LyoDEA: In-process sensing technology for control of the freeze-drying cycle

LyoDEA™是一种允许使用单个小瓶的阻抗分析在线测量冷冻干燥过程的技术。简单地说，它测量的电容变化在一个频率范围内的冷冻干燥过程的进展，通过其关键阶段;冷冻，退火和升华（初级干燥）。在冷冻和退火阶段，冰结构的变化对最终产品质量至关重要，因此监测和控制这些变化非常重要。LyoDEA促进了在线结构变化的表征，作为产品开发的一部分。因此，它有可能缩短开发时间，并产生更有效的生产过程，从而节省能源。LyoDEA™系统通过样品的电阻测量与冻干小瓶玻璃壁的界面极化相关的“伪弛豫”过程。由等效电路（下文）表示的模型描述了在冷冻干燥循环过程中冷冻干燥小瓶中的样品的行为，其中，C 0是由电极和小瓶的玻璃壁形成的电容，C1是小瓶的内部体积的电容，R1是样品的电阻。最初的挑战是生产足够灵敏的设备，以检测超出仪器正常波动的这些变化，即提高信噪比。第二个挑战是将电容的变化与过程中的实际物理变化联系起来。我们现在看到记录的信号与物理变化之间的相关性·LyoDEA光谱的Z视图拟合提供了与共晶、玻璃化转变和早期初级干燥相关的有价值的信息。·峰值数据可有效记录冷冻退火过程中的相变或温度变化。·在特定频率（1 kHz）下采集的乳糖和蔗糖基配方的T切片数据令人满意地描述了初级干燥的结束，与热电偶响应一致。该项目现已进入第四年。有三个LyoDEA™系统运行，因此数据不断生成和分析，这导致了对数据的更好理解，它向我们展示了什么，并改进了LyoDEA™系统。这个项目是四个合作伙伴的合作结果，每个合作伙伴都有自己的专业知识。Astra Zenecare介绍了一个技术终端用户;使用LyoDEA™专注于冻干产品的开发？Occesses。德蒙福特大学已经开发出了初始的介电理论，并继续产生和分析数据。AmetekAdvanced Measurement Technology是信号处理硬件的OEM，GEA Pharma Systems是冻干机的OEM，是项目的主要合作伙伴。该项目仍在进行中。到目前为止，产出主要是传播;在新奥尔良的AAPS和维也纳的PDA上介绍了该技术。我们正在德蒙福特大学建立一个设施，向潜在的最终用户展示这项技术。LyoDEA™技术的专利正在申请中。

LyoDEA™ is a technology that allows in-line measurement of the freeze drying process using impedance analysis of a single vial. Put simply it measures electrical capacitance changes over a range of frequencies as the freeze drying process progresses through its’ key stages; freezing, annealing & sublimation (primary drying). The changes in ice structure during the freezing & annealing stages are critical to the final product quality so it is important that these can be monitored and controlled. LyoDEA facilitates the characterization of structural changes in-line as part of product development. As such it has the potential to shorten development time and produce a more efficient production process,thus saving energy.The LyoDEA™system measures a “pseudo-relaxation” process associated with the interfacial polarization of the glass wall of the freeze-drying vial through the resistance of the sample. The model represented by the equivalent circuit (below) describes the behaviour of a sample in a freeze drying vial in a course of freeze drying cycle,Where,C0is the capacitance formed by the electrodes and glass walls of a vial, C1 is the capacitance of the internal volume of a vial and R1 is the electrical resistance of a sample.The measured changes in electrical capacitance are very small. The initial challenge was to produce equipment sensitive enough to detect these changes beyond the normal fluctuations from the instrument, i.e. to increase the signal to noise ratio. The second challenge is to relate the changes in capacitance to the actual physical changes in the process. We are now seeing a correlation between the signal recorded & physical changes• Z-view fitting of the LyoDEA spectra provides valuable information relating to eutectic, glass transition and early primary drying.• Peak data effectively records and phase transition or temperature changes during freezing annealing.• T slice data from lactose and sucrose based formulations taken at specific frequency (1 kHz) satisfactorily described the end of primary drying in agreement with the thermocouple response.The project is now in its’ fourth year. There are three LyoDEA™ systems running so data is being constantly generated & analysed which is leading to a greater understanding of the data, what it is showing us and to improvement’s to the LyoDEA™ system.This project is the result of the collaboration of four partners each with their own specific expertise. Astra Zenecarepresents a technology end user;using LyoDEA™tofocuson the development of the freeze dried products ?ocesses. De Montfort University have developed the initial dielectric theory & continue to produce and analyse data.AmetekAdvanced Measurement Technology is an OEM of signal processing hardware & GEA Pharma Systems are an OEM of freeze dryers and are the project lead partner.The project is still on-going. The output so far has largely been dissemination; presentations of the technology have been given at the AAPS in New Orleans, & the PDA in Vienna. We are in the process of establishing a facility at De Montfort University for demonstrating the technology to potential end users. A patent is pending for the LyoDEA™technology.