Premises

27
Willem Boeke and Paul Le Brun

Contents 27.6.3 Floors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606

27.6.4 Ceilings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
27.1 Processes as a Starting Point for the Design of Areas 27.6.5 Heating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
and Installations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 27.6.6 Furniture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
27.2 Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 27.7 The Implementation Phase of Building or Rebuilding 607
27.2.1 Main Layout Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
27.2.2 Sterile Stock Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
27.2.3 Aseptic Stock Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
27.2.4 Aseptic Extemporaneous Preparations . . . . . . . . . . . . . . . . . . . 588
27.2.5 Non-sterile Stock Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
27.2.6 Non-sterile Extemporaneous Preparations . . . . . . . . . . . . . . . 588 Abstract
27.2.7 Storage Rooms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589 This chapter outlines the general aspects of premises
27.3 User Requirements Specification . . . . . . . . . . . . . . . . . . . . . . 589 designed for pharmaceutical preparation activities and
the steps to consider in order to achieve a justified design,
27.4 Functional Specification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
27.4.1 Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590 construction and qualification of these premises. Also the
27.4.2 Classification of Premises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590 built-in technical facilities are discussed. Premises and its
27.4.3 Interlock Systems for Air Locks . . . . . . . . . . . . . . . . . . . . . . . . . 593 technical facilities are an essential link in achieving good
27.4.4 Communication and Interior Design . . . . . . . . . . . . . . . . . . . . . 593 preparation practice. Their design and qualities should be
27.4.5 Routing and Gowning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
derived from the kind of products that will be produced
27.5 Built-in Installations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593 in it.
27.5.1 Installations for Heating, Ventilation and Air
European and WHO GMP define in general terms
Conditioning (HVAC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
27.5.2 Installations for Storage and Distribution preconditioned criteria that have to be met by premises,
of Pharmaceutical Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 including storage areas, weighing areas etc. However this
27.5.3 Provisions for Pressurised Air, Vacuum and Various chapter does not define exactly what is appropriate in any
Gasses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
27.5.4 Electrical and ICT Provisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
specific facility. The emphasis is on the interrelationship
27.5.5 Building Control Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 between the demands, the building, the installations and
the provisions. The scope is general so that all small-scale
27.6 Detail Specification and Building . . . . . . . . . . . . . . . . . . . . . . 604
27.6.1 Inner and Outer Walls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 production facilities for healthcare establishments and
27.6.2 Doors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 preparation centres are covered in the discussion. Also
ready-made premises or modules can be assessed by
comparison of their qualities with the ones mentioned in
this chapter.
Based upon the chapter Ruimten en Installaties by Willem Boeke, This chapter’s arrangement follows the general
Marco Prins and Jeannine van Asperen in the 2009 edition of approach of best practices in qualification. Important
Recepteerkunde.
subjects covered are:
W. Boeke (*) • Processes that underlie the necessity to build a prepa-
Klinische Farmacie Ziekenhuisgroep Twente, Hengelo,
ration facility
The Netherlands
e-mail: boeke@wxs.nl • Products and the legislative framework
• Routing of goods and personnel and communication
P.P.H. Le Brun
Apotheek Haagse Ziekenhuizen, The Hague, The Netherlands • Specification and classification of premises
e-mail: p.lebrun@ahz.nl2 • Built-in installations for HVAC, water and gasses

