PDHengineer.

com

Course

M-5010 HVAC Design for Pharmaceutical Facilities (GMP’s)

To receive credit for this course

This document is the course text. You may review this material at your leisure either
before or after you purchase the course. To purchase this course, click on the course
overview page: http://www.pdhengineer.com/pages/M-5010.htm or type the link into your
browser. Next, click on the

Take Quiz

button at the bottom of the course overview page. If you already have an account, log in to
purchase the course. If you do not have a PDHengineer.com account, click the

New User Sign Up

link to create your account. After logging in and purchasing the course, you can take the
online quiz immediately or you can wait until another day if you have not yet reviewed the
course text. When you complete the online quiz, your score will automatically be calculated.
If you receive a passing score, you may instantly download your certificate of completion. If
you do not pass on your first try, you can retake the quiz as many times as needed by simply
logging into your PDHengineer.com account and clicking on the link

Courses Purchased But Not Completed

. If you have any questions, please call us toll-free at 877 500-7145.

PDHengineer.com 5870 Highway 6 North, Suite 310 Houston, TX 77084 Toll Free: 877 500-
7145 [email protected]
HVAC Design for Pharmaceutical Facilities

In pharmaceutical manufacturing, how space conditions impact the product being made is of
primary importance. The pharmaceutical facilities are closely supervised by the U.S. food
and drug administration (FDA), which requires manufacturing companies to conform to
cGMP (current Good Manufacturing Practices). These regulations, which have the force of
law, require that manufacturers, processors, and packagers of drugs to take proactive steps
to ensure that their products are safe, pure, and effective. GMP regulations require a quality
approach to manufacturing, enabling companies to minimize or eliminate instances of
contamination, mix ups, and errors. The GMP for HVAC services embraces number of issues
starting with the selection of building materials and finishes, the flow of equipment,
personnel and products, determination of key parameters like temperature, humidity,
pressures, filtration, airflow parameters and classification of cleanrooms. It also governs the
level of control of various parameters for quality assurance, regulating the acceptance
criteria, validation of the facility, and documentation for operation and maintenance.
Various countries have formulated their own GMPs. In the United States, it is regulated by
several documents such as Federal Standard 209, code of Federal regulations CFR 210 & 211
etc, which are revised and updated from time to time. The European Community has a
"Guide to Good Manufacturing Practice for Medicinal Products” and in the United Kingdom
it is BS 5295. The World Health Organization (WHO) version of GMP is used by
pharmaceutical regulators and the pharmaceutical industry in over one hundred countries
worldwide, primarily in the developing world. In some countries, the GMP follows largely the
country of the principal technology provider. All GMP’s have one common theme……

“CLEANLINESS, CLEANLINESS and CLEANLINESS” What can HVAC do?

HVAC system performs four basic functions: 1. Control airborne particles, dust and micro-
organisms – Thru air filtration using high efficiency particulate air (HEPA) filters. 2. Maintain
room pressure (delta P) – Areas that must remain “cleaner” than surrounding areas must be
kept under a “positive” pressurization, meaning that air flow must be from the “cleaner”
area

towards

the adjoining space (through doors or other openings) to reduce the chance of airborne
contamination. This is achieved by the HVAC system providing more air into the “cleaner”
space than is mechanically removed from that same space. 3. Maintain space moisture
(Relative Humidity) – Humidity is controlled by cooling air to dew point temperatures or by
using desiccant dehumidifiers. Humidity can affect the efficacy and stability of drugs and is
sometimes important to effectively mould the tablets. 4. Maintain space temperature -
Temperature can affect production directly or indirectly by fostering the growth of microbial
contaminants on workers. Each of above parameter is controlled and evaluated in light of
its potential to impact product quality.

What HVAC can’t do?

1. HVAC can not clean up the surfaces of a contaminated surfaces, room or equipment 2.
HVAC can not compensate for workers who do not follow procedures We will learn about
the specific design aspects later in this course, but first we will briefly discuss the generic
pharmaceutical process.

Pharmaceutical Process

The task of the pharmaceutical manufacturer is to combine the medicinally active agents
provided by a fine chemicals plant, or by extraction from vegetable, animal or other source,
with suitable inactive ingredients so that the end product may be used in the correct dosage
to produce the effect needed.

Simplified Process Figure below illustrates a simplified diagram of the chemical synthesis
process for pharmaceuticals. There are five primary stages in chemical synthesis: (1)
reaction, (2) separation, (3) crystallization, (4) purification, and (5) drying. Each of these five
stages is described below.

Reaction(s) –

In the reaction process, raw materials are fed into a reactor vessel, where reactions such as
alkylations, hydrogenations, or brominations are performed. The most common type of
reactor vessel is the kettle-type reactor generally made of stainless steel or glass-lined
carbon steel, range from 50 to several thousand gallons in capacity. The reactors may be
heated or cooled, and reactions may be performed at atmospheric pressure, at elevated
pressure, or in a vacuum. Generally, both reaction temperature and pressure are monitored
and controlled. Nitrogen may be required for purging the reactor, and some intermediates
may be recycled back into the feed. Some reactions are aided via mixing action provided by
an agitator. A condenser system may be required to control vent losses. Reactors are often
attached to pollution control devices to remove volatile organics or other compounds from
vented gases.

Separation –

The main types of separation processes are extraction, decanting, centrifugation, and
filtration. The extraction process is used to separate liquid mixtures.

Extraction

process is used to separate liquid mixtures. It takes advantage of the differences in the
solubility of mixture components i.e. a solvent that preferentially combines with only one of
the mixture components is added to the mixture. Two streams result from this process: the
extract, which is the solvent-rich solution containing the desired mixture component, and
the raffinate, which is the residual feed solution containing the non-desired mixture
component(s).

Decanting

is a simple process that removes liquids from insoluble solids that have settled to the
bottom of a reactor or settling vessel. The liquid is either pumped out of the vessel or
poured from the vessel, leaving only the solid and a small amount of liquid in the vessel.

Centrifugation

is a process that removes solids from a liquid stream using the principle of centrifugal force.
A liquid-solid mixture is added to a rotating vessel—or centrifuge—and an outward force
pushes the liquid through a filter that retains the solid phase. The solids are manually
scraped off the sides of the vessel or with an internal scraper. To avoid air infiltration,
centrifuges are usually operated under a nitrogen atmosphere and kept sealed during
operation.

Filtration

separates fluid/solid mixtures by flowing fluid through a porous media, which filters out the
solid particulates. Batch filtration systems widely used by the pharmaceutical industry
include plate and frame filters, cartridge filters, nutsche filters, and filter/dryer
combinations.

Crystallization -

Crystallization is a widely used separation technique that is often used alone or in

combination with one or more of the separation processes described above. Crystallization
refers to the formation of solid crystals from a supersaturated solution. The most common
methods of super saturation in practice are cooling, solvent evaporation, and chemical
reaction. The solute that has crystallized is subsequently removed from the solution by
centrifugation or filtration.

Purification -

Purification follows separation, and typically uses the separation methods described above.
Several steps are often required to achieve the desired purity level. Re-crystallization is a
common technique employed in purification. Another common approach is washing with
additional solvents, followed by filtration. Drying -

The final step in chemical synthesis is drying the product (or intermediates). Drying is done
by evaporating solvents from solids. Solvents are then condensed for reuse or disposal. The
pharmaceutical industry uses several different types of dryers, including tray dryers, rotary
dryers, drum or tumble dryers, or pressure filter dryers. Prior to 1980, the most common
type of dryer used by the pharmaceutical industry was the vacuum tray dryer. Today,
however, the most common dryers are tumble dryers or combination filter/dryers. In the
combination filter/dryer, input slurry is first filtered into a cake, after which a hot gaseous
medium is blown up through the filter cake until the desired level of dryness is achieved.
Tumble dryers typically range in capacity from 20 to 100 gallons. In tumble dryers, a rotating
conical shell enhances solvent evaporation while blending the contents of the dryer. Tumble
dryers utilize hot air circulation or a vacuum combined with conduction from heated
surfaces.

Product Extraction

Active ingredients that are extracted from natural sources are often present in very low
concentrations. The volume of finished product is often an order of magnitude smaller than
the raw materials, making product extraction an inherently expensive process. Precipitation,
purification, and solvent extraction methods are used to recover active ingredients in the
extraction process. Solubility can be changed by pH adjustment, by salt formation, or by the
addition of an anti-solvent to isolate desired components in precipitation. Solvents can be
used to remove active ingredients from solid components like plant or animal tissues, or to
remove fats and oils from the desired product. Ammonia is often used in natural extraction
as a means of controlling pH.

Fermentation -

In fermentation, microorganisms are typically introduced into a liquid to produce

pharmaceuticals as by-products of normal microorganism metabolism. The fermentation
process is typically controlled at a particular temperature and pH level under a set of aerobic
or anaerobic conditions that are conducive to rapid microorganism growth. The process
involves three main steps: (i) seed preparation, (ii) fermentation, and (iii) product recovery.

Seed preparation -

The fermentation process begins with seed preparation, where inoculum (medium
containing microorganisms) is produced in small batches within seed tanks. Seed tanks are
typically 1-10% of the size of production fermentation tanks (U.S. EPA 1997).

Fermentation -

After creating the inoculum at the seed preparation stage, the inoculum is introduced into
production fermentors. In general, the fermentor is agitated, aerated, and controlled for pH,
temperature, and dissolved oxygen levels to optimize the fermentation process. The
fermentation process lasts from hours to weeks, depending on the product and process.

