35

Part 4: Facility layout and air handling system considerations

4.1 Design steps of a clean facility

With the elements discussed so far, the necessary background for designing a clean
facility has now been compiled. Point of departure for a specific investment object is
(Fig. 4.03) a User Requirement Specification (URS), where the basic cornerstones
of the forthcoming project are identified, and a design specification developed from it.
Project design is usually developed in three stages (Fig. 4.04):
- conceptual design for developing, based upon the design specification for the
facility and its cleanroom system, a fundamental concept together with a coarse
cost estimate as base for the go-ahead decision;
- basic design for developing the conceptual design into a set of layouts, func-
tional diagrams and specifications, until it is mature for a detailed cost estimate
and the invitations for tendering;
- detail design with execution drawings, material lists etc. as the prerequisite for
the realization of the facility, for supply and installation of the supporting utilities
as well as construction and installation of the production equipment.

From the contamination control point of view, the conceptual design phase (Fig.
4.05) is initiated with the elaboration of a basic cleanroom system specification,
the objective of which is to establish the fundamental stipulations and quality re-
quirements for the building design and construction materials, for the corresponding
infrastructure systems such as the HVAC system (heating ventilating and air-
conditioning system), for process media circuits such as those for ultraclean water
and water for injection, process gases etc.. The principal elements of the basic de-
sign specification are compiled in Figs. 4.06-4.07.

During the conceptual design phase, the 1st draft of the Qualification Master Plan for
the cleanroom system should also be developed. This important document will be
discussed in detail in Chapter 6.5 of this manual.

4.2 GMP requirements for pharmaceutical premises

Facilities used for pharmaceutical manufacturing operations – cleanrooms and others

– have to comply with certain basic principles, such as those listed in Chapter 3 of
the GMP guideline of the European Union and PIC/S (Figs. 4.08-4.09; for more de-
tails, see [4.01-4.02], items 3.6-3.17). They must permit effective cleaning and main-
tenance in order to avoid adverse effects on the quality of the product such as cross-
contamination or the build-up of dust or dirt. Facilities employed for hygienically
more exacting tasks have to go much beyond that: as an example, the requirements
for premises employed for manufacturing sterile medicinal products according to An-
nex 1 to the GMP guideline of the European Union and PIC/S are summarized in
Figs. 4.10-4.11 ([4.03], items 46-55).
 36

4.3 Facility layout development

4.3.1 Normative guidance

In developing the facility layout, the point of departure is:

- the sequence of process steps and their air cleanliness requirements;
- personnel, material and waste flows (Figs. 4.12-4.14).

A clean facility's layout is always developed from the inside out: the outer shell can
only be determined after due consideration of all processing requirements.

ISO 14644-4 [4.04] offers comprehensive guidance for all aspects of facility design.
For developing the layout, for example, the shell concept introduced therein and
reproduced in Fig. 4.15 provides a most appropriate point of departure. For effective
domination of contamination, the contamination control requirements should be in-
creased stepwise towards the critical areas and the core area with the highest air
cleanliness requirements be limited to the absolute minimum. This approach will not
only provide effective contamination control but will also address the economic issue
of cost minimisation in investment and operation.

ISO 14644-4 also offers a systematic compilation of all the determinations having to
be agreed between purchaser/user and designer/supplier during design and devel-
opment of a cleanroom system. It is condensed into a comprehensive checklist
covering 12 subject areas with a grand total of 133 items (Fig. 4.16)! Cross-checking
the design with its help, it is almost impossible that something of importance has
been overlooked!

4.3.2 Layout examples

Fig. 4.17 (from Whyte [4.05]) presents the layout of a simple facility with its corres-
ponding air locks for material and personnel as well as the corresponding pressure
differentials.