Y. Bouwman-Boer et al. (eds.), Practical Pharmaceutics, 585

DOI 10.1007/978-3-319-15814-3_27, # KNMP and Springer International Publishing Switzerland 2015
586
• Detail specification and building execution
• Walls, doors, floors, ceilings, heating, fixtures and
fittings
Keywords
Premises
Building
HVAC
Construction
Built-in
facilities
Water
27.1 Processes as a Starting Point
for the Design of Areas and Installations
At the initial design stage for a new preparation facility
attention should be paid to a variety of subjects, such as:
• The type and product range of medicines that will be
required from the facility
• Developments within the pharmaceutical and medical
environments and possible future product and process
demands
• The production scale and the batch volumes per product,
considering peak loads and annual volume
• The scope of the facility and its requirements, e.g. to
supply other pharmacies with pharmacy prepared
medicines
Whatever motives there might be for a (re-)building project
it should always be kept in mind that the design is specific to
the type and volume of products for which it is built. Cutting
out one detail might ruin the possibilities to achieve a
validated production process.
Small Detail; Big Consequences. . .
Standard doors will always have certain tolerances in
their rate of warping. However the entry doors to
premises with an air pressure hierarchy, as required
by the production process, must be checked for this
property in advance. This is to avoid the almost
unsolvable problems in the qualification of the air
pressure hierarchy due to leakages by not perfectly
closing doors. Neither the suppliers of doors nor
contractors are usually aware of the importance of
assessing these tolerances in advance. After all, if
this air pressure hierarchy really was required but
could not be qualified as such, a validated production
process will not be achieved.
Therefore, at the initial design stage in the construction of
premises for pharmaceutical preparations the responsible
pharmacist or an advisor who has proven capabilities in
this specific area must have a decisive input and a coordina-
tive role. He will have to deal with architects, companies of
consulting engineers, (sub-)contractors and installers, all of
W. Boeke and P.P.H. Le Brun
them having substantial knowledge in their fields. Still the
specific knowledge of the design and qualification of a
pharmaceutical preparations facility and its installed equip-
ment might be insufficient among those parties, unless a
specialist company is chosen for the design and building.
Conversely consulting engineers are important for the
incorporation of every aspect of safe building which usually
is an unfamiliar topic for the pharmacist. This should prevent
failures in construction stability, escape routes, fire and
explosion prevention, etc.
It should be decided which categories of products are to
be prepared and on what scale. The products involve prepa-
ration processes that basically determine what is necessary
for a specific facility, taking into account legislation.
Pharmacy preparation processes can arbitrarily be
subdivided into the following categories each with their
own specific premises:
I. Extemporaneous sterile and non-sterile preparations
Examples of this kind of preparations are: Aseptic
handling, i.e. uncomplicated operations with sterile
medicines in closed containers after which they get a
very short usage period, reconstitution of sterile and
non-sterile authorised medicines and extemporaneous
non-sterile preparations from raw materials.
II. Extemporaneous preparations involving specific risks,
such as complex aseptic handling and preparation with
hazardous substances. Involved in this category is aseptic
handling with most antineoplastics, medication cartridges,
radiopharmaceuticals, biological or advanced therapy
medicinal products (ATMP’s).
III. Sterile and non-sterile stock preparations. Involved are:
• Non-sterile stock preparations
• Sterile stock preparations (sterilisation in final
container)
• Sterile aseptic stock preparations
The products to be prepared can be organised into a table as
in Table 27.1, related to their categories. This may help to
estimate the extent of provisions and the level of required
standards that are necessary per product type.
27.2 Design
27.2.1 Main Layout Considerations
Starting from the classification of preparation processes a
rough preliminary design is drafted indicating the position of
production areas, their interrelationship and logistics. The
relations between departments and premises, flow of goods
and persons are plotted. This start document is preferably
formulated by the one who will be responsible in future for
the preparation processes.
27 Premises
Table 27.1 Categorisation of products for designing premises
A. Stock preparations Categories
A1 Sterile
Aseptic preparations (vials, ampoules, infusion fluids III
in bags, prefilled syringes)
Autoclavable preparations (vials, ampoules, infusion III
fluids in bags or bottles)
Eye drops III or II
Sterile ointments and creams III
A2 Non-sterile
Packaging e.g. in Unit Dose III
Tabletting III
Fluids (solutions and suspensions) III
Ointments and creams III
Suppositories III
B. Extemporaneous preparations
B1 Sterile
Aseptic handling (complex, see Sect. 31.3.2) II
Total parenteral nutrition, medication cassettes
Aseptic handling (hazardous, see Sect. 31.3.5)
Antineoplastics, radiopharmaceuticals
Simple aseptic handling; short shelf-life I the same set of weighing apparatus in a pharmacy.
B2 Non-sterile
Capsules, suppositories, fluids, ointments and creams I
Reconstitution of licensed pharmaceutical preparations I • The location of the preparation department in relation to
The preliminary design should be drawn up based on the
following considerations:
• The extent of the preparation department: Available
premises usually are confined. However, sufficient room
must be available for apparatus and materials. Apparatus
should be stored in a way that minimises contamination.
Therefore, a separate accommodation near the prepara-
tion premises is preferred over the placement in the
preparation room itself.
Sufficient room should be available for the operators to
work efficiently and safely.
• Avoiding crossing routes for personnel and goods: In a
pharmacy several products are usually being prepared on
the same day. This brings about a higher risk of cross
contamination when compared to a large pharmaceutical
industry producing only one product on a dedicated pro-
duction line. Inadvertent mixing up of a sterile and a not
yet sterilised product or of products of different batches
constitutes a similar threat.
• Entrance: The entrance to premises for preparation
should be provided by means of, preferably
sex-separated, gowning rooms for staff and a separate
air locked entrance exclusively for goods. If necessary
the separation of the sexes might be achieved by
separating in time. However it should be realised that
this may jeopardise the efficiency of the production.
587
A correct constructional design has to be derived from
the process and will prevent any confluence or cross-
ing of routes. However, in practice crossing cannot
always be avoided. In that case procedural solutions
should warrant that all goods are to be labelled and
packed securely (e.g. in closed boxes) before being
exposed to crossing lines. Routing questions at the
design of a layout of premises will frequently be with
regard to processes such as weighing raw materials,
sampling, input and output to and from any temporar-
ily deposit store for intermediates or quarantine,
cleaning of reusable utensils and label printing.
For example, it is important to consider if the weighing
process will or will not be carried out in a centralised
weighing room thus requiring subsequent transport of
the labelled portions to the preparation room. In a
centralised weighing room, thorough precautions
should be taken to prevent cross contamination of the
raw materials. The same goes when two workers use
logistic functions, etc. For example radiopharmaceuticals
(see Sect. 15.6.1) should be prepared nearby or at the
nuclear medicine department.
• The required apparatus and utensils, the preparation pro-
cesses they are used for and the required provisions such
as air conditioning, clean water, electricity, compressed
PRODUCTION
air and gasses. For extremely hazardous preparations
(antineoplastics, radiopharmaceuticals, see Sect. 26.3.5)
and for sterile preparations separate premises may be
required to protect products and operators adequately, as
is also laid down in GMP. Scaling up of the processes
may lead to partitioning of the rooms into areas for
dedicated functions.
After classifying the preparation processes and the corres-
ponding premises and its outlines the preliminary design will
be drafted. Some examples are given below for a few prepa-
ration processes.
27.2.2 Sterile Stock Preparations
Separate rooms are necessary for the preparation and for
filling into e.g. infusion bags or ampoules prior to final
heat sterilisation. In addition, one or more sterilisers with
corresponding technical rooms (including the access) are
needed.
The premises for the most critical preparation steps
(e.g. filling) must be built as a clean room (see Sect. 27.3)
and require a controllable air conditioning installation.
588
Those premises must comply with GMP class C (see
Sect. 27.4.2 and Table 27.2) [1].
Sterile stock preparations usually require such high
volumes of water that separate technical installation
premises are required to accommodate the installation for
the production of water for injections.
Finally, premises for examining and for packaging and
labelling are necessary.
Appropriate rooms (laboratories) for pharmaceutical
microbiological control and for chemical quality control
should not be left out. However the possibility of
microbiological contamination from this laboratory requires
a completely separated air handling.
Alternatively the microbiological control could be out-
sourced implying yet other, more procedural complications
such as the need for Service Level Agreements and meeting
the requirements of GMP Chap. 7 (Outsourced activities).
27.2.3 Aseptic Stock Preparations
In premises for aseptic preparation from sterile raw materials
the preparation room usually is combined with the filling
room because carrying the bulk product into another room
will introduce an additional contamination risk. In this situ-
ation a separate room for preliminary operations, e.g. disin-
fection of utensils and surfaces of containers, is required.
At the most critical places, especially at the filling point
of the aseptic fluids, the premises must meet GMP class A
conditions [1]. A class A condition usually needs a back-
ground condition of class B to be able to maintain the class A
condition during operation. However exceptions to this rule
can be warranted, e.g. using an isolator.
Classified premises are expensive both in procurement
and maintenance. Therefore, it is justified to analyse each
preparation process for all critical steps and to limit their
number as far as possible.
Premises for examining and for packaging and labelling
can be combined with those for sterile stock preparations.
27.2.4 Aseptic Extemporaneous Preparations
Also in this situation a separate room is required for prelim-
inary operations, e.g. disinfection of utensils and surfaces of
materials. In the preparation room medicines are
reconstituted, e.g. filling of syringes, infusion bags, medica-
tion cartridges, disposable infusion pumps and irrigations. In
addition, parenteral nutrition fluids, antineoplastics,
radiopharmaceuticals and eye preparations may be prepared
in these premises. Radiopharmaceuticals and other very
W. Boeke and P.P.H. Le Brun
hazardous products, may require dedicated rooms and con-
tainment conditions (see Sect. 26.7).
For aseptic handling in closed systems a cabinet with
unidirectional airflow (LAF or safety cabinet) or an isolator
can be used (see Sect. 28.3). The requirements for the back-
ground room depend on national guidelines and on the types
of containment in the cabinets. Adjustments are allowed but
must be based on a risk assessment.
Strictly, air quality class A cannot be claimed if the
background qualification is less than class B. However
this class A safeguard is strictly only required for
aseptic stock preparation and any aseptic handling
that is executed with non-closed systems. Under spe-
cific conditions a class C condition as background
might be acceptable. On the basis of a thorough risk
assessment and a monitoring and validation program
even a class D background for well-defined aseptic
handling may be justified, see Sect. 31.3.4.
27.2.5 Non-sterile Stock Production
This department can be divided into separate premises for
solid (dusty), semisolid and fluid preparations. Preparation
processes with inflammable substances may require specific
provisions such as a fume cupboard or more intensive venti-
lation. Premises for tableting and similar dust-producing
preparation processes should be equipped with a suitable
installation for air conditioning and dust exhaustion. Apply-
ing a negative pressure will prevent dust from active
substances escaping from the preparation room. Even for
repackaging activities (e.g. into unit dose package) a sepa-
rate room is to be preferred. Specific GMP classification
A-D is not required for non-sterile preparations. However
the GMP principles such as cleanability are applicable.
Therefore, in practice, facilities for non-sterile preparation
are often classified as grade D.
27.2.6 Non-sterile Extemporaneous
Preparations
The underlying principles for premises for non-sterile stock
preparations should be used for extemporaneous prepara-
tions as well. Preparation activities in a community phar-
macy usually are confined to reconstitution, aseptic
handling, manipulation of licensed medical products and
non-sterile preparation from raw materials. The avoidance
of crossing process lines in small-scale situations is a
27 Premises
challenge but it is almost impossible to prevent crossing
lines just by the layout of the premises. Routing has to be
specified by procedures and organisational measures have to
be taken, e.g. working with trays or closed boxes per
activity.
The requirements for the premises may turn out to be
quite moderate, provided that they are based on a well-
documented risk assessment. It will at least imply that
premises shall be exclusively dedicated for preparation
activities, e.g. shall not give direct access to toilets and
will have to be physically separated from any public area.
The layout should not compromise a logical sequence of
activities. Specific gowning and cleaning procedures must
apply.
Attention should be paid to the ventilation of any premise
and its upkeep. In newly built premises, the ventilation
capacity might have been minimised due to energy saving
policy, especially in northern countries. Therefore the risk
has to be assessed that the ventilation might fail to meet
minimal requirements. Any so-called ’natural ventilation’
might clear the way for insects to enter, unless specific
measures are taken (e.g. insect screens). Air quality can be
improved by using a recirculating dust exhaust cabinet
which should be available in every community pharmacy,
e.g. for the reconstitution of antibiotic oral liquids.
27.2.7 Storage Rooms
Apparatus to achieve specific, usually low temperature, stor-
age conditions are described in Sect. 28.9. The design of
storage rooms should take into account that the temperature
should not exceed 25  C for prolonged periods (see Sect.
36.9.4). This may involve the necessity of air conditioning.
Additional provisions should be provided to avoid long
lasting humidity levels over 60 % RV or below 20 % RV
or penetration of direct sunlight.
Specific conditions, like lockable safety cupboards, may
be required for the storage of any specific class of hazardous
(e.g. inflammable or poisonous) products.
A properly considered location of storage rooms,
separated quarantine storage and laboratory may ease rout-
ing very much.
There should be ample space for input and output of goods
without the need of rearranging the goods at each occasion
(first-in first-out principle). Especially the manoeuvring of
pallets should be accounted for.
Empty packing material is usually wrapped in airtight
wrappings or transport casings. However after opening the
wrap, packing materials are open to the rather unconditioned
environment of the storage room and thus open for pollution
589
with dust or even insects. So either only complete units have
to be used or the remaining materials should be rewrapped or
repacked.
Storage rooms should be kept clean at a normal house-
hold level and vermin-free. No specific additional demands
are made because the package of the products should protect
them sufficiently against any contamination.
27.3 User Requirements Specification
As soon as the draft design, the program of requirements and
a thorough (risk) analysis of the anticipated production
activities is gathered, this information should be ’translated’,
usually by professional advisors, into a keynote document or
user requirements specification (URS). This document
should describe and specify in detail the required situation
after the (re-)building. It should clearly underpin the listed
demands and points of departure, which for their part should
be traceable to relevant legislation. In addition the URS
should, after realisation of the building, offer direct control
points to all critical aspects of the intended processes. The
conformity of the final situation to the original plan must be
proven which only can be done by checking systematically
all critical control points of the completed premises to the
original plan as previously specified in the URS.
The delivery of this evidence is called the performance
qualification (PQ), see further Sect. 34.15. It is important to
pay attention to the future PQ as, in contrast to other
PRODUCTION
qualifications, the PQ cannot be outsourced. A well-
formulated URS takes account of the implementation of
the future PQ tests and therefore its tenor extends far beyond
a more trivial ’Plan of Demands’.
The URS should account for regulatory demands of
GMP, Occupational Safety and Health and Environmental
Care. Additionally preparation demands, required apparatus,
HVAC (installations for Heating, Ventilation and Air Con-
ditioning) controls, routing of personal and goods as well as
gowning and cleaning instructions should be specified. It
should be stated explicitly which regulations (e.g. GMP,
ISO standards, Occupational Safety and Health legislation)
do apply, thus delimiting the legislative framework. By
adding the prefix ’c-’ (current) to the name of any law
(e.g. c-GMP) it is stated that the regulation may be develop-
ing during the life of the premises and that always the most
recent version has to be consulted.
Clean rooms are usually involved in the design of a
pharmaceutical production facility. The term ’cleanroom’
is specified in detail in the ISO standards 14644 (parts 1, 2,
4, 5 and 7) and 14698 (parts 1 and 2) [2–5]. Particularly ISO
14644 part 4 deals with the design, the construction and the
590
initial start-up of a clean room and includes a useful
checklist [4].
27.4 Functional Specification
27.4.1 Contents
Next step in the design process is drawing the functional
requirements specification (FRS), also called the physical
requirements specification. The FRS documents elaborated
demands for connections, heat burden, floor load, acoustic
demands, specifications of the walls, HVAC etc.
The heat burden is the amount of heat that is generated in a
room per unit of time by humans and apparatus. Provisions for
air supply have direct impact on product quality. In the FRS
for clean rooms the limits are specified for the allowable
number of particles at rest and in operation, i.e. the clean
room class (see Sect. 27.4.2 below), along with desired turbu-
lence limits, limits for air pressure and microbiological limits.
It provides the final specifications for premises, fixtures and
fittings and a map with the positions of furniture and appara-
tus. The FRS contains also technical or procedural measures
to prevent cross contamination or crossing lines for personal
or goods [5]. Obviously all specifications in the FRS are
substantiated at the base of their application. As an example,
in premises intended for complex aseptic handling or recon-
stitution of hazardous sterile medicines, any choice for the
classification of the background conditions should be justified.
27.4.2 Classification of Premises
The idea behind GMP is to preclude any factor with an
unpredictable or undetermined impact on the production pro-
cess as this impairs the process validity. Particles, micro-
organisms and (gaseous) chemical contaminants arising
from the air from outside might constitute such a factor,
especially relevant for the process of producing sterile and
aseptic preparations. Therefore, GMP requires that premises
for this kind of preparations must be classified. Since the
absence of invisible micro-organisms and dust is hard to
Table 27.2 Grades of air conditioning according to GMP
Maximum permitted number of particles per m3 equal to or greater than the tabulated size
At rest
Grade 0.5 μm 5.0 μm
A 3,520 20
B 3,520 29
C 352,000 2,900
D 3,520,000 29,000
W. Boeke and P.P.H. Le Brun
be proved at any moment and place, measures are prescribed
that should guarantee this absence with substantial safety
margins:
• The inlet air should be filtered, through HEPA (Highly
Efficient Particulate Air) filters.
• A specified air replacement factor per hour (ventilation
factor; see Sect. 27.5.1 HVAC) should be achieved.
• The premises must be kept clean in relation to lower
classified neighbouring premises by the application of
pressure differences.
Annex 1 of the GMP applies. This document specifies four
grades for low particulate premises: A, B, C and D. See
Table 27.2.
GMP Annex 1 states that a certain air quality class can
only exist when the access to the room is achieved through
an air lock in which the same class prevails. The Annex
1 classification refers to the ISO classification (see
Table 27.3) that define intermediate air quality specifications
by decimal class designations.
According to ISO 14644–1 the air classification scheme is
distinguished by a mathematically coherent approach and
based upon a formula:
Cn ¼ 10N ð0:1=DÞ2, 08 ð29:1Þ
where
Cn ¼ maximum number concentration of particles per m3
with diameter  the considered particle diameter,
rounded to a maximum of 3 digits;
N ¼ ISO classification number;
D ¼ considered particle diameter;
0.1 ¼ the reference diameter, a constant with the
dimension mm.
As the ISO classification is defined by a continuous
formula with the particle size as a variable and the GMP
grades are defined in discrete counts for specific particle
sizes, the comparison between GMP grades and ISO
classifications is formally not possible. Additionally ISO
classifications can be formulated in decimals where the
GMP grades cannot. However as a practical approach the
comparison is possible as e.g. grade B at rest will match ISO
5 for most practical purposes.
In operation
0.5 μm 5.0 μm
3,520 20
352,000 2,900
3,520,000 29,000
Not defined Not defined
27 Premises
Table 27.3 ISO 14644–1 classification of air cleanliness
Maximum permitted number of particles per m3 equal to or greater than the tabulated size
(in operation)
Class 0.1 μm 0.2 μm
1 10 2
2 100 24
3 1,000 237
4a 10,000 2,370
5(GMP B at rest) 100,000 23,700
6 1,000,000 237,000
7 (GMP grade B in operation, Grade C at rest)
8 (GMP grade C in operation, Grade D at rest)
9 35,200,000
a
EU GMP Grade A meets ISO 4.8
How Is the Classification of the Premises Actually
to be Derived from the URS?
A basic principle is that raw materials, intermediate
products and final products that are not yet in their
final, primary package should never be exposed to any
unconditioned air. The primary package is the airtight
enclosing package of the final product that is in direct
contact with the product. Should therefore also
non-sterile extemporaneous preparations (Category I;
community pharmacy or small hospital pharmacy) be
prepared in a classified premise? The principal objec-
tive is that during preparation of non-sterile products no
contamination from whatever source can occur. To that
end adequate procedures should be organised such as a
warranted adequate maintenance (cleaning, prevention
of impairment) and also warranted procedures should
apply to prevent disturbances such as any opening of
doors or windows during preparation activities. Under
such conditions, a specific classification of premises has
limited meaning and usually can be left out. After all
Class D only specifies a maximum number of particles
at rest which is usually easy achievable except when a
current badly functioning ventilation system is in action
or during specific (weather) conditions, incurring a high
concentration of fine particles or pollen.
Also if products are sterilised in their primary pack-
age a low microbial starting contamination is essential.
Therefore products to be sterilised must be filled under
class C conditions but the preparation of the bulk
solution may take place under class D conditions.
Aseptic handling and preparation must be executed
under class A conditions, usually a LAF (Laminar Air
Flow) cabinet, a LDF (Laminar Down Flow) cabinet, a
safety cabinet or an isolator see Sect. 28.3. The back-
ground room for stock preparations in a LAF, or LDF
(continued)
591
0.3 μm 0.5 μm 1 μm 5 μm
10 4
102 35 8
1,020 352 83
10,200 3,520 832 29
102,000 35,200 8,320 293
352,000 83,200 2,930
3,520,000 832,000 29,300
8,320,000 293,000
cabinet is at least class B. The background room for
aseptic reconstitution or handling in a LAF, or safety
cabinet may have a lower classification than B,
provided that it is based on risk assessment. Confor-
mation to the latest views of inspectorates and profes-
sional associations e.g. PIC/S [1] is advised.
For premises designed for non-sterile preparations over-
pressure is preferable to prevent any penetration of uncon-
trolled air. For premises designed for sterile or aseptic
preparations this is required by GMP.
Generally working with hazardous substances – as almost
PRODUCTION
all active substances are – requires containment. In the
specific case of radiopharmaceuticals, Nuclear Energy legis-
lation requires the application of negative pressure (see Sect.
15.6.3). In the situation of aseptic handling, which requires
positive pressure, with radiopharmaceuticals, this results
essentially in contradictory pressure demands. A solution
may be achieved by putting the whole complex of prepara-
tion rooms with air locks at negative pressure relative to its
environment. The system of walls, floors and ceilings should
be completely airtight in that case. Pipe entries, electrical
sockets as well as porous stone in the wall parts above the
ceiling are frequent sources of (substantial) leakage of
contaminated air. Thus all chinks and gaps have to be filled
and porous stone has to be coated.
By now putting the air locks at some additional negative
pressure a relative overpressure in the preparation premises
is created relative to the admission air locks. The deeper
negative pressure in the air lock will however lead to a
vigorous influx of contaminated air as soon as the outer
door is opened, contaminating the lock and compromising
its function. To prevent this an additional ’front air lock’
should be considered. The front air lock should have a slight
592 W. Boeke and P.P.H. Le Brun