Product Recovery -

When fermentation is complete, the desired pharmaceutical byproducts need to be

recovered from the fermented liquid mixture. Solvent extraction, direct precipitation, and
ion exchange may be used to recover the product. Additionally, if the product is contained
within the microorganism used in fermentation, heating or ultrasound may be required to
break the microorganism’s cell wall. In solvent extraction, organic solvents are employed to
separate the product from the aqueous solution. The product can then be removed from the
solvent by crystallization. In direct precipitation, products are precipitated out of solution
using precipitating agents like metal salts. In ion exchange, the product adsorbs onto an ion
exchange resin and is later recovered from the resin using solvents, acids, or bases.

Formulation of Final Products

The final stage of pharmaceutical manufacturing is the conversion of manufactured bulk

substances into final, usable forms. Common forms of pharmaceutical products include
tablets, capsules, liquids, creams and ointments, aerosols, patches, and injectable dosages.
Tablets account for the majority of pharmaceutical solids. To prepare a tablet, the active
ingredient is combined with a filler (such as sugar or starch), a binder (such as corn syrup or
starch), and sometimes a lubricant (such as magnesium state or polyethylene glycol). The
filler ensures the proper concentration of the active ingredient; the purpose of the binder is
to bond tablet particles together. The lubricant may facilitate equipment operation during
tablet manufacture and can also help to slow the disintegration of active ingredients. Tablets

are produced via the compression of powders. Wet granulation or dry granulation processes
may be used. In wet granulation, the active ingredient is powdered and mixed with the filler,
wetted and blended with the binder in solution, mixed with lubricants, and finally
compressed into tablets. Dry granulation is used when tablet ingredients are sensitive to
moisture or drying temperatures. Coatings, if used, are applied to tablets in a rotary drum,
into which the coating solution is poured. Once coated, the tablets are dried in the rotary
drum; they may also be sent to another drum for polishing. Capsules

are the second most common solid oral pharmaceutical product in the United States after
tablets (U.S. EPA 1997). Capsules are first constructed using a mold to form the outer shell of
the capsule, which is typically made of gelatin. Temperature controls during the molding
process control the viscosity of the gelatin, which in turn determines the thickness of the
capsule walls. The capsule’s ingredients are then poured (hard capsules) or injected (soft
capsules) into the mold. For liquid pharmaceutical formulations, the active ingredients are
weighed and dissolved into a liquid base. The resulting solutions are then mixed in glass-
lined or stainless steel vessels and tanks. Preservatives may be added to the solution to
prevent mold and bacterial growth. If the liquid is to be used orally or for injection,
sterilization is required. Ointments

are made by blending active ingredients with a petroleum derivative or wax base. The
mixture is cooled, rolled out, poured into tubes, and packaged. Creams

are semisolid emulsions of oil-in-water or water-in-oil; each phase is heated separately and
then mixed together to form the final product. In designing the air-conditioning system for
pharmaceutical plants, it is very important to study the application, identify various factors
affecting the particulate count and decide the level of contamination that can be permitted.

What is Particulate?
Simply stated, airborne particles are solids suspended in the air. The size of contaminants
and particles are usually described in microns; one micron is one-millionth of a meter. In
English units one micron equals 1/25,400 inch. To give a perspective, a human hair is about
75-100 microns in diameter. Air, whether it is from outside or re-circulated, acts as a vehicle
for bacterial and gaseous contaminants brought in by the movement of people, material,
etc. Since many of these air borne contaminants are harmful to products and people, their
removal is necessary on medical, legal, social or financial grounds. There are two main
sources of particulates, external and internal sources.

External sources consist of the following:

Outside make-up air introduced into the room: this is typically the largest source of external
particulates

Infiltration through doors, windows and other penetration through the cleanroom barriers

Control Action:

Make-up air filtration

Room pressurization

Sealing of all penetrations into the space

Internal sources consist of the following:

People in the clean area: people are potentially the largest source of internally generated
particulates

Cleanroom surface shedding •

Process equipment

Material ingress

•
Manufacturing processes

Control Action:

Design airflow path to shield humans from surroundings

Use of air showers [to continually wash occupants with clean air]

Using hard-surfaced, non-porous materials such as polyvinyl panels, epoxy painted walls,
and glass board ceilings

Proper gowning procedures, head wear

A super clean environment with controlled temperature and relative humidity has now
become an essential requirement for a wide range of applications in Pharmaceutical Plants.

What is a Cleanroom?

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 contaminants. Cleanroom
classifications are established by measurement of the number of particles 0.5 micron and
larger that are contained in 1 ft

of sampled air. Generally class 100 to 100,000 rooms are used in the pharmaceutical
industry. [Note - rooms may be classified as clean at class 1 or 10 for other applications,
particularly in the microchip /semiconductor industry]. Cleanrooms classified in the United
States by Federal Standard 209E of September 1992 and by the European Economic
Community (EEC) published guidelines “Guide to Good Manufacturing Practice for Medical
Products in Europe, which are more stringent than U.S. FDA regulations. U.S FEDERAL
STANDARD 209E

Table below derived from Federal Standard 209E shows the air cleanliness classes:

Class Limits

Class Names 0.5 Micron 5 Micron

SI English m
3

ft

ft

M 3.5 100 3,530 100 - -

M 4.5 1,000 35,300 1,000 247 7

M 5.5 10,000 353,000 10,000 2,470 70

M 6.5 100,000 3,530,000 100,000 24,700 700

Table Interpretation: 1. Class 100 (M 3.5) is the area where the particle count must not
exceed a total of 100 particles per cubic foot (3,530 particles per m

) of a size 0.5 microns and larger. 2. Class 10,000 (M 5.5) is the area where the particle count
must not exceed a total of 10,000 particles per cubic foot (353,000 particles per m

) of a size 0.5 microns and larger or 70 particles per cubic foot (2,470 particles per m

), of a size 5.0 microns and larger. 3. Class 100,000 (M 6.5) is the area where the particle
count must not exceed a total of 100,000 particles per cubic foot (3,530,000 particles per m

) of a size 0.5 micron and larger or 700 particles per cubic foot (24,700 particles per m

) of a size 5.0 microns and larger. 4. All pharmaceutical facilities belong to one or other class
of cleanroom. General acceptance is:

Tabletting facilities - Class 100,000

•

Topical & oral liquids - Class 10,000

Injectables class - Class 100 EUROPEAN COMMUNITY 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 and
operating 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.

At Rest In Operation

Grade

Maximum permitted number of particles per

equal to or above 0.5 micron

Maximum permitted number of particles per

equal to or above 5 micron

Maximum permitted number of particles per

equal to or above 0.5 micron

Maximum permitted number of particles per

equal to or above 5 micron

A (Laminar Airflow Workstation)

3500 0 3500 0

35,000 0 350,000 2,000

350,000 2,000 3,500,000 20,000

3,500,000 20,000 Not defined Not defined

Notes

Grade-A classification is the most stringent of all. It requires air in the immediate proximity
of exposed sterilized operations to be no more than 3500 particulates per cubic meter, in a
size range of 0.5 micron and larger, when measured not more than one foot away from the
work site and upstream of the air flow, during filling/closing operations. This applies both at
“at rest” and “in-operation” condition. Grade-A areas are expected to be completely free
from particles of size greater than or equal to 5 micron both “at rest” and “in-operation”
condition. Besides “at-rest” and “in-operation” cleanroom states, another condition most
commonly used by HVAC contractors is “As – Built” condition. ‘As built’ cleanrooms are
those which are ready with all services connected but without equipment and personnel.
The HVAC contractors responsibility generally lies up to the ‘as built’ or ‘at rest’ cleanroom
stage and often the pharmaceutical companies specify higher cleanliness levels for these
stages than the ’operational’ stage.

Typical Examples

Typical examples of Grade- A areas include filling zone, Stopper bowls, Open ampoules and
vials making aseptic connections Typical examples of Grade-B areas are Aseptic preparation
and filling area, Aseptic receiving area, Aseptic changing room and solution preparation
room. These are less critical areas. Typical examples of these areas are 1) Changing room, 2)
Material Entry air locks

Comparison of US Federal standard 209E v/s EEC

Class 100 is equivalent to (Grades A and B) Class 10,000 is equivalent to (Grade C) Class
100,000 is equivalent to (Grade D)

FACILITY CLASSIFICATION

Pharmaceutical facility typically consists of a series of integrating classes of rooms to match

with the requirements of the manufacturing process. There are some basic requirements
that must be satisfied so that the air in the sterile rooms is correct for the activities related
to the manufacturing process. Each sterile room must be clinically independent from the
surrounding area and are produced by “aseptic” processing. Aseptic processing

is a method of producing a sterile (absence of living organisms) product. The objective of

aseptic processing methods is to assemble previously sterilized product, containers and
closures within specially designed and controlled environments intended to minimize the
potential of microbiological or particulate contamination. Cleanrooms classifications differ
for sterile and non-sterile areas. These are called by many names viz.: Non-sterilized
operation = controlled area = non-aseptic application Sterilized operation = critical Area =
aseptic application

Controlled Areas

U.S standards define the “controlled area” as the areas where Non-sterilized

products are prepared. This includes areas where compounds are compounded and where
components, in-process materials, drug products and contact surfaces of equipment,
containers and closures, are exposed to the plant environment. Requirement

Air in “controlled areas” is generally of acceptable particulate quality if it has a per cubic
foot particle count of not more than 100,000 in size range of 0.5 micron and larger (Class
100,000) when measured in the vicinity of the exposed articles during periods of activity.
With regard to microbial quality, an incidence of no more than 2.5 colony forming units per
cubic foot is acceptable. In order to maintain air quality in controlled areas… airflow
sufficient to achieve at least 20 air changes per hour and, in general, a pressure differential
of at least 0.05 inch of water gauge (with all doors closed) is recommended.

