Q3C残留溶剂中英文

杂质：残留溶剂的指导原则

1．介绍

本指导原则旨在介绍药物中残留溶剂在保证人体安全条件下的可接受量，指导原则建议使用低毒的溶剂，提出了一些残留溶剂毒理学上的可接受水平。

药物中的残留溶剂在此定义为在原料药或赋形剂的生产中，以及在制剂制备过程中产生或使用的有机挥发性化合物，它们在工艺中不能完全除尽。在合成原料药中选择适当的溶剂可提高产量或决定药物的性质，如结晶型。纯度和溶解度。因此．有时溶剂是合成中非常关键的因素。本指导原则所指的溶剂不是谨慎地用作赋形剂的溶剂，也不是溶剂化物，然而在这些制剂中的溶剂含量也应进行测定，并作出合理的判断。

出于残留溶剂没有疗效，故所有残留溶剂均应尽可能．去，以符合产品规范、GMP或其他基本的质量要求。制剂所含残留溶剂的水平不能高于安全值，已知一些溶剂可导致不接受的毒性（第一类，表1），除非被证明特别合理，在原药、赋形剂及制剂生产中应避免使用。一些溶剂毒性不太大（第二类，表2）应使用，以防止病人潜在的不良反应。使用低毒溶剂（第三类，表3）较为理想。附录1中列出了指导原则中的全部溶剂。

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表中所列溶剂并非详尽无遗，其他可能使用的溶剂有待日后补充列人。第一、二类溶剂的建议限度或溶剂的分类会随着。新的安全性资料的获得而调整。含有新溶剂的新药制剂、其上市申请的安全性资料应符合本指导原则或原料药指导原则（Q3A新原料药中的杂质）或新药制剂（Q3B新药制剂中的杂质）中所述的杂质控制原则，或者符合上述三者。 2. 指导原则的范围

指导原则范围包括原料药、赋形剂或制剂中所含残留溶剂．因此，当生产或纯化过程中会出现这些溶剂时。应进行残留溶剂的检验。也只有在上述情况下，才有必要作溶剂的检查。虽然生产商可以选择性地测定制剂，但也可以从制剂中各成分的残留溶液水平来累积计算制剂中的残留溶剂。如果计算结果等于或低于本原则的建议水平，该制剂可考虑不检查残留溶剂，但如果计算结果高于建议水平则应进行检测，以确定制剂制备过程中是否降低了有关溶剂的量以达到可接受水平。果制剂生产中用到某种溶剂，也应进行测定。

本指导原则不适用于临床研究阶段的准新原料药、准赋形剂和准制剂。也不适用于已上市的药品。

本指导原则适用于所有剂型和给药途径。短期（如30天或更短）使用或局部使用时，允许存在的残留溶剂水平可以较高。应根据不同的情况评判这些溶剂水平。

有关残留溶剂的背景附加说明见附录2。

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3．通则

3.1 根据危害程度对残留溶剂分类

“可耐受的日摄人量”（TDI）是国际化学品安全纲要（IPCS）用于描述毒性化合物接触限度的术语。“可接受的日摄人量”（ADI）是WHO及一些国家和国际卫生组织所用的术语。新术语“允许的日接触量”（PDE）是本指导原则中用于定义药物中可接受的有机溶剂摄人量，以避免与同一物质的ADI混淆。

本原则中残留溶剂的评价以通用名和结构列于附录1，根据它们对人体可能造成的危害分为以下三类； （1）第一类溶剂：应避兔的溶剂

为人体致癌物、疑为人体致癌物或环境危害物。 （2）第二类溶剂。应的溶剂

非遗传毒性动物致癌或可能导致其他不可逆毒性测神经毒性或致畸性）的试剂。

可能具其他严重的但可逆毒性的溶剂。 （3）第三类溶剂：低毒性溶剂

对人体低毒的溶剂，无须制定接触限度；第三类溶剂的PDE为每天50mg或50mg以上。 3.2 建立接触限度的方法

用于建立残留溶剂的PDE方法见附录3。用于建立限度的毒理数据的总结见Pharmeuropa，Vol . 9，No . l，Suplement，April 1997.

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3.3 第二类溶剂限度的选择方法

制定第二类溶剂的限度时有两种选择。

方法1: 使用表 2中以 ppm为单位的浓度限度，假定日给 药量为10g，以方程(1)计算。 1000 X PilE方程(1) C(ppm)=

剂量

PDE：mg／天 剂量：g／天

这些限度对所有原料药、赋形剂和制剂均适用。因此，这一方法可用于日剂量未知或未定的情况、只要在处方中所有的赋形剂和原料药都符合方法1给定的限度，就可以以任何比例用于制剂。只要日剂量不超过10g，就无须进一步计算。服用剂量超过 10g／天，应考虑用方法 2。

方法2：制剂中的每一种成分不必符合方法1的限度。药物中允许的残留溶剂限度水平，可根据表2中 PDE mg／天及已知最大日剂量，用方程（1）来计算。只要证明已降低至实际最低水平，便可以认为这种限度是可接受的、该限度能说明分析方法的精度、生产能力和生产工艺的合理变异，并能反映当前生产的标准水平。

应用方法2时可将药物制剂的每种成分中残留溶剂叠加起来，每天的总溶剂量应低于PDE给定的值。

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下面举例说明如何用方法l和2来考虑制剂中的乙睛限度。乙睛的允许日接触量是4.1 mg／天，因此由方法1算出限度是410PPm；如现在日最大给药量是5.0g，制剂中含两种赋形剂，制剂中的成分和计算得到的最大残留乙睛量见下 表：

成分 处方量 乙睛量 日（摄人）量 原料药 0.3g 800ppm 0.24mg 辅料一 0.9g 400ppm 0.36mg 辅料二 3.8g 800PPm 3.04mg 药物制剂 5.09 728ppm 3.mg

辅料1符合方法1限度，但原料、辅料2和药物制剂不符合方法1限度，而制剂符合方法2规定的4.1mg／天，故符合本指导原则的建议值。

乙睛作为残留溶剂的另一例子，曰最大给药量5刀g，制剂中含两种赋形剂，各组分及计算得到的最大残留的乙睛最见 下表：

成分 处方量 乙睛量 日（摄人）量 原料药 0.3g 800ppm 0.24mg 辅料1 0.9g 2000ppm 1.80mg 辅料 3.8g 800ppm 3.04mg 药物制剂 5.0g 1016ppm 5.08mg

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此例制剂中乙睛限度总量既不符合方法1也不符合方法2。生产厂可先测定制剂，以确定在处方工艺中能否降低已睛水平，如果不能将乙腈水平降至允许范围，生产厂应采取措施降低制剂中的乙腈量；若所有措施均不能降低残留溶剂的水平，厂方应提供其尝试降低残留溶剂以符合指导原则所做工作的总结报告，并以利弊分析报告证明允许该制剂存在的较高水平的残留溶剂。 3.4 分析方法

