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Decreased capital expenditure for equipment and facility

Using one-time use bioreactors drastically reduces costs to buy as single-use plastic vessels are cheaper than stainless-steel / lass vessels. The life-time operating costs of disposable are also much lower and do not require immediate upfront investment of the different systems within a traditional bioreactor such as the pH system and piping because they don't require permanent infrastructures.

Disposable bioreactors also do not require regular maintenance or fixing for the different compartments that are also made of stainless-steel which ultimately helps productivity and reduces down-time.

Disposable bioreactors also eliminate the need for CIP and SIP and reduces the water and utility consumption. Traditional bioreactors use heaps of water and energy for heating and cleaning, along with the different cleaning agents used which are expensive. Not to mention the cost of validating sterility of the bioreactors via swab-tests and rinse-tests which can also be heavily labor intensive.

Disposable bioreactors come pre-sterilized and are single-use thus extra labor and costs do not need to go into avoiding cross-contamination which also helps increase productivity.

Disposable bioreactors not only reduce costs but also reduce down-time which in turn produces more products to enhance revenue earned, which is a win-win situation.

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Productivity and Cost-Saving Benefits of Single-Use Bioprocessing

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Disposable solutions are transforming development & manufacturing.

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Disposable bioreactors are better than fixed-in-place bioreactors:

In terms of flexibility, efficiency, and operating costs, disposable bioreactors are clearly superior to fixed-in-place systems for small to medium-scale production. They enable quicker turnaround times and increase production by doing away with the need for cleaning and sterilization, which also drastically lowers labor, utility, and downtime costs. By doing this, contamination concerns are also reduced, improving product safety and lessening the regulatory load related to cleaning validation. They are also perfect for clinical manufacturing, pilot studies, and multi-product facilities where quick adjustments are required due to their scalability to specific project needs.

Although there are issues with plastic waste and restricted scalability, these disadvantages are frequently outweighed in situations where priority is given to speed, ease of use, and less infrastructure. Because the cost of single-use components is still affordable and the environmental impact may be reduced through sophisticated waste management techniques, disposable systems are particularly beneficial in small-batch production. With the growing need for adaptability and responsiveness in biomanufacturing, disposable bioreactors offer a viable and effective substitute for conventional fixed systems.

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A significant disadvantage of using disposable bioreactors is the need for ongoing forecasting of consumable usage. Unlike traditional stainless-steel bioreactors, which rely on reusable components, disposable bioreactors require single-use bags, filters, and tubing for each production run. This reliance on consumables demands precise inventory management to ensure uninterrupted operations. Poor forecasting can lead to shortages, halting production, or overstocking, which ties up capital and increases waste. Additionally, fluctuations in supply chain availability or costs for consumables can disrupt planning and escalate operational expenses, making long-term scalability more challenging and less predictable.

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Single Use Bioreactor: Overview, Types, Advantages, Limitations and Future of Single Use Bioreactors

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Elimination of cleaning requirements:

The removal of cleaning regimes in disposable bioreactors offers numerous benefits that increases productivity and save costs. By eliminating the requirement for cleaning-in-place (CIP) and sterilization-in-place (SIP), which are common procedures of fixed-in-place bioreactors, the downtime between batches in disposable bioreactors are significantly reduced, allowing for quicker turnaround times and operational efficiency. Through this, disposable bioreactors also eliminate expenses associated with using cleaning solutions and sterilizing agents, along with the utilities needed for these operations such as energy, steam and water hence, further reducing the wastewater treatment costs. Additionally, as disposable bioreactors come pre-sterilized, the risk of product contamination from improper cleaning is also reduced, ensuring an increase in product safety and quality.

Also, by eliminating the requirements for intricate cleaning and sterilization process, the need for complex validation is removed, further reducing the operational burdens to streamline regulatory compliance. Despite generating waste, disposable bioreactors also further prevent the negative environmental impact of using harsh cleaning chemicals and excessive water and energy by adopting advanced disposal processes that provide sustainable alternatives. Together, all of these advantages derived from the elimination of cleaning regimes makes disposable bioreactors a more cost-effective and practical choice for modern bioprocessing.

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Single Use Bioreactor: Overview, Types, Advantages, Limitations and Future of Single Use Bioreactors

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Contamination exceedingly rare:

Disposable bioreactors are pre-sterilized by the manufacturer before selling it to companies. They often use gamma irradiation or ethylene oxide to sterilize the bioreactors before it is safe to use. These bioreactors are then discarded after a single use. This allows users to use the bioreactors without wasting time to perform on-site sterilization and also reduces errors during cleaning and sterilizing which can lead to rare cross contamination of the bioreactors.

Traditional bioreactors require cleaning-in-place and sterilization-in-place systems to sterilize and remove microbial contaminants, which happen quite often. These systems require more effort to maintain the bioreactor. Moreover, they are more susceptible to human error when cleaning and can leave contaminants due to incomplete or inaccurate cleaning or sterilization.

However, disposable bioreactors does not require a cleaning or sterilizing process as it has already been sterilized by the manufacturer and it is disposed after a single use, so there is no need for a cleaning process. Thus, reducing cross contamination risks from microbial contaminants remaining from possible improper sterilization and other residues.

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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.

Advantages of single-use bioreactors

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.

Obstacles to adoption

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.

Future innovations

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.

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The Pros And Cons Of Single-Use Bioreactors

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Since its introduction more than 10 years ago, single-use bioreactor technology has now become an established addition to today's biotechnology manufacturing facility.

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Capacity Limitations

Compared to fixed-in-place bioreactors, disposable bioreactors are significantly smaller in size where the current largest size holds around 2000L while fixed in place bioreactors hold up to 20000L.

The disposable bioreactor's smaller volume makes it less favorable when looking to scale up bigger cell cultures as it would be more time consuming and labour intensive.

Some instances where a fixed in place bioreactor would be more beneficial would be culturing cells for the biopharmaceutical industry where large batches of mammalian cells are cultured to ensure that biologics such as monoclonal antibodies, viral vectors and recombinant proteins are readily available for use.

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Exploring Principles of Bioreactor Scale-Up

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Bioreactor scale-up requires optimization of operating parameters for the large-scale bioreactor to be used in a production process.