1. Prepared By:
Vinay Prajapati .
M. Pharm Sem-II
Roll no:13
Department of Quality Assurance
Guided By:
Mr. Jignesh Shah 11
S.J.Thakkar Pharmacy College, Rajkot.
3. INTRODUCTION
To understand:
The need and reason for pharmaceutical
air handling systems.
The technical requirements for air handling
systems.
Different types of air handling systems.
Qualification and Validation requirements
3
4. WHAT IS CLEAN ROOM?
A room in which the concentration of
airborne particle is controlled and which is
constructed and used in a manner to
minimize the introduction, generation and
retention of particles inside the room and in
which other relevant parameters.
e.g.. Temperature, humidity and pressure,
are controlled as necessary.
(ISO 14644-1) 4
5. WHY CLEAN ROOM NECESSARY?
It controls 3 types of contamination transfer
Air borne contamination
Direct contamination by personnel,
equipment etc.
Contamination from fluids like cleaning
fluids, solutions etc.
As airborne particulate are reduced,
chances of particles entry in the process
reduced. 5
Protects product, personnel & environment.
6. HOW IT IS ACCOMPLISHED?
• A clean room is continuously flushed
with highly filtered air that is forced in
through HEPA filters.
6
7. TYPES OF CLEAN ROOMS
Horizontal Clean Room – Horizontal
Laminar flow
(HEPA filters in a wall force clean air from one side
of the room to other.)
Vertical Clean Room – Vertical Laminar
flow
(HEPA filters on the ceiling push clean air down to
the floor.)
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8. FOUR BASIC PRINCIPLES OF CLEAN
ROOM
Not To Bring Any Dust
Not To Accumulate Any Dust
Not To Generate Any Dust
To Remove Any Dust Quickly
8
9. INTRODUCTION
Air handling systems,
Play a major role in the quality of
pharmaceuticals.
Must be designed properly, by professionals.
Must be treated as a critical system.
9
10. INTRODUCTION
The manufacturing environment is critical for product
quality.
Environment consists of,
Light
Temperature
Humidity
Air movement
Microbial contamination
Particulate contamination
Uncontrolled environment can lead to product
degradation
product contamination 10
loss of product and profit
12. US FDA
21 CFR part 211
(Requirement for building & Facilities)
Under 211.42 (c)
Operation shall be performed within the specifically
defined areas and such other controls, necessary to
prevent contamination or mix ups.
Temperature and Humidity controlled.
An air supply filtered through HEPA filter under
positive pressure.
A system of monitoring environmental conditions.
Under 211.46 (C)
Air filtration system, including pre-filters and
particulate matter air filtration shall be used when 12
appropriate on air supplies to production areas.
13. EU GUIDELINES
(PREMISES & EQUIPMENT)
Under 3.12,
Production areas shall be effectively ventilated with
air control facilities including temperature & where
necessary humidity and filtration.
13
14. SCHEDULE – M
PART – 1 (GMP FOR PREMISES AND
MATERIALS)
Under point 8.21,
The licensee shall prevent mix-ups and
cross contamination of Drug Materials and
Drug Products (from environment dust) by
proper air handling system.
Part 1A (GMP for Sterile preparation)
Section 3 – Details of HVAC system
Section 4 – Parameterrs for Validation and
14
Frequency of Monitoring
15. INTRODUCTION
HVAC (AHU) is
HEART
of Pharmaceutical Industries
15
16. INTRODUCTION
Area - 1
I
Area - 2 M
9 P
0 U
HVAC R
%Impure Air Pure Air
Area - 3 E
A
I
Area - 4 R
10% Return
Air
Impure Air
16
Exhaust
17. CONTAMINATION
W are contaminants ?
hat
Contaminants are
1. Products or substances other than the product
being manufactured.
2. Foreign products.
3. Particulate matter.
4. Micro-organisms.
5. Endotoxins (degraded micro-organisms).
Cross-contamination is a particular case of
17
contamination
18. CONTAMINATION
Cross-Contamination
From where does Cross-Contamination
originate?
