Gas analysis technologies for pharmaceutical production

This article from Servomex explains which gas analysis technologies are likely to be most suitable for particular applications in pharmaceutical production equipment.

Gas quality control

For on-site nitrogen production, on-line analysis of oxygen content can be used to control the process, plus it is vital to ensure that oxygen content is maintained at or below the defined limit, otherwise the safety of downstream processes could be jeopardised when the nitrogen is used for inerting or blanketing. Even if the nitrogen is bought-in from another supplier, it must be analysed to ensure it meets the specification. Oxygen may, itself, be produced on-site or bought-in. Either way, it is important to monitor the purity, as any variation could affect reaction rates, yields and quality.

Inerting applications

Reaction vessels and centrifuges can be at risk of explosion if solvents are present with oxygen and a potential source of ignition (such as a static discharge, metal-onmetal spark or hot spots due to mechanical wear). Nitrogen is usually introduced to displace the air and, therefore, remove the oxygen. If the exhaust gases are analysed for oxygen content, the nitrogen feed can be controlled automatically, which is more efficient than the use of time, flow or pressure-based nitrogen addition.

Similarly, waste ducts used to convey vapours away for destruction or recycling are inerted and, therefore, require monitoring.

Nitrogen inerting is also frequently employed on granulating and coating machinery, so these can benefit from online analysis of the headspace gases in the same way as reaction vessels and centrifuges.

There are several alternative technologies available for measuring oxygen in such inerting applications, with electrochemical cells being the traditional option. While these sensor cells are relatively low cost, they have a limited lifespan. Consequently a planned replacement programme has to be in place to ensure that every cell is changed before the end of its useful life. This is essential, as an expired cell can give a low reading that might lead to a dangerous situation. Electrochemical cells are therefore not recommended for safety-critical applications or, indeed, those where long-term cost-of-ownership is important.

Magnetodynamic paramagnetic sensor cells, which rely on the magnetic properties of oxygen, have a long life, very low drift and are almost immune to cross-interference from other gases. While the initial purchase price is slightly higher than for other oxygen sensing technologies, life cycle costs are usually much lower, so paramagnetic technology is popular for nitrogen inerting.

Bioreactors and fermenters

Biological reactors and fermenters can be monitored by analysing the oxygen and carbon dioxide in the headspace, enabling the process conditions to be optimised and alarms raised should any problems arise. Typically a paramagnetic sensor will be used to measure oxygen and an infrared used for determining carbon dioxide concentration, often in a multiplexed arrangement so that several streams feed in turn into just one analyser.

However, care must be taken on two counts. Firstly, as the sample gas is warm and wet, it must be conditioned to prevent risks of condensation or contamination inside the gas analyser. Secondly, the infra red sensor should be able to reject cross interference or drift from residual gaseous water vapour or other background components. This can be achieved by careful selection of the measurement wavelength and if necessary, use of a second reference wavelength (single beam, dual wavelength technology).

Solvent recovery

Solvents play a major role in the production of pharmaceuticals, with solvent recovery processes creating their own requirements for gas analysis. Typically vapours will be adsorbed onto the carbon beds, then desorbed using steam. However, there is a risk of combustion in the carbon beds, so a fast-response infrared analyser capable of measuring carbon monoxide in flammable samples is often employed to quickly detect any problems and allow remedial action to be taken.

Once the solvents have been desorbed from the carbon beds, they must be dried; monitoring enables the process to be completed as quickly as possible, with no wasteful over-drying. In this case an online analyser offers a faster response than offline analysis of grab samples, with the added advantage that there is no risk of the sample being contaminated during sampling or transit to the laboratory, and without the hazards associated with manual handling of potentially toxic solvents. Online infrared analysers can be used to provide a continuous reading of the ppm water content for this purpose, with negligible cross-interference from the solvents present.

Incinerator and thermal oxidiser applications

The two main applications for gas analysis in incinerators or thermal oxidisers are combustion control and emissions monitoring. Typically the oxygen and combustibles (COe) are measured in the flue gases to ensure that the optimum amount of air is being fed in to the incinerator, as too much air wastes fuel and too little leads to incomplete combustion. Oxygen is commonly measured using a zirconium oxide (zirconia) sensor, which gives high accuracy, a fast response and can handle the elevated temperatures and moist gases present. Carbon monoxide levels are monitored using a thick film calorimeter that gives high precision, with sufficient sensitivity and speed of response to enable continuous fine-tuning of the combustion process. Furthermore, this type of combustibles transducer is considerably less affected by cross-interference from other background gases such as water and carbon dioxide than are transducers using alternative sensing technologies. Both zirconia and thick film calorimeter technologies are highly reliable, non-depleting, and can operate for extended periods without requiring attention, though care should be taken that the acidic gases produced during solvent destruction do not damage the sensors. One of the best ways to do this is to mount the sensors in a heated enclosure attached to the flue rather than actually placing them inside it.

Emissions resulting from solvent combustion are frequently legislated, with operators being required to monitor the oxides of sulphur and nitrogen (SOx and NOx). Two alternative measuring techniques are commonly used here: cross-stack and extractive. Although cross-stack measurements are, in principle, easier to make, the equipment tends to be more difficult to install, calibrate and maintain. Extractive systems, on the other hand, involve removing a sample, conditioning it and analysing it, but this is, nevertheless, preferred due to better traceability. While the sample system adds complexity and the hardware is more costly, subsequent calibration and maintenance operations are easier. In either case, infrared or ultraviolet measurement technologies can be employed, but UV sources have a limited life and this technology can be susceptible to crossinterference.

With a single-beam infrared system using gas filter correlation however, it is possible not only to virtually eliminate problems with spectral interference, but also to benefit from reduced maintenance through longer source lifetimes, and reduced drift, and thus calibration demands, as this technique minimises the effects of gradual cell contamination. Furthermore, the fast response enables a single analyser to monitor multiple flues by multiplexing, which can make the overall CEMS (continuous emissions monitoring system) considerably more cost-effective.

Conclusion

Clearly the applications for gas analysis within pharmaceutical production are many and varied, leaving machine builders and plant operators with a broad choice of technologies. These include electrochemical, magnetodynamic paramagnetic, infrared, ultraviolet, zirconium oxide (zirconia) and thick film calorimetry - and the decision as to which to use is not always clear-cut. Factors to be taken into account inevitably differ from one project to the next, but the gas composition, condition and contaminants will be important, and there is also a balance to be struck between the initial purchase cost and the cost of ownership. Lastly, applications usually have specific requirements in terms of accuracy, traceability and/or safety, which will also influence the final decision.

Fortunately there are companies such as Servomex that have product portfolios built on more than one technology, coupled with a wealth of experience of pharmaceutical production applications, which enables them to provide advice on the optimum gas analysis technology for any given set of application requirements.

For more information about gas analysis technologies and to discuss particular pharmaceutical production applications, please contact Servomex.