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Freeze Drying - Articles and news items
Issue 5 2012, Lyophilisation / 22 October 2012 / Henning Gieseler, Associate Professor at the Division of Pharmaceutics, University of Erlangen & CEO, GILYOS GmbH and Peter Stärtzel, Pharmaceutical Scientist, GILYOS GmbH
The stochastic nature of nucleation during the freezing step of the freeze-drying process has been regarded as a demerit in a process which is considered under rigorous control. The freezing performance of a product can impact its subsequent drying behaviour and the final product quality attributes. Hence, the idea to control this stochastic event and thus to directly influence the product morphology seems highly appealing. Sound understanding of the nature of nucleation and its link to drying performance, as well as the choice of a suitable technical concept, is of fundamental importance and the prerequisite to profit from the opportunities offered by controlled nucleation.
Freeze-drying is a commonly used method within the pharmaceutical industry. One of the key steps of the entire process is the initial freezing procedure. During freezing of an aqueous solution, the formation of ice does not start at the equilibrium freezing temperature, Tf (Figure 1, page 64). Instead, the solution shows supercooling below Tf until the first ice nuclei are formed at the nucleation temperature, Tn. Nucleation itself proceeds in a three-phase process. ‘Primary nucleation’ describes the point where initial crystal nuclei appear from molecular clusters exceeding a critical size1,2. The formed nuclei are further grown to ice crystals by secondary nucleation (also referred to as ‘crystallisation’) passing through the already nucleated volume1.
The underlying concept for the stabilisation of proteins during freeze drying is the formation of a glassy matrix in which the macromolecules remain isolated and immobilised. The concept relies on the so-called ‘vitrification hypothesis’ which assumes that the formation of an amorphous phase by lyoprotectants is mandatory to interact with the amorphous protein molecule. The use of lyoprotectants has also been found to be beneficial to preserve the original particle size distribution of nanoparticles during freeze drying. Until today, it has been speculated that the predominant mechanism to suppress physical instabilities of such colloidal particle systems is their embedment in a rigid glass. Today, there are various types of colloidal particles used in drug development, and sometimes the scientific literature gives evidence that glass formation was not necessarily required for stabilisation during freezing thawing or even freeze drying. The purpose of this article is therefore to briefly provide the latest insight into potential stabilisation mechanisms when freeze drying nanoparticles, a key knowledge for rational formulation and process design for such systems.
In general, the overall goal of nanotechnology is to improve the performance of materials by the formation of particulate structures in the nanometre range1. With regard to the pharmaceutical sector, the purpose of using nanoparticles focuses on the improvement of direct interaction of an active pharmaceutical ingredient (API) with biological systems, enhancement of the stability of API’s or improvement of drug solubility2.
Pharmaceutical freeze-drying is used to stabilise delicate drugs which are typically unstable in solution over a longer shelf life. The liquid formulation is converted into a solid, highly porous cake which can be easily reconstituted prior to administration. The majority of freeze-dried products in the pharmaceutical industry are used for parenteral application. This route of administration demands high quality for both the drug product and the primary packaging material. Today, glass vials are routinely used for freeze-dried products as they provide some indispensable characteristics. Depending on glass composition, surface treatment, processing and geometry, a vast number of different glass vials are commercially available for customers. Selection of the optimum vial for a given product seems to become more and more difficult as manufacturers of moulded and tubing glass have refined their products over the last decades to fulfil market needs.
Process Analytical Technology (PAT) in Freeze Drying: Tunable Diode Laser Absorption Spectroscopy as an evolving tool for Cycle Monitoring
The most important critical product parameter during a freeze-drying process is the product temperature at the ice sublimation interface, Tp1. Once the product temperature in this area of interest exceeds the critical formulation temperature (typically denoted as “collapse temperature”, Tc) during primary drying, a stepwise loss of the cake structure may be observed2,3. This, in turn, can greatly impact the product quality attributes with regard to product appearance, reconstitution times, sub-visible particles and residual moisture content4.
