A CMC worst-case scenario
A CMC worst-case scenario:
- A recombinant drug candidate expressed in E. coli contained several Host Cell Proteins (HCPs), including flagellin.
- Clinical trials were suspended in Phase II after a patient suffered a severe reaction during infusion.
Following the failed clinical trials, the developer required more than a decade to eliminate the HCPs and bring the drug to market.
This case study underscores the need for enhanced analytical methods to ensure the safe and effective development of drugs. Failure to identify and monitor problematic HCPs puts patients and projects at risk.
However, you can minimize the risk with proper assay characterization and coverage analysis.
Host Cell Proteins in clinical trials
Host Cell Proteins are process-related impurities that can co-purify with therapeutic proteins in biopharmaceutical drugs and end up in the final drug product administered to clinical trial participants. Some protein impurities can compromise patient safety, treatment efficacy, or the quality of the drug product.
In worst-case scenarios, residual Host Cell Proteins may cause harmful immune reactions in patients.
The cost of ignoring Host Cell Protein impurity risks
Adverse immune reactions can put clinical trial participants and future patients at risk - and jeopardize the development success of biopharmaceutical drugs.
Discovering severe adverse reactions during clinical studies typically results in delays of several years as the cause is investigated and the manufacturing process is optimized. It may even force the withdrawal of a promising compound from the pipeline.
Early identification of Host Cell Proteins of concern
In the past, HCPs causing adverse immune responses were often not discovered until clinical trials. However, at this stage, conducting a root cause analysis and optimizing the process are both costly and time-consuming.
In this case, the developer created a processāspecific ELISA and measured an HCP concentration that was a factor of 3-4 higher than the initial result measured using a commercial, generic E. coli HCP ELISA. However, it's now enough to keep HCP levels low; you also need to ensure none of the HCPs are of concern.
Mass spectrometry (LC-MS)-based Host Cell Protein analysis can identify and quantify individual protein impurities during development, enabling data-driven risk assessment to ensure the safety, efficacy, and quality of biologics.