Purpose

The purpose of this manuscript is to demonstrate that implementation of gravimetric measurements provides the same assurance of product quality and process control as spectroscopic measurements (1) for control of drug content in a fixed-dose combination (FDC) tablet and (2) for identification of non-conforming material.

Methods

A wet granulation continuous tableting line was used to make the FDC drug product batches. Comparative data was generated for ten batches using near-infrared (NIR) spectroscopy for core tablets, and gravimetric in-process control measurements (IPCs) applied to the ratio control of intra- and extra-granular blend (IG and EG). HPLC reference data were collected to further demonstrate uniformity at each stage of the production process, including IG, final blend, and core tablets. All possible sources of variation not directly detectable by the gravimetric measurements were considered and quantified.

Results

The two IPC measurement techniques showed excellent agreement where both were within 2% of the target drug concentrations and within 2% of each other for the ten comparative batches. The NIR was more sensitive to material and process variations than the gravimetric IPCs; thus, it was more variable within and across batches. Gravimetric IPCs were demonstrated as an effective replacement for spectroscopic measurements for continuous tableting operations, capable of ensuring on target manufacturing and detection of non-conforming material.

Conclusions

As pharmaceutical companies continue to push toward operational simplicity and sustainable manufacturing processes, soft-sensor and gravimetric controls as alternatives to their spectroscopic counterparts will be applied more broadly for process monitoring and control.

中文翻译：

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药品连续制造过程的过程控制—简化运营和持续改进的研究

目的

本手稿的目的是证明重量分析法的测量可提供与光谱法测量相同的产品质量和过程控制保证（1）用于控制固定剂量组合（FDC）片剂中的药物含量和（2）用于鉴定不合格材料。

方法

使用湿法制粒连续压片生产线来制备FDC药品批次。使用近红外（NIR）光谱对核心片剂生成了十批次的比较数据，并将重量分析过程中的控制测量（IPC）应用于颗粒内和颗粒外混合物（IG和EG）的比例控制。收集HPLC参考数据以进一步证明在生产过程的每个阶段（包括IG，最终混合物和核心片剂）的均一性。重量测量无法直接检测到的所有可能的变异源均已考虑并量化。

结果

两种IPC测量技术显示出极好的一致性，对于十个比较批次，两者均在目标药物浓度的2％范围内，彼此在2％的范围内。NIR比重量IPC对材料和工艺变化更敏感。因此，它在批次内和批次之间变化更大。重量法IPC被证明是连续压片操作中光谱测量的有效替代品，能够确保目标制造和不合格材料的检测。

结论

随着制药公司不断追求简化操作和可持续制造流程，软传感器和重量控制作为其光谱对应物的替代品将在过程监控中得到更广泛的应用。