Basic Clean Room Design Requirements and Considerations

03/04/2020 Basic clean room design requirements and considerations
 info@pharmout.net  My Account   
Services Industries Cannabis Training Forums
Free Tools Blogs About Us Contact Us  
Basic Clean Room Requirements | Designs for GMP

Clean Rooms

Home / Blogs, Cleanroom GMP Clean Room, ISO 14644 and Cleanrooms / Basic Clean Room
Requirements | Designs for GMP Clean Rooms
Australian
Medicinal
Cannabis
 Conference 
2020,
November 16-
17, Melbourne
REGISTER ONLINE
VIEW SCHEDULE
VIEW PROSPECTUS
By Trevor / 08/07/2014  54630 Views  12 Comments

SPONSORS
GMP &
Basic Clean Room Engineeri
Requirements | Designs ng
FORUM,
for GMP Clean Rooms August 3-4,
2020
What is a clean room?

https://www.pharmout.net/basic-cleanroom-requirements/
FIND OUT 1/16
FIND OUT
A clean room (GMP cleanroom), in my mind are a
MORE
combination of engineering design, fabrication, finish
and operational controls (control strategy) that are
required to convert a “normal” room to a “clean room”.
In this blog I will attempt to explain the necessary Follow
characteristics of a regulated company clean room not PharmOut on
producing potent chemicals or active or hazardous LinkedIn
biologicals. If there are significant containment
requirements, the requirements would be outside the Follow
scope of a “simplistic” blog like this. In a pharmaceutical PharmOut on
sense, clean rooms are those rooms that meet the code LinkedIn to
of GMP requirements as defined in the sterile code of receive news of
GMP, i.e. Annex 1 of both the EU and PIC/S Guides to regulation
GMP and other standards and guidance as required by updates, events
local health authorities. and training
and networking
So why do I need a clean room? opportunities
There is no GMP requirement in the EU and PIC/S (i.e.
TGA) GMP guidance’s for the manufacture of non-sterile
medicinal products in a “clean room”, but we do use
clean areas that are effectively ventilated with filtered
 air where the products or open clean containers are 
Blogs
exposed. On the other hand, for the manufacture of
sterile medicinal products, clean rooms are mandatory,
as defined in Annex 1 of the EU and PIC/S GMPs. This Blogs
Annex defines a number of additional requirements Select Catego
besides the airborne particulate concentration limits
used to classify clean rooms.
In a nutshell, if you manufacture a non-sterile medicinal

product, you should be very careful about classifying or
grading your clean areas, for example, classifying a
room as “Grade D”. Whilst not a code requirement,
many regulators, like the Australian TGA will expect you
to fully comply with all of the requirements for a Grade
D room as defined in Annex 1, even if it’s not a GMP
code requirement. If you have classified the room as
Grade D, you will need to live with the consequences
and costs of maintaining this level of clean room
cleanliness during operation.
What type of clean room do I need? 
https://www.pharmout.net/basic-cleanroom-requirements/ 2/16
If you are a manufacturer of non-sterile medicinal

products, you should define your own clean room / area
standards using national and international standards.
Usually manufacturers will define an airborne
particulate concentration standard class such as ISO
14644-1 ISO 8 (at rest), outline gowning and a pressure
cascade regime, defining a “clean corridor” design or a
“dirty corridor” design.
If you are a manufacturer of sterile medicinal products,

you must follow the EU or PIC/S GMPs, namely Annex 1.
“Clean corridor” or a “Dirty corridor”?

When considering pressures cascades, the
pharmaceutical engineers should consider a design
philosophy to have a “clean corridor” or a “dirty
corridor” design, which we will now explain through an
example. Typically, low moisture medicinal products
such as tablets or capsules are dry and dusty, therefore
more likely to be a significant cross-contamination risk.
If the “clean” area pressure differential was positive to
the corridor, the powder would escape out of the room
 
and enter the corridor, and is likely then to be
transferred into the next door cleanroom. Thankfully,
most dry formulations do not readily support microbial
growth, so as a general rule, tablets and powders are
made in “clean corridor” facilities, as opportunistic
microorganisms floating in the corridor don’t find
environments in which to thrive. This means that the
rooms are negatively pressurised to the corridor.
For aseptic (processed), sterile, or low bio-burden and

liquid medicinal products, the opportunistic
microorganisms usually will find supportive media in
which to flourish, or in the case of an aseptically
processed product, a single microorganism could be
catastrophic. So these facilities are normally designed
with “dirty corridors” as you want to keep potential
microorganisms out of the cleanroom. Unlike powders,
droplets of liquid don’t generally “leap up” and float
around the facility.