Fig. 4.18 illustrates a facility where the containment principle is employed: the lay-
out of a bulk production of non-sterile semi-solid cosmetic and pharmaceutical prod-
ucts. Prevention of cross-contamination was the principal contamination control ob-
jective, and the entire area was classified according to the ISO Class 8 air cleanli-
ness level in the at rest occupancy state. Fig. 4.19 illustrates the pressure zoning
concept selected, which ensures that active substances liberated during the produc-
tion process in a given room are not transmitted to other rooms via cross-contamina-
tion. Fig. 4.20 shows the air locks for personnel and material; with the objective of
optimizing the personnel and material flows, they were positioned at opposite ends of
 37

the production area. Fig. 4.21 summarizes the different contamination control fea-
tures employed in this job.

4.3.3 Air locks: essential features of clean facilities

Air locks are an essential feature of all clean facilities irrespective of the facility's
utilization. They ensure controlled transfer of persons and materials into a clean
area, or from one clean zone to another. Air locks are also instrumental for assuring
maintenance of the required pressurization levels of the different air cleanliness
zones without interruption, thus impeding infiltration of contaminated air from the out-
side or from a zone with a lower air cleanliness level. Two kinds of air locks can be
distinguished: personnel air locks and material air locks.

A comprehensive requirement profile for personnel air locks (Fig. 4.22) can be found
in Annex 1 of the GMP guideline of the European Community and PIC/S [4.01-4.02],
and Fig. 4.23 presents a personnel air lock designed and built for meeting this pro-
file.

All air locks are subdivided into a cleaner and a less clean area; the cleaner part has
to meet – at least in the at rest occupancy state – the air cleanliness level of the area
into which it leads. The cleaner and the less clean part of personnel air locks are
separated by a sit-over bench which may also serve for shoe storage (Fig. 4.24).
Hand washing facilities as well as waste bins should be located in the less clean part
of the air lock. Sufficient locker space for the factory uniform and for personal be-
longings as well as for the fresh cleanroom garment components must be foreseen,
plus hangers for cleanroom garments in use. Doors must be interlocked, in order to
impede that they are opened simultaneously. Final hand disinfection gear, where
required, should be positioned close to the door leading into the cleaner zone.

Material air locks (Fig. 4.25) should be clearly subdivided into a cleaner and a less
clean part by appropriate floor markings. All material entering the controlled area has
to comply with the surface cleanliness requirements to be observed there. Standard
operational procedures should specify the appropriate decontamination procedures
and where to perform them: either immediately before entering, or within, the air
lock. If only small quantities have to be transferred (for example: samples), a dou-
ble-door pass-through with interlocked doors may also serve (Fig. 4.26).

4.4 Requirements for cleanroom walls, floors and ceilings

Fig. 4.27 summarizes the principal requirements for wall elements, Fig. 4.28-4.29
those for floors and ceilings and Fig. 4.30 those for doors [4.04]. In cleanrooms for
biocontamination control purposes, particular attention is to be given to hygienic as-
pects:
- ease of cleaning and disinfection;
 38

- compatibility of the surface materials with cleaning and disinfecting agents;

- the absence of joints in which dirt and micro-organisms might accumulate.

For the selection of the right construction materials, see VDI 2083 Part 4.1 [4.06] and
Kouri/Schneider [4.07].

Examples for wall and ceiling elements compatible with biocontamination control re-
quirements are shown in Figs. 4.31-4.35. Smooth joints and rounded edges are im-
portant features from the cleaning and disinfection point of view. Fig. 4.36 gives an
example for the integration of fluorescent lighting units into the ceiling, and Fig. 4.37
for that of glazing panels into a wall panel. Fig. 4.38 shows an example of a wall-to-
floor junction; Fig. 4.39 how airtight floor penetrations of pipes can be realized. In
order to impede damaging the delicate wall elements, protective rails as shown in
Fig. 4.40 are worth serious consideration.

For reducing the transfer of foot- or wheel-borne particles from a less controlled into
a cleaner area, polymeric flooring has been found to be particularly efficient [4.08-
4.09].

