Antibody–drug conjugates (ADCs) are increasingly
prevalent
as investigational and marketed treatments for a variety of cancers
and other diseases. The structures of most ADCs comprise a small-molecule
component (the drug-linker) chemically conjugated to a monoclonal
antibody, and this hybrid construct presents a number of challenges
for Chemistry, Manufacturing, and Controls (CMC) development. A Small
Molecule Considerations for ADC Development Working Group (WG) has
been established within the IQ Consortium to serve as a forum for
biopharmaceutical industry companies to discuss development strategies
for ADCs, with a focus on the drug-linker portion. The preceding paper
from the WG presented results from a benchmarking survey of IQ member
companies on a number of topics relating to drug-linker development.
One of the key findings was that ultrafiltration/diafiltration (UF/DF)
is used by all responding companies for purification of the ADC following
the conjugation step and is a critical operation for control of small-molecule
impurities in the ADC drug substance. UF/DF is well established in
monoclonal antibody processing, but to date, there are relatively
few literature reports detailing its application to ADCs. To help
address this gap, this manuscript presents results and analysis from
a more focused survey of IQ member companies on the application of
UF/DF for post-conjugation purification of ADCs. Insight is provided
into practical considerations such as common operating parameters,
relative efficiency of removal of different types of impurities, technical
challenges, and application of emerging technologies. In addition,
recommendations are offered on where to start when developing a UF/DF
process for a new ADC. The overall goals are to provide an overview
of current industry practices for UF/DF purification of ADCs and to
spur further communication and innovation in this area.