Process safety in fluid management of ADCs

Antibody-Drug Conjugates (ADCs) are highly promising novel biopharmaceuticals that have the potential to shape the oncologic landscape in the present decade. Billions are invested by big pharma and biotechnology start-up companies alike and the market is expected to show double digit growth rates. ADCs are targeted therapies and most of them shuttle extremely active cytotoxic molecules to the desired target by means of monoclonal antibodies (mAbs).

Thus, their production involves the handling of toxic solutions in the biotechnology manufacturing setting. Naturally, process safety in fluid management is of utmost importance for biopharmaceutical manufacturing companies.

This article will give you an overview of ADCs, their applications and fluid management issues while handling them, and how to address them.

What are Antibody-Drug Conjugates (ADCs)?

Antibody-Drug Conjugates (ADCs) are a relatively new class of biopharmaceuticals. They combine the remarkable specificity of monoclonal antibodies (mAbs) and the high potency of small molecule cytotoxins (cell killing agents). In fact, the used cytotoxins are so potent that their toxicity makes them almost useless on their own due to severe side effects. The key feature of ADCs is the sparing of healthy cells through selective delivery of the toxic substance into cancer tissue, where they cause cell death. 

Due to the mAb component of ADCs, they are generally considered members of the large molecule class, and more specifically large biomolecules, that have small toxic molecules attached to them by means of a linker. As such, the biomolecular portion has to be manufactured by biotechnological means: usually recombinant technology to produce cells capable of expressing the desired antibody, followed by cell culture in bioreactors to get an antibody rich culture media mixture. Several downstream processes separate cell fragments, salts, solvent and impurities in order to isolate the pure mAb product. The subsequent attachment of linker and small molecule finishes the ADCs.

Vaccines and Cell and Gene Therapies (CGT) are related to ADCs in the sense that they are biopharmaceuticals as well and are generally manufactured by biotechnological processes.

Fields of application for Antibody-Drug Conjugates

The vast majority of today’s ADCs are approved or developed for treating various hideous oncologic diseases, i.e. especially hard to treat cancers.

The first ADCs to gain FDA approval, gemtuzumab ozogamicin, sold as Mylotarg ®, is used to treat acute myeloid leukemia (AML), a type of blood cancer. In fact, most ADCs target malignant blood cells or cells of the lymphatic system, e. g. Hodgkin lymphoma, anaplastic large-cell lymphoma, B-cell lymphoma and multiple myeloma. Additionally, some types of solid tumors exhibiting unique molecular surface features can be targeted by ADCs: HER2-positive metastatic breast cancer, and some recurrent or metastatic cervical cancers.

Recent innovations are the development of ADCs to treat autoimmune diseases. In this application, the mAb is selective for hyperactive immune cells that cause disease states. The ADC carries its cytotoxic payload to the overstimulated immune cells, thus reducing symptoms or even curing the patient.

Safe manufacture of ADCs - the challenges and solutions

ADCs bring several major challenges that are distinct from the underlying biology. Since they are composed of an mAb and a highly toxic small molecule combined via bioconjugation, their manufacture is no easy undertaking. The whole complexity of biotechnology, including recombinant technology and cell culture, is multiplied by the hurdles of handling highly toxic substances on commercial scale.

Both components are usually handled in solution as liquids to ensure the stability of the antibodies as well as avoiding working with toxic powders, thus increasing the production yields as well as reducing toxicity risks for workers.

To sum up, major challenges in the supply chain of ADCs include

• mAb production, with concern to achieving high product quality by adequate fill/filtration processes
• safety concerns when handling highly toxic substances on a larger scaleadequate freeze/thaw processes, adapted to the respective product requirements
• space efficiency during ultra-cold storage and transport

Safe handling of ADCs with closed systems

The safe manufacture of ADCs is extremely simplified by embracing fluid management with single-use equipment, such as sterile tubing, filter cartridges, storage bags etc. These tools allow the handling of manufacturing intermediates and finished products in closed systems without exposing them to the environment (and vice versa): With manual handling of the substances not being necessary throughout the filling process, the risks for staff to get in contact with them is extremely minimized.

Further development to minimize risks

But still, there’s residual risk of contamination of workers and product loss as a consequence of e. g. bag rupture. As a leading specialist in the field of fluid handling, Single Use Support developed solutions to minimize such risks even further: RoSS.Shell, an innovative container for the safe handling of single-use bags that is even suitable to contain ADCs during controlled freezing. By significantly reducing the risk of bag rupture, the single-use bag container does not only avoid product loss, but also minimizes the risk for staff to be harmed by the contained substances. Key players in the biopharma field collaborated with Single Use Support to gain access to their equipment and expertise.

The growing ADC market will increasingly rely on trusted partners like Single Use Support that bring years of specialized experience to the table.