4.5 HVAC systems for contamination control

Apart from having to ensure maintenance of the stipulated air cleanliness and airflow
patterns, the air handling system is required to control the following parameters:
- room air temperature;
- room relative air humidity;
- room air change rates;
- room pressurization.

The GMP stipulations for HVAC systems, i.e. Heating, Ventilating and Air-
Conditioning systems, are summarized in Fig. 4.41.

The room temperature determinations are only exceptionally influenced by product

or process requirements. As a rule, human comfort considerations prevail. They
assume particular significance where sophisticated garmenting schemes are re-
quired. These are normally very inflexible from the thermal comfort point of view: a
reasonable level of comfort is only assured if room temperatures are maintained
within a narrow tolerance band (see VDI 2083 Part 5.1 [4.10], Annex I).

Also regarding relative humidity of the room air, only rarely product or process re-
quirements are the driving forces. One such case is tabletting, especially of effer-
vescents: they are hygroscopic and therefore require an environment maintained at
very low air humidity. In most cases, human comfort considerations may prevail: the
range 35-65 % relative humidity is appropriate. Below 35 %, also electrostatic
 39

charges could cause a risk, and supply air humidities above 80 % may possibly fa-
vour the growth of microorganisms – especially moulds – in the HEPA filter media.

It is somewhat anachronistic having to include requirements for a minimum air

change rate into modern zoning concepts. Although such requirements have been
eliminated from the GMP guide of the European Union and PIC/S [4.01-4.02], the
FDA guideline for aseptic processing [4.11] still contains the requirement of a mini-
mum hourly air change rate of 20 for the controlled areas surrounding aseptic cores.
This requirement dates back to U.S. Federal Standard 209B of 1973 – i.e. to the
stone age of contamination control. From all subsequent editions of U.S. Federal
Standard 209 this requirement was deleted as irrelevant and misleading for air
cleanliness classification purposes.

Pressure differentials between rooms are essential for preventing cross-contamina-

tion, and are recognized as such in the GMP guidelines.

4.6 Room air recirculating units

The simplest way to protect a workplace with clean air is the clean work station,
also called clean work bench. An example with horizontal airflow is shown in Fig.
4.42. This concept is appropriate if a single, isolated work process requires protec-
tion against contamination risks originating from the environment and from the opera-
tor. On the other hand, vertical airflow is indicated if the environment and the opera-
tor have to be protected against the process. Particularly good containment and
worker protection is provided by biosafety work stations: they are employed, for
example, for handling highly contagious or genetically modified micro-organisms, or
for working with highly active pharmaceutical ingredients such as the reconstitution of
cytotoxics in hospital pharmacies (Fig. 4.43).

Clean work stations are autonomous room air recirculation units: they are posi-
tioned in the room just like any piece of furniture, draw their air supply from the room
and need nothing but connection to the electricity network to become operational.
Control of temperature and humidity is left to the room air conditioning system.

Cabins for drawing samples or for dispensing purposes are other examples of room
air recirculation units.

The use of clean work stations or other clean air devices is indicated if clean air pro-
tection is required only on a very limited scale within a facility. A dense population of
such units in a room is undesirable: temperature and humidity control are prejudiced,
and the noise level will tend to increase to unacceptable levels. As soon as this limit
is reached, the function of providing clean air should be integrated into the HVAC
system.

4.7 Air handling systems with turbulent airflow

 40

For many contamination control tasks in the pharmaceutical industry, maintenance of

turbulent mixing airflow, with terminal HEPA filters integrated into the supply air outlet
elements, is perfectly sufficient for meeting the air cleanliness requirements. Room
grades C and D according to the GMP guidelines of the European Union and PIC/S
[4.01-4.02], i.e. ISO Class 8 in the occupancy state in operation, and, as a rule, also
grade B requirements, i.e. ISO Class 7 in operation, can be met with this air flow pat-
tern.

