Department of Chemical Engineering, University of Massachusetts Lowell, 1 University Ave, Lowell, MA 01854, USA.
Landrau Scientific Innovations, LLC, 22 Laurel Street, Leominster, MA 01453, USA.
Int J Pharm. 2020 Jul 30;585:119473. doi: 10.1016/j.ijpharm.2020.119473. Epub 2020 May 27.
In this work, the manufacturing process of a complex liposomal amphotericin B (AmB) product was optimized using quality by design (QbD) approach. A comprehensive QbD-based process understanding and design space (DS) to the critical process parameters (CPPs) is essential to the drug development and consistent quality control. The process was based on the acid-aided formation of drug-lipid complexes in a methanol-chloroform mixture (step I) followed by spray drying (step II), hydration and liposome formation by microfluidization (step III), and lyophilization (step IV). Firstly, the risk assessment was conducted to identify the critical process parameters among the four key steps. Nine CPPs and five CQAs (API Monomer identity (absorbance main peak at 321 nm), API Aggregation identity (absorbance peak ratio, OD 415 nm/321 nm), particle size, in-vitro toxicity, and the cake quality) were determined based on their severity and occurrences with their contribution to the quality target product profile (QTPP). Based on the risk assessment results, the final screening design of experiments (DoE) was developed using fractional factorial design. Secondly, the empirical equation was developed for each CQA based on experimental data. The impact of CPPs on the CQAs was analyzed using the coefficient plot and contour plot. In addition to the effect of individual formulation parameters and process parameters, the effects of the four key separate steps were also evaluated and compared. In general, the curing temperature during microfluidization has been identified as the most significant CPP. Finally, design space exploration was carried out to demonstrate how the critical process parameters can be varied to consistently produce a drug product with desired characteristics. The design space size increased at the higher value of the curing temperature, the API to phospholipid ratio (API:PL), and the lower value of the DSPG to phospholipid ratio (PG:PL) and aspirator rate.
在这项工作中，采用质量源于设计（QbD）方法优化了复杂两性霉素 B（AmB）脂质体产品的制造工艺。全面的基于 QbD 的工艺理解和设计空间（DS）对于关键工艺参数（CPPs）对于药物开发和一致的质量控制至关重要。该工艺基于在甲醇-氯仿混合物中酸辅助形成药物-脂质复合物（步骤 I），然后进行喷雾干燥（步骤 II），通过微流化进行水化和脂质体形成（步骤 III），以及冷冻干燥（步骤 IV）。首先，进行风险评估以确定四个关键步骤中的关键工艺参数。基于其严重程度和发生频率及其对质量目标产品概况（QTPP）的贡献，确定了九个 CPPs 和五个 CQAs（API 单体身份（在 321nm 处的吸收主峰），API 聚集身份（吸收峰比，OD415nm/321nm），粒径，体外毒性和蛋糕质量）。基于风险评估结果，使用部分因子设计开发了最终筛选的实验设计（DoE）。其次，根据实验数据为每个 CQA 开发经验方程。使用系数图和等高线图分析 CPP 对 CQA 的影响。除了单独制剂参数和工艺参数的影响外，还评估并比较了四个关键单独步骤的影响。一般来说，微流化过程中的固化温度已被确定为最重要的 CPP。最后，进行设计空间探索以证明如何可以改变关键工艺参数，以始终如一地生产具有所需特性的药物产品。设计空间尺寸在固化温度，API 与磷脂比（API:PL）较高值以及 DSPG 与磷脂比（PG:PL）和吸气器率较低值时增大。