negative pressure relative to the environment and will be Weighing of solid substances will release dust. A dust
supplied with clean HEPA filtered air. Alternatively, a clean extract cabinet, equipped with a High Efficiency Particulate
air lock or corridor giving access to other (positive pressure) Air (HEPA) or Ultra Low Particulate Air (ULPA) filter (see
premises can serve as a front air lock to a negative pressure Table 27.4) in the rear wall or in the exhaust, or both, will
premise. See Fig. 27.1. limit the exposure of operators to active substances. Addi-
tional options are the wearing of respirators (see Sect.
26.4.1) and a closed weighing vessel.
In many respects the hazards of many antineoplastics
The air turbulence from a dust extract cabinet may disturb
and radiopharmaceuticals for staff are similar. Also the
the functioning of electronic balances. A dedicated construc-
required skills for aseptic handling are similar. This
tion in each of the preparation premises to manage this is
may lead to the consideration of designing a standard
layout for all premises for handling with extremely
hazardous substances. However, for antineoplastics Table 27.4 Survey of HEPA and ULPA filters
no formal requirement for pressure applies (see Sect. Filter class according
26.8). Therefore, the viewpoint that overpressure to EN 1822:2009 Efficiency % Penetration %
warrants a better microbiological air quality usually E10 85 15
will prevail. In addition the validity of negative pres- E11 95 5
sure premises may be impaired as a result of almost E12 99.5 0.5
unavoidable air leakages. H13 99.95 0.05
The objective can also be achieved with the use of H14 99.995 0.005
negative pressure cabinets sited in positive pressure U15 99.9995 0.0005
rooms. U16 99.99995 0.00005
U17 99.999995 0.000005

Fig. 27.1 Model plan for

pressure hierarchy around
negative pressure premises.
Adapted from Recepteerkunde
2009, #KNMP

clean air corridor

+15 Pa

sliding
door LDF
underpressure
cabinet
gowning lock -30 cleanroom -15 Pa

Materials
lock

surrounding area; 0 Pa
27 Premises
expensive and therefore cannot always be achieved. If for
this reason a separate weighing chamber is designed all
measured portions should be transported in well-closed and
identified vessels.
27.4.3 Interlock Systems for Air Locks
For the maintenance of an air pressure regime and an air
quality class of a preparation premise an air lock is required.
It controls access from any lower qualified premise. Person-
nel locks should be discriminated from materials locks. In
personnel locks the required gowning regime has to be
determined in advance. In most cases this results in the
requirement of sex-separated gowning locks.
For materials locks the prevailing transport direction and
the usual volume of materials is important. If possible the
transport direction should be assured for instance by means
of a catch that transmits a standardised vehicle (e.g. a crate)
in only one direction.
All air locks must be equipped with a so-called interlock
system. This system ensures that both doors of the air lock
will never be opened at the same time.
Different interlock principles exist:
• Both doors are permanently closed by magnets,
necessitating a separate hand operated switch to
open one of them.
• Both doors are permanently unlocked, in which
case the opposite door is locked by opening the
other door.
Considerations for the choice are: the hand operated
switch is a potential source of cross contamination,
magnets consume electricity and emergency escape
routes depend on easy access.
27.4.4 Communication and Interior Design
Employees who are working in separate rooms within the
premises should be able to communicate with each other. If
no well-designed communication resources were in place the
personnel would be forced to communicate to each other
through windows, locks, opened doors, etc. Routing of per-
sonnel and goods will then be seriously jeopardised.
Mobile telephones in preparation premises are notori-
ous sources of cross contamination and thereby not
appreciated. The same goes for a hand operated
(continued)
593
intercom apparatus. A ‘voice actuated system’ - the
voice of the speaker actuates the communication line -
might be a better solution. Background noise
(e.g. from LAF cabinets) however may impart the
correct functioning of such a system. A wireless head-
set or a mobile telephone that stays within the premise
and is cleaned / disinfected daily may be an
alternative.
27.4.5 Routing and Gowning
The FRS design document should consider the usual tracks
of personnel. Routing of personnel and thus required
gowning rooms are principally independent of the routing
of materials. Therefore, materials locks or transmission
cabinets are indispensable in a good design. A correct
gowning procedure for personnel can hardly be maintained
when employees have to use the changing lock for material
transport.
For a gowning lock the following requirements can be put
forward:
• A clear division between the ’dirty’ and the ’clean’ part,
preferably by means of a step-over bench
• A correct location of a washbasin and a dispenser for
hand disinfectant
• Drains (from washbasins) should not be sited on the
PRODUCTION
’clean’ side of the lock
• A cabinet for clean, unused clothing, and a bin for used
clothing is provided
• A locker to stow away personal belongings
Toilets should not be accessible directly from a preparation
premise from the clean part of a gowning lock [2].
For the design of the routing and communication it might
be useful to have well in advance the future staff ‘virtually’
preparing the products, based on concept drawings and let
them document all of their detailed activities. Together they
should properly review all process steps in detail to find out
which provisions have to be taken.
27.5 Built-in Installations
Built-in installations that will be dealt with in this chapter
are:
• Air conditioning installations
• Installations for storage and distribution of pharmaceuti-
cal water
• Provisions for pressurised air, vacuum and gasses
594 W. Boeke and P.P.H. Le Brun

• Electrical installations (power supply, emergency power
supply, signalling and ICT provisions.
In a community pharmacy (category I preparations; see
Table 27.1) usually limited provisions will be sufficient,
e.g. if water of suitable pharmaceutical quality is purchased
in bottles. See also subsection 27.2.5.
27.5.1 Installations for Heating, Ventilation
and Air Conditioning (HVAC)
A HVAC installation is quite space consuming as air ducts
usually must be voluminous to warrant the distribution of the
required air volumes within acceptable noise nuisance
limits. In existing constructional premises the layout of the
air ducts often is not possible without any compromise.
Ideally, but expensive, each room is to be equipped with
its own separate air inlet and outlet. In practise overflow
grids are used frequently to transport air from one room with
relative high air pressure to an adjacent room or air lock with
a lower air pressure. However, in that case no independent
control of the air pressure or the ventilation factor is possi-
ble. So during the design it is necessary to consider any
possible contamination of overflow air from an adjacent
room and the limitations to control it.
In principle a HVAC installation consists of three
components, i.e. the preliminary treatment installation
(make-up casing), the recirculation- and control installation
(recirculation casing) and the distribution network with fine
tuning per room. See the example in Fig. 27.2.
27.5.1.1 Preliminary Treatment Installation
The make-up casing draws in fresh air through a bird grid
and a rough dust filter. Subsequently the air is, according

