近日，WHO在其技术报告TRS1060中发布了新的《药用辅料GMP》-2025，现将中英文翻译分享给大家： 

 

Appendix 2

附录 2

 

List of examples of high - risk excipients and contaminants

高风险辅料和污染物示例列表

 

1.Introduction

1.引言

 

The purpose of this appendix is to provide a list of examples of high - risk excipients and contaminants, where manufacturers of such excipients (as well as manufacturers of finished pharmaceutical products (FPPs) containing such excipients) are alerted to implement control measures to ensure the safety, purity and quality of these excipients and FPPs.

本附录的目的是提供一份高风险辅料和污染物的示例列表,提醒辅料制造商(以及含有此类辅料的最终药品成品(FPPs)的制造商)采取控制措施,以确保此类辅料和FPPs的安全性、纯度和质量。

 

Manufacturers should perform risk assessments to identify and assess the level of risk and potential harm associated with the production, control, storage, distribution and use of excipients, and implement appropriate levels of control to mitigate the risks and harm.

制造商应进行风险评估,以识别和评估生产、控制、储存、分发和使用辅料相关的风险和潜在危害,并采取适当的控制措施来减轻这些风险和危害。

 

The list is not exhaustive, but provides examples of high - risk excipients and contaminants that require appropriate levels of control to mitigate the risks and harm. The list will be updated at intervals.

该列表并非详尽无遗,但提供了需要采取适当控制措施以减轻风险和危害的高风险辅料和污染物的示例。该列表将定期更新。

 

Excipients may be at high risk due to:

辅料可能因以下原因而处于高风险状态:

 

the nature of the material;

材料的性质;

contamination with toxic substances as a result of (for example) the production process, other chemicals, solvents or carry - over from residue on equipment;

由于生产过程、其他化学品、溶剂或设备残留物的残留等原因导致的有毒物质污染

having been mixed with other industrial products that are toxic;

与其他有毒工业产品混合;

unintentional or intentional contamination by suppliers, packers, packaging material or other means.

供应商、包装商、包装材料或其他手段造成的无意或故意污染。

Additional considerations and controls may have to be implemented.

还需考虑的控制措施可能需要额外实施。

 

Manufacturers, suppliers and distributors of excipients should:

 

辅料制造商、供应商和分销商应:

 

perform risk assessment to determine the potential risks and harms in using raw materials in the production of excipients and implement appropriate controls to mitigate such risks and harms;

进行风险评估,以确定使用生产辅料所需原材料的潜在风险和危害，并采取适当的控制措施来减轻这些风险和危害；

purchase materials suitable for use from reliable suppliers;

从可靠的供应商处采购适合使用的材料;

use solvents of appropriate quality;

使用适当质量的溶剂;

ensure that appropriate sampling and testing is done to determine whether the excipient contains any unwanted contaminant;

确保进行适当的取样和检测,以确定辅料是否含有任何不必要的污染物；

consider comprehensive quality control testing throughout the manufacturing and distribution chain;

考虑在整个生产和分销链中进行全面的质量控制检测。

ensure excipients are manufactured in line with good manufacturing practices;

确保辅料的生产符合良好生产规范

 

keep accurate, complete and appropriate records of distribution of materials and their testing;

保持准确、完整且适当的材料分发及其检验记录;

 

check for signs of falsification and physical condition of materials across the manufacturing, storage and distribution chain;

在生产、存储和分发链中检查伪造迹象和材料的物理状态;

 

ensure full batch traceability from manufacture through the supply chain to customers;

 

确保从生产到供应链最终客户的整个批次可追溯性;

 

provide assurance of excipient quality and purity, including through certificates of analyses based on appropriate testing results as per specification.

