Printed by: Date: 10.10.

2014 GMP MANUAL © Maas & Peither AG

3.A Official Requirements
Up08 Dr. Michael Hiob, Dr. Ralph Gomez

Here you will find answers to the following questions:

● What are the general requirements operating rooms have to comply with?
● Which official requirements must be observed when designing rooms in accordance with the EU GMP Guide and the U.S. cGMP regulations?
● What do the terms “layout” and “room book” mean and what is their purpose?

“Premises and manufacturing equipment shall be located, designed, constructed, adapted and maintained to suit the intended operations.“
(EC Directive 2003/94/EC, Article 8.1, see Chapter C.2).
“… buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate
cleaning, maintenance, and proper operations. Any such building shall have adequate space for the orderly placement of equipment and materials to
prevent mix-ups … and to prevent contamination.”
(21 CFR Sec. 211.42 (a) (b), see Chapter D.1.2).
Premises and equipment are the basic technical components of pharmaceutical production. From the GMP standpoint they have a great significance,
being in contact with pharmaceutical products from the raw material stage through to the finished product.
The design of rooms is crucial to the quality of the pharmaceutical products and also relates to the cost effectiveness of production – both directly
(investment costs) and indirectly (e.g. flow of materials). The construction, dimensions and layout of operating rooms contribute to the assurance that
operations can be carried out adequately regardless of type, size, number, location and facility, particularly with respect to the faultless production,
analysis, storage, packaging and distribution of medicinal products. The requirements for the design of the operating rooms depend on the type and
scope of the production processes they are used for. As a basic rule, the lighting, temperature, humidity and ventilation (see Chapter 3.A.4 Lighting,
ventilation, air-conditioning) must be suitable for the relevant production step, and must not have a negative impact on the quality of the products or
operability of the facilities and equipment. Lighting is particularly important in areas where visual checks must be carried out during the course of
production. Essentially, the rooms should be built of such high quality as necessary for the product quality and as simply and economically as possible.
However, as important as controlling cost is, one must be careful not to hold back on necessary quality in favor of lower costs.
Decreasing on quality very well may cost much more in the long run since it may lead to incidents of product reworks, rejections and, in the extreme
case, recalls. More information on design aspects is given in Chapter 3.D Construction elements.
A room inside a pharmaceutical production building performs the same kinds of tasks as a cell in an organism. Essentially, while performing the function
of an envelope in which an individual processing step takes place – by isolating it from other processing steps that are running at the same time – it
must also perform a range of other tasks:
● the supply of energy and utilities for the manufacturing process (see Chapter 3.A.3 Installation and supply of utilities),
● the creation of suitable climatic conditions (see Chapter 3.A.4 Lighting, ventilation, air-conditioning);
● and the supply and disposal of materials.

The optimum location of the rooms and their arrangement in relation to one another not only ensures the quality of production, but also greatly
influences cost effectiveness.
● The rooms should be arranged in a way that production may be carried out using a logical step-by-step approach that corresponds with the
sequence of work steps (see Chapter 3.B Material flow, personnel flow and layout).
● The receipt and dispatch areas should be organized so that materials and products are protected from external influences (see Chapter D.7).
● Areas for carrying out in-process controls should be physically segregated from production. If this is not possible, suitable measures must be taken
to ensure that the controls will not be affected by current production (see Chapter 11.I In-process control).
● Control laboratories should be separated from the production rooms to exclude external influences. Defined and sufficient storage conditions must
exist for the storage of samples and records.
● Staff rooms must be segregated from other areas.
● The number of changing rooms, wash rooms and toilet facilities should be appropriate for the number of users. Toilets should not open directly onto
production rooms.
● Rooms where animals are kept must be separated from other areas and also have their own access and ventilation system.

The size of operating rooms must be adequate to ensure suitability for their intended use (see Chapter 3.A.2 Size, area, height): Sufficient space must
be available in the manufacturing zone for the provision and interim storage of materials. Facilities must be assembled in such a way that they can be
accessed to carry out the necessary scope of cleaning and maintenance work. Sufficient space should also be available in the storage area to ensure
that the various categories of materials and products are properly stored. The rooms must be clean and dry and the appropriate temperature and
humidity range must be maintained (see Chapter D.7).
Production hygiene is another important aspect to consider with view to product quality and safety: It should be possible to clean the premises
thoroughly and also to disinfect them. The compatibility of substances that act on floors and walls, as well as the rest of the facility during production,
cleaning and disinfection, must be verified. An adequate standard of hygiene in these rooms (to be specified by the manufacturer) is essential to ensure
the quality of the medicinal products (see Chapter 3.A.5 Hygienic construction and Chapter 11.C Production hygiene). The use of appropriate controls
assures that the required standard is maintained (see Chapter D.7. The necessary precautions must be taken to prevent the entry of insects, rodents,
birds and other animals (see chapter Chapter D.7). The operating rooms must be maintained in a good state of repair.
Cross-contamination in the production areas must be prevented through appropriate layout of the rooms, adequate material flow and personal flow (see
Chapter 3.B Material flow, personnel flow and layout), but also by application of a suitable ventilation concept (see Chapter 3.G Heating Ventilation Air
Conditioning (HVAC)). Particular attention must be paid to the production of highly potent medicines (e.g. beta-lactam antibiotics, hormones,
zytostatics). Suitable measures, such as separate manufacturing areas and ventilation systems or campaign manufacturing, must be utilized to ensure
the prevention of cross-contamination (see Chapter D.7).
Drawings of the existing operating rooms are an integral part of the company description (see Chapter D.7) and should be available drawn to scale.
The description of rooms should include the points listed in Figure 3.A-1.
Figure 3.A-1 Description of operating rooms
Description of operating rooms

