Analytical Tools for a Quality-by-Design Approach to Lyophilization

Lyophilization presents challenges in defining and accurately measuring critical process and product parameters (CPPs) in laboratory and commercial scales. Pharmaceutical Technology spoke to Henning Gieseler, group leader, Freeze Drying Focus Group, in the Division of Pharmaceutics at the University of Erlangen-Nuremberg; Yves Mayeresse, director, Manufacturing Center of Excellence Filling and Freeze-Drying Operations, at GSK Biologicals; Steven Nail, principal scientist at Baxter Pharmaceutical Solutions; Trevor Page, group technical director, and Manfred Steiner, area sales manager, both at GEA Pharma Systems; and Michael J. Pikal, professor of pharmaceutics at the School of Pharmacy, University of Connecticut, to discuss analysis and scale-up methods.

PharmTech: What analytical tools and techniques are essential for a quality by design (QbD) approach to a lyophilized product? Are there any gaps in current technology in this area?

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

In addition to the batch method, it is also necessary to have a noninvasive measurement (i.e., no contact with the product) of a CPP in a single vial. The reason for such a combination is simple. A batch method gives a global, average picture of 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 or 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.

Mayeresse (GSK Biologicals): One of the current weak points of freeze drying is the absence of direct measurement during the process. In the past, product probes were used to monitor the freeze-drying cycle, but they were not really reliable. There are many reasons for this, but mainly they are invasive. As you modify the freezing of a vial with a metallic wire probe, it creates void around the wire that allows vapor to escape more quickly. Today, automatic loading systems mean that these probes cannot be used anymore. However, new PAT tools are appearing on the market.

Nail (Baxter Pharmaceutical Solutions): We use tuneable diode laser absorption spectroscopy (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 6% 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 Pharma Systems): The most important aspects of understanding the lyophilization process are those that provide insight into 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 (i.e., equipment, vials, and 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. Inserting temperature probes reduces the degree of super-cooling, making the measured temperatures nonrepresentative of the batch as a whole. This problem can be circumvented by using controlled ice nucleation. However, although this technique is 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 manometric temperature measurement or, particularly, TDLAS, that could be used in manufacturing, but so far, this is not common practice.