The determination of structural changes of biopharmaceuticals during Freeze-Drying using Fourier Transform Infrared Spectroscopyb
Peptides and proteins are powerful active therapeutic ingredients used in a wide variety of serious conditions and illnesses such as diabetes, arthritis or cancer. The application of these so-called biopharmaceuticals has been rapidly increasing since the middle of the 1990s, facilitated by improvements in modern recombinant DNA technology and biotechnological manufacturing. The worldwide sales of the biotech drug market grew from 43 billion US$ in 2003 to over 75 billion US$ in 2007 according to a recent IMS Health market analysis. The major challenge in the development of stable protein formulations and dosage forms is to ensure their process and shelf life stability.
Freeze drying of pharmaceuticals requires an adequate formulation design to prevent low-temperature, freezing and drying stresses. The goal is to achieve a final product with long storage stability and elegant appearance. To meet these specifications the product temperature must be controlled below the critical formulation temperature during the freeze drying cycle. DSC is an established tool to measure this critical formulation property in the development of freeze dried pharmaceuticals as it allows rapid sample preparation and analysis time. The introduction of modulated DSC (MDSC) by Reading in 1992 has greatly facilitated the interpretation of DSC results. The overlapping transitions in the same temperature range can be distinguished and characterisation of the nature of transitions is facilitated.
Rational freeze-drying process design is based on a representative and accurate measurement of the critical formulation temperature. To avoid product shrinkage or collapse, it is indispensable to control the product temperature just below this key temperature during primary drying. Over the last decades, DSC was routinely used to determine the glass transition temperature of the maximally freeze concentrated solute (Tg’), information which was then applied to freeze-drying process design. Recently, Freeze-Dry Microscopy (FDM) was introduced as a new technology to determine an even more representative critical temperature: the collapse temperature (Tc). Today, important technological improvements in FDM even allow more sophisticated observations of collapse behaviour and therefore, further cycle optimization.
During the past 10-15 years, close attention has been paid to the development of optimal lyophilization cycles for different types of pharmaceuticals1-4. Recent advances in process control, such as the Smart Freeze-DryerTM technology or similar approaches,5-7 make cycle development a routine procedure. The attention of many researchers has shifted to the aspects of cycle transfer and scale up that still require significant investment in understanding the differences in lyophilization processes between laboratory and commercial dryers8-14. Conducting numerous experiments in an attempt to demonstrate that a laboratory cycle is not only optimal but also robust, requires significant material and time investment. Mathematical modelling of lyophilization processes proved to be a very useful tool, not only for cycle development15-19 but also for cycle transfer and scale up11,14. The same mathematical approach (as discussed in experiment14) was applied to the process tolerances design and estimation of cycle robustness in regard to the product temperature.
Issue 3 2007 / 23 May 2007 / Heiko A. Schiffter, Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford
Over the last decade, the development of new drug delivery methods and devices for dry powder inhalation1, needle-free intradermal powder injection2 or sustained parenteral drug delivery3 has led to an increasing demand for powder formulations incorporating an active pharmaceutical ingredient (API)4,5.
Freeze drying is generally known to be a time consuming and therefore expensive process. In order to lower costs during manufacturing, the effective cycle time must be reduced. This goal can be achieved by optimising a freeze drying cycle in the laboratory – in particular the primary drying phase. Applying PAT in the laboratory can provide valuable information about product and process behaviour and may help to identify the critical process parameters during cycle development and optimisation.
ABB Analytical Measurement Analytik Jena AG Azbil BioVigilant, Inc. B&W Tek, Inc. bioMérieux BMG LABTECH GmbH Bruker Daltonik GmbH CAMO Software AS Catalent Pharma Solutions Chemspec Europe Ltd CI Precision Dow Chemical Company Ltd EUROGENTEC FOSS NIRSystems, Inc. GE Analytical Instruments Gerresheimer Group I Holland Limited IDBS IONICON Analytik GmbH LI-COR Biosciences Lonza Natoli Engineering Company, Inc. Pall Life Sciences Patheon Inc PhyNexus, Inc. ReAgent Roche Sirius Analytical Instruments Ltd Vala Sciences Veltek Associates Inc. Waters Corporation