 

提供辅料质量与纯度的保证,包括基于适当测试结果的分析证书。

 

Manufacturers (and, where appropriate, suppliers and distributors) of FPPs containing high risk excipients should:

 

含有高风险辅料的FPP(成品药品)制造商(以及在适当情况下,辅料供应商和分发商)应:

 

perform risk assessment to determine the potential risks and harms in using excipients in the production of an FPP and implement appropriate controls to mitigate such risks and harms;

进行风险评估,以确定使用辅料在生产FPP过程中潜在的风险和危害,并实施适当的控制措施以减轻这些风险和危害;

purchase pharmaceutical grade excipients from qualified suppliers;

从合格供应商处购买药品级辅料;

conduct appropriate testing upon receipt of supplies and before use in manufacture of FPPs;

在接收辅料并用于FPP生产之前,进行适当的检测;

provide assurance of excipient quality, including through certificates of analyses based on appropriate testing results as per registered specifications;

提供辅料质量的保证,包括基于适当测试结果的分析证书,符合注册规格;

keep accurate, complete and appropriate records of purchase of materials and their testing;

记录购买材料及其检测的准确、完整和适当的记录;

check for signs of substandard material, falsification and poor physical condition of materials;

检查材料是否有不合格的迹象、伪造和不良物理状态;

perform robust inspection of incoming goods, quality control testing and material release according to applicable monographs or equivalent validated and appropriate internal methods;

根据适用的药典或等效的验证和适当的内部方法,对到货商品进行严格的检查、质量控制检测和材料放行;

ensure full traceability of the supply chain back to the original excipient manufacturer;

确保供应链的完全可追溯性,追溯到原始辅料制造商;

perform on-site audit of the manufacturing site of the excipient, where appropriate;

在适当情况下,对辅料制造商的生产现场进行现场审核;

keep accurate, complete and appropriate records relating to the medicines and their distribution and sale.

记录与药品及其分销和销售相关的准确、完整和适当的记录。

 

For more guidance on risk assessment, see Appendix 1.

 

有关风险评估的更多指导,请参见附录1。

 

2.List of excipients

2.（高风险）辅料列表

 

Note: Identified excipients will be added to the list from time to time.

注：已识别的辅料将不时添加到列表中。

 

Ethanol (ethyl alcohol)

乙醇（酒精）

2-Propanol (isopropyl alcohol)

2-丙醇（异丙醇）

 

Glycerol

甘油

Hydrogenated starch hydrolysates

氢化淀粉水解物

Maltitol solution

莫尔糖浆溶液

 

Propylene glycol

丙二醇

Sorbitol solution

山梨醇溶液

 

2.1 Ethanol (ethyl alcohol) and 2-propanol (isopropyl alcohol)

2.1 乙醇（酒精）和2-丙醇(异丙醇)

 

Introduction and use

简介与用途

 

Ethanol is a clear, colourless, volatile organic compound with a characteristic odour. It is highly flammable.

 

乙醇是一种清澈、无色、易挥发的有机化合物,具有特有的气味。它极易燃烧。

 

Toxicity

毒性

 

Ethanol is sometimes used in pharmaceutical products such as oral liquid medicine, and other products such as mouthwashes and sanitizer products. Overdose may result in mental confusion, vomiting, seizure, slow - ing of heart rate and breathing. It may also lead to brain damage and death.

乙醇有时被用作制药产品中的口服液剂,以及其他产品如漱口水和消毒剂产品中的成分。过量摄入可能导致意识混乱、呕吐、抽搐、心率和呼吸减缓。还可能导致脑损伤甚至死亡。

 

Risks and controls

风险与控制

 

Besides the toxic effects of ethanol, another risk is that it may be contaminated with, or substituted with, methanol.

除了乙醇的毒性作用外,另一个风险是乙醇或异丙醇可能被甲醇污染或替代。

 

Controls should therefore include supply chain management with appropriate tests to identify the solvent and, in particular, the amount of methanol present in ethanol and isopropyl alcohol data. Reliance solely on a certificate of analysis may not be appropriate.

因此,控制措施应包括供应链管理,并进行适当的检测以识别溶剂,特别是乙醇和异丙醇中甲醇的含量。仅依赖分析证书可能不够适当。

 

Recommendations

建议

 

Repackers of ethanol and isopropyl alcohol to be supplied to manufacturers of FPPs should ensure the appropriate quality of ethanol and isopropyl alcohol.

