAC need to be verified to assure that they are installed properly.

26. Conti…. Change Parts and Replacement Parts Verification
Maintenance Procedures Verification
Critical Systems Change Request Procedure verification
Lubricants Verification

27. Operation Qualification
The purpose of OQ is to establish, through documented testing, that all critical components are capable of operating within established limits and tolerances.
The purpose of OQ is to verify and document that an HVAC system provides acceptable operational control under “at-rest” conditions.
Scope of OQ is to test the individual components of the system such as AHU, blowers and others.

28. Conti… Operation Qualification Checks -
Ability to provide air of sufficient quality and quantity to ensure achievement of specified clean room conditions.
Ability to maintain temperature, relative humidity and pressure set points.
Ability to maintain any critical parameters stated in the DQ consistently.

29. Conti….
Includes the tests that have been developed from knowledge of processes, systems and equipment.
Tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as ‘worst case’ conditions.

30. OQ also includes:- Testing Equipment Calibration Verification
Instrumentation Calibration verification
SOP Verification
Operation Qualification tests

31. Conti…
OQ protocols to be written and approved prior to completion. It includes following:
All relevant SOPs should be in place
Temperature measurement report
Humidity measurement report
Differential pressure measurement report
Air flow direction measurement report
Room particle count measurement report
All maintenance/ cleaning instructions available
All O & M staff to be trained to use and maintain the system.
Sign off. (Compliance Certificate by Engineering Dept & QA)

32. Performance Qualification
The purpose of PQ is to verify and document that an HVAC system provides acceptable control under ‘ Full Operational ‘ conditions.
PQ should follow successful completion of IQ and OQ.
PQ verifies that the critical parameters, as defined in the DQ are being achieved.

33. Conti… PQ Should include -
Test to include a condition or set of conditions encompassing upper and lower operating limits.
Tests should be conducted under “in use”, condition either or simulated as close as possible to the actual process

34. Conti…
PQ is used to demonstrate consistent achievement of critical parameters over time. ( under manufacturing conditions)
PQ and OQ tests are sometimes performed in conjunction with one another.
Any changes to the HVAC system should be revalidated before proceeding to the PQ phase.

35. Validation Parameters
Air flow measurement
Room air changes per hour.
Filter Integrity Testing (HEPA Leak test)
Pressure Differentials
Particulate count measurement
Recovery test
Temperature and Relative Humidity
Air Flow Pattern
Microbial Count

36. Conti… A. PHYSICAL TESTS A1. NON-VIABLE PARTICLE COUNTS Equipment
Optical Particle Counter (Discrete Particle Counter)
Air sample is drawn into the instrument & passed through light scattering device. The signal that this generates is electronically processed to display particle counts at different size ranges.
Sample Volume
1 cubic ft
Sample Time
1 Min

37. Conti… Acceptance criteria: Frequency: GMP compliance:- Quarterly
Sch M - 6 Monthly
Acceptance criteria:
1. Critical environments: The particle concentration under the dynamic condition should not more than 100 particle of 0.5µm and larger per cubic meter (for class 100 area)

38. Conti… Equipment A2. PRESSURE DIFFERENTIALS Introduction
Correct degree of overpressure can be maintained relative to the adjacent areas of lower classification to ensure that air moves from clean areas to less clean areas.
Equipment
Electronic manometer (portable and easy to use),
Incline manometer

39. Conti… Sample location Frequency of sampling
Between adjacent areas connected either by a door or grille.
Frequency of sampling
Continuously by gauges / manometer & recorded daily.

40. Conti… Acceptance Criteria Action
> 10 Pa between classified area & adjacent area of lower classification
> 15 Pa between classified area & unclassified area
Action
HEPA filter blockage
Increase fan speed
Increase air flow to specific area by altering dampers

41. Conti… A3. AIRFLOW VELOCITY Equipment :- Anemometer
Reading should be taken 10cm from the surface of filter.
Record velocity reading from all the four corners and the Centre of the filter surface.
Repeat twice at each location
For Grade A laminar flow workstations, the air flow rates shall be 0.3 meter per second + 20% (for vertical flows) and % (for Horizontal flows)
No value may deviate from the mean by more than +20 %

42. Conti…
Air velocity exceeding the stated value may cause excessive air movement & affect work zone protection.
Air velocity below the limit may be insufficient to maintain critical work zone protection.
Deviation indicates the blockade of filter
Solution : Alteration of fan speed or HEPA filter replacement

43. Conti… A4. HEPA filter integrity test (DOP test) Purpose :
To confirm that no damage to filter, seals and no leakage of particles.
Equipment :
1. Aerosol generator
2. Photometer
Scan at 1 inch from filter surface.
Make separate passes at peripheries.

44. Conti… Acceptance criteria:
An unacceptable leak is defined as a penetration of 0.03% or more of particle, 0.3µm and larger than the reference calibration curve for 99.97% efficient filter

45. Conti… A5. Temperature and Relative Humidity:
Use a sling psycrometer to measure the dry bulb and wet bulb temperature of the air.
Check the wick of the sling psycrometer, it should be always in wet conditions in order to record correct wet bulb temperature.
Sling the psycrometer in air for about a minute’s time and record the dry bulb and wet bulb temperature.
Check the wet bulb depression i.e. difference between dry bulb and wet bulb temperature.

46. Conti… Acceptance criteria: Frequency : Daily
Temperature : NMT 27 degree centigrade
Humidity : NMT 55 %
Frequency : Daily

47. Conti… A6.Air change rate:
Measurement of the air supply volume and determination of the air change rate (ACR) is a measure of the frequency of air turnover in the clean room.
This gives some idea as to how quickly contamination may be removed from the clean room provided there is acceptable mixing of air in the room.
The ACR can be determined by measuring the mean air velocity at the supply HEPAs or grilles and calculating the air change rate based on the mean air supply volume.

48. Conti…
Equipment: Anemometer
Sample locations
At least four positions are tested across the filter or grille face to obtain the mean supply air velocity.
Frequency of sampling
Sch M - 6 Monthly
GMP compliance – Quarterly

49. Conti… A7. MICROBIOLOGICAL TESTS
Solid growth media (e.g. settle and contact plates) Soybean Casein Digest Agar medium can be used for both Bacteria & Fungi tested.
The recommended size of solid media is 90 mm in diameter (for settle plates)
55 mm for contact plates.

50. Conti… Sampling condition: Incubation condition:
Sampling in the at rest condition may be continued at an agreed frequency to monitor baseline contamination levels
The operational conditions and the activities being performed at the time of testing should be recorded
Incubation condition:
Incubation of samples, inverted, at 20 – 25o C for at least 5 days is suitable for the growth of mould and fungi.
Incubation of samples, inverted, at C for at least 2 days is suitable for the growth of bacteria.

51. Conti… Acceptance criteria for Airborne Bioburden test:
Critical Environment: no more than 1 CFU/m3, or CFU/ft3(USP monograph)
Acceptance criteria for Surface Bioburden test:
Critical Environment: no more than 1 CFU/12.9cm2, or 2 in2 (FDA Aseptic Processing Guidelines)

52. References
Supplementary guidelines on good manufacturing practices for HVAC systems for non-sterile pharmaceutical dosage forms. (WHO Technical Report- Series, No. 937), Annex 2.(2006)
Validation of pharmaceutical process, sterile product
2ndEdition, edited by Fredrick J. Carleton, James P. Agalloco, page no

53. Thank you