Division of Complex Drug Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Maryland, 20993, Silver Spring, USA.
Division of Lifecycle API, Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
AAPS J. 2023 May 6;25(3):50. doi: 10.1208/s12248-023-00815-4.
Pentosan polysulfate sodium (PPS) is an orphan drug with anticoagulant activity. PPS is prepared from the chemical processing of xylan extracted from beechwood tree to yield a mixture of 4-6 kDa polysaccharides. The chain is mainly composed of sulfated xylose (Xyl) with branched 4-O-methyl-glucuronate (MGA). During generic drug development, the quality attributes (QAs) including monosaccharide composition, modification, and length need to be comparable to those found in the reference list drug (RLD). However, the range of QA variation of the RLD PPS has not been well characterized. Here, multiple PPS RLD lots were studied using quantitative NMR (qNMR) and diffusion ordered spectroscopy (DOSY) to quantitate the components in the mixture and to probe both inter- and intra-lot precision variability. The DOSY precision assessed using coefficient of variation (CV) was 6%, comparable to PPS inter-lot CV of 5%. The QAs obtained from 1D qNMR were highly precise with a precision CV < 1%. The inter-lot MGA content was 4.8 ± 0.1%, indicating a very consistent botanical raw material source. Other process-related chemical modification including aldehyde at 0.51 ± 0.04%, acetylation at 3.3 ± 0.2% and pyridine at 2.08 ± 0.06%, varied more than MGA content. The study demonstrated that 1D qNMR is a quick and precise method to reveal ranges of variation in multiple attributes of RLD PPS which can be used to assess equivalency with generic formulations. Interestingly, the synthetic process appeared to introduce more variations to the PPS product than the botanical source of the material.
戊聚糖多硫酸钠（PPS）是一种具有抗凝活性的孤儿药。PPS 是通过对从山毛榉木中提取的木聚糖进行化学处理制备而成的，得到的是 4-6 kDa 多糖的混合物。该链主要由硫酸化木糖（Xyl）和支化 4-O-甲基-葡萄糖醛酸（MGA）组成。在仿制药开发过程中，质量属性（QAs），包括单糖组成、修饰和长度，需要与参比制剂（RLD）中发现的质量属性相当。然而，RLD PPS 的 QA 变化范围尚未得到很好的描述。在这里，使用定量 NMR（qNMR）和扩散有序光谱（DOSY）研究了多个 PPS RLD 批次，以定量混合物中的成分，并探测批内和批间精密度变异性。使用变异系数（CV）评估的 DOSY 精密度为 6%，与 PPS 批间 CV 的 5%相当。从 1D qNMR 获得的 QA 具有很高的精密度，精密度 CV<1%。批间 MGA 含量为 4.8±0.1%，表明植物原料来源非常一致。其他与工艺相关的化学修饰，包括醛基（0.51±0.04%）、乙酰化（3.3±0.2%）和吡啶（2.08±0.06%），变化比 MGA 含量更大。该研究表明，1D qNMR 是一种快速而精确的方法，可以揭示 RLD PPS 多个属性的变化范围，可用于评估与仿制药制剂的等效性。有趣的是，与材料的植物来源相比，合成过程似乎给 PPS 产品带来了更多的变化。