残留溶剂通常用色谱技术，如用GC法测定，如可能，对药典上规定要检测的残留溶剂，应采用统一了的测定方法。生产厂也可选用更合适的、经论证的方法来测定。若仅存在第三类溶剂；可用非专属性的方法如干燥失重来检查。

残留溶剂的方证应遵循ICH指导原则：“分析方证：定义和术语”及“分析方证：方法学”。 3.5 残留溶剂的报告水平

制剂生产商需要了解有关赋形剂或原料药中残留溶剂量的信息，以符合本指导原则的标准。以下阐述了赋形剂或原料药供应商应提供给制剂牛产商的信息的～些例子。供应商应选择以下一项：

·仅可能存在第三类溶剂，干燥失重小于0.5％。 ·仅可能存在第M类溶剂，X、Y……

全部应低于方法1的限度。（这里供应商应将第二类溶剂用X、Y……来表示）

·仅可能存在第二类溶剂X、Y……和第三类溶剂，残留的第三

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类溶剂低于方法1的限度，残留的第三类溶剂低于0．5％。 如果可能存在第一类溶剂，应进行鉴定并定量。

“可能存在”系指用于工艺最后一步的溶剂和用于较前几步工艺的溶剂经论证不能全部除尽。如果第二类溶剂高于方法1的限度或第三类溶剂高于0.5％，应鉴定并定量。 4. 残留溶剂的限度 4.1应避免的溶剂

因其具有不可接受的毒性或对环境造成公害，第一类溶剂在原料药、赋形剂及制剂生产中不应该使用。但是，为了生产一种有特殊疗效的药品而不得不使用时，除非经过其他论证，否则应按表1控制，1，1，1－三氯乙烷因会造成环境公害列人表1，其限度1500ppm是基于安全性数据而定的。

表1 药物制剂中含第一类溶剂的限度（应避免使用） 溶剂 浓度限度（ppm） 备注 苯 2 致癌物 四氯化碳 4 毒性及环境公害 1,2－二氯乙烷 5 毒性 1,1－二氯乙烷 8 毒性 1,1,1－三氯乙烷 1500 环境公害 4.2 应的溶剂

列于表2的溶剂，由于其具毒性，在制剂中应予，规定 PDE

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约 0.1mg／天，浓度约10ppm。所列值不能反映测定所必需的分析精度，精度应为方证的一部分。 表2 药品中第二类溶剂

溶剂 PDE（mg/天） 浓度限度（ppm） 乙晴 4.1 410 氯苯 3.6 360 氯仿 0.6 60 环氧乙烷 38.8 3880 1,2－二氯乙烯 18.7 1870 二氯甲烷 6.0 600 1,2－二甲亚砜 1.0 100 N,N－二甲乙酰胺 10.9 1090 N,N－二甲基甲酰胺 8.8 880 1,4－二恶烷 3.8 380 2－乙氧基乙醇 1.6 160 乙二醇 6.2 620 甲酰胺 2.2 220 正己烷 2.9 290 甲醇 30.0 3000 2－甲氧基乙醇 0.5 50 甲基丁酮 0.5 50 甲基环己烷 11.8 1180 N-甲基吡咯烷酮 48.4 4840 硝基甲烷 0.5 50 吡啶 2.0 200 二氧噻吩烷 1.6 160 四氢萘 1.0 100 甲苯 8.9 0 1,1,2-三氯乙烯 0.8 80 二甲苯* 21.7 2170

*通常为60% m-二甲苯，14% p-二甲苯，9% o-二甲苯和17%乙基苯。

４.３ 低毒溶剂

第三类溶剂（见表３）可能低毒，对人体危害很小。第三类溶剂包括人们认为在药物中以一般量存在时对人体无害的溶剂，但该类溶剂中许多尚未进行长期毒性或致癌研究。急性毒性或短期毒性试验表明这类溶剂几乎无毒、无遗传毒性。每日50mg或更少量无须论证即

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可接受（用方法１计算。即5000ppm或0.5％）。如果能够反映生产能力和ＧＭＰ的实际情况，更大的量也可接受。 表３ 在GＭＰ或其他质量要求中应的第三类溶剂

醋酸 乙醇 甲乙酮 丙酮 醋酸乙酯 甲基异丁酮 苯甲醚 乙醚 2-甲基-1-丙醇 1-丁醇 甲酸乙酯 戊烷 2-丁醇 甲酸 正丙醇 醋酸丁酯 正庚烷 正戊醇 叔丁基甲基醚 醋酸异丙酯 醋酸异丁酯 醋酸甲酯 2-丙醇 异丙基苯 3-甲基-1-丁醇 醋酸丙酯 二甲亚砜 四氢呋喃

4.4 没有足够毒性资料的溶剂

以下溶剂（表４）在赋形剂、原料药和制剂生产中也许会被生产商采用，但尚无足够的毒理学数据，故无ＰＤＥ值，生产厂在使用时应提供这些溶剂在制剂中残留水平的合理性论证报告。 表４ 无足够毒理学数据的溶剂

1,1-二乙氧基丙烷 甲基异丙酮

1,1-二甲基甲烷 甲基四氢呋喃 2,2-二甲丙烷 石油醚 异辛烷 三氯乙酸 异丙醚 三氟乙酸

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术 语

遗传毒性致癌 指通过影响基因或染色体而致癌。 LOEL：lowest-observed effect level的缩写。

能观察到反应的最低量（lowest-obserued effect leuel）是在研究人体或动物接触某种物质时产生任何反应的频率或严重性在生物学上显著增加的最低剂量。

