PFAS Analysis Methods: Regulatory Alignment, QA/QC, and Contamination Control

Abstract

Accurate determination of Per- and polyfluoroalkyl substances (PFAS) demands precise quantification, rigorous contamination control, and validated analytical performance. This article outlines integrated approaches for reliable PFAS analysis across environmental and biological matrices, highlighting the balance between targeted LC–MS/MS workflows and broader screening techniques. Emphasis is placed on method validation, matrix-specific optimization, and harmonized global practices that ensure consistency and confidence in PFAS monitoring. 

Section Overview

• Why PFAS Analysis is Challenging
• Contamination Control Essentials (Before Sampling and in the Laboratory)
• QA/QC Essentials
• Regulatory Landscape Snapshot
• Conclusion

At a Glance

• Choose the right method for your matrix and goal (compliance vs screening) using validated EPA/ISO/ASTM workflows.^1-7
• Strong contamination control is essential at ng/L/ppt detection; avoid common PFAS sources in sampling and lab hardware, and run blanks.^1,2,8
• Use isotope dilution and defined QA/QC acceptance criteria.^1,2
• Align to validated regulatory workflows for defensible results.⁶

Why PFAS Analysis is Challenging

PFAS analysis poses unique analytical challenges due to their large chemical diversity and emerging/unmonitored compounds, ultra-low regulatory targets that require very high sensitivity, and ubiquitous background contamination that easily biases results.³

• Chemical diversity: Thousands of PFAS have been identified, varying in chain length, functional groups (carboxylates, sulfonates, phosphates, fluorotelomers), and polarity. Analytical methods must often focus on a small subset for which reference standards are available, while suspect and non-targeted screening are required to detect emerging or unknown PFAS.²
• Low concentration levels: Regulatory thresholds, such as the U.S. EPA's health advisory levels and the EU Drinking Water Directive limits, require quantitation in the low-ppt (ng/L) or even sub-ppt range. Achieving such sensitivity demands advanced instrumentation (e.g., LC–MS/MS or high-resolution MS) and meticulous contamination control.
• Background contamination: PFAS are present in many laboratory materials (e.g., PTFE tubing, seals, bottle caps, solvent containers) and field sampling gear, leading to false positives if contamination is not rigorously controlled. Both field blanks and laboratory reagent blanks are mandatory in regulated PFAS methods.
• Matrix effects: PFAS analysis in complex matrices such as wastewater, sludge, or biota suffers from ion suppression or enhancement during electrospray ionization. Isotope dilution with labeled analogs is the preferred approach to correct for these effects.

Given these challenges, PFAS analytical workflows must integrate contamination prevention, matrix-specific extraction, isotope dilution, and strict QA/QC as outlined in validated methods such as EPA 537.1, EPA 533, EPA 1633, SW-846 8327, the EU Drinking Water Directive (2020/2184), and Australia PFAS NEMP 3.0

Contamination Control Essentials (Before Sampling and in the Laboratory)

• Avoid fluoropolymer contact: Sampling and analytical hardware containing PTFE, FEP, PVDF, ETFE, or related fluoropolymers can introduce trace-level contamination. Use HDPE, polypropylene, stainless steel, or glass materials when compatible.^2,8
• Minimize personal sources: Wear powder-free nitrile gloves and avoid potential contamination from treated clothing, packaging materials, or personal care products.
• Implement rigorous blanks: Employ field, trip, equipment, and laboratory reagent blanks to identify and quantify background contributions; document any potential bias associated with sampling sites.^1,2
• Control contamination in LC systems: Use low-bleed chromatographic columns, PFAS-tested solvents and caps, and delay or guard columns. Run system blanks routinely to monitor and correct for background levels^.2

QA/QC Essentials

Isotope dilution: The use of isotopically labeled internal standards is standard practice to ensure quantitative accuracy and precision across analytical methods.¹

Quality control samples: Apply calibration verification, laboratory control samples, matrix spikes, duplicates, and defined acceptance criteria as outlined in standard operating procedures (SOPs). Record surrogate recoveries and blank thresholds in accordance with program requirements.^1,2

Reporting requirements: Ensure that method-specific limits of quantitation (LOQs) and reporting limits are achieved. Document any method modifications, such as alternative cleanup procedures, and demonstrate equivalent analytical performance.^1,2,7,8

When to use AOF/EOF/TOF/TOP and ¹⁹F NMR (Sum-Parameter Screening)

Sum-parameter approaches are applied to assess the total organofluorine or fluorine burden prior to compound-specific identification and quantification by targeted LC–MS/MS.

