TITLE:
Trifluoroacetic Acid (TFA) Use in Pharmaceutical Manufacturing and Potential Environmental Implications
AUTHORS:
Sheng Peng, Andrew A. Lindley, Neil C. Sturchio, Paul B. Hatzinger
KEYWORDS:
Trifluoroacetic Acid (TFA), Therapeutic Peptides, Solid-Phase Peptide Synthesis, Semaglutide, Tirzepatide, Pharmaceutical Manufacturing, Wastewater Treatment
JOURNAL NAME:
Journal of Geoscience and Environment Protection,
Vol.14 No.9,
September
24,
2026
ABSTRACT: Trifluoroacetic acid (TFA) is a persistent pollutant that has been increasing in concentrations in aqueous environments over the past few decades. Anthropogenic sources of TFA include atmospheric degradation of certain volatile fluorinated compounds, degradation of fluorinated pesticides, including plant protection products (PPPs), and biotransformation of fluorinated pharmaceuticals in wastewater treatment plants (WWTPs) and other environments. Another significant potential source of TFA in the environment that has received less attention is its use in the manufacture of therapeutic peptides, such as insulin and GLP-1 agonists (large-scale weight loss and diabetes drugs). Large volumes of wastewater containing low concentrations of TFA can be generated from some of the GLP-1 manufacturing processes. Moreover, the production of some therapeutic peptides is expected to increase several-fold during the next few years. Herein, we review the manufacturing protocols for key therapeutic peptides and other drugs requiring TFA during manufacture and estimate the potential quantities of TFA released to the environment from these processes. Overall, a conservative estimate of total TFA used in the FDA-approved therapeutic peptide industry (excluding tirzepatide) was 555 - 979 metric tonnes per year, which gives an estimated 11,100 - 19,600 metric tonnes of accumulated TFA usage over the two decades ending in 2024. For comparison, this amount is equivalent to 33% to 58% of the global production of TFA in 2023 and is likely to increase substantially in the coming years. The large quantities of TFA currently used, which may be discarded as waste in the pharmaceutical industry, and the potential for large increases in coming decades, may result in significant point source discharges to WWTPs. Estimates of these discharges and potential emissions are not yet possible owing to the lack of available data necessary for such determination. Treatment systems deployed at manufacturing facilities, which utilize reverse osmosis and/or ion exchange among other unit processes, are most likely to be effective for TFA removal from these complex waste streams.