建议向FPP制造商供应乙醇和异丙醇的重新包装商应确保乙醇和异丙醇的质量符合要求。

 

Manufacturers of FPPs should ensure that the manufacturers of ethanol and isopropyl alcohol in the supply chain are appropriately qualified.

FPP制造商应确保供应链中乙醇和异丙醇的制造商具备相应的资质。

 

Quality control should consist of sampling and testing of every container, in consignment, according to the specification in a monograph of a pharmacopoeia, which includes an identification test and a limit test for methanol.

质量控制应包括根据药典中相应药典法典的规定对每批货物中的每个容器进行采样和检测,其中包括识别测试和甲醇限量测试。

 

The FPP analytical procedure should be appropriate and ensure that when testing for ethanol or isopropyl alcohol (assay), the method also distinguishes between the active ingredient and ethanol.

FPP 分析程序应当适当,并确保在检测乙醇或异丙醇(含量测定)时,该方法还能区分有效成分与乙醇。

 

2.2 Glycerol

2.2 甘油

 

Introduction and use

简介与应用

 

Glycerol is a naturally occurring odourless alcohol. It is used as a solvent, sweetening agent and medicine.

甘油是一种天然存在的无味醇类化合物。它用作溶剂、甜味剂和药物。

 

Toxicity

毒性

 

Documented side - effects may include nausea, gastrointestinal discomfort, dizziness and headache.

毒性已记录的副作用可能包括恶心、胃肠道不适、头晕和头痛。

 

Risks and controls

风险与控制

 

Glycerol is considered a high - risk excipient, as it is often contaminated with toxic substances such as DEG. Controls should be applied to ensure that glycerol is of the required purity, and is not contaminated with a contaminant (such as DEG) that can cause death when ingested.

甘油被视为高风险辅料,因为其常被有毒物质如二甘醇(DEG)污染。应采取措施确保甘油达到所需的纯度标准,并且不含可能在摄入时导致死亡的污染物(如DEG)。

 

Agents, suppliers and repackers should test glycerol for contamination prior to its distribution, when the intended use is in the production of pharmaceutical products. As glycerol may be handled by several importers, exporters and suppliers before reaching an end destination, manufacturers of FPPs must adequately test glycerol for its purity and the presence of contaminants such as DEG. Appropriate, suitably validated analytical methods should be used. As infrared spectroscopy tests may not be sufficient to detect DEG contamination in glycerol syrup, a gas chromatography method capable of separating and detecting glycerol, EG and DEG can be used to determine that glycerol is free of these contaminants (see also the section on DEG).

在甘油用于制药产品的生产之前,其分销商、供应商和分装商应对其进行污染检测。由于甘油可能在到达最终目的地之前经过多个进口商、出口商和供应商的处理,生产FPP(仿制药)的制造商必须对其纯度和是否存在DEG等污染物进行充分检测。应使用适当的、经过验证的分析方法。由于红外光谱测试可能不足以检测甘油糖浆中的DEG污染,可以使用能够分离和检测甘油、乙二醇(EG)和二甘醇(DEG)的气相色谱法来确定甘油是否不含这些污染物(参见DEG部分)。

 

2.3 Hydrogenated starch hydrolysates (HSHs)

2.3 氢化淀粉水解物（HSHs）

 

Introduction and use

简介与应用

 

Hydrogenated starch hydrolysates (HSHs) are common ingredients used in the manufacture of over - the - counter allergy, cough and cold medicines. HSHs are mixtures of sorbitol, maltitol and higher - order sugar alcohols. They are food ingredients because of their sweetness and useful functional properties. Polyglycitol syrup is a mixture of several sugar alcohols (a type of sugar substitute). HSHs are similar to sorbitol.

氢化淀粉水解物(HSHs)是常用于非处方抗过敏、止咳和感冒药物制造的常见成分。HSHs 是山梨醇、麦芽糖醇及其高聚糖醇的混合物。由于其甜味和实用的功能特性,它们被视为食品添加剂。聚甘油醇糖浆是由几种糖醇(一种糖替代品)组成的混合物。HSHs 与山梨醇相似。

 

HSHs are often used both as a sweetener and as a humectant (moisture - retaining ingredient). As a crystallization modifier, they can prevent syrups from forming crystals of sugar. They are used to add bulk, body, texture and viscosity to mixtures, and can protect against damage from freezing and drying.