• AOF (Combustion Ion Chromatography, CIC): Used for prescreening adsorbable organofluorine retained on activated carbon. The measurement is non-specific and may include non-PFAS compounds and therefore, targeted LC–MS/MS analysis is required for definitive speciation.
• EOF (CIC): Applied for prescreening extractable organofluorine in environmental and biological matrices. Interpretation is subject to the same non-specificity caveats as AOF, and targeted LC–MS/MS should follow for compound identification.
• TOF (CIC): Provides a mass-balance perspective by measuring total organofluorine content. Due to its non-specific nature, results must be interpreted cautiously and supported by targeted LC–MS/MS.
• TOP Assay: Converts oxidizable precursors to their terminal perfluoroalkyl acids (PFAAs), thereby revealing hidden precursor burdens. Results are semi-quantitative and should be confirmed using targeted LC–MS/MS. High-resolution mass spectrometry (HRMS) may be applied to detect suspected or non-target PFAS species.
• ¹⁹F NMR (Sum-Fluorine): Quantifies total fluorine in sample extracts, including short-chain species such as trifluoroacetic acid (TFA). As a non-specific screening tool, it provides a bulk fluorine signal and must be followed by targeted LC–MS/MS for speciation and quantification.

Decision guidance

• Unknown profile or broad screening: Start with AOF/EOF/TOF (CIC) or 19F NMR; if elevated, proceed to targeted LC–MS/MS.
• Suspected precursors: Run TOP; compare pre/post sums; confirm with targeted LC–MS/MS; consider HRMS for suspects.
• Compliance reporting: Use targeted LC–MS/MS (EPA/ISO/DIN workflows) with isotope dilution and full QA/QC; treat sum‑parameters as supporting screens.

Regulatory Landscape Snapshot

The monitoring and regulation of PFAS varies globally, yet several authoritative analytical methods and legislative frameworks provide the foundation for compliance testing. These approaches specify target analytes, performance criteria, and quality control measures to ensure accurate detection at ultra-trace levels.

• ISO 21675:2019: International standard for determining PFAS in drinking water, surface water, and wastewater using solid-phase extraction followed by LC–MS/MS. Provides harmonized guidance on sample preparation, target analytes, and quality control requirements.

United States (EPA)

The National Primary Drinking Water Regulation (NPDWR) has been finalized. EPA Methods 537.1 and 533 are applied for drinking water analysis. Method 1633 is used for multiple environmental matrices. Method 8327 supports direct-injection screening, and Method 1621 (AOF) is employed for organofluorine prescreening.

• EPA Method 537
  LC–MS/MS method for the determination of 14 selected PFAS in drinking water, including PFOA and PFOS. Uses solid-phase extraction (SPE) for analyte concentration and cleanup, followed by negative electrospray ionization for quantitation. Designed for U.S. drinking water compliance monitoring before the expanded analyte list in 537.1 was introduced.
• EPA Method 537.1
  EPA Method 537.1 is designed for the determination of 18 selected PFAS in drinking water using solid-phase extraction (SPE) followed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The method targets longer-chain PFAS such as PFOS and PFOA, as well as some short-chain perfluoroalkyl acids, and is used under the Unregulated Contaminant Monitoring Rule (UCMR).
• EPA Method 533
  EPA Method 533 complements 537.1 by focusing on 25 short-chain PFAS, including perfluoroalkyl acids and fluorotelomer sulfonates not addressed in Method 537.1. It employs weak anion-exchange SPE, isotope dilution, and LC–MS/MS to achieve low-ppt detection limits. Combining EPA 533 and 537.1 provides broader PFAS coverage for drinking water compliance monitoring.
• EPA Method 1633
  EPA Method 1633 is the first multi-matrix PFAS method validated by the U.S. EPA and Department of Defense (DoD). It quantifies 40 PFAS in aqueous, solid, and tissue matrices using isotope dilution LC–MS/MS, with matrix-specific extraction protocols for wastewater, surface water, groundwater, soil, sediment, biosolids, and fish tissue.
• EPA Method 1621
  A qualitative adsorbable organic fluorine (AOF) method for wastewater, surface water, and other aqueous matrices. Measures total organofluorine content as a screening tool for fluorinated compounds, including PFAS, without identifying individual species. Involves adsorption onto activated carbon, combustion, and fluoride ion measurement via ion chromatography.
• EPA Method 8327
  EPA Method 8327 is intended for the rapid, direct injection analysis of 24 PFAS in non-potable waters without solid-phase extraction. It is primarily used for industrial discharges, groundwater, and wastewater matrices when high-throughput screening is required.