11

P
6 7 9 10

2
3 4 5
1 8
12
P
13

19 17 16 15

14
20 20 20 18
21 21 21

22 22 22

Legenda Figure 27.2

1. Bird grid (air inlet) 12. Recirculation ventilator
2. Coarse dust filter 13. Restriction with pressure difference measurement (Dp)
3. Inlet ventilator 14. Regulating valve
4. Restriction with pressure difference measurement (Dp) 15. Steam injector (moistening)
5. Regulating valve 16. Heat exchanger for heating
6. Steam injector (moistening) 17. Heat exchanger for cooling and drying
7. Heat exchanger for cooling and drying 18. Drain for condensate
8. Drain for condensate 19. Dust filter
9. Heat exchanger for heating 20. Heat exchanger for temperature adjustment in the premise
10. Dust filter 21. HEPA filter and inlet grid
11. Pretreatment installation 22. Premise

Fig. 27.2 Schematic representation of a HVAC installation for clean rooms

27 Premises
to weather conditions, heated, cooled, moistened or dried.
In the (almost) airtight classified clean rooms, with
recycled air, atmospheric humidity can easily increase
above limits by water vapour or exhaled human air. This
will not level with environmental air conditions as quickly
as usual in normal, non-airtight buildings. Drying of
(inlet or recirculated) air is achieved by condensing
over a cold heat exchanger placed in the air stream.
Provisions for drying and moistening are critical installa-
tion parts because moist air can easily foster growth of
accumulating moulds. A well-designed control plan
should prevent this.
27.5.1.2 Recirculation- and Control Installation
To save energy, as well as to control air quality a substantial
portion (usually 80 %) of air returning from the premises is
reused by means of a recirculation ducting. The remaining
20 %, leaving the premises by leakage and by direct exhaust
to the outside of the building has to be replenished by the
make-up ducting. The recirculation ducting controls air
quality by:
• Filtering the supply air through a central HEPA filter
• Adjusting temperature and humidity
• Adjusting airflow rates (volume of air per unit of time) to
the distinct rooms
The air drying over cold heat exchangers makes independent
control of humidity and temperature difficult. Apart from
that the circulation of air through filters generates frictional
heat. The prediction of the amount of heat and moisture
generated from the production process therefore is both
complex and important design information.
The HEPA filter makes the distributed air (almost) free
from particles (see Table 27.4). Preferably the pressure fall
over the filter is continuously monitored to signal leakages
(pressure fall is too low) or blockage by pollution (pressure
fall is too high and has usually gradually increased).
The volume of each room and the required ventilation
factor determine the airflow rate that has to be achieved in
the room. The ventilation factor or replacement factor is the
number of times that the volume of a room is completely
replaced with fresh air. In the ISO standard 14644-4 [4]
advisory ventilation factors are given in relation to the air
quality class in a classified premise. Occupational safety and
health legislation will also add requirements to the ventila-
tion factor.
Air Velocity, Ventilation Factor and Airflow Rate
Control
Starting from ISO class 5 no ventilation factor is given
as this class can only be achieved by a unidirectional
(continued)
595
or laminar airflow, having a velocity of about 0,4 m/s.
Higher velocities soon give raise to turbulence of the
air; lower velocities displace any particles too slowly.
The airflow rate (volume per unit of time; D) can be
derived from this air velocity s and the area A of the air
inlet grid [5]: D ¼ s  A.
It has to be decided whether the total airflow rate to
be distributed over the premises is controlled by a
so-called fixed volume controller or by a variable
volume controller. A fixed volume controller main-
tains a constant pressure fall over a fixed constriction
in the main air transportation channel. The controller
thus serves to maintain a steady air volume per unit of
time independent of variations in input air pressure
(wind!), pressure fall over filters and leakage through
chinks and gaps. A variable volume controller delivers
the air at a slightly variable flow rate as this controller
directs the airflow at the basis of a specific air pressure
in one or more reference rooms.
The consequence of a fixed volume controller is
that small variations in the amount of air leaking
through chinks and seams soon give raise to substan-
tial differences in the air pressure hierarchy. In this
case pressure steps between different rooms need a
level of 15 Pa to cope with any unavoidable variations
in leakage.
With a variable volume controller there is a direct
feedback from the air pressure in each separate room.
Small variations in air leakages will result in adjusting
PRODUCTION
the air control valve in such a way that the air pressure
differences are maintained. Usually a smaller pressure
step between rooms, e.g. 10 Pa, will be sufficient to
maintain the pressure difference and airflow. The ISO
standard 14644-4 mentions pressure steps of 5 – 20 Pa.
However it should be borne in mind that 1 Pa
(1/100.000 bar) is a very small pressure difference,
which is hard to control. In the design therefore a
certain margin should be observed. GMP specifies a
guidance value of 10–15 Pa between rooms.
Although at first glance a variable volume control-
ler would be preferred it has a drawback that the
recovery time of a clean room after the introduction
of contaminating particles at validation will not easily
show reproducible results.
An additional problem may be raised by the con-
troller. The opening of a door for instance will create a
zero pressure difference. If the controller reacts too
fast overcompensation of the feedback loop takes
place resulting in fierce auto-reinforcing fluctuations
of air pressure [5].
(continued)
596
Apart from the fixed volume controller and the
variable volume controller also hybrid controllers are
available: a variable volume controller with a limited
range of variation or a fixed volume controller with a
variable controlled exhaust volume. Which type suits a
specific clean room depends on the level of control of
the flushing pattern of the air inside the room, the air
pressure differences and the recovery time.
27.5.1.3 Distribution Net and Fine Tuning
For the design of preparation premises an air balance per
room should be drafted regarding:
• The free volume of the room (room volume minus the
volume of fixtures and fittings)
• The required overpressure relative to linked premises
• The required ventilation factor
• Any volume of direct exhaust (e.g. through safety
cabinets)
• The heat burden (amount of heat generated by apparatus
and humans)
Additionally the required air quality class (GMP, see
Table 27.2 or ISO, see Table 27.3) must be documented
and it should be documented that the pattern of air flushing
through the room is effective at all functionally relevant
spots. The actual air sweep will have to be validated after
construction and must meet the specifications.
The ventilation factor and the room pressure determine
the volume of air that has to be let in and thus the dimensions
of the air duct, the number of inlet grids and the position of
the metering valve of the involved supply channel or the area
of the involved overflow grid. The heat burden and the
admitted airflow rate furthermore determine the maximum
inlet air temperature or the required capacity of any after-
heating radiator.
The air quality class determines the type of HEPA filter
(see Table 27.4) mounted in the inlet grid and the thereby
raised air friction. All HEPA filters should be entered into a
maintenance plan; at least once a year a leakage test and a
filter integrity test should be performed [5].
In premises equipped with direct external exhaust it has to
be determined in advance if the connection to the exhaust
duct will be fixed or achieved by means of a so called
draught diverter (Fig 27.3).
Examples of equipment with an external exhaust are
e.g. fume cupboards and flue gas exhausts, fitted to an
ampoule filling machine or to an atom absorption spectro-
photometer. Also a safety cabinet or a non-recirculating dust
suction cabinet (e.g. Wibojekt®) and negative pressure
isolators have external exhausts. When the equipment has a
fixed connection the exhaust ventilator must be switched on
continuously and thus the equipment has a direct impact on
W. Boeke and P.P.H. Le Brun
Exhaust
Ceiling
One-way
valve
Exhaust
ventilator
LDF safety workbench
Floor
Fig. 27.3 Draught diverter
the designed air balance within the room. The use of a
draught diverter facilitates the possibility to switch off the
cabinet itself as the extraction ventilator will then bypass
it. The functioning of the extraction ventilator should be
interlinked with the HVAC installation in such a way that
if the latter fails or is switched off, the capacity of the
extracting ventilator should be adjusted, or, in case of fire
alarm, switched off. In addition any direct or indirect failure
of the extracting ventilator must lead to an alarm condition
as this impairs directly staff safety.
Principle Draught Diverter
When a so called draught diverter is implemented the
exhaust channel is placed over the outlet of the equip-
ment like an inverted funnel. At switched-off status,
air will be sucked out from the room, bypassing the
equipment. When switched-on the air leaves the room
mainly through the equipment. Accounting for the
volume of air that passes through the equipment is
necessary in the calculation of the air balance. For
the air pressure or ventilation factor in the room it
doesn’t matter whether the equipment is switched on
or off.
In any case it should be warranted, whether the
equipment is fitted with a draught diverter or with a
(continued)
27 Premises 597

knowledge of the specifications of pharmaceutical quality

fixed outlet connection, that never, e.g. in the case of
breakdown of the external exhaust ventilator, outside
air can enter the preparation premise. The opposite
should be prevented as well: if a safety cabinet shuts
down the exhaust should close at the same time,
because otherwise environmental air could exchange
with the air from within the premises, thus
contaminating the HEPA filter. A well-designed
draught inverter with a one-way valve provides all
those functions.
27.5.2 Installations for Storage and Distribution
of Pharmaceutical Water
In this subsection only built-in installations required for
storage and distribution of pharmaceutical water are
discussed. Apparatus for the production of pharmaceutical
water are discussed in Sect. 28.4.
Water of pharmaceutical quality is used as a raw material,
excipient, solvent, and as cleansing agent. In addition the
pharmaceutical production facility needs water for (thermal)
disinfection or sterilisation and for the preparation of phar-
maceutical quality reagents [6].
Engineering of installations for the storage and distribu-
tion of pharmaceutical water can only be understood with
water. The most important characteristics and the
categorisation of pharmaceutical water, according to the
European Pharmacopoeia, is discussed in Sect. 23.3.1.
The leading principle in storage and distribution of phar-
maceutical water in bulk is continuous circulation in a loop
that includes at least the following:
• Apparatus for the measurement of temperature, conduc-
tivity and TOC (Total Organic Carbon; i.e. the total
carbon load of organic, carbon containing substances)
• A storage vessel
• Filter(s) in the production part of the installation and for
pressure levelling out with air from the outside of the
system
• Apparatus for heating
• Apparatus for cooling
• Taps
• Apparatus for disinfection (only for cold water systems).
See Fig 27.4
Distinct requirements that apply for different qualities of
pharmaceutical water will be discussed below.
27.5.2.1 Purified Water in Bulk
The most commonly used systems for the production of
purified water deliver water with temperatures around
room temperature. Therefore adequate measures have to be

PRODUCTION
tank vent with
air filter UV-lamp (only cold
water systems)

temperature conductivity temperature

conductivity

taps

spray ball

Ozon generator (only

apparatus for water purification level measurement cold water systems) restriction

cold
water
tap

tap
cooler

pre-filter
storage vessel
Softener or RO
drinking water supply apparatus or EDI distiller flowmeter
via non-return valve apparatus or any
and break tank combination of those drain pump

