Multiproduct Cultivation Equipment

To contain costs and to respond quickly to the ever-changing needs of the market, it is desirable to build multi-product facilities, where two or more products can be produced with the same, or shared manufacturing equipment. The main concern of regulatory authorities is the risk of cross-contamination between the different products. The important issues to address with multi-product manufacturing facilities are therefore the engineering design, the procedural, temporal or spatial

Figure 14.11 Schematic flowsheet of an upstream processing plant for a fed-batch process. The figure shows the main vessels for cultivation and media preparation. The production stage consists of four bioreactors, for which two inoculum expansion trains are required. Thawing of the working cell bank and laboratory cultivation are not represented. Manual transfer panels are used to transfer inoculum from one bioreactor to any bio-reactor of the next step. At each scale, a single common tank is used for the preparation of the culture medium (see Section 14.2.1); in this example, the transfer route for medium is selected via valves (only the main ones are shown) instead of transfer panels; the medium is directly transferred into the bioreactors after preparation (sterilizing filters not shown), without storage, except at the 20 litre scale, where disposable bags are used. At the production stage (10 000 litres), the feed is prepared in a single common tank but is then transferred into hold tanks dedicated to each bioreactor, to allow maximum flexibility of the feeding regime.

Bioreactor

a

Preparation tank

a

Storage tank

d

Storage bag

Figure 14.11 Schematic flowsheet of an upstream processing plant for a fed-batch process. The figure shows the main vessels for cultivation and media preparation. The production stage consists of four bioreactors, for which two inoculum expansion trains are required. Thawing of the working cell bank and laboratory cultivation are not represented. Manual transfer panels are used to transfer inoculum from one bioreactor to any bio-reactor of the next step. At each scale, a single common tank is used for the preparation of the culture medium (see Section 14.2.1); in this example, the transfer route for medium is selected via valves (only the main ones are shown) instead of transfer panels; the medium is directly transferred into the bioreactors after preparation (sterilizing filters not shown), without storage, except at the 20 litre scale, where disposable bags are used. At the production stage (10 000 litres), the feed is prepared in a single common tank but is then transferred into hold tanks dedicated to each bioreactor, to allow maximum flexibility of the feeding regime.

separation of production activities, the use of validated closed systems, and the implementation of a validated cleaning/changeover program (Odum 1995).

One approach is to manufacture products in campaigns, i.e. sequentially. Only one product is then present in the facility at a time. Generally, campaigning involves the manufacturing of several batches of one product over an extended period of time (weeks or months), before the changeover to the next product takes place. In this case, a very comprehensive changeover procedure must be established and validated, particularly regarding cleaning of all common equipment. Cleaning studies are typically performed in triplicate and removal of previous product, process chemicals and cell material must be demonstrated by appropriate analytical procedures. Assays more specific than TOC measurements are recommended (Shahidi et al. 1995). For biocontainment areas, decontamination to remove viable organisms must be demonstrated. Good cleanability of the plant is thus essential. The use of disposable equipment, for instance plastic storage bags, can greatly simplify these cleaning requirements. For an accelerated changeover, one solution in upstream processing is to start growing cells for the new product in the laboratory while cells of the current product are still growing in the larger vessels. Since cell cultivation and handling in the laboratory are considered to take place in an open system, two segregated laboratories are required for this purpose. The relatively modest capital investment is, however, largely offset by a more efficient utilization of the plant capacity, thanks to faster changeover procedures.

Another approach is the simultaneous production of different products in segregated areas or systems within the same facility; this is often referred to as concurrent manufacturing. Segregation between the different processes may be achieved by the use of dedicated rooms (including HVAC), and/or by the use of validated closed systems. Typically, two or more suites with their own air handling module and personnel access will be required for the seed laboratories. For bioreactors, which are considered as closed systems, common rooms can, in principle, be used. It is, however, safe practice to vent all the off-gases directly to the outside of the facility in order to avoid risk of cross-contamination due to recirculation via the HVAC system. Physical separation of bioreactors (for instance in two groups in the same room) and operating procedures are also recommended to minimize the risk of mix-ups due to human error. Some equipment may however be shared, for instance media preparation vessels. Since operations are typically very short, one common area may be sufficient to serve several cell culture suites. In this case, media preparation should be performed in campaigns, and adequate cleaning validation is required for each 'changeover'.

In both cases (campaigning or concurrent manufacturing), cultivation equipment should be designed so that it can be readily used for different processes. However, the level of flexibility should be carefully evaluated because, in general, as the level of flexibility increases, so do the associated costs (DePalma 2003). As a general rule, bioreactors should be designed so that stirring (impeller type and number) and gassing methods (sparger type, flow rates) can be readily adapted. The location of peripheral equipment inside the vessel, such as CIP spray balls, probes and inoculum tubes, should be designed so that the bioreactor can be operated over a relatively broad range of working volumes. For the storage of culture media and feed solutions, the use of disposable bags is recommended at all scales, where possible, for both perfusion and fed-batch processes in order, to maximize flexibility. Further discussion on the design and general organization of multi-product plants can be found in Odum (1995) and Shahidi et al. (1995).

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