Pharmaceutical clean Room

clean room:
A clean room is a combination of engineering design, fabrication, finish and
operational controls (control strategy) that are required to convert a “normal” room
to a “clean room”.

Clean rooms are now used in a variety of industries, including microelectronics,

nanotechnology, defence, pharmaceuticals and biotechnology.
When it comes to the pharmaceutical industry, regulation and quality come first.
Strict guidelines in this cutting-edge industry create the need for high specification
cleanrooms that meet all regulations.
Clean rooms are defined as specially constructed, environmentally controlled enclosed
spaces with respect to airborne particulates, temperature, humidity, air pressure, airflow
patterns, air motion, vibration, noise, viable (living) organisms, and lighting.

 “British Standard 5295” defines a clean room as a room with control of particulate
contamination, constructed and used in such a way as to minimize the introduction,
generation and retention of particles inside the room and in which the temperature,
humidity, airflow patterns, air motion and pressure are controlled.

 IES Recommended Practice, which states that : “A room in which the air supply, air
distribution, filtration of air supply, materials of construction and operating
procedures, pressurization, temperature, humidity are regulated to control airborne
particle concentrates to meet appropriate cleanliness levels as defined by Federal
Standard 209 D or latest issue”.
 The principal function of a clean room is to protect the manufacturing product from contamination. In
the pharmaceutical sector the commercial survival of the manufacturer depends on the integrity of the
finished product.
Therefore, it is important to identify a potential source of contamination, which could include the
working environment itself.

Contamination is a process or act that causes materials or surfaces to be soiled with contaminating substances.
Contamination is the direct or indirect scratch of a product activity by an alien, particle, micro-organism and
chemicals.
Pharmaceutical clean room suites consist of different clean rooms, where are made several steps of production.
Standards of environmental control increase step by step when product materials and packaging components are
carried out processes into different rooms. So, it is needed to know a potential source of contamination, which could
include the working environment itself.
The source of the contamination is categorized as external sources and internal sources.
• External Sources - External contamination is brought in primarily through the air
conditioning system.
• Internal Sources - The potentially largest source is from people in the clean room, plus
shedding of surfaces, process equipment and the process itself.

This is a partial list of some of the commonly known contaminants that can cause problems in
some clean room environments.
• People ~75%
• Ventilation ~15%
• Room Structure ~ 5%
• Equipment ~ 5%
Raw Material and Product People
 Skin flakes and oil
• Isolation of material with transport tunnels
 Hanging shields  Cosmetics and perfume
 Nitrogen purged processing  Spittle / Saliva
 Vacuum processing  Clothing debris (lint, fibers etc.)
 Laminar flow stations isolation
 Hair
 Clean room debris
 Deionized water  Fingerprints
 Metal particles  Coughing
• Before any raw material or product is brought into  Handling
the clean room it must be cleaned.
 Improper cleanroom gowning protocol for
particular class
Facilities
 Floor finishes and ceilings  Infrequent change out intervals of suits
 Paint and coatings  Socks and floor mats
 Construction material
 Air conditioning debris
 Room air and vapors
 Spills and leaks
• Processing equipment and tools
• Introduction of equipment and even running equipment are sources of contamination. Proper evaluation of the materials
used in manufacturing the equipment and any chemicals used internally or externally must be done. Some tools and
equipment generate contamination during use and must be kept away from processes or product.

 Friction and wear particles

 Lubricants and emissions
 Vibrations
 Brooms, mops and dusters

• Cleaning chemicals
• Regular household or industrial cleaning products are not acceptable for cleanroom maintenance. Non - particulating wipes
must be used for all cleaning. Special cleaners designed for specific cleanroom use must also be used.
Contamination Control
List of equipment and supplies needed to clean the cleanroom
All supplies must meet the minimum requirements
1. Cleaning and disinfecting solutions
2. Cleanroom mops
3. Cleanroom vacuum cleaner (if allowed)
4. Clean room wipers

