Single-Use Equipment As an Enabler of ADC Conjugation in a Standard Protein Plant Using Closed Systems

Presented by Berthold Boedeker

Dr Berthold Boedeker is chief scientist of global biological development WUP, Bayer, Germany.

Antibody–drug conjugates (ADCs) are biopharmaceuticals consisting of a monoclonal antibody linked with a stable or cleavable linker to highly potent cytotoxic drug. ADCs can treat cancer because the antibody portion of the them binds with high specificity to receptors on tumor cells. Once a cell internalizes the cytotoxic drug and cleaves it from the linker, the molecule can exert its cytotoxic effect.

A major focus during the manufacture of biopharmaceuticals is protecting a product from contaminants in the environment of a production facility. By contrast, the focus of highly potent chemical drug manufacture is the protection of the environment and employees within that environment from exposure to what can be very hazardous substances. The manufacture of ADCs is where those two worlds come together. The conventional approach that the industry has adopted to ADC manufacture has been to produce the antibody portion of the drug in standard mammalian cell culture facilities and the cytotoxic drug in a separate plant by chemical synthesis. Companies then perform the conjugation reaction and subsequent ADC processing steps in a separate facility with the capability to handle safely both biologics and high potency molecules.

Figure 1: Ultrafiltration (UF) and diafiltration (DF) of antibody–drug conjugates (ADCs)

Bayer decided to challenge that convention when they expanded their ADC production capacity. Designing and building a new facility dedicated to ADC production would have taken three years to build and required a significant capital investment. Instead, they chose to install the new capacity within the Class C, final antibody formulation suite of an existing mammalian cell culture production plant using isolator technology.

The company contacted Sartorius Stedim Biotech to assist in the design of a functionally closed, fully single-use solution to perform the ADC conjugation and subsequent steps leading to the filling and frozen storage of drug substance in Flexboy® bags. The production system was successfully designed for batch sizes of 10–100 L and can use a disposable bioreactor for conjugation, a single-use FlexAct® UD system for concentration and diafiltration, a potential purification step, and disposable sterile bulk filtration assemblies. The design of the system required customization of off-the-shelf components because of specific ADC processing requirements, including the need for operation within the isolator.

Single-use processing technology for ADCs must be resistant to such chemicals and have low hold-up volumes to minimize losses of drug substance with very high value. Using single-use technologies for ADC production reduces the work operators must perform in a suite because suppliers provide assemblies preassembled and sterilized. If those systems are connected as closed systems, there is significantly reduced risk of batchto- batch failure or contamination.

Regulators will accept a single-use approach if companies can demonstrate that there is no risk to patients, the product, the environment, or employees. ADC manufacturers that opt for disposable technologies should consider the risks of chemical reactions occurring between the film and process solutions and ensure that they receive a comprehensive extractables and leachables guide from their vendors.