Fig. 27.4 Schematic diagram of water storage and distribution systems. Source Recepteerkunde 2009, #KNMP
598
taken to manage and control total viable aerobic counts
during preparation and storage (see Sect. 23.3.1).
The design capacity should be balanced with the
predicted need per instance, e.g. for the most water consum-
ing activity and the predicted need over time. Involved are
considerations of production time per batch, investment
costs and the time to re-fill the storage vessel. It should be
taken into account that drawing off or flushing out the water
will curtail the ongoing growth of micro-organisms.
During transport through the loop the water passes sev-
eral valves in which biofilm formation may occur (see Sect.
19.3.5). This biofilm can easily extend beyond the valve as
the system for purified water usually is not heated. Therefore
the most critical place in the loop is the point beyond valves,
i.e. where the water runs back into the storage vessel. That is
the right spot for placing critical measurement apparatus in
the loop, such as for temperature and conductivity.
27.5.2.2 Water for Injections in Bulk
The Ph. Eur. specifies that ’water for injections in bulk is
obtained from water that complies with the regulations for
water intended for human consumption or from purified
water by distillation in an apparatus of which the parts in
contact with the water are of neutral glass, quartz or a
suitable metal and which is fitted with an effective device
to prevent the entrainment of droplets.’ So the quality of this
water is essentially defined by the very specific way it is
produced. The reason for this is that there is no reference
water quality to compare.
During production and storage adequate measures should
be taken to monitor and control the total viable count (see
Sect. 19.6.3). This can be measured in freshly tapped water
for injections in bulk (maximum 10 CFU/100 ml). Ph. Eur.
actually gives this value as an action limit, but to control
microbial contamination it is better used as a maximum
value. During production by means of distillation, water
for injections reaches a temperature between 94 and 99  C.
By maintaining high temperatures in the storage vessel and
the loop any growth of micro-organisms is prevented. In this
way the content of endotoxins (see Sects. 19.3.4 and 32.8)
can be kept low (standard: less than 0,25 IU/ml), as well as
the total viable count.
The water for injections limit for conductivity is lower
than that for purified water. At 80  C water for injections
may have a conductivity of maximal 2,7 microSiemens/cm.
Usually only the storage vessel and not the loop is heated.
So during the passage of the loop the water will cool down
gradually. Additionally any inadvertent leakage of a valve
(e.g. the one that provides a washing machine with water for
injections) may impair the quality of the water in the system.
These facts underline the choice of the most critical spot for
all measurements being the place where the water runs back
into the storage vessel.
W. Boeke and P.P.H. Le Brun
27.5.2.3 Design Criteria for the Quality of Water
For the chemical specifications of pharmaceutical water see
Sect. 23.3.1. A sufficient low conductivity, specified in the
Ph. Eur., warrants that any metals, ions and inorganic
contaminants will be practically absent. During the produc-
tion, storage and distribution Water for Injections in bulk is
tested continuously at conductivity, temperature and at TOC
content. TOC can be measured either in-line, involving a
metering sensor that is permanently mounted into the loop,
or off-line, implying periodical measurement in tapped
water samples [7]. Water samples should be tested off-line
periodically on nitrates, aluminium (especially in water
intended for dialysis applications), heavy metals and bacte-
rial endotoxins. Purified water in bulk should be monitored
at the same parameters. The (expensive) TOC assay might
be partly replaced by periodical testing on oxidisable
substances. Bacterial endotoxins in purified water should
be monitored, especially when the water is used in
haemodialysis. In purified water additional monitoring
might be indicated, e.g. of ozone (during and after disinfec-
tion), the hardness of the feeding water and the luminosity of
the UV source (decaying ozone).
Suppliers of equipment usually use American termi-
nology in their documentations, including the term
“sanitisation” referring to disinfection methods that
are known to be effective to sterilisation processes,
however in which (formally defined) sterility as a final
result will not be proven.
27.5.2.4 Measuring Conductivity
Measurement of conductivity during production, storage and
distribution of (highly) purified water and water for
injections is indispensable. One conductivity sensor usually
will be mounted into the pipe that carries the hot, freshly
distilled water from the distiller into the storage vessel.
Usually this sensor is combined with a temperature sensor.
Additionally a conductivity and temperature sensor must be
mounted into the return flow of the loop. This is necessary to
prove that the water that runs back into the vessel still has
adequate quality.
Ph. Eur. extensively describes the procedure for the
measurement of conductivity, the calibration of the
conductivity sensor and the calibration of the system.
The measurement is complicated as there is no refer-
ence for low-level conductivity measurements. When
the off-line conductivity turns out to be too high a
(continued)
27 Premises
second measurement is prescribed after previously
stirring atmospheric carbon dioxide into the water.
When this second measurement still reads too high a
third step is prescribed adding a potassium chloride
solution and measuring pH. Only then a conclusion
can be drawn about the quality of the conductivity
measurement.
27.5.2.5 Total Organic Carbon (TOC)
TOC is an indicator for any existent (decayed) organic
material in the water, often originating from living or dead
micro-organisms. A low TOC (less than 0.5 mg/ml) may be
interpreted as a useful indicator that the water has a proper
microbiological quality [7, 8]. This assay can be performed
easily and immediately before use.
27.5.2.6 Microbiological Quality of Water
Operations, storage and transport methods all can influence
the growth of micro-organisms.
In practice microbiological quality of water is monitored
by action and alert levels. Thus the user will be early notified
about any deviation of critical parameters. For instance
an alert level might be put at a factor 10 below an action
level. To determine these levels a good set of total viable
aerobic counts, endotoxin assay results and TOC assay
results should be available. For the collection of these
results, particularly in the start-up phase very frequent
measurements must be executed.
The development of a biofilm (see Sect. 19.3.5) in the
water production system has to be prevented. The rougher
the surface the easier a biofilm will develop. Nevertheless
even onto polished metal, synthetic materials, glass and in
streaming water it may develop, therefore the micro-
biological quality of the water has to be controlled fre-
quently. In demineralised water the growth proceeds faster
than in distilled water as a consequence of more available
nutrients. As soon as a biofilm causes contamination the
term biofouling is used. The best way to eliminate a once
formed biofilm is mechanical cleaning, which is becoming
more and more common in industry. However, when the
surface is not accessible for mechanical cleaning, other
cleaning methods must be applied, such as flushing with
hot alkaline followed by hot acetic acid or flushing with
concentrated sodium chloride solution followed by hot acid
solution or hot alkaline. The microbiological safety of the
installation thus not only depends on the application of heat
but on the (im-)possibilities to dispose of any formed biofilm
as well. Risky surfaces are demineralisation resin, tubes,
599
transport pipes made of stainless steel or synthetic materials,
the inner side of storage vessels, taps and membranes in
valves.
27.5.2.7 Systems for the Storage
of Pharmaceutical Water
At the design of the pharmaceutical water installation the
capacity of the storage vessel should be determined based on
the maximum daily consumption, the average consumption
and the maximum peak consumption per product batch. The
water consumption by sterilisers and washing / disinfection
machines should also be taken into account.
The higher the peak water consumption, the larger the
storage vessel. If the demand for water has a more steady
character then the vessel can be smaller. In case of a large
vessel the available floor area and its load capacity must be
accounted for. Continuous production implies that one or
more tanks are being filled and drained continuously. Qual-
ity control should take place in a continuous way, completed
with intermittent additional tests. After maintenance and
also periodically the system should be disinfected. The fre-
quency of the disinfection depends on the results of the
process validation [9, 10]. Further specifications of the sys-
tem follow the required water quality. The required storage
temperature also plays a role:
• Cold storage implies storage conditions between 4  C and
10  C at which micro-organisms grow very slowly. Cold
storage renders the system effective and reliable. Disin-
fection occurs only occasionally and can be performed
PRODUCTION
with hot water. Drawbacks are the expense of a cooling
installation and its considerable energy consumption.
Stainless steel, PVDF, polypropylene and polyethylene
cross-linked (PEX) all are suitable as a material for the
storage of purified water at low temperatures. The design
of the vessel should be aimed at the lowest possible total
viable aerobic count. This implies that all surfaces, pipe
holes, valves, etc. should be accessible and made of very
smooth material.
• Storage and distribution at ambient temperatures (15  C -
30  C) is reasonably effective and reliable and the invest-
ment and operation is comparatively cheap. However the
risk of building up a biofilm is substantial. Therefore,
non-cooled storage systems should be disinfected fre-
quently by flushing with hot water or by adding ozone.
Materials for loop and storage vessel are similar as for
cold storage [9, 10] however the method of disinfecting
can limit the choice. More aggressive methods such as
treatment with steam are preferable, but require expen-
sive materials such as stainless steel.
• Hot storage and distribution means storage and distribu-
tion at a temperature continuously kept over 70  C [1]. In
600 W. Boeke and P.P.H. Le Brun

practice an ample safety margin is implemented and

usually the actual storage and distribution temperature is Only during tapping the heat exchanger is temporarily
well above 85  C. Hot storage is the most effective and flushed with cold water, locally chilling the pharma-
reliable way to prevent growth of micro-organisms. With ceutical water. Only a very limited amount of the
the aid of well mounted isolation material in the heating chilled pharmaceutical water will return to the loop
mantle a storage vessel can be kept at high temperature at by means of mounting a so-called restriction disc just
low expense. The loop piping should also, preferably, be before the junction. So chilled product water will
insulated. Taps should be placed at short distances from hardly mix with the main stream in the loop. When
the loop. Before use the tap has to be flushed with hot no chilled water is tapped sufficient water will pass the
water. Hot storage involves relative high investment costs heat exchanger, the tap valve and the restriction disc to
and moderate running costs. It introduces a specific risk maintain this part of the loop at the required
of rouging. Hot storage does not diminish the content of temperature.
endotoxins. The distribution loop can be combined with
taps equipped with sanitary coolers to deliver the phar-
maceutical water at ambient temperature.
The water level in the storage vessel has to be controlled
continuously, preferably with the aid of a building control
Rouging
system (see Sect. 27.5.5). Thus a low level signals to restart
At sustained exposure to very pure hot water or steam
the production, however a very low level should produce an
a thin red, reddish brown, orange, light blue or black
alarm signal shutting down the complete installation to pre-
deposit (tarnish) might built up. This is seen particu-
vent, among other things, the circulation pump running dry.
larly at less polished spots, e.g. burrs, scratches, sharp
A high level will stop the production and an extra high level
edges, material transition areas or bad welds and is
should give an alarm signal to alert the risk of overflow
called rouging. In fact rouging is an oxidation process.
through the vent filter.
When metal ions in micro-caves dissolve into the
The storage vessel and the loop for water for injections is
water potential differences might occur at a micro-
preferably made of stainless steel AISI 316 L and polished to
scopic scale leading to hydrolysis and oxidation. The
a roughness grade of 0.4-0.6 μm mean pore diameter [9,
coloured material consists of iron oxide, iron carbon-
10]. The water should return from the loop into the vessel
ate or iron hydroxide or any combination of these.
through a (rotating) spray ball. By this means the empty
Rouging itself doesn’t yield any immediate hazard.
upper part of the vessel will be kept hot and germ free. The
However once rouging has been built up it might
vessel or at least the lowest point in the loop should be
expand and eventually lead to development of rust in
equipped with a sanitary bottom valve ensuring that after
which case the smoothness of the texture is affected
complete draining (e.g. for maintenance purpose) no tainting
and the risk of biofilm formation increases. Therefore,
water will stay behind in the system [10].
highly polished stainless steel constitutes a barrier
both against rouging and biofilm formation. Removal
of rouging is a very expensive process involving Tank Vent
experts [10, 11]. A level control system can only be used if the system
has been designed according to GMP. Tapping of
water from the storage vessel will lower the level in
the tank. The sucked-in air entering the vessel has to
be filtered through a 0.2 μm hydrophobic membrane
filter that can be tested and which should be mounted
Tap for Cooled Water in a stainless steel casing onto the vessel. A pressure
A tap cooler mounted into a hot distribution loop safety provision is mounted to safeguard against any
requires a special design. The loop and the storage possible overpressure in the vessel. The filter has to be
vessel must be kept at high temperature while no replaced at least once yearly as a preventive measure.
long branches filled with stationary (colder) water During the hot storage of pharmaceutical water the
can be accepted. Therefore the loop splits near the filter also has to be kept at a high temperature to
cold tap into two parallel pipes both continuously prevent the occurrence of condensate. This condensate
being flushed with the hot pharmaceutical water. In would provide an ideal substrate for micro-organisms
one of the two branches a heat exchanger is mounted. which might grow through the filter.

