Nordiska R

3
Freningen


Guidelines for controlling pres-
surization


Cleanrooms and other controlled facilities


November 2005






Guidelines for controlling
pressurization



Cleanrooms and other controlled facilities

November 2005




Benedikte Rosling Winter








Ref 5793010
617-050121
Version 01
Date 2005-11-15
Prepared by BRW

Rambll Danmark A/S
Teknikerbyen 31
DK-2830 Virum
Danmark

Phone +45 4598 6000
www.ramboll.dk
Table of contents


1. Introduction 1
2. Why maintaining pressurization? 2
2.1 Regulatory requirements 2
3. Pressure and Theory 3
4. The building / the facilities - the physical boundaries 5
5. HVAC Control Systems 7
5.1 Generally 7
5.2 Doors 10
5.3 Variable airflow volumes 10
6. How do we succeed? 11
7. The future 12
8. References 13



1. Introduction
This Guideline for pressure control is written based on a scholarship given by The
R3-Nordic Association for Contamination Control and Cleanrooms.
The guide will be presented as arranged with the board of The R3-Nordic.
Pressurization control is a major subject. Some of the things that for some reason
have influence when you are talking pressure control are listed below.


The guide is meant as a short reference that can be used when planning, designing,
constructing, and running facilities in which the rooms are to maintain positive or
negative pressures.
The guide can be used in relation to Cleanrooms, Bio safety and Containment areas.
All examples etc. in this guide are based on Cleanrooms where a positive pressure is
1/14 1/13
Room
volume
Cleanroom
Disease
control
Production
facilities
Negative
or positive
pressure?
Active /
non-active
systems
Measuring
accuracy
Monitoring
pressure
Room
pressures
Standards
/ Test
methods
HVAC
Plants
Rooms
Leakage
PRES-
SURIZA-
TION


to be maintained, but the considerations are the same if you are dealing with a con-
tainment demand and therefore have to maintain a negative pressure.
The guide will concentrate on the considerations that are important when pressure
differentials between rooms are to be maintained. The guide is neutral, meaning it
does not take in favour any specific systems or products.
2. Why maintaining pressurization?
Well, there are many good reasons to do so
This guide will be starting from the unequivocal requirements that are set for the
pharmaceutical industry. We have to maintain a positive pressure to ensure that the
products/drugs are not contaminated by contamination coming from the outside.
This is not the whole truth as the industry has been aware that e.g. handling penicil-
lin must be in facilities maintaining negative pressures; as the penicillin must be kept
in containment. With todays product development in the pharmaceutical industry
where you for instance are dealing with nuclear medicines, more and more areas
where you would like to maintain a negative pressure are arising.
Shortly put, you want to maintain a positive pressure to protect the process and
product from contamination from the outside, and a negative pressure in order to
protect the surroundings/environment from the product.
Maintaining pressurization and having controlled environments are also an everyday
occurrence in e.g. the electronic industry, health care (hospitals and disease control)
and research and development laboratories (R&D).
2.1 Regulatory requirements
In Europe (or other parts of the world, where the SI-units are used) the most com-
mon used pressure differential is 15 Pa between Cleanrooms of different classifica-
tions. But where does it come from?
Going back to US Federal Standard 209B a minimum positive pressure differential of
0.05 in.w.g. (Inches of water gauge) ~ 12.4 Pa was specified. In newer revisions of
the US Federal Standard 209 no minimum pressure differential was specified. The US
FED STD 209E was withdrawn in November 2001, and replaced by ISO 14644 parts
1 and 2. These parts of ISO 14644 do not talk about pressure differentials. ISO
14644 part 4 recommends a minimum pressure differential of 5-20 Pa, but it is not a
requirement.
The EudraLex: The Rules Governing Medicinal Products in the European Union, Vol-
ume 4 - Good Manufacturing Practices. Medicinal Products for Human and Veterinary
use. do not specify requirements for maintaining pressure differentials, but there is
a recommendation that pressure differentials should be maintained. 2/14 2/13


