Impact of antioxidant excipients on N-nitrosamine formation and bioequivalence in metformin formulations (review article)

Summary

The discovery of N-nitrosamine impurities in pharmaceutical products has raised serious quality concerns, particularly in metformin products, which are widely used in the treatment of type 2 diabetes mellitus. The detection of N-nitrosodimethylamine (NDMA) in metformin products has led to global recalls and increased regulatory investigations. Generic manufacturers face the challenge of balancing stringent bioequivalence requirements for Biopharmaceutical Classification System (BCS) Class III drugs, which require strict control of excipient composition while ensuring N-nitrosamine control and therapeutic equivalence.

Highlights

Antioxidant excipients reduce NDMA formation in metformin formulations.

Bioequivalence of metformin is preserved despite antioxidant modifications.

pH-modifying agents provide additional NDMA mitigation strategies.

Regulatory insights are proposed for safer pharmaceutical formulations.

This review highlights strategies to address N-nitrosamine impurities.

The use of antioxidants as a strategy to reduce N-nitrosamine formation requires careful consideration to maintain both bioequivalence and product safety. This article evaluates the use of antioxidants for the prevention of N-nitrosamine formation in metformin formulations, addressing the implications of this strategy on bioequivalence and its relationship with the regulatory framework.

Introduction

Since 2018, the pharmaceutical industry has been struggling with N-nitrosamine impurities in various pharmaceutical products. This has triggered regulatory actions and significant market disturbances worldwide. N-Nitrosodimethylamine (NDMA) is classified as a probable human carcinogen by the International Agency for Research on Cancer (IARC) [1].

While NDMA requires metabolic activation to form DNA-reactive molecules, it is regarded as a DNA reactive carcinogen in risk assessment [2]. According to ICH M7(R1), long-term exposure to NDMA from pharmaceutical products is estimated to result in 1 additional cancer case per 100,000 patients, representing the generally accepted risk level for impurities in pharmaceutical products [3], [4]. This risk assessment specifically addresses pharmaceutical exposure, while additional exposure may come from other sources such as food, drinking water, and air, potentially resulting in higher cumulative risk [5].

Metformin hydrochloride is an oral medication prescribed for the treatment of type 2 diabetes mellitus (T2DM) [6], [7]. In 2022, metformin was prescribed 86 million times in the United States [8]. A multicenter European study revealed metformin as the predominant first-line treatment across all surveyed countries, with utilization rates ranging from 65% in Italy to 88% in the United Kingdom [9]. In France, the prevalence of treated diabetes is estimated at 4.6%, affecting over 3 million individuals [10]. Regional differences are notable, with the prevalence rising to 5.2% in Northern France. According to recommendations from the French Health Authority (HAS), 68.6% of treated patients use oral antidiabetic drugs, with metformin emerging as the most frequently prescribed medication in this group, accounting for 43.8% of prescriptions.

The identification of N-nitrosamine contamination in metformin formulations was first reported in Singapore, where regulatory authorities detected NDMA impurities in certain products, leading to market withdrawal in December 2019 [11]. This discovery triggered a global investigation, leading to widespread product testing and regulatory actions. In June 2020, the U.S. Food and Drug Administration (FDA) took regulatory action, beginning with recalls by Apotex Inc. and Amneal Pharmaceuticals Inc., followed by product withdrawals from 13 additional manufacturers [12]. On January 7, 2022, Viona Pharmaceuticals Inc., recalled its metformin extended-release (ER) products after detecting NDMA [13]. In November 2022, Teva Pharmaceuticals USA also withdrew specific lots of Metformin Hydrochloride Extended-Release 1000 mg tablets due to NDMA levels exceeding the acceptable daily intake threshold [14].

To mitigate the risk of N-nitrosamine formation in metformin formulations, various strategies are under investigation, including the addition of antioxidants to the formulation. Furthermore, researchers are exploring the possibility of obtaining waivers from in vivo bioequivalence studies following these modifications. However, while the incorporation of antioxidants into pharmaceutical formulations has the potential to improve product performance, there is currently no consensus on how these changes may affect bioavailability and bioequivalence. This article aims to evaluate the impact of incorporating antioxidants into metformin formulations on NDMA formation and to assess the implications for bioavailability and bioequivalence.