(continued)
27 Premises
27.5.2.8 Maintenance and Disinfecting Water
Storage and Distribution Systems
Biofilm will emerge especially fast on ion exchange resins,
Reversed Osmosis (RO) -membranes and piping made of
stainless steel or plastics. Therefore, systems for pharmaceu-
tical water should not contain stationary water and should be
disinfected at start-up and after each maintenance process.
Even systems for the preliminary treatment of feed water
have to be constructed as a recirculating system [10].
Cold water systems usually cannot be steamed. Instead
chemical disinfection or disinfection using ozone is custom-
ary. An important benefit of ozone treatment compared to
other chemical methods is that it can be executed
automatically.
Frequent hot water disinfection is a good alternative as a
preventive measure, provided that all materials are sufficient
heat-resistant. It is carried out at a temperature of 90–95  C
during at least 2 h of exposure. This process must be
validated [10]. The problems to remove a once formed
biofilm is discussed above in Sect. 27.5.2.6.
RO membranes may not be exposed to ozone. The pro-
ducer of the membrane should indicate how to treat and
disinfect it in a correct way.
27.5.2.9 Chemical Disinfection
If the equipment is provided with adequate connection
systems a chemical disinfection is possible. Commonly a
solution of hydrogen peroxide and per-acetic acid is diluted
to 8-10 % and then flushed through the equipment. The
system must be thoroughly rinsed afterwards.. The method
is quite effective, however it involves the additional efforts
of purchasing, storage and handling of the disinfecting
agent.
27.5.2.10 Ozonisation
Ozonisation is a specific means of chemical disinfection as
the active agent (ozone) is generated in the equipment itself.
Ozone is used for the periodical disinfection of pharmaceu-
tical water installations when disinfection by steaming or
with hot water is not possible. Ozone is a strong oxidising
agent and kills micro-organisms in water. To obtain suffi-
cient disinfecting power ozone should be present in the
water for a sufficient time and in an adequate concentration,
according to the guidance of the producer of the ozonisation
apparatus. Concentrations with a maximum of 10-50 ppm
(sometimes even less) are most common. The ozone genera-
tor that is mounted in the loop produces the ozone gas.
However after ozonisation the utilised pharmaceutical
water must be freed of ozone again. Therefore, UV lamps
are included in the loop at a spot that is transparent to UV
light. UV light of 254 nm degrades ozone turning it into
oxygen. Thus quality control of the lamp is necessary; it
601
usually consists of continuously monitoring the intensity of
the UV light. An alarm signal should indicate when the lamp
has to be replaced [9, 10].
27.5.2.11 UV-light for Germ Reduction
UV-light with a wavelength of 200–300 nm not only
degrades ozone but also reduces the total viable aerobic
count in pharmaceutical water, especially in systems with
cold storage and distribution. UV-light disrupts the DNA of
micro-organisms and thus obstructs their growth. Irradiation
with UV-light is not intended to replace any disinfection
method. The effectiveness of the irradiation process depends
on water quality, light intensity, flow rate of the water,
duration of the irradiation and the identity of the micro-
organisms in the water and thus is difficult to validate
[9, 11].
27.5.2.12 Clean Steam
Only the USP includes a monograph for pure steam [12],
also called clean steam. Clean steam is obtained from
purified water heated over 100  C and brought into the
vaporised phase in such a way that no drops of feeding
water are carried over. In any situation where steam or
steam condensate might stay in immediate contact with
critical, product affecting surfaces, clean steam must be
utilised. An example is the interior surface of a filling appa-
ratus. Technical steam is steam generated at some central
location in the building. The quality is defined with pressure
and temperature. Clean steam may be utilised during prepa-
ration, in steam sterilisation and during controlled steaming
PRODUCTION
of installation as a sterilisation method after cleaning [13].
Quality control of clean steam is carried out on its con-
densate. Additional requirements are in force when the
steam is utilised for sterilisation (see Sect. 30.5.1).
27.5.2.13 Transport Systems for Pharmaceutical
Water
A system for transport or distribution of pharmaceutical
water should meet at least four requirements:
• It should deliver water that meets all quality requirements
(see Sect. 23.3.1).
• The water should always flow at the required flow rate,
especially at the instance of drawing off.
• The water should be delivered at the temperature required
for the process at hand.
• The system should function at acceptable investment and
running costs.
27.5.2.14 Piping
By means of a sanitary pump and a flow rate meter showing
the flow rate, the water circulates in a loop through a sanitary
(hygienic, well-disinfectable) piping system. Unused water
602
runs back into the storage vessel. Micro-organisms, corro-
sion, (hidden) construction flaws and aging can all affect the
loop system. The loop should not contain any branches in
which water is stationary. For this purpose specific calcula-
tion schemes exist. Generally the length of any branch in the
loop never should exceed 6D (diameter of the loop pipe)
but in practice 3D or even 2D is to be preferred. Also
purified water as feeding water for a distiller installation
should recirculate when nothing is drawn off.
The support and mounting of the piping should be
constructed in such a way that no sagging occurs, a risk
that is more prominent with synthetic materials at higher
temperatures than with stainless steel. Preferably the piping
is mounted at a slight slope with the bottom valve at its
lowest point. The usual angle of the slope of horizontal
piping at short distances is advised at 2 % and at 0,5-1 %
for greater lengths.
Joints must never be mounted at a residual strain because
that could cause leakages, which can lead to considerable
damage. The support system for the piping must not cause
any galvanic corrosion. The distribution system must be
immune to ozone or the heat of steam. It has to resist a
specified water pressure and turbulence as well. The interior
of the piping should have a surface as smooth as possible to
prevent corrosion and formation of a biofilm. Stainless steel
piping must be polished at the inside for this reason. Piping
of synthetic materials used for the distribution of pharma-
ceutical water are smooth plastics like PVDF, polypropylene
or PEX. The piping may not release any substances or
(metal) ions and should be corrosion resistant [9, 10].
Welding, Mordanting and Passivation
Stainless steel contains chrome that generates a tarnish
of chrome dioxide, which protects against rust. How-
ever over time some form of corrosion will develop;
totally non-rusting steel does not exist.
The installer should weld the piping work orbitally.
Orbital welding is the partly automated method of
welding highly alloyed steel pipes together using a
tungsten electrode under inertial gas, also indicated
as TIG-welding (tungsten inert gas). By this method
a very smooth weld develops. Subsequently the instal-
lation must be cleaned, mordanted, passivised and
finally be flushed and steamed. Cleaning after welding
is done by flushing with caustic detergents and water.
Mordanting implies that the corrosion resistant tarnish
is removed temporarily using strong acids (chromic
acid or strong nitric acid). Immediately thereafter the
reactive metal alloy is passivised by oxidising in the
air. Passivation is also executed by flushing with
(continued)
W. Boeke and P.P.H. Le Brun
oxygen-rich water, diluted nitric acid or oxalic acid.
When all residues of acid are flushed away with water
for injections the installation can be steamed and put
into operation.
The welds in a stainless steel loop never should
corrode, leak or become a source of rouging or biofilm.
Welding work therefore should be inspected closely
and be thoroughly documented. Specialised instruments
are being used for this purpose. The welder must be
qualified. All handmade welds should be fully con-
trolled; in orbital welded pipework usually 20–30 %
of the welds are tested.
Other, also demountable, fittings between pipes and
installations are of the type clamp, flange or screw
fitting.
For transport of water for haemodialysis and
purified water, plastics may be used for the tubing.
However for these materials it is also required that
connections are meticulously welded, inspected,
documented and cleaned. The use of glues (e.g. the
glue to join classical grey plastic, PVC, tubes for
non-pharmaceutical use) introduces an unacceptable
uncertainty because residues of the glue and solvents
may contaminate the water. Analysis of this kind of
contaminants preceding the formal acceptance of the
system is not a realistic option [9, 10].
For pharmaceutical water guidelines of, among
others, FDA and DIN 11864 apply for these kind of
fittings. Anyhow, the number of fittings should be kept
as low as possible.
27.5.2.15 Pump
A circulation pump should have a highly polished finish and
should be well cleanable. It must resist any disinfecting
process, preferably steaming. Also the pump must allow
complete drainage. The latter implies that no water residue
must stay behind when the complete loop is drained during
maintenance.
The pump should be able to generate a flow rate of
1–2,5 m per second in the loop, still achieving an acceptable
water pressure. The pressure depends also on the loop resis-
tance. Usually a restriction disk mounted in the loop serves
to prevent a major pressure drop when water is withdrawn by
opening a tap. The flow rate causes the flow to be turbulent
and thus prevents the risk at (almost) stationary water
e.g. near valves and other small bulges in the loop. After
all, any stationary water would substantially increase the risk
of building up biofilm [9, 10].
27 Premises
27.5.2.16 Tapping Points
Membrane valves must be completely drainable and
disinfectable, preferably by steam. The membrane made of
plastic should be replaced 1–2 x per year. Sometimes globe
valves are used to shut off steam pipes, because they are
more wear-resistant.
A sufficient number of sample tapping points should be
available. The tapping of water during any dysfunction
(e.g. deviation of temperature, deviation of conductivity or
low level) of the water installation must be prevented. This
can be done by automatically blocking all tapping points at
the basis of any alarm signal originating from the installation
[9, 10].
27.5.2.17 Responsibility for the Validation
and Qualification of Water Systems
The validation of this equipment has to account for its built-
in status. Therefore the validation plan already has to be part
of the design and realisation phase of the installation.
The person responsible for the water quality to be used in
pharmaceutical preparations usually is the pharmacist who is
also responsible for the preparation processes. This person is
accountable for all procurement, validations, qualifications,
maintenance, deviations and changes of the installation(s).
He should always be fully informed about all those aspects.
This also applies when the water preparation installation is
installed outside of the premises of the pharmacy e.g. in the
premises of the technical services or any laboratory [11].
27.5.3 Provisions for Pressurised Air, Vacuum
and Various Gasses
27.5.3.1 Gasses and Pressurised Air
Medical gasses (including medical air) are gasses that as
such are used in the treatment of patients. Medical gasses
administered to patients are medicines [13], see also Sect.
23.13.
Gasses used in production processes are called pharma-
ceutical gasses. They are applied as:
• Gasses that are immediately immersed into the interme-
diate medicinal product, e.g. nitrogen as a means to dispel
oxygen from aqueous solutions or pressurised air to carry
over fluids.
• Gasses that are necessary at the preparation or filling
process, but are not directly in contact with the product,
e.g. natural gas and oxygen for opening and sealing of
ampoules.
• Gasses used for pharmaceutical analyses, such as acety-
lene for atomic absorption spectrophotometry and helium
for gas chromatography.
• Gasses (usually pressurised air) for technical purposes
such as pneumatic operation of installations.
603
Requirements depend on the use and therefore may differ
from those to medical gasses. Gasses that are in direct
contact with the (end-) product should meet the requirements
derived from the product itself.
The requirements for medical gasses may differ from
those for pharmaceutical gasses. As an example,
requirements to safeguard continuous availability
carry more weight with the clinical process of artificial
respiration than with a pharmaceutical application.
But the chemical purity of e.g. nitrogen used for filling
ampoules will be more important in pharmaceutical
than in medical applications. Purity has to be backed
by traceability of the origin. Certain suppliers there-
fore provide cylinders with designations such as ‘trace
pharma’.
The requirements for gasses can be:
• Technical (capacity, pressure, availability)
• Chemical (content assay, contaminants, moist content)
• Physical (absence of particles and oil)
• Microbiological
A low moisture content (dew point) in a gas under pressure is
most important because at expansion moist could lead to
condensation, which would enable micro-organisms to grow
[9, 13].
27.5.3.2 Vacuum
PRODUCTION
A vacuum installation may have impact at the final product,
e.g. when vacuum is used to prevent air being beaten into a
viscous mass or to remove air from it. A choice has to be
made between a central installation and a local one such as a
water jet pump or an electrical vacuum pump. At a centrally
placed installation a provision has to prevent the pressure
inside the tubes rising above a predefined value. Otherwise
contaminated air could enter a negative pressure room if the
pump were to break down.
27.5.4 Electrical and ICT Provisions
At the design of preparation premises the availability of
electrical and ICT provisions should be well considered in
advance. Sufficient data and electrical sockets should be
provided in walls and at worktops.
Keyboards and mouses should easily be cleaned and
disinfected and therefore must be chemically resistant. The
casings of the computers should be installed in such a way
that accumulation of dust is diminished, for the protection of
the computer as well as the pharmaceutical product. The air
in classified rooms will hardly carry any dust, but
604
nevertheless the casing should be opened at least once a year
to remove any dust. The casing should also being placed as
far from the critical places as possible, if possible outside of
the room. Wireless tablets may circumvent all difficulties
with cables and fans. Cleaning and disinfecting of worktops
is much easier when cables are tucked in cable ducts or
under the worktop.
For each apparatus or installation it should be considered
whether it has to be provided with emergency power supply
or preferential power supply. Therefore, the risks of any
short or longer lasting power cut should be analysed in
advance. Especially the consequences of any disturbance
of air pressures and the breakdown of exhaust installations
must be considered.
27.5.5 Building Control Systems
Apart from the pharmaceutical installations, already men-
tioned in this chapter, buildings are generally equipped with
heating and cooling equipment, fire prevention equipment,
burglar security systems, personal access control, sun blinds,
elevators, sewage pumps, etc.
So altogether the building incorporates a vast multitude
of technical systems, several of them influencing each other.
This might raise a need for an overall monitoring and control
system.
Usually control and monitoring are integrated in one
system providing a central point from which the functioning
of all systems can be monitored, registered and adjusted.
Furthermore, failure alarm signals are channelled through
the building monitoring system.
When pharmaceutically critical systems (refrigerators,
HVAC systems, purified water systems, etc.) are to be mon-
itored by a building monitor system it has to be independent
from more general systems in the building and its validity
has to be assessed in advance. Additionally systems for the
registration of measurements must be independent of
systems that operate the installations and all installations
(i.e. their sensors, adjustment tuners and alarm signals)
must be fit to be connected to the building control system.
All possible alarm signals have to be listed and
documented regarding alert- and action levels, hysteresis
(to prevent them from switching on and off continuously at
a non-stable parameter) and timeliness (providing short-
termed deviations without unnecessary alarms or providing
a reaction time before exciting the alarm). A scheme of
procedures has to be defined to be followed after any alarm
is triggered. The follow-up instruction after any alarm
should include an indication about its urgency, e.g. if imme-
diate action is obligatory when the alarm occurs in the night
or in the weekend. No alarm signal should be overruled,
covered up or left invisible in case of concurrent triggering
W. Boeke and P.P.H. Le Brun
of independent alarms. Also rules have to be implemented
regarding the procedure for the resetting of any alarm and for
the documentation of its actual follow-up.
27.6 Detail Specification and Building
The documenting of the functional specification (FRS) of a
preparation facility is followed by the detail specification
(DS) or tendering specifications. A subtle difference between
DS and tendering specifications is that the latter will be
drafted for the purpose of contracting-out. However the DS
is primarily aimed at verifiability during the IQ phase. Usu-
ally just one document will serve both functions. In this
document choices are made (usually a professional advisor
does the job) for floor and wall covering, ceiling materials,
etc. The HVAC installation will now be specified in full
detail, communication means are specified and detailed
building and arrangement maps are drafted and updated.
The choices must comply with the FRS, which in turn
must comply with the URS. Therefore each choice should be
well documented and justified at this basis.
What should be attended to in the assessment of the DS?
In premises intended for sterile and aseptic preparations
(clean rooms) the most severe requirements apply to the
walls, doors, floors, ceilings, heating and furniture, see fur-
ther subsections. Premises which are only intended for
non-sterile preparations can do with less far-reaching
demands. Nevertheless in practice it might be wise to
apply the requirements for sterile premises also for
non-sterile premises if both are at stake. In the first place in
a new building the itemisation of methods and materials
between premises meant for sterile preparation and for
non-sterile preparation usually doesn’t yield much cost
reduction. Additionally many of the starting points for the
requirements for sterile preparations more or less apply to
’non-sterile’.
27.6.1 Inner and Outer Walls
Where premises for preparation are adjacent to any outer
wall a specific problem emerges. Constructional walls, also
outer walls, never will be completely airtight. In case of
wind pressure always air from outside will influx, bringing
pollen (in spring), mould spores (in autumn) and fine partic-
ulate dust (in winter). This can only be prevented by building
a double wall system, i.e. by complete separation of the
preparation premises from all outer walls (so-called box-in-
box principle) which is usually accomplished by building a
gallery corridor. If this is no option, then at least a separate
secondary glazing is necessary in the windows of outer walls
to level out any wind pressure. Such a secondary glazing
27 Premises 605

