The Evolution of Freeze-Drying

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is freeze-drying. Reconstitution by adding water results in a product with the same functionality as before, whereas with other dehydration methods this is not the ...
Ingredients, Formulation & Finishing

The Evolution of Freeze-Drying By Jos Corver at IMA Edwards

Advances in freeze-drying have evolved on a gradual basis, rather than by stepchanges; for the future, macro-trends such as global warming and personalised medicine will drive further advances in the pharmaceutical sector. In ancient Egypt, the culture of mummification as the key to immortality was developed to a high level. The whole process of quickly removing the organs and embalming a body could take weeks – but the result was that the remains of the deceased were almost completely deprived of humidity. The final encapsulation of the mummy in resin provided a perfect isolation against rehydration. As well as this culture of mummification that has been practiced all around the world, natural mummies have also been found. Some were conserved thanks to the removal and absence of water, others to the complete absence of oxygen – both of which are necessary for the natural reduction process to develop. The removal of water for conservation purposes has been extensively developed for the preservation of food. The Inuit use the cold dry atmosphere to dry fish and then seal it for use during their long hikes; the Northern people of Europe, the Samisk, are also known to use this conservation method. Even today, the native people of the high Andes dry their potatoes using the low temperatures of the night and the low humidity of the day. The essence of these examples is that the removal of water is the key to reducing material degradation, leading to a prolonged shelf life. There are a couple of ways that water removal can be achieved. Water can be removed with chemicals, such as those the Egyptians used during

mummification, or by supplying heat (boiling out) – but the best way to remove water without harm to the structure is freeze-drying. Reconstitution by adding water results in a product with the same functionality as before, whereas with other dehydration methods this is not the case. FREEZE-DRYING The freeze-drying process (to the primary drying stage) is illustrated in Figure 1. The essence of the process is the removal of water while keeping the chemical and physical structures of the material intact; therefore, the first step is to stabilise the structure of the material by freezing. This freezing is a complicated step where ice crystals are grown intertwined with crystalline or amorphous components of the active product and excipients. The composition of the material determines the freezing curve, and even annealing steps are introduced to generate favourable crystal structures. The second step is to introduce a vacuum until the state is below the triple point of water. In this state, the water can convert from ice to vapour without melting, which would destroy the physical structure that is to be achieved. In the vicinity of the frozen product is located an ice-condenser – a structure of metal pipes, cooled to temperatures well below that of the frozen product. Therefore the partial watervapour pressure near the condenser is significantly lower than near the frozen product, and this leads to transport of water to the condenser, followed by condensation.

Figure 1: Phase diagram of water with reference to freeze-drying. The product is first cooled down until freezing starts. After further cooling down, the pressure is reduced until below the triple point of water. The supply of heat results in vaporisation of the ice. This vapour is removed by a device with the surface held at a very low temperature where the vapour condenses: the ice-condenser.

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For this sublimation process (primary drying) to continue, it is necessary to supply energy to the sublimation front to compensate for the latent heat of evaporation. This energy is commonly supplied by heat, and the shelves on which the vials of pharmaceutical product are standing are brought to higher temperatures. In all cases, however, care has to be taken that all the product contained in the vial stays in a frozen state, and even glass transition temperatures or eutectic temperatures have to be respected. Collapse of the product would lead to rejection.

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Once the crystalline water has sublimed, the product is usually not sufficiently dried. The remains of absorbed or interstitial water lead to moisture concentrations of above five per cent, which is usually too high for adequate

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INDUSTRIAL DEVELOPMENT A methodical approach to freeze-drying was first published by Altmann in 1890 for the preparation of biological tissues for research (1). After several variations of creating a vacuum or lowering water vapour concentrations, it was Shackell who used an electrically driven electrical pump for establishing the vacuum (2). Tival (1927) and later Elser (1934) patented systems for freeze-drying, and established improvements on the freezing and condenser concepts. The industrial importance of freeze-drying became apparent in World War II, when large quantities of blood plasma and penicillin needed to be available in the field. In the 1950s and 60s, there was much optimism for the broad use of freeze-drying for pharmaceutical and food purposes. But since, with freeze-drying, process times are long and energy efficiency is low, the food industry adopted different methods such as spray drying. This method is suitable for production in bulk – but for pharmaceutical applications, this approach is not suitable because, on the one hand, the spraying results in relatively high shear stresses, and on the other, the small and accurate dosages required per vial are difficult to achieve with powder filling. Therefore, for pharmaceutical purposes, freeze-drying takes place in containers fitted with accurate fluid filling systems. Over the years, freezedrying has evolved in a number of ways: N

