The steps of ADC drug pharmacy include:
For production process validation, the requirements are very complex in terms of both quality control and quality assurance:
In terms of production process quality control, it is necessary to detect the physical and chemical heterogeneity, structural integrity, amino acid sequence, advanced structure, and glycosylation modification of monoclonal antibody drugs; it is necessary to test the appearance, structure, physical and chemical properties, purity, content of the linker. It is necessary to detect the conjugable impurities and chiral isomers of small molecule drugs, unknown impurities, and the stability of small molecule drugs.
In terms of production process quality assurance, it is necessary to ensure the consistency of the production process of monoclonal antibodies, the inactivation or removal of infectious factors, the removal of product and process impurities, and the removal of product and process impurities. Stability and batch-to-batch consistency, production process consistency, impurity limits, etc. are guaranteed; the product quality stability and batch-to-batch consistency of small molecule drugs, production process consistency, magazine limits, etc., need to be guaranteed.
From the perspective of drug quality control, DAR is a key factor in the quality of ADC drugs. If the DAR is too low, the cytotoxin will become smaller and cannot kill the tumor; if the DAR is too high, it will be recognized by the immune system and eliminated. Therefore, DAR affects the safety and efficacy of ADC drugs, and the homogeneity of DAR directly affects the homogeneity of drugs, so it should be controlled within an appropriate narrow range to ensure product consistency.
Other critical quality factors include toxicity, pharmacokinetics and safety of DNA species composition, safety of free drug, immunogenicity, pharmacokinetics, toxicity and residual solvent safety of polymers or fragments.
The evaluation of the pharmacodynamics, pharmacokinetics and safety of ADCs is also complicated. Even ADCs acting on the same target may have different effects due to differences in the antigenic epitopes, linking sites, linkers and small molecule drugs they recognize. Mechanisms, plasma stability, metabolic processes in vivo, and toxic side effects will also vary.
Due to the structural complexity of ADC drugs and the diversity of in vivo processes, a variety of detection methods are required to complete the data detection required for pharmacokinetics; at the same time, ADC has dynamic variability, such as DAR values will vary with time points.