修正因子 是由毒理学家评定的、由生物测定的结果转换成与人体安全性相关的系数。

神经毒性 某种物质引起神经系统不良反应的能力。 NOEL：no-observed effect level的缩写。

不能观察到反应的量（no-obserued effect leuel）某种物质被人体或动物接触后，任何反应频率或严重性在生物学上无 明显增加的最高剂量。

ＰＤＥ 是 permitted daily exposure的缩写，指每日摄入药物中残留溶剂的可接受最大摄入量。

可逆毒性 指接触某种物质时产生毒性反应，不接触时反应即消失。

深疑为人体致癌物 某种物质没有致癌作用的流行病学表征，但基因毒性数据阳性，对啮齿动物具致癌作用表征。

致畸作用 怀孕期间服用某一物质而产生的胎儿发育畸形。

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附录1 指导原则中所列的溶剂

溶剂 英文 结构式 类别 醋酸 Acetic acid CH3COOH 3 丙酮 Acetone CH3COCH3 3 乙晴 Acetonitrile CH3CN 2 OCH3甲氧基苯 Anisole 3 苯 Benzene 1 正丁醇 1-Butanol CH3(CH2)3OH 3 2-丁醇 2-Butanol CH3CH2CH(OH)CH3 3 醋酸丁酯 Butyl acetate CH3COO(CH2)3CH3 3 叔丁基甲醚 tert-Butylmethyl ether (CH3)3COCH3 3 1 四氯化碳 Carbon tetrachloride CCl4 Cl 氯苯 Chlorobenzene 2 2 氯仿 Chloroform CHCl3 CH(CH3)2 异丙基苯 Cunene 3 环己烷 Cyclohexane 2 1 1,2-二氯乙烷 1,2-Dichloroethane CH2ClCH2Cl 1 1,1-二氯乙烯 1,1-Dichloroethene H2C=CCl2 2 1,2-二氯乙烯 1,2-Dichloroethene ClHC=CHCl 2 二氯甲烷 Dichioromethane CH2Cl2 2 1,2-二甲氧基乙醚 1,2-Dimethoxyethane H3COCH2CH2OCH3 2 N,N-二甲基乙酰胺 N,N-Dimethylacetamide CH3CON(CH3)2 2 N,N-二甲基甲酰胺 N,N-Dimethylformamide HCON(CH3)2 3 二甲亚砜 Dimethyl sulfoxide (CH3)2SO OO 1,4二恶烷 1,4-Dioxane 2 3 乙醇 Ethanol CH3CH2OH 2-乙氧基乙醇 2-Ethoxyethanol CH3CH2OCH2CH2OH 2 3 乙酸乙酯 Ethylacetate CH3COOCH2CH3 2 乙二醇 Ethyleneglycol HOCH2CH2OH 3 乙醚 Ethyl ether CH3CH2OCH2CH3 3 甲酸乙酯 Ethyl tormate HCOOCH2CH3 3 甲酰胺 Formamide HCONH2 2 甲酸 Formic acid HCOOH 3 正庚烷 Heptane CH3(CH2)5CH3 2 正己烷 Hexane CH3(CH2)4CH3 异丁基乙酸酯 Isobutyl acetate CH3COOCH2CH(CH3)2 3 3 异丙基乙酸酯 Isopropyl acetate CH3COOCH(CH3)2 第 11 页 共 18 页

ICH Q3c 杂质：残留溶剂的指导原则

溶剂 英文 结构式 类别 甲醇 Methanol CH3OH 22-甲氧基乙醇 2-Methoxyethanol CH3OCH2CH2OH 2乙酸酯 Methyl acetate CH3COOCH3 33-甲基丁醇 3-Methy-1-butanol (CH3)2CHCH2CH2OH 32-己酮 Methylbuty ketone CH3(CH2)3COCH3 2 CH3甲基环己酮 Methylcyclohexane 22-丁酮 Methylethyl ketone CH3CH2COCH3 2甲基异丁基酮 Methylisobutyl ketone CH3COCH2CH(CH3)2 3异丁基乙醇 2-Methy-1-propanol (CH3)2CHCH2OH 3 ON2N-甲基吡咯烷酮 N-Methylpyrrolidone CH3 硝基甲烷 Nitromethane CH3NO2 2戊烷 Pentane CH3(CH2)3CH3 3戊醇 1-Pentanol CH3(CH2)3CH2OH 31- 丙醇 1-Propanol CH3CH2CH2OH 32- 丙醇 2-Propanol (CH3)2CHOH 3乙酸丙酯 Propyl acetate CH3COOCH2CH2CH3 3 N 吡啶 Pyridine 2 S2二氧噻吩烷 Sulfolane OO 3四氢呋喃 Tetrahydrofuran O 2 四氢萘 Tetralin 2CH3甲苯 Toluene 三氯乙烷 1,1,1-Trichloroethane CH3CCl3 1三氯乙烯 1,1,2-Trichloroethene HClC=CCl2 2CH3 CH3二甲苯* Xylene* 2 *一般为60% m-二甲苯，14% p-二甲苯，9% o-二甲苯和17%乙基苯。

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附录２ 其他背景

A2.1 有机挥发性溶剂的环境管理几种药物生产中常用的残留溶剂作为有毒化合物列于环境健康标准（EHC）和危险信息系统大全（IRCS）。一些组织如国际化学品安全性纲要（IPCS）、美国环境保护机构（EPA）和FDＡ的目标包括测定可接受的接触水平。目的是防止长期接触化学品后可能对人体健康和对整个环境造成危害。评估最大接触安全限度通常应进行长期试验，当无长期试验数据时，可对短期研究结果进行修正，如对短期研究数据用较大的安全因子校正后使用，其中主要描述的项目与人群长期或一生接触的周围环境有关，如：周围空气、食品、饮用水或其他介质。

A2.2 药物中的残留溶剂

本指导原则中的接触限度是参考ＥＨＣ和ＩＲＩＳ中的毒性数据和方法学而建立的。然而，在建立接触限度时，应考虑用于合成和制剂处方中溶剂残留的一些特定的假设。即：

（１）病人（不是一般人群）使用药物是为了治疗疾病或预防疾病，免受感染。

（２）对大多数药物来说不必假设病人终身服药的接触量，但作为一种工作假设可能有助于减少对人体健康产生危害。

（３）残留溶剂是药物中不可避免的成分，常常是制剂中的一部分。

（４）除特殊情况外，残留溶剂不能超过推荐水平。 （５）用于确定残留溶剂可接受水平的毒理学研究数据，应

第 13 页 共 18 页

ICH Q3c 杂质：残留溶剂的指导原则

该在一些草案中（如DECD、EPA和FDA Red BooK）已有收载。

附录３ 建立接触限度的方法

Gaylor-Kodell危害评估方法(Gaylor,D,W.AndKodell,R.l.:Linear Interpolation algoeithm for low dose assessment of toxic substance. J Environ. Pathology, 4, 305)适用于第一类致癌溶剂，只有掌握了可信赖的致癌数据，才可以用数学模型外推来建立接触限度。第一类溶剂接触限度应根据不产生反应的量（ＮＯＥＬ）、并使用较大的安全系数（如 10000~10000）来确定。这些溶剂的检测和定量应该用现代化分析技术。

本指导原则中第二类溶剂的可接受接触限度是根据药物中接触限度的规定方法（药典论坛NOV-Dec19）和IPCS采用的评估化学品对人体危害的方法（环境健康标准１７０，ＷＨＯ，１９９４），计算ＰＤＥ值而得。这些方法与ＵＳＥＰＡ （ＩＲＩＳ） 和ＵＳＦＤA（ＲｅｄＢｏｏｋ）及其他一些方法相似。在此简述本法有助于更好地了解ＰＤＥ值的由来，在使用本文件第４节表中的ＰＤＥ值时不必再进行计算。

第 14 页 共 18 页

ICH Q3c 杂质：残留溶剂的指导原则

ＰＤＥ由对大多数相关动物研究得到的不产生反应量（ＮＯＥＬ），或刚能观察到的反应量（ＬＯＥＬ），按下式推导而

得：

ＮＯＥＬ Ｘ 体重调整 ＰＤＥ= (1)