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The first steps involved optimisation of the process in terms of refrigeration systems, components and control The demands of drug regulatory authorities subsequently prompted a drive for predictive process operation. This meant more reliable equipment, support for aseptic processing and process validation Increased requirements for aseptic conditions in the surrounding area led to the development of automated loading systems that minimised human intervention Most recently, launch of the FDA’s Process Analytical Technology (PAT) initiative has driven the development of process measurement equipment that may also lead to optimisation of production yield

Innovations in Pharmaceutical Technology

Figure 2: Evolutionary steps in freeze-drying 3.5 3 Drying efficiency

prolonged shelf life. Therefore an additional drying step (secondary drying) is performed where the temperature of the product is further increased. Since the free water is already sublimed, this can be done safely provided that the maximum allowable temperature for the product is not reached.

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PREDICTING THE FUTURE Trying to predict future developments in freeze-drying represents a major challenge; it might thus be useful to first make a little excursion in the semicon industry. In the semicon industry, developments can be identified with roadmaps. The so-called Moore’s law plays an important role since it points out the key element of industrial achievement: either pursue the miniaturisation of patterns or increase the number of active elements per unit area. Moore’s law was established by retrospective analysis of the growth of the microelectronics industry. After publication of this relationship, the industry adopted it as a roadmap standard and, until now, the industry seems to have lived up to it. The conceptual flaw here is that we will never know how progress would have been without this approach. It is not easy to identify a similar approach for the pharmaceutical industry – but below we give this a try (see Figure 2). Whereas Moore used the number of switch elements per unit area, we try a formula that maximises the output per unit time related to the required quality. An increase in the efficiency of the process can be noticed here; this efficiency metric incorporates the amount of resulting dry matter divided by the established moisture level and the amount of process time. Note that although – strictly speaking – automated loading systems are not maximising the freeze-drying output, they do enable an increase in the scale of operation in a GMP-acceptable manner. If we look at the indicative points from 2000 onwards, there are two elements that need some elaboration: PAT tools and new freeze-drying methods (continuous freezedrying). Both elements represent a model for a family of possibilities. PAT is a driver for better understanding of pharmaceutical production processes. The flow of activities under PAT is first to use scientific methods to understand all steps and system elements from base materials until effective disease treatment. With this knowledge the critical parameters can be identified, and engineering can focus on improvement of the control mechanisms to keep the values

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Figure 3: The practical implementation of Lyoflux®

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within a specified band. This control can only take place when the appropriate measurement systems are applied; this explains why the PAT initiative led to an intensified development of measurement systems. An example of this is an optical method to determine the rate of water vapour transport in the connecting tube between chamber and condenser (Lyoflux®, see Figure 3). Essentially, in an industrial freeze dryer, the ‘process’ is the transport of water vapour from the product to the condenser where the vapour condenses to ice again. With the Lyoflux(r) system, the near-infrared light beam crosses the tube and the detector on the other side measures the absorption, which is linearly dependent of the concentration of water vapour. As the beam is oblique to the vapour flow, the absorption spectrum is shifted due to the Doppler effect (see Figure 4). This information, combined with the dimensions of the tube, results in the continuous measurement of vapour flow. And this – in turn – forms a continuous monitor of the state the freeze-drying process. The application opens the window to related possibilities such as end-point detection of primary and secondary drying, product temperature and parametric scale up. Eventually, this will lead to a more efficient process with more output per unit time and of the right quality. Alternative methods are available to establish information on the state of the freeze-drying process. One of the Figure 4: Doppler shift of absorption spectrum. A laser beam is obliquely fed through the channel between the chamber and ice-condenser. The absorption spectrum is then shifted due to the Doppler effect The instantaneous measurement of the water vapour flow rate and, by extension, the product temperature: 1.2

