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Current trends in the pharmaceutical industry led to a demand for more flexible manufacturing processes with smaller batch sizes. Prepackaged nested vials that can be processed as a unit were introduced into the market to fulfill this need. However, vial nests provide a different thermal environment for the vials compared to a hexagonal packaging array and could therefore influence product temperature profiles, primary drying times, and product quality attributes. Polymer caps with the possibility of vial closure inside the freeze-drying chamber were developed to remove the risks and need of a crimping process. A general concern with the use of such caps is the possibility of an increase in resistance to water vapor flow out of the vial. This case study investigated the effect of the LyoSeal ® and PLASCAP ® polymer caps and EZ-fill ® nests on the freeze-drying process. Amorphous and partially crystalline model formulations were freeze-dried. Process data and product quality attributes were compared for regularly stoppered vials and vials with polymer caps as well as vials in a hexagonal packaging array and nested vials. The results indicated no increased resistance or impeded water vapor flow by the polymer caps. Differences in the macro- and microscopic appearances of products and a trend towards lower product temperatures were observed for the investigated nest type compared to a regular hexagonal packaging array. Consequently, the polymer caps could be used as an alternative to regular stoppers without affecting freeze-drying process data or product quality attributes, while the different thermal environment of nested vials should be considered.

To alleviate concerns in health security, emergency flu vaccine stockpiles are required for ensuring rapid availability of vaccines when needed. Cold chain preservation, at high cost and risk, is necessary to maintain vaccine efficacy. This study aimed to develop a dry, easily storable formula for influenza vaccine preparation. The formulation with mucoadhesive properties is expected to facilitate rapid delivery via nasal administration. Chitosan, a cationic polymer, was used as cryo-protectant and to promote mucoadhesion. Optimal concentrations and molecular weights of chitosan polymers were screened, with short chain chitosan (10 kDa) being most suitable. H1N1 dry powder, in different formulations, was prepared via freeze-drying. A series of cryo-protectants, trehalose (T), chitosan (C), fetal bovine serum (FBS; F), or a combination of these (TCF), were screened for their effects on prolonging vaccine shelf life. Physicochemical monitoring (particle size and zeta potential) of powders complexed with mucin revealed that the order of cryo-protectant mixing during preparation was of critical importance. Results indicated that the TCF formula retains its activity up to 1 year as indicated by TCID 50 analysis. This approach was also successful at prolonging the shelf life of H3N2 vaccine, and has the potential for large-scale implementation, especially in developed countries where long-term storage of vaccines is problematic.

Inter- and intra-batch variability in heat and mass transfer during the drying phase of lyophilization is well recognized. Heat transfer variability between individual vials in the same batch arise from both different positions in the vial array and from variations in the bottom contour of the vials, both effects contributing roughly equally to variations in the effective heat transfer coefficient of the vials, K v . Both effects can be measured in the laboratory, and variations in average K v values as a function of vial position in the array for lab and production can be calculated by use of the simple steady-state heat and mass transfer theory. Typically, in the laboratory dryer, vials on the edge of the array, "edge vials," run 2-4°C warmer than "center vials," but differences between laboratory and manufacturing temperatures are modest. The variability in mass transfer can be assigned to major variations in ice nucleation temperature (both intra-batch and inter-batch), including major differences between laboratory and manufacturing. The net effect of all random variations, for each class of vial, can be evaluated by a simple statistical model-propagation of error, which then allows prediction of the distribution in product temperatures and drying times, and therefore prediction of percent of vials dry and percent of vials collapsed and proximity to the edge of failure for a given process. Good agreement between theoretical and experimentally determined maximum temperatures in primary drying and percent collapsed product demonstrates the calculations have useful accuracy.

Dehydration is a commonly used method to stabilise protein formulations. Upon dehydration, there is a significant risk the composition of the formulation will change especially if the protein formulation contains volatile compounds. Phenol is often used as excipient in insulin formulations, stabilising the insulin hexamer by changing the secondary structure. We have previously shown that it is possible to maintain this structural change after drying. The aim of this study was to evaluate the residual phenol content in spray-dried and freeze-dried insulin formulations by Fourier transform infrared (FTIR) spectroscopy and near infrared (NIR) spectroscopy using multivariate data analysis. A principal component analysis (PCA) and partial least squares (PLS) projections were used to analyse spectral data. After drying, there was a difference between the two drying methods in the phenol/insulin ratio and the water content of the dried samples. The spray-dried samples contained more water and less phenol compared with the freeze-dried samples. For the FTIR spectra, the best model used one PLS component to describe the phenol/insulin ratio in the powders, and was based on the second derivative pre-treated spectra in the 850-650 cm(-1) region. The best PLS model based on the NIR spectra utilised three PLS components to describe the phenol/insulin ratio and was based on the standard normal variate transformed spectra in the 6,200-5,800 cm(-1) region. The root mean square error of cross validation was 0.69% and 0.60% (w/w) for the models based on the FTIR and NIR spectra, respectively. In general, both methods were suitable for phenol quantification in dried phenol/insulin samples.

The purpose of this research was to evaluate a new wireless and battery-free sensor technology for invasive product temperature measurement during freeze-drying. Product temperature is the most critical process parameter in a freeze-drying process, in particular during primary drying. The product temperature over time profile and a precise detection of the endpoint of ice sublimation is crucial for comparison of freeze-drying cycles. Traditionally, thermocouples are used in laboratory scale units whereas resistance thermal detectors are applied in production scale freeze-dryers to evaluate temperature profiles. However, both techniques show demerits with regard to temperature comparability and biased measurements relative to vials without sensors. A new generation of wireless temperature sensors (Temperature Remote Interrogation System, TEMPRIS) were used in this study to investigate for the first time their value when applied to freeze-drying processes. Measurement accuracy, capability of accurate endpoint detection and effect of positioning were delineated by using product runs with sucrose, mannitol and trehalose. Data were compared to measurements with 36-gauge thermocouples as well as to non-invasive temperature measurement from Manometric Temperature Measurements. The results show that the TEMPRIS temperature profiles were in excellent agreement to thermocouple data when sensors were placed center bottom in a vial. In addition, TEMPRIS sensors revealed more reliable temperature profiles and endpoint indications relative to thermocouple data when vials in edge position were monitored. The results of this study suggest that TEMPRIS may become a valuable tool for cycle development, scale-up and routine manufacturing in the future.