Are there any requirements for maintaining pressure differentials?
Not when referring to present Cleanroom standards; - but the requirements are
there. Indirectly the requirements are defined by the Regulatory Agencies, like the
FDA for the pharmaceutical industry. We also have to remember that the US FED
STD 209 is not forgotten, even though it has been withdrawn for many years. Espe-
cially in the pharmaceutical industry people still tend to refer to it. In addition other
national and international authorities will normally have requirements for facilities
with controlled environments due to for instance products, which the environment
must be protected from. Therefore these authorities must be contacted.
When designing and constructing we are always obligated to use our common sense,
and take all the assessed risks into consideration.
The recommendation set by ISO 14644 for a pressure differential of 5-20 Pa is in my
opinion not good enough. Meaning that if you decide on a pressure differential of 5
Pa as your set point, there is a high risk that in periods there will be no pressure
differential, or in worst case the pressure differential will change from positive to
negative pressure differential. This is due to instrument accuracy, natural fluctua-
tions in the regulating system and outside influence like wind. In practice, I have
never come upon anybody deviating from a pressure differential of minimum 15 Pa.
Between which rooms do you define the pressure differential of 15 Pa? Normally
when going from a clean zone to a less clean zone; - for instance when going from
an ISO class 7 to ISO class 8. Then the next question arises; what if there is an air-
lock between the two clean zones of different cleanliness? The requirement is that
the pressure is between clean zones of different classifications. Often an extra pres-
sure step is added by having one pressure level for the less clean zone, another
pressure level for the airlock and a third pressure level for the cleanest zone. The
disadvantage by doing so is that you easily end up with a total pressure differential
of 60 Pa or more, between neutral and the cleanest zone.
Therefore define the cleanliness of the different rooms and the pressure levels for
each room. Do a risk assessment; it can help you identify risks that e.g. cause you
to decide on a separate pressure level for one of the airlocks.
3. Pressure and Theory
How to maintain the pressure differentials discussed? What can affect the pressure
differentials and what should have our utmost attention?


3/14 3/13


Basically it is the laws of physics that apply. Starting with Boyle-Marriottes Law for a
closed system at constant temperature:
t tan cons V p =
Where, p pressure
V volume
When considering Cleanrooms and other controlled environments you have a fixed
volume (the room or enclosure), but it is not a closed system. Who can honestly say
that they have been in a Cleanroom without any tiny chinks or leakages? That is
the reality we have to adapt to.
The airflow through a leakage is due to the differential pressure between two rooms.
As the differential pressure between two rooms is the same as the dynamic pressure,
the formula below can be used:
2
d
v p =
Where, p
d
the dynamic pressure [Pa]
density of air 1,2 kg/m by 20C
v velocity of the airflow [m/s]
The velocity of the airflow is defined by:
l
v
A
q
v =
Where, q
v
airflow through the leakage [m/s]
A
l
area of the leakage (opening) [m]
The differential pressure p is equal to the dynamic pressure p
d
. From the formulas
above you have that (at app. 20C):
p A 29 . 1 q
l V
=
When talking of Cleanrooms and other controlled environments it is very small leak-
ages we are talking about (a maximum size of 0.01 m
2
0.02 m
2
). Therefore the
coefficient of contraction must be taken into account. The coefficient of contraction,
is for openings of the size mentioned above, somewhere between 0.60 and 0.75,
depending on the shape of the opening.
Refering to Cleanroom Design ref. [1] a coefficient of contraction of 0.66 is used,
which gives that:
p A 85 , 0 q
l V
=
4/14 4/13