Critical Areas

U. S standards define “Critical Areas”, as the areas where Sterilized

operations are carried out. These shall have aseptic cleanrooms. Requirement
-

Air in “critical areas” is generally of acceptable particulate quality if it has a per cubic foot
particle count of not more than 100 in size range of 0.5 micron and larger (Class 100) when
measured in the vicinity of the exposed articles during periods of activity. With regard to
microbial quality, an incidence of no more than 0.1 colony forming units per cubic foot is
acceptable. In order to maintain air quality in sterile areas… laminar airflow at velocity of 90
feet per minute ± 20 and, in general, a pressure differential of at least 0.05 inch of water
gauge (with all doors closed) is recommended. No specific air change rate is specified by Fed
and EEU standards.

TYPES OF CLEANROOMS

Cleanrooms are also categorized by the way supply air is distributed. There are generally two
air supply configurations used in cleanroom design: 1) Non-unidirectional and 2)
Unidirectional.

Non-unidirectional air flow

In this airflow pattern, there will be considerable amount of turbulence and it can be used in
rooms where major contamination is expected from external source i.e. the make up air.
This turbulent flow enhances the mixing of low and high particle concentrations, producing a
homogenous particle concentration acceptable to the process. Air is typically supplied into
the space by one of two methods. The first uses supply diffusers and HEPA filters. The HEPA
filter may be integral to the supply diffuser or it may be located upstream in the ductwork or
air handler. The second method has the supply air pre-filtered upstream of the cleanroom
and introduced into the space through HEPA filtered work stations. Non-unidirectional
airflow may provide satisfactory control for cleanliness levels of Class 1000 to Class 100,000.

Unidirectional air flow

The unidirectional air flow pattern is a single pass, single direction air flow of parallel
streams. It is also called 'laminar' airflow since the parallel streams are maintained within 18
deg - 20 deg deviation. The velocity of air flow is maintained at 90 feet per minute ±20 as
specified in Federal Standard 209 version B although later version E does not specify any
velocity standards. Unidirectional cleanrooms are used where low air borne contaminant
levels are required, and where internal contaminants are the main concern. They are
generally of two types: 1. Vertical down-flow cleanrooms where the air flow is vertical
‘laminar’ in direction. 2. Horizontal flow where the air flow is horizontal ‘laminar’ in
direction. In vertical down-flow arrangement, clean make-up air is typically introduced at
the ceiling and returned through a raised floor or at the base of the side walls. Horizontal
flow cleanrooms use a similar approach, but with a supply wall on one side and a return wall
on the other.

Typically a down-flow cleanroom consists of HEPA filtered units mounted in the ceiling. As
the class of the cleanroom gets lower, more of the ceiling consists of HEPA units, until, at
Class 100, the entire ceiling will require HEPA filtration. The flow of air in a down-flow
cleanroom bathes the room in a downward flow of clean air. Contamination generated in
the room is generally swept down and out through the return. The horizontal flow
cleanroom uses the same filtration airflow technique as the down-flow, except the air flows
across the room from the supply wall to the return wall.

Between the two, the vertical down-flow pattern yield better results and is more

adaptable to pharmaceutical production.

How do Cleanrooms HVAC different from a normal comfort air conditioned space?

A cleanroom requires a very stringent control of temperature, relative humidity, particle

counts in various rooms, air flow pattern and pressure differential between various rooms of
the clean air system. All this requires: 1.

Increased Air Supply:

Whereas comfort air conditioning would require about 2-10 air changes/hr, a typical
cleanroom, say Class 10,000, would require 50 - 100 air changes. This additional air supply
helps, to dilute the contaminants to an acceptable concentration. 2.

High Efficiency Filters:

The use of HEPA filters having filtration efficiency of 99.97% down to 0.3 microns is another
distinguishing feature of cleanrooms. 3.

Terminal Filtration and Air Flow pattern:

Not only are high efficiency filters used, but a laminar flow is sought. 4.

Room Pressurization:

With the increased fresh air intake, cleanrooms are pressurized in gradients. This is
important to keep external particulates out of clean spaces.

SYSTEM DESIGN

The HVAC design process begins with meetings with process engineers, architects, and
representatives from the owner or facility user. The process and instrument diagrams
(P&IDs) are reviewed, and a general understanding of the process is conveyed to all
interested parties. Operation of the facility is reviewed, and any plans for future additions or
modifications are discussed. After the initial meeting, a written basis of design is produced
that describes the regulations and codes that will govern the design. Spaces are defined by
function, and temperature and humidity requirements are determined. Room classifications
are listed and adjacency of spaces and pressure relationships are documented. Any unusual
or unique facility requirements must also be designed into the HVAC system at this time,
such as emergency backup or redundancy for HVAC systems. This is also the stage of the
design process during which alternate studies are conducted to compare options for the
HVAC system. The cost of a backup or redundant HVAC supply system may be compared
with the cost of product loss or experiment interruption should temperatures or airflow go
out of control or specification. Heat recovery from exhaust systems and thermal storage are
examples of other potential areas for study. Airflow diagrams are produced that show areas
served by a particular air handling system including supply, return, exhaust, and transfer air
between spaces. The basis of design also describes major equipment to be used and the
level of quality of components and construction material. The efficacy of the system design
is based on proper consideration of the following factors: 1. Building construction and layout
design 2. Defining the HVAC requirements system-wise and then room-wise. – Cleanliness
level – Room temperature, relative humidity – Room pressure – Air flow pattern 3. Cooling
load and Airflow compilation 4. Selection of air flow pattern 5. Pressurization of rooms 6. Air
handling system 7. Duct system design and construction 8. Selection, location and mounting
of filtration system 9. Defumigation requirement 10. Commissioning, performance
qualification and validation 11. Testing and validation 12. Documentation

BUILDING DESIGN, CONSTRUCTION AND LAYOUT

Proper building design and planning of the flow of personnel, material and equipment is
essential for achieving and maintaining the design levels of cleanliness and pressure
gradients. If the building layout and its construction are poor there is very little that an air-
conditioning system designer can do to satisfy the end-user needs.

Building Layout From an HVAC standpoint it is desirable to keep similarly classified areas as
physically close to each other as possible so they can be connected to the same air handling
system, thereby minimizing duct runs, cost, and air system complexity. It is also imperative
that spaces be arranged to allow people to move around without disrupting the cleanliness
or containment of the spaces. It is NOT desirable to mix dirty and clean systems or suites
that may allow the possibility of cross-contamination from one suite to another. Leaks can
develop in a filter, or some source of contamination could find its way through the air supply
or return systems, providing a source for cross-contamination. Sterile zones are normally
divided into three sub zones: 1. Main sterile zone or white zone 2. Cooling zone which is
also a white zone 3. Set of three change rooms: black, grey and white in ascending order of
cleanliness In order to achieve a pressure gradient, it is imperative that zones are located
such that the gradient is unidirectional, i.e. the room with the highest pressure should be
located at one end and the room with the lowest pressure should be located near the
opposite end. This type of planning can simplify balancing of system pressures to a great
extent. Entry for people to the main sterile room should be from a set of three change
rooms: black, gray and white …in that order. Entry for equipment and material must be
through “AIRLOCKS”. No area should directly open into the sterile room.

Building Construction

The internal particulate generation always is the focus of any cleanroom design. The internal
generation consists of those from building elements such as walls, floor, ceiling, etc., from
equipment, and most importantly from operators. The building construction itself has to be
"tight" with minimum of uncontrolled infiltration and leakages. This is very important in the
case of buildings for formulation and sterile production. Materials used in the construction
of the pharmaceutical facilities should be hard-surfaced. There are few special points of
interest as noted below: 1. All material used is construction should be non chipping and
cleanable. Wall and floor finishes should not shed particulates and should provide self-
cleaning surfaces. 2. All exposed surfaces should be smooth, impervious and unbroken 3. No
un-cleanable recesses and a minimum of projecting ledges, shelves, cupboards and
equipment 4. Sharp corners should be avoided between floors, walls and ceiling 5. False
ceilings and the tile joints in the floor should be completely sealed 6. Pipes, ducts and other
utilities should be installed so they do not create recesses 7. Sinks and drains should be
prohibited in grade Class 100 areas 8. All doors in the sterile area should have airtight
construction. Special gaskets should be provided on the door frame and drop seals provided
at the bottom of the door, if necessary. 9. Epoxy painting should be carried out in these
areas.

Areas w/o False Ceiling

Special attention should be given to the type of ceiling. The commonly followed trend is to
eliminate false ceilings and to provide instead a concrete slab on top of which are located
the air handling units and ducting. Cutouts in this slab are used for housing the terminal
filters. Access to these filters is from top of the slab. Care should be taken to adequately
reinforce this slab to accommodate the weight of the air handling units, piping and ducting.
In the case of NO false ceiling is considered, the air-conditioning system is required to be
designed before slab construction is started. Make sure: 1. To correctly identify the location
and size of the cutouts for terminal filters. Mounting frames for terminal filters/terminal
filter boxes should be grouted at the time of casting the slab. 2. To correctly identify the
location and size of the cutouts for return air risers and inserts in the slab. 3. To correctly
identify additional cutouts required for other MEP services. 4. To correctly determine the air
handling equipment size and location that should be matched with the cut-out location and
size. 5. To provide curbing at the perimeter of the cutouts to prevent water seepage into
the working area. 6. To correctly provide floor drain locations for air handling units. 7. To
consider water proofing in areas where air handling units are located.

Areas with False Ceiling

In the case of a false ceiling in the sterile area, the following points should be considered: 1.
Inserts should be provided for false ceiling supports and mounting of filters. 2. To prevent
fungus growth and eliminate air leakage, the false ceiling should be of NON-shedding
variety, such as aluminum or PVC coated CRCA sheet. 3. False ceiling members should be
designed to support part of the weight of terminal filters. 4. Proper sealing must be
provided between panels and between filters and panels to avoid air leakage.