F1×F2×F3×F4×F5

ＰＤＥ首先由ＮＯＥＬ计算，如果无ＮＯＥＬ值，可用ＬＯＥＬ。此处所用的用于人体的修正系数与ＥＨＣ所用的“未定系数”和“药典论坛”所用的“校正系数’及“安全系数”相似，无论何种给药途径均假定为１００％的全身接触来计算。

以下是修正系数：

Ｆ1为考虑种类之间差异的系数。

Ｆ1＝５ 从大鼠剂量推断人用剂量的系数。 F1=１２ 从小鼠剂量推断人用剂量的系数。 Ｆ1=２ 从狗剂量推断人用剂量的系数。 F1=2.5 从兔剂量推断人用剂量的系数。 F1=3从猴子剂量推断人用剂量的系数。 F1=10从其他动物剂量推断人用剂量的系数。 F1考虑相对体表面积：有关动物种类与人的体重比。 体表面积计算式：S=kM (2)

其中Ｍ=体重，常数ｋ为１０，方程中所用的体重见表A3.1. F2=10 ，说明个体间的变异。

第 15 页 共 18 页

0.67ICH Q3c 杂质：残留溶剂的指导原则

对有机溶剂Ｆ2系数一般为１０，本指导原则一律用１０。 Ｆ３为短期接触急性毒性研究的可变系数。

Ｆ３=1 研究时间至少为动物寿命一半（鼠、兔１年，猫、狗、猴７年）。

Ｆ３=１ 器官形成的整个过程的生殖研究。

Ｆ３=２ 对啮肯动物６个月研究或非啮齿动物３－５年的研究。

Ｆ３=５ 对啮肯动物３个月研究或非啮齿动物２年的研究。 Ｆ３=１０ 更短时间的研究。

在所有情况下，对研究时间介于上述时间点之间的研究，应用较大的系数，如对啮齿类动物９个月毒性研究；其系数用２。

Ｆ４为用于产生严重毒性情况的系数，如：非遗传致癌毒性、神经毒性或致畸性，研究生殖毒性时，用以下系数：

F4=ｌ 与母体毒性有关的胎儿毒性。 F4=５ 无母体毒性的胎儿毒性。 F4=５ 受母体毒性影响的致畸反应。 F4=１０ 无母体毒性影响的致畸反应。

F5=一个可变系数 可用在没有建立不产生反应的量（ＮＯＥ

Ｌ）时。

当只有刚产生反应的量（ＬＯＥＬ）时，根据毒性的严重 性，系数可达到１０。

‘体重调整”假定一个任意的成人体重（不论性别）为５０ｋｇ，

第 16 页 共 18 页

ICH Q3c 杂质：残留溶剂的指导原则

相对于常用于这类计算的标准体重为６０ｋｇ或７０ｋｇ的人，这一相对低的重量提供了一个附加的安全因素，应该指出有些成年病人体重小于５０ｋｇ。对这些病人，应考虑用已建立的用于测定Ｍ的安全系数进行调节。如果儿童用药的处方中含有溶剂，用较轻的体重进行调节是合适的。

举例说明方程的应用，小鼠中乙睛毒性研究总结于Pharmeuropa,Vol. 9, No. 1增补本，1997年4月第S24页。NOEL为50.7mg/(kg.d), 乙睛的ＰＤＥ如下计算。

ＰＤＥ= =4.22mg / d 本例中，

Ｆ1=１２ 说明从小鼠剂量推断到人用剂量的系数。 Ｆ2=１０ 说明不同人体的差异。 Ｆ3=５ 因为研究时间只有１３周。 Ｆ4=ｌ 因为未发现严重的毒性。 Ｆ5=１ 因为不产生反应的量已测得。 表Ａ3.1本文件中用于计算的值

大鼠体重 425g 小鼠呼吸量 43L/天 怀孕大鼠体重 330g 兔呼吸量 1440L/天 小鼠体重 28g 豚鼠呼吸量 430L/天 怀孕小鼠体重 30g 人呼吸量 28800L/天

第 17 页 共 18 页

50.7mg/(Kg.d)×50kg 12×10×5×1×1 ICH Q3c 杂质：残留溶剂的指导原则

豚鼠体重 500g 猴呼吸量 1150L/天 罗猴体重 2.5g 狗呼吸量 9000L/天 兔体重（无论是否怀孕） 4kg 小鼠水消耗量 5ml/天 beagle狗体重 11.5ｋｇ 大鼠水消耗量 30ml/天 大鼠呼吸量 290ml/天 大鼠食物消耗量 30g/天 理想气体方程：PV＝nRT，用于将吸人研究的气体浓度ppm转换为mg/L或mg/m³。例如以大鼠吸入四氯化碳（分子量153.84）的生殖毒性研究为例见Pharmeuropa,Vol. 9, No. 1,增补本，1997年4月。S9页。

N V ＝ P R T = 300×10ˉ大气压×153840mg/mol 0.082 • 大气压 /（ K•mol ）×298K 6 =

46.15mg 24.45L

=1.mg / L

1000L=1M³ 可用于将单位转换为mg / m³

第 18 页 共 18 页

Guidance for Industry

Q3C Impurities: Residual Solvents

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)

December 1997

ICH

Guidance for Industry

Q3C Impurities: Residual Solvents

Additional copies are available from:

Center for Drug Evaluation and Research (CDER),

Division of Drug Information (HFD-240),5600 Fishers Lane, Rockville, MD 20857

(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm

or

Office of Communication, Training, andManufacturers Assistance (HFM-40),

Center for Biologics Evaluation and Research (CBER)1401 Rockville Pike, Rockville, MD 20852-1448,

http://www.fda.gov/cber/guidelines.htm;(Fax) 888-CBERFAX or 301-827-3844

(Voice Information) 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)

December 1997

ICH

TABLE OF CONTENTS

I.

INTRODUCTION (1).............................................................................................................1

II.SCOPE OF THE GUIDANCE (2).........................................................................................2III.GENERAL PRINCIPLES (3)................................................................................................2

A.B.C.D.E.

Classification of Residual Solvents by Risk Assessment (3.1).................................................3Methods for Establishing Exposure Limits (3.2)....................................................................3Options for Describing Limits of Class 2 Solvents (3.3).........................................................3Analytical Procedures (3.4)....................................................................................................5Reporting Levels of Residual Solvents (3.5)...........................................................................5

IV.LIMITS OF RESIDUAL SOLVENTS (4).............................................................................6

A.B.C.D.

Solvents to Be Avoided (4.1).................................................................................................6Solvents to Be Limited (4.2)..................................................................................................6Solvents with Low Toxic Potential (4.3).................................................................................6Solvents for Which No Adequate Toxicological Data Were Found (4.4)................................7

GLOSSARY....................................................................................................................................8APPENDIX 1: ADDITIONAL BACKGROUND..........................................................................9APPENDIX 2: METHODS FOR ESTABLISHING EXPOSURE LIMITS.............................10

Guidance for Industry1

Q3C Impurities: Residual Solvents

This guidance represents the Food and Drug Administration's (FDA's) current thinking on thistopic. It does not create or confer any rights for or on any person and does not operate to bindFDA or the public. An alternative approach may be used if such approach satisfies therequirements of the applicable statutes and regulations.I. INTRODUCTION (1)

The objective of this guidance is to recommend acceptable amounts for residual solvents in

pharmaceuticals for the safety of the patient. The guidance recommends use of less toxic solventsand describes levels considered to be toxicologically acceptable for some residual solvents. Acomplete list of the solvents included in this guidance is provided in a companion documententitled Q3C — Tables and List.2 The list is not exhaustive, and other solvents may be used andlater added to the list.

Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are usedor produced in the manufacture of drug substances or excipients, or in the preparation of drugproducts. The solvents are not completely removed by practical manufacturing techniques.

Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, ordetermine characteristics such as crystal form, purity, and solubility. Therefore, the solvent maysometimes be a critical parameter in the synthetic process. This guidance does not addresssolvents deliberately used as excipients nor does it address solvates. However, the content ofsolvents in such products should be evaluated and justified. This guidance was developed within the Expert Working Group (Quality) of the International Conference on

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject toconsultation by the regulatory parties, in accordance with the ICH process. This document was endorsed by the ICH SteeringCommittee at Step 4 of the ICH process in July 1997. At Step 4 of the process, the final draft is recommended for adoption tothe regulatory bodies of the European Union, Japan, and the United States.

Arabic numbers in subsections reflect the organizational breakdown in the document endorsed by the ICH Steering Committee atStep 4 of the ICH process.

2

This guidance was published originally in the Federal Register on December 24, 1997 (62 FR67377). At that time

the list was included as Appendix 1. In this reformatted version, the list has been removed and made into a companion document,and the remaining appendices have been renumbered.

1

1

Since there is no therapeutic benefit from residual solvents, all residual solvents should beremoved to the extent possible to meet product specifications, good manufacturing practices, orother quality-based requirements. Drug products should contain no higher levels of residual

solvents than can be supported by safety data. Some solvents that are known to cause unacceptabletoxicities (Class 1, see Table 1 in the companion document Q3C — Tables and List) should beavoided in the production of drug substances, excipients, or drug products unless their use can bestrongly justified in a risk-benefit assessment. Some solvents associated with less severe toxicity(Class 2, see Table 2 in the campanion document ) should be limited in order to protect patientsfrom potential adverse effects. Ideally, less toxic solvents (Class 3, see Table 3 in the companiondocument) should be used where practical.

Recommended limits of Class 1 and 2 solvents or classification of solvents may change as newsafety data becomes available. Supporting safety data in a marketing application for a new drugproduct containing a new solvent may be based on concepts in this guidance or the concept of

qualification of impurities as expressed in the guidance for drug substance, Q3A Impurities in NewDrug Substances (January 1996) or drug product, Q3B Impurities in New Drug Products(November 1997), or all three guidances.II.

SCOPE OF THE GUIDANCE (2)

Residual solvents in drug substances, excipients, and drug products are within the scope of thisguidance. Therefore, testing should be performed for residual solvents when production or

purification processes are known to result in the presence of such solvents. It is only necessary totest for solvents that are used or produced in the manufacture or purification of drug substances,excipients, or drug products. Although manufacturers may choose to test the drug product, acumulative method may be used to calculate the residual solvent levels in the drug product fromthe levels in the ingredients used to produce the drug product. If the calculation results in a levelequal to or below that recommended in this guidance, no testing of the drug product for residualsolvents need be considered. If, however, the calculated level is above the recommended level,the drug product should be tested to ascertain whether the formulation process has reduced therelevant solvent level to within the acceptable amount. Drug product should also be tested if asolvent is used during its manufacture.

This guidance does not apply to potential new drug substances, excipients, or drug products usedduring the clinical research stages of development, nor does it apply to existing marketed drugproducts.

The guidance applies to all dosage forms and routes of administration. Higher levels of residualsolvents may be acceptable in certain cases such as short-term (30 days or less) or topicalapplication. Justification for these levels should be made on a case-by-case basis.See Appendix 1 for additional background information related to residual solvents.III.

GENERAL PRINCIPLES (3)

2

A. Classification of Residual Solvents by Risk Assessment (3.1)

The term tolerable daily intake (TDI) is used by the International Program on Chemical Safety(IPCS) to describe exposure limits of toxic chemicals and the term acceptable daily intake (ADI)is used by the World Health Organization (WHO) and other national and international health

authorities and institutes. The new term permitted daily exposure (PDE) is defined in the presentguidance as a pharmaceutically acceptable intake of residual solvents to avoid confusion ofdiffering values for ADI’s of the same substance.

Residual solvents assessed in this guidance are listed in a companion document entitled Q3C —Tables and List. Common names and structures are used. They were evaluated for their possiblerisk to human health and placed into one of three classes as follows:Class 1 solvents: Solvents to be avoided—

Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.

Class 2 solvents: Solvents to be limited—

Nongenotoxic animal carcinogens or possible causative agents of other irreversibletoxicity such as neurotoxicity or teratogenicity.

Solvents suspected of other significant but reversible toxicities.

Class 3 solvents: Solvents with low toxic potential—

Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3solvents have PDE's of 50 milligrams (mg) or more per day.B.

Methods for Establishing Exposure Limits (3.2)

The method used to establish permitted daily exposures for residual solvents is presented inAppendix 2. Summaries of the toxicity data that were used to establish limits are published inPharmeuropa, Vol. 9, No. 1, Supplement, April 1997.C.

Options for Describing Limits of Class 2 Solvents (3.3)

Two options are available when setting limits for Class 2 solvents.

Option 1: The concentration limits in parts per million (ppm) stated in Table 2 (see companiondocument) can be used. They were calculated using equation (1) below by assuming a productmass of 10 mass of 10 grams (g) mass of 10 grams administered daily.

3

(1)

Concentration (ppm) = 1000 x PDE dose

Here, PDE is given in terms of mg/day and dose is given in g/day.

These limits are considered acceptable for all substances, excipients, or products. Therefore, thisoption may be applied if the daily dose is not known or fixed. If all excipients and drug substancesin a formulation meet the limits given in Option 1, then these components may be used in anyproportion. No further calculation is necessary provided the daily dose does not exceed 10 g. Products that are administered in doses greater than 10 g per day should be considered underOption 2.

Option 2: It is not considered necessary for each component of the drug product to comply with thelimits given in Option 1. The PDE in terms of mg/day as stated in Table 2 (see companion

document) can be used with the known maximum daily dose and equation (1) above to determinethe concentration of residual solvent allowed in drug product. Such limits are considered

acceptable provided that it has been demonstrated that the residual solvent has been reduced to thepractical minimum. The limits should be realistic in relation to analytical precision, manufacturingcapability, and reasonable variation in the manufacturing process and the limits should reflectcontemporary manufacturing standards.

Option 2 may be applied by adding the amounts of a residual solvent present in each of the

components of the drug product. The sum of the amounts of solvent per day should be less than thatgiven by the PDE.