HSHs 通常既用作甜味剂,又用作保湿剂(保持湿润的成分)。作为结晶修饰剂,它们可以防止糖形成结晶。它们被用于增加混合物的体积、质地和粘度,并能防止因冻结和干燥造成的损害。

 

Toxicity

毒性

 

HSHs could be contaminated with diethylene glycol or ethylene glycol (DEG or EG) (see section on DEG and EG toxicity).

HSHs 可能会受到二甘醇或乙二醇(DEG 或EG)的污染(见二甘醇和乙二醇毒性部分)。 

 

Risks and controls

风险与控制措施  

 

HSHs are considered high-risk excipients, as they are often contaminated with hazardous substances such as DEG. Controls should be applied to ensure that HSHs are of the required purity, and are not contaminated with a contaminant (such as DEG) that can cause death when ingested.

HSHs 被视为高风险的辅料,因为它们经常受到诸如 DEG 等有害物质的污染。应采取措施确保 HSHs 达到所需的纯度标准,并且不含如 DEG 等可导致摄入后死亡的污染物。

 

Agents, suppliers and repackers should test HSH for contamination prior to its distribution, when the intended use is in the production of pharmaceutical products. As HSH may be handled by several importers, exporters and suppliers before reaching an end destination, manufacturers of FPPs must adequately test HSH for its purity and the presence of contaminants such as DEG. Appropriate, suitably validated analytical methods should be used (see section on DEG).

在HSHs 用于制药产品生产之前,其分销前的代理商、供应商和重新包装商应对其进行污染检测。由于 HSHs 可能会经过多个进口商、出口商和供应商之手才能到达最终目的地,因此 FPPs 的制造商必须充分检测 HSHs 的纯度及其是否含有如DEG 等污染物。应采用合适的、经过验证的分析方法(见二甘醇部分)。

 

2.4 Maltitol solution

2.4 甘露糖醇溶液

 

Introduction and use

简介与应用

 

Maltitol is a sugar alcohol and also considered a carbohydrate. Sugar alcohols are found naturally in some fruits and vegetables. They are typically manufactured rather than being used in their natural form.

甘露糖醇是一种糖醇,也可被视为一种碳水化合物。糖醇在某些水果和蔬菜中自然存在。通常,它们是通过制造而不是以天然形式使用。

 

Toxicity

毒性

 

Maltitol solution can be contaminated with DEG or EG (see sections on DEG and EG toxicity).

甘露糖醇溶液可能受到二甘醇(DEG)或乙二醇(EG)的污染(参见DEG和EG的毒性部分)。

 

Risks and controls

风险与控制

 

Maltitol solution is considered a high-risk excipient, as it is often contaminated with hazardous substances such as DEG. Controls should be applied to ensure that maltitol solution is of the required purity, and is not contaminated with a contaminant (such as DEG) that can cause death when ingested.

蔗糖醇溶液被视为高风险的赋形剂,因为它经常受到如DEG等有害物质的污染。应采取措施确保蔗糖醇溶液达到所需的纯度标准,并且不含可能在摄入时导致死亡的污染物(如DEG)。

 

Repackers should test maltitol solution for contamination prior to its distribution, when the intended use is in the production of pharmaceutical products.

在制药产品生产中使用前,再包装商应测试甘露糖醇溶液是否存在污染。

 

Appropriate, suitably validated analytical methods should be used (see also the section on DEG).

应使用适当的、经过验证的分析方法进行检测(参见DEG部分)。

 

2.5 Propylene glycol

2.5 丙二醇

 

Introduction and use

简介与用途

 

Propylene glycol, a diol alcohol, is an organic compound. It is a tasteless, viscous, colourless, nearly odourless liquid. It possesses a faintly sweet taste.

丙二醇是一种二醇醇类有机化合物。它是一种无味、粘稠、无色、几乎无味的液体。它具有轻微的甜味。

 

Propylene glycol is produced for the production of polymers and various other industrial applications.

