Overcoming Common Lyophilization Scale-Up Issues

Jul 15, 2011

The same recipe obtained in laboratory-scale equipment cannot, without modifications, generally be used to freeze-dry the product in a pilot-scale or industrial-scale freeze-dryer. This is because scale up does not guarantee that you will obtain the same dynamics of product temperature and ice content (i.e., the same primary drying length) as those at the laboratory scale. Product temperature can often exceed the limit value, and/or the length of the process can be different.

Two of the main sources of the problem relate to the freezing and primary drying steps. The level of undercooling and, thus, nucleation can be different in the two apparatus, and heating conditions may also vary. In a laboratory freeze-dryer, heat is mainly supplied by radiation, and the large transparent window of a freeze dryer has a big influence. In these conditions, there is a small influence and relationship between shelf temperature and process evolution. This aspect is often overlooked, even if it can be evidenced quite easily. On several occasions I have seen presented data where the product temperature was higher than the shelf temperature, while the speaker was explaining the several trials conducted to improve the quality of the cake! As the process is endothermic, product temperature can be higher than shelf and fluid temperature only if heat is supplied by radiation.

The list of variables that have to be considered is quite long, but is summarised below:

  • environmental conditions in the manufacturing area, which can affect nucleation as explained above
  • shelf surface temperature distribution
  • contribution by radiating heat
  • chamber pressure
  • heating and cooling rates.

A large amount of literature has been published in this area (1–9).

Up until now, the influence of pressure distribution over the shelves has been generally neglected, but is important in the case of small clearances (to increase the loading) and high sublimation rates. Finally, because of the strong effect the chamber pressure has on the process, pressure control must be similar and effective—higher impedance of the dryer can cause chocked flow conditions and, thus, uncontrolled and higher pressure in the chamber. Obviously, human errors such as using different types of pressure sensor, like a capacitance manometer and a Pirani gauge, with the same pressure set point, must be avoided.

When it comes to freeze drying, the freezing and ice-nucleation steps are a concern, so any technology that can control nucleation will greatly improve the situation. Recently, a system based on rapid pressure reduction during cooling has been presented and seems very promising (10). Other systems are also under study. In particular, I believe that solutions based on ultrasound can become competitive if some mechanical problems are solved (11, 12).

Scaling up the drying recipe

Up until now, much attention has focused on the scale up of the drying recipe. A survey of literature shows (3–9) that scaling up a freeze-drying recipe is an open problem. The PAT Guidance for Industry released by the FDA in 2004 emphasises the need for a deep understanding of biotech processes to improve manufacturing efficiency, with the goal of building product quality into the process.

A first proposed approach to the problem was to design a robust recipe (or a robust design space) that could be used in both the lab-scale and pilot-scale freeze-dryer under the hypothesis that the two pieces of equipment are equivalent. In this case, no scale-up is actually carried out because the same recipe is used in different freeze dryers. The recipe that is used can be excessively conservative, and the procedure is based on a trial and error approach because it is hard to establish if the recipe is robust enough.

Sidebar: Previous attempts to use moldelling in scale up.
Recently, some papers were published that consider process modelling (see sidebar 1). Process modelling is an important improvement, but the model was used as an accessory tool, without giving the requested answer in a simple way, as will be discussed later.

Figure 1: Modification of the drying recipe (shelf temperature) passing from equipment 1 to equipment 2 for uniform batches: the same product temperature (TB) and the same ice thickness evolution are obtained.
A simple and effective methodology for recipe-scale-up and process transfer that takes into account the variation of product resistance during the main drying, as well as the possibility that product resistance may change between freeze-dryers, is now available, and is described in detail in the literature (1, 2). Such an approach involves using mathematical modelling to simulate product evolution for a selected recipe, as well as a few experiments to determine model parameters and to characterise different freeze-dryers. The effect of parameter uncertainty can be easily accounted for, as can batch non-uniformity. Differences in the cake resistance, a consequence of differences in ice nucleation, can also be easily accounted for, but it will be necessary to characterise the cake obtained in industrial equipment.

Figure 1 shows an example application of the proposed procedure. The red line is the new recipe that takes into account the higher heat transfer coefficient obtained in the industrial scale apparatus.

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