Gavi Emmanuela, Dischinger Angela
F. Hoffmann-La Roche Ltd, Pharma Synthetic Molecules Technical Development, Pharmaceutical R&D, Basel, Switzerland.
AAPS PharmSciTech. 2021 May 5;22(4):148. doi: 10.1208/s12249-021-02013-x.
A practice-based approach for the scale-up of fluid bed granulation in the context of drug product development is presented and evaluated in this work in the context of clinical drug product manufacturing development. The approach is based on the use of a scale-independent parameter, the evaporation energy to drying capacity ratio (EE/DC), and a process model. The EE/DC ratio is used to quantify, in one scale-independent parameter, the combined effect of the most impacting process parameters and to identify the spray rates to be used at different scales to achieve similar granule moisture rate of change. The process model is used to de-risk scale-up, by allowing the consideration of equipment differences across scales and process dynamics, which are aspects not accounted for by the EE/DC ratio. This approach was tested by scaling up the fluid bed granulation process of two formulations, one placebo and one active, from laboratory to pilot scales. This work showed how it was possible to use a simple scale-up approach coupled with a process model to achieve right first-time scale-up of a fluid bed granulation process and show how a placebo formulation could be used instead of active material, first to define the process at laboratory scale and then to de-risk the scale-up, by identifying scale-dependent differences.
在临床药品制造开发的背景下，本文提出并评估了一种基于实践的方法，用于在药品开发中扩大流化床制粒规模。该方法基于使用一个与规模无关的参数，即蒸发能量与干燥能力比（EE/DC），以及一个过程模型。EE/DC比用于在一个与规模无关的参数中量化最具影响力的过程参数的综合效应，并确定在不同规模下使用的喷雾速率，以实现相似的颗粒水分变化率。过程模型用于通过考虑不同规模的设备差异和过程动态来降低放大风险，而这些方面是EE/DC比未考虑的。通过将两种制剂（一种安慰剂和一种活性制剂）的流化床制粒过程从实验室规模扩大到中试规模，对该方法进行了测试。这项工作展示了如何使用简单的放大方法与过程模型相结合，实现流化床制粒过程的首次正确放大，并展示了如何使用安慰剂制剂代替活性材料，首先在实验室规模定义过程，然后通过识别与规模相关的差异来降低放大风险。
