杂质

对病人安全的考量促使监管力度不断提升，这使得原料药（APIs）和药物产品的杂质鉴定、定量和控制成为药物开发的基本步骤。在工艺开发、优化和转换过程中进行杂质分析是保证原料药和成品质量的一个基本要求。

ICH Q3A指南将杂质分为3组：有机物（起始材料、副产品、半成品、转化产物、相互作用产物、降解产物、试剂、配体和催化剂）、无机物（试剂、配体、催化剂、重金属或残留金属、无机盐和其他材料如木炭或助滤剂）和溶剂。ICH Q3A中没有考虑多晶体和对映体，但它们代表了另一种需要识别、量化和控制的污染物类型。杂质分析包括药物材料和药物制剂中的杂质和降解产物的鉴定、结构阐释和定量测定。

色谱和光谱技术，无论是单独使用还是与其他技术结合使用，通常都是使用LC-MS和GC-MS。 由于磁共振的定量性质，可以直接进行杂质分析和降解研究（如聚山梨醇），从而实现快速和简单的测试，不需要反应因子的计算，也不需要传统LC方法所要求的方法重建活动，从而节省时间和降低成本。

Structure elucidation of unknown impurities, degradants and force-degradation products are typically done by a combination of isolation/preparation step followed by NMR and MS data analysis. For an API dose at < 2 g/day, the organic impurities threshold is 0.1%. Any impurity above that threshold need to be identified. Once the structure is known the allowed threshold might increase to 0.5%, alleviating the pressure on the synthesis and purification steps. EPR spectroscopy shines light on otherwise unseen impurities such as free radicals and transition metals, which is of particular importance in forced-degradation (e.g. oxidation) studies and shelf-life determination. EPR is the only technique for the direct and non-invasive detection, identification, and quantification of paramagnetic impurities (organic free radicals and transition metals) at LODs down to parts per billion levels.

Heavy metal impurities can be identified, quantified, and monitored by X-ray fluorescence (TXRF, XRF) down to parts per billion levels. Both, USP and ICH establish (T)XRF as a tool to analyze heavy metals such as As, Hg, Co, V, Ni, and typical catalyzer elements such as like Pt, Pd, Rh, and V as detailed in USP 232, 233, 735, and ICH Q3D.

XRD directly probes the crystal structure and therefore enables detection and differentiation of different polymorphs. This allows control of and anticipation of polymorphic changes that may occur and adversely affect drug substance quality down to levels of ~0.1% weight percent.