Designs can become complicated if the products or raw

materials are highly potent, which cause occupational
health and safety issues, or if there is a need for
biological containment. These are outside the scope of
clean room basics, reading this blog on dedicated
facilities could assist. If you want to know more, our
clean room designers can help.
Which way should my clean room

doors swing?
Unless you have power-assisted doors, all doors should
open into the room with the higher pressure. Double-
leafed doors are notorious for causing the pressure
differential balancing of rooms to drift off as the door
springs gradually weaken and the doors leak air
between rooms at levels outside of the design
parameters.
Annex 1, Clause 47 specifically states that sliding

doors are not permitted in sterile plants as they
typically create uncleanable recesses, projecting
 ledges and recesses. For these reasons they should 
not be used in non-sterile facilities either.
What are the sources of

contamination in a clean room?
It should be noted that cleanrooms do not eliminate
contamination altogether, they control it to an
acceptable level.
Our real concern is actually microbial contamination in

most cases. Traditionally the technology did not exist to
directly measure microbial contamination in real-time,
so the “all airborne particulates” limits were used and
extrapolated /assumed to be representative of possible
airborne microbial contamination risk.
So the GMP’s set out defining and controlling sources of

particulates in an attempt to control possible “microbial
contamination”.
Personnel present in a cleanroom are normally the 

highest source of the airborne particulates and/or
microbial contamination risk, so proper gowning and

limiting the number of staff into a room must be
carefully controlled to be within the cleanroom design.
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”:
1. The internal surfaces of the clean room and the

equipment within them;
2. The control and quality of air through the clean
room;
3. The way the clean room is operated (i.e. the number
of staff).
Each of the three items above are equally important.

Let’s look at them in more detail:
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

Clean rooms need a lot of air and usually at a controlled
temperature and humidity. This means that in most
facilities the cleanrooms Air Handling Units (AHU)
consume over 60% of all the site power. As a general
rule of thumb, the cleaner the cleanroom needs to be,
the more air it will need to use. To reduce the expense
of modifying the ambient temperature or humidity,
AHU or systems are designed to recirculate (if product
characteristics permit) about 80% air through the room,
removing particulate contamination as is it generated
 and whilst keeping the temperature and humidity 
stable.
Particles (contamination) in the air tend to either float

around. Most airborne particles will slowly settle, with
the settling rate dependent on their size.
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. 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. 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.
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.
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.
As a rule of thumb, within a facility the room you need

to be the cleanest operates at the highest or the lowest
pressure.
A good air handling system makes sure that air is kept

moving throughout the cleanroom. The key to good
cleanroom design is the appropriate location of where
the air is brought in (supply) and taken out (exhaust).
 
Supply air and exhaust (return) air
The location of the supply and exhaust (return) air
grilles should take the highest priority when laying out
the cleanroom. The supply (from the ceiling) and return
air grilles (at a low level) should be at the opposite sides
of the cleanroom, to facilitate a “plug” flow effect. If the
operator needs to be protected from a high potency
product, for example, the flow should be away from the
operator.
For sterile or aseptic process that need Grade A air, the

airflow typically mimics a plug flow from top to bottom
and is unidirectional or “laminar”. Careful consideration
should be made to ensure that the “first air” is never
contaminated before it comes into contact with the
product.
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.
Some clean room jargon

Some basic cleanroom jargon, acronyms and technical
aspects for next conversation with your pharmaceutical
engineering colleagues are provided below.
Air change rate

This refers to the number of times the air is changed
within a cleanroom. It is simply calculated by taking the
 
total volume of air introduced into the cleanroom over
an hour and dividing it by the volume of the room. It is
expressed as air changes per hour (ACH) and for
cleanrooms, this is normally between 20 and 40 air
changes per hour.
Room type ACH
Commercial kitchens & Toilets 15–30
Smoking rooms 10–15
Laboratories 6–12
Classrooms 3–4
Warehousing 1–2
Micron
A micron (or micrometre) is a millionth of a metre. A
human hair is around 100 microns thick. Particles less
than 50 microns cannot be seen by a naked eye. 
Bacteria measure 1 or 2 microns.
HEPA filters
HEPA stands for High-efficiency particulate air. HEPA
filters are one of the most important elements of a
cleanroom. They consist of a large, box shaped filter
that removes airborne particles of specific sizes very
efficiently. They must also be monitored and tested
regularly to make sure they are still integral.
HEPA filters are composed of a mat of randomly

arranged fibres, which are typically composed of
fiberglass with diameters between 0.5 and 2.0 microns.
Key factors affecting function are fibre diameter, filter
thickness, and filter face velocity.
Dispersed oil particle testing / Integrity

Testing
Dispersed oil particle testing or integrity testing is a
testing procedure to ensure that a HEPA filter meets its
efficiency specification and is properly seated and
sealed in its frame.
Airlock
 
An airlock is a room where personnel, materials or
equipment are transferred into or out of a cleaner
environment. It can be the size of a small “cupboard”, or
a large room where personnel change into and out of
cleanroom garments, or where a forklift can enter.
Clean room classification – ISO Class

This refers to the level of cleanroom particulate
cleanliness based on a number of airborne particles of a
certain size per cubic metre. ISO 8 is the starting
cleanroom level. A sterile cleanroom for the
pharmaceutical industry will need to achieve ISO 5.
Classes better than ISO 5, that is ISO 4 are generally
only required for the electronics industry.
Clean room classification – Annex 1 or ISO?

