How molecular filtration can help reduce exposure to airborne NOx and support nitrosamine risk management

Overview

Nitrosamines have become a critical concern across the pharmaceutical industry due to their potential carcinogenic and genotoxic properties. Regulatory agencies worldwide, including the FDA and EMA, have established stringent requirements for the identification, assessment, and control of nitrosamine impurities in pharmaceutical products. While much of the industry’s focus has been placed on raw materials, manufacturing processes, and packaging interactions, environmental contamination remains an often-overlooked source of nitrosamine formation.

This case study explores how airborne contaminants can contribute to nitrosamine risk and how Purafil’s molecular filtration technologies can help pharmaceutical manufacturers reduce exposure to nitrosating agents and improve contamination control strategies.

The Challenge

What Are Nitrosamines?

Nitrosamines are organic compounds formed through reactions between nitrosating agents (primarily nitrites and nitrogen oxides) and amines. Many nitrosamines are classified as probable human carcinogens and can cause DNA damage at extremely low concentrations.

Common sources of nitrosamine formation include:

• Reactions between amine-containing drug substances and airborne nitrogen oxides (NOx)
• Contaminated raw materials
• Process chemicals and solvents
• Packaging interactions
• Environmental exposure during manufacturing, storage, and transportation

The Environmental Risk

Many pharmaceutical manufacturing facilities are located in areas where airborne nitrogen oxides are prevalent, including:

• Near major transportation corridors: Highway interchanges and freight routes often have elevated NOx from vehicle emissions.
• Adjacent to roads and motorways: Continuous traffic can contribute to sustained ambient NO₂ concentrations.
• Close to airports: Aircraft operations and support equipment can increase local NOx levels.
• Near shipping ports: Marine traffic and cargo handling activities can be significant sources of NOx.
• Within developed industrial parks and light industrial zones: Industrial combustion processes, backup generators, and other equipment may contribute additional NOx.

When outside air is introduced into pharmaceutical facilities through HVAC systems, these contaminants can enter clean manufacturing environments. In facilities producing amine-containing active pharmaceutical ingredients (APIs) or drug products, airborne nitrogen oxides can create conditions favorable for nitrosamine formation.

Regulatory Context

No specific ambient-air limit: There is currently no single, binding global regulatory limit for NO₂ or NOx concentrations in ambient air specifically for pharmaceutical manufacturing facilities.

Industry operating targets: Recent industry research and case studies suggest a target concentration of <10 ppb NO₂/NOx to mitigate nitrosamine formation risk. Some manufacturers operating critical processes such as fluid bed drying aim for <5 ppb with an upper control limit of 8 ppb.

FDA and EMA focus: Neither the FDA nor the EMA has established a legally binding numerical limit for NO₂ or NOx in pharmaceutical manufacturing air. Instead, guidance focuses on controlling nitrosamine levels in the final product and evaluating atmospheric NO₂/NOx as a potential root cause in quality risk assessments.

Customer Situation

A pharmaceutical manufacturer in Europe producing solid oral dosage forms was conducting a comprehensive nitrosamine risk assessment in response to evolving regulatory requirements.

The company’s facility is located in a light industrial area near a major highway interchange and regional transportation hub. Environmental monitoring identified periodic elevations in ambient NO₂ concentrations, particularly during peak traffic periods.

The manufacturer’s concerns included:

• Potential exposure of amine-containing products to airborne nitrosating agents
• Regulatory scrutiny surrounding nitrosamine control strategies
• Product quality and patient safety risks
• Need for documented mitigation measures as part of their contamination control strategy
• Protection of warehouse and manufacturing environments receiving outside air

Solution: Purafil Molecular Filtration System

Following an evaluation of the facility’s air handling requirements and nitrosamine risk profile, Purafil recommended a multi-stage PSA (Purafil Side Access) molecular filtration system designed to achieve maximum removal of nitrogen oxides (NOx) from incoming outside air.

The selected configuration consisted of a three-pass which can use PK12 to PK18 module systems or for larger concentration of gases the DBS (bulk) is also an option:

Pass 1: Purafil PSP
Pass 2: Purafil PSP
Pass 3: Purafil PKL

This staged approach was designed to progressively remove NO₂ and other gaseous contaminants, ensuring exceptionally low contaminant concentrations in the air supplied to critical manufacturing spaces.

The dual PSP stages provide high-capacity removal of acidic and oxidizing gases, including nitrogen dioxide, while the final PKL polishing stage captures residual contaminants and helps maintain consistent air quality performance over time.

Integrated into the facility’s HVAC system, the PSA unit continuously treats incoming air before it enters production, packaging, and storage areas, helping minimize the potential for airborne NOx to contribute to nitrosamine formation.

Results

After implementation of the three-pass PSA filtration system, the manufacturer achieved:

• Significant reduction of NO₂ and NOx concentrations in critical manufacturing areas.
• Improved ability to maintain airborne NOx levels within industry-recommended targets for nitrosamine risk mitigation.
• Enhanced contamination control and environmental monitoring programs.
• Additional protection for amine-containing APIs, intermediates, and finished products.
• Greater confidence in demonstrating a comprehensive, science-based nitrosamine risk management strategy during audits and regulatory inspections.

The installation provided a proactive environmental control measure that addressed a recognized nitrosamine root-cause pathway while supporting the facility’s overall product quality and patient safety objectives.

Why Purafil?

For more than 50 years, Purafil has specialized in molecular air filtration technologies that remove harmful gaseous contaminants from critical environments.

Key benefits for pharmaceutical manufacturers include:

• Removal of nitrogen oxides (NOx), sulfur compounds, ozone, and other reactive gases
• Support for contamination control strategies and quality risk management programs
• Protection of APIs, intermediates, and finished drug products
• Reduced risk associated with environmental sources of nitrosamine formation
• Solutions tailored for pharmaceutical manufacturing, laboratories, cleanrooms, and warehouses

Conclusion

As pharmaceutical manufacturers continue to address nitrosamine risks, controlling environmental sources of nitrosating agents should be considered alongside raw material and process controls. Facilities located near transportation hubs, industrial areas, airports, ports, and major roadways may face elevated exposure to airborne nitrogen oxides that can contribute to nitrosamine formation.

Purafil’s molecular filtration solutions provide a proactive approach to removing these contaminants from incoming air streams, helping pharmaceutical manufacturers strengthen contamination control programs, reduce risk, and protect product quality throughout the manufacturing process.