丙二醇主要用于聚合物的生产以及各种其他工业应用。

 

It is used in food, cosmetics and pharmaceuticals.

它被用于食品、化妆品和制药领域。

 

Toxicity

毒性

 

Propylene glycol should be of an appropriate grade when used in pharmaceutical products. It can be toxic to the kidneys and liver, especially in children, when given in high doses.

在制药产品中使用丙二醇时,其纯度应符合相应标准。高剂量下,它可能对肾脏和肝脏有毒性,尤其是在儿童身上。

 

Risks and controls

风险与控制

 

Although propylene glycol is relatively safe for use in pharmaceutical products, it has sometimes been contaminated with toxic substances such as DEG and EG. Controls should be in place to prevent such contamination.

尽管丙二醇在制药产品中的使用相对安全,但有时会被二甘醇(DEG)和乙二醇(EG)等有毒物质污染。应采取措施防止此类污染。

 

Controls should be in place to detect contaminants (such as DEG and EG) in propylene glycol.

应建立检测措施以检测丙二醇中的污染物(如二甘醇和乙二醇)。

 

Note: See also pharmacopoeia for the determination of ethylene glycol, diethylene glycol, and triethylene glycol in polyethylene glycol.

注意事项:参见药典中关于聚乙二醇中乙二醇、二乙二醇和三乙二醇的测定方法。

 

2.6 Sorbitol solution

2.6 山梨醇溶液

 

Introduction and use

简介与应用

 

Sorbitol is a sugar alcohol with a sweet taste. It is used as a natural sweetener, and is sometimes presented in soft gel capsules. It is also used in the manufacture of allergy, cold and cough medication.

 

山梨醇是一种具有甜味的糖醇,常被用作天然甜味剂,并有时以软胶囊形式呈现。此外,它还用于过敏、感冒和咳嗽药物的制造。

 

Toxicity

毒性

 

Sorbitol solution is not toxic.

山梨醇溶液无毒。

 

Risks and controls

风险与控制

 

Although sorbitol solution is relatively safe for use in pharmaceutical products, it has sometimes been contaminated with hazardous substances. Controls should be in place to prevent such contamination, and controls should be in place to detect contaminants (such as DEG and EG).

尽管山梨醇溶液在制药产品中的使用相对安全,但有时会受到有害物质的污染。应采取措施防止此类污染,并应建立检测措施以发现污染物(如二甘醇和乙二醇)。

 

2.7 Other excipients that may be contaminated by DEG and EG

2.7 其他可能被二甘醇（DEG）和乙二醇（EG）污染的辅料

 

Other excipients that may be contaminated by DEG and EG include:

其他可能被二甘醇(DEG)和乙二醇(EG)污染的辅料包括:

 

Polyethylene glycol (macrogol)⁹

聚乙二醇（聚环氧乙烷）⁹

Diethylene glycol stearates

二甘醇硬脂酸酯

Polyethylene glycol monomethyl ether 350/550 (molecular weight below 600 only)

聚乙二醇单甲醚 350/550（仅分子量低于 600 的）

Polyoxyl 35 castor oil

聚氧乙烯 35 蓖麻油

Polysorbate 20/40/60/80

聚山梨酯 20/40/60/80

Polyoxyl 15 hydroxystearate

聚氧乙烯 15 羟基硬脂酸酯

Polyoxyl 20 cetostearyl ether

聚氧乙烯 20 鲸蜡硬脂基醚

Polyoxyl 18 stearate

聚氧乙烯 18 硬脂酸酯

Octoxynol 9

辛苯昔醇 9

Nonoxynol 9.

壬苯醇醚 9

 

DEG and EG can be present as contaminants or impurities in some of the excipients listed above. The seller of an excipient should ensure adequate controls and, where appropriate, tests to assure acceptable quality and purity of the excipient.

