Examine the regulatory crossroads resulting from the ubiquitous presence of PFAS in widely prescribed drugs.

PFAS in pharmaceuticals is an inherently complex area to navigate. Drugs with chemical structures that fall under some recent definitions of PFAS have been developed and prescribed since the 1950s. Broadly prescribed drugs, Prozac and Lipitor, are examples of those defined as PFAS under the most inclusive definitions.

Balancing the continued production of life-altering medicines while attempting to adhere to mandates limiting the production and distribution of pervasive environmental contaminants results in a challenging regulatory path. In turn, affected organizations such as pharmaceutical companies and analytical testing laboratories face an uncertain future in ensuring testing methods and results meet the changing standards.

A background on fluoro-pharmaceuticals 

Fluorine-containing pharmaceuticals (also called fluoro-pharmaceuticals) have been in circulation for around 70 years, with the first, a corticosteroid called fludrocortisone (marketed as Florinef), introduced in 1954. Following the success of fluorinated corticosteroids, numerous fluoro-pharmaceuticals were developed in the 1980s and 1990s, including fluoroquinolones, such as ciprofloxacin, norfloxacin, and levofloxacin, and popular cholesterol drug atorvastatin (Lipitor). Authors of a 2022 study compiled a database of 340 fluoro-pharmaceuticals and found that the percentage of fluoro-pharmaceuticals among the total number of registered synthetics increased from 34% to 43% between 2015 and 2019. 

"Several reasons contribute to the rising development of fluoro-pharmaceuticals," explains Leo Yeung, Associate Professor in Chemistry at the Man-Technology-Environment (MTM) Research Centre of Örebro University, Sweden. "Most chemicals contain hydrogen or a C-H bond. Replacing a hydrogen atom with a fluorine atom may not alter the parent compound's structure significantly, as fluorine is the second smallest atom after hydrogen. Additionally, the C–F bond is one of the strongest bonds, enhancing the metabolic stability of fluoro-pharmaceuticals. Fluorine, the most electronegative element, induces bond polarization, potentially altering the lipophilicity/hydrophilicity balance of a particular compound. These and other properties contribute to fluorine having possible impacts on the absorption, distribution, metabolism, and excretion (ADME) of pharmaceuticals."

Pharmaceutical PFAS definitions

Depending on the definition used, not all fluoro-pharmaceuticals will fall under the class of PFAS. According to a recent Organisation for Economic Co-operation and Development (OECD) definition: "PFASs are defined as fluorinated substances that contain at least one fully fluorinated methyl or methylene carbon atom (without any H/Cl/Br/I atom attached to it), i.e. with a few noted exceptions, any chemical with at least a perfluorinated methyl group (–CF3) or a perfluorinated methylene group (–CF2–) is a PFAS."

"When we look at the definition of PFAS from Buck et al. and OECD 2018, PFAS are referring to highly fluorinated synthetic chemicals," says Yeung. "With the update of the definition of OECD in 2021, it will cover fluorinated substances. Different definitions will give different interpretations of the number and percentage of organofluorine pharmaceuticals as well as organofluorine compounds/PFAS."

Indeed, a 2022 study examined nine definitions of PFAS and used these to screen 260 organofluorine drugs. It found that some of the broadest PFAS definitions included widely prescribed pharmaceuticals such as fluoxetine (Prozac) and Lipitor. 

PFAS regulations and testing for the pharmaceutical industry

The regulatory landscape around PFAS is in its relative infancy, with current regulations mainly focused on drinking water. Examples include the latest EU drinking water directive and US regulations pertaining to the Safe Drinking Water Act (SDWA). But significant changes are anticipated in the near future. For example, the European Chemicals Agency (ECHA) published a PFAS restriction proposal in early 2023, with a six-month consultation period ending in September 2023. Meanwhile, the Government of Canada released its Risk Management Scope for Per- and Polyfluoroalkyl Substances (PFAS) in May 2023, and in the US, the Environmental Protection Agency (EPA) is taking regulatory steps to address PFAS.

While the implications of proposed regulations on the pharmaceutical industry remain unclear, laboratories can prepare to some extent based on what is known so far. Of course, the type of testing will depend on which regulations must be followed. "For example, in the new EU drinking water directive, two parametric values have been given: PFAS Total and Sum of PFAS," advises Yeung.

"'PFAS Total' means the totality of per- and polyfluoroalkyl substances with the parametric value of 0.5 μg/L. 'Sum of PFAS' means the sum of per- and polyfluoroalkyl substances considered a concern as regards water intended for human consumption listed in point 3 of Part B of Annex III—these contain a perfluoroalkyl moiety with three or more carbons (–CnF2n–, n ≥ 3) or a perfluoroalkylether moiety with two or more carbons ( –CnF2nOCmF2m–, n and m ≥ 1) with the parametric value of 0.1 μg/L," explains Yeung. "Sum of PFAS is relatively straightforward to test as most of the listed compounds have been studied, and analytical methods (such as US EPA 533, ISO 21675:2019, and prEN 17892) and reference standards are available."

"As for PFAS Total, it is not yet decided what method can be used to capture the totality of PFAS because the method should be able to capture ‘old’ PFAS as well as ‘new’ PFAS," adds Yeung. "Several research articles have been published to show the capability of measuring PFAS Total using methods such as adsorbable organofluorine (AOF)-combustion ion chromatography, extractable organofluorine (EOF)-combustion ion chromatography, particle-induced gamma-ray emission spectrometry (PIGE), continuum source molecular absorption spectrometry (CS-MAS), and 19F NMR." Yeung notes that a technical guideline on the EU drinking water directive will be developed and published in 2024 to give more information. "We don't yet know how ‘new’ compounds will be developed," adds Yeung. "Analytical capability should cover small polar compounds to large compounds, as well as those well ionized to those non-ionizable compounds. This is challenging, but it may stimulate more innovative development from this aspect."

As regulations around PFAS evolve, there is a pressing need for pharmaceutical companies and testing laboratories to stay informed and adapt. With regulatory bodies worldwide ramping up their efforts to address PFAS concerns, the next few years promise to be transformative for the pharmaceutical sector. Only through collaboration, continued research, and a commitment to both human health and environmental stewardship can the industry navigate this intricate and shifting terrain.

Aimee Cichocki is the managing editor for Separation Science. She can be reached at acichocki@sepscience.com.

Cover of PFAS analysis magazineThis article is featured in our October publication, 'PFAS: Unraveling the Analytical Challenges.' From cutting-edge analytical methods to the unexpected avenues of PFAS exposure in everyday items, explore the multifaceted challenges and solutions surrounding this pervasive contaminant.

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