CHAPTER-09-10: Pharmaceutical HVAC system.

Introduction:
In pharmaceutical industry manufacturing environment of drug products is of
primary importance, because the quality attributes of drug products includes not
only the strength of the drug but also the safety and purity of drug products.
Manufacturing environment is one of the potential sources of contamination and
cross-contamination. Manufacturing space temperature and moisture content
(RH) directly affects the quality and stability of the drug product.
In pharmaceutical industry, HVAC (Heating, Ventilation and Air Conditioning)
System is designed and built to control the environment and it has four basic
functions:

1. Control airborne particles, dust and micro-organisms – Through air filtration

using high efficiency particulate air (HEPA) filters.
2. Maintain the room pressure to keep air pressure differential with surrounding
area to prevent contamination and cross-contamination.
3. Maintain space moisture (Relative Humidity) – Humidity is controlled by
cooling air to dew point temperatures or by using desiccant dehumidifiers.
4. Maintain space temperature - Temperature can affect production directly or
indirectly by fostering the growth of microbial contaminants on workers.

Pharmaceutical Clean Rooms and Cleanliness Standards:

A cleanroom is defined as a room in which the concentration of airborne
particles is controlled. The cleanrooms have a defined environmental control of
particulate and microbial contamination and are constructed, maintained, and
used in such a way as to minimize the introduction, generation, and retention of
such contaminants.
Cleanrooms classified in the United States by Federal Standard 209E of
September 1992 and by the European Economic Community (EEC) published
guidelines. European Community defines cleanrooms in alpha Grades A, B, C
and D. The classification is given on two different conditions: 1) “At-Rest” and
2) ‘In-Operation”
“At –Rest” - ‘state of cleanrooms is the condition where the production
equipment is installed but without any operating personnel.

“In- Operation” - state of cleanrooms is the condition where the installation is

functioning in the defined operating mode with the specified number of
personnel working.

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 3
Maximum permitted number of particles per m :
Grade At rest In operation
0.5µ 5µ 0.5µ 5µ
A(LAF) 3520 20 3520 20
B 3520 20 352,000 2,900
C 352,000 2,900 3,520,000 29000
D 3,520,000 29000 Not defined Not defined
Federal Standard 209E shows the air cleanliness by measuring total number of
3
particles per ft and defines as class. Class 100, 1000, 10000, 10,000 but these
are similar considering 1 M³= 35 Ft³
3 3
Classes Maximum particles /ft Equivalent to Maximum particles / m
Class-100 (LAF) 100 3,500
Class-1000 1,000 35,000
Class-10000 10,000 350,000
Class-100000 100,000 3,500,000
Recommended limits for microbiological monitoring of clean areas during
operation:
Grade Air sample Settle plates Contact plates Glove print
cfu/m³ (diam. 90 mm), (diam. 55 mm), 5 fingers
cfu/4 hours (b) cfu/plate cfu/glove
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
LAF: Laminar air flow, 0.45 M/S ± 20 %( 0.36-0.54 M/S).

Components of HVAC System:

Major component of HVAC system is
A. Air Handling Unit(AHU),
B. Air Filters
C. Ducting.

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 A. Air Handling Unit(AHU)- AHU is composed of
 Blower/Fan
 Pre-filter,
 Heating(Steam/Electrical) system
 Cooling(Chilled Water from chiller)
 dehumidification system and
 Hepa-Filter (In case of AHU hepa filter)

B. Air Filter-Different grades of Filters are used in different parts of total

system based on filtering efficiency
Grade Efficiency Usage
G-4 50-70% Retention Pre-filter in AHU
Return Air Filter
F7 >80% Retention Mid Stage in AHU
Hepa- 99.95% Retention for Final filter for air supplying
Filter H13 0.5µ or larger particles. to Grade C or D
Hepa- 99.995% Retention for Final filter for air supplying
Filter H14 0.5µ or larger particles. to Grade A or B
Hepa-Filters are placed in AHU or terminally just above the room.

C. Ducting:
Ducts are to supply the processed air to the clean room and return the air
from the room to either AHU or exhaust system. HVAC design uses
considered two types in terms of air processed. 100% exhaust and
recirculated air. In case of 100% exhaust return duct takes the air to the
exhaust system and in case of recirculated air return duct takes the room
air to the AHU and mix with fresh air (15-20%).

