Mass spectrometry-based analysis of biologics will soon have its own chapter in the US Pharmacopeia.

MS analysis delivers significantly more detailed and informative data than today’s most widely used methods and marks a breakthrough that could revolutionize impurity control in the drug industry.

On December 1st, 2024, a new general chapter will be available in the US Pharmacopeia (USP), which will provide biopharmaceutical developers with guidelines for mass spectrometry-based quantification of host cell protein (HCP) impurities in biologic drugs. With this, the medical industry stands on the threshold of a paradigm shift that could reduce unwanted side effects of biologics while clearing the way for more advanced products.

Host cell proteins are unintended impurities produced during the process of developing and manufacturing biotherapeutic medicines such as vaccines, antibody treatments, and gene therapies. To ensure the quality of biologic drugs, it is necessary to remove these residual proteins, which could otherwise limit drug effectiveness or cause side effects in patients.

Some protein impurities currently escape detection by the widely used ELISA (enzyme-linked immunosorbent assay) analysis. Going forward, regulatory authorities will encourage drug manufacturers to use mass spectrometry in combination with ELISA, or MS analysis on its own, for the control and documentation of product impurities.

– 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 standardize the use of mass spectrometry in the industry,says Derrick Zhang, Senior Scientist with the US Pharmacopeia.

Revolutionary technological development

MS-based HCP analysis has been under development since the 1990s. The Danish contract research organization Alphalyse A/S has specialized in MS-based HCP analysis since 2007, and the company has developed and implemented many of the analytic methods described 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. This method is also suitable for complex products such as cell and gene therapies for the treatment of cancers, Alzheimer’s, and genetic disorders', says Ejvind Mørtz, PhD in protein chemistry and molecular biology and co-founder of Alphalyse A/S. He elaborates:

'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'.

Besides increasing biologic drug quality, mass spectrometry also offers a much faster development pathway than conventional methods. Process-specific ELISA analysis requires up to 24 months to develop, while an MS-based HCP analysis can be carried out in under three months. Another significant factor is that Alphalyse’s method is highly reproducible whereas traditional analysis can yield varied results.

'This means we can compare analytical results and use our experience across projects to help biologics developers improve their products. 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', explains Ejvind Mørtz.

Potentially industry reforming

MS-based HCP analysis is already being used in the development of all types of biologics including the new mRNA vaccines and cell and gene therapies targeting an array of diseases, such as diabetes, Parkinson’s, and AIDS. According to Bryant McLaughlin, an experienced CMC executive in the biopharmaceutical industry, this analytical method is a huge benefit.

'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', explains Bryant McLaughlin, who himself has used the analytical method for several biologics.

Mass spectrometry-based analysis of host cell proteins could revolutionize the quality assurance of biopharmaceuticals, since its inclusion in the US Pharmacopeia is expected to lead to stricter requirements from regulatory authorities such as the US Food and Drug Administration.

About Alphalyse

Alphalyse A/S is a global specialist in protein analysis. The company is the first in the world to succeed in creating a GMP-certified mass spectrometric analysis of Host Cell Proteins (HCPs) for product release testing.