European Union (DWD)

National implementations define specific analyte lists and limits of quantitation (LOQs). Validated LC–MS/MS workflows aligned with ISO and CEN standards are employed for targeted analysis. Sum-parameter approaches are applied where total PFAS determinations are required.

• European Union
  Drinking Water Directive (2020/2184): The EU Drinking Water Directive (DWD) establishes parametric values for PFAS in water intended for human consumption. From 12 January 2026, Member States must monitor either the sum of 20 PFAS at a limit of 0.10 µg/L, or total PFAS at a limit of 0.50 µg/L. Analytical methods must achieve a limit of quantitation (LOQ) ≤ 30% of the parametric value and follow risk-based monitoring from source to tap. Laboratories are encouraged to adopt LC–MS/MS or HRMS-based methods validated for trace-level PFAS determination.
• DIN 38407-42
  German national standard for quantifying selected PFAS in water using solid-phase extraction and LC–MS/MS. Serves as the methodological basis for ISO 21675 and is widely applied across European laboratories for regulatory compliance.

Australia/NZ

The National Environmental Management Plan (NEMP) provides national guidance for PFAS monitoring and QA/QC across multiple matrices. Solid-phase extraction (SPE) followed by LC–MS/MS with isotope dilution is the recommended analytical approach.

• The PFAS National Environmental Management Plan (NEMP) 3.0
  Provides a unified approach for assessing, monitoring, and managing PFAS across Australian states and territories. It includes updated guideline values for water, soil, sediments, and biota; expanded PFAS grouping approaches; and revised biosolids reuse criteria. Analytical recommendations align closely with U.S. EPA methods, emphasizing isotope dilution LC–MS/MS, strict contamination control, and matrix-specific QA/QC protocols.

China

Standard GB 5749-2022 references PFOS and PFOA in drinking water. Broader regulation of PFAS in food contact materials is established under the GB 4806 series, including GB 4806.8-2022 for paper and paperboard. Additional limits may be introduced through local or provincial regulations.

• GB 5749-2022
  Establishes national drinking water quality limits for PFAS, specifying maximum levels of 0.04 µg/L for PFOA and 0.08 µg/L for PFOS.
• GB/T 5750.8-2023
  Defines the analytical method for PFAS in drinking water using SPE followed by LC–MS/MS, covering 11 target PFAS compounds at ng/L concentrations.

Japan

A provisional combined management target of approximately 50 ng/L for PFOS + PFOA has been implemented, with progress toward formal national standards. Laboratories should follow ongoing guidance and updates from the Ministry of Health, Labour and Welfare (MHLW) and the Ministry of the Environment. (Sources: sustainability.chemlinked)

Other International Guidelines and Emerging Standards

Other countries and regions have adopted or are in the process of developing PFAS monitoring and management programs. For instance, Canada has established drinking water quality guidelines for several PFAS, while Japan has set interim targets for PFOS and PFOA in surface and groundwater. In parallel, international research consortia are advancing non-targeted and total fluorine analytical approaches, which are expected to inform and shape future regulatory testing frameworks.

Conclusion

PFAS analysis demands rigorous contamination control, matrix-specific extraction, and validated LC–MS/MS or HRMS techniques to achieve low-ppt detection while ensuring data integrity. Regulatory methods such as EPA 533, 537.1, and 1633, the EU Drinking Water Directive (2020/2184), and Australia’s PFAS NEMP 3.0 set strict performance and LOQ requirements, yet the analytical scope is expanding toward suspect screening, total oxidizable precursor (TOP) assays, and extractable organic fluorine (EOF) analysis. Integrating compliance-focused workflows with advanced research capabilities will be essential to address both current regulatory obligations and the evolving chemical space of PFAS contamination.

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