The 2019 World ADC conference in San Diego, CA, held October 8 – 11, 2019, started with a day of 9 interactive workshops on a variety of topics, addressing challenges in the development of antibody-drug conjugates.

One of the workshops focused on Reference Standards and Specifications. This workshop was chaired by Shawn Novick, an independent consultant, who, for nearly 14 years was the director of the Quality Control Department at Seattle Genetics where she was responsible for release and stability testing of all clinical and commercial products being developed by the company.

Attendees included people with varying degrees of experience in antibody-drug conjugates and Chemistry, Manufacturing and Controls (CMC).

The workshop was divided into two sections:
• Reference Management and
• Specifications.

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ADC Reference Management
The workshop explored ways to identify and manage reference standard materials and how to bridge references as the product moves towards commercialization and beyond.

Topics included where to derive the first reference material (most often from toxicology material), how to change (and why to change) references during clinical studies, and how to establish a commercial primary and working reference.

Comparability, potency, and characterization were discussed as well as stability requirements. For stability, it was agreed that an annual review (either by testing or control chart) was sufficient for regulatory purposes but monitoring the reference each time it is used helps to catch potential issues in real time.

Potency of the reference (and how to monitor that for change) was highlighted as a challenging issue best addressed by having an assay control lot (separate from the reference) and monitoring the assay parameters.

Changing reference material during the clinical phase, establishing the commercial reference, and changes made post-commercial were also highlighted.

The final take-home message was: ‘Archive all reference materials’ to allow use for comparability studies when change is necessary.

ADC Specifications
The Specifications section started off with the reminder that specifications are in place to assure safety and efficacy. Many Critical Quality Attributes (CQAs) for an ADC result from the intermediates (antibody and DL), but this workshop focused on CQAs related to the ADC: Drug-to-Antibody Ratio (DAR), Potency, % unconjugated antibody, and the amount of free-drug.

Some strategies for setting scientifically justified ranges for the DAR at FIH were reviewed as well as possible development experiments that could help define what % unconjugated antibody would be problematic.

The attendees discussed the challenge of setting commercial ranges with very few data points and the meaning of ‘clinically relevant specifications’. The use of dose escalation and toxicology study data was provided as a path to justify some ranges for impurities.

Finally, the group was encouraged to add variability during manufacturing – different lots of antibodies linked with different DL batches, or using older batches of Intermediates or DS to help justify the specifications and the expiration dating.

The final takeaways:
• Scientifically justify the ranges proposed with development data, characterization, and CQA understanding and
• Include variability (if possible) in materials used during clinical studies as this will provide greater confidence in ranges.

Workshop F: From FIH to Post-commercial: ADC Reference Standard Management & Setting Specifications. October 8, 2019. Held during World ADC, San Diego, CA.

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