The Current State of PAT in Freeze-Drying
The Current State of PAT in Freeze-Drying
January/February 2005
1Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwing-Maximilians-University, Munich
2Boehringer Ingelheim
Freeze drying is a widely used method to stabilize protein pharmaceuticals. The stability of proteins and the biological activity can be influenced by several factors, which may lead to conformational changes and to denaturation, aggregation or absorption to surfaces [1]. To develop a formulation which is stable for up to two years is challenging. Aqueous, ready-to-use solutions are preferable dosage forms (convenience, cost, customer acceptance), but often insufficient stability in solution can not be overcome. Therefore, many protein dosage forms are produced by freeze drying. Freeze drying comprises three different stages, beginning with the freezing procedure followed by the primary drying and finally the secondary drying step. In order to develop an economical and sustainable freeze drying cycle, it is crucial to minimize the process time, especially for the primary drying. The ice sublimation rate is the most important factor within this process step [2]. To stabilize proteins against denaturation stress, a variety of basic principles can be applied. These measures include adjusting the pH and buffer system, the addition of cryoprotectants and the selection of lyprotectants to create amorphous matrices with high Tg and water replacement properties. Aresidual moisture content below 2% has to be reached and maintained during storage [3,4]. Accordingly, when amorphous matrices shall be dried, the main drying temperature has to be kept very low and that consequently leads to longer drying cycles. Latter cycles increase the need for cycle time optimization with modern monitoring tools, the process analytical technologies (PAT). PATsystems include fundamental process design and optimization, as well as control devices but also statistical response strategies and other measures. After such techniques have been adapted and approved, the quality level of products can be maintained in a very narrow range, time consuming analytical measurements may be reduced, or even cancelled for the end products, finally leading towards parametric release concepts.
Process Monitoring Methods
For freeze drying where the process development is a critical preparation step, process analytical technology is a mandatory part of the entire quality system. Freeze drying of a particular formulation requires the optimization of numerous parameters, because product presentation (e.g. volume, packaging material) and formulation dictate the process conditions. Process monitoring methods can be divided into two groups. The first group comprises temperature probe, conductivity probes, balances, and offline analytics after sampling via the sampling theft. The second group is formed by all methods which monitor the entire batch, not single vials, and barometric temperature measurement, pressure rise test, windmill devices, mass spectroscopy, and moisture sensors have to be named here (see Table 1). The pros and cons of all these methods are reported in the literature. In the following we want to exemplify some major issues.
By using temperature and electrical resistance probes conditions in selected samples can be monitored in a rather precise and meaningful way. However, irritations and complications, connected to the latter methods are well known. For example, temperature probes can serve as a crystallization point during freezing and strongly affect heat conduction in the drying cake [5]. This invasive method, however, can still be entitled as the gold standard for process development. Noninvasive methods, including the pressure-rise test [6] and the barometric temperature measurement [7], involve short interruption of the drying cycle with the associated danger of partial ice-melting or product collapse. Furthermore, these methods are highly dependent on the leak rate of the equipment and therefore very sensitive to maintenance issues. Comparative pressure measurement using Pirani sensors and capacitance manometers provide quantitative information but require repeated calibration [8]. In fact this method only delivers indirect information about the end of primary drying. The lack of new methods to characterize the true situation inside freeze drying processes relates to their extensive experimental set up. Yet the combination of such tools could finally increase the understanding of manufacturing processes and is therefore of high value. Novel methods to determine the status of lyophilized formulations online are the microbalance system, near-infrared-spectroscopy (NIRS) and massspectroscopy.
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