1. Poorly designed air handling systems
and dust extraction systems
2. Poorly operated and maintained air
handling systems and dust extraction
systems
18
3. Inadequate procedures for personnel
and equipment
19. CONTAMINATION
Cross-contamination can be minimized by:
1. Personnel procedures
2. Adequate premises
3. Use of closed production systems
4. Adequate, validated cleaning procedures
5. Appropriate levels of protection of product
6. Correct air pressure cascade
19
20. AIR FLOW PATTERNS
Prefilter
AHU
Main filter
1 2 3
Turbulent Uni-directional Turbulent
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22. HVAC 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.
22
24. HE 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
24
Change control
References to documents
26. USER REQUIREMENT
SPECIFICATION
Capacity of HVAC depends on,
1.Room Volume.
2.No. of Air Changes Required.
3.Production / Consumption Data
4.Seasonal fluctuation.
5.Air Classification of Rooms.
6.Future Development.
26
27. USER REQUIREMENT
SPECIFICATION
Parameters to be defined in Levels of Protection :
Air cleanliness requirements
1. filters type and position,
2. air changes,
3. air flow patterns,
4. pressure differentials,
5. contamination levels by particulate matter
& micro-organisms.
27
• User Requirement Specification should be
approved by Production, Engineering and
28. DESIGN QUALIFICATION
Based on the URS supplier designs the
equipment-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. 28
29. DESIGN QUALIFICATION
Compliance with GMPs and other regulatory
requirements.
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. 29
7. Details all equipment that must be ordered.
31. INSTALLATION QUALIFICATION
IQ Should include,
Instrumentation checked against current
engineering drawings and specifications
Verification of materials of construction
Installation of equipment and with piping
Calibration of measuring instruments
requirements
Collection and collation of supplier
operating and working instructions and
maintenance requirements 31
32. INSTALLATION QUALIFICATION
Practical aspect of IQ (Cont….)
Calibration of measuring instruments.
Calibration of additionally used instruments.
Initial cleaning records.
Basic commissioning checks.
Maintenance requirements.
IQ process checks that the correct components
are installed in
the correct location.
Materials of construction
32
Spare parts
Change controls
33. INSTALLATION
QUALIFICATION
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.
33
Completed calibration of measuring
instruments.
34. OPERATION QUALIFICATION
ISPE definition : 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.
34
35. OPERATION QUALIFICATION
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. 35
36. OPERATION QUALIFICATION
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.
36
37. OPERATION QUALIFICATION
IQ reports must be completed and signed off.
OQ protocols to be written and approved prior
to completion.
Measurement reports are required to
demonstrate achievement of critical parameters
as detailed in DQ.
Eg: * 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
37
* All drawings etc. – done in ‘as-built’ status
* All maintenance/ cleaning instructions available
* All O & M staff to be trained to use and maintain the
38. 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 over time, the critical
parameters, as defined in the DQ are being
achieved.
38
39. PERFORMANCE QUALIFICATION
PQ Should include,
Tests, using production materials, qualified
substitutes or simulated product, that have
been developed from knowledge of the
process and facilities, systems or equipment.
Test to include a condition or set of
conditions encompassing upper and lower
operating limits.
PQ is used to demonstrate consistent
achievement of critical parameters over time. 39
( under manufacturing conditions)
40. QUALIFICATION
COMPLETE DOCUMENTATION
Verification of design documentation,
including
Description of installation and
functions
Specification of the requirements
Instructions for performance control
Operating procedures
Maintenance instructions
Maintenance records
Training of personnel (program and records)
Environmental records
40
Discussion on actions if OOS values
Walking around the plant
41. VALIDATION
Document act of proving that any procedure,
process, system / equipment ACTUALLY leads
to expected results.
To ensure that system provides continuously
required environmental conditions.
41
42. VALIDATION PARAMETERS
1. Air flow measurement
2. Room air changes per hour.
3. Filter Integrity Testing (HEPA Leak test)
4. Pressure Differentials
5. Particulate count measurement
6. Recovery test
7. Temperature and Relative Humidity
8. Air Flow Pattern
9. Microbial Count
42
43. VALIDATION PARAMETERS
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
43
•1 Min
44. VALIDATION PARAMETERS
Sample Location (ISO 14644)
No. of sampling location = NLT Sq. Rt.A
Where A = Area of entrance plan in
Sq.Meter
No. of location rounded to nearest higher
integer
Minimum location 3
Evenly distributed within the area under test
and at a position related to the working
activity (typically at bench height 1m from the 44
floor and NMT 1 Ft from work station.).