Where, q
v
airflow through the leakage [m/s]
A
l
area of the leakage (opening) [m]
p the differential pressure [Pa]
To indicate the variousity of the value for the coefficient of contraction, then Sauter,
ref. [2], uses a value of 0.72; which means that the same formula will be as follows:
p A 93 , 0 q
l V
=
In the memo Sauter, ref. [2], writes that the formula can be used for large openings
such as e.g. a 2 m
2
doorway. I, nor others, share that opinion. Even when consider-
ing an opening in the wall for a conveyer belt between a filling room and a room for
autoclaving, where the opening is app. 30 cm x 30 cm, the opening is so big that the
coefficient of contraction have no influence; put in another way the coefficient of
contraction is very close to 1.0.
An exampel is given below:
Example 1:
What is the airflow underneath a door, where there is a 3 mm chink? The door
is 0.90 m wide and the differential pressure across the door (between the two
rooms) is 15 Pa..
h m 32 s m 0089 , 0 s m 15 ) 003 , 0 90 , 0 ( 85 , 0 q
3 3 3
V
= = =
If the chink is increased to e.g. 10 mm, then the airflow will be increased to
h m 107 q
3
V
=
4. The building / the facilities - the physical boundaries
We all know that the rooms must be tight when talking Cleanrooms and other con-
trolled environments. Who can blow up a balloon, if there are holes in it? But how
tight should the rooms be?
Ideally it is preferred that a Cleanroom is made as a room in the room, meaning that
none of the walls are part of the outer facade of the building. It can be very hard to
seal a facade to the point where the wind has no effect on the room pressure. The
wind pressure can vary from 10-15 Pa in calm weather (a wind speed of app. 4 m/s
in Denmark) and up to about 300-350 Pa (a wind speed of app. 24 m/s).
The tightness of the room is a much discussed and problematic issue. One of the
issues discussed is where to seal / where to define the barrier? Some mean that the 5/14 5/13


tight barrier must be in the room separation (inner walls, the floor, the ceiling) oth-
ers mean that the separation must be done by sealing the building structure.
Designing a true room in the room Cleanroom there is no doubt that the barrier is
the floor, inner walls and ceiling.
If the Cleanroom is located on a middle floor of a multi-storey building, where the
ceiling can be the concrete slab or a ceiling put up, then both options for choosing
where to seal the room are present. The first question to ask is do we need access
to installations above the ceiling, or can components that need servicing be placed
outside the Cleanroom area? It is clearly an advantage if the components can be
placed outside the Cleanroom area, then service and maintenance can be done with-
out entering the Cleanroom and opening to the not controlled space/environment
above the ceiling. In practice it is often necessary to have installations above the
ceiling. But you should carefully choose which components are placed above the
inaccessible ceiling even though hatches for inspection are made. Once the Clean-
room is up and running it is not easy to access the installations above the ceiling, as
it is not clean and the pressure differential will drop.
Back to the barrier / where to seal; - the ceiling must be tight to ensure that impuri-
ties do not enter the Cleanroom through the ceiling. Also lead-ins through the part of
the walls above the ceiling must be sealed. Why is that? Remember the theory
changes in room pressure will affect the space above the ceiling. If there is a
crack/hole to the space above the ceiling of the adjacent room then the room pres-
sure in the adjacent room can be affected. It is therefore recommended that you
seal the ceiling and all lead-ins for installations above the ceiling.
Can you and/or must you seal the rooms 100%? NO!
(Notice that this statement is not valid when dealing with areas for Bio safety and
Containment.)
There are more reasons why you need some leaks from the room, but the leaks
must be controlled. Meaning you should have a defined chink under the door (5-10
mm), or a valve in the Cleanroom wall that can be adjusted according to the room
pressurization. The controlled leakage has two major aims (1) when opening and
closing doors, and (2) when regulating pressure differentials (the latter will be dis-
cussed in section 5).
Opening a door will be against a higher pressure. The force needed to open a door is
rather high. A door of app. 1.8-2.0 m to be opened against a pressure differential of
15 Pa normally requires a door closer of 4-5 kg. Closing the door can be a problem if
the door and the room is 100% sealed. Normally a door closer of 3-5 kg can close a
door up to 1.2m wide; if the width increases up to 1.6m a door closer of 5-7 kg is
needed. The heavy door closers can give problems when the doors are to be opened
manually, because they are just as heavy to open. In those situations auto-
matic/electric opening/closing of the doors by a sensor can be a possibility.
6/14 6/13


