The demand for complex biopharmaceuticals has skyrocketed in recent years, pushing innovation in sterile manufacturing technology. Despite advancements, aseptic material transfer remains a persistent challenge for producing these crucial drugs at scale and with speed.
Two distinct options exist within the industry: single-use transfer solutions, such as beta bags, and multi-use (or permanent) transfer solutions, such as stainless-steel canisters. This article examines the benefits and limitations of each.
The challenge of aseptic production
The crux of the issue is that sensitive active pharmaceutical ingredients (APIs) must be developed and maintained without introducing contamination.
These sensitive materials are typically produced within an isolator or restricted access barrier system (RABS) to ensure aseptic conditions—which means that operators must perform the necessary production steps from the outside without breaking containment.
To further complicate this already complex process, biopharmaceutical manufacturers must balance patient safety, product integrity, increasingly stringent regulations and the need to produce medications quickly and efficiently.
A reliable aseptic transfer solution is essential for ensuring that production goes smoothly and products remain uncontaminated.
Material transfer basics
Single-use and multi-use transfer components are sometimes referred to as beta assemblies, as they both dock to an alpha port.
The alpha port is the core interface mounted into an isolator, glove box or RABS unit. It provides a controlled pathway into the contained environment through which production components can pass.
Alpha ports are fairly standardised, and compatible beta assemblies are readily available in single-use and multi-use versions. The process of docking the beta assembly to the alpha port is essentially the same regardless of beta assembly type.
However, each beta assembly type has unique implications for production processes.
As the name implies, single-use solutions are designed to transfer one set of materials one time. Items are placed in the single-use solution (typically a beta bag) and sterilised, either by autoclave or gamma radiation. The sterilised materials within the bag are then ready to be transferred into the containment system for use in production. While the same single-use beta bag can be docked to the alpha port more than once, bags can only be sterilised once, so each bag can only transfer one batch of materials. After use, these bags are discarded.
Multi-use transfer solutions, also known as permanent transfer solutions, are designed for repeated use.
They are typically constructed from durable materials like stainless steel. The transfer process is nearly identical for single-use and multi-use systems, but multi-use transfer solutions are not discarded after use. Instead, they require thorough cleaning and sterilisation (usually autoclaving) between each use.
Containment solutions from CRL
Sterility considerations
In hygienic applications where strict adherence to regulations is essential and sterility is key, such as biopharma manufacturing, single-use transfer solutions are preferred.
This is because sterility begins at the point of manufacture.
“Single-use beta assemblies are built entirely in a cleanroom, and that means every component is cleanroom-manufactured. We injection-mould our beta bags in a cleanroom. All of the assembly is done in a cleanroom. We package them within the cleanroom. Then we ship them to the customer, who follows their own procedures to bring them into their cleanroom,” explains James Peterson, Sales Manager for Central Research Laboratories, a company that provides single-use and multi-use transfer systems.
Companies that manufacture single-use beta bags must have thorough compliance processes in place—and they are subject to audits to ensure production meets regulatory requirements and customer expectations. A compliance report must be provided with every batch of bags.
This unbroken chain of cleanliness drastically reduces contamination risks, making single-use more appealing for sensitive biopharmaceutical applications.
For multi-use components, the onus is on the end-user to sterilise and validate them before each use.
"Permanent or multi-use components are generally not going to be built in a cleanroom," Peterson notes. "They're going to be built in a more typical manufacturing environment, and then they are cleaned for purpose each time that they're used."
This cleaning and revalidation is labour-intensive and introduces a potential point of contamination if protocols are not rigorously followed. In the nuclear industry, which CRL has provided solutions for since the company’s inception, multi-use solutions are still widely used. However, the additional sterilisation steps required for multi-use beta assemblies make them a less attractive option for hygienic industries such as biopharma manufacturing.
Comparing costs
Financial considerations are another driving factor for selecting the optimal transfer system for a given process.
Multi-use canisters have a higher initial investment cost because they are constructed of durable materials and built to last.
Beyond the price of the equipment itself, there are high labour costs associated with components for multi-use transfer systems. Manufacturers must pay for the canisters to be thoroughly cleaned, sterilised and revalidated, and these costs can add up. However, in markets where labor is inexpensive, multi-use transfer solutions may be the preferred option.
Beta bags are comparatively inexpensive but the cost is recurring, as they must be restocked regularly. However, manufacturers save on labor with single-use components because they do not require cleaning and revalidation.
Manufacturers must also factor in the likelihood of contamination in their cost analysis, as any breach of containment can result in steep fines, operational shutdowns and a loss of public trust. Particularly in critical industries like biopharma manufacturing, contamination can put patient safety at risk and cause irreparable damage to a company’s reputation.
Containment solutions from CRL
Flexibility and scalability
Aseptic transfer solutions must be flexible enough to fit process requirements and scalable enough to support high-speed production.
Multi-use transfer systems are typically easier to customise in terms of form factor. Biopharmaceutical manufacturers have approached CRL for beta assemblies for a wide range of specific applications, including beta assemblies with outlets, connectors and even hoses for liquid transfer. CRL also provides beta assemblies to cover alpha ports during cleaning and downtime.
“The sky’s the limit in terms of what our engineers can embed into beta assemblies,” Peterson says. “Whatever our customers can envision, we build.”
Single-use transfer systems also offer flexibility, as they can be used to build custom kits that serve specific process needs. Tubes or valves can also be integrated into single-use beta bags, but production is constrained because any additions must be completed within a cleanroom.
Single-use beta assemblies generally enable more scalable processes because they don’t require cleaning and revalidation between uses, delivering the operational efficiency that facilitates smooth large-scale production.
The future of aseptic manufacturing
Both single-use and multi-use transfer systems have evolved over time, primarily with design considerations that improve usability and ergonomics of operation. The easier it is to securely dock the beta assembly to the containment system, the faster production can move, so these considerations also improve operational efficiency.
The next generation of transfer solutions will aim to integrate with automated processes, which will further reduce the risk of contamination. In addition to removing another potential source of contamination and human error, automation in biopharmaceutical manufacturing supports the level of production necessary to meet rising demand. These solutions are currently in development, and the industry is ripe for innovation.
Ultimately, single-use transfer solutions, such as beta bags, are more widely used for highly regulated, hygienic applications like biopharmaceutical manufacturing; however, multi-use beta assemblies still offer advantages for select applications.