bursting, especially for the production of infectious materials [89]. In principal, SUBs

are simple to install and universally applicable with low capital costs, reduced vali-

dation efforts, low downtimes, and flexible footprints. By eliminating cleaning in-

place operations, faster turnarounds between batches or switching between products

(for vaccines between viruses) with reduced cross-contamination risks can be

achieved. The use of disposables including SUBs is therefore often seen as an enabler

for continuous manufacturing of biologicals seamlessly linking upstream and

downstream operations [18]. Moreover, commission of new production facilities that

fully rely on disposables is typically fast as the complexity involved in planning,

installation, and validation is drastically reduced. Particularly for vaccine production,

this has significant advantages in case of pandemics (as recently demonstrated by the

COVID-19 pandemic). Also, the transfer between areas of different biosafety levels is

facilitated [90]. It is envisioned that such systems could even be placed at the site of

need in containers readily transported on trucks. Manufacturers can order custom-

made solutions with different disposable sensors, sparging systems, and mechanical

agitation systems (top- or bottom-mounted impellers, rockers, orbital shakers, etc.)

from several vendors [89]. One example for SUBs is the SB-X single-use OSB (or-

bital shaken bioreactor) series from Kuhner shaker that allows disposable-based

vaccine productions up to 2,500 L scale (see Figure 6.11).

Despite the many advantages, there are still some challenges with the use of SUBs

that are listed (Table 6.4). Direct transfer of large-volume vaccine production pro-

cesses into disposable systems is often not possible due to volume restrictions and can

only be circumvented by using multiple parallel systems. For optimization of the

latter, additional laboratory-scale investigations might be required. The parallel use of

many smaller SUBs also enhances the complexity of process operations, and in-

creases the risk of leaky tubings and welds and of plastic bag breakage [89,90].

Finally, key issues such as GMP regulatory requirements, standards in bag and tubing

manifold systems, need for standardization in extractables and leachables (E&L)

testing procedures, lack of ON/OFF sterile connectors, relevant validation studies,

etc. must be addressed. Furthermore, in particular for HCD virus vaccine

FIGURE 6.11 Possible scale-up line for SUBs. Here orbital shaken bioreactors 4–12 L,

15–50 L, 50–200 L, and 500–2500 L scale from Kuhner shaker. Alternatively, STRs or wave

or other bioreactor types as SUBs are available. Pictures were kindly provided by Kuhner

shaker.

Process intensification

165