Majority of metformin drugs have acceptable nitrosamine levels, finds study

With recalls on metformin products containing nitrosamines ongoing, a study suggests >80 percent of metformin APIs and final drug products are within safe limits.

Metformin 500mg white tablets on white background [Credit: LeviMax/].

[Credit: LeviMax/].

Researchers analysing metformin-containing medicines for the presence of N-nitrosodimethylamine (NDMA), an impurity and probable human carcinogen, found that over 80 percent of active pharmaceutical ingredients (APIs) and finished dosage forms were within acceptable limits.

Nitrosamine impurities have sparked numerous recalls over the past couple of years; however, prior to the recalls in 2020, Official Medicines Control Laboratories (OMCLs) from the OMCL Network participated in an international collaboration of regulatory laboratories to analyse metformin APIs and drug products.

Collaborators from the General European OMCL network (from Germany, Poland, Switzerland and the Netherlands), Therapeutic Good Administration (TGA, Australia), Health Sciences Authority (HSA, Singapore) and the US Food and Drug Administration (FDA) gathered more than 1000 samples (215 APIs and 875 drug products) to analyse. Overall, the studies conducted between November 2019 and July 2020 covered 13 unique API producers and about 90 unique producers of finished dosage forms worldwide.

In all the analyses, only one nitrosamine impurity, NDMA, was identified. The laboratories found that, of the 215 API samples, 213 (99 percent) had no measurable level of NDMA. With the drug product samples, 156 of 875 (17.8 percent) had NDMA above the acceptable daily intake (ADI) of 96 ng/day. Based on these data, although the presence of NDMA was of concern, 82.2 percent of the samples of metformin drug products tested met quality and safety standards for patients.

The researchers noted that because “more batches were taken from manufacturers deemed to be at risk of contamination, 80 percent is potentially an underestimate of acceptable products that were present in the market”.

As a potential carcinogen, the presence of NDMA in metformin batches must be minimised. In addition to testing for NDMA before drug product release, as some regulators have requested, the authors of the paper stated that mitigating the risks posed by nitrosamine impurities should be achieved by applying greater product and process knowledge, as well as learnings from the products which have been found to contain nitrosamines, and implementing mitigation steps in manufacturing processes.

They concluded: “Ultimately, drug substance and drug product manufacturers are responsible for understanding their processes, which includes preventing the presence of unacceptable impurities. Importantly, global co-operation by regulatory laboratories has allowed rapid development and publication of analytical procedures that can help manufacturers develop and validate their own methods more quickly.”

Regulatory agencies continue to collaborate extensively and work with marketing authorisation holders to understand the root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches.

The results of the studies were published in The AAPS Journal.