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founding fathers of the MTM (manometric temperature measurement) application was Professor Michael Pikal (3). By determining the pressure rise behaviour of the vapour in the chamber, characteristic information on product temperature can be determined using thermodynamic balance equations. The downside to this method is that it requires a temporary closure of the valve between the chamber and condenser, thereby fundamentally influencing the freeze-drying process. Both methods – Lyoflux® and MTM – rely on measuring the product temperature with respect to the heat transfer characteristics of the various media. And this requires adequate calibration – which may be complicated. Equipment also exists to determine the moisture level in the chamber in a continuous manner; this may be used to determine the endpoint of primary drying, but it does not provide adequate information on the instantaneous status of the process, since during a large portion of the primary drying (sublimation) phase the humidity is close to 100 per cent without a lot of variation. The most direct way to measure the temperature of a product during freeze-drying is with thermocouples or resistive methods. Non-contact, infrared measurements cannot be used due to the glass being opaque for this wavelength. A temperature mapping method using thermo-elements is commonly used during engineering and validation, but not in routine production operations. GMP requirements dictate minimal human intervention, and the placing of the sensors represents such an intervention. Wireless measurement systems are therefore under development. THE FUTURE Looking at current macroscopic trends, global warming is forcing the industry of the developed world to devote more attention to energy-efficient production. Freeze-drying, as practiced nowadays, is extremely inefficient related in terms of energy use. Another trend in the pharmaceutical industry is the need for flexibility and reduction of batch sizes. Looking first at the energy aspects, Figure 5 (see page 70) shows the energy consumption of a range of five freeze dryers. (The numbers 1, 10, 20, 30 and 40 refer to the effective area of the shelves.) The theoretical required energy (Process) for temperature changes and phase transitions is compared with the electromechanical properties of the components (Process and Equipment). The graph illustrates how energy is wasted during freezedrying; it also shows that larger freeze dryers are more efficient than small ones. The latent heat dissipation and absorption is achieved in a very inefficient way. Also, the

Innovations in Pharmaceutical Technology

Figure 5: Energy consumption of freeze-drying and freeze-dryers 100 90 80 70 60 50 40 30 20 10 0

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practiced previously, the new design is based upon a wellengineered vacuum brazing process. This results in a significantly reduced amount of stainless steel and a reduced volume for the diathermal fluid, and so the energy needed to achieve the required temperatures is reduced. An additional advantage is an improvement in the thermal homogeneity and mechanical strength of the shelves. A schematic outline of the brazed shelf system is shown in Figure 6. Note also the specific improvement in the bottom of the shelves (the PLUS option), designed to provide an uninterrupted release of rubber stoppers during automated stoppering. The rubber stoppers will no longer stick to the bottom of the shelves after the automated stoppering process – increasing the yield of the batch and therefore the efficiency of the process.

Figure 6: Improved shelf design

Personalised medicine can be seen as having significant implications for the pharmaceutical industry, whereby there will be a growing need for flexibility (fewer ‘block buster’ products) and the size of the batches will decrease. It is not yet clear where this trend will lead. One possibility would be smaller but more numerous freeze dryers, and consequently more flexible loading systems. Conceptual thinking might also lead to continuous solutions, but the ramifications of this for the pharmaceutical industry are still unclear.

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non-optimised use of cool-compressors is a big contributor to the waste. Scenarios are being developed to link heat sources and sinks in a more efficient way. Advances in freeze-drying rarely occur in step-changes – hence, use of the word ‘evolution’ for the title of this article. Another example of evolutionary improvement is the novel design of hollow shelves flushed with diathermal fluid to provide the source or sink of heat for the product to be treated. Instead of welding the top and bottom plate together with bars forming the channels, as widely Jos Corver has a background in Aero- and Hydro-dynamics and Applied Physics; he graduated from Delft University of Technology (Delft, Netherlands) in 1981. After a research project at Eindhoven University of Technology (Eindhoven, Netherlands) on early detection of atherosclerosis, he joined Océ Technologies (Venlo, Netherlands), where he developed new colour printing processes, managed the industrialisation of a novel photoconductor and was eventually responsible for the engineering and release of wide format printers. He joined IMA Edwards in 1999 to develop new products related to primary packaging with a focus on freeze-drying, filling processes and loading systems. He acquired patents on measurement systems and some improvement on freeze dryers (FUSIONTM PLUS). Email:

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CONCLUSION Although the use of pharmaceutical freeze-drying is relatively young, the process has been in practical existence for ages. The development of pharmaceutical freeze-drying has been slow, and has proceeded in an evolutionary manner. For the future, macro-trends such as ‘global warming’ and ‘personalised medicine’ are likely to have a significant impact on freeze-drying within the context of the pharmaceutical industry. Acknowledgement The author wishes to thank Alexander Schaepman and Carlo de Best for their respective contributions on Lyoflux® and the energy aspects of freeze-drying. References 1.

Altmann R, Die Elementarenorganismen Und Ihre Bezeihungen Zu Den Zellen, Veit, Leipsig, Germany, 1890

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Shackell LF, Am J Physiol xxiv, 325, 1909

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Tang Xiaolin, Nail Steven L and Pikal Michael J, Evaluation of manometric temperature measurement, a process analytical technology tool for freeze-drying: Part I, product temperature measurement, AAPS

PharmSciTech Vol 7, No 1, March 2006

Innovations in Pharmaceutical Technology