HVAC Design Considerations:

HVAC requirements system-wise and then room-wise, these requirements are :
1) Room temperature,
2) Relative humidity,
3) Cleanliness level
4) Room pressure (DAP-Differential Air Pressure) & Air Locks
5) Air Change Rate
6) Once Through (100% Exhaust) or Recirculation design requirements.
1) Room temperature: Room temperature is not critical as long as it provides
comfortable conditions.
Generally areas are designed to provide room temperatures 15-25°C with a
control point of 22°C. Lower space temperatures may be required where people
are very heavily gowned and would be uncomfortable at “normal” room
conditions.
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2) Relative humidity: Relative humidity (RH) on the other hand, is of greater
importance in all the production areas. While most of the areas could have a RH
of 50 ± 5%, facilities designed for handling hygroscopic powders need to be at
30 ± 5%. Automatic control of the RH is essential for maintaining continued
product quality. Control of humidity is necessary for personal comfort, to
prevent corrosion, to control microbial growth, and to reduce the possibility of
static electricity.
3) Cleanliness level: Of all the design goals, it is the quality of air cleanliness of
the space and prevention of contamination which are of utmost importance.
Externally generated particulates are prevented from entering the clean space
through the use of proper air filtration. The normally accepted air quality
standards for both sterilized and non-sterilized areas are tabulated below:
Grade Recommended activities
A Aseptic filling and handling of sterile components for injectable
products.
B Surrounding of Grade-A
C Formulation of injectable products prior sterilization, Formulation of
terminally sterilized product.
D Manufacturing and primary packaging of oral solids and liquids.

4) Room pressure.
Cleanroom pressurization is desired to prevent infiltration of air from adjacent
areas. The normally accepted air pressurization is 12 Pascale (10-15 Pascale)
from a higher cleanliness area to lower cleanliness area.

Clean room air locks design is an integral part of HVAC design consideration
because differential air pressure (DAP) is created by HVAC and that is the key
for control of particulate contamination and containment of the clean room.
Three types of air locks are designed:

 Cascade Air Lock

 Bubble Air Lock
 Sink Air Locks

Cascade Air Lock:

This airlock are very common having higher pressure on one side and lower
pressure on another side. In this system positive air pressure flows from the
higher pressure internal zone to be airlock and from the airlock to the lesser
lower pressure grade area. This prevents to entry dust and contamination from
outside to airlock and from airlock to inner side.

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Application of Cascade Air Locks:

1. Any manufacturing facilities where the product requires protection from

particulate but the people outside the clean-room do not need protection
from the product in the clean room.
2. Aseptic Processing area where the products are not possible to sterilize by
terminal sterilization and are safe to the adjacent corridor.

Bubble Air Lock:

These types of airlock having higher pressure inside the airlock and lower
pressure both outside. It creates a barrier where contaminants within either area
pushed back into their own respective areas.

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 Application of Bubble Air Locks:

1. Used in areas where the product needs protection and the people external
to the cleanrooms require protection from the product.
2. To reduce the possibility of viable articulate from entering the lesser
pressure clean-room.
3. Area such as higher potency, compounding areas terminal sterilization is
not an option.

Sink Air Locks:

Airlocks having lower pressure inside the airlock and higher pressure on both
sides of the airlock. This airlock pulls air from both adjacent areas creating a
low pressure barrier and reduces the opportunity of contaminations passing to
the internal zone.

Application of sink air locks:

In the facility where outside contamination is has to prevent entering into the
processing area but the air coming from the cleanrooms must be contained . It
is used in manufacturing facilities of harmful products like aseptic filling
operation of a cytotoxic product.

5) Air Change Rates:

Air change rate is a measure of how quickly the air enters in an interior space is
replaced by cleaned and conditioned air. For example, if the amount of air that
enters and exits in one hour equals the total volume of the cleanroom, the space

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is said to undergo one air change per hour. Air flow rate is measured in
appropriate units such as cubic feet per minute (CFM) and is given by

Air flow rate = Air changes x Volume of space/ 60

Widely accepted Air Change Rate for pharmaceutical clean room:
Clean Room Grade Air Changes Requirements
B Higher than 50
C 20-50
D Min 20
Grade-A is designed to get a Laminar Air Flow (LAF) surrounded by grade-B.
 vertical 0.3 m/s
 horizontal 0.45 m/s

For example if a wet granulation room for tablet manufacturing has a dimension
(L x W x H) of 15ft x 20ft x 10ft is designed to get 30 air changes per hour and
to calculate air flow rate (CFM)
Air flow rate = 30x (15 x 20 x 10) / 60= 1500 CFM.

6) Once Through (100% Exhaust) or Recirculation design requirements.

1. Once –through Air – Air is conditioned enters the clean room and then
exhausted.

2. Recirculated Air - Air is conditioned, enters the clean room and portion is
exhausted and mostly recirculated through return air duct to AHU mixing with
15-20% fresh air.

