Challenges the Pharmaceutical Industry Faces While Working with Gases

From synthesis and processing through to packaging, the pharmaceutical industry is reliant on gases. The need for ultra-high purity at all stages in the pharmaceutical supply chain means that impurities in these gases can have dire consequences. This article looks at the importance of purity in pharmaceutical gases and how pharmaceutical-grade gases from Air Products provide an easy solution.

Common Pharmaceutical Gases

Several gases are essential to the pharmaceutical industry – most notable among these are nitrogen, oxygen and carbon dioxide.

As an abundant inert gas, nitrogen is the most-used gas (besides air) and fulfills a variety of functions at multiple stages of pharmaceutical production.¹ One of the main applications of nitrogen is inerting: the protection of sensitive chemical precursors, reagents or products from reactive oxygen and other chemical species in the air. 

In this capacity, nitrogen is also used during packaging, where it provides an oxygen- and moisture-free environment inside blister-packs and vials that protect medicines from degradation. Nitrogen is also used as a pressurising agent to test process equipment (such as pipes, tanks and vessels) for leaks; for transferring fluids from storage tanks; and as carrier gas in chromatographic analysis.

Oxygen is a vital reagent during synthesis of pharmaceutical compounds. In order to minimise combustion risks, oxygen is typically used in the form of “synthetic air”, a mixture consisting of around 10% oxygen with nitrogen.² Oxygen is also used in biopharmaceutical applications to enrich the atmosphere within incubators, thus improving growth rates and productivity of cell cultures.

Carbon dioxide is commonly used under supercritical conditions for extractions of organic compounds. This process was first developed for the decaffeination of coffee, but is now commonplace in various pharmaceutical syntheses.^3,4Carbon dioxide also doubles up as an inerting gas, fulfilling some of the same roles as nitrogen.

The Importance of Purity in Pharmaceutical Gases 

Purity is a measure of the extent to which we know the true identity of a substance.⁵ Insofar as the goal of any pharmaceutical synthesis is to produce a specific compound, impurities fundamentally oppose the goals of the industry. It’s impossible to overstate the importance of purity in the pharmaceutical industry – and pharmaceutical gases are no exception. Impurities in pharmaceutical gases can have an impact in several ways.

During research, impurities in gas chromatography carrier gases (e.g., oxygen and moisture) are a limiting factor in the accuracy of chemical analyses, essentially providing a “noise floor” below which no detail can be accurately discerned. 

Throughout synthesis, impurities in process gases (nitrogen, carbon dioxide), solvents (supercritical carbon dioxide) and reagent gases (oxygen) run the risk of undergoing chemical reactions with precursors and products. These arbitrary unwanted reactions can affect yields, produce harmful products, and overall threaten the integrity of the synthesis itself.

Finally, after synthesis has been carried out, the existence of unwanted moisture or oxygen in medicine packaging can substantially reduce the shelf-life of drugs, ultimately rendering them unsuitable for use.⁶

As a result, materials for clinical use require detailed characterisation and must meet rigorous purity requirements as described by global pharmacopoeial and regulatory frameworks. Air Products pharmaceutical-grade gases are manufactured to meet and exceed these requirements and deliver reliable performance in both analytical and research applications.

Our pharmaceutical-grade gases are compliant with the requirements of European directives 2001/83/ EC and 2001/82/EC; as amended by Directives 2004/27/EC and 2004/28/EC; directives relating to use and quality of Active Product Ingredients (API). Air Products pharmaceutical-grade gases eliminate the need for costly onsite filtration and moisture removal, and can be used in all pharmaceutical applications all with complete peace of mind.

For the most demanding pharmaceutical applications, Air Products BIP® gases feature built-in filtration technology to provide the lowest possible levels of critical impurities. BIP® gases have impurity levels as low as 10 ppb total hydrocarbons,10 ppb oxygen and 20 ppb moisture.

1. Sandle, T. Microbiological Assessment of Compressed Gases in Pharmaceutical Facilities. Journal of Validation Technology 21, 1–8 (2015).
2. Hone, C. A., Roberge, D. M. & Kappe, C. O. The Use of Molecular Oxygen in Pharmaceutical Manufacturing: Is Flow the Way to Go? ChemSusChem 10, 32–41 (2017).
3. Kaiser, C. S., Römpp, H. & Schmidt, P. C. Pharmaceutical applications of supercritical carbon dioxide. Pharmazie 56, 907–926 (2001).
4. Kitada, K. et al. Supercritical CO2 extraction of pigment components with pharmaceutical importance from Chlorella vulgaris. J. Chem. Technol. Biotechnol. 84, 657–661 (2009).
5. Pauli, G. F. et al. Importance of Purity Evaluation and the Potential of Quantitative 1H NMR as a Purity Assay. J. Med. Chem. 57, 9220–9231 (2014). 6. Hunt, D. G. Moisture Permeation of Pharmaceutical Packaging. (2013).