List of Cleaning Tasks to be Completed in the Cleanroom

Frequency may vary depending upon local requirements

1. Cleaning of all work surfaces in the controlled environment.
2. Vacuuming (if allowed) of the floors and work surfaces.
3. Emptying of appropriate trash and waste.
4. Cleaning of the doors, door frames and lockers in the pre-staging area and gowning areas using the
approved cleaning solution.
5. Mop clean room floors.
 So what makes a clean room a “clean room”?
Cleanrooms and clean areas are defined in the GMP’s as having the following characteristics.
There are three things that keep a cleanroom “clean”:
i. The internal surfaces of the clean room and the equipment within them;
ii. The control and quality of air through the clean room;
iii. The way the clean room is operated (i.e. the number of staff).
1. The internal surface
For GMP compliance and to achieve the cleanliness specification, all surfaces in a cleanroom
should be “smooth and impervious”, and:
• not generate their own contamination i.e., don’t create dust, or peel, flake, corrode or provide
a place for microorganisms to proliferate
• are easy to clean i.e., all surfaces are easily accessible, there should not be any ledges or
recesses
• are rigid and robust and won’t crease, crack, shatter or dent easily.
• There are a wide variety of suitable material choices, ranging from the more
expensive Dagard paneling, as shown in the photo below, with sliding doors
(not recommended as mentioned earlier), or the best and most aesthetically
pleasing option is glass, i.e., as at the end of the corridor. Among the
cheapest options, can be plaster-board with a two pot epoxy coating, and
there are a range of other options available.
2. Clean room airflow
a) Clean rooms need a lot of air and usually at a controlled temperature and humidity.
b) A well-designed air handling system should deliver both “fresh” and “recirculated” filtered clean
air into the cleanroom in such a way and at a rate so that it flushes the particles from the room.
c) Depending on the nature of the operations, the air taken out of the room is usually recirculated
through the air handling system where filters remove the particulates.
d) High levels of moisture, noxious vapours or gases from processes, raw materials or products
cannot be recirculated back into the room, so the air in these cleanrooms is often exhausted to
atmosphere and then 100% fresh air is introduced into the facility.
e) Rooms occasionally experience high levels of airborne particulates during routine operation,
such as in a sampling room or dispensary. In these cases, the room needs to be cleaned quickly
between operations to prevent cross-contamination.
f) The volume of air introduced into a cleanroom is tightly controlled and so is the volume of air
that is removed. Most cleanrooms are operated at a higher pressure to the atmosphere, which is
achieved by hiving a higher supply volume of air into the cleanroom than the supply of air being
removed from the room. The higher pressure then causes air to leak out under the door or
through the tiny cracks or gaps that are inevitably in any cleanroom.
Operating a clean room

• The most effective way of maintaining the air quality in a cleanroom is to operate and
maintain it correctly.
• This involves:
• minimising the amount of potential contamination that escapes from your manufacturing
operations
• strictly controlling access to the cleanroom to only trained personnel and limiting the
number, as even trained operators are the most significant source of cleanroom
contamination
• regularly cleaning your facility to strictly controlled procedures
• regular maintenance of the facility and equipment
• regular monitoring of the air filters and air flows and frequent recertification of the
cleanroom.
CLASSIFICATION OF CLEANROOMS AND CLEANROOM STANDARDS
Cleanrooms are classified by the cleanliness of their air. The method most easily understood and
universally applied is the one suggested in the earlier versions (A to D) of Federal Standard 209 in which
the number of particles equal to and greater than 0.5 m m is measured in one cubic foot of air and this
count is used to classify the room.

Terminology used for clean room systems:

1. Particle size: Micron = 10-6 m
2. Number of air changes: Integer number indicating ratio of blower capacity of air handling unit to
the room volume.
3. Particle count: Number of particles of specified size per of air inside the clean room.
4. Quality standards for the clean rooms:
a. US FED STD 209E clean room standards
b. ISO 14644-1 clean room standards
c. BS 5295 clean room standards
d. GMP EU classification
5. AHU: Air handling units
6. HEPA: High-efficiency particulate air
Cleanroom zoning
Clean rooms are classified by the cleanliness of their air. There are four types (A, B, C & D zone) of
clean zones in manufacturing sterilized pharmaceutical products. The grade is defined by the type
of product and a part of process which needs to be protected from contamination.