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Once – Through HVAC
Advantages of this system:
1. Fresh air – lots of it
2. Can handle hazardous materials, although will need to clean up air leaving
the space
3. Exhaust duct is usually easy to route as high velocity, smaller diameter
Disadvantages:
1. Expensive to operate, especially when cooling and heating
2. Filter loading very high, frequent replacement
3. Potential need for dust collection/scrubbers/cleanouts
Applications
1. Labs with hoods, potential hazards
2. Bulk Pharmaceutical Chemical (API) plants handling flammable materials
3. Oral Solid Dosage (OSD) plants where potent products/materials exposed
4. Where high potential of product cross-contamination – segregation
5. Some bio API facilities with exposed potent materials

Recirculated HVAC

Advantages
1. Usually less air filter loading, lower filter maintenance and energy cost
2. Opportunity for better air filtration
3. Less challenge to HVAC, better control of parameters (T, RH, etc)
4. Less throw-away air, lower cooling/heating cost
Disadvantages
1. Return air ductwork routing to air handler may complicate above ceiling
2. Chance of cross contamination, requires adequate supply air filtration
(sometimes return air filtration)

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Applications
1. Classified spaces such as sterile manufacture (few airborne materials, very
clean return air)
2. Finished oral solid dosage (OSD) manufacture where product is not airborne
with other products in the facility
3. Final bulk APIs, usually with dedicated air handler for each room

Validation of pharmaceutical HVAC System

No operation or production can start until the cleanroom is validated and the
clean room validation requires two major parts facility qualification and
environment qualification. HVAC system is a major part of facility and the
environment control so validation of HVAC system is utmost importance in
pharmaceutical industry.
Like other systems HVAC has a number of equipment so the validation
program includes the same qualifications starting from URS to Performance
qualification. Like other equipment URS, DQ FAT/SAT is user specific and not
discussed, next part will detail the IQ, OQ and PQ.

Installation Qualification (IQ):

1. Identification of various systems, their functions, schematics & flow
diagrams, sensors, dampers valves etc.
2. Installation date showing manufacturers, model no., ratings of all
equipment such as fans, motors, cooling & reheat coils, filters, HEPA
filters, controls etc
3. As Built Layout plans showing various rooms & spaces and the critical
parameters like:

 Room temperature
 Room humidity
 Room pressures and differential pressures between room and room
and passages.
 Critical instruments, recorders
4. Equipment performance and acceptance criteria for fans, filters, cooling
coils, heating coils, motors & drives.

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 5. Duct & pipe layouts showing air inlets, outlets air quantities, flows and
pressures.
6. Scanning for leakages.
7. Calibration of instrumentations

Operation Qualification (OQ):

1. Identification of rooms, RDS (Room Data Sheet) with specifications of
all critical parameters.
2. HEPA filter integrity tests
3. Testing for air quality (Temperature, Humidity, DAP, Particle count), Air
flow rate.

Performance Qualification (PQ):

Performance qualification of HVAC system is the final step of HVAC
qualification before using the clean rooms. HVAC system is critical system that
ensures the clean room environment and it needs to monitor to verify that it is
under the state of controls and hence it the re-qualified periodically. Grade-A/B
is re-qualified every 06 months and Grade-C/D is re-qualified once in year by
repeating the performance qualification.
Following tests are included in HVAC performance qualification:
1. Room data and air quality monitoring for consecutive 03 days
 Temperature
 Humidity
 DAP
 Particle count, at rest and in operation.
 Microbial monitoring, in operation.
2. Hepa-Filter integrity testing
3. Air Change Rate determination
4. Air flow visualization/Air flow pattern test.
5. Particle recovery testing (For Grade B/C Only)

Hepa-Filter Integrity Testing:

Hepa-filter integrity test is done by DOP (Disperse oil particulate) test. DOP
test uses dioctyl phthalate (DOP) or Polyalpha olefin (PAO), which are oil type
chemical. PAO (Poly Alpha Olefin) is a non-carcinogen liquid which is a most
common replacement for dioctyl phthalate.
DOP test involves an aerosol generator and a calibrated photometer. Oil is
dispersed as an aerosol into the upstream flow of the filter media, while the
number of particles in the downstream flow is measured using the photometer
by holding the probe approximately 1 inch away from the face of the filter.
Scanning of entire filter face including perimeters is done with the probe of
photometer in overlapping strokes; traversing at approximately 2 feet per

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minute (FPM). The measurement of downstream of the filter is presented in
percentage penetration which is compared to the efficiency of the heap-filter.

Air Change Rate Determination:

(Discussed in HVAC system design consideration)

Air flow Visualization

Air flow visualization or smoke test is done by taking video of smoke,

generated in the clean room. Titanium tetra Chloride or dry ice in water is used
for generation of Smoke. Videography of smoke flow is taken and the video
must show the exact area name and supply return grill’s ID. Visually, the flow
pattern of air inside the cubicle and flow with adjacent area is ensured.

Particle Recovery Testing

The purpose of the test is to establish how long it takes for the cleanroom to
recover from a challenge concentration to the Target Cleanliness Level. The
recovery test is only performed on non-unidirectional airflow systems and
should be carried out upon an installation in the as-built or at-rest state. It is not
recommended to conduct this test “in production” (for obvious reasons) and
further it is not recommended that the test be applied to Grade-C and Grade-D
environments due to the excessive challenge concentrations that would be
required.
An artificial aerosol is used at 100 times than the Target Cleanliness Level. As
described in the standard, the particle measurements were made inside the time
range where the decay of particle concentration. The recovery period to the
expected cleanliness level should not exceed 15 minutes.

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