DEG和EG可能作为杂质存在于上述列出的一些辅料中。辅料的供应商应确保采取适当的控制措施,并在适当的情况下进行测试,以确保辅料的质量和纯度符合要求。

 

3.List of contaminants

3.污染物清单

 

The subsections below consider the following contaminants:

污染物列表以下子节考虑了以下污染物:

 

Diethylene glycol (DEG)

二甘醇（DEG）

Ethylene glycol (EG)

乙二醇（EG）

Nitrosamines.

亚硝胺

 

3.1 Diethylene glycol (DEG)

3.1 二甘醇（DEG）

 

Introduction and use

简介与用途

 

DEG is a contaminant, and is not an excipient. It is however sometimes present in some excipients.

DEG 是一种污染物,而不是赋形剂。然而,在某些赋形剂中有时会检测到 DEG 的存在。

 

DEG is a colourless chemical for use in industrial applications only, such as industrial solvents, coolants, brake fluids and antifreeze agents. It is not approved for use in food and pharmaceutical applications.

DEG 是一种仅用于工业应用的无色化学物质,如工业溶剂、冷却剂、刹车液和防冻剂。它未被批准用于食品和制药应用。

 

Because of its solubility, some manufacturers have inappropriately used it in pharmaceutical products such as cough syrups and acetaminophen syrup in place of glycerol. In some cases, instead of using safer, more expensive diluents such as pharmaceutical grade glycerol, manufacturers have used alternative diluents that have been contaminated with DEG.

 

由于其溶解性,一些制造商不当将其用于制药产品,如咳嗽糖浆和对乙酰氨基酚糖浆,替代甘油。在某些情况下,制造商没有使用更安全但成本更高的稀释剂,如药用级甘油,而是使用了可能被二甘醇(DEG)污染的替代稀释剂。

 

Toxicity

毒性

 

Due to its toxicity DEG is potentially fatal, especially for young children, for example when it is inadvertently or deliberately incorporated as a component of a medicinal syrup or other liquid pharmaceutical formulation. The effects may include severe kidney damage, potentially resulting in death.

由于其毒性,DEG有可能致命,尤其是对于儿童,例如当其意外或故意作为药物糖浆或其他液体制剂的成分时。其影响可能包括严重的肾损伤,甚至可能导致死亡。

 

The possibility of some DEG contamination of raw materials during the raw ingredient and final product manufacturing process cannot be excluded. In these particular situations, DEG may simply be a minor impurity created during the manufacturing process of chemicals used to formulate drugs and consumer products.

在原料和最终产品制造过程中,DEG污染原材料的可能性不能排除。在这种特定情况下,DEG可能是化学药物和消费品配方过程中产生的微量杂质。

 

The first known case of DEG poisoning with medicine occurred in the United States in 1937, when DEG was used in an elixir of an antibiotic, sulfanilamide. Other DEG - related poisonings have also been reported in Argentina, Bangladesh, China, Haiti, India, Nigeria and Panama. Some of these countries have a history of multiple events, even though incidents are preventable with the right quality controls and risk assessments.

DEG中毒的第一例发生在1937年的美国,当时DEG被用于一种抗生素合剂——磺胺酏剂。此后,DEG相关的中毒事件也在阿根廷、孟加拉国、中国、海地、印度、尼日利亚和巴拿马等地报告过。尽管这些事件是可预防的,但一些国家多次发生此类事件,因为正确的质量控制和风险评估可以预防此类事件。

 

Risks and controls

风险与控制

 

DEG can enter the supply chain in several ways, for example through mislabelled products, human error, or unintentional contamination or intentional adulteration by manufacturers, repackers or suppliers.

 

DEG可以通过多种方式进入供应链,例如通过标签错误的产品、人为错误、无意污染或制造商、分装商或供应商有意掺假。

 

Appropriate controls, including supplier approval of raw materials and excipients and sampling and testing of raw materials and excipients, can be used to detect the presence of DEG. Appropriate analytical procedures should be used when testing for the presence of DEG.

适当的控制措施,包括原材料和辅料的供应商审批、原材料和辅料的取样和检测,可以用于检测DEG的存在。检测DEG时应使用适当的分析程序。

 

End - product testing alone is not appropriate, given the complex production, control and supply chain of excipients.