5. HVAC Control Systems
5.1 Generally
Pressurization is generated by the HVAC system; therefore it is essential that it is
designed to do so. A CAV system (Constant Air Volume) cannot do it! There are too
many variables in a HVAC system, meaning pressure drop across coils, filters etc.
when the pressure drop increases due to dirt the airflow will be reduced, and the
room pressures will change, if the HVAC system cannot compensate for these varia-
tions.
Maintaining stable room pressurization requires a VAV system (Variable Air Volume).
All subsequent matters are described based on a Cleanroom in which you want to
maintain a positive pressure by regulating the airflow of the HVAC system. That
sounds easy
Even in the simple situation there are things to remember, such as:
Requirement for the positive pressure? 15 Pa x Pa
Accuracy of the manometer? y Pa
What are the values for x and y?
Often you have a project specifying that the HVAC system shall maintain a given
differential pressure between the rooms, - and that is all that is written. But when it
comes to the final commissioning, documentation and qualification of the HVAC sys-
tem and Cleanrooms a discussion often arises concerning accuracy and limits, and
how the system was originally designed.
In the simple situation many factors come into play:
7/14 7/13


8/14 8/13


In the pharmaceutical Industry the requirements for the simple situation could be:
A minimum air change rate in the room of 20 times per hour.
A positive pressure of minimum 15 Pa.

Maintaining a stable positive pressure is affected by numerous factors. In order to
comply with the first bullet it is recommended that the supply airflow to the room is
constant, - as the air change rate for a Cleanroom with a positive pressure normally
is calculated based on the supply airflow. The return/exhaust airflow is var-
ied/regulated in order to maintain a stable positive pressure. The tightness of the
room is the first parameter that needs to be in order to maintain the pressure.
When a positive pressure is established it must be kept within the specified limits.
This is the first challenge, because often these limits are not defined - what should
the limits be?
The unwritten rule for the limits for a positive pressure difference could be 15 Pa 5
Pa. How is that obtained?
Regulator
P







Room with a positive pressure
Differential pres-
sure manometer;
e.g. 15 Pa
P
Supply air; constant
(1) Variable airflow regulator or motorized damper
Exhaust air; variable
(1)
THE SIMPLE SITUATION


Now it is not the HVAC system in the traditional way, but the HVAC control system
that is the important part. The aim is to maintain 15 Pa at all times, but as weather
conditions (sunshine, wind, temperature etc.) affect the whole building and thereby
the room pressurization, the HVAC control system must be able to compensate for it.
They are often very small influences. Therefore the control system must be able to
regulate in steps corresponding to the influence on the room pressure, but opposite.
Also the oscillations in the ductwork, despite that HVAC systems for Cleanrooms are
normally designed to maintain a constant pressure in the ductwork, but in reality this
pressure is not constant. The room is sealed well enough to maintain the positive
pressure differential, but it is not 100% tight, the airflow through the leakages
depend on the pressure differentials between the rooms. Controlling a positive pres-
sure differential is therefore done on a system that is not in control.
What airflow is needed to change the room pressure by 1 Pa? A good question, but a
simple answer cannot be given, because the same airflow will affect a room volume
of 50 m more than it will affect a room of for instance 80 m, as well as the size of
the leakages (see section 3). Basically, very small changes in the total airflow are
needed. Some times it can be worth considering controlling the room pressure dif-
ferentials by only regulating on app. 20% of the airflow from the room. This is to be
seen in connection to the smallest step/change that the motor on the regulated
damper can make in order to change the position of the damper, indirectly the
change in the airflow volume that one step gives. The motor is the same no matter
the size of the damper, the bigger the damper the bigger the change in air flow vol-
ume as a result of one single step. Suddenly the motor reduces the accuracy by
which the room pressure differentials can be maintained - one must say that the
more or less extinct (at least in Denmark) pneumatic control systems had its advan-
tages.
In the simple situation the positive pressure in the room is in relation to the sur-
roundings, which function as a zero reference. Often a number of rooms are regu-
lated in relation to a shared zero reference. The shared reference is chosen neutral
to outer influences on the building, for instance a shaft or a definite reference link, in
order to establish the most steady control system for regulating the room pressuriza-
tion.
The risk by defining and controlling in relation to a shared reference, if you are re-
quired to maintain 155 Pa between all rooms within the Cleanroom area, is that the
absolute positive pressure in the individual rooms is 15, 30 and 45 Pa, and the limits
within each room where a positive pressure must be controlled is 5 Pa. One room
has a positive pressure of 18 Pa, and the adjacent room has a positive pressure of
26 Pa, individually each room complies with the room pressure and limits specified,
but the actual differential pressure between the two rooms is only 8 Pa in worst
case the pressure differential will be only 5 Pa. Probably the direction of the airflow
will not change, but only if the accuracy of the pressure transmitters is 2 Pa. An-
other player in the game of pressure control
9/14 9/13


