Site Location And Layout

At the beginning of a project decisions will be made on:

• site location and permit requirements;

• the optimum number of storeys, for example to allow the location of utilities above and below the manufacturing level as appropriate;

• the list of rooms and their functions;

• the provision of utilities generated within the facility or taken from the site;

• the use of 'grey space' to minimize clean room volume;

• any provision in the design for future expansion;

• the extent of prefabrication and pre-testing of equipment modules.

The location of the facility on a particular site has GMP implications. Surrounding industry and farming should not have a deleterious affect on the products, and a reliable infrastructure is needed.

International GMP regulations have a common requirement that the layout of the facility should encourage operators, visitors, equipment and materials to move or flow in a controlled and logical manner that will avoid mix-ups. For example, the flow of people from an unclassified area to a classified one is via a changing room (or series of rooms) so that the cleanliness of the working area is not compromised. Flow patterns around the facility will help ensure that mistakes and cross-contamination are avoided. Materials and equipment must not be stored in corridors.

Unidirectional flow of people in and out of process rooms is not common in API plants for therapeutic proteins. However the concept of a flow-and-return corridor is still prevalent, gives a straightforward pattern and has frequently been employed in vaccine facilities. The flow corridor supplies materials and clean equipment to the processing rooms and stores, and the 'return' corridor is used to transfer equipment to the washing room and to the waste collection points or decontamination room.

A useful tool called an adjacency diagram is illustrated in Figure 12.3 where adjacencies and key flows between rooms are defined. In this case the facility will be located on an existing site where there are already staff and analytical facilities. The provision of space for future expansion can be included.

Within any area there must be adequate space around equipment for operation, cleaning and maintenance. Processing equipment should be located so as to achieve a logical flow. Good ergonomics is critical, especially if isolators are used, and mock-ups of these are recommended during the design phase. Where solid material flows occur, such as in media preparation, the receiving equipment should be located vertically below, with good access to the chute for cleaning.

The layout is affected by the room air quality classifications or grades. In the USA there are commonly three grades of clean room or area within a room, namely Class 100 in operation, Class 10 000 in operation and Class 100 000 in operation. These grades approximately conform to the EU GMP grades A, B and C respectively (see Section 12.7). It is the custom in Europe for there to be a progression from 'unclassified' to grade D, to grade C and if required to grade B, with a lobby or a corridor at each transition. The gowning should take place in the innermost lobby and the lobby should be the same grade (at rest) as the room it serves. This is not a requirement in the USA where a progression from unclassified to class 100 000 is permitted provided the differential air pressure exceeds 12.5 pascals.

This requirement for lobbies and airlocks can have a major impact on layout. The grade of room should be the minimum required for the duty, then the corresponding lobby can be designed. Sometimes rooms are set at a higher grade than needed in order to save on the number and sequence of lobbies or airlocks. This is not logical and leads to failures to meet the room environmental quality standards and to the ongoing unnecessary cost of environmental monitoring and gowning. However a clean corridor giving access from a gowning room to several clean rooms is acceptable.

A clear policy on gowning is also needed, with the exact details of what happens in each of the gowning rooms specified. This will ensure that gowning rooms are the correct size and that there is sufficient space for storage of clothes and shoes. Hand washing facilities are needed in the outermost part of gowning rooms.

Figure 12.4 shows the typical segregation of rooms.

Material receipts-Product dispatch

Sample

Waste

Decon

Decon.

dispatch

store

autoclave

Raw Materials

Return circulation

Raw materials warehouse

>

- A/L

A/L

Weigh+ dispense

Equip wash

W m

i

Cell culture suite

Initial Purification Suites

Equip. Prep.

Final Purification Suite

Final Purification Suite

Pack+ label m

Cell bank

: Buffer prep

Media prep

Media prep

Cell line Evaluation

Ch.

Write

Equip, wash

Wash/

+autoclave

Ch.

Writs

Up.

Conference

Meeting

room

WC -Restarea- Kitchen m

Offices in

Reception lobby

Personnel Entrance

WC+ shower

Male change

Female change

WC+ shower

Supply circulation

Calibration cGMP Key

Unclassified

IcGMP Unclassified I Grade 'D'

Final bulk product store

Figure 12.3 Adjacency diagram.

Production building

Labs/Change/Admin. ^

Canopy ¡Materials Entrance!

Store after Decon.

Store after Decon.

Cell Culture-1

Calib.

CO CD

W/Shop

1m

Change

Airlock

4.

£ o>

Cell Culture-2

£

Pass Through

Material flow (manual transfer) Material flow (piped)

KEY

cGMP Grade

Ü

cGMP Grade

cGMP Grade

Material flow (manual transfer) Material flow (piped)

Figure 12.4 Segregation.

Segregation of areas where there are viable and killed microorganisms is essential, and is a key feature of vaccine facilities to avoid the transfer of live organisms into the product.

For mammalian cell culture, the segregation of purification stages before and after a viral inactivation step is a key feature. Almost all mammalian cell lines contain some form of endogenous viruses and, in addition, viruses might be introduced inadvertently during processing (see Chapter 31). The entire purification process must be validated to remove or inactivate harmful viruses (see Chapter 19). A process procedure or step in the purification sequence is identified where viruses are removed to an acceptable level, and at this point the purification process is divided into pre- and post-viral inactivation stages. All purification steps contribute to the removal of viruses and the user must decide which step constitutes the virus removal stage.

There have been some changes in the provision of pre-and post-viral facilities. For example, where processes are closed and the removal and inactivation of viruses has been validated, then the whole train of purification steps can take place in the same room. For open processes, such as solvent/detergent or low pH treatments, it would be expected that the inactivation would be performed in one vessel in room A before being transferred to a clean vessel, usually via a wall port, in room B. There would be separate air handling units for the two areas and personnel would not cross from the pre-inactivation area to the post-activation area without a change of gowning, including footwear. Post-in-activation equipment would be dedicated unless it could be sterilized. Wheeling mobile vessels from pre-inactivation areas into post-inactivation areas would not be allowed unless cleaning is validated.

Many companies have a rule that there can be only one lot of one product in the same room at the same time. So where the entire purification process takes several days, several adjacent purification rooms can be installed and thus the process separated in order to increase productivity, as several lots can be processed at the same time in different rooms.

Where the purification suites have to accommodate different processes, the best approach is to create a well-serviced room or suite, often at grade C, for additional flexibility if the processes might not be closed. Process equipment is then brought from a secure store and connected by hard pipe or fluid transfer panels. At the end of the campaign, the stream can be cleaned and disassembled and a new line created. Utilities can be supplied from service stations within the suites.

Some parts of certain process equipment can be contained in a service area, with only those parts that need access for operation held in the clean room. This method means that there is a minimum of expensive classified clean room volume and also the design permits easy access for maintenance and qualification. This 'grey' side technology has long been used for autoclaves, washing machines and lyophilizers. It is now also used for bioreactors, for example.

The renovation of an existing building to accommodate biopharmaceutical manufacture is challenging. The building might have to be decontaminated. The building's location and shape might not be ideal and compromises are inevitable. It is recommended that the fabric of the existing building is carefully surveyed before it is reused.

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