仅对最终产品进行检测是不合适的,因为辅料的复杂生产、控制和供应链过程。

 

Analytical methodology, such as gas chromatography with flame ionization detection (GC/FID) or high - performance liquid chromatography with refractive index detection (HPLC/RID), may be considered.

气相色谱-火焰离子化检测(GC/FID)或高效液相色谱-折射率检测(HPLC/RID)等分析方法可能被考虑使用。

 

DEG should comply with the requirements of an official pharmacopeia. Otherwise, in - house methods should be suitably validated for their intended use and should be appropriately validated. The satisfactory application of such methods requires the necessary analyst expertise, suitable equipment and validated procedures.

DEG应符合官方药典的要求。否则,内部方法应适合其预期用途,并应适当验证。此类方法的有效应用需要必要的分析员专业知识、合适的设备和验证的程序。

 

3.2 Ethylene glycol (EG)

3.2 乙二醇（EG）

 

Introduction and use

简介与用途

 

EG is a contaminant, and is not an excipient. It is however sometimes present in some excipients.

EG 是一种污染物,而不是辅料。然而,在某些辅料中可能会检测到 EG。

 

EG is a colourless, odourless, sweet - tasting chemical. It is mainly used in antifreeze, coolants, detergents, paints, lacquers, adhesives and cosmetics.

EG 是一种无色、无味、甜味的化学物质。它主要用于防冻剂、冷却剂、洗涤剂、油漆、清漆、粘合剂和化妆品。

 

EG is poisonous if swallowed. It is a central nervous system depressant that produces acute effects similar to those of ethanol. Ingestion can cause serious or fatal toxicity.

口服 EG 是有毒的。它是一种中枢神经系统抑制剂,其急性效应与乙醇相似。摄入 EG 可能导致严重甚至致命的毒性。

 

Toxicity

毒性

 

Symptoms after ingestion may include nausea, vomiting, convulsions, stupor and coma. An overdose of EG can damage the brain, lungs, liver and kidneys. The poisoning causes metabolic acidosis, shock, organ failure and death.

摄入后可能出现的症状包括恶心、呕吐、抽搐、昏睡和昏迷。EG 过量可损害大脑、肺、肝和肾。中毒可导致代谢性酸中毒、休克、器官衰竭和死亡。

 

Risks and controls

风险与控制

 

Appropriate controls, including supplier approval of raw materials and excipients and sampling and testing of raw materials and excipients, can be used to detect the presence of EG. Appropriate analytical procedures should be used when testing for the presence of EG.

适当的控制措施,包括供应商对原材料和辅料的批准、原材料和辅料的取样与检测,可以用于检测 EG 的存在。在检测 EG 存在时,应使用适当的分析方法。

 

End - product testing alone is not appropriate, given the complex production, control and supply chain of excipients.

仅通过最终产品的检测是不合适的,考虑到辅料的复杂生产、控制和供应链。

 

3.3 Nitrosamines

3.3 亚硝胺

 

Note: See WHO good practice considerations for the prevention and control of nitrosamines in pharmaceutical products (Annex 2, Technical Report Series No. 1060, 2025).

注意:有关制药产品中亚硝胺预防和控制的良好实践考虑,请参见世界卫生组织的技术报告系列第1060号,2025年版(附件2)。  

 

Introduction and use

引言与使用  

 

Nitrosamines are a contaminant, and not an excipient. Nitrosamines are formed by a reaction between nitrites and vulnerable (especially secondary) amines. Nitrosamines and their precursors can be found in various foods and consumer products, and in some pharmaceutical products.

亚硝胺是一种污染物,而非辅料。亚硝胺是由亚硝酸盐与敏感胺(尤其是二级胺)反应生成的。亚硝胺及其前体可在多种食品、消费品以及某些制药产品中被发现。

 

Toxicity

毒性

 

Nitrosamines can be carcinogenic when ingested at certain doses over a period of time.

亚硝胺在特定剂量下长期摄入时具有致癌性。

 

Risks and controls

风险与控制

 

The presence of nitrosamines in pharmaceutical products can present a carcinogenic risk. Manufacturers of excipients and FPPs should perform a risk assessment to determine whether there is a possibility of nitrosamine formation during the production of an excipient or during the production of an FPP, for example as a result of a chemical reaction between nitrites and vulnerable (especially secondary) amines.

