Literature
Understanding the risks of Host Cell Proteins (HCPs) in biopharmaceuticals
by Thomas Kofoed, CEO, and Jette Friis Thirup, Head of Business Development, Alphalyse
Why HCP contamination matters and how to ensure drug safety
Host Cell Proteins (HCPs) are process-related impurities that originate from the living cells used to produce biologic drugs, such as monoclonal antibodies (mAbs), vaccines, and recombinant proteins. While these proteins are unintended byproducts, their presence in the final drug product can significantly impact safety, efficacy, and stability.
If not adequately removed, HCPs can trigger immune responses, interfere with biological activity, or degrade critical drug components. With increasing regulatory scrutiny from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), biopharmaceutical companies must implement robust strategies to monitor and control HCP contamination.
Here we will explore the key risks associated with residual HCPs and how advanced analytical methods can ensure regulatory compliance and product safety.
The risks of residual HCPs
Immunogenic reactions – Triggering unwanted immune responses
Even at trace levels, HCPs can be highly immunogenic, meaning they can provoke an unwanted immune response in patients. The immune system recognizes these foreign proteins as threats, leading to antibody production or, in severe cases, hypersensitivity reactions.
Example: Clusterin – A known immunogenic HCP
Clusterin, a chaperone protein found in some biologics, has been linked to increased immunogenicity. If present in a therapeutic drug, it can reduce efficacy or cause patient safety concerns. Regulatory agencies require thorough risk assessments and documentation to prevent such complications.
Biological activity interference – Disrupting drug function
Some HCPs have biological activity that can interfere with the intended mechanism of action of the drug, leading to inconsistent therapeutic effects.
Example: Heat shock proteins (HSPs) – A risk factor for thrombosis
Heat Shock Proteins, commonly present in mammalian cell cultures, can inadvertently influence coagulation pathways. If not detected and removed, they may increase the risk of thrombosis in patients receiving the drug.
Enzymatic degradation – Reducing drug stability
Certain HCPs exhibit enzymatic activity that can degrade the drug substance or essential excipients, leading to reduced potency and shorter shelf life.
Example: Lysosomal Acid Lipase – A silent threat to drug stability
Lysosomal Acid Lipase is an enzyme known to degrade polysorbate, a widely used excipient in biologics. If left unchecked, it can compromise the long-term stability of the drug, leading to unexpected formulation failures and regulatory delays.
(the article continues below the picture..)
On demand webinar
Problematic HCP impurities can stop your biologics project!
In several clinical trials and during the development of many biologics, specific HCPs, such as flagellin, proteases, and the infamous PLBL2, have proved problematic.
The future of HCP detection: Liquid Chromatography-Mass Spectrometry (LC-MS)
Liquid Chromatography-Mass Spectrometry (LC-MS) is increasingly recognized as the new gold standard for HCP analysis due to its superior specificity and sensitivity.
Advantages of LC-MS:
- Identifies individual HCPs – Unlike ELISA, LC-MS can detect and quantify each HCP separately, providing precise risk assessment.
- Higher sensitivity and accuracy – LC-MS can detect HCPs at trace levels (parts per million), improving batch-to-batch consistency.
- Regulatory alignment – Regulatory bodies are encouraging the adoption of LC-MS. The United States Pharmacopeia (USP) General Chapter <1132.1> outlines best practices for using LC-MS in HCP detection.
Integrating LC-MS into the quality control strategy, biopharmaceutical companies can enhance product purity and accelerate regulatory approvals.
Conclusion
HCP contamination remains a significant challenge in biopharmaceutical manufacturing. Immunogenicity, biological interference, and enzymatic degradation can all impact drug safety, efficacy, and stability. As regulatory expectations evolve, companies must adopt more advanced analytical techniques to ensure product purity.
While ELISA remains a useful tool, LC-MS offers superior HCP identification and quantification, making it the preferred method for ensuring compliance and product quality.
Key Takeaways:
- HCPs can cause immunogenic reactions, interfere with drug function, and degrade formulations.
- Regulatory authorities require robust detection and control strategies for HCPs.
- LC-MS provides more accurate and comprehensive HCP analysis than ELISA alone.
Next Steps
- Evaluate your current HCP detection strategy - does it align with regulatory expectations?
- Consider integrating LC-MS as an orthogonal method for enhanced risk assessment.
- Stay ahead of evolving compliance requirements, including USP <1132.1> and FDA guidelines.
Would you like a deeper dive into specific HCPs or analytical techniques? Please contact us now!
Talk to us
Whatever protein-related challenge or question you may have, we would love to help. Our experts can help you decide on the best analytical approach for your project by email or online meeting - providing advice without obligation.