On the Use of Infrared Thermography for Monitoring a Vial Freeze-Drying Process

Monitoring a vial freeze-drying process without interfering with product dynamics is a challenging issue. This article presents a novel device constituted by an infrared camera designed to be placed inside the drying chamber, able to monitor the temperature of the vials, very close to that of the product inside. By this way it is possible to estimate the ending point of the primary drying, the heat transfer coefficient to the product (K_v), and the resistance of the dried product to vapor flux (R_p). Experiments were carried out in a pilot-scale freeze-dryer, processing 5% and 10% sucrose solutions at different values of shelf temperature and chamber pressure, using both thermocouples and the IR camera to track product dynamics. Results evidence that the measurements (of temperature) and the estimates (of the ending point of the main drying and of K_v and R_p) obtained using the 2 systems are very close, thus validating the IR camera as an effective process analytical technologies for the freeze-drying process. Besides, it was shown that the presence of the IR camera in the chamber is not responsible for any additional heating to the product and that monitored vials are representative of the majority of the vials of the batch.     

Effects of Product Handling Parameters on Particle Levels in a Commercial Factor VIII Product: Impacts and Mitigation

To reduce the risk of immunogenicity that may be caused by therapeutic protein products, it is important to properly characterize subvisible particles and to develop strategies to reduce the levels of particles delivered to patients. In the present study, by using state-of-the-art methods to quantify particle levels, we found that the factor VIII product, Kogenate FS, contained relatively high levels of protein particles and silicone oil droplets, the vast majority of which were submicron in size. In a test of effects of product mishandling, the Kogenate FS vial was shaken instead of swirled during reconstitution. Levels of silicone oil droplets and protein particles were increased. In contrast, these levels were greatly reduced by 2 mitigation strategies tested, using a nonsiliconized syringe for the diluent container or using submicron pore size syringe filters during simulated infusion. Thus, to avoid potential adverse effects due to mishandling-induced increases in particle levels, it is important to educate end-users about proper product handling. Furthermore, effective particle mitigation and reduction strategies should be developed for factor VIII, and other therapeutic protein products. Such efforts could lead to clinically useful approaches to reduce the levels of particles delivered to patients and to an associated reduction in adverse immunogenicity.     

不同干燥方式对连翘花主要成分的影响

目的:建立测定阴干、真空冷冻干燥、烘箱干燥(30、50、70℃)、晒干等干燥方式下连翘花中4种成分含量的方法并进行比较,以评价不同干燥方式对连翘花主要成分含量的影响,筛选其最佳干燥方式.方法:采用超高效液相色谱法.色谱柱为Waters ACQUITY UPLC BEH C18,流动相为乙腈-0.1％磷酸水溶液(梯度洗脱...     

Imaging Techniques to Characterize Cake Appearance of Freeze-Dried Products

Pharmaceutically elegant lyophilisates are highly desirable implying a stable and robust freeze-drying process. To ensure homogenous and intact cake appearance after process scale-up and transfer, characterization of lyophilisates during formulation and cycle development is required. The present study investigates different imaging techniques to characterize lyophilisates on different levels. Cake appearance of freeze-dried bovine serum albumin formulations with different dextran/sucrose ratios was studied by visual inspection, three-dimensional laser scanning, polydimethylsiloxane embedding, scanning electron microscopy, and microcomputed tomography (μ-CT). The set of techniques allowed a holistic evaluation of external cake appearance and internal structure providing complementary information at macroscopic and microscopic scale. In comparison to state of the art technologies like visual inspection or scanning electron microscopy, three-dimensional laser scanning and μ-CT provided quantitative information allowing comparison of visual cake appearance. In particular μ-CT enables a global, qualitative, and quantitative characterization of external and internal cake structure with a single measurement detecting heterogeneities of lyophilisates. We even demonstrated the use of noninvasive μ-CT for qualitative imaging of internal cake structure through the glass vial. Providing meaningful characterization of the entire lyophilisate, μ-CT can serve as a powerful tool during development of freeze-drying cycles, process scale-up, and transfer.     