Consider an example of the use of Option 1 and Option 2 applied to acetonitrile in a drug product.The permitted daily exposure to acetonitrile is 4.1 mg per day; thus, the Option 1 limit is 410 ppm. The maximum administered daily mass of a drug product is 5.0 g, and the drug product containstwo excipients. The composition of the drug product and the calculated maximum content ofresidual acetonitrile are given in the following table.ComponentDrug substanceExcipient 1Excipient 2Drug product

Amount inFormulation0.3 g0.9 g3.8 g5.0 g

AcetonitrileContent800 ppm400 ppm800 ppm728 ppm

Daily Exposure0.24 mg0.36 mg3.04 mg3. mg

Excipient 1 meets the Option 1 limit, but the drug substance, excipient 2, and drug product do notmeet the Option 1 limit. Nevertheless, the product meets the Option 2 limit of 4.1 mg per day andthus conforms to the recommendations in this guidance.

4

Consider another example using acetonitrile as residual solvent. The maximum administered dailymass of a drug product is 5.0 g, and the drug product contains two excipients. The composition ofthe drug product and the calculated maximum content of residual acetonitrile are given in thefollowing table.ComponentDrug substanceExcipient 1Excipient 2Drug Product

Amount inFormulation0.3 g0.9 g3.8 g5.0 g

AcetonitrileContent 800 ppm2,000 ppm 800 ppm1,016 ppm

Daily Exposure0.24 mg1.80 mg3.04 mg5.08 mg

In this example, the product meets neither the Option 1 nor the Option 2 limit according to thissummation. The manufacturer could test the drug product to determine if the formulation processreduced the level of acetonitrile. If the level of acetonitrile was not reduced during formulation tothe allowed limit, then the manufacturer of the drug product should take other steps to reduce theamount of acetonitrile in the drug product. If all of these steps fail to reduce the level of residualsolvent, in exceptional cases the manufacturer could provide a summary of efforts made to reducethe solvent level to meet the guidance value, and provide a risk-benefit analysis to supportallowing the product to be utilized with residual solvent at a higher level.D.

Analytical Procedures (3.4)

Residual solvents are typically determined using chromatographic techniques such as gaschromatography. Any harmonized procedures for determining levels of residual solvents as

described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would befree to select the most appropriate validated analytical procedure for a particular application. Ifonly Class 3 solvents are present, a nonspecific method such as loss on drying may be used.Validation of methods for residual solvents should conform to ICH guidances, Q2A Text onValidation of Analytical Procedures (March 1995) and Q2B Validation of AnalyticalProcedures: Methodology (November 1996).E.

Reporting Levels of Residual Solvents (3.5)

Manufacturers of pharmaceutical products need certain information about the content of residualsolvents in excipients or drug substances in order to meet the criteria of this guidance. The

following statements are given as acceptable examples of the information that could be providedfrom a supplier of excipients or drug substances to a pharmaceutical manufacturer. The suppliermight choose one of the following as appropriate:•

Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5 percent.

5

• •

Only Class 2 solvents X, Y, . . . are likely to be present. All are below the Option 1 limit. (Here the supplier would name the Class 2 solvents represented by X, Y, . . . .)

Only Class 2 solvents X, Y, . . . and Class 3 solvents are likely to be present. ResidualClass 2 solvents are below the Option 1 limit and residual Class 3 solvents are below 0.5percent.

If Class 1 solvents are likely to be present, they should be identified and quantified.

“Likely to be present” refers to the solvent used in the final manufacturing step and to solvents thatare used in earlier manufacturing steps and not removed consistently by a validated process.If solvents of Class 2 or Class 3 are present at greater than their Option 1 limits or 0.5 percent,respectively, they should be identified and quantified. IV. A.

LIMITS OF RESIDUAL SOLVENTS (4)Solvents to Be Avoided (4.1)

Solvents in Class 1 (Table 1; see companion document) should not be employed in the manufactureof drug substances, excipients, and drug products because of their unacceptable toxicity or theirdeleterious environmental effect. However, if their use is unavoidable in order to produce a drugproduct with a significant therapeutic advance, then their levels should be restricted as shown inTable 1, unless otherwise justified. The solvent 1,1,1-Trichloroethane is included in Table 1 (seecompanion document) because it is an environmental hazard. The stated limit of 1,500 ppm isbased on a review of the safety data.B.

Solvents to Be Limited (4.2)

Solvents in Class 2 (Table 2; see companion document) should be limited in pharmaceuticalproducts because of their inherent toxicity. PDEs are given to the nearest 0.1 mg/day, andconcentrations are given to the nearest 10 ppm. The stated values do not reflect the necessaryanalytical precision of determination. Precision should be determined as part of the validation ofthe method.C.

Solvents with Low Toxic Potential (4.3)

Solvents in Class 3 (Table 3; see companion document) may be regarded as less toxic and oflower risk to human health. Class 3 includes no solvent known as a human health hazard at levelsnormally accepted in pharmaceuticals. However, there are no long-term toxicity or

carcinogenicity studies for many of the solvents in Class 3. Available data indicate that they areless toxic in acute or short-term studies and negative in genotoxicity studies. It is considered thatamounts of these residual solvents of 50 mg per day or less (corresponding to 5,000 ppm or 0.5percent under Option 1) would be acceptable without justification. Higher amounts may also be

6

acceptable provided they are realistic in relation to manufacturing capability and goodmanufacturing practice (GMP).D.

Solvents for Which No Adequate Toxicological Data Were Found (4.4)

The solvents listed in Table 4 (see companion document) may also be of interest to manufacturersof excipients, drug substances, or drug products. However, no adequate toxicological data on whichto base a PDE were found. Manufacturers should supply justification for residual levels of thesesolvents in pharmaceutical products.

7

GLOSSARY

Genotoxic carcinogens: Carcinogens that produce cancer by affecting genes or chromosomes.LOEL: Abbreviation for lowest-observed effect level.

Lowest-observed effect level: The lowest dose of substance in a study or group of studies thatproduces biologically significant increases in frequency or severity of any effects in the exposedhumans or animals.

Modifying factor: A factor determined by professional judgment of a toxicologist and applied tobioassay data to relate that data safely to humans.

Neurotoxicity: The ability of a substance to cause adverse effects on the nervous system.NOEL: Abbreviation for no-observed-effect level.

No-observed-effect level: The highest dose of substance at which there are no biologicallysignificant increases in frequency or severity of any effects in the exposed humans or animals.PDE: Abbreviation for permitted daily exposure.

Permitted daily exposure: The maximum acceptable intake per day of residual solvent inpharmaceutical products.

Reversible toxicity: The occurrence of harmful effects that are caused by a substance and whichdisappear after exposure to the substance ends.

Strongly suspected human carcinogen: A substance for which there is no epidemiologicalevidence of carcinogenesis but there are positive genotoxicity data and clear evidence ofcarcinogenesis in rodents.