● Plan, to scale
● Inclusion of room numbers
● Visual representation of positions of windows, doors, locks, hatches
● Assignment of functions to each of the rooms
● Assignment of hygiene categories to each of the rooms

The suitability of rooms used to carry out manufacturing operations that are of decisive importance for the quality of medicinal products must be
demonstrated by qualification. The type and scope of the qualification requirements depend on the specific operations that are to be carried out in the
various premises (see Chapter 3.I Qualification of premises and air-conditioning systems).
Figure 3.A-2 shows the most important factors used to assess the suitability of operating rooms.
Figure 3.A-2 Factors used to assess the suitability of
operating rooms
Factors used to assess the suitability of operating rooms

● Location, connection with other rooms

● Size: area and height
● State of repair (maintenance)
● Hygiene status, including pest control
● Installations/supply of utilities
● Lighting, ventilation and/or air-conditioning
● Construction of doors and/or locks
● Materials: floors, walls, ceilings

An acceptance inspection is carried out by the relevant authorities to assess the suitability of the rooms before manufacturing authorization is
granted. Manufacturing authorization may be denied to manufacturers who do not have suitable operating rooms, or withdrawn if rooms are subsequently
determined to be unsuitable.

3.A.1 Location, connection to other rooms

“Premises should be situated in an environment which [...] presents minimal risk of causing contamination of materials or products.”
(Chapter 3.1 EU GMP Guide, see Chapter C.4.3).
“There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination …”
(21 CFR Section 211.42(c), see Chapter D.1.2).
In addition to the requirement to prevent contamination a suitable room location ensures an appropriate flow of materials together with compatibility with
other manufacturing procedures in other rooms. The arrangement of rooms in the building should facilitate a linear sequence of individual processing
steps. This reduces the risk of confusion and the possibility that quality-determining manufacturing and control steps will be missed. The arrangement of
rooms in the sterile area plays an essential role in ensuring compliance with the various room classes (keyword: locks). Additionally, the choice of
location is an equally decisive factor – not only in terms of size but also for supply to and disposal from the rooms.
When planning the arrangement of the rooms, in new buildings as well as conversions, the building features presented in Figure 3.A-3 must also be
considered in order to select suitable locations.
Figure 3.A-3 Building features
Building features

Building structure ● Construction: dimensions, materials, number and height of stories, column grid, suspended ceilings, static
● Building services: air-conditioning technology, utilities (compressed air, nitrogen, steam), range of water qualities

Building use ● Effects of other production operations, e.g. via ventilation system (hormones, highly potent substances)
● Effects of personnel: are special access arrangements necessary?

Two examples are described below for illustration:

● IPC laboratory: in a laboratory, visual controls must often be carried out and assessed (color, friability, microbiological growth, etc.). It is therefore
recommended that rooms where these kinds of activities take place be located in areas where natural light is available.
● Granulation of highly potent substances: personnel and other products are to be protected in this area. The building features must be considered
when choosing the location: is it possible to prevent contamination using air-conditioning technology? Does the structure of the building make
hermetic shielding of different areas from one another possible? Is it possible to include locks?

3.A.2 Size, area, height

The area and floor plan required for the overall production, control and storage of a product are the decisive factors rather than the actual size of the room
itself. Only one batch of one product may be processed in a room at any time (see Chapter D.7).
Oversized rooms are often partially used as storage areas for previous or subsequent orders. If rooms are too small, materials are often stored directly
outside, e.g. in the corridor. The risk of mix-up is high in both instances.
A suitable layout plan for rooms in which several production steps are processed in sequence is the prerequisite for preventing mix-ups through
crossing-free logical structuring of operations. See Chapter 3.8 EU GMP Guide (Chapter C.4.3) and 21 CFR section 211.42(c) (Chapter D.1.2) and Figure
3.A-4.
Figure 3.A-4 Crossing-free flow of materials in granulation operations

The height of a room is largely determined by the building structure and the requirements of building legislation in relation to use. Room height must be
considered in relation to factors such as the installation height of machines, the number and type of air vents as well as room classes.

