When I first stood in front of a mass spectrometer nearly two decades ago, I was an eager postdoc completely swept up by the thrill of deciphering the unknown. Back then, we focused on discovery: a new protein, a new story. It didn’t really cross my mind at the time that the very tools we were fine-tuning for basic science would become so relevant to the biomanufacturing of life-saving biological drugs.
Today, mass spectrometry is a cornerstone of chemistry, manufacturing and controls (CMC) development for biologics valued for its depth, versatility, and accuracy. I’m really grateful that as Head of Omics & Informatics at Lonza, I get to witness advancements impacting pharma manufacturing happening firsthand: new analytical technologies are continuously being developed and optimized to ensure drug safety and efficacy.
The challenge of residual host cell proteins
Host cell proteins (HCPs) are process-related impurities in therapeutic proteins produced in recombinant hosts, such as E. coli, P. pastoris and Chinese hamster ovary (CHO) cells. The vast majority of these host-derived proteins are successfully removed during purification. However, some may persist throughout the downstream processing and potentially pose a risk for patients.
Risks may include immunogenicity and other adverse reactions, as well as a possible reduced efficacy where specific HCPs could cause degradation of the drug itself or of the excipients leading to a reduced shelf life.
The comfort of (low) numbers and the emerging of new requirements
Regulatory authorities explicitly require a control strategy for impurities, meaning any sponsor applying for the approval of a new drug should demonstrate HCPs have been measured in a consistent manner using a fit-for-purpose analytical method and reduced to a safe level.
Historically, HCP monitoring in biotherapeutics has been a task owned almost exclusively by Enzyme-Linked Immunosorbent Assay (ELISA). HCP-ELISA is a simple analytical method, relatively high-throughput, and blessed with decades of regulatory and technical familiarity. It provides a single validated number for the total amount of HCPs and for many years there has been consensus that levels in the low part-per-million (ppm) of total HCP relative to the drug are acceptable.
However, after more than 20 years of industry experience in HCP assessments and over 200 biological drugs approved, it has now become evident that it is not only the quantity that counts. In fact, especially when looking at drug efficacy and shelf life, issues may arise from the presence of traces of specific HCPs rather than from overall total HCP amounts. For example, the degradation of polysorbate, a common excipient in biologics, by host cell-derived lipases can significantly impact the cost of commercial drugs, reducing their shelf life and potentially requiring changes in storage conditions or formulation. Early detection of the presence of specific “high-risk” HCPs could significantly de-risk the manufacturing process and lead to improved drug product stability.
Unfortunately, ELISA cannot directly reveal the identity of individual HCPs. Crucially, mass spectrometry can provide this input.
Precision analytics applied to patient-centric quality: a new knowledge-driven, risk-based approach
The gradual move to mass spectrometry for HCP analysis reflects a broader evolution in regulatory thinking. In fact, agencies like the FDA and EMA now strongly advocate for knowledge-driven, risk-based approaches under the umbrella of ICH Q8–Q12. Mass spectrometry offers unmatched specificity and provides confident identification of individual components, even at trace levels.
In recent years, regulators have increasingly relied on mass spectrometry support data in biologics filings and new guidance has been recently released by the US Pharmacopeia to better define the use of mass spectrometry as a platform for enhanced process understanding and HCP risk assessment. As a matter of fact, a hybrid approach using ELISA for batch release and mass spectrometry for development and characterization is becoming more commonplace in industry.
There is a growing trust in mass spectrometry and in what it can deliver: a platform for data-driven process development and informed risk-based decision making.
A demand for simplicity and standardisation: the role of a trusted CDMO
However, while mass spectrometry offers unmatched analytical power, it remains a technically demanding method that requires specialized expertise, up-to-date equipment setup, rigorous method development, and careful data interpretation to ensure reliable results. Entrusting such critical work to a partner without the right capabilities can introduce significant regulatory and operational risk.
At Lonza, our promise as a trusted CDMO is to pioneer the simplification and standardisation of analytical methods, ensuring compliance with evolving regulatory requirements. Our commitment to staying at the forefront of residual HCP analysis helps our partners remove several potential pitfalls due to fragmented outsourcing. This translates into clear benefits, including a seamless integration of analytical data into process development, allowing faster decision-making, as well as the trusted support of subject matter experts who understand the full analytical history, thus minimizing the risk of discrepancies and misalignments.
This approach reflects Lonza’s vision of being the single trusted partner for our customers, grounded in operational excellence, regulatory confidence, and strategic adaptability.
