Quality control measurements for medicinal gas filling

Medicinal gases must be regulated as medicinal products, with applicable pharmacopeias specifying requirements around product quality, assay or purity, impurities, identification, and employed analytical test methods.

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Requirements differ between the United States Pharmacopeia (USP), European Pharmacopoeia (Ph. Eur.), and Japanese Pharmacopoeia (JP).

This article summarizes widely utilized filling plant measurement points alongside a range of Ph. Eur. and USP requirements related to analyzer selection.

This article should not be considered a substitute for the current official monograph, including national requirements, marketing authorization, or a validated analytical procedure.

Regulatory and analytical framework

Pharmacopeial specifications utilize official monograph methods as reference methods.

Alternative analytical methods may be used for testing under Ph. Eur. regulations following agreement with the relevant authority and the implementation of sufficient validation to demonstrate equivalence to the specified method.

Tests designed for manufacturers apply where a hospital manufactures medicinal gas on site, for example, oxygen (93%) from a PSA plant. The responsible pharmacist is required to define quality controls, operating procedures, maintenance controls, batch or traceability arrangements, and the applicable risk assessment.

The filling process and packaging must also meet applicable safety, pressure, and quality requirements where a PSA plant fills cylinders.

Process measuring points

Medicinal gas cylinders may be filled at a dedicated filling plant or at a facility utilizing an air separation unit. Cryogenic storage vessels may also be used to supply bulk medicinal gas to healthcare facilities. This product is generally stored as a cryogenic liquid before being vaporized and transferred to the filling manifold.

Single gases typically utilize a dedicated manifold, with mixtures requiring precise controls to prevent cross-contamination.

A single medicinal gas filled via a multi-cylinder manifold would require the testing of at least one cylinder from each manifold filling cycle for identity and assay. This testing is done when cylinders are changed.

Cylinders filled individually require that at least one cylinder from each uninterrupted filling cycle be tested for identity and assay.

Every cylinder should be tested for identity and assay of each component for Ph. Eur. mixtures made from two or more gases, while USP sampling and testing requirements should be implemented in line with the applicable current monograph and approved procedure.

European Pharmacopoeia measurements

The tables below feature selected manufacturer tests and limits. This list does not represent every required test; rather, it is intentionally limited to common gases.

Source: Servomex

Scope note: Additional monograph tests may include other impurities and identification requirements. Consult the current ofÏcial monograph and the approved quality-control procedure.

United States Pharmacopoeia measurements

Selected USP requirements are summarized below.

Source: Servomex

Alternative methods

Several USP monographs specify the use of detector tube methods for impurity measurements, including carbon dioxide and carbon monoxide.

Validated analytical instruments may be used as alternative methods, where allowed by applicable regulations and quality systems, provided that these methods offer equivalence to the pharmacopeial method and that this has been demonstrated and documented.

Users should confirm acceptance of any alternative method under the current USP–NF requirements and approved quality procedures.

On-site PSA oxygen

Some healthcare facilities manufacture the oxygen and supply it directly to the medical gas pipeline system, meaning that these on-site PSA systems necessitate the implementation of a distinct quality and governance approach.

For example, single-stage PSA plants can produce oxygen (93%), with an assay range of 90.0% to 96.0% V/V. The remainder of this mixture is primarily argon and nitrogen.

Continuously monitor this output for oxygen assay, and implement continuous monitoring for carbon dioxide, carbon monoxide, and moisture in line with the relevant pharmacopeia specification.

Plant capacity should also be validated at maximum design flow to ensure that product quality remains within specification. Oxygen concentration can be reduced by demand above the design output.

It is important that the risk assessment considers the location of ambient air intake, locally credible contaminants, electrical resilience, maintenance, supply redundancy, traceability, and out-of-specification response.

ISO 7396-1 principles require the implementation of three independent sources of supply able to meet the design demand under a single fault condition.

Servomex measurement solutions

Source: Servomex

Source: Servomex

Validation and implementation checklist

A number of steps should be in place to validate and implement these systems, including:

• Confirmation of the current official monograph and market-specific regulatory basis
• Determining and confirming whether the test should be performed by the manufacturer, the end user, or both.
• Documenting sample point, temperature, pressure, flow, materials, and vent arrangements.
• Setting measurement range, detection limit, precision, accuracy, linearity, specificity, and response-time requirements.
• Defining calibration gases, frequency, traceability, and acceptance criteria.
• Validating the complete method against the approved reference method or filing. This should include sampling and data handling.
• Defining out-of-specification handling, alarms, product diversion, shutdown, and record retention.
• Confirm cybersecurity, electronic record, and audit trail requirements where necessary.

Acknowledgments

Produced from materials originally authored by Servomex.

About Servomex

For more than 70 years, Servomex has been at the forefront of gas analysis innovation, helping customers around the world improve process efficiency, product quality, safety, and regulatory compliance.

As a global leader in gas measurement solutions, Servomex designs, manufactures, and supports a comprehensive range of gas analyzers and sensing technologies for industrial, environmental, semiconductor, healthcare, pharmaceutical, energy, and research applications. The company's portfolio includes solutions for oxygen, moisture, trace impurity, and multi-gas analysis, delivering accurate and reliable measurements even in the most demanding operating conditions.

What sets Servomex apart is its unique combination of technology expertise and sensor manufacturing capability. By developing and producing many of its own core sensing technologies, Servomex maintains complete control over performance, quality, and long-term reliability. This enables customers to benefit from market-leading accuracy, low cost of ownership, and dependable operation throughout the analyzer lifecycle.

Servomex supports customers globally through dedicated engineering, service, and application teams, providing expert guidance from specification and installation through to maintenance, calibration, and long-term operational support.

With a commitment to continuous innovation and customer success, Servomex helps industries worldwide achieve greater productivity, sustainability, and operational confidence through trusted gas analysis solutions.

Servomex is part of Spectris Ltd, the productivity-enhancing instrumentation and controls company. Spectris is a leading supplier of productivity-enhancing instrumentation and controls.

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