3.A.3 Installation and supply of utilities

In addition to the type of installation that must facilitate easy cleaning, a process-oriented supply of utilities and energy must be aimed at, where the
number and dimensioning of utilities must be harmonized with the process to achieve quality and economic efficiency. See Chapter 3.10 EU GMP Guide
(Chapter C.4.3)
and 21 CFR 211.42(c)(10)(i) (Chapter D.1.2).
Examples:
● Main ring (loop) for purified water: the dimensions of the pipes for purified water must be harmonized for all consumers in a loop, as the flow rate
necessary to provide protection against microbial contamination may otherwise not be achieved, e.g. due to under-dimensioning.
● Power supply: the power supply may fluctuate within specific limits (400 V ± 20 V) or may fail completely. With sensitive measuring or control
equipment, or analytical instrumentation, these (permissible) tolerances may lead to inaccurate results: in such cases, appropriate technical
measures must be taken (e.g. an emergency power supply).

For more detailed information on utilities see: Chapter 3.F Building services, Chapter 3.H Process Gases and Chapter 5 Pharmaceutical Water.

3.A.4 Lighting, ventilation, air-conditioning

Air-conditioning provides for the supply of air to rooms and processes. As well as complying with the requirements of the guidelines for workplaces, the
room air supply must be designed to meet the requirements of the products being manufactured. The requirements range from variations in air humidity
and air temperature to pressure differentials or flow directions between individual rooms. (See Chapter 3.G.5 Design criteria for the ventilation of
premises.)
The process air supply must satisfy only the requirements of the product or process, as it is normally in direct contact with the products (e.g. fluid-bed
drying). Depending on the requirements, it may be necessary for the conditioning of the air to be monitored using suitable recording systems.
The number and arrangement of lights must be determined in accordance with the guidelines for workplaces with respect to illumination levels. See 21
CFR 211.44 (Chapter D.1.2) and EU GMP Guide 3.16 (Chapter C.4.3). To facilitate easy cleaning and maintenance of light fittings, it is recommended,
particularly in sterile areas, that these be accessible from the outside. See Chapter 3.10 EU GMP Guide (Chapter C.4.3) and Chapter 3.D.4 Ceilings).

3.A.5 Hygienic construction

Production rooms must be designed in such a way that (uncontrolled) accumulation of dust and product particulate material cannot occur, or alternatively
they should be easy to clean and disinfect (if necessary). See Chapter 3.9 EU GMP Guide (Chapter C.4.3) and 21 CFR, section 211.46(b) (c) (Chapter
D.1.2). This general requirement must be weighed according to the use of the room. The requirements are most stringent in the sterile area and are
considerably lower in the packaging area. Whatever the case, suitable protective measures must be taken to make sure that the ingress of animals and
insects into the pharmaceutical production areas is prevented (see Chapter 3.4 EU GMP Guide (Chapter C.4.3) and 21 CFR, 211.56(a) (Chapter D.1.2)
and Chapter D.7). More detailed information on constructional aspects is given in Chapter 3.D Construction elements.

3.A.6 Room book and layout

When designing rooms, a range of data must be collected in order to provide appropriate solutions in response to requirements.
Figure 3.A-5 Requirements for use
Requirements for use

Requirements derived from the product characteristics ● Room climate (temperature, humidity,
(temperature and sensitivity to moisture, warehouse stability, sensitivity to light, toxicity, etc.): flow direction)
● Fenestration or type of lighting
● Necessity of climate monitoring

Requirements derived from the manufacturing process ● Quality of walls, ceilings and floors
(sterile, aseptic or non-sterile process, previous and subsequent processing steps and their connection, ● Ventilation technology (recirculating air,
warehouse, packaging, control laboratory etc.): fresh air, laminar flow)
● Type, number and area requirements of
process equipment
● Connected loads and heat output of
facilities
● Type and quality of utilities (compressed
air, nitrogen, steam)
● Type and quality of water
● Warehouse areas for format and spare
parts
● Working hours
● Number of personnel
● Flow of materials
● Personnel flow

The “room book”, as it is referred to, is a useful document in which all data relevant to the room can be compiled. Together with the layout, the room
book presents the specification of a room. Both documents may also be used to illustrate company operations during inspections and also as the basis
for the qualification of rooms.
The data for the room book (see Figure 3.A-6) and layout design are determined by the requirements for use (Figure 3.A-5).
Figure 3.A-6 Room book
Summary
Rooms have great significance from the GMP standpoint, since they surround pharmaceutical products from the raw material to the finished product
stage.
The design of rooms affects the economic efficiency of production.
The construction, dimensions and layout of operating rooms contribute to the assurance that operations may be carried out properly, particularly with
respect to the faultless production, analysis, storage, packaging and distribution of medicinal products. The individual requirements depend on the type
and scope of the production.
The arrangement of rooms in the building should facilitate a linear sequence of individual processing steps.
Production rooms must be designed in such a way that accumulation of dust and product particulate material cannot occur, or alternatively, so that
they will be easy to clean and disinfect (if necessary).
Rooms are specified by the room book and layout.