Freeze drying is widely used in pharmaceuticals to improve the long-term storage stability of labile drugs. Most new biotechnology products require a stabilising process (often lyophilisation) where developers use scientific techniques that define the correct parameters for new processes.1
Because of the great number of biotechnological products used during the last 20 years, several techniques have been developed to increase knowledge into the lyophilisation process. Stabilisers used in biotechnology products (for the most part proteins) generate formulations difficult for freeze drying.2
Often, the use of cryo- and lioprotectors involves using polyols, such as sugars; specific examples being sucrose, maltose, lactose, trehalose and sorbitol. The amorphous behaviour of these sugars (the low glass transition temperature [Tg'] of sorbitol is well known) tends to promote the collapse of the cake. This necessitates a greater knowledge of thermal properties of the product once the suitable formulation is developed.Knowledge derived from these studies is generally applied to new products, but the lyophilisation processes of a large number of well-known products — mainly generic and old formulations — are purely historical. This gives rise to long cycles that tend to be unreliable because of poor initial process development.
Detailed study and/or revision of these established formulations that results in process/cycle improvement would be extremely beneficial. 'Thermal fingerprinting' could not only provide shortened cycles (thus improving cost), but the revised process would be entirely appropriate to the product being processed. This, in turn, would optimise residual moisture, appearance, reconstitution time and potency.
Inaccurate cycles can induce microcollapse and microconcentrations, which can lead to an eventual reduction of product stability. The development process applied to established and generic product cycles will be much simpler than those that apply to biotech products; however, surprises may be evident, caused by the specification change at the time-release because of the evolution of pharmacopoeias. The data written in the laboratory log files permit easy detection of out-of-date specifications when a new registration of a generic drug is done.
A simple way to optimise the process
We have developed a simple system that has been shown to shorten and rationalise the lyophilisation process. The procedure consists of establishing the thermal fingerprint (TF), which characterises the thermal behaviour of the formulation of a well-known antibiotic macrolide. The use of techniques such as differential scanning calorimetry (DSC) and freeze dryer microscope (FDM) permit the determination of the critical product input temperatures required for the freeze-drying process: total solidification temperature (Tts), Tg' and collapse temperature (Tco).
The development procedure begins based on the current process/cycle that we seek to shorten. In this initial process, bottom breakage was observed. Inputs such as shelf temperature and chamber pressure during the different steps of the process (freezing, primary and secondary drying) are tested and initially developed in a pilot plant before being scaled up to the industrial plant when appropriate. The final product specifications of the new cycle are compared with those obtained in the original cycle.
The lyophilisation recipe has to be based on the structural characteristics of the product and on its thermal behaviour when subjected to freezing and drying processes.3
The physical models of the freeze-drying process are based on the thermal behaviour of the defined formulation; that behaviour is supported by the thermodynamic laws that governed it. Thermal behaviour is defined by studies that allow us to determine temperature values, but temperature is an intensive magnitude and we cannot use it to quantify and control the heat and mass transfer. Therefore, we must find the quantified results by implementing these laws (Ohms' Law: 'Law applied to fluid dynamics'; Newton's Law of cooling; Clausius-Clapeyron relationship: thermodynamics of open systems and so one). These models, as well as those based on mathematical or statistical methods, can add a high level of complexity to the resolution of the problem. A simpler approach, however, can be made based on knowledge such as the TF. The TF only attempts to reduce up to five or six intensive magnitudes of the product's thermal behaviour.
These five temperatures are crucial elements that define the TF of the formulation. They are divided into two groups; one group sets the freezing process, whilst the second group sets the primary drying process. 'Solidification' depends on the freezing and melting temperatures, whereas 'sublimation' is affected by the eutectic, glass and collapse temperatures.