Ceiling Construction

The ceiling of the cleanroom is another potential location for contaminants to enter the
clean zone. Pressurization of the cleanroom helps to prevent this; however this can lead to
contaminants from the processes in the cleanroom being forced out into the area
surrounding the cleanroom. To reduce the chance of this happening, the cleanroom ceiling is
sealed. The type of seal is determined by the cleanliness class of the cleanroom. For Class
1,000 and higher (less clean), the ceiling grid can be gasketed aluminum T-bar with a 1” face
tee. A Class 100 cleanroom should have a gasketed aluminum T-bar grid with 2” face tees
and Class 10 and cleaner should have a modular / T-bar ceiling grid with a gel seal.

The gasketed T-bar system has an integral vinyl, or similar material, gasket. The gasket is
compressed between the base of the tee and the ceiling panel or diffuser. Hold down clips is
used to maintain the compression on all non-access related panels.

The gel grid T-bar system has a groove running the full length of both sides of the tee. The
groove is filled with a suitable sealing gel. This type of ceiling is typically used in cleanrooms
where 100% of the ceiling consists of filters or fan filter units. The filters and/or fan filter
units have a knife edge around the perimeter which goes into the gel forming a seal.

The type of ceiling panels used in a cleanroom ceiling also depends on the cleanliness class
of the space. Class 1,000 and above (less clean) can have cleanroom approved, vinyl covered
panels or blank aluminum panels while Class 100 and cleaner can only have blank aluminum
panels.

Ceiling grid support is determined by cleanliness class as well. Class 100 and cleaner should
have all-thread rod with strut and turnbuckles while Class 1,000 and above should have 12
ga hanger wires to the grid and 10 ga hanger wires to the filters. The hanger wires should be
installed at the grid intersections.

Summarizing

Cleanroom Classification

Ceiling System
Class 100

2" T-bar with gasket, extruded aluminum

Class 1,000

1" T-bar with gasket, extruded aluminum

Class 10,000

1" T-bar with gasket, extruded aluminum

Class 100,000

Side access HEPA filter housings

HVAC REQUIRMENTS

Define the HVAC requirements system-wise and then room-wise. The requirements defined
are: 1) room temperature, 2) relative humidity, 3) cleanliness level and 4) room pressure.

Room Temperature (T)

Room temperature (T) is not critical as long as it provides comfortable conditions. Generally
areas are designed to provide room temperatures from 67 and 77°F with a control point of
72°F. Lower space temperatures may be required where people are very heavily gowned
and would be uncomfortable at “normal” room conditions.

Relative Humidity (RH)

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. We will discuss more about the RH control in the subsequent sections.

Control Airborne Particles (C)

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:

Operation Parameters United States European Economic Community

Cleanroom type Class 100,000 Grade C

Non-sterilized product or container (U.S : Controlled

Maximum particle size (0.5 micron or

100,000/ft

350,000/m

Operation Parameters United States European Economic Community

above)

Area) Maximum viable organisms

2.5/ft

100/m

Cleanroom type Class 100 in Class 10,000 background

Grade A in Grade B background

Maximum particle size (0.5 micron or above)

100 /ft

3,500/m

Sterilized product or container (U.S: Critical Area) Maximum viable organisms

0.1 /ft

Grade A

1 /m

Grade B

background

5/m

Room Pressure Differential (DP)

Cleanroom positive pressurization is desired to prevent infiltration of air from adjacent

areas. The normally accepted air pressurization standards for both sterilized and non-
sterilized areas are tabulated below:

Operation Parameters United States European Economic Community

Non-sterilized product or container (U.S : Controlled Area)

Space pressurization

0.05 inch-w.g Positive

Sterilized product or container (U.S: Critical Area)

Space pressurization

0.05 inch-w.g or higher

Positive

COOLING LOADS

Pharmaceutical buildings as a rule are totally enclosed without any fenestrations. This is to
maintain a 'tight' building to minimize uncontrolled infiltration. As a result, the room
sensible loads are essentially a contribution from process equipment, lighting and personnel.
Fan heat from recirculating fans can also be a large heat contributor in clean spaces. The
density of equipment loads is low excepting in the tablet manufacturing facility covering
granulation, drying and tabletting. Heat-loss calculations must also be made to determine
heat loss through walls, roof, and floor. No credit should be taken for process heat gain in
this calculation, since the process could be dormant and the space would still need to be
maintained at proper temperature. A major contribution of the cooling load comes from
outside air entering the air handling unit. There is also considerable diversity in the
equipment loads based on the production patterns. All these result in a low room sensible
load density varying from as low as 15 Btu/hr sq-ft to 40 Btu/hr sq-ft. Hence the system
design lays emphasis on control and maintenance of relative humidity. The room
temperature is normally held at 70°F, whereas the relative humidity is held at 50± 5% in
most of the areas. In a few areas it is maintained at 35± 5% or lower depending on the
product characteristics. Formulas to determine cooling loads are available from HVAC
handbooks and ASHRAE standards.

AIRFLOW SHEETS

Once the cooling load is determined, the next step is to calculate the dehumidified airflow
using psychrometric analysis or computer analysis. These results are compared with airflow
quantities required to establish the minimum air required to satisfy both the space cooling
load requirements and air cleanliness classification. The airflow sheets should be developed
on full-size drawings and should show air quantities supplied, returned, and exhausted from
each space. They also must show air transferred into and out of spaces, and, while quantities
should be shown, they will probably require field modification to attain pressurization. The
airflow sheet is a useful tool for transfer of information to the owner or user, for agency
reviews, for transmission of information to HVAC designers, and for other engineering
disciplines. These documents are also invaluable to construction contractors and for system
checking by construction managers and balancing contractors. Airflow sheets provide a
pictorial description of each air system and show how the elements comprising the system
are related.

AIRFLOW PATTERN

The air distribution has to be appropriate with the class of cleanroom. Air turbulence in the
space can cause particulates which have settled onto the floor and work surfaces to become
re-entrained in the air. Air turbulence is greatly influenced by the configuration of air supply
and return grilles, people traffic and process equipment layout. The following measures are
normally taken to control the air flow pattern and hence the pressure gradient of the sterile
area: 1. Class 100 and lower zones must necessarily have unidirectional (laminar) flow with
100% HEPA filter coverage in the ceiling or wall. Return must be picked up from the opposite
side. 2. Air flow velocities of 90 fpm ±20 (70 fpm to 110 fpm) are recommended as standard
design for Class 100 cleanroom systems. 3. The vertical down-flow configuration is
preferred. Per EEC standards, laminar work station with vertical flow requires 0.3 m/s
velocity whereas the horizontal work stations require 0.45 m/s velocity. When horizontal
flow is used the work place must be immediately in front of the clean air source so that
there is nothing in between which could emit or cause uncontrolled turbulence and
consequent contamination. 4. Class 1000 and above are generally non-unidirectional with
the supply air outlets at the ceiling level and the return air at the floor level. 5. This air
should be supplied at a much higher volume than its surrounding area ensuring a higher
velocity and pressure in the clean zone relative to the perimeter.

Return Air System The air return system is another critical component of the cleanroom air
distribution system. The return points shall be positioned low down near the floor in the
walls and spaced as symmetrically as building construction allows. Return grilles shall be
made as long as convenient to increase the collection of dust particles over a larger area.
Return air grilles in the main sterile zones should be located to avoid dead air pockets. While
locating the return grille, care should be taken to avoid placing the grille near a door opening
into an adjoining lower pressure room. This is done to prevent creation of a low pressure
zone near the door, thus preventing air leakage from the low pressure to high pressure room
at the time of door opening. On each return air riser manually operated dampers shall be
provided for control. These dampers should preferably be operated from the non-sterile
areas.

Mixed Areas

It is possible to create Class 100 space within Class 10,000 areas at background. For example,
if a small localized operation in big Class 10,000 volume requires Class 100 standard, there is
no point to put the entire area as Class 100. This will be very expensive. For such areas,
install “localized laminar flow workstations”, which are commercially available in horizontal
or vertical flow patterns generally recirculating within the clean space.
AIR CHANGES

Air change rate is a measure of how quickly the air in an interior space is replaced by outside
(or 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 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 The normally accepted air
change rates for both sterilized and non-sterilized areas are tabulated below: Operation
Parameters United States European Economic Community

Non-sterilized product or container (U.S : Controlled Area)

Airflow rate Minimum 20 air changes/hr

Higher than 20 air changes/hr

Sterilized product or container (U.S: Critical Area)

Airflow rate 90 ft/min ± 20 Grade A

Laminar work station, vertical 0.3 m/s and horizontal 0.45 m/s Grade B

Higher than 20 changes per hour

Even though various design guidelines and standards are available, there is no clear-cut
guidance for air changes per hour especially for “sterilized areas”. Table below indicates a
typical range of air change rates generally used to achieve the desired room cleanliness
classifications and to meet federal and local regulations. These air change rates vary widely
in actual practice due to the level of activity, number and type of particulate generators in a
room (such as people and equipment), and room size and quality of air distribution. It is
generally best to use historic data to establish airflows, which is usually done with significant
input from the owner based on past experience or preference. There is nothing sacred about
an air change rate as long as minimum airflow rates required by code are maintained. The
goal is to achieve desired particulate cleanliness levels and stay at or above a 20 air
changes/h minimum.
Class ACH % HEPA Coverage

Air Velocity (FPM)

100,000 24 -50 10 - 20% 5 -10

10,000 50 - 100 20 - 40% 10 - 20

1,000 150 - 200 40 – 60% 25 - 35 100 270 - 330 80 – 100% 70 -110

How to estimate air change rate?

