Mass spectrometry-based analysis of biologics will soon have its own chapter in the US Pharmacopeia, marking a significant advancement in the quality assurance of biopharmaceuticals.
On Sunday 1st December 2024, a new general chapter in the US Pharmacopeia (USP) will provide guidelines for mass spectrometry (MS)-based quantification of host cell protein (HCP) impurities in biologic drugs. This development signals a transformative moment for the pharmaceutical industry, offering an advanced method to detect and manage impurities, potentially reducing side effects and enabling the creation of safer, more effective treatments.
Host cell proteins are unintended by-products of the development and manufacturing processes for biotherapeutic medicines such as vaccines, antibody treatments, and gene therapies. If not adequately removed, these impurities can compromise drug efficacy or pose risks to patients.
The widely used enzyme-linked immunosorbent assay (ELISA) has limitations in detecting certain HCP impurities. To address these shortcomings, regulatory authorities are now recommending MS analysis as a complementary or standalone method for impurity control and documentation. Derrick Zhang, Senior Scientist with the US Pharmacopeia, explained the rationale for this advancement:
“It is an industry-wide challenge to control HCPs to ensure the safety and quality of biopharmaceutical products. Mass spectrometric methods have now been developed to the point where they can detect and identify even very small amounts of impurities. And it is in this light that we choose to publish a new method chapter to standardise the use of mass spectrometry in the industry.”
A technological breakthrough decades in the making
MS-based HCP analysis has been in development since the 1990s. Danish contract research organisation Alphalyse A/S, a pioneer in this field, has been instrumental in creating many of the analytical methods featured in the new USP chapter.
“We’re facing a breakthrough in the pharmaceutical industry. Mass spectrometry is a quick and effective method that can identify tens of thousands of different host cell proteins while detecting their respective amounts, allowing the targeted removal of harmful impurities in drugs,” said Ejvind Mørtz, co-founder of Alphalyse A/S and PhD in protein chemistry and molecular biology.
Mørtz highlighted that MS-based analysis is particularly beneficial for complex biologics like cell and gene therapies aimed at treating cancers, Alzheimer’s, and genetic disorders. He added, “Achieving regulatory approval for complex drugs has been difficult because conventional analytical methods are unable to detect all types of impurities. The recognition of mass spectrometry as a complementary method opens the door for us to support biopharmaceutical developers in getting their drugs approved for clinical trials and patient treatment.”
In addition to its precision, MS-based HCP analysis offers a much faster timeline compared to ELISA. While process-specific ELISA analysis can take up to two years to develop, MS-based methods are completed in under three months. Moreover, the reproducibility of MS analysis provides a level of consistency that ELISA cannot achieve.
“This means we can compare analytical results and use our experience across projects to help biologics developers improve their products,” explained Mørtz. “We hope the new method chapter from the USP will lead to increased knowledge and control of impurities across the industry, allowing companies to work together to make better, cleaner, and safer drugs.”
A leap forward for biopharmaceutical development
The use of MS-based analysis is already advancing the development of biologics, including mRNA vaccines and therapies for diseases such as diabetes, Parkinson’s, and AIDS. Bryant McLaughlin, a seasoned CMC executive in the biopharmaceutical industry, underscored its transformative potential:
“Even the best of the conventional methods can only measure around 80–90% of the impurities that could potentially be in a drug. There is a risk that the authorities might reject a drug due to the lack of documentation of impurities, which is why some drug manufacturers have never been able to release their product to the market. The opportunity to use mass spectrometry-based protein analysis as documentation for drug purity is therefore a great leap forward for all companies struggling with the limitations of earlier methods.”
With the inclusion of mass spectrometry-based analysis in the US Pharmacopeia, regulatory authorities such as the US Food and Drug Administration are likely to impose stricter quality assurance requirements. This shift has the potential to redefine industry standards, ensuring safer and more effective biopharmaceutical products for patients worldwide.