Teratogenicity: The occurrence of structural malformations in a developing fetus when asubstance is administered during pregnancy.

8

APPENDIX 1: ADDITIONAL BACKGROUND

Environmental Regulation of Organic Volatile Solvents (A2.1)

Several of the residual solvents frequently used in the production of pharmaceuticals are listed astoxic chemicals in Environmental Health Criteria (EHC) monographs and the Integrated RiskInformation System (IRIS). The objectives of such groups as the International Programme onChemical Safety (IPCS), the U.S. Environmental Protection Agency (EPA), and the U.S. Food andDrug Administration (FDA) include the determination of acceptable exposure levels. The goal isprotection of human health and maintenance of environmental integrity against the possible

deleterious effects of chemicals resulting from long-term environmental exposure. The methodsinvolved in the estimation of maximum safe exposure limits are usually based on long-term studies.When long-term study data are unavailable, shorter term study data can be used with modificationof the approach such as use of larger safety factors. The approach described therein relates

primarily to long-term or lifetime exposure of the general population in the ambient environment(i.e., ambient air, food, drinking water, and other media).Residual Solvents in Pharmaceuticals (A2.2)

Exposure limits in this guidance are established by referring to methodologies and toxicity datadescribed in EHC and IRIS monographs. However, some specific assumptions about residualsolvents to be used in the synthesis and formulation of pharmaceutical products should be takeninto account in establishing exposure limits. They are as follows:• • • • •

Patients (not the general population) use pharmaceuticals to treat their diseases or forprophylaxis to prevent infection or disease.

The assumption of lifetime patient exposure is not necessary for most pharmaceuticalproducts but may be appropriate as a working hypothesis to reduce risk to human health.Residual solvents are unavoidable components in pharmaceutical production and will oftenbe a part of drug products.

Residual solvents should not exceed recommended levels except in exceptionalcircumstances.

Data from toxicological studies that are used to determine acceptable levels for residualsolvents should have been generated using appropriate protocols such as those described,for example, by the Organization for Economic Cooperation and Development, EPA, andthe FDA Red Book.

9

APPENDIX 2: METHODS FOR ESTABLISHING EXPOSURE LIMITS

The Gaylor-Kodell method of risk assessment (Gaylor, D. W., and R. L. Kodell, \"LinearInterpolation Algorithm for Low Dose Assessment of Toxic Substance,\" Journal of

Environmental Pathology and Toxicology, 4:305, 1980) is appropriate for Class 1 carcinogenicsolvents. Only in cases where reliable carcinogenicity data are available should extrapolation bythe use of mathematical models be applied to setting exposure limits. Exposure limits for Class 1solvents could be determined with the use of a large safety factor (i.e., 10,000 to 100,000) withrespect to the NOEL. Detection and quantitation of these solvents should be by state-of-the-artanalytical techniques.

Acceptable exposure levels in this guidance for Class 2 solvents were established by calculationof PDE values according to the procedures for setting exposure limits in pharmaceuticals

(Pharmacopeial Forum, Nov-Dec 19), and the method adopted by IPCS for Assessing HumanHealth Risk of Chemicals (EHC 170, WHO, 1994). These methods are similar to those used bythe U.S. EPA (IRIS) and the U.S. FDA (Red Book) and others. The method is outlined here to givea better understanding of the origin of the PDE values. It is not necessary to perform thesecalculations in order to use the PDE values tabulated in Section 4 of this document. PDE is derived from the NOEL or the LOEL in the most relevant animal study as follows:

NOEL x Weight AdjustmentPDE = F1 x F2 x F3 x F4 x F5

(1)

The PDE is derived preferably from a NOEL. If no NOEL is obtained, the LOEL may be used.Modifying factors proposed here, for relating the data to humans, are the same kind of uncertaintyfactors used in EHC (EHC 170, WHO, Geneva, 1994), and modifying factors or safety factors inPharmacopeial Forum. The assumption of 100 percent systemic exposure is used in allcalculations regardless of route of administration.The modifying factors are as follows:

F1 = A factor to account for extrapolation between species.F1 = 5 for extrapolation from rats to humans.F1 = 12 for extrapolation from mice to humans.F1 = 2 for extrapolation from dogs to humans.F1 = 2.5 for extrapolation from rabbits to humans.F1 = 3 for extrapolation from monkeys to humans.

F1 = 10 for extrapolation from other animals to humans.

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F1 takes into account the comparative surface area:body weight ratios for the species concernedand for man. Surface area (S) is calculated as:

(2)S = kM0.67in which M = body mass, and the constant k has been taken to be 10. The body weights used in the

equation are those shown below in Table A3.1.

F2 = A factor of 10 to account for variability between individuals.

A factor of 10 is generally given for all organic solvents, and 10 is used consistently in thisguidance.

F3 = A variable factor to account for toxicity studies of short-term exposure.

F3 = 1 for studies that last at least one half-lifetime (1 year for rodents or rabbits; 7 yearsfor cats, dogs and monkeys).

F3 = 1 for reproductive studies in which the whole period of organogenesis is covered.F3 = 2 for a 6-month study in rodents, or a 3.5-year study in nonrodents.F3 = 5 for a 3-month study in rodents, or a 2-year study in nonrodents.F3 = 10 for studies of a shorter duration.

In all cases, the higher factor has been used for study durations between the time points (e.g., afactor of 2 for a 9-month rodent study).

F4 = A factor that may be applied in cases of severe toxicity (e.g., nongenotoxic carcinogenicity,neurotoxicity or teratogenicity). In studies of reproductive toxicity, the following factors are used:

F4 = 1 for fetal toxicity associated with maternal toxicity.F4 = 5 for fetal toxicity without maternal toxicity.F4 = 5 for a teratogenic effect with maternal toxicity.F4 = 10 for a teratogenic effect without maternal toxicity.

F5 = A variable factor that may be applied if the NOEL was not established.

When only an LOEL is available, a factor of up to 10 could be used depending on the severity ofthe toxicity.

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The weight adjustment assumes an arbitrary adult human body weight for either sex of 50

kilograms (kg). This relatively low weight provides an additional safety factor against the standardweights of 60 kg or 70 kg that are often used in this type of calculation. It is recognized that someadult patients weigh less than 50 kg; these patients are considered to be accommodated by thebuilt-in safety factors used to determine a PDE. If the solvent was present in a formulationspecifically intended for pediatric use, an adjustment for a lower body weight would beappropriate.

As an example of the application of this equation, consider a toxicity study of acetonitrile in micethat is summarized in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997, page S24. The NOELis calculated to be 50.7 mg kg-1 day-1. The PDE for acetonitrile in this study is calculated asfollows:

50.7 mg kg-1 day-1 x 50 kgPDE = 12 x 10 x 5 x 1 x 1 = 4.22 mg day-1

In this example,

F1 = 12 to account for the extrapolation from mice to humans.F2 = 10 to account for differences between individual humans.F3 = 5 because the duration of the study was only 13 weeks.F4 = 1 because no severe toxicity was encountered.F5 = 1 because the NOEL was determined.