Now we need to have a look at the regulatory requirements. Normally you must
document the differential pressure between each room. In regard to the personnel
and product safety it is common to put up pressure differential manometers showing
the actual differential pressure; the manometers are often placed next to the en-
trance door, which gives you the opportunity to check that the room pressures are
as required before entering.
What do you do in the situations when the room pressures are within the specified
control limits according to the shared reference for the room pressures, but the mu-
tual differential pressures are not within the specified limits? Now you need to distin-
guish between room pressure control and room pressure monitoring, which in the
case described do not agree, one tells you that the room pressurization is within the
specified limits, the other that you are outside the specified limits. The only problem
is that very often QA only sees the result of the monitoring system, because that is
the system defined to be used for documenting the room pressurization within the
Cleanroom to regulatory agencies and customers. In order to deal with this situation
the shared zero reference cannot be used, as the control system and the monitor-
ing system must be the very same in order to satisfy QA.
5.2 Doors
We cannot do without doors, but at the same time they are subject to major atten-
tion. Are they tight enough? Do we need a door switch? Etc.
The doors are ideally to establish the wanted controlled/known leakage from a
Cleanroom simply by a chink underneath it.
Door switches register whether the doors are open or closed, and give a signal to the
room pressure control system to stop regulating while the door is open. But is it nec-
essary? Naturally you want to re-establish the room pressure as quickly as possible
when a door has been open; the answer depends on the control system. Some peo-
ple believe that, if the control system is quick it is not necessary to have door
switches, while a slower control system can have an advantage being locked in the
position where it was in control just before the door was opened. I believe that door
switches are nessecary in both situations. Another thought when desiding on door
switches or not, can be the periode of time for which the doors are open. For in-
stance airlocks for bringing products in and out can be a specific place to have door
switches as the doors are often kept open for a longer period.
5.3 Variable airflow volumes
Normally variable airflow volumes are not wanted in areas where you have a re-
quirement to maintain room pressurization, as changes in airflow volumes affect the
room pressure at once. Often the process and the demand for personnel protection
result in installation of fume cupboards, safety cabinets, and local extraction arms
that can be turned on and off, etc.
If it is only one local extraction arm it could be used as a part of the constant ex-
haust airflow from the room, as the airflow for an extraction arm is often smaller (for
10/14 10/13


