Three Unit Operations for ADC Manufacturing on One Skid: Eliminating Transfer Steps to Increase Operator Safety

Reducing Production Bottlenecks Could Be the Key to Making ADCs  More Widely Available

^{This article is posted on our Science Snippets Blog}

Antibody–drug conjugates (ADCs) have shown increasing promise in recent years for the treatment of a variety of cancers due to their ability to target potent anticancer compounds to the tumor site. ADCs are typically comprised of three moieties:

1. the cancer drug needed for treatment
2. the antibody which targets the drug to specific cancer cells
3. the linker that ties them both together

Adding specific targeting to cancer drugs should increase the efficiency with which they can kill cancer cells. It also means that treatment can be done with a lower systemic drug concentration. This is important for reducing potential side effects of drugs, but it also allows compounds that were considered too toxic for systemic administration to be used at lower concentrations.

Monoclonal antibodies (mAbs) provide specificity for novel drugs in ADCs, and the therapy is provided by a cytotoxic agent, in combination with the linker. To be effective, the cytotoxic agent must be released, and this is often achieved by incorporating a linker that will be broken down in the tumor microenvironment. For example, the linker could be degraded by tumor-associated enzymes, which would then only release the cytotoxic payload at the site of the tumor.

This makes ADCs extremely attractive candidates for new anticancer drugs. However today, there are problems that are preventing their more widespread use. One of the main problems is the handling of the extremely high toxic compounds. This makes every stage of R&D and manufacture more difficult as intricate safety protocols need to be in place, requiring highly trained staff and additional equipment. 

At Sartorius, we have developed a DSP system that can significantly improve the production of therapeutics such as ADCs by combining three unit operations on one skid, and automating them, to reduce the safety risks associated with manual labor.

Sartoflow^® Expert SU combines Tangential Flow Filtration (TFF), sterilizing grade filtration and mixing all in one skid. For ADCs, these would usually be carried out over three different skids which increases the footprint of production, but also requires the transfer of highly toxic material between stages. Having the main three steps of  the ADC production in one instrument is therefore a huge benefit for safety and productivity.

To fully illustrate how ADCs can be synthesized in one instrument, here is a recap of the synthesis steps. 

1. Conjugation
   Firstly, the linker|payload combination are conjugated to the mAb of choice. This requires thorough mixing.
2. Quenching
   A quencher molecule is used to sequester all of the unbound linker|payload molecules. Aggregates and precipitatee are then removed with a 0.2µm filter and chased to wash out all residual product from the transfer line.  
3. TFF
   TFF is used to remove all the unbound and quenched linker|payload molecules to prepare the ADCs for their final use. From here, any final adjustments to the buffer and product concentrations can be made before they are ready for use.

Sartoflow^® Expert SU handles each of these steps in a completely automated way. The conjugation reaction is performed in a single-use bag containing mAbs as the toxin is gradually flowed in. Once completed, the quencher can then be automatically added before removal of precipitates with a 0.2 µm filter, while transferring to the TFF recirculation bag. Subsequently, TFF is performed in the fully closed loop to adjust concentration and exchange the buffer. After this, TFF can be used as the ADC product is flowed into a new single-use bag where it is effectively ready for use. There are a range of different TFF membranes available that can be used with different molecular cut-offs.  

While the manufacture can be automated, that doesn’t mean that there’s no control. The Sartoflow^® Expert SU provides granular control over each step of the process to make sure that every part of the production is optimized and finely tuned. 

Producing therapeutics like ADCs is very costly however with Sartoflow^® Expert SU, you can reduce the risk of things going wrong that could jeopardize production. The automation reduces the chance of human error and the combination of three process steps in one skid means nothing is lost in the transfer process. Our batch sizes can range from 1 liter to 20 liters meaning you can start small with your optimization and go right up to pilot scale using the exact same system. Manufacture is a small but vital part of the ADC puzzle. By reducing the barriers and the risks to pilot scale production, the Sartoflow^® Expert SU enables a reduced time to market for ADCs.

Scaling up in this range is critical to saving money on small batches at the start, as well as ensuring that pilot batches behave as expected. You can have a peace of mind knowing that production working on an R&D level will easily scale up to a 20-liter pilot production.

Larger batches also increase the safety concern therefore minimizing human exposure to the drugs during ADC manufacture reduces the risks to the operators. With its 3-in-1 automation concept, the Sartoflow^® Expert SU is the optimal choice to eliminate the risk of exposure to toxic compounds in ADC manufacturing.

ADCs are a particularly good example for illustrating how the Sartoflow^® Expert SU works, but they are not the only application by a long stretch. Our platform is extremely flexible allowing you to produce pilot scale batches of many biologics in a reproducible way; from nucleic acids, peptides, mAbs to a variety of bioconjugates.

With its 3-in-1 approach, single-use closed loop and high flexibility in process design, the Sartoflow^® Expert SU is the perfect tool for producing ADCs from PD to pilot scale with unparalleled safety. It can be widely applied for all sorts of biomolecules beyond bioconjugates, especially where a single-use flow path with aseptic connection or mixing in small scales with temperature control are beneficial. 

Learn More About the Sartoflow^® Expert SU | Sartorius