Stepping Up Process Control with Single-Use Systems

Spivey,Chris;

The human digestive system provides a layer of protection from undesirable microbes and foreign bodies through acidic digestive processes. This protection allows a certain tolerance vis-à-vis delivery of oral delivery methods.

However, parenteral drugs are not subject to that same level of tolerance as they are injected directly into tissue or bloodstream. For these dosage forms, there is a particular need to guard against other risks, such as contamination and blood vessel occlusion.

Single-use systems (SUS), which are by nature more sterile, have therefore found a home naturally and with more celerity in parenteral drug manufacture. In fact, the global single-use bioprocessing market is projected to experience double digit growth between 2022 and 2030, reaching $15.1 billion by the end of that specified period (1).

Regulations concerning particulates

As adoption of SUS in parenterals is becoming firmly established, attention turns to both process optimization of therapeutic segmentation, alongside regulation evolution. “Visible particulate contamination in SUS is typically performed using procedures adapted from USP [United States Pharmacopeia] <790> (2), Visible Particulates in Injections,” says Mark Bumiller, technology manager, Entegris. “The USP <729> protocol calls for sampling General Inspection Level II, single sample plan, AQL [acceptable quality limit] of 0.65% (3). SUS products typically approach 100% of guidance goals for visual particulate contamination before final packaging. USP <790> suggests testing against black and white background with illumination between 2000 and 3750 lux (2). Many SUS products are tested using normal fluorescent cleanroom lighting on a light table and against a black background.”

Bumiller goes on to state that the extraction method to collect loose particles from the SUS surfaces for testing components and assemblies comes from the ASTM E3230-20 validating extraction process (4). “The approach was inspired by an automotive industry standard used for parts which require critical cleanliness,” he explains. “The guidance on the method for counting the particles is not provided.”

Polymer materials predominate

A wide-range of high-performance polymer materials are used for SUS as a result of their ability to withstand the varying and challenging bioprocessing conditions. For example, polyethylene and polypropylene can withstand a range of conditions; polyethersulfone is used when heat resistance is required; polytetrafluorethylene (also known as Teflon) are useful as inner layers of SUS when using more aggressive materials; cellulose acetate is a hard material that is popular for filtration cartridges; and polyamide (nylon) is a suitable material for outer layers in composite components (5).

As a result of the unique properties of each polymer and the challenging characteristics of the compounds being processing in bioreactors, it is common for SUS to consist of more than just one plastic material. It is common for bioreactors to comprise several layers that all work to contain and protect the expensive and sensitive materials being processed (5).

SUS and advanced therapies

Initially, SUS were employed for larger batch volumes in the production of vaccines, biosimilars, and monoclonal antibodies. Nowadays, in line with the industry’s increased focus on developing novel therapies to treat conditions such as cancer and autoimmune diseases, more highly potent drugs are being processed (6).

While useful therapeutically, highly potent drugs are challenging from a manufacturing perspective as they are dangerous not only to the manufacturing operators but also to the environment, which means they must be contained effectively. Furthermore, such potent compounds are difficult to remove from stainless steel surfaces, leading manufacturers to favor SUS for their bioprocessing needs (6).

In addition to the greater use of highly potent compounds, industry is also witnessing a vast movement into cell and gene therapy applications—or simply for cell expansion activities. With these shifts, SUS is creating a need for accurate yet inexpensive disposable sensing equipment, so that a closed environment is maintained across the whole production process. PreSens, for example, is tackling this issue through the development of non-invasive online optical oxygen sensors for use in perfusion systems (7).

SUS benefits

Across the world, all industries are facing decisions around how to be more environmentally friendly, which usually involves using less disposable plastic and more reusable materials. Ironically, within the biopharma industry, using plastics a single time, then throwing it all away, can be a more sustainable and environmentally friendly option, particularly when compared with traditional stainless-steel technologies—once all the water costs and energy budgets for cleaning and decontamination are taken into account. It has been commonly reported throughout the industry that SUS reduces or eliminates requirements to clean and then validate that cleaning, between batches.

Additionally, it is widely believed that SUS sidestep the age-old problem of cross batch contamination, as everything is thrown away. The disposable nature of SUS also provides the flexibility and nimbleness to act quickly when either opportunity knocks, or when there is an unexpected need to quickly scale back down. Furthermore, manufacturing costs can be reduced with SUS, which will ultimately transfer to more cost-effective options for patients.

References

Airlift Single-Use Disposable Bioreactor Systems

Cellexus has pioneered airlift single-use disposable bioreactor systems that reportedly eliminate the need for mechanical mixing. Instead, the systems use bubbles to move cells and nutrients, providing optimal aeration for rapid growth of cells. This method of gentle agitation is suitable for microbial fermentation and cell culture.

Because of the low mechanical sheer forces inherent to the system (no impellers are used), phage and lentiviral production have been early use applications/adopters. Traditional stirred-tank bioreactors use mechanical agitation to provide mixing and aeration of the culture volume. This method of agitation can generate large shear forces that can damage the health of the cells, thus reducing lentiviral vector yields.

The single-use airlift technology uses disposable bioreactor bags to eliminate cleaning and contamination, reducing downtime between runs and decreasing time to market. The system can work in volumes from 1.5 L to 50 L, with compact systems offering a comparably low footprint (1).

Reference

Spivey, C. A Look at New Airlift Technology in Single Use Bioreactor Systems. BioPharmInternational.com, Dec. 11, 2023.

—Chris Spivey

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Citation

When referring to this article, please cite it as Spivey, C. Stepping Up Process Control with Single-Use Systems. BioPharm International 2024 37 (2) 20–21.