Noncontact Infrared-Mediated Heat Transfer During Continuous Freeze-Drying of Unit Doses

Recently, an innovative continuous freeze-drying concept for unit doses was proposed, based on spinning the vials during freezing. An efficient heat transfer during drying is essential to continuously process these spin frozen vials. Therefore, the applicability of noncontact infrared (IR) radiation was examined. The impact of several process and formulation variables on the mass of sublimed ice after 15 min of primary drying (i.e., sublimation rate) and the total drying time was examined. Two experimental designs were performed in which electrical power to the IR heaters, distance between the IR heaters and the spin frozen vial, chamber pressure, product layer thickness, and 5 model formulations were included as factors. A near-infrared spectroscopy method was developed to determine the end point of primary and secondary drying. The sublimation rate was mainly influenced by the electrical power to the IR heaters and the distance between the IR heaters and the vial. The layer thickness had the largest effect on total drying time. The chamber pressure and the 5 model formulations had no significant impact on sublimation rate and total drying time, respectively. This study shows that IR radiation is suitable to provide the energy during the continuous processing of spin frozen vials.     

脂质体冻干因素研究概况

对制备冻干脂质体过程中的影响因素方面研究进行了文献整理和分析。以冻干脂质体为主题词,在中国学术文献总库(CNKI)中收集冻干脂质体制备方面的文献,根据其相关性引用了35篇文献,对冻干脂质体制备过程中的影响因素进行了归纳和总结。结果显示冻干脂质体制备过程中冻干保护剂及用量、预冻方式及速度、冻干真空度、干燥时间、水化介质等因素影响冻干脂质体质量。综上制备冻干脂质体过程中必须考虑好各种因素才能制备出包封率高、稳定性好、粒径变化小的药物脂质体。应用冻干技术可防止药物氧化、延长药物脂质体保质期,为脂质体药物的推广应用奠定了基础。     

支架剂及pH值对珠子参冻干粉针成型工艺的影响研究

目的：制备珠子参冻干粉针,并考察其成型工艺。方法：采用冻干技术,以粉针外观、颜色、再分散性为指标,通过综合评分,优选了不同种类、组合及用量的支架剂;从粉针外观色泽、总皂苷含量、复溶溶液澄明度3方面考察、确定了合理的pH值范围。结果：以5%甘露醇为支架剂;冻干制品pH值的理想范围是7-9。结论：经冷冻干燥法制备的珠子参冻干粉针,成型性、水溶性好,色泽均匀,质量稳定。     

大容量人血小板冻干保存的初步研究

目的为使血小板冷冻干燥保存技术用于军队临床战创伤救治,在小容量冻干保存的基础上研究大容量人血小板的冷冻干燥技术。方法采用特制血盒作为冻干容器,以20%(w/v)海藻糖和1%(w/v)牛血清白蛋白作为冻干保护剂。冻干样品复水后测量血小板的数值恢复率和体积分布参数,应用流式细胞仪检测血小板的凋亡率和活化率,采用二磷酸腺苷和肾上腺素检测血小板的聚集功能。结果大容量血小板冻干复水后的数值恢复率为(66.3±2.1)%,平均血小板体积较新鲜血小板有明显增加,冻干血小板的细胞凋亡率达20%左右;冻干和复水过程还造成小部分血小板被激活,其最大聚集率为新鲜血小板的50%左右。结论大容量血小板冻干复水后的恢复率较低,形态结构、活性和功能指标均低于新鲜血小板,但基本可以满足血小板临床止血功能标准。     

冷冻干燥对载环孢素A的pH敏感性纳米粒粒径的影响

研究了冻干保护剂种类和浓度对载环孢素A的pH敏感性纳米粒冻干品粒径稳定性的影响.结果表明,以海藻糖为冻干保护剂的冻干纳米粒粒径稳定性较好.含5%或20%海藻糖的冻干纳米粒于4500lx光照、40℃、高湿的条件放置5d,复水化后粒径均明显增大.40℃下的纳米粒聚集尤为明显,无法测得粒径.     

山梨醇载体沉积法和冷冻干燥法制备番木鳖碱固体脂质体的研究

目的:探讨番木鳖碱固体脂质体的最佳制备方法.方法:采用山梨醇载体沉积法和冷冻干燥法制备番木鳖碱固体脂质体,以外观、水溶化性、包封率、粒径大小及分布等为指标对两种方法进行比较.结果:山梨醇载体沉积法制备的番木鳖碱前体脂质体在外观和水溶化性方面不如冻干脂质体,但包封率高,粒径小而均匀,便于生产.结论:山梨醇载体沉积法制备番木鳖碱固体脂质体优于冷冻干燥法.