BioPharm: What analytical tools and techniques are essential for monitoring an enhanced approach to a lyophilized product?

Gieseler (University of Erlangen-Nuremberg): An innovative PAT approach for freeze-drying would requires a PAT tool that allows the determination of a critical product parameter, such as product interface temperature and product resistance, for the batch as a whole (batch method). Ideally, the technology should be applicable in all scales of equipment. As a compromise, two different technologies (one applied in the laboratory, one in production) can be used, but they must provide a reliable and comparable measure of the same parameter without inherent scale factor.

In addition to the batch method, a complementary single-vial technology is also necessary that allows a noninvasive measurement (no contact with the product) of a critical process or product parameter in a single vial. The reason for such a combination is simple. A batch method draws a global, average picture of the product drying performance, while the single vial method determines specific product drying performance at a given spot in the freeze dryer. This would help to delineate drying heterogeneity between vials (e.g., edge effects, hot or cold spots on the freeze dryer shelf) which is always present in a freeze dryer in whatever scale and which might even change over time in a given unit.

Nail (Baxter): As indicated above, we use TDLAS as the main PAT for design space development. It isn't essential, but it greatly decreases the time and effort required to construct a design space. We have found TDLAS to give accurate mass flow rates on laboratory scale equipment, usually within about 3% as compared with gravimetric determination. We do this by weighing the filled vials and stoppers before and after freeze-drying. However, TDLAS on production-scale equipment is considerably less accurate because of complexities in the dynamics of water vapor flow from the chamber to the condenser in large-scale freeze-drying equipment.

Page/Steiner (GEA): The most important aspects of understanding the process are those that give an insight into the experience of the individual vial rather than simply measuring the integrated effect on the headspace. Simple aggregated measurements, such as chamber pressure or more complex measurements like the application of mass spectrometers to the chamber gas, all have value for overall process control.

To understand the range of process conditions caused by both forced and natural variation within the overall system of the equipment, the vials and the product, it is important to be able to characterize the range of experiences of individual vials. However, the problem is that techniques examining the individual vial that can be used during development and validation are frequently difficult to deploy in a large production dryer.

Pikal (University of Connecticut): The key properties to measure are product temperature and primary drying time. Unfortunately, product temperature in given vials cannot be measured in a representative way. Insertion of temperature probes reduces the degree of supercooling, making the measured temperatures nonrepresentative of the batch as a whole. This problem can be circumvented, however, by using controlled ice nucleation, but although this technique is now available in both laboratory and production equipment, it is not routinely used in manufacturing. Hopefully, this will change in the near future. There are also indirect ways to measure batch average temperature, such as MTM or TDLAS that could be used in manufacturing (particularly TDLAS), but so far, this is not common practice.