Grades A through to D refer to cleanroom cleanliness
for sterile products only, these Grades can be related to
the ISO Classes, but they are not the same.

The classification of 100, 10,000, and 100,000 normally

refers to the withdrawn FED-STD-209 E Airborne
Particulate Cleanliness Classes in Cleanrooms and Clean
zones which was cancelled on November 29, 2001 by
the U.S. General Services Administration (GSA).
This was superseded by International Standard ISO

14644, Cleanrooms and controlled environments-Part 1:
Classification of air cleanliness, and Part 2:
Specifications for testing and monitoring to prove
continued compliance with ISO 14644-1.
Room recovery rate

The time it takes from a contamination event to the
room regaining its designed cleanliness level as per the
GMP requirements.
Particle count
A test that samples a fixed volume of air and captures,
filters and counts airborne particles by their size. This is
performed when the cleanroom is “at rest” or “in
operation”. For pharmaceutical operations, both
 airborne viable (alive) and non-viable (not alive) particle

counts are performed. This is performed as part of the
certification of a cleanroom and during regular
environmental monitoring.
Cleanroom certification
Cleanroom certification is a series of tests that are
performed to show that a cleanroom is operating at to
its required class or grade and you have a certificate
issued by a competent tester.
More clean room jargon

If you would like to know more, you can follow the links
below.
A clean room explained in simple terms, 15 things you

should never see in a clean room, 12 deadly clean room
sins, what is your clean room costing you, optimising
your clean room, getting QA buy in, now you know it all,
take the clean room quiz. 
Eudralex Vol 4:
http://ec.europa.eu/health/documents/eudralex/vol-
4/index_en.htm
FED-STD-209E: https://en.wikipedia.org/wiki/FED-STD-
209E
WHO Annex 3:
http://web.archive.org/web/20151106050031/http://app
s.who.int:80/medicinedocs/documents/s18679en/s1867
9en.pdf
WHO Annex 5:
http://apps.who.int/prequal/info_general/documents/TR
S961/TRS961_Annex5.pdf
WHO Annex 6:
http://apps.who.int/prequal/info_general/documents/TR
S961/TRS961_Annex6.pdf
Page last updated July 16, 2019
 
Cleanroom EU GMP Cleanroom GMP Cleanrooms
GMP Clean Room Requirements
     
Related Posts
Past, Present The PIC/S GMP The PIC/S

and Future PIC/S Pipeline Part 3 Pipeline Part 4
GMP Part 1 of 4 of 4 of 4
24/02/2011 09/03/2011 17/03/2011
(12) Comments
Arun Purohit
10/07/2014 at 2:28 pm / Reply /
Very informative article.
Vinsensius Surjana
10/07/2014 at 11:09 pm / Reply /
Everything you want to know about

 Cleanroom, 
but were afraid to ask.
Thank you for your esteemed
contribution, alltogether a window to
your company,
trusting I can refer your company to my
Clients whenever there is a suitable
requirement.
Kind regards,
v. surjana
srinivasan
23/07/2014 at 10:34 pm
/ Reply /
nice and informative
narayan 24/07/2014 at 8:33 pm

/ Reply /
comprehensive account of clean room

with links required
narayan 24/07/2014 at 8:34 pm

/ Reply /
comprehensive information
Dee 25/07/2014 at 3:54 pm / Reply /
I also have foudn this to be most

informative.
Of particular interest are the comments
for non- sterile manufacture not
requiring cleanroom classification by
 the code and PICs however TGA fully 
expects you to comply with these. I dont
understand how you they can expect
you to comply with something thye have
not mandated? Is that not hte purpose
of the code?
Any insight into this will be greatly

appreciated.
Thanks
Trev 26/07/2014 at 5:22 am / Reply /
Dee, thanks for the clarification request,

I should have been clearer in my blog.
In my mind, one of the basis tenants of

GMP or QMS are, “say what you are

going to do” and the “do what you said”,

it you don’t you are not complying with
your own QMS and any auditor should
cite the non compliance.
Specifically relating to this subject, if the

company assesses the risk associated
with your (non-sterile) product requiring
Grade D air classification, then the
regulatory will assess your company
against this standard.
Hope that makes sense?
Sudhir 27/07/2014 at 3:06 pm