instance 75-150 m/h), and then you have one less problem to worry about. When
dealing with fume cupboards and safety cabinets the airflow volumes are bigger, you
need to decide on whether to keep lower working expenses or increase the total con-
stant airflow volume and at the same time ensure more stable room pressurization.
Can the room pressure control system keep up with for instance a fume cupboard?
Not by itself. You still need a momentary change in the supply airflow, as you open
the hatch on for instance the fume cupboard, like in normal control systems for fume
cupboards. Then the room pressurization system will take care of the rest. It may
cause problems if the two control systems do not act equally rapid. Often it turns out
that the control system for the room pressurization is the slower one.
Another thing to consider when handling variable airflows is the size of the variable
airflow compared to the basic airflow for the room (the airflow that gives the mini-
mum air change rate for the room). It will result not only in major changes in the
total airflow in the room, but may result in major changes for the HVAC system, and
then you may have a situation where the HVAC system cannot regulate. Referring to
section 3, you can see how changes in airflow affect the room pressurization, dou-
bling the airflow will definatly change the room pressurization; can the room stand
that pressure? It has been seen that ceilings have been lifted so much that they
nearly fell down afterwards.
Conclusion: avoid variable airflows, if at all possible, when having to maintain
room pressurization.
6. How do we succeed?
In the end we all succeeded during the years. But often it has been a struggle to get
there. Wouldnt it be nice if we could all (contractors, consulting engineers and own-
ers) sleep at night, while commissioning of the HVAC system and control systems
takes place.
My personal opinion and experience is that many of the problems are based on atti-
tudes. And what do I mean by that? If you ask around I would say that 9 out of 10
firmly believe that maintaining room pressures has to do with the contractor putting
in the HVAC system. Isnt it the HVAC system that controls the room pressures? But
as I have tried to say in this guideline, the HVAC system cannot do it by itself.
For instance the carpenter (walls and ceilings), the electrician, the plumber etc. all
have a part in sealing the rooms in order for the HVAC system to maintain the room
pressures.
Below is listed numerous topics which as a minimum you need to consider when de-
signing rooms/areas that require maintaining room pressurization. Every topic is
discussed in this guideline; therefore they are only listed shortly: 11/14 11/13


The use of the rooms?
Positive or negative pressure, and why?
The magnitude of the positive and/or negative pressure?
The requirement? Is it a differential pressure, or an absolute pressure com-
pared to a reference?
Limits within which the pressure must be maintained?
Accuracy for the measuring instruments.
Tightness of the room?
Controlled leakages from the room?
Control systems
door switches?
the rapidity of the control system?
Variable airflows?
Make sure that it is not only in the design of the HVAC system that you can
see that there is a requirement for maintaining room pressurization!!!

Finally I believe that a tip top design only results in success if the contractors know
what they are dealing with along with the site manager and the supervisors. Unfor-
tunately it is seldom the persons designing that are on site as supervisors, and
thereby many points are lost. A suggestion could be to gather the people on site
(site managers, supervisors and contractors) to inform of the importance of comply-
ing with the specifications in the project design.
7. The future
Im not a fortune teller, but I will bring up a few topics that I believe will change
within the decades to come.
The automatic control systems are developing rapidly, so it is possible to find a con-
trol system that regulates within the specifications set in the design.
But what do we want to specify, as the regulatory requirements are not unequivo-
cally defined? How will FDA and other regulatory agencies look at it if the risk as-
sessment says that a positive pressure of 5 Pa in for instance an aseptic production
12/14 12/13


is sufficient? The standards we have to comply with need to be more specific, mean-
ing that they need to guide the user as to when a positive pressure of 5 Pa is suffi-
cient, and when it must be higher; an opportunity could be to graduate the pressuri-
zation in regard to the use of the room. Are there situations where it is sufficient to
show that the direction of the airflow is in or out of a room I believe that it is just
as good a solution as to document 5 Pa.
In the future is it a possibility that we will see that the requirement for the differen-
tial pressures will be reduced due to the technological development greater accu-
racy on measuring instruments, regulators etc. If that happens the uncertainties we
must assess today will be reduced.
The guideline is the truth, but not the whole truth. It discusses the considerations to
make when planning and designing rooms for which it is a requirement to maintain a
positive or negative pressure differential. I believe that it will be years before the
considerations to make will change.
8. References
[1] Cleanroom Design. Second Edition.
Edited by W. Whyte, University of Glasgow, UK
[2] PharmaControls. Basiswissen Raumdruckregelung.
Rolf Schulze, Fr. Sauter AG
13/14 13/13