45. VALIDATION PARAMETERS
Frequency
Sch M - 6 Monthly
GMP compliance – Quarterly
Acceptance Criteria
AT REST IN OPERATION
Grade Maximum number of permitted particles per cubic metre equal to or
above
0.5µ 5.0µ 0.5µ 5.0µ
A 3520 29 3500 29
B 35,200 293 3,52,000 2930
C 3,52,000 2,930 35,20,000 29,300
D 35,20,000 29,300 Not defined Not defined 45
46. VALIDATION PARAMETERS
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
Sample Location
Between adjacent areas connected either by
a door or grille. 46
Frequency of sampling
Continuously by gauges / manometer &
47. VALIDATION PARAMETERS
– Acceptance Criteria
> 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
47
48. VALIDATION PARAMETERS
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 0.45 + 20% (for 48
Horizontal flows)
49. VALIDATION
PARAMETERS
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.
Action: Deviation indicates blockage of filter
Solution : Alteration of fan speed
HEPA filter
replacement
49
50. VALIDATION PARAMETERS
A4. HEPA FILTER INTEGRITY TEST
(DOP Test)
Purpose : To confirm that there is no damage to
filter, seals and there is no leakage of particles.
Equipment : 1. Aerosol generator (Using
Dioctylphthalate)
2. Photometer
Scan at 1 inch from filter surface. Traverse at
NMT 10Ft. Min. Cover entire range.
Make separate passes at peripheries.
50
51. VALIDATION PARAMETERS
A5. TEMPERATUR & RELATIVE HUMIDITY
E
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. 51
Refer the psycrometric chart to check the
53. VALIDATION PARAMETERS
A6. AIR CHANGE R ATE (ACR)
Introduction
Conventional clean rooms operate on the principle
that the air supplied to the room is of sufficient
quantity to dilute or remove the contamination
generated within the room.
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. 53
The ACR can be determined by measuring the
mean air velocity at the supply HEPAs or grilles and
54. VALIDATION PARAMETERS
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 54
55. VALIDATION PARAMETERS
Results and interpretation of results
The ACR (per hour) can be calculated using the
following formula: ACR = Air supply volume
(m³/s) x 3600/ Room volume (m³)
Air Volume = Sum ( Avg. Velocity x Filter
area)
Where there is more than one supply HEPA in a
room the air supply volume for each filter should be
determined and the volumes summed (to give a
total air supply volume) before multiplying by 3600 55
and dividing by the room volume.
56. VALIDATION PARAMETERS
Requirement : Class B = 60, C & D = 20 ACPH
Action
• Change the filter
• ACR to be rebalanced
B. 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 56
mm in diameter (for settle plates)
55 mm (surface area 25 cm²) for contact
57. VALIDATION PARAMETERS
• Sampling conditions
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 conditions
Incubation of samples, inverted, at 20 - 25C
for at least 5 days is suitable for the growth of
mould and fungi. 57
Incubation of samples, inverted, at 30 - 35C
for at least 2 days is suitable for the growth of
58. VALIDATION PARAMETERS
Recommended Limits for microbiological
monitoring of clean areas
Total Viable Count
(Guidelines)
Conditions : In operation
Grade EU Schedule – M
US Air Sampling
(90mm / 4 Hrs) (90mm / 2 Hrs) (90mm / 4
Hrs) (1000cc)
A <1 <1 <1
<1
B <10 <5 <3
<7
58
59. REFERENCES
1. “Validation in pharmaceutical industry” ; edited by
P.P. sharma ;first edition 2007 ; 169-192
2. “Pharmaceutical Process Validation”; An
international 3rd edition; edited by R. A. Nash and A. H.
Wachter; 413-432
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60. GTU QUESTIONS
• Describe validation parameters of HVAC
system
60
