Impact of post approval quantitative changes in excipient composition on nitrosamine formation: De-risking strategy

Abstract

Between 2018 and 2021, losartan was the most often recalled product (24% of total recalls) followed by metformin tablets (19% of total recalls) due to the presence of nitrosamine impurities. The objective of this work is to analyse the de-risking method in terms of reducing nitrosamine generation and establishing nitrite specifications in excipients. In light of these recalls, we simulated the influence of post-approval level 1 and level 2 changes in excipient compositions on nitrosamine formation in metformin SR (sustained release) and losartan film coated tablets. Furthermore, we investigated the de-risking approach in terms of reducing nitrosamine formation and establishing nitrite specifications in excipients. Level 1 changes in excipient composition resulted in no discernible increase in nitrosamine impurities for both metformin SR and losartan film coated tablets. On the other hand, level 2 changes resulted in more than 7% and 18% increase in nitrosamine levels in metformin SR and losartan film coated tablets, respectively. In fact, level 2 changes could cause nitrosamine impurities to exceed the AI (acceptable intake) limits. When low-nitrite level (LNL) excipients were employed, level 2 changes resulted in no significant increase in nitrosamine formation from their original values. Finally, specifications for nitrite in excipients were established. Selecting formulation excipients with LNLs is critical for risk mitigation as was demonstrated in this study. To continue enjoying the regulatory flexibility in terms of reducing post approval variation submissions, it is paramount to assess the impact of nitrite load of excipients on the total nitrosamine burden of the product during product development.

Introduction

NDMA (N-nitrosodimethylamine) levels were found in valsartan tablets in 2018 in concentrations that may have presented a serious risk to the health of patients [1], [2], [3]. Since then, several nitrosamines have been detected in a wide range of pharmaceutical products. Nitrosamines exert their mutagenic and genotoxic behavior owing to their conversion by cytochrome P450s into alkyl diazonium and alkyl carbonium ions via a sequence of processes. These substances can alkylate macromolecules such as DNA, RNA, and chromosomes, causing them to be damaged and potentially leading to cancer [4], [5]. Risk factors for nitrosamine generation in a pharmaceutical product include drug substances with secondary and tertiary amines as well as secondary amide functional groups, the presence of nitrites and nitrate in formulation ingredients, the formulation microenvironment, the presence of moisture, heat, etc [6], [7]. Nitrosamine generation has been demonstrated to occur when these risk variables coexist [8].

Nitrosating impurities (nitrites and nitrates) have been shown to be present in common excipients such as hydroxypropyl methyl cellulose, pregelatinized starch, croscarmellose sodium, polyvinyl pyrrolidone, lactose, starch, etc. In fact, effective approaches for controlling NMDA levels in metformin below the ICH (The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) M7 control threshold include lowering residual DMA (dimethyl amine) in the Metformin drug substance as well as nitrite levels from excipients [9], [10]. Effective communication between drug product manufacturers and excipient suppliers to agree on nitrite and nitrate specifications in excipients, as well as changing the excipient suppliers to one with lower nitrite and nitrate levels, has been comprehensively reviewed [8], [10]. Lhasa Limited maintains a comprehensive database on the nitrite concentrations in common excipients that are determined using validated analytical methods [11].

The SUPAC (scale up and post approval changes) guidance documents provide recommendations for changes that may be implemented during the post approval period [12], [13]. The changes cover the impact of changes in components or composition; the site of manufacturing; the scale-up/scale-down of manufacturing; and/or the manufacturing (process and equipment) of an immediate release oral formulation. The guidance documents define: (1) levels of change; (2) recommended chemistry, manufacturing, and controls tests for each level of change; (3) in vitro dissolution tests and/or in vivo bioequivalence tests for each level of change; and (4) documentation that should support the change (Table 1).

Between 2018 and 2021, more than 1400 medicinal products were recalled or withdrawn from the market in the USA (United States of America) alone due to nitrosamine levels exceeding acceptable daily intake (ADI) limits [14]. Losartan was the most often recalled product, accounting for approximately 24% of total recalls, with 324 lots containing losartan being pulled from the market [15], [16], [17]. Metformin accounted for the second-highest percentage of recalls, with almost 19% of all recalls in the USA. The sartans (valsartan, losartan, irbesartan, etc.) alone accounted for 81% of all recalls. In the context of these recalls, we simulated in this work the impact of post approval level 1 and level 2 changes in the excipient compositions on small molecule nitrosamine formation in metformin SR (sustained release) tablets and losartan film coated tablets. In addition, we analysed the de-risking method in terms of reducing nitrosamine generation and establishing nitrite specifications in excipients.

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Composition of metformin sustained release tablets

Glucophage® SR tablets are available in three strengths, i.e., 500 mg, 750 mg and 1000 mg [18], [19]. The tablets contain hydroxypropyl methylcellulose (HPMC), croscarmellose sodium and magnesium stearate as the excipients. The weight of the Glucophage® SR tablets is approximately 1450 mg

Naseem A. Charoo, Syed Ahmad Untoo, Ziyaur Rahman, Impact of post approval quantitative changes in excipient composition on nitrosamine formation: De-risking strategy, European Journal of Pharmaceutics and Biopharmaceutics, Volume 223, 2026, 115058, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2026.115058.