Control Strategy for Small Molecule Impurities in Antibody-Drug Conjugates
Hai H. Gong, Nathan Ihle, and colleagues present valuable insights into controlling impurities in ADCs, a promising class of biopharmaceuticals. With the backing of the International Consortium for Innovation and Quality in Pharmaceutical Development, the team lays out a science-based strategy addressing the challenges of small molecule impurities in ADCs.
Understanding ADCs and Their Challenges
Antibody-drug conjugates combine protein and small molecule structural elements, introducing unique control challenges. This blend typically involves a monoclonal antibody (mAb) and a low molecular weight linker attaching a drug. ADCs mainly target oncology, though the principles discussed apply broadly. The conjugation process sees the drug and linker merge chemically before latching onto a mAb.
The Dilemma with Small Molecule Impurities
Like all drugs, ADCs can host impurities, stemming from synthesis, purification, or storage. These impurities either relate to mAbs or small molecules, with this paper focusing on the latter. Given the vast molecular weight difference between ADCs and these impurities, understanding and managing associated risks become crucial.
Proposed Strategy for Managing Impurities
The low molecular weight of impurities, compared to ADCs, results in minimal patient exposure. A risk-based evaluation is consistent with existing ICH guidelines. Controlling conjugated small molecule impurities is most effective during the linker-drug manufacturing phase, rendering stringent ICH Q3A limits unnecessary at the linker-drug stage. Fortunately, standard manufacturing processes typically clear non-conjugated impurities.
In Conclusion: A Fresh Perspective on ADC Impurity Management
Gong and team have highlighted unique challenges of ADCs compared to traditional drugs. However, the risks from small molecule impurities remain low. Adopting a risk-based approach, aligned with ICH guidelines, ensures safe and efficient ADC production.
Gong HH, Ihle N, Jones MT, Kelly K, Kott L, Raglione T, Whitlock S, Zhang Q, Zheng J. Control Strategy for Small Molecule Impurities in Antibody-Drug Conjugates. AAPS PharmSciTech. 2018 Apr;19(3):971-977. doi: 10.1208/s12249-017-0943-6. Epub 2018 Jan 4. PMID: 29302872.