PHARMACEUTICALS
Figure 2- Kilo-scale production synthesis of LUNA18
Figure 2
exhaustive, but rather to provide a brief overview of key aspects for consideration and to stimulate further discussion.
Trifluoroacetic acid( TFA) is widely used within medicinal chemistry and pharmaceutical development, thanks to its strong acidity, high volatility, anhydrous format and excellent solubility in many solvents. However, TFA carries significant toxicity, even at low concentrations, it is highly corrosive and has significant environmental persistence. It is also one of the most abundant PFAS detected in the environment. 8
Despite these drawbacks, the inherent properties of TFA render it extremely useful, with utility as a global deprotection and cleavage agent in peptide synthesis, an ionpairing agent in reverse-phase liquid chromatography( RPLC) or mass spectrometry( MS), as a catalyst, and even as a counter-ion in salt formation. While there have been moves towards replacing TFA, in many cases the use of an alternative has not proven possible, delivering inferior results or requiring extensive additional development.
1,1,1,3,3,3-Hexafluoroisopropanol( HFIP) has rapidly become a commonly used organic solvent due to its unique physicochemical
References: 1: Royal Society of Chemistry, Cleaning Up UK Drinking Water. https:// www. rsc. org / policy-and-campaigning / sustainability / cleaning-up-ukdrinking-water( Accessed March 2026) 2: J. C. Hanekamp, L. Bergkamp, W. M. Briggs & M. Wilson, Toxics 2025, 13, 885 – 897. https:// doi. org / 10.3390 / toxics13100885 3: European Chemicals Agency, ECHA Publishes Updated PFAS Restriction Proposal. https:// echa. europa. eu / de /- / echa-publishesupdated-pfas-restriction-proposal( Accessed March 2026) 4: N. D. Tyrrell, Organic Process Research & Development 2023, 27, 1422 – 1426. https:// doi. org / 10.1021 / acs. oprd. 3c00199 5: UK Parliament, Environmental Audit Committee. https:// committees. parliament. uk / committee / 62 / environmental-audit-committee /( Accessed March 2026) 6: Swedish Chemicals Agency, What You Need to Know About the Updated PFAS Restriction Dossier, 23 October 2025. https:// www. kemi. se / download / 18.41d27938199c91391bdef17 / 1760345188927 / What % 20you % 20need % 20to % 20know % 20about % 20the % 20 updated % 20PFAS % 20restriction % 20dossier. pdf properties, and has particular utility within catalysis, materials science, lyophilisation, and for removal of impurities. While in some instances HFIP can be recycled, it is highly corrosive, can cause long-term toxicity, and is environmentally persistent.
As well as the use of PFAS as solvents or catalysts, fluorinated materials are also used as protecting groups, especially for peptide synthesis. There are several protecting groups that could be classified as PFAS materials, by virtue of the – CF2 – or CF3 groups present, which may no longer be permitted as they would not be present in the final API. These include hexafluoroacetone and trifluoroacetyl, both of which are vital for large-scale peptide synthesis, such as the kilo-scale of LUNA18( paluratide, Figure 2). 9
The use of excipients is another area where PFAS materials may not be permitted. While in some cases there are alternatives, in others there are not. AstraZeneca recently submitted a response to the ECHA proposals highlighting the possible detriment to drug delivery through use of pressurised metered-dose inhalers( pMDIs). In this case, they showcased HFO-1234ze( E), a novel propellant under development, that,
7: EFPIA, Evidence Shows More Than 600 Essential Medicines at Risk, 28 September 2023. https:// www. efpia. eu / news-events / the-efpia-view / statements-press-releases / evidence-shows-more-than-600-essentialmedicines-at-risk-and-manufacturing-in-europe-will-grind-to-a-halt-ifwide-ranging-chemical-ban-is-implemented / 8: H. P. H. Arp, A. Gredelj, J. Glüge et al., Environmental Science & Technology 2024, 58, 19925 – 19935. https:// doi. org / 10.1021 / acs. est. 4c06189 9: Z. Hou, S. Komiya, K. Iwasaki et al., Organic Process Research & Development 2025, 29, 2764 – 2782. https:// doi. org / 10.1021 / acs. oprd. 5c00260 10: T. J. Wallington, M. P. Sulbaek Andersen & O. J. Nielsen, Chemosphere 2015, 129, 135 – 141. https:// doi. org / 10.1016 / j. chemosphere. 2014.06.092 11: PFAS concentration thresholds: 25 ppb for individual non-polymeric PFAS; 250 ppb for sum of non-polymeric PFAS; 50 ppm for total fluorine including polymeric PFAS while classified as PFAS, has been shown to be non-persistent, nonbioaccumulative and non-toxic. 10
Summary
While changes to laws that would lead to a ban on manufacture, supply and use of most PFAS materials are extremely important steps towards addressing their presence in the environment, a blanket ban without industry-specific consideration could lead to severe difficulties within the chemical and( bio) pharma industries in Europe. There are three restriction options( ROs) on the table:
• RO1, a full ban after an 18-month transition
• RO2, a ban with time-limited derogations( including extensions for medical devices( pMDIs)
• RO3, continued use of PFAS with strict emission limits or control measures.
Within the pharmaceuticals industry, PFAS materials, both as chemicals and within hardware, are essential to manufacture. Their replacement may lead to substandard manufacture or a shorter lifespan of hardware, which will also be detrimental to the environment.
Furthermore, the proposed concentration limits above which manufacture, use and marketing is prohibited11 will probably be extremely challenging to achieve and difficult to determine in the context of pharmaceutical analysis and evaluation. ●
Dr Julien Northen
TECHNICAL DIRECTOR
ONYX SCIENTIFIC k + 44( 0) 191 516 6507 J julien. northen @ onyxipca. com j www. onyxipca. com
24 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981