Fig. 4.44 shows the schematic flow diagram of an air handling system with air recir-
culation, with turbulent airflow maintained in the working rooms [4.12]. In order to
minimize the risk of cross-contamination, only a sequence of rooms serving a similar
purpose should be served by the same air handling unit.

In facilities requiring a number of separate air handling circuits it makes sense (Fig.
4.45) to dedicate a specific primary air handling unit to the conditioning of the out-
side air [4.12]. This unit provides the necessary quantities of outside air for the sec-
ondary air handling units, where it is mixed with recirculated air. Each of these
secondary units serves a specific facility sector composed of rooms which permit
linking their air-conditioning together. As there is no recirculation of the outside air
fraction, no airborne cross-contamination can take place between the zones served
by different secondary air handling units. Thus, they may well serve facility sectors
serving different purposes and differing in their contamination control requirements.

Fig. 4.45 also illustrates how process exhaust air containing highly active or toxic
contaminants can be prevented from causing detrimental effects to the outside envi-
ronment. It is exhausted into the atmosphere only after due purification: by air filtra-
tion in the case of an aerosol composed of dangerous particles or contagious micro-
organisms, or by means of scrubbers for gaseous contaminants.

Air recirculation is the most effective option from the energy conservation point of
view. If, however, the cross-contamination risk is such that – even with HEPA filtra-
tion – air recirculation is deemed unacceptable, the air handling system will have to
be operated with 100 % outside air. Operation with 100 % outside air is also re-
quired where volatile solvents or odorous substances are liberated into the room air
during processing, as fibre filters are ineffective against them.

Fig. 4.46 shows an air handling system operating with 100 % outside air [4.12]. In
order to minimize the heating and cooling requirements, energy exchange between
outside and extract air by means of closed-loop heat exchangers should be foreseen,
interlinked through a coolant circuit. Thus, during the winter season, the outside air
is pre-heated by withdrawing energy from the extract air. On hot summer days, the
outside air is pre-cooled by the extract air. Heat recovery by means of closed loop
heat exchangers guarantees that no contamination can be transferred from the ex-
tract air to the supply air.
 41

Fig. 4.46 also illustrates how pressure differences between rooms can be established
and maintained: by installing, for instance, in the final supply air duct branches, con-
stant air volume valves, and variable air volume valves in the extract air ducts.

4.8 Air handling systems with unidirectional airflow

4.8.1 Spot, linear and area protection

Unidirectional airflow is capable of complying with the highest air cleanliness re-
quirements posed at present and in the foreseeable future, and is indispensable
when product is exposed to the airflow in the aseptic core of the filling equipment dur-
ing aseptic processing. A high penalty, however, has to be paid when utilizing this
airflow pattern, as high air flow rates are intrinsically linked with it: the GMP guide of
the European Union and PIC/S [4.01-4.02], for example, stipulates maintenance of
an air velocity of 0.45 m/s ± 20 % when employing unidirectional airflow during sterile
and aseptic processing.

Therefore, utilization of unidirectional airflow is expensive, and consequently it should

be employed as sparingly as possible. No restrictions should impede creativity and
ingenuity in serving this objective. Design concepts can, however, be narrowed
down into three basic principles (Fig. 4.47): spot, linear and area protection [4.13].
Spot protection (Fig. 4.48), is employed when only areas of limited extension within a
room require protection with unidirectional airflow of clean air. Fig. 4.49 shows, as
example for linear protection, a tunnel line in a semiconductor facility - a so-called
wafer fab - and Fig. 4.50 a huge scale example for area protection: a so-called ball-
room again serving the microelectronics industry.

4.8.2 Spot protection options

Spot protection utilizing unidirectional airflow predominates in pharmaceutical appli-

cations. Fig. 4.51 presents three conceptual alternatives:
- free airflow around a work station;
- a work station shielded from its surroundings by means of curtains or partitions;
- a work station fully integrated into a machine.