Most pharmaceutical cleanrooms depend on the principle of dilution to control their

particles. The air-change rate leads to dilution of space. Simply put, the dilution rate in terms
of air change rate per hour is given by following equation, assuming no infiltration as the
room is pressurized:

v = g / (x – s)

Where

is the supply air particulate concentration in particles per ft

is the supply air volume flow rate in terms of air-change rate per hour

is the internal generation rate in particles per ft

per hour
•

is room or return air concentration in particles per ft

Example

For a typical Class 10,000 cleanroom space with a typical internal generation of
approximately 5,000 per CFM, and supply air through 99.97% HEPA filters, what shall be the
required air-change rate?

Solution

The supply rate can be estimated using equation: v = g / (x – s) Where

g = 5000 * 60 ft

per hour

x = 10,000 •

s = 3 for 99.97% efficient HEPA filters v = 5000 * 60 / (10000 – 3) = 30 air changes per hour
Of course, in the case that internal generation is significantly higher, more air changes
would be required. It is important to note that high air change rate (ACR) equate to higher
airflows and more energy use. In most cleanrooms, human occupants are the primary source
of contamination. Once a cleanroom is vacated, lower air changes per hour to maintain
cleanliness are possible allowing for setback of the air handling systems. Variable speed
drives (VSD) should be used on all recirculation air systems allowing for air flow adjustments
to optimize airflow or account for filter loading. Where VSD are not already present, they
can be added and provide excellent payback if coupled with modest turndowns. The benefits
of optimized airflow rates are: 1) Reduced Capital Costs - Lower air change rates result in
smaller fans, which reduce both the initial investment and construction cost. A 20 percent
decrease in ACR will enable close to a 50 percent reduction in fan size. 2) Reduced Energy
Consumption - The energy savings opportunities are comparable to the potential fan size
reductions. According to the fan affinity laws, the fan power is proportional to the cube of
air changes rates or airflow. A reduction in the air change rate by 30% results in a power
reduction of approximately 66%. A 50 percent reduction in flow will result in a reduction of
power by approximately a factor of eight or 87.5 percent. Designing a flexible system with
variable air flow can achieve the objectives of optimized airflow rates. Existing systems
should be adjusted to run at the lower end of the recommend ACR range through careful
monitoring of impact on the cleanroom processes.

PRESSURIZATION

Pressurization prevents the infiltration from adjacent spaces. Pressurization of clean areas is
required to keep products from being contaminated by particulate and/or to protect people
from contact with harmful substances by physical means or inhalation. This can be easily
accomplished by supplying more air than the cumulative of what is returned, exhausted or
leaked from the room. Standard 209E specifies that the minimum positive pressure
between the cleanroom and any adjacent area with lower cleanliness requirements should
be 0.05 in. w.g with all entryways closed. During facility operation as doors are opened, the
design differential is greatly reduced, but air must continue to flow from the higher to lower
pressure space, even though at a reduced flow rate. To maintain a differential of 0.05 in
water, a velocity of approximately 900 ft/min (4.7 m/s) should be maintained through all
openings or leaks in the room, such as cracks around door openings. In theory the actual
required velocity is less, but in actual practice it is prudent to use 900 ft/min. [

Note that one-inch water gauge pressure is approximately equivalent to wind velocity of
4000 feet per minute

]. The amount of air being returned has a bearing on room pressurization and will depend on
the process taking place within the clean space. For a space requiring positive pressurization,
the return air volume is typically 15% less than the total supply air volume. While calculating
supply air quantities for various rooms, allowances should be made for process equipments
like tunnels that cross room pressure boundaries and open doors, if any. Of particular
importance is exhaust air from equipment and hoods that may be on or off at different times
during occupied periods. These variations must be dynamically compensated for to maintain
room pressurization. To maintain the required balance, numerous systems are employed
using manual and automatic dampers, constant and variable volume air control boxes, and
elaborate airflow sensing devices. These components are combined with control systems
and sensing devices to ensure that the room pressurization is maintained. The pressure
gradients are monitored with 'U' tube manometers or magnahelic gauges. Alarm and
warning systems may also be provided when the pressure gradients are disturbed.

Pressure Gradient

There should be a net airflow from aseptic rooms to the non-aseptic areas. This is possible
only if there is pressure gradient between two adjacent rooms. Air always flow from high
pressure to low pressure region. Pressure between two rooms is differential pressure “DP”.
With reasonably good building construction and airtight doors and windows, it is normally
possible to achieve and maintain the following pressures between various zones.
Atmosphere Change rooms Non-aseptic areas

0 Pa 25 Pa 25 Pa
Aseptic areas

Cooling corridors Access corridors Manufacture laboratory Filling rooms Change rooms

45 Pa 35 Pa 55 Pa 55 Pa 25 Pa

Note: [10 Pa = 1 mm w.g. = 0.04 inch w.g.] Where major demarcations of pressure are
required, air locks are used. These are small rooms with controlled airflows acting as barriers
between spaces. It minimizes the volume of contaminated air that is introduced into the
cleaner room when its door is opened…remember, with ZERO pressure differential and on
open door, the entire volume of the dirtier room can eventually find its way to the cleaner
room. It is important that

Doors open/close FAST (to minimize time of contamination). Both airlock doors should not
be opened simultaneously.

High air changes (high airflow or small volume room) to permit faster “recovery”.

People use smaller airlock (faster recovery time = less time to wait in airlock) The pressure
differential exerts a force on the door. If the force is too great (0.15 in water/36 Pa), the
door may not close fully or may be difficult to open. This is particularly important in large
complex facilities where many levels of pressurization may be required. Many facilities now
use sliding doors, and it is essential that the seals be carefully designed to allow minimum
leakage and proper containment or pressurization. Alarms that sound to indicate loss of
pressurization are valuable features and essential in the HVAC design of critical areas.

Room Seals and Doors

In most facilities the openings around the doors between rooms are where leaks occur due
to pressure differentials between rooms. In making rooms tight any room openings must be
sealed with a proper sealant that will not promote growth of organisms and can be easily
cleaned. Areas to be sealed include ceiling tiles, lighting fixtures, pipe penetrations,
telephone outlet penetrations, and any cracks or openings that appear in the structure. A
typical door would have the following dimensions and crack area at the perimeter: door size,
3 ft wide by 7 ft high; cracks at top and sides, 1/8 in with an undercut of 1/4 in. The
calculated area around the door is equal to 0.24 ft

. To achieve 0.05 in water pressure differential across the door, approximately 215 CFM of
airflow through the cracks is required. Door seals around the top and sides are usually made
of closed cell neoprene and should generally be used to reduce the crack area. To reduce the
undercut, a drop type seal, which is commercially available, should be used. The drop type is
preferred to a wipe type, since it will not mar or leave residue on the floor. Air used for
pressurization must be accounted for in system calculations. Air through cracks or openings
is accounted for as transfer air and shown in the HVAC room balance table.

FILTRATION

Proper air filtration is crucial for cleanroom controls. In dusty production areas such as
grinding, granulation, coating, tabletting etc., the filters not only control the atmosphere
contamination but also hold the internally generated particulates. Atmospheric dust is a
mixture of dry particles, fibers, mist, smoke, fumes, live or dead organisms. The air-borne
particle size varies from 0.01 micron to as much as 100 microns. Less than 2.5 micron
particles are considered as fine and particles over 2.5 micron is regarded as “coarse”. Fine
particles are airborne for a longer time and could settle on vertical surfaces. Coarse particles,
products of mechanical abrasion like in grinding and granulation departments, have lower
airborne life time and are subject to gravitational settlement. The air conditioning systems in
the pharmaceutical industry have to handle both fine and coarse particulates depending on
the production pattern and the filter regime has to be appropriate.

Air Filters

Air filters capture solid materials

Can be “roughing” filter to capture a significant percentage of total mass (30%)

Can be “high efficiency” to capture a higher percentage of mass, plus some of the
“weightless” fine particles (85% - 95%)

Can be “high efficiency particulate” to remove virtually 100% of the material weight and
99.97% or more of all particles

Terminal HEPA Filters

HEPA (High efficiency particulate air)

filters have 99.97% to 99.997% removal efficiency on 0.3µ particles. In other words, only less
than 0.03% of all particles of 0.3 microns or larger can get through such a filter. So if the
return air contains 10,000 particles per ft

3
, its concentration would be reduced down to three particles per ft

after it goes through the filter. Ultra low particulate air (ULPA) filters have 99.9997%
removal efficiency on 0.12µ particles, but these are generally recommended for cleanliness
lever of Class 10 and low (more cleaner classification), primarily for semi-conductor
industry. HEPA filters use sub-micron glass fiber media housed in an aluminum framework
and are available in two types of constructions: 1) Box type and 2) Flanged type. Box type
filters are more suitable for housing within the ceiling slab cutout where removal of filter is
from above. Whenever filter removal is not from above e.g. in case of filter being mounted
in false ceiling, flanged type

of filters is required. With flanged type of filters, additional housing is also required to
facilitate the mounting of filters and transfer the load to false ceiling members. Aluminum /
stainless steel slotted type protective grilles can be provided under the terminal filters. The
housing and grilles should be epoxy/stove enamel painted. Sealing of filters to frames is an
installation problem and is best solved by using a filter frame with a gel-like seal into which
the filter fits. The sealant selected should not promote growth of organisms and can be
easily cleaned. These filters are available in thicknesses of 6” and 12” and have pressure
drop of 1 inch-w.g. when clean and generally need to be replaced when the pressure drop
exceeds 2 inch-w.g. The most popular HEPA filter location is in the room ceiling using
standard laminar flow outlets nominally 24” x 48”.

