原辅料相容性研究

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（一）原料药

3、相容性研究

本相容性研究指药物与辅料间及药物与药物间相互作用研究。前者将在下面辅料部分进行阐述。后者主要是复方制剂研究中需要考虑的问题，实验可参照药物稳定性指导原则中影响因素的实验方法进行。

（二）辅料

2、相容性研究

药物与辅料相容性研究为处方中辅料的选择提供了有益的信息和参考。药品申请人可以通过前期调研，了解辅料与辅料间、辅料与药物间相互作用情况，以避免处方设计时选择不宜的辅料。对于缺乏相关研究数据的，可考虑进行相容性研究。例如口服固体制剂，可选若干种辅料，若辅料用量较大的（如稀释剂等），可按主药：辅料=1：5的比例混合，若用量较小的（如润滑剂等），可按主药：辅料=20：1的比例混合，取一定量，参照药物稳定性指导原则中影响因素的实验方法或其他适宜的实验方法，重点考察性状、含量、有关物质等等，必要时，可用原料药和辅料分别做平行对照实验，以判别是原料药本身的变化还是辅料的影响。

如处方中使用了与药物有相互作用的辅料，需要用实验数据证明处方的合理性。

2.1.2辅料

申报者应针对各种辅料的作用，详述其选择过程、配比以及可能影响制剂性能（如稳定性、生物利用度）或可生产性的特性。处方中应包括制剂生产中所用到的所有物质，不论其是否出现在成品中（如：工艺辅助剂）。必要时，应建立辅料之间的相容性（比如双重防腐系统中防腐剂的组合）。同时，应阐述辅料（如抗氧剂、渗透促进剂、崩解剂、控释剂）是否能实现预期的作用，是否能在预期的有效期内发挥作用。可能的情况下，可以利用有关辅料性能的资料，来论证辅料的选择和质量属性，并支持证明制剂质量标准的合理性（3.2.P.5.6）。

有关辅料安全性方面的资料，可以被交叉引用（3.2.P.4.6）。

ATTACHMENT 2: QbR QUESTIONS - DRUG PRODUCT(CHEMISTRY)

9. What evidence supports excipient-drugsubstance compatibility and if applicable, excipient-excipient compatibility?

2.1.2.1 Excipient Compatibility Studies 辅料相容性研究

Note to Reader: Excipient compatibility is animportant part of understanding the role of inactive ingredients in productquality. The selection of excipients for the compatibility study should be basedon the mechanistic understanding of the drug substance and its impurities,excipients and their impurities, degradation pathway and potential processingconditions for the drug product manufacture. A scientifically sound approachshould be used in constructing the compatibility studies. The commercial gradesof the excipients are not provided in this example to avoid endorsement ofspecific products. However, in an actual pharmaceutical development report, thenames of the commercial grades are expected.

致读者：辅料相容性是理解非活性成分在产品质量中作用的重要部分。对于相容性研究的辅料选择应基于理解原料药和其杂质，辅料和其杂质，制剂生产的降解路径和潜在加工条件的机理。科学合理的方法应用于构造相容性研究中。该实例中不提供市售级的辅料以避免为某些特定产品代言。但是，在实际药物开发报告中，可预期市售级的名称。

Excipient-drug substance compatibility wasassessed through HPLC analysis of binary mixtures of excipient and drugsubstance at a 1:1 ratio in the solid state. Samples were stored at 25 °C/60 %RHand 40 °C/75 % RH in both open and closed containers for 1 month. Commonexcipients functioning as filler, disintegrant, and lubricant were evaluated inthe excipient compatibility study.

Table 14 summarizes the results.

通过HPLC 分析固态下辅料与原料药以1:1 比例的二元混合物，来评估辅料-原料药的相容性。敞口容器和密封容器中的样品贮存在25 °C/60 % RH 40 °C/75 % RH 下各1 个月。辅料相容性研究中评估作用为填充剂，崩解剂和润滑剂的普通辅料。表14 总结了结果。

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Loss in assay ordetection of degradants indicative of an incompatibility was not observed forthe selected excipients except magnesium stearate. An interaction was seen withmagnesium stearate at 40 °C/75 % RH. This interaction caused lower assayresults for acetriptan. The mechanism for this interaction was indentified asformation of a magnesium stearate-acetriptan adduct (AD1) involving stearicacid. To further evaluate if this potential interaction could cause druginstability, an additional experiment was performed in which several differentmixtures of drug and excipients

were prepared. Only theexcipient types used in the RLD formulation were selected for this study.

The first mixtureconsisted of drug and all excipients in the ratio representative of thefinished product. In subsequent mixtures, one excipient was removed at a time.These mixtures were stored at 25 °C/60% RH and 40 °C/75% RH in both open andclosed containers for 1 month. Table 15 presents the results of the study.

对于所选的辅料除硬脂酸镁外，未观察到表示不相容性的含量损失或检测到降解物。在40°C/75% RH 下，观察到与硬脂酸镁的相互作用。该相互作用引起acetriptan 含量结果较低。该相互作用的机理确定为形成一种包括硬脂酸的硬脂酸镁- acetriptan 加合物(AD1)。为进一步评估该潜在相互作用是否可引起药物不稳定，进行了一额外实验，制备了药物和辅料的几种不同混合物。

该研究仅选择RLD 处方中使用的辅料类型。第一种混合物包括代表成品比例的药物和所有辅料。在随后的混合物中，每次去掉一种辅料。在25 °C/60 % RH 和40°C/75% RH 下，这些混合物贮存在敞口容器和密封容器中各1 个月。研究的结果见表15。

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No loss in assay was observed in any of these mixtures at40 °C/75% RH or at 25 °C/60% RH.There is no incompatibility with the selectedexcipients except for the noted interaction with

magnesium stearate in the binary mixture study.Therefore, magnesium stearate was still selected,

but contact of the drug substance with magnesium stearatewas limited by only using extragranular

magnesium stearate. Intragranular lubrication requiredfor the roller compaction process was achieved by using talc. Subsequentassurance of compatibility was provided by long-term stability

data for formulations used in the pilot BE study and theongoing prototype stability studies using

the formulation proposed for commercialization. Theimpurity method is able to identify and

quantify AD1. Adduct formation was below the limit ofquantitation in the long-term stability

study and is controlled by the limit for any unspecifiedimpurity.

在40 ℃/75%RH 或25 ℃/60%RH下，在这些混合物中的任意一种未观察到含量损失。在二元混合物研究中，除注意到与硬脂酸镁相互作用外，与所选辅料无不相容性。因此，仍然选择硬脂酸镁，但是通过仅使用外加硬脂酸镁来限制原料药与硬脂酸镁的接触。通过使用滑石粉来实现碾压所需的颗粒内润滑。随后通过提供用于中试BE研究的处方的长期稳定性数据和正在进行的，使用拟定用于工业化的处方的原型稳定性研究来保证相容性。杂质方法能鉴定和定量AD1。长期稳定性研究中形成的加合物低于定量限，通过该限度来控制任何未指定杂

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gumou66

一世英名 发表于 2020-4-23 10:23
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老师您好，请问复方制剂怎么做原辅料相容性呢

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