Getting Lyophilization Under Control with PAT Techniques

A look at on-line mass spectrometry and NMR as control tools for drying samples

By Emil W. Ciurczak, Contributing Editor

At first glance lyophilization, or freeze-drying, should be straightforward and simple. All one has to do is freeze a tray or several of vials containing a solution of API. Once frozen, a vacuum is applied and the samples (sometimes) are warmed to drive off the solvents and leave a nice, dry cake of drug and, possibly, a bulking agent like Mannitol. When ready for use, pure water is added, the cake dissolved and the material injected.

Nevertheless, any number of things can go wrong during lyophilization. One major problem is basic heat flow; when the large trays of vials are cooled, it is nearly impossible to cool all of them at the same rate. This leads to temperature variations along the samples. Other than having closer temperature and vacuum control of the process or making smaller batch sizes, it is nearly impossible to know that a batch is under control without real-time monitoring.

It goes without saying that the manufacturer cannot have thermometers in every vial; the computer power alone would be a nightmare. However, there are a number of “macro” and “micro” methods that allow both control during and QC after the freeze-drying process. This note will discuss on-line mass spectrometry and NMR as control tools for drying samples. (Note: As much as I love near-infrared for pan-drying, it is not that useful here. But more on NIR below.)

Some drying work has been reported by workers at Pfizer and the University of Rhode Island [1]. Several different solvents were needed, and mass spec was used to monitor the drying end point of single and multiple solvent wet cakes. (Results are applicable to freeze-drying.)

The microwave drying rates for polar solvents were shown to have a linear correlation with solvent heat of vaporization. Mass spectrometry profiles were also shown to correlate with other drying end point parameters, including rate of recovered solvent, product temperature, and microwave reflected power. This information may be applied to heating of multiple “cakes,” a.k.a. lyophilized materials, to aid in setting heating parameters for the drying of the vials.

Another instrument designed for on-line applications is the ATEX, from InProcess Instruments (Bremen, Germany). The instrument has the ability to monitor several lines simultaneously. The gas is drawn directly from the multiple exhaust lines in a drying process. Several other instrument manufacturers will have similar equipment in the very near future and these are merely examples of advantages of mass spectrometry.

Another technique, not immediately associated with on-line analyses, is nuclear magnetic resonance (NMR). The instruments used in a laboratory setting, usually in the 200-600 MHz range, are excellent for just that: laboratory work. These instruments need liquid nitrogen to cool the magnets (the high frequency ones need liquid helium) and are not good for a process line. Metal objects cannot be brought near the magnets, nor can credit cards or pacemakers. These are of course severe limitations for process work.

However, 60 MHz instruments, with their permanent magnets, can be re-designed for process analyses. In some work shown in 2007 [2], a 60 MHz NMR was designed to perform check weighing, on-line, at full filling speed prior to lyophilization. The current technique, sampling at random with balances, is obviously not fast enough. An on-line weighing device will not be able to distinguish variations in vial and stopper weights and might lead to erroneous values for fill variation. The NMR is responding only to the filled material and is giving values for 100% of the vials being filled. The down side, of course, is that any NMR in the near future will have to be built to order as there are no commercially available NMR process instruments.

Both examples, MS and NMR, show how lyophilization can be brought into the 21st century using PAT concepts.

After the lyophilized vials are produced, the current practice of select sampling seems archaic when using tools such as MS and NMR. Here is where a rapid near-infrared (NIR) instrument comes into play. A number of companies provide rapid NIR instruments that could be used for the purpose. NIR can not only measure the residual moisture, but assay each vial to assure content uniformity.

So, now we know there are tools to measure fill, drying, and finished product in a lyophilization process, this is one more application of PAT. What’s next?

1. Hettenbach, et al.,Org. Proc. Res. Dev., 2004, 8 (6), pp. 859–866.
2. Denkinger, Boehringer Ingelheim GmbH & Co. “PAT in Aseptic Processes,” at PAT—Quality by Design and Process Improvement, London, March 2007.

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