Optimizing lyophilization primary Drying: A vaccine case study with experimental and modeling techniques.

In this study, we present the lyophilization process development efforts for a vaccine formulation aimed at optimizing the primary drying time (hence, the total cycle length) through comprehensive evaluation of its thermal characteristics, temperature profile, and critical quality attributes (CQAs). Differential scanning calorimetry (DSC) and freeze-drying microscopy (FDM) were used to experimentally determine the product-critical temperatures, viz., the glass transition temperature (Tg') and the collapse temperature (Tc). Initial lyophilization studies indicated that the conventional approach of targeting product temperature (Tp) below the Tc (determined from FDM) resulted in long and sub-optimal drying times. Interestingly, aggressive drying conditions where the product temperature reached the total collapse temperature did not result in macroscopic collapse but, instead, reduced the drying time by ∼ 45 % while maintaining product quality requirements. This observation suggests the need for a more reliable measurement of the macroscopic collapse temperature for product in vials. The temperature profiles from different lyophilization runs showed a drop in product temperature following the primary drying ramp, of which the magnitude was correlated to the degree of macroscopic collapse. The batch-average product resistance, Rp, determined using the manometric temperature measurement (MTM), decreased with increasing dried layer thickness for aggressive primary drying conditions. A quantitative analysis of the product temperature and resistance profiles combined with qualitative assessment of cake appearance attributes was used to determine a more representative macro-collapse temperature, Tcm, for this vaccine product. A primary drying design space was generated using first principles modeling of heat and mass transfer to enable selection of optimum process parameters and reduce the number of exploratory lyophilization runs. Overall, the study highlights the importance of accurate determination of macroscopic collapse in vials, pursuing aggressive drying based on individual product characteristics, and leveraging experimental and modeling techniques for process optimization.

Normative values of cardiac chamber dimensions and global longitudinal strain in Indians: the Indian Normative Data of Echocardiography Analyzed (INDEA) study.

Ethnic-specific normal reference ranges for various echocardiographic measurements are essential for accurate diagnostic interpretation and clinical decision-making. Unfortunately, such normative data for Indians is lacking. A total of 880 healthy volunteers (mean age 39.7 ± 12.3 years, 63.8% men) from six centers across different regions of India were enrolled in this study. Comprehensive transthoracic echocardiographic study was performed in all subjects, in accordance with the existing guideline recommendations. Cardiac chamber dimensions [Left ventricular (LV) end-diastolic diameter and volume; right ventricular (RV) basal diameter, left atrial volume] were obtained and indexed to body surface area. LV ejection fraction, LV global longitudinal strain (LVGLS) and measures of RV systolic function were also obtained. The subjects were divided into 3 age groups (35 years or less, 36-55 years and 56 years or above) for analysis. Age- and gender-specific reference values for various clinically relevant echocardiographic parameters were derived. Compared with women, men had larger cardiac chamber dimensions and volumes, but not when indexed. In contrast, the women had higher LV systolic function, but right ventricular systolic function was not different. The indexed LV volumes in our study were much smaller than those recommended in the American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) 2015 chamber quantification guidelines but were similar to those reported in the Indian patients included in the recent World Alliance Societies of Echocardiography (WASE) Normal Values Study. LVGLS was also comparable with the WASE data. INDEA study is the first, multi-centric study to provide normal echocardiographic references values for Indian adults. Our findings underscore the need to follow India-specific reference values, instead of those recommended by the ASE/EACVI, which are largely applicable to the western populations.

Application of near-infrared spectroscopy in real-time monitoring of product attributes of ribbed roller compacted flakes.

This study assessed the utility of near-infrared (NIR) spectroscopy for the real-time monitoring of content uniformity and critical quality attributes (tensile strength, Young's modulus, and relative density) of ribbed roller compacted flakes made by axially corrugated or ribbed rolls. A custom-built setup was used to capture off-line NIR spectra from the flakes containing micronized chlorpheniramine maleate, microcrystalline cellulose, lactose, and magnesium stearate. The partial least square regression method was employed to build calibration models from these off-line NIR spectra using experimental design and validated using test set validation. During calibration model development, various factors, such as spectral acquisition mode, probe positioning, spectral preprocessing method, and beam size, were investigated to improve the prediction ability of the models. The statistical results obtained for calibration models and their validation revealed that dynamic spectral acquisition and proper probe positioning were very crucial to minimize the incorporation of variability in NIR spectra resulting from the flake's undulation. Calibration and validation statistics also suggested the importance of selecting appropriate spectral preprocessing method and beam size. In this study, best calibration models resulted from standard normal variate followed by first derivative preprocessed dynamic spectra captured using beam size ~1.2 mm. Best calibration models constructed from off-line NIR spectra were used in real-time analysis of flake attributes. Finally, adequacy of best calibration models was established from real-time prediction results. Overall, with the proposed setup, it was possible to monitor the roller compaction process in real time for various properties associated with the ribbed flakes in a rapid, efficient, and nondestructive manner.

In-line quantification of micronized drug and excipients in tablets by near infrared (NIR) spectroscopy: Real time monitoring of tabletting process.

The objectives of this study were to assess the utility of near infrared (NIR) spectroscopy for simultaneous in-line quantification of the contents of drug and excipients in tablets and to monitor the tabletting process in real time. Direct compression tablet formulations comprising micronized chlorpheniramine maleate, lactose, microcrystalline cellulose and magnesium stearate were used. A custom built NIR setup was used for in-line spectral acquisition (980-1900nm with 1nm resolution) during the tabletting process. Calibration models using dynamic spectral acquisition were prepared and validated using design of experiment approach. During tabletting, stratified sampling of tablets was also carried out to compare the NIR prediction results and subsequent UV analysis results for drug content. The results obtained with calibration and validation statistics confirmed the accuracy of models used to predict contents of tablet components. Stratified sampling results for drug content did not exhibit any significant statistical variation. However, in-line quantification enabled the content analysis of individual tablets in the production batch and detection of content uniformity problems towards the end of the tabletting process. Furthermore, it provided the assurance of in-process content uniformity monitoring of the individual excipients during the tabletting process.