Headspace Gas Analysis: What’s on the Shelf?

Many injectable drugs are sealed into containers (typically glass vials or ampoules) after processing, in protective atmospheres to avoid contact with air that can damage quality & effectiveness. Nobody would like to open a yogurt jar and find fungus or buy medicine and find it has lost its effectiveness due to oxidation.

Here we are identifying two main impacts: Business Impact and GMP (Good Manufacturing Practice) Impact. In the first case, the company can lose business, in the second, it could cause serious illness to people. Different Container Closure Integrity Testing (CCIT) methods can be put in place to avoid the above: Vacuum Decay, Pressure Decay, Force Decay, Lid Deflection, Spark Test and last but not the least Headspace Gas Analysis (HGA).

Pharmaceutical Companies are required to protect their products not only with proper and safe enclosures, but they must also fill the space that surrounds the product (i.e. headspace), with some particular gases (e.g. Nitrogen, Carbon Dioxide) or simply maintain a high level of vacuum inside the enclosure, to avoid contact with oxygen or moisture.

At this point dear reader, I hope you have understood why it is so important to know what’s happening inside the headspace of your container. Headspace Gas Analysis plays an important role among the CCITs. Let’s add some more details.

Two different methods can be used to inspect headspace: destructive and non-destructive methods. In the destructive method, measurement of gas percentage present inside closed package requires the necessity to bring part of its internal atmosphere in contact with a proper sensor (e.g. chemical cell or zirconium oxide for oxygen) to be able to produce electricity proportionally to the gas concentration or use optical fluorescence technologies in case of oxygen detection. Both inspection methods result in package destruction.

Tunable Diode Laser Absorption Spectroscopy (TDLAS) is a non-destructive method, able to measure the concentration of a certain gas in closed container, with a sufficient headspace size to pass through with a laser beam with fairly good transparency to laser light: glass and plastic containers can be inspected as well if these conditions are satisfied. TDLAS is a technology based on laser absorption spectroscopy, wherein the wavelength diode laser is tuned over the absorption line of the gas under test (760 nm for Oxygen, 1854 nm for Moisture, 2000 nm for Carbon Dioxide) and the intensity of the transmitted radiation is measured.

More the gas molecules are present in the head space, less the energy will arrive at the photodiode used to convert light into an electrical signal. The transmitted intensity can be related to the gas concentration by the Beer-Lambert law. It is possible to obtain information related to the gas under test measuring Area and Width of the Absorption Curve.

However, these measurements are unitless, so a Calibration Procedure is necessary to correlate these values to Gas Concentration (%) or Total Pressure (mbarA).

Calibration Procedure is strictly related to the Standards concept. It is possible to apply techniques of modulation in high frequency to further improve the signal-to-noise ratio, ensuring the detection of small variations of signals in front of a wider operating range: WMS (Wavelength Modulation Spectroscopy) and FMS (Frequency Modulation Spectroscopy) are the most common types of modulation techniques. FMS has a higher modulation frequency (some MHz) than WMS (some KHz); a lower laser residual noise is its main advantage; however, the detectable minimum quantity of gas is less dependent on laser residual noise than Etalon Effect for instance.

Furthermore, working at such high frequencies has another drawback: we need to use analog electronic components instead of digital ones thereby renouncing great advantages coming from them.

Now that we have more knowledge of this technology, we could be interested to understand how to take advantage from a non-destructive method.

You can focus on the following comparisons between the standard destructive method and the non-destructive HGA method to draw your own conclusions:

• Standard Methods to measure gas concentration or pressure value are destructive.

The packages can’t be recovered even if we have a conforming test… HGA is a non-destructive measurement method; packages can be recovered after confirming tests.

More valuable the product, more the item is important;

• Standard Methods are slow; they can’t guarantee 100% check of the whole production… HGA is very fast and it can be placed into an in-line process to test 100% of the production.

It is more expensive, but the return of investment covers the overall expenses;

• Standard Methods of Leak Detection don’t find non-conforming packages due to process anomalies if they are properly sealed… HGA finds non-conforming packages even if they are properly sealed; it measures the gas partial pressure in the headspace.

It is important to remember however, that HGA is not a leak detector if the quarantine period is not part of the production process.

I hope you have found some interesting food for thought about these intriguing arguments.

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