硝胺类物质在制药产品中的存在会带来致癌风险。辅料和药用辅料产品的制造商应进行风险评估,以确定在辅料或药用辅料产品生产过程中是否有可能形成硝胺,例如由于亚硝酸盐与敏感(尤其是二级)胺发生化学反应所致。

 

4.Summary and recommendations

4.总结与建议

 

Excipients for use in pharmaceutical products should be produced, controlled, stored and distributed in compliance with the relevant WHO good practice guidelines.

制药产品中使用的辅料应按照相关世卫组织良好实践指南进行生产、控制、存储和分发。

 

Excipients for pharmaceutical use should be of appropriate quality and purity.

制药用辅料应具备适当的品质和纯度。

 

Manufacturers should identify excipients that may be at high risk of being contaminated with a hazardous substance.

生产商应识别出可能高度风险被有害物质污染的辅料。

 

Due to the high risk of some excipients being contaminated with hazardous substances, a risk assessment should be performed and controls implemented to ensure the excipients are of the required purity and for their intended use and, if contaminants such as DEG and EG are present, they are not above the limiting level.

鉴于某些辅料高度风险被有害物质污染,应进行风险评估并实施控制措施,以确保辅料符合其预期用途所需的纯度标准,若存在如二甘醇(DEG)和乙二醇(EG)等污染物,则其含量不得超过限制水平。

 

This document lists examples of excipients that may be at high risk of being contaminated.

本文件列出了可能高度风险被污染的辅料示例。

 

All high-risk excipients identified should be appropriately controlled.

所有识别出的高风险辅料均应实施适当的控制措施。

 

Controls may include the following.

控制措施可能包括以下内容:

 

Production, control, storage, repackaging and distribution should be in compliance with WHO good practices.

生产、控制、存储、重新包装和分发应符合WHO的良好实践标准。

 

Specifications with authoritative excipients should be equal to or better than those in the recognized pharmacopoeia.

对辅料的规格应不低于认可药典中的标准。

Specifications should include limits for impurities.

规格应包含杂质的限度。

Suppliers, distributors, repackers and agents supplying excipients for use in pharmaceutical products should implement appropriate controls to prevent any contamination of these excipients.

为制药产品提供辅料的供应商、分销商、重新包装商和代理应实施适当的控制措施,以防止这些辅料被污染。

The original certificate of analysis from the excipient manufacturer should be available for every batch of the excipient.¹⁰

每批辅料应提供可追溯制造商的原始分析证书。

Repackers of excipients for use in pharmaceutical products should comply with WHO good manufacturing practices and good trade and distribution practices.

制药辅料的重新包装商应遵守世界卫生组织(WHO)的优良制造规范和优良贸易与分销规范。

 

Manufacturers of intermediate or finished pharmaceutical products should:

 

制造中间体或成品药品的生产商应:

 

ensure that all personnel are aware of the risks associated with the contamination of excipients, and are trained in good practices;

确保所有人员了解辅料污染的风险,并接受优良操作规范的培训;

 

purchase these excipients from approved suppliers, through a known supply chain (including repacker and distributor);

从已批准的供应商处通过已知的供应链(包括重新包装商和分销商)采购这些辅料;

 

sample every container of each batch or lot of the listed excipients, and perform an identity and limit test for contaminants such as methanol or DEG and EG. Each sample should meet the predefined specification, including the safety limit for contaminants such as DEG and EG, for example not more than 0.10% volume in volume (v/v). Where the sample does not meet the specification, the consignment (batch) of excipient should be rejected and not used.

对每批或每个批次所列辅料的每一容器进行采样,并对甲醇或DEG和EG等污染物进行身份和限量测试。每个样本应符合预定义的规格,包括对DEG和EG等污染物的安全限量,例如不超过0.10%(体积比)。若样本不符合规格,则应拒收该辅料批次并不得使用。

来源：Internet

关键词： 药用辅料