Wherever possible, partition elements should be foreseen between the critical proc-
ess area and its surroundings: thus, clear separation of this area from its less exact-
ing surroundings is achieved by means of an effective aerodynamic barrier [4.04,
4.14]. Moreover, clear separation of worker and process results: the operator ob-
serves the process from the outside and only interferes in case of emergency (Fig.
4.52).

Where direct and unimpeded access to the critical process area is essential - as in
surgical interventions - partial airflow guidance elements (Fig. 4.53) should be fore-
 42

seen down to immediately above head level. They will improve the stability of the
unidirectional airflow quite considerably.

Whether such guidance elements are foreseen or not: after providing protection with
displacement airflow for the critical area, the air will spill over into the peripheral room
areas. Whether this spill-over will be sufficient for maintaining the required air
cleanliness level there, or whether additional ceiling air outlets will have to be fore-
seen, has to be decided case-by-case. Computer-based airflow simulation during
the installation's design stage is a potent and cost-efficient tool for decision making;
it is also very helpful for a preliminary assessment of complex flow situations ex-
pected in the vicinity of process equipment [4.15-4.17], thus avoiding unpleasant,
costly and time-consuming surprises after having realized the job.

4.9 HVAC system design

Point of departure in the dimensioning of the air circulation system is the determina-
tion of the cooling load it has to dominate (Fig. 4.54). The air flow rate determined
through these calculations may be insufficient for also meeting the required air
cleanliness levels and/or for fulfilling formal GMP requirements. Therefore, additional
aspects have to be taken into consideration (Fig. 4.55):
- the extension of the areas to be protected with unidirectional airflow and the air
velocity to be maintained there;
- the FDA requirement of not less than 20 hourly air changes in the controlled area
associated with an aseptic core area;
- the European GMP recommendation of a recovery time of 15-20 min in classified
areas with turbulent airflow;
- eventual sources of intense particle dissemination;
- dissemination of micro-organisms by human beings and other sources.

Having determined the air flow rate in rooms with turbulent airflow, the concentration
of airborne micro-organisms can be estimated by means of balance equations as
shown in Fig. 4.56, especially when persons are the only dissemination source of
micro-organisms in the room. For a first estimate, the dissemination value for per-
sons given in Fig. 1.21 can be utilized. This value reflects dissemination of people
wearing normal laboratory garments; for garments compatible with a grade C envi-
ronment a dissemination value of 100 CFU/min is more appropriate. Grade B gar-
ments are capable of reducing shedding to as little as 10 CFU/min [4.18].

HVAC systems for clean areas and their components should obey a high standard of
hygiene. Guidance for good hygienic design practice is compiled in the German
guideline VDI 6022 Part 1 [4.19].

4.10 HVAC perceived from the risk perspective

 43

HVAC systems do not only provide benefits to processes, products and the facility
personnel: there are also risks associated with them requiring attention [4.12]. Risks
inherent in improperly designed HVAC systems are listed in Fig. 4.57. Among these,
the indirect risk of false air infiltration merits particular attention in Egypt, where - es-
pecially during the spring - sandstorms are frequent.

Besides risks originating from particles, particular attention should be focused upon
microbiological risks. Species of micro-organisms known to interact with HVAC sys-
tems are compiled in Fig. 4.58. Risk analysis and assessment is the appropriate tool
for assessing the effective relevance of such risks under specific contamination con-
trol circumstances: this is the first step towards their domination. In doing so, the
philosophy should be to combat each risk with at least two effective countermeasures
[4.12]. As examples, Fig. 4.59 presents measures for dominating particles and mi-
cro-organisms borne in the outside air. Fig. 4.60 presents countermeasures against
micro-organisms capable of multiplying in the humid components of air handling
units, and Figs. 4.61-4.62 address the cross-contamination risk and that of false air
infiltration into buildings.