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Table A3.1 – Values Used in the Calculations in This Document

Rat body weightPregnant rat body weightMouse body weightPregnant mouse body weightGuinea pig body weightRhesus monkey body weightRabbit body weight(pregnant or not)Beagle dog body weightRat respiratory volume

425 g330 g28 g30 g500 g2.5 kg4 kg11.5 kg290 L/day

Mouse respiratory volumeRabbit respiratory volumeGuinea pig respiratory volumeHuman respiratory volumeDog respiratory volumeMonkey respiratory volumeMouse water consumptionRat water consumptionRat food consumption

43 liter(L)/day1,440 L/day430 L/day28,800 L/day9,000 L/day1,150 L/day5 milliliter(mL)/day30 mL/day30 g/day

The equation for an ideal gas, PV = nRT, is used to convert concentrations of gases used ininhalation studies from units of ppm to units of mg/L or mg/cubic meter (m3). Consider as an

example the rat reproductive toxicity study by inhalation of carbon tetrachloride (molecular weight153.84) summarized in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997, page S9.

n = P = 300 x 10-6 atm x 153840 mg mol-1 = 46.15 mg = 1. mg/LV RT 0.082 L atm K-1 mol-1 x 298 K 24.45 L

The relationship 1000 L = 1 m3 is used to convert to mg/m3.

13

Guidance for Industry

Q3C — Tables and List

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)

November 2003

ICH

Revision 1

Guidance for Industry

Q3C — Tables and List

Additional copies are available from:

Center for Drug Evaluation and Research (CDER)

Division of Drug Information (HFD-240)

Food and Drug Administration

5600 Fishers Lane Rockville, MD 20857(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htmor

Office of Communication, Training, andManufacturers Assistance (HFM-40)

Center for Biologics Evaluation and Research (CBER)

Food and Drug Administration

1401 Rockville Pike Rockville, MD 20852-1448

http://www.fda.gov/cber/guidelines.htm;(Tel) Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)

November 2003

ICH

Revision 1

Contains Nonbinding Recommendations

Guidance for Industry1Q3C — Tables and List

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. Itdoes not create or confer any rights for or on any person and does not operate to bind FDA or the public.You can use an alternative approach if that approach satisfies the requirements of the applicable statutesand regulations. If you want to discuss an alternative approach, contact the FDA staff responsible forimplementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriatenumber listed on the title page of this guidance.

I.INTRODUCTION

This is the companion document for the International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use (ICH) guidance for industryQ3C Impurities: Residual Solvents (1997), which makes recommendations as to what amounts ofresidual solvents are considered safe in pharmaceuticals.

This document may be updated if proposals for change are submitted to the InternationalConference on Harmonisation (ICH) Steering Committee. Proposals for change and the ICHSteering Committee final decision on any proposed changes will be announced through a noticein the Federal Register prior to the updating of this document.

FDA's guidance documents, including this guidance, do not establish legally enforceable

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and shouldbe viewed only as recommendations, unless specific regulatory or statutory requirements arecited. The use of the word should in Agency guidances means that something is suggested orrecommended, but not required.

1

This document was developed within the Expert Working Group (Quality) of the International

Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This documentwas endorsed by the ICH Steering Committee at Step 4 of the ICH process in July 1997. At Step 4 of the process,the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the UnitedStates. This guidance was published in the Federal Register on December 24, 1997 (62 FR67377), and isapplicable to drug and biological products.

1

Contains Nonbinding Recommendations

II.LIST OF SOLVENTS INCLUDED IN THE Q3C GUIDANCE

Solvent Acetic acidAcetoneAcetonitrileAnisoleBenzene1-Butanol2-ButanolButyl acetatetert-Butylmethyl etherCarbon tetrachlorideChlorobenzeneChloroformCumeneCyclohexane1,2-Dichloroethane1,1-DichloroetheneOther NamesEthanoic acid2-PropanonePropan-2-oneMethoxybenzeneBenzoln-Butyl alcoholButan-1-olsec-Butyl alcoholButan-2-olAcetic acid butyl ester2-Methoxy-2-methyl-propaneTetrachloromethaneTrichloromethaneIsopropylbenzene(1-Methyl)ethylbenzeneHexamethylenesym-DichloroethaneEthylene dichlorideEthylene chloride1,1-DichloroethyleneVinylidene chloride2

Structure CH3COOHCH3COCH3CH3CNCH3(CH2)3OHCH3CH2CH(OH)CH3CH3COO(CH2)3CH3(CH3)3COCH3CCl4CHCl3C6H5-CH(CH3)2CH2ClCH2ClH2C=CCl2ClassClass 3Class 3Class 2Class 3Class 1Class 3Class 3Class 3Class 3Class 1Class 2Class 2Class 3Class 2Class 1Class 1Contains Nonbinding Recommendations

1,2-DichloroetheneDichloromethane1,2-DimethoxyethaneN,N-DimethylacetamideN,N- DimethylformamideDimethyl sulfoxide1,4-DioxaneEthanol2-EthoxyethanolEthyl acetateEthyleneglycolEthyl etherEthyl formateFormamideFormic acidHeptaneHexaneIsobutyl acetateIsopropyl acetateMethanol2-MethoxyethanolMethyl acetate1,2-DichloroethyleneAcetylene dichlorideMethylene chlorideEthyleneglycol dimethyl etherMonoglymeDimethyl CellosolveDMADMFMethylsulfinylmethaneMethyl sulfoxideDMSOp-Dioxane[1,4]DioxaneEthyl alcoholCellosolveAcetic acid ethyl ester1,2-Dihydroxyethane1,2-EthanediolDiethyl etherEthoxyethane1,1’-OxybisethaneFormic acid ethyl esterMethanamiden-Heptanen-HexaneAcetic acid isobutyl esterAcetic acid isopropyl esterMethyl alcoholMethyl CellosolveAcetic acid methyl ester3

ClHC=CHClCH2Cl2H3COCH2CH2OCH3CH3CON(CH3)2HCON(CH3)2(CH3)2SOCH3CH2OHCH3CH2OCH2CH2OHCH3COOCH2CH3HOCH2CH2OHCH3CH2OCH2CH3HCOOCH2CH3HCONH2HCOOHCH3(CH2)5CH3CH3(CH2)4CH3CH3COOCH2CH(CH3)2CH3COOCH(CH3)2CH3OHCH3OCH2CH2OHCH3COOCH3Class 2Class 2Class 2Class 2Class 2Class 3Class 2Class 3Class 2Class 3Class 2Class 3Class 3Class 2Class 3Class 3Class 2Class 3Class 3Class 2Class 2Class 3Contains Nonbinding Recommendations

3-Methyl-1-butanolMethylbutyl ketoneMethylcyclohexaneMethylethyl ketoneMethylisobutyl ketone2-Methyl-1-propanolN-MethