Rationale for number of personnel per cleanroom

Progress-PME
Author: C. Marsman
Introduction
In order to prevent contamination of products precautions are necessary during all
pharmaceutical activities in cleanrooms. One of the most important sources of contaminants
in pharmaceutical processes is the personnel working in the cleanrooms. Even when fully
dressed in special cleanroom clothing still particles, fibres and micro-organisms will be
spread by personnel. This is why the number of persons in a cleanroom should be
considered to be an important parameter with potential impact to the environmental
conditions; where possible the number of personnel should be limited to the minimum
required.
Mainly as a consequence of the design of processes or lay-out of the clean areas many
companies have had trouble in determining an allowed number of personnel in their
cleanrooms and provide a scientific sound justification for such number.
Often the allowable number is based on the number of personnel present during the PQphase of the room without further explanation. If discussion arises on the allowable number
of personnel in a later phase, then such approach can lead to unnecessary deviation reports
and investigations.
This article purports to provide a calculative method to come to a rationale for a maximum
allowable number of personnel in a cleanroom. The calculations include the capacity of the
HVAC system, the surface area of the cleanrooms and the number of particles shed by the
personnel present in the involved cleanrooms. In general this method will show that the
calculated maximum allowable number of personnel will exceed the number of personnel
actually needed for the execution of production processes and related activities.
Method
The method discussed in this article will make it possible to calculate the maximum allowed
number of personnel for cleanrooms, based on the capacity of the HVAC system, the surface
area of the room and the number of personnel needed to perform the necessary processes.
First the number of personnel needed to perform the processes needs to be determined. For
this number not only the primary process, but also secondary processes should be taken in
account. Secondary processes include amongst others cleaning, training, maintenance and
environmental monitoring.
The number of personnel needed for primary and secondary processes combined will be
called the practical maximum. Only under exceptional circumstances this practical
maximum number of personnel will actually be present in a cleanroom at the same time.
After determining the number of personnel maximally needed calculations can be performed
to determine the theoretical allowable maximum number of personnel. The here presented
calculations take in account the shedding of particles in the 0.5m range by personnel, the
particle removing capacity of the HVAC system (by means of dilution and deposition) and
the maximum allowed level of particles based on the EU-GMP, volume4, Annex-1.

For this calculation only particles of 0.5m and larger have been included, since these are
typically the size of particles related to the regular shedding by personnel fully dressed in
cleanroom garments and exhibiting normal standardized cleanroom behaviour.
Excursions in particles sized 5.0m or larger, as well as excursions in microbial
contamination are more related to technical problems or deviating cleanroom behaviour
then to normal cleanroom behaviour. Consequently the larger particle sizes and microbial
contamination are not taken in account.
Finally it needs to be stated that for cleanrooms in which the most critical processes are
executed (aseptic processing, filling, etcetera) the number of personnel should always be
limited to the number needed for the primary process only. Any additional activity requiring
entry of additional personnel should only be executed when the primary process is stopped
and the product salvaged.
Risk-evaluation
In all instances the maximum allowed occupation of cleanrooms should be based on riskevaluation. Such risk evaluation can include the here below discussed calculations, the
manufacturing process and technical measures taken to limit access to process rooms. Also
the use and classification of the different rooms should be included.
In general it can be stated that gowning areas and corridors will pose a lower risk to
products and processes than process-rooms, but the possibility of product or process
contamination through contaminated clothing should not be underestimated.
Preparation-rooms intended for weighing raw materials and preparation of intermediate
products will in most cases pose a low or medium product contamination risk. In general the
prepared materials and intermediate products will be sterilized before being used in the final
formulation and filling operations. For products that cannot be sterilised, or that do not need
to be sterile it is advisable to perform every process step as clean as possible and to assign
a high risk evaluation.
Rooms intended for aseptic processing should be considered to be the most critical areas.
These rooms hold a sincere risk of product contamination by airborne particles. Such rooms
require specific measures in order to prevent contamination and exert sufficient control over
the processes. Also activities involving working with pathogenic organisms or highly
sensitising materials will require specific measure in order to prevent cross-contamination
and hold sufficient control over the processes. The necessary measures will include special
clothing, a defined level of air quality and limitation of the number of personnel.
Another measure often applied is the complete enclosure of the process equipment by
means of an isolator or RABS (restricted access barrier system). Fully enclosed systems
have a grade A uni-directional air flow over the critical area and intervention by personnel is
restricted to the absolute minimum.
For all processes the general rule should be applied that direct intervention and potential
product contact by personnel should be prevented at all times. Critical process areas should
only be entered by trained and qualified personnel, or personnel in training under
supervision. Technical measures should be taken to prevent entry of non-qualified personnel
whenever possible.

