Drug Component Could Lead to Adverse Events, Regulatory Failure

Sugar excipients may cause unwanted immunogenicity in patients.

Findings from a new study suggest that impurities in a certain drug component used for stabilization could potentially make the drugs fail regulatory testing.

“The biopharmaceutical industry should now consider new excipient quality criteria for safer drug development,” said lead researcher Daniel Weinbuch, PhD candidate at the University of Leiden.

Biopharmaceuticals are a growing class of drugs used to treat serious conditions, such as multiple sclerosis, diabetes, and cancer. Active substances in the drugs are typically large proteins, including antibodies that are much larger than other active drug molecules.

Since these large proteins need to be folded properly to take elicit the desired effect, they are very fragile. If the proteins are damaged during production, storage, shipment, or administration, they can unfold and cluster, according to the study. The aggregates could become large enough to be spotted without the use of magnifying equipment.

The immune system may go on to attack the large particles, and could cause life-threatening immunoglogical adverse events for the patient. Nanometer and micrometer-sized molecules are omnipresent, and do not necessarily develop from the protein itself, according to the study.

“It was very important to establish new techniques in order to understand where these particles come from and how dangerous they might be for the patient,” Weinbuch said.

Due to a lack of analytical techniques that could measure and differentiate these molecules, Weinbuch tested novel approaches, such as resonant mass measurement and flow imagine microscopy.

Sugar excipients are crucial for long-term stabilization of medications, and are also known as bulking agents due to the ability to increase the mass of solid drugs. While commonly used in pharmaceuticals, the findings suggest that sugar excipients could make drugs unsafe.

“We found that sugar excipients themselves contain nanometer-sized particles, which can damage proteins and make drugs unsafe,” Weinbuch said. “Potentially, these nanoparticle impurities in sugar could themselves even trigger the immune system — causing unwanted immunogenicity. We are investigating that right now.”

This was not something that was previously known, and now researchers are advising for new regulatory requirements to ensure safe drug development, according to the study.

“The biopharmaceutical industry needs to be aware of potentially harmful impurities in their excipients, which are added to the drug products,” Weinbuch said. “Also the sugar industry has the challenge of producing sugars excipients without these impurities.”

These findings could lead to the creation of safer biopharmaceuticals that do not include impurities, according to the study. This research could even save pharmaceutical companies money due to a better understanding of how certain excipients may cause drugs to fail. These companies may choose to re-evaluate drug formulations to determine whether a sugar excipient could be substituted and elicit a more stable drug.

“If a drug fails, it might not be due to the drug substance itself but due to an improper formulation,” Weinbuch concluded. “Using safe formulation excipients potentially gives failed drugs a second chance.”