Critical: (Grade A zones) - local zone. For operations that affords high risk for product quality,
e.g. filling, closing, ampoule and bottle opening zones. Usually in such zones is used
laminar air flow which provides similar velocity 0.36-0.54 m/s.
Intermediate: (Grade B zones) - Any area in the clean room that circled A-zone in case of aseptic
preparation & may come into contact with product e.g. bench in clean room, transfer device of
isolator.
Non-critical: (Grade C & D zones) - Any area external to the clean room e.g. where
product/materials may be stored in a clean support room. Less critical stages in the aseptic
preparation process e.g. labelling, documentation, checking. In case of aseptic preparation D is the
minimum acceptable background environment.
 Cleanroom classification
Cleanrooms are divided into different classes in standards.
The equivalence of classes form different international standards is shown in table 1. For the
manufacturing sterile products there is certain classification (table 2) with grades A to D which are
characterized to activity category (tables 3 and 4).
Class limits for Federal 209D and ISO Standards
Table 2. Air particle classification system for the manufacturing of sterile products.
Remarks:
(а) In order to reach the B, C, and D air grades, the number of air changes should be related to the size of
the room and the equipment and personnel present in the room.
The air system should be provided with appropriate filters such as HEPA for grades A, B, and C.
(b) At rest should be received unmanned state after the 15-20 min “clean up” period.
(c) Appropriate alert and action limits should be set for the results of particulate and
microbiological monitoring.
If these limits are exceeded, operating procedures should prescribe corrective action.
Demands for other parameters like temperature, relative humidity, etc. depend on product and
manufacturing operation nature. These parameters have no connections to purifying classes.
 Air supply, Airflow distribution and control
Three aspects of the clean room definition — air supply, distribution & filtration - are very closely connected.

Depending on the degree of cleanliness required, it is common for air systems to deliver considerably more air than
temperature and humidity design. Because airflow is such an important aspect of particle control

The design of a clean room requires careful consideration of air motion and airflow patterns. “The solution is
dilution”

Air Change - A volume of air equivalent to the room volume that enters and exits a room. Air change rate depends on
air flow rate and size of the clean room.

For example: 60 air changes an hour means that a volume of air equivalent to the room passes through the room each
minute.

FDA guidelines only specify a minimum of 20 air changes per hour. The number of air changes required to meet
specification is determined for each individual cleanroom.
 Unidirectional Airflow

(Sometimes referred as laminar flow) is an airflow pattern in

which air within a confined area moves with uniform velocity
and in single direction with generally parallel airstreams.

Unidirectional airflow usually vertical at a uniform speed of

between 60 to 90 fpm throughout the entire space.
Unidirectional airflow tends to remain parallel until it encounters
obstacles such as people, process equipment and work
benches.
• Why Laminar Flow?
 Non-turbulent air flow, reduces the possibility of contamination
caused by the movement of particles.
 Scrubs the room with air flowing from ceiling to floor.
 Unidirectional Airflow
 Air changes per unit of time are many times greater in unidirectional flow design.
 Unidirectional airflow can also be provided horizontally. Its use much less popular at the present time, because air
quality destroys quickly.
 Unidirectional airflow is used when low airborne concentrations of particles or bacteria are present.
 The air velocity is sufficient to remove particles before they settle onto surfaces. Clean rooms; class 100 and below have
unidirectional airflow pattern.
 Unidirectional airflow requires greater attention to strict design guidelines.

Unidirectional Flow System Designs

Single Pass System:

Filtered air enters the room, exits through the lowers and is not re-circulated. The system is ideal for 100% makeup air or
when ambient temperatures are favorable and acceptable.

Re-circulated System:

Filtered air enters the room, exits through plenum walls and is re-circulated through a sealed plenum using motorized fan
modules with HEPA filters. This is the most popular design.
 Non-unidirectional airflow

Non-unidirectional airflow is not unidirectional by having a varying velocity, multiple pass

circulation or nonparallel flow direction. Turbulent flow is a conventional flow (class 1000 &

10000) design.

Non-unidirectional flow is used where particle sizes are relatively large. It is used in clean

rooms where terminal outlets form. The non-unidirectional turbulent airflow ventilation system

relies on mixing and dilution to remove contamination.

 Non-unidirectional airflow
Turbulent areas can have counter currents of higher velocity, reverse flow or even stagnant or
no flow. Small clusters of particles can cluster in stagnant areas and finally settled.

The non-unidirectional or mixed air flow patterns differ in the location of the supply and return
air registers and air filter locations. In non-unidirectional arrangement, the airflow is typically
supplied through diffusers with HEPA filters in them.

Cleanliness levels as high and can be achieved when HEPA filters are installed in terminal
housings. Air flows are predictable but impossible to guarantee.

Mixed patterns combine some of each flow type. Conventional flow clean rooms have
mixed air flow patterns. Clean spaces of different classes and airflow patterns can be
combined in the same room by proper design and arrangement.
 Differentiates unidirectional to non-unidirectional flow
Unidirectional airflow pattern is in one direction, usually horizontal or vertical at a uniform speed of
between 60 to 90 FPM throughout the entire space. The air velocity is sufficient to remove particles
before they settle onto surfaces.

The non-unidirectional turbulent airflow ventilation system relies on mixing and dilution to remove
contamination.