Pre-filters to HEPA Filters

In order to prolong the service life of HEPA filters, pre-filters are recommended to filter out
majority of particles above 1 micron. However, dust holding capacity of these filters is poor.
Therefore, in case the application requires a filtration system with good dust holding
capacity, bag type filters with fiberglass scrim cloth media are recommended to give
efficiencies ranging from 85% (down to 20 microns) to 99.97% (down to 5 microns). Pre-
filters are available in various sizes with 6” and 12” thickness and with pressure drop in the
range of 0.2 to 0.25 inch- w.g. Pre-filters are normally mounted in a separate plenum with
access door after supply air fan discharge at an appropriate location. Normally flanged filters
are used for mounting in such plenums. It should be convenient to clean and replace these
filters without disturbing the rest of the filtration system.

Roughing Filter

These filters are normally provided before the cooling coil in the air handling unit and at
fresh air intakes. Efficiency of these filters is in the range of 80% down to 20 microns and
they can be easily cleaned by washing. Filters with synthetic media sandwiched between
HDPE layers in thickness of 2 inches are highly suitable for such applications.

Filters Performance Ratings

Filters are distinguished by their efficiency, airflow resistance and dust holding capacity. Air
filters are commonly described and rated on their collection efficiency, pressure drop (or
airflow resistance), and particulate-holding capacity. The American Society of Heating,
Refrigerating, and Air Conditioning Engineers (ASHRAE) have developed standards 52.1-1992
and 52.2-1999 that classify filters in terms of “Arrestance” and “Efficiency”. Per ASHRAE
standards 52.1-1992, Arrestance means a filter’s ability to capture dust and describes how
well an air filter removes larger particles such as dirt, lint, hair, and dust. The

dust holding capacity

of a filter is the amount by weight of standard dust that the filter will hold without
exceeding the resistance 0.18 inch-w.g. for low-resistance filters, 0.50 inch-w.g. for medium-
resistance filters and 1.0 inch-w.g. for high-resistance filters. Be aware that arrestance values
may be high; even for low-efficiency filters, and do not adequately indicate the effectiveness
of certain filters for chemical or biological protection.

Dust spot efficiency

measures a filter's ability to remove large particles; those tend to soil building interiors.
Dust arrestance can be expressed as

a = 1 - Ca / Cb Where

a = dust arrestance

Ca = dust concentration after filter

Cb = dust concentration before filter Since large particles make up most of the weight in an
air sample, a filter could remove a fairly high percentage of those particles while having no
effect on the numerous small particles in the sample. Thus, filters with an arrestance of 90
percent have little application in cleanrooms. Per ASHRAE standards 52.2-1999,

Efficiency

measures the ability of the filter to remove the fine particles from an airstream by
measuring the concentration of the material upstream and downstream of the device. If a
supplier of filter only indicates efficiency as 95% or 99%, it does not really mean anything
unless
it specifies the particle size range

. The ASHRAE Standard 52.2-1999 quantifies filtration efficiency in different particle size
ranges and rates results as MERV (Minimum Efficiency Reporting Value) between 1 and 16.
This numbering system makes it easier to evaluate and compare mechanical air filters and
eliminates some of the confusion regarding the overall effectiveness of any type of a
mechanical air filter on removing airborne particulates, especially those that are less than 2
microns in size. A higher MERV indicates a more efficient filter.

Filter Testing

The efficiency of a filter is of paramount importance and must be measured in an

appropriate way. The common tests on the filters include the dust spot test and DOP tests.
The dust spot test is a measure of the ability of the filter to reduce soiling and discoloration.
High efficiency filters are tested using Di-octyl Phthalate (DOP) method. The DOP test is
conducted by counting upstream and downstream particulates through a light scattering
photometer or any other particulate counter. Test particulates are of uniform 0.3 micron
diameter with a density of 80mg/cum produced by condensation of DOP vapor (Dioctyl
phthalate or bis - 2 ethylexyl). In essence, if ten thousand (10,000) 0.3 micron sized particles
are blown into a HEPA air filter, only 3 particles are allowed to pass through. Thus, you get
the 99.97% at .3 micron rating. Typically the filters are shop tested and the manufacturers
typically provide the quality certification for required efficiency to the end user. Table below
is a guide line to filter selection.

Areas

Efficiency

Arrestance

Type

Non-aseptic Areas

Pre-filter 1 Pre-filter 2 Final

20-40% dust spot 80-85 dust spot 95% DOP

75 to 85% 98% -

Panel or bag Panel Panel

Aseptic Areas
Pre-filter 1 Pre-filter 2 Final

20-40% dust spot 80-85% dust spot 99.97% DOP

75 to 85% 98% -

Panel or bag Panel Panel

All filters are dry type with synthetic and glass fiber. While pre-filters could be cleanable, the
final filters are disposable.

BASIC HVAC SYSTEMS

1. Once –thru Air

– Air is conditioned, enters the space and is discarded 2. Recirculated Air

- Air is conditioned, enters the space and portion is reconditioned. Some may be discarded.

Once – Thru HVAC What are the 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

In pharmaceutical facilities large quantities of air may be required to promote unidirectional

flow and air cleanliness. This is particularly true in a class 100 space. In many cases the large
quantities of air exceed the requirements for cooling, so it is desirable and possible to
recirculate air within the space and only pass enough air through the air handling unit to
perform the heating or cooling.

What are advantages here?

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 (an sometimes return air
filtration) 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

Constant Volume Systems

The most reliable system for pharmaceutical manufacturing areas is constant volume system
with terminal reheat (CVRH). This is because; ensuring constant pressure gradient between
the adjacent areas is of prime importance. In a terminal reheat system the air leaving the
cooling coil is set at a fixed temperature, and the terminal reheat responds to a space
thermostat, turning on heat to satisfy the load. This can waste energy, since air is cooled and
then reheated. Many energy codes prohibit this practice for comfort applications, however,
where close control of temperature and humidity is required for process areas the energy
conservation requirement is waived. The advantages of reheat systems are that humidity is
always controlled (since dehumidification always takes place at the cooling coil) and each
space or zone that needs temperature control can easily be accommodated by adding a
reheat coil and thermostat. Another advantage of the CVRH system is that airflow is
constant, which makes balancing and pressurization easier to main maintain. A reheat
system is probably the simplest and easiest of all systems to understand and maintain.

Variable Air Volume Systems

A variable air volume (VAV) system is generally used in administrative areas and some
storage spaces where pressure control is not critical, humidity control is not essential, and
some variations in space temperature can be tolerated. The VAV system works by delivering
a constant temperature air supply to spaces with reductions in airflow as cooling loads
diminish. This eliminates the energy used for reheat and saves fan energy, because the total
amount of air moved is reduced. Some form of perimeter heating must be supplied for
spaces with exterior walls or large roof heat losses. The perimeter heating can be baseboard
radiation or some form of air heating using heating coils. Finned radiation or convection
heating devices should not be used in clean spaces, since they are not easily cleaned and
allow places for unwanted particulate buildup. Combinations of systems can be used,
especially if variable quantities of supply and exhaust air are required for fume hoods or
intermittent exhausts.

HVAC EQUIPMENT SPECIFICATIONS Air Handling Unit

Pharmaceutical air handling systems support clean aseptic environments, so the equipment
must be air-tight and epoxy coated. Conventional air handling units consist of filters, coils,
and fans in a metal casing, with an insulation liner applied to the inside of the casing. For
pharmaceutical applications the unit casing must be a double skin sandwich of metal with
insulation between the metal sheets to provide a smooth, cleanable interior surface that
does not foster the growth of organisms. Units should contain good access doors, view
ports, electrical convenience outlets, and interior lighting for maintenance. The casings
should be tightly sealed and designed for pressures that are higher than commercial
applications due to the generally high system air pressures required for pharmaceutical
applications. All sealants and lubricants exposed to the airstream should be food grade to
minimize the chance of air contamination. Chilled water or propylene glycol solutions are
generally used for cooling and dehumidification. Direct expansion refrigerant, in which the
refrigerant is in the air unit coil, may be used, but these systems are less reliable than chilled
water or glycol and are more difficult to control in the narrow air temperature ranges
required. Units designated as draw-through have the coils on the suction side of the fan.
Blow-through units have the coils on the discharge side of the fan and have the advantage of
a filter downstream of the coils, reducing potential contamination of the supply duct system.
On blow through units an air distribution plate must be installed to properly distribute air
evenly over the filter and coils. While selecting the fan, it should be ensured that at the
lower speed the fan does not operate in the un-balanced region. Fans should be provided
with a shaft seal near the bearings. Cooling coil section should be provided with sandwich
type of drain pan to collect condensate. It may also be necessary to provide an eliminator
after the cooling coil in order to prevent water carry-over into the system. In case of a
heating coil, at least a 0.5 meter space should be kept between coils. All sections consisting
of pre-filters, cooling coil, heating coil, etc should be mounted in between the SA and RA
fans. Two sets of fresh air dampers should be provided, one for 10% to 20% and the second
for 100% of fan capacity. These dampers are located on the suction side of the return air fan.
Proper access should be provided in each section of the air handling unit for routine
maintenance and cleaning. 100% intake damper is especially useful during “defumigation”
operation discussed later in the course.