At places where damage could occur the wall should usually as a metal corner bracket or metal u-moulding,
be made of impact-proof and scratch-proof material, which must be protected against rust. This again
e.g. melamine resin sheet material like Trespa®. At requires early planning of the right layout of any
other places, e.g. above breast height, cheaper gypsum suspended cupboards, worktops, etc.
board walls can be used, provided that they are treated
with a specific water-resistant coating that can also
resist the chemicals used for cleaning and disinfecting.
Seams, e.g. at places where fixed cupboards are
concrete floor
placed against the wall, should be closed with a well-
chosen acid-resistant joint sealant. Any seam should
have a width between 2 and 4 mm to safeguard that the
sealant will stick firmly into the joint. Wall connectors profile
for electricity and ICT provisions must not give entry for
compression
contaminated air or vermin. Therefore the interior sup- ribbon
ply pipes should be made airtight with sealant. In prac- coating
tice usually a hollow wall modular construction is used gypsum
for clean room building (‘Metal Stud’, see Figure 27.5) double board
with all pipework and tubes sealed within the wall. version
All pipework and tubes (electricity, water, gasses,
air ducts, etc.) should be documented by photographs
25 12,5
before the wall is finally closed during construction.
Those pictures can demonstrate later that the finished 45
construction indeed does correspond with the as-built
drawings. As-built drawings are the drawings that 82,5
exactly represent the finally built constructive reality.
At places where the wall should be loaded with objects
to be mounted, the constructor should apply back Fig 27.5 Metal Stud wall. Source: Recepteerkunde 2009,
styles. These are fortifications introduced in the wall, #KNMP

PRODUCTION
(continued)