/ Reply /
So good.
sir can u elaborate why we dont want
fungus inside clean room or sterile
 preparations? 
although we avode gram negative
bacteria bcoz of it has cell wall as
endotoxin. Bt fungi dosent have any
cellwall even terminal sterilization kill
spores also so stil why we avoide fungi?
Cleanroom Equipment
Manufacturer
08/12/2015 at 5:23 pm / Reply /
good blog about clean room equipment.
Lucky 21/02/2018 at 7:21 pm

/ Reply /

Very specific information on the clean

rooms. now sir can you help me to get
the information for three different
condition for pressure differential. WHO
says 5 to 20 Pascal’s will be safe limit
but if I want to decide NLT limit for
these different conditions. only one limit
for each condition (no lower and upper
limits).
1. What will be the DP limit for classified
to unclassified rooms
2.What will be the DP limit for classified
to classified rooms with different grades
e.g. C to D.
3.What will be the DP limit for classified
to classified rooms with same grades
e.g. D to D.
Anna Taylor 31/08/2018 at 5:15 pm

 / Reply / 
With an increasing emphasis on
maximizing product yield, improving
quality control and ensuring safety,
companies throughout many industries
are looking to install clean-rooms in
their facilities.
Gil Ortiz 18/02/2020 at 2:55 am

/ Reply /
What is the consensus of clean room

expert in using a pneumatic tube
terminal?
Leave a Reply
Name* Email* Website
Comment...
Save my name, email, and website in this browser for the next
time I comment.
POST COMMENT
This site uses Akismet to reduce spam. Learn how your

comment data is processed.
 
© 2006-2020 PharmOut Pty Ltd | ACN 117 673 766 | ABN 85 117 673 766
Privacy Policy | General Terms & Conditions | Training Terms & Conditions | ISO
9001 Certificate
Australia China Hong Kong New Zealand Singapore
South Africa United Kingdom

Basic Clean Room Design Requirements and Considerations

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Basic Clean Room Design Requirements and Considerations

Uploaded by

Copyright:

Available Formats

03/04/2020 Basic clean room design requirements and considerations

Services Industries Cannabis Training Forums

Free Tools Blogs About Us Contact Us  

Basic Clean Room Requirements | Designs for GMP

By Trevor / 08/07/2014  54630 Views  12 Comments

In a nutshell, if you manufacture a non-sterile medicinal

What type of clean room do I need? 

If you are a manufacturer of non-sterile medicinal

If you are a manufacturer of sterile medicinal products,

“Clean corridor” or a “Dirty corridor”?

For aseptic (processed), sterile, or low bio-burden and

Designs can become complicated if the products or raw

Which way should my clean room

Annex 1, Clause 47 speciﬁcally states that sliding

What are the sources of

Our real concern is actually microbial contamination in

So the GMP’s set out deﬁning and controlling sources of

Personnel present in a cleanroom are normally the 

microbial contamination risk, so proper gowning and

So what makes a clean room a “clean

There are three things that keep a cleanroom “clean”:

1. The internal surfaces of the clean room and the

Each of the three items above are equally important.

1. The internal surface

not generate their own contamination i.e., don’t

There are a wide variety of suitable material choices,

2. Clean room airﬂow

Particles (contamination) in the air tend to either ﬂoat

A well-designed air handling system should deliver both

Rooms occasionally experience high levels of airborne 

sampling room or dispensary. In these cases, the room

The volume of air introduced into a cleanroom is tightly

As a rule of thumb, within a facility the room you need

A good air handling system makes sure that air is kept

For sterile or aseptic process that need Grade A air, the

Operating a clean room

minimising the amount of potential contamination

Some clean room jargon

Air change rate

Room type ACH

Commercial kitchens & Toilets 15–30

Smoking rooms 10–15

HEPA ﬁlters are composed of a mat of randomly

Dispersed oil particle testing / Integrity

Clean room classiﬁcation – ISO Class

Clean room classiﬁcation – Annex 1 or ISO?

The classiﬁcation of 100, 10,000, and 100,000 normally

This was superseded by International Standard ISO

Room recovery rate

More clean room jargon

A clean room explained in simple terms, 15 things you

Page last updated July 16, 2019

GMP Clean Room Requirements

Past, Present The PIC/S GMP The PIC/S

24/02/2011 09/03/2011 17/03/2011

Very informative article.

Everything you want to know about

nice and informative

narayan 24/07/2014 at 8:33 pm

comprehensive account of clean room

narayan 24/07/2014 at 8:34 pm

Dee 25/07/2014 at 3:54 pm / Reply /

I also have foudn this to be most