Unidirectional airflow tends to remain parallel until it encounters obstacles such as people, process
equipment and work benches.

Turbulent areas can have counter currents of higher velocity, reverse flow or even stagnant or no flow.
Small clusters of particles can cluster in stagnant areas and finally settled.

Unidirectional airflow is used when low airborne concentrations of particles or bacteria are present.

Non-unidirectional flow is used where particle sizes are relatively large.

 Air changes per unit of time are related to the volume of the room and are many
times greater in unidirectional flow design than those supplied to a turbulent airflow
clean room.

 Unidirectional airflow requires greater attention to strict design guidelines. A vertical

flow room would have air supplied through a perforated ceiling with HEPA filters and
returned through a raised floor, producing nominally parallel airflow.

The non-unidirectional or mixed air flow patterns differ in the location of the supply and
return air registers and air filter locations. In non-unidirectional arrangement, the
airflow is typically supplied through diffusers with HEPA filters in them. Grated or
perforated floors are suitable, low-level sidewall returns are used.
 Air flow design
Clean room airflow design conventionally decide on the airflow pattern,
average velocities and air changes per hour.
A clean room differs from an ordinary ventilated / conditioned room mainly in (3)
three ways.
1.Increased air supply
The increased air supply is an important aspect of particle control. Normal air-conditioning
systems are designed for 0.5 to 2 air changes per hour essentially based on the occupancy level
or as determined from the building exhaust levels. A clean room would have at least 10 air
changes per hour and could be as high as 600 for absolute cleanliness. The large air supply is
mainly provided to eliminate the settling of the particulate and dilute contamination produced
in the room to an acceptable concentration level.
2. The use of high efficiency filters
High efficiency filters are used to filter the supply air into a clean room to ensure the removal of
small particles. The high efficiency filters used in clean rooms are installed at the point of air
discharge into the room.
3. Room pressurization
The clean room is positively pressurized with respect to the adjacent areas. This is done by
supplying more air and extracting less air from the room than is supplied to it. Room
pressurization is mainly provided to ensure that untreated air does not pass from dirtier
adjacent areas into the clean room.
 ULPA Filter
Ultra low penetration air filters

Most ULPA filters are replaceable extended media dry filters that have a minimum particle
collection efficiency of 99.9997 % efficient for particles greater than or equal to 0.12-micron in
size.

Typically filters use glass fiber paper technology and are generally constructed in deep pleats
with aluminum, coated-string or fiber paper pleating separators. They vary in depth from 2 to
12 inches or more.

The high efficiency filters belong to the 'interception' family of filters and are referred to as
'absolute' super interceptor.

Both HEPA & ULPA types fall in extremely high level of cleanliness or purity category filters.
 HEPA Filter
High efficiency particulate air or High efficiency particulate arrestance air filter.
HEPA filters are composed of a mat of randomly arranged fibres. The fibres are typically
composed of fiberglass.
The common assumption that a HEPA filter acts like a sieve. To qualify as HEPA by US
government standards, an air filter must remove (from the air that passes through) 99.97% of
particles that have a size of greater than 0.3 µm.
Most traditional HEPAs for Class-1 and Class-10 environments.
Filters meeting the HEPA standard have many applications, including use in medical
facilities, automobiles, aircraft, and homes.
The filter module units are mounted into clean room ceilings, walls or work benches.
 Key factors affecting function are fibre diameter, filter thickness, and face velocity.
 Do not filter out gasses and odor molecules.
 Requiring filtration of volatile organic compounds, chemical vapors, cigarette, odors
use of an activated carbon (charcoal) filter instead of or in addition to a HEPA filter.
 Temperature & Humidity Control
Temperature and humidity variations cause process equipment misalignment, impact the
repeatability of the developed process, and eventually reduce the product's output and
increase the quantity of waste.

Temperature control - Clean rooms with stringent temperature control requirements (68
to 72 degrees F) and set point (70 degrees F, +/– 2.0 degrees).

Humidity control - Humidity control is critical and takes precedence over temperature
control. The clean rooms HVAC design should consider the high operational ambient dry -
wet bulb data. The relative humidity for each clean room is controlled by a zone
humidistat. Typical design criteria is RH: 50 to 60% and Fresh Air: 20% to 100% fresh air.
If there is a high relative humidity in the room, the humidistat lowers the cooling coil
discharge air temperature to provide more dehumidification. At the same time, the
reheat coil provides heat to maintain the room temperature.
If the relative humidity falls below the design limit, the humidistat actuates the
humidifier to increase the supply air's moisture content