Host cell protein (HCP) in biomanufacturing

In the early 2000s, scientists were focused on discovery: a new protein, a new story. What scientists couldn’t have known at the time was that the very instruments they were fine-tuning for basic science – including mass spectrometers – would become essential to the biomanufacturing of life-saving biological drugs.

In the modern day, mass spectrometry is a foundation of chemistry, manufacturing, and controls (CMC) development for biologics. It is especially valued for its accuracy, versatility, and depth.

As Head of Omics & Informatics at Lonza, Sabrina Liberatori has witnessed advancements in pharma manufacturing firsthand: new analytical technologies are continually being developed and optimized to ensure drug efficacy and safety.

Residual host cell proteins and their challenges

Host cell proteins (HCPs) are process-related impurities in the therapeutic proteins produced in recombinant hosts, such as E. coli, P. pastoris, and Chinese hamster ovary (CHO) cells. Most of these host-derived proteins are successfully removed during purification.

However, some can persist throughout downstream processing, potentially posing a risk for patients. Such dangers include immunogenicity and other unfavorable reactions, as well as a potential reduction in efficacy, in which specific HCPs could degrade the drug itself or its excipients, leading to a shorter shelf life.

The comfort of (low) numbers and the emergence of new requirements

Regulatory authorities specifically require a control strategy for impurities, meaning that any sponsor seeking approval of a new drug should demonstrate that HCPs have been measured consistently using a fit-for-purpose analytical method and reduced to a safe level.

Conventionally, HCP monitoring in biotherapeutics has exclusively been performed using Enzyme-Linked Immunosorbent Assay (ELISA). HCP-ELISA is a simple analytical method with relatively high throughput; it is also well established with many years of regulatory and technical familiarity, delivering a single validated number for the total amount of HCPs.

For a long time, it was thought that levels in the low parts per million (ppm) of total HCP relative to the drug were suitable. However, following more than 20 years of industry experience in HCP assessments and the approval of over 200 biological drugs, it has become apparent that quantity alone does not count.

In fact, particularly when considering drug efficacy and shelf life, issues can arise from traces of specific HCPs being present, rather than from overall total HCP amounts. For example, polysorbate is a common excipient in biologics, and its degradation by host cell-derived lipases can significantly increase the cost of commercial drugs, potentially requiring changes in storage conditions or formulation and reducing the product’s shelf life.

Early detection of specific ‘high-risk’ HCPs could substantially reduce risk in the manufacturing process, thereby improving drug product stability. Unfortunately, ELISA cannot directly identify individual HCPs. Cass spectrometry, however, can provide this crucial input.

Precision analytics applied to patient-centric quality: a new risk-based, knowledge-driven approach

The shift toward mass spectrometry for HCP analysis mirrors a broader change in regulatory thinking. Agencies such as the FDA and EMA now strongly promote knowledge-driven, risk-based approaches under the larger umbrella of ICH Q8–Q12.

Mass spectrometry offers unparalleled specificity and allows users to confidently identify individual components, even at trace levels.

In recent years, regulators have relied more on mass spectrometry support data in biologics filings. As a result, new guidance has recently been released by the US Pharmacopeia to better define mass spectrometry as a platform for improved process understanding and HCP risk assessment.

A hybrid approach that employs ELISA for batch release, followed by mass spectrometry for development and characterization, is becoming increasingly common in industry settings. There is growing trust in mass spectrometry and its capabilities: it is now considered a platform for informed, risk-based decision-making and data-driven process development.

Demanding simplicity and standardization: the role of a trusted CDMO

While mass spectrometry has unmatched analytical potential, it is a technically demanding method that requires rigorous method development, specialized expertise, up-to-date equipment, and careful data interpretation to yield reliable results. Entrusting important work like this to a partner without the correct capabilities can introduce substantial regulatory and operational risk.

As a trusted CDMO, Lonza pioneers the simplification and standardization of analytical methods to comply with evolving regulatory requirements. The company commits to staying at the forefront of residual HCP analysis, helping partners avoid several potential pitfalls arising from fragmented outsourcing.

This results in clear benefits, including seamless integration of analytical data into process development, which facilitates faster decision-making. Customers also benefit from the trusted support of experts who understand the full analytical history, thus reducing the risk of misalignments and discrepancies.

This approach reflects Lonza’s vision of being the single trusted partner for customers, grounded in regulatory confidence, strategic adaptability, and operational excellence.

Acknowledgments

Produced using materials originally written by Sabrina Liberatori from Lonza.

About Lonza

Lonza is one of the world’s largest contract development and manufacturing organizations (CDMOs) dedicated to serving the healthcare industry. Working across five continents, our global team of approximately 20,000 colleagues works alongside pharma and biotech companies to turn their breakthrough innovations into viable therapies. We support our customers in bringing life-saving and life-enhancing treatments to patients worldwide with a combination of cutting-edge science, smart technology, and lean manufacturing.

Our company generated sales of CHF 6.5 billion with a CORE EBITDA of CHF 2.1 billion in Full-Year 2025.

Find out more at www.lonza.com.

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