Air Handling Unit Location

To avoid cross contamination independent air handling systems should be provided for
various discrete operations like manufacturing, coating, tabletting, inspection and packing. In
some departments there is further segregation of operations which requires a certain
degree of control, if not an altogether independent air handling unit. Air handling systems
should be located on a separate equipment floor or zone in order to facilitate service and
maintenance without disturbance to the sterile room. They should also be located as close
as possible to the main rooms they are serving to minimize larger and longer duct runs.
Location of outdoor air-inlet louvers must be carefully considered. Intakes should be located
on the building sidewall high off the ground to minimize dust intake. Intakes should also be
away from truck docks or parking lots, where undesirable fumes and particulate are
generated. In locating inlets the prevailing winds should also be considered, and any nearby
exhausts or fume concentrations should be avoided to prevent recirculation of exhaust air
back into the supply system. Exhaust Fans Location
Building exhausts are generally collected and ducted to exhaust fans in groups or clusters.
Exhaust fans should be located as near to the building discharge as possible since this keeps
the duct under a negative pressure and any leaks will be into the duct, and not
contaminated air from the duct into an occupied space or mechanical room. For this reason
roof locations of fans are preferred, even though this may make service difficult in severe
weather conditions. When fans are located in mechanical rooms or interstitial spaces, it is
essential to tightly seal the discharge duct before it exits the building in a roof vent or wall
louver. Roof penetrations should be kept to a minimum to prevent leaks. Fumes and toxic
exhausts should be extended through the roof and terminated well above the roof line in a
suitable stack head. Extremely toxic or dangerous active biological agents may require HEPA
filtration or other treatment, such as incineration, before exhaust to the atmosphere.

Return Fans

Return fans are recommended on systems with long duct returns where pressure drops
greater than 0.5 in water (120 Pa) are expected. This allows proper total system balance and
minimizes suction pressure required from the supply fan. If a return fan is not used, the
capacity of the supply fan can be overextended and it may be difficult to limit and properly
control the amount of outside air being admitted to the unit. Outside air fluctuations are
also more susceptible to exterior wind conditions. Return fans are also needed when
required to provide a negative pressure in rooms that require containment. Return fans can
be of standard centrifugal type or an in-line type, which works nicely for installation directly
into return ducts in crowded equipment rooms. Return fans may also be required to handle
varying quantities of air or provide a constant flow of air at varying pressure conditions. To
achieve these conditions some form of damper control, inlet vane, or variable frequency
drive motor control is generally used.

Redundancy

If return or exhaust fans are used as part of maintaining containment, it may be desirable to
have a backup fan or redundant system. This is essential, if loss of containment can be
harmful to humans or would result in an expensive loss of product. Airflow switches, which
give a warning in case of fan system failures, are also desirable options for critical systems.
The airflow sensing method to prove flow is preferred to an electrical motor indication since
the motor could be running with a broken fan belt and the operator would not know that
the fan is not moving air.

Dehumidifiers

Dehumidifiers are used to control relative humidity (RH) to lower levels. RH of 50±5% can be
achieved by cooling the air to the appropriate dewpoint temperature. When chilled water is
supplied at 42–44°F to the cooling coils, a minimum dew point of about 50–52°F can be
obtained. This results in a minimum room relative humidity of approximately 50% at 70°.
Spaces with high moisture content, it is important to use a cooling coil that is deeper i.e.
with higher number of rows. Sometimes additional brine cooling coil is incorporated to
further dehumidify the supply air. This will lead to lowering of supply air temperatures
downstream the cooling coil, which is reheated by hot water coil or electrical strip heaters
before dumped into the space. In some cases where hygroscopic (products sensitive to
moisture) materials are handled, the room RH requirement may be as low as 30 to 35% and
may require the use of chemical dehumidifiers. Chemical dehumidifiers are commercially
available air handling units that contain a sorbent material (desiccant) that can be a solid or
liquid. Wet dehumidifiers use absorbents that change physically during the process. Lithium
salt solutions are generally used to remove moisture from conditioned air and are then
regenerated by heat, usually using a steam heat exchanger. Dry dehumidifiers use
adsorbents that do not experience phase changes during the process. Silica gel and activated
alumna are generally used. A rotating wheel is commonly used to remove moisture from the
conditioned air. The wheel is regenerated by passing heated outdoor air over the wheel to
dry it out. Steam or electric coils are usually employed for regeneration. Depending on the
amount of dehumidification required and the amount of outdoor air (usually with a high
moisture content), it may be best to combine the dehumidifier with a conventional air
handling unit and only dehumidify a small portion of the air or just the outdoor air. The
dehumidifier has a high initial cost compared with a conventional air handling unit. The size
should be optimized to do only the required duty with an appropriate safety factor.
Knowledgeable vendors in this specialized area should be consulted to find the best
combination of dehumidification equipment, system arrangement, and control for the
application. These systems also require considerable physical space, energy consumption,
and service—important criteria to be considered in system selection.

Humidifiers

In drier locations, makeup air may require the addition of moisture for RH control. There are
many commercially available humidifiers, but the most commonly used is “steam grid”
humidifier. These are controlled by modulation of a steam valve at the humidifier, and
include a chamber to prevent condensation and water droplets in the duct. The valve is
controlled by a signal located in the return or exhaust airstream or in a room humidistat. A
high-limit stat is placed in the duct downstream of the humidifier to override the controlling
stat and prevent condensation in the duct. Placement of the humidifier in the duct is critical
and must follow the manufacturer’s recommendations to prevent condensation and provide
proper dispersion space. It is important to use clean steam, not plant steam, which may
contain boiler chemicals and impurities from deteriorating piping and equipment.

Ductwork Design, Materials & Cleanability Duct Pressures

Ductwork in pharmaceutical facilities tends to have higher system pressure due to extensive
use of filters, volume control devices, and physically complex arrangements. The duct
system pressures must be calculated and clearly stated on the contract documents to allow
the fabricator to provide the proper metal thickness and construction methods for the
required system pressures. System pressures will also change as the system is operated with
filters that get dirty or space pressure conditions that vary. Duct systems must allow for
these pressure fluctuations and the fans may require speed controls, inlet vanes, or variable
pitch blades to match the varying flow and pressure conditions.
Duct materials and shape

Unlined galvanized steel, stainless steel or aluminum ductwork is used in rectangular,

round, and elliptical (or flat oval) configurations for the majority of the systems. Round
ducting is a natural choice, being self cleaning in shape, wherever space permits. Because
galvanized duct can flake off or rust, it should not be used downstream of the HEPA filters to
avoid contamination from the duct system itself. When the HEPA filter is located upstream
of the room terminal and a long run of duct is present, the material of choice for the duct is
stainless steel, but this is expensive and its use should be minimized. Many systems may also
be fumigated or cleaned in place, and the duct material chosen should not be affected by
the cleaning agent.

Cleanability

Cleanability of duct systems is important to ensure that if an installed system gets dirty or
contaminated it can be cleaned. In the design stage care must be taken to locate access
doors in the duct, where they can be easily reached without compromising a process or
violating a controlled space. All sealed duct shipped to the site should have only end seals
broken, and then quickly resealed, during final installation. In very critical applications the
duct is factory cleaned and sealed before shipment to the site. This step removes the oil and
other contaminant present during duct construction but is expensive. It may be difficult to
find sheet-metal fabricators willing to do this work, since they are not always set up for such
procedures. Following precautions should be taken: 1. Ducts should be sealed with silicone
sealant at longitudinal joints in order to make the system airtight. Rubber gaskets should be
used at transverse joints. 2. GI flanged joints must be avoided and instead pocket slips or
angle iron flanged joints should be used. 3. No acoustic insulation should be provided inside
the ducts. 4. Dampers provided in the system should be of compatible duct materials and
should have extended handle to accommodate insulation thickness. 5. Return air risers
should be designed for velocities not exceeding 1800 fpm with a minimum velocity of 1200
fpm at the highest point in order to carry particulate matter along with return air. However,
the inlet velocity at the return grille should be in the range of 300 to 400 fpm gradually
increasing the same to 1200 to 1800 fpm. 6. Grilles and diffusers should be flush mounted
into ceiling, walls or duct work and all such grilles shall be fabricated from stainless steel or
stove enamel/epoxy coated construction. 7. Whenever terminal filters are mounted in the
false ceiling, proper sealed access door should be provided to reach the dampers above each
filter.

Supply Terminals

In clean spaces, the desired distribution of air is unidirectional. This carries particulate from
the ceiling to the floor return and helps to prevent airborne particulate matter from
recirculating and contaminating the work space. In most cases it is desirable to recirculate
air within a space through a filter since the return air has less particulate than typical
outdoor air and does not require extensive heating and cooling. Air terminals should be
selected of materials that are non-flaking, non-oxidizing, and are easily wiped clean.
Return Terminals

Return terminals are also an important consideration and are generally located low in the
walls for cleanrooms. In class 10,000 to 100,000 rooms low cleanable wall registers are
generally used. In cleaner areas low return wall systems, termed

air walls

, are used. The air wall is an almost continuous opening at the base of the wall with the air
ducted up in the wall system and collected for return to the air handling system. Air wall
inlets are generally located not more than 15 ft in plain view from a supply terminal to
reduce the likelihood of turbulence. The material of construction for the return grilles will be
determined by the process taking place in the clean space, though stainless steel is used
quite often for its appearance and cleanability. Due to its corrosion resistance, the use of
stainless steel grilles also allows for processes to be changed periodically without changing
grilles.

Defumigation

Sterile areas are periodically fumigated with formaldehyde vapor that is circulated through
areas and air-conditioning equipment in order to sterilize the system. However,
formaldehyde vapor must be removed effectively after fumigation is over before starting the
actual operations. During defumigation 100% fresh air is provided and this is fully exhausted
to remove formaldehyde vapor. The fresh air and exhaust air ducting should be designed for
100% air volume with appropriate dampers to re-set at normal position during normal
operation sequence. The procedures must be developed to accommodate a product spill or
accident in a contained space. The ramifications of a spill on the air system, controlled space,
and adjacent operations must be evaluated. Cleanup procedures could include fumigation of
the air system, which would require operation of a relief connection to the ductwork for
venting the fumigant.

