Theoretical and Experimental Assessment of Nitrosamine Risk in Industrial Solvent Recovery

Abstract

The recovery of solvents in pharmaceutical manufacturing offers substantial sustainability benefits but raises concerns about the potential carryover of mutagenic impurities, particularly N-nitrosamines (hereinafter: nitrosamines). This study presents a validated, comprehensive framework for in-silico assessment of nitrosamine risk in industrial solvent recovery processes by distillation. Its application was demonstrated exemplarily using three small molecule nitrosamines and 32 commonly used solvents. The proposed procedure consists of vapor–liquid equilibria (VLE) prediction, followed by risk estimation using a newly introduced key performance indicator (KPI), and detailed risk assessment using process simulation. Two state-of-the-art methods for nitrosamine-solvent VLE prediction were tested and successfully validated. The average relative volatility (ARV), as a KPI for separation efficiency, was shown to be suitable for estimating the risk of nitrosamine-solvent combinations. A Monte Carlo simulation demonstrated that ARVs ≥3 reliably predict nitrosamine purge factors exceeding 1000, supporting safe reuse in most cases. Nitrosamine risk for specific recovery processes can be assessed quantitatively by obtaining nitrosamine purge factors from process simulation. In a case study, this procedure was applied to an industrial acetonitrile recovery process, showing complete nitrosamine removal. Lab-scale distillations confirmed these findings. Overall, the results support a science-based, process-specific risk assessment strategy for solvent recovery, addressing regulatory concerns and enabling safer, more sustainable practices.

Introduction

The Healthcare industry contributes more than 4% of the global CO2 emissions, of which ca. 25% are linked to the manufacture of active pharmaceutical ingredients (API). (1) Solvents contribute to 40–50% of the carbon footprint in API manufacturing, with 80% of this due to solvent synthesis and waste disposal. (2) Therefore, the use of recycled solvents can contribute significantly to reduce the carbon footprint and costs of API manufacturing. The current recovery rate is estimated to be ca. 30–35%. (3) Producing 1 kg of fresh solvent emits 1–6 kg CO2 equivalents, (4−6) while incinerating used solvent generates an additional 2–6 kg CO2 equivalents per kg. (6) In contrast, recycling emits only 0.2–0.8 kg CO2 equivalents per kg of solvent. (7) Thus, replacing virgin production + incineration with recycling avoids approximately 2–12 kg CO2 equivalents per kg per recycling cycle. This represents ca. 70–95% reduction in CO2 equivalents emissions.

Although solvent recovery is practiced throughout the chemical industry, the risk associated with nitrosamine contamination has particular relevance for pharmaceutical manufacturing, where recovered solvents are used in the production of materials for human use and are therefore subject to stringent regulatory oversight. Current regulations support the recovery and reuse of solvents, provided they meet appropriate standards. (8,9) However, recent concerns over N-nitrosamine (hereinafter: nitrosamine) contamination have heightened awareness of potential risk from using recycled solvents. (10) The draft revision of the EMA guideline on the chemistry of active substances recommends restricting the use of recovered solvents to the same or earlier process steps, and to avoid their use in the final manufacturing step. (9) The recently published WHO guideline for the prevention and control of nitrosamines in pharmaceutical products highlights particular nitrosamine risk if solvents are mixed from different processes, not properly purified or recovered off-site without adequate oversight and quality monitoring. (8,11) Regulatory concerns around solvent recovery may stem from the origins of the nitrosamine crisis, which began with the detection of NDMA in sartan drugs. (12,13) This contamination was traced back to the formation of NDMA from dimethylamine (DMA), an impurity in the solvent dimethylformamide (DMF). Another potential source for concern is the nitrogen-containing solvent NMP, which is known to form the NMBA precursor 4-methylaminobutyric acid through ring-opening hydrolysis. This pathway was identified as part of the root cause of NMBA contamination observed in certain batches of losartan. (14,15)

Many nitrosamines, particularly low molecular weight species such as NDMA and NDEA, are known mutagens; moreover, 82% of the tested nitrosamines are in vivo carcinogens, and the entire class is therefore assigned to the ICH M7 “cohort of concern”, for which compound-specific acceptable intake limits are required. (16,17) Based on the latter, nitrosamines have been responsible for a significant number of drug recalls since 2018, (18) as patient exposure is tightly regulated between 18 ng/day and commonly not exceeding 1500 ng/day. (19) These factors contribute to the strong regulatory caution surrounding the use of recovered solvents in pharmaceutical manufacturing and highlight the need for prediction methods that ensure adequate purge capability.
Several in-silico approaches exist for assessing risks of nitrosamine formation, (20) purge factor calculations (21,22) or modeling of nitrosamines in extraction processes. (23) However, for distillation processes as the most common unit operation for solvent recovery, such approaches do not exist to date. To address regulatory and safety concerns surrounding nitrosamine contamination in recovered solvents, this work establishes a predictive and experimentally validated framework for modeling nitrosamine carryover risk, supporting safer distillation processes that enable more sustainable pharmaceutical manufacturing.

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Theoretical and Experimental Assessment of Nitrosamine Risk in Industrial Solvent Recovery, Peter Ritzler, Holger Bauer, Michael Burns, Brunhilde Guessregen, Andrés González de Castilla, Stephanie Peper, Naiffer Romero, Joerg Schlingemann, Jonathan Stanway, and Simone Tomasi, ACS Sustainable Chemistry & Engineering Article ASAP, DOI: 10.1021/acssuschemeng.6c02602

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