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Pharmaceutical Technology Europe
Since its introduction more than 10 years ago, single-use bioreactor technology has now become an established addition to today's biotechnology manufacturing facility.
Since its introduction more than 10 years ago, single‑use bioreactor technology has now become an established addition to today’s biotechnology manufacturing facility. Many single‑use options are available, each with its advantages and disadvantages, although scalability is often touted as one of the biggest general limitations.
Salavadi S. Easwaran. Technology Manager-PMT, at Merck Millipore, India.
The willingness of the industry to use single‑use bioreactors is currently influenced by the criticality of the step, the value of the product and the time for product development and production. The rate of implementation is, however, lower than the rate of acceptance because it takes time to complete comparative studies with conventional stainless steel bioreactors. For this reason there is a need for more clarity in understanding the regulatory requirements for single-use bioreactor technology. At present, for instance, the FDA’s CBER regulations do not mention anything directly about single‑use bioreactors, even though the FDA has approved several INDs developed using such systems.
One of the biggest advantages of single‑use bioreactors is flexibility. The increasing trend towards multi‑drug facilities demands the production of different drugs using the same facility, with minimum time and cost, without compromising the quality of the drug. In such situations, the main manufacturing bottleneck is the line clearance and validation of cleaning to ensure there is no carry over from earlier batches. Such downtime reduces the number of batches produced in a given period of time.
One of the main contributors to downtime is the preparation of the bioreactor in the upstream process. Single‑use bioreactors provide maximum savings on the time spent to prepare the bioreactor for the next batch. The extent of time depends on the nature of the batch. As an example, however, a 2‑h changeover time with a single‑use bioreactor (including the time taken to make all connections) would equate to a 6–10 h changeover time with a stainless steel bioreactor for the same product, and 3 weeks for a full product changeover. The full product changeover time depends on the manufacturing model. In a hybrid system (a combination of single‑use systems in upstream processing and stainless steel systems in downstream processing), the changeover time would be about two weeks. If the manufacturing line has disposable bioreactors connected to disposable filters and bags using single‑use sterile connectors, then the full product changeover would not take more than 48 h.
The potential time savings for highly trained personnel is also a huge benefit of single‑use bioreactors. In general, drug development research, scale-up and process development activities are conducted by highly qualified and trained personnel — these individuals are involved in every stage of a study from early stage research through to benchtop manufacturing. With stainless steel or glass benchtop bioreactors, individual components must be cleaned, assembled, leak tested, sterilised and cooled before every trial batch is taken. However, single‑use bioreactors almost completely eliminate these steps, leaving the scientist with more time for their developmental studies.
Single‑use bioreactors are also considered safe, simple and clean, and the possibility of batch‑to‑batch contamination by adventitious microorganisms or through product cross‑contamination is significantly controlled with such systems. In the case of stainless steel reactors, sterility is dependent on the validation of the sterilisation process (SIP/autoclave), which involves multiple parameters, such as non‑fluctuating temperature, exposure time, pressure, vacuum cycles, etc. CIP can also be completely eliminated with single‑use systems.
Whilst several key advantages are associated with the use of single‑use bioreactors, there are also some key challenges, including:
Non‑customisable — The current trend in biopharmaceutical manufacturing is to build a tailor-made plant for the given molecule in accordance with its specific bioprocessing requirement. However, molecules do not behave in the same way during the development, scale-up or manufacturing phases. Customising single‑use bioreactors to make them suitable for processing the specific molecules defeats their key advantage of plug‑and‑play.
Scale-up — The success of developmental trials to optimise the process conditions for manufacturing depends on the implementation of those parameters in the scale-up and production scale processes. The availability of single-use bioreactors that can translate those precise conditions at large fermentation volumes is a key challenge; volume size is restricted (no more than 2000 L) and questions still remain regarding the quality of the end-product following large-scale manufacture.
Scale-down — Scale‑down is also a potential bottleneck with single‑use bioreactors. Scale‑down studies are generally conducted to establish the potential root cause of any deviation that has occurred or to perform a risk‑based study. The lower limits in working capacity of the single‑use bag type or single‑use system is prohibitively high to conduct such studies.
Mixing — Stirring is one of the key elements in a bioreactor system on which mass transfer and energy transfer depend on. In wave bag type single‑use bioreactors, the mixing principle is unconventional and limited to a rocking movement, which limits the use of such culture bags to low volume and simple applications such as the seed‑train expansion of cells (inoculum production).
Disposal — In many cases, single‑use bioreactors are produced from plastic derivatives. In addition to validation concerns related to potential leachable and extractable materials, the large‑scale disposal of such plastic reactors on a regular basis is also an environmental concern. This is a key challenge, particularly in countries where the disposal of plastics is strictly controlled.
Oxygen transfer — Low oxygen transfer coefficients (kLa) achieved in existing single‑use bioreactors excludes the majority of bacteria and yeast fermentations from their scope of applications. As such, single‑use systems are mainly designed for mammalian cell cultivation only.
The most important future development in single‑use bioreactor technology will be the increase in capacity to match common large‑scale process capacities. The processing of multiple smaller batches controlled centrally using single‑use bioreactors will be another important step in the technology’s evolution. We will see improvements in the design, control, data logging and automation levels of single‑use bioreactors. As part of the monitoring process, I also believe that the development of robust and accurate single‑use sensor technologies will speed up the adoption of fully single‑use bioreactors.