EMERGENCY ELECTRICAL POWER

An essential step in the HVAC design process is coordination with the electrical design team.
Motor lists for HVAC equipment must be prepared and reviewed with the electrical design
team. The need for motors designated for emergency power, variable speed, reduced
voltage starting, or other special characteristics must be communicated to the electrical
designers early in the design process. The sizing of the emergency generator can be greatly
affected by motors required on emergency power from the HVAC system. Fans, equipment,
or sensing devices that require interlocks must also be picked up by the electrical designers.
The motor list must be kept up to date from project inception through commissioning. The
motor list is useful for a reviewing agency, a valuable tool in training plant operators, and a
great aid in understanding the HVAC system.

BUILDING CONTROL AND AUTOMATION SYSTEMS

The automatic control system that controls and monitors the HVAC system is called by many
names: the automatic temperature control system (ATC), the energy management and
control system (EMCS), the building automation system (BAS), or the building management
system (BMS). The control system of choice for major facilities, and even for some small
systems, is a direct digital control (DDC) system. Most major control system vendors and
many of the smaller vendors offer DDC systems that are similar but contain internal
differences. The systems are computer based and have the ability to communicate within
and outside the system by coded digital signals. System architecture refers to the major
components of the DDC system and their interrelationship. The architecture is developed by
determining what components are initially required, what may be required in the future,
and how the system may expand as additional requirements are added.

Sequence of Operations

The first element in the design of the system is the development of a sequence of operation,
which is a written description of the HVAC and related systems operation. A separate
sequence is usually written for each air handling system, describing the complete operation
of the system from control of coils and humidifiers to control of the room temperature and
humidity. Starting and stopping of the air handling unit fans is outlined, along with
interlocking of exhaust or return fans in relation to the main air system fan operation.
Generally all fans operate at the same time, which is necessary to maintain pressurization.
The sequence also addresses abnormal occurrences such as a smoke detection alarm or
failure of an exhaust fan. The sequence describes what happens to system components
during an abnormal occurrence. It may be necessary to shut a supply fan down if a major
exhaust fan should fail to prevent or minimize the loss of pressurization. The sequence also
describes any energy management strategies to be included in the system, such as a night
temperature setback or reduced ventilation and exhaust rates during unoccupied periods.

Points List

After the sequence of operation is completed and the airflow diagrams are defined, the next
step is to develop the alarm, control, and monitoring points list. This is an all inclusive list of
points that are to be connected to the DDC system. There are two major types of points:
digital and analog. A digital point is simpler, generally less expensive, and works on a simple
on–off or contact principle. Digital points are used to start and stop fans, indicate an on–off
condition, or anything that requires only a single contact. An analog point is used to
measure variables such as temperature, pressure, and flow rate. These points generally use
4- to 20-mA signals that provide varying signals in response to the parameter measured. The
electronic signals used by the BAS may be transduced from variable pneumatic or pressure
signals. The points list should include analog control points such as cooling coil valves and
room temperatures. Monitoring points can be digital or an analog, and can include fan run,
room temperature indication, damper position, and room pressure indication. Alarm points
can be either digital or analog and can include smoke detection in an air handling unit
system, high or low environmental chamber temperature, high room humidity, or loss of
room pressurization.

Estimate of System Cost

The automatic control and monitoring system is a major cost element in the overall HVAC
system for a pharmaceutical facility. After the points list is developed a good estimate can be
made for the system cost. Several estimating numbers can be used in providing an educated
guess of the cost, with a general range from a low of $500/point to as high as $1,200/point.

TESTING, BALANCING, AND CLEANING

For pharmaceutical facilities, establishing pressure differentials between adjacent spaces is

the most critical and is very tedious to balance. These differentials are obtained by adjusting
airflows, smoke tests, taking pressure readings, and setting controls. This effort can take
some time as each facility is different and each room has different leakage characteristics
that affect pressurization. As part of the balancing, you may find that the duct systems or
rooms are not as tight as designed and may require additional sealing to obtain the required
pressure differentials. Recall that airflows shown on drawings are design values and
generally require minor adjustment to achieve the required pressure differentials. A simple
solution to many pressurization problems is to keep increasing outdoor air to the system.
This can lead to problems, if design values are exceeded, with heating or cooling coils not
meeting this need, resulting in off-design room temperatures and humidity levels. The air
handling unit coils will use available cooling capacity to condition excessive quantities of
outdoor air, resulting in room supply temperature higher than as designed. Therefore, the
best solution first is to tighten the spaces. The optimum time to balance is when few
construction workers or facility personnel are in the spaces. The balance should be done
with all doors closed, since opening and closing results in system pressure upsets and make
balancing difficult. In general, testing and pre-commissioning test procedures cover the
following parameters: 1. HEPA filter integrity by DOP testing for pinhole leaks in the filter
media, across sealants and frame gaskets, supporting frame and wall. 2. Air stream velocity
under each filter panel. Airflow measurements should be made at supply, return and
exhaust outlets, as well as traverses across the face of hoods, to verify proper flows and
capture patterns. 3. Establish a spectrum of particulates from appropriate air samples. 4.
Smoke testing for establishing flow patterns if possible and if required similar test are
desirable with the cleanroom in operation and at rest for a complete validation. 5. Pressure
differentials between rooms to passage to change rooms. 6. Pressure drop across the final
filters. 7. Room temperatures and relative humidity. Temperature and humidity sensors at
critical areas should also be checked for accuracy at this time by actually reading space
conditions and checking against values reported by the BMS. 8. A comprehensive
documentation of the testing procedures and test readings is prepared before the facility is
handed over for production. For proper evaluation of the facility, the system

should be

tested while at rest, and during production. VALIDATION

NO production can start until the cleanroom is validated. When a pharmaceutical facility is
to be validated, the validating agency will peruse the HVAC documentation and should
communicate with the design engineers to establish the validation protocol as it relates to
the HVAC system. If the design is proper, the system is properly installed, and the
components perform as specified, the systems should be easily validatable. The validator will
follow a master plan and protocols to verify the actual system installation and operation
against design values and intent. The physical parameters reported by the BMS system shall
be verified by measurements using calibrated instruments to verify accuracy.

DOCUMENTATION

Good manufacturing practices govern the level of control of various parameters for quality
assurance, regulating the acceptance criteria, validation of the facility, and documentation
for operation and maintenance. The documentation should cover design, operation and
performance qualifications of the system.

Design Qualification

The design qualification document should cover all the following issues: 1. Identification of
various systems, their functions, schematics & flow diagrams, sensors, dampers valves etc.,
critical parameters & fail-safe positions. 2. 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

Process equipment locations and power inputs

Critical instruments, recorders and alarms, if any 3. Equipment performance and acceptance
criteria for fans, filters, cooling coils, heating coils, motors & drives. 4. Duct & pipe layouts
showing air inlets, outlets air quantities, water flows and pressures. 5. Control schematics
and control procedures.

Operation Qualification

This is a commissioning documentation which shall provide all the details of equipment
various points of performance, test readings, statement of compliance and noncompliance
with the acceptance criteria. Broadly the features are as follows: 1. Installation date showing
manufacturers, model no., ratings of all equipment such as fans, motors, cooling & reheat
coils, filters, HEPA filters, controls etc. 2. As-built drawings showing equipment layouts, duct
and pipe runs, control & fire dampers, settings of various sensors and controllers. 3.
Contractor's rest readings covering rotation tests, megger readings, air quantities,
temperatures and RH pressures of each space, dry & wet run of controls, air and water
balance, HEPA filter integrity tests at final operating velocities testing of limits & alarms. 4.
Identification of items spaces, parameters not meeting the acceptance criteria but cannot be
corrected.

Performance Qualification

This is essentially for the system operating under full production conditions and covers
among others: 1. Identification of agency for commissioning, for equipment and instruments
and their calibration. 2. Test readings of all critical parameters under full operating
conditions and full production, modification of readings in the contractors test results,
acceptable and unacceptable departures from design qualification and acceptance criteria.

SUMMARY

HVAC systems in manufacturing portions of facilities are closely supervised by the FDA

and must meet other global current good manufacturing practices (cGMP’s). Per US

GMP, Design and Construction Features Standard (211.42), sterile area cleanrooms

have the following distinct characteristics: 1. Air should be of a high microbial quality. 2. Air
handling system is provided with a central HEPA filter bank along with mandatory terminal
filters in order to extend the life of terminal filters. 3. The filtration regime is generally three
stages with two stages of pre-filters, 10 micron (EU 4), 3 micron (EU 8) and one central final
filter 0.3 micron (EU 12) along with terminal HEPA filter. 4. All sterile critical operations shall
be in a laminar flow work station. 5. Critical areas should have a positive pressure
differential relative to adjacent LESS clean areas: a positive pressure differential of 0.05 inch
of water (12.5 Pa) is acceptable. 6. Supply air outlets are provided flush at the ceiling level
with perforated stainless steel grilles and terminal absolute filters. Return air grilles to be
provided at the floor level with a return air riser for better scavenging 7. Walls, floors, and
ceilings for cGMP areas are to be constructed of smooth, cleanable surfaces, impervious to
sanitizing solutions and resistant to chipping, flaking, and oxidizing. Maintaining proper
pressurization gradient between adjacent spaces is important to prevent infiltration and
cross-contamination. Air filtration techniques and air conditioning components shall be
constantly monitored and upgraded in order to improve the finished product and reduce
energy consumption. Remember, overstating quality requirements and tolerances may
result in unnecessary costs. Higher air flows and pressures require more HVAC capacity.
Since most engineering decisions will have an impact on HVAC systems, it is important to
recognize opportunities to seek the best engineering solutions.