4.11 References

[4.01] Eudralex, the rules governing medicinal products in the European Union - Vol.
4: EU guidelines to Good Manufacturing Practice for medicinal products for
human and veterinary use. European Commission, Brussels (frequently up-
dated).

[4.02] PIC/S PE 009-9: Guide to Good Manufacturing Practice for medicinal prod-
ucts (divided into four parts: Introduction, Part I, Part II, Annexes). Pharma-
ceutical Inspection Convention PIC, Pharmaceutical Inspection Co-operation
Scheme PIC/S, Geneva (1 September 2009).

[4.03] Eudralex: The rules governing medicinal products in the European Union,
vol. 4: EU guidelines to Good Manufacturing Practice - Medicinal products for
human and veterinary use: Annex 1: Manufacture of sterile medicinal prod-
ucts. Brussels, 14 February 2008.

[4.04] ISO 14644-4: Cleanrooms and associated controlled environments - Part 4:

Design, construction and start-up. International Organization for Standardiza-
tion ISO, Geneva (April 2001).

[4.05] Whyte W.: Cleanroom Technology. J. Wiley & Sons, Chichester (2001).

[4.06] VDI 2083 Part 4.1: Cleanroom technology - Planning, construction and start-
up of cleanrooms. Beuth Verlag, Berlin (October 2006).
 44

[4.07] Kouri S.A., Schneider R.K.: Must-haves vs. nice-to-haves: Selecting the right
cleanroom construction materials. CleanRooms 20 (2006) 6, 35-39.

[4.08] Sandle T.: The use of polymeric flooring to reduce contamination in a clean-
room changing area. European Journal of Parenteral & Pharmaceutical Sci-
ences 11 (2006) 3, 75-79.

[4.09] Clibbon Caroline: An evaluation of polymeric flooring compared with "peel-

off" mats to reduce wheel- and foot-borne contamination within cleanroom
areas. Ibid. 7 (2002) 1, 13-15.

[4.10] German guideline VDI 2083 Part 5.1: Cleanroom technology – Thermal com-
fort: Annex I: Thermal comfort. Beuth Verlag, Berlin (September 2007).

[4.11] Guidance for industry: Sterile drug products produced by aseptic processing
- current Good Manufacturing Practice. U.S. Department of Health and Hu-
man Services, Food and Drug Administration (September 2004).

[4.12] Schicht H.H.: HVAC requirements and design concepts for facilities manufac-
turing non-sterile dosage forms. In: Utilities used by the manufacturer of
pharmaceuticals. Pharmaceutical Inspection Convention PIC, Pharmaceuti-
cal Inspection Co-operation Scheme PIC/S (ed.), Geneva (2002).

[4.13] Schicht H.H.: Cost-efficiency and energy-saving concepts for cleanrooms.

In: Whyte W. (ed.): Cleanroom design, 2nd ed. John Wiley & Sons, Chiches-
ter (1999).

[4.14] Ljungqvist B., Reinmüller Berit: Clean room design - Minimizing contamina-
tion through proper design. Interpharm Press, Buffalo Grove IL/USA (1997).

[4.15] Blackmore B.: Model formula. Cleanroom Technology 14 (2007) 5, 25-26.

[4.16] Manning A.: Airflow modelling in cleanroom design. CleanRooms 19 (2005)

5, 22-25.

[4.17] Barp St. et al.: Numerical simulation to assess airflow behaviour in buffers.
Pharmaceutical Engineering 23 (2003) 3, 136-145.

[4.18] Reinmüller Berit: People as a contamination source - Clothing systems. In:

Dispersion and risk assessment of airborne contaminants in pharmaceutical
cleanrooms. Royal Institute of Technology, Building Services Engineering,
Bulletin no. 56, Stockholm (August 2001), p. 54-77.

[4.19] German guideline VDI 6022 Part 1: Hygiene requirements for air handling
systems and units. Beuth Verlag, Berlin (April 2006).