introduces a wasted space between the inner glazing and the
outer one, in which at some time vermin will emerge.
Cleaning might be facilitated by having the outer glazing
accessible from the outside.
27.6.1.1 Inner Walls
A requirement for premises for sterile preparations (clean
rooms) is that walls are free from any ledges and seams to
enable effective cleaning and disinfection. The provision of
ample glazing for supervision and well-being of personnel
should be considered. The ledge free and seamless mounting
of windows and doors into walls is known as ’flush fitting’.
In order to adequately flush the room with clean air the
exhaust should not be positioned near the inlet grids in the
ceiling. Special inlet grids (diffusers) should generate turbu-
lent airflow. In air class B exhaust at floor level is mostly
preferred. A hollow wall construction offers the possibility
of incorporating air ducts (exhaust channels) within the wall.
These may make, however, other provisions on that particu-
lar part of the wall impossible.
Light switches, as being touched by many persons, can be
best placed outside of the room e.g. at the entrance to
personnel gowning locks. In that way an important source
of cross contamination is ruled out.
If carrying in or out large apparatus must be possible, a
demountable, resealable, partition in the wall should be
considered.
27.6.2 Doors
Doors in clean rooms must be flush mounted, smooth, clean-
able, if necessary disinfectable and as far as possible seam-
less. This especially goes for doors in GMP classified
premises as indicated in Sect. 27.4.2. Points of special inter-
est are:
• Air leakage through chinks between doorframe or thresh-
old and a shut door will render the air pressure within the
room out of control and it may raise an annoying wheezing
noise. Therefore, doors should close firmly and not warp.
606
Fig. 27.6 Dropseal. Source
Recepteerkunde 2009, #KNMP
• Air leakage by the bottom of the shut door may be
prevented by implementing dropseals mounted within
the bottom part of the door (see Fig. 27.6). A pawl at
the hinge side actuates a lever mechanism at shutting the
door. This mechanism pushes a rubber strip against the
floor. At the opening of the door a spring mechanism
pulls the strip back up again into its casing.
• Doors should never shut against the air pressure, as the
higher air pressure behind the door may raise leakages. If
the preferred turning direction is not feasible, e.g. in case
of an emergency route from a positive pressure room, the
door should seal on all sides, including top and bottom,
into a soft rubber groove. In some cases the preferred
turning direction of a door based on function is opposite
to the preferred turning direction based on air pressure
hierarchy. A sliding door may solve that problem,
provided that it is equipped with an effective push mech-
anism when shut and is well cleanable.
27.6.3 Floors
Floors must be easily cleaned and disinfected. Drains should
be avoided, as these are important sources of contamination.
If a drain is unavoidable because the equipment demands it,
it should be equipped with a sanitary valve, preferably a type
that closes automatically when the connected equipment is
shut down. Such a drain requires a well-documented disin-
fection procedure.
Floors should be practically seamless because seams can
easily become filthy. However each type of floor covering
will come with seams and dilatation joints are necessary to
allow for any shrinkage or dilatation, also in clean rooms. At
least any seams and dilatation joints must be avoided near
the most critical places.
W. Boeke and P.P.H. Le Brun
Floor Covering Materials
The choice for floor covering materials depends on the
kind of activities. As an example, in a preparation
room where iodine or organic solvents will be
processed, the floor should be chemically resistant in
the first place. When processing inflammable products
the generation of sparks due to static electricity has to
be prevented. For aseptic handling chemical resistance
of course is much less important. The primary empha-
sis for a floor in a premise for handling radiopharma-
ceuticals or other very hazardous substances, is on
suitability for thorough and effective decontamination
and disinfection.
A synthetic floor covering, e.g. like marmoleum or
a good quality of vinyl, laid in strips or tiles and sealed
with synthetic laces is a quite frequently used material.
As an alternative a floor made of epoxy resin (a
so-called cast floor) can be considered, with its
advantages of high load bearing capacity, smooth sur-
face and absence of seams. A drawback is its slipperi-
ness, especially if wet there is a risk of skidding.
Additionally it is very critical to have the cast floor
applied completely free of dust or dirt.
The floor covering material preferably should butt
to the walls by means of a hollow skirting. Fitted
furniture that is not mounted hovering over the floor
should be placed upon pre-mounted dado’s, after
which the floor covering can be installed with a hollow
skirting against the dado.
27.6.4 Ceilings
Ceilings are preferably completely closed, i.e. manufactured
from fixed mounted, smooth and cleanable sheets.
Pipework should be tucked away behind the ceiling,
because otherwise dust builds up. If possible pipes or
tubes transporting water should be avoided at the top of
any preparation premise because leakage would have disas-
trous consequences. This is in regard not only to pipes
transporting pharmaceutical water but also to the sewer
system, rainwater drains, condensate drains and steam
pipes. The possibility of the occurrence of condensate on
cold water pipes during warm weather should also be con-
sidered. If the pipes cannot be avoided, any leaking water
should drain off by a gutter. Regular maintenance of the
pipework and timely replacement of gaskets will be neces-
sary as well.
27 Premises
System Ceilings or Closed Ceilings
A lowered, so-called system ceiling can be used, how-
ever it has several snags: the joining to the walls
usually results in a right angled corner that is difficult
to clean. Additionally the system sheets, lying rather
loosely within the frame, can easily snap open, espe-
cially when air pressure jolts occur at the opening or
closure of doors. If that occurs unpredictable amounts
of dust and dirt will enter the room. Even special clips
to fix the ceiling tiles cannot prevent this completely,
as after maintenance work those clips are frequently
not replaced. Sealed ceilings are free of those
drawbacks and they force the designer of the building
to create an alternative entry to the space above the
ceiling. This entry will not come from the preparation
room, but by means of an admission hatch e.g. from a
neighbouring gallery corridor or by means of a trap-
door from an upper storey. The benefit of this is that
maintenance or repair work, e.g. at pipework or the
replacement of lamps, situated behind the ceiling, can
be executed without entering the premise itself. If
completely sealed ceilings are not feasible in all
rooms entrance to the space above the ceiling from
gowning rooms or connection corridors are preferred;
the ceiling should never be entered from the prepara-
tion room itself.
Light fittings do easily attract dust as a consequence of
their static electricity. Therefore they should be incorporated
in the ceiling and be shut off by means of a glazed or
transparent synthetic sheet. In classified premises no sub-
stantial air leakage must occur past the fitting.
27.6.5 Heating
The cleaning of heating radiators is very laborious and not
very feasible in practice. Therefore, they are unsuitable for
pharmaceutical preparation premises. If they nevertheless
cannot be avoided, sheet radiators mounted at sufficient
distance from the wall to allow effective cleaning, are to
be preferred. However, in GMP classified premises as meant
in Sect. 27.4.2 even sheet radiators are absolutely undesir-
able. Heating and cooling in that case should be achieved by
means of the ventilation system (see Sect. 27.5.1).
In using air for heating, attention should be paid to the
type of inlet grid. In a well-designed preparation premise a
high ventilation factor will prevail. If not a specific whirl
grid is mounted draught will occur. This is not only annoying
for those working within the premise, it also may lead to
inadvertent displacement of weighed portions of active
607
substances. The flow pattern in a safety cabinet can easily
be disturbed by an incorrectly placed or ill-chosen air inlet
grid in the ceiling [5].
27.6.6 Furniture
The upper side of cupboards should join to the ceiling, or
alternatively a slant finishing should connect the upper side
to the ceiling. Personnel should not be able to place objects
on top of a cupboard. As far as cupboards are made from
wood, plywood or chipboard these parts should be laminated
on all sides, e.g. also at the backside of shelves. Holes to
adjust shelves in height should be filled up. ‘Open’ wood or
chipboard may release spores. Workbenches should prefera-
bly hover or be attached to the wall. Floors under worktops
must be well accessible for cleaning. Fixed furniture prefer-
ably should be placed upon pre-mounted dado’s.
Refrigerators and freezers within the preparation premise
are unwanted for several reasons such as that the expansion
radiator at their backside cannot be cleaned. If a refrigerator
or freezer in the preparation premise is indispensable it
should be airtight separated from the room, e.g. by means
of a flat shaft of sheets up to the ceiling or a throughput
through the wall.
Chairs should not possess seats made of wood or covered
with textile. The undercarriage should be easily cleanable.
PRODUCTION
27.7 The Implementation Phase of Building
or Rebuilding
During the execution phase of newly built or rebuilt phar-
maceutical premises (including clean rooms) the building
control department should take a few particularities into
account. The ISO 14644-4 standard [4] specifies those
particularities for clean rooms.
• Verification of matters that cannot be demonstrated after
implementation. Design drawings should be continuously
updated such as to be finally correct ’as-built’ drawings.
Pictures of the inner part of hollow walls can support the
verification process. The sealing of any pipe holes or
cutaways must be checked systematically.
• Special attention should be paid to prevent the fouling of
air channels during their mounting. Air channel
components must be supplied clean and closed on both
ends. Partly mounted air ducts again must be shut at the
open end to keep them clean inside. The building area
should be swept clean daily.
• Eating, drinking and smoking in the building area has to
be forbidden and this ban should be enforced strictly to
prevent that any organic material (like bread or tobacco
608
crumbs) are left in hollow walls, under or behind
cupboards or in air channels.
As a consequence of its high costs the execution phase of
a building usually is very tight. Especially in the end phase
this can result in working against the clock. A common
completion process assumes the premises to be put into
operation immediately after completion, accepting the doc-
umentation of a few residual points that will be settled later,
in practice already during operation. For clean rooms this is
not possible. The starting-up procedure involves many steps
that must be planned well in advance and are described in a
Validation Plan. This plan encompasses general examina-
tion, qualification and validation. During examination the
as-built premises are checked against the detail specification
(DS). In addition some of the specifications will be checked
that are described in the FRS and even the URS e.g. the
smoothness of the walls. The control of all these
specifications is also called as-built verification. If all
specifications are met the premises and built-in equipment
is qualified. Next all systems such as HVAC are put in use
and checked for their proper operation and safety. The air
balance is adjusted. Calibration of e.g. pressure difference
meters is performed. This phase is also called commission-
ing and is usually executed by the contractor.
All deficiencies found during commissioning have to be
solved. The premises and installations are cleaned and sub-
sequently the validation can start based on procedures
approved by the owner, usually the pharmacist. Validation
has several standard structures with the main subjects: IQ,
OQ and PQ (Sect. 34.10). Validation is a formal GMP
requirement.
In case of a (new) building with installations the IQ and
OQ phase comprises a verification of the checks done during
the as-built verification and the commissioning including the
check of all GMP critical aspects. It is not necessary to
repeat all tests of the commissioning. Some additional tests
are done such as challenging critical limits of documented
functional specifications in practice and adjusting them if
necessary, provided that they still comply with the FRS.
Also the documentation is completed such as manuals,
cleaning, disinfecting and maintenance procedures,
instructions, a monitoring program. Microbiological (con-
tact) samples (see Sect. 31.6) are taken, recovery time of the
W. Boeke and P.P.H. Le Brun
rooms after disturbance is checked, viable and non-viable
particles are counted, temperature- and humidity are
measured, etc.
The IQ and OQ are usually executed by the contractor in
cooperation with the customer. When this phase is
completed, the work is delivered up to the customer and
accepted. Then the performance qualification (PQ) is
executed by the customer. In this phase it will be proven
that the premises will work as they were meant to be work-
ing as defined in the URS. Installations will function and
classifications of the rooms are met (see Sect. 34.15).
The validation requires time and manpower. For a small
scale preparation facility a time frame of 3 to 6 month is not
uncommon. It is quite obvious that the start-up process to
operational status of preparation premises will never allow
time for any delayed activity for a constructive residual point
such as the mounting of another light fitting afterwards.
Planning in advance is paramount.
References
1. PIC/S Guide to Good Practice for the Preparation of Medicinal
Products in Health Care Establishments. PE 010–3, 2008
2. NEN-EN-ISO 14644 Cleanrooms and associate controlled
environments; parts 1, 2, 4, 5 and 7
3. NEN-EN-ISO 14698 Cleanrooms and associated controlled
environments - Biocontamination control; parts 1 and 2
4. NEN-EN-ISO 14644-4:2001(E) Cleanrooms and associate con-
trolled environments part 4: Design, construction and start-up
5. NEN-EN-ISO 14644-5:2004(E): Cleanrooms and associate con-
trolled environments; part 5: Operations
6. Note for Guidance on quality of water for Pharmaceutical use.
EMEA 2002
7. Bader K, Hyde J, Watler P, Lane A (2009) Online Total Organic
Carbon (TOC) as a process analytical technology for cleaning
validation risk management. Pharm Eng 29(1):8–21
8. Collentro WV (2007) Pharmaceutical water, system design, opera-
tion and validation. Informa Healthcare, Richmond
9. ISPE Water and Steam Systems; Baseline guide. ISPE, 2001
10. Mathiesen T, Rau J, Frantsen JE, Terävä J, Björnstedt P-A, Henkel
B (2002) Using exposure tests to examine rouging of stainless steel.
Pharm Eng 22(4):90–97
11. ISPE Good Practice Guide: Commissioning and Qualification of
Pharmaceutical Water and Steam Systems. ISPE, 2007
12. Pure Steam (2014) USP Unites States Pharmacopoeia 27:5176
13. NEN-EN-ISO 7396-1:2007(E) Medical gas pipeline systems – part
1: Pipeline systems for compressed medical gases and vacuum