Single-Use technology in biopharma manufacturing: one company's perspective

 

Ruud Verstegen, process engineer at Byondis, a Nijmegen-based clinical-stage biopharmaceutical research and development company, discusses his experience with single-use materials.

 

Single-use technology – products or solutions that are made from various forms of disposal plastic and intended for one-time use – has emerged as an important solution for biopharmaceutical companies. There are many advantages, including: elimination of cleaning needs and in-house sterilization requirements; reduced use of cleaning chemicals; fewer storage requirements; increased process flexibility and optimization; reduced cross contamination risks; and lower investment costs. But there are also challenges.

 

Byondis creates precision medicines targeting intractable cancers and autoimmune diseases. The company focuses on the development and production of monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs) and small molecules. Verstegen is mainly involved in the production of investigative ADCs, therapies composed of a mAb that is linked via a chemical linker to a cytotoxic drug. The mAb binds to receptors found on cancer cells and the linked drug enters these cells, killing them without harming healthy cells.

 

The switch to single-use: flexibility, speed, EHS

Verstegen cites production process optimization as the main reason for Byondis’ increased use of single-use solutions over time. “In 2013, when we started producing monoclonal antibodies and antibody-drug conjugates, we didn't employ many different single-use materials,” says Verstegen. “Later on, with the addition of several production processes, we expanded our single-use options considerably.”

 

“Single-use materials provided more flexibility. For example, if we wanted to design a slightly different process, or switch to the production of new or different batches of medicines, we could do it faster,” he explains.

 

The risk of cross-contamination also played a role, according to Verstegen. “With single-use materials, our employees were better protected against the dangers of the toxic substances they often handle.” The cytotoxic drug in ADCs is delivered in powder form coupled to a linker-drug, which must  first be dissolved in an organic solvent because it is poorly soluble in water. This can be a risky step for employees and is done in an isolator.

 

“Once dissolved, the risk is more manageable,” says Verstegen. “Then the conjugation part, in which the linker-drug is linked to the antibody and purified, can take place. As much as possible, these steps occur in fume hoods with single-use materials. These materials can be disposed of after use in special drums that are subsequently destroyed. In this way, employees do not have to clean and are therefore not in contact with hazardous materials.”

 

Single-use materials and the elimination of cleaning steps also optimizes production and benefits the environment. “Cleaning produces a lot of liquid waste streams that have to be collected and destroyed, with all the EHS (Environmental Health & Safety) requirements that this entails. After that, everything needs to be sterilized again. With single-use products, we eliminate all that,” Verstegen explains.

 

The challenges: continuity, compatibility

While the benefits of single-use systems far outweigh the risks, Verstegen identified some challenges that he and his team have encountered over the years, as well as solutions.

 

“You have to be flexible with your production plan. Before start, everything is carefully engineered. When introducing single use materials – for example, for certain filter steps, a mixing vessel or transfer to another vessel – we need to connect everything together. Not all the connections are the same and fit together so we have to find a solution. Moreover, there is usually little space in a fume hood and you really have to think and engineer carefully how to outline the production plan.”

 

“Another thing to take into account is that the organic solvent for dissolving the linker-drug is sometimes incompatible with the plastic in the single-use product and can therefore lead to leachables. To prevent this, we always request information from the manufacturer, but we also conduct tests ourselves,” says Verstegen.

 

Finally, there could be supply issues. According to Verstegen: “When choosing complex single-use products, you can become dependent on the supplier. And if that supplier is temporarily unable to supply a product or product component like we have seen during the Covid period, or if they make a component change, you have a problem. So you have to figure out the consequences for your production process and come up with a solution.”

 

“Single-solution technology can save time, money, avoid risks and benefit the environment,“ says Verstegen. “While it requires careful planning, coordination and at times, troubleshooting, it’s well worth the effort,” he concludes.

 

Interview John Rook - Lonza

Innovation Support and Growth hub - automation in bioprocessing

 

“We are looking at production processes in cell and gene therapy that have so far mainly been done manually,” says Tim Jaarsma of IMI. “Together with companies that are active in this field, we analyze the risks that occur in the manual processes by which batches are lost and think about what kind of products we can develop to automate the actions.”

 

Tim Jaarsma talks about the development of products within the Growth Hub, an innovation platform of IMI in which solutions and/or new products are developed together with the customer based on problems from the market. IMI is an engineering company that focuses on industrial automation, transportation and life sciences. Jaarsma is involved in bioprocessing within the life sciences section.

“By talking to R&D persons from life science companies or via a questionnaire that can be filled in online on our website, we learn about the problems that people encounter”, says Jaarsma. “By collaborating with them on new developments, we help to bring products to the market faster.”

 

Mass flow controller

“For example, we have developed a miniaturized mass flow controller for bioreactors to dose the supply of gases. Comments from the market indicated that customers considered the existing mass flow controllers rather large and expensive. Since we produce special valves in our facility in Switzerland that are also used in other mass flow controllers, we already possessed the knowledge and facilities. On the inside of such a controller there is a proportionally switched valve that ultimately regulates the flow. It also contains a piece of electronics and a sensor. By connecting it to a bioreactor, various gases can be supplied. In order to be able to dose several gases at the same time, we have built a valve island on which several valves are located next to each other, each of which ensures the dosing of a different gas.”

 

Pinch valve

A pinch valve has also been developed on which a special io-link sensor has been built that provides a visual indication of the status (open/closed) of the valve. Pinch valves are used, for example, in downstream processing, where waste products are removed and buffers are supplied for ultrafiltration. Valves are needed to direct those fluids in a certain direction to supply something or control the pH. The valves only come into contact with the outside of the hoses through which the fluid flows. They are therefore both suitable for single use and multi use. However they are especially suitable for applications requiring a high level of hygiene control since a key feature of the valve is that it has no dead volume where fluid can get trapped.

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