Calculations
When personnel enter an empty cleanroom the concentration of airborne contaminants will
first build-up and then settle to a steady-state. The steady-state will in general be reached
within 10 minutes. During this time preparations for the production process can be
performed, but there should be no open product yet. In order to assure this either a timelimit, or a reading of a continuous particle measurement system (PMS) can be used to
define when the steady-state is obtained and work with open product can begin.
In this article only the steady-state is considered for the calculation of the theoretical
allowable number of personnel for cleanrooms. The build-up and decay phases will not
be considered since process activities should only take place during the steady state of the
air-ventilation.
For the ease of reasoning within this document it is assumed that the potential air borne
particle contamination in the rooms is solely due to the presence of personnel. No other
contributors to air-contamination are deemed to be sufficiently significant.
Further assumptions of importance for the calculations:
- There will be no effect by the heat generated by the personnel; the generated heat will be
levelled out by the cooling capacity of the HVAC system.
- Air supplied by the HVAC system is virtually free from particles when this has passed the
HEPA filters and enters the cleanroom.
- Each person occupies surface area of approximately 0,5m2 and a volume of 1m3.
- Each person in a grade B room, properly clothed in cleanroom garment, will shed
approximately 104 particles per second.
- Each person in a grade C or D room, properly clothed in cleanroom garment, will shed
approximately 105 particles per second.
- The numbers of particles referred here above are all particles in the range of 0,5m and
larger. This type of particles will be the most abundant present and direct related to the
shedding of particles by personnel.
- The numbers of particles assumed to be shed by personnel may be considered to
represent a worst-case situation; in general they will be lower. The differences between the
different types of rooms are mainly caused by a difference in type of clothing.
The number of particles theoretically present during the steady state is mainly determined
by shedding from personnel and their dilution by air supply plus removal through air
exhausts. To a lesser extent also a fraction of the particles will settle on surfaces.
The formula here below takes in account the following parameters; air supply to the room
as a measure of dilution and removal; settlement of particles to surfaces and particles shed
by personnel. The formula can be used to calculate the theoretical allowable number of
personnel.

Formula:
C=D/ (Q+Vd.A)
C=
Concentration of contaminants per m3 in a room at a given time (maximum under
operational conditions defined per GMP guidelines)
D=
Release rate of particles per second from personnel (arbitrarily set at 10 5/sec for
grade D and C and 104/sec for grade B)
Q=
Air volume supply rate of the HVAC (m3/sec)
Vd = Deposition velocity (textbook value set at 4.6x10-3)
A=
Horizontal surface area. (Total surface area per room, including equipment surfaces)
Based on the above stated equation and the allowable number of particles, as defined by
the EU-GMP, a theoretical maximum allowable number of people can be calculated per room
(see table 1; column theoretical maximum allowed # of personnel). Since the theoretically
maximum allowed number of personnel will in most cases exceed the practical maximum it
is highly advisable to determine the practical maximum number based on the number of
personnel required for processes and additional activities.
The practical maximum and theoretical allowable numbers can be documented in
applicable SOPs and/or validation documentation.
Example calculation for a grade B room:
C=D/(Q+Vd.A)
C= 352000 particles/m3
D=104.X-persons

Q= 0.488
Vd = 0.0046
A = 20 ; (surface are cleanroom)

C.(Q+Vd.A)= D;
D =205779;
205779/104 = X; X=20 persons
The allowable number of persons should always be rounded off to the first lower whole
figure; therefore the number of persons in the example is 20.
The room of the example is a grade B room intended for aseptic critical operations in grade
A LAF-hoods. The calculated allowable number of personnel will lead to an overcrowded
room since the available surface area of the room is 20m2.
The limited available space clearly shows that the practical maximum number is the number
of choice in this example. Since the example concerns a room in which critical aseptic
operations are executed the maximum allowable occupation should be limited to the
number of personnel needed for execution of the primary processes. The fewer disturbances
occurring in the cleanrooms the better.
The next page provides a table with results for several rooms, including personnel- and
material locks.

Table 1; Example overview of rooms, processes and personnel.

Room

Process/ activity

#
Personnel
needed
for
process

Material lock
Gowning

3
4

Preparations area
Cleaning +
Storage clean material

Corridor

ND

Process area

Gowning

8
9
10
11
12

Material lock
Storage clean material
Cleaning area
Corridor
Preparations/processing

13
14

Material lock
Gowning

15
16
17

Corridor
Unloading autoclave
Aseptic process area

Note 3:
Note 4:

Actual M2
surface of
room;
estimated

Practical
maximum
#of
personnel
present
(= Max
allowed)

(=A +
=A
equipmt)
Grade D areas; 3.520.000 part/m3
ND
6.7
6.7
(NA)
2m2/
9.5
9.5
4
person
6
96.0
80
10
3
27.9
25
10

1
2

Note1:
Note 2:

M2
surface
of
room

24.5

24.5

10

165
100
10
Grade C areas; 3.520.000 part/m3
2m2/
4.8
4.8
2
person
ND
4.9
4.9
(NA)
2
11.9
11.9
8
2
7.2
6
5
ND
24.5
24.5
10
2
10.1
8
5
Grade B areas; 352.000 part/m3
ND
5.4
5.4
(NA)
2m2/
5.4
5.4
2
person
ND
46.2
46.2
10
3
28.4
25
3
3
27.3
21
3

Air
supply
rate to
room
(M3/sec)
=Q

Theoretical
maximum
allowed #
Personnel
(from
calculations)

0.228
0.204

10
20

1.661
0.386

70
17

0.402

18

3.197

139

0.108

0.083
0.196
0.121
0.692
0.169

3
8
5
25
7

0.096
0.096

20
4

0.806
0.734
0.488

35
29
20

NA = Not Applicable
Material air-locks indicated as NA since they are not intended for personnel
activities other than bringing in, or taking out goods.
General maximum per room arbitrarily defined at 10, even when calculated
numbers are much higher. This can differ per company.
Gowning air locks require a bit more space per person, to allow proper
donning of personnel and minimize the risk of contamination of the gowns.
The required space is arbitrarily set at 2m2 per person.

Table 2; Maximum permitted number of particles per m3 equal to or greater than

the tabulated size (EU-GMP)
Grade
A
B
C
D
ND = not defined

At rest
0.5 m
3.520
3.520
352.000
3.520.000

5.0m
20
29
2900
29000

In operation
0.5 m
3.520
352.000
3.520.000
ND

5.0m
20
2900
29000
ND

Discussion and conclusions:

In the here discussed model the calculated theoretical allowable number of personnel will in
general exceed the number of people actually needed during processing. It will also exceed
the number of people that may be present when several occasions and processes coincide.
As long as the actually needed number of personnel is not exceeding the calculated
theoretical maximum number it will in general be better to use the practical maximum
number based on primary processes and additional activities as the maximum allowable
number of personnel for a cleanroom. This number can then be recorded as the maximum
allowed number in applicable documentation. The maximum allowable number should
preferably also include a small safety margin in order to prevent unnecessary deviation
reports.
For critical process-rooms the maximum allowed number of persons should be limited to the
number strictly needed for the execution of the primary process. Also for personnel locks
the allowable number should be limited in order to provide sufficient room for a proper
donning process. For both these cases no exceptions should be allowed and the defined
maximum numbers should be accepted as absolute values.
For several rooms the maximum allowable number of personnel can be defined as not
critical based on the size or actual use of the rooms. This is for instance applicable for grade
D rooms. Despite this non-critical designation it is still strongly advisable to use the
number of personnel determined as practical maximum allowable as the maximum
number of people per cleanroom and include these numbers in applicable SOPs and other
documentation.
The data for practical maximum presented in table 1 for grade B rooms are based on the
number of personnel needed for the primary process only. The data for grade C and D
rooms are based on the maximum number of persons present under exceptional
circumstances when several activities (process, cleaning, monitoring, maintenance) take
place at the same time.
The values presented in table 1 were derived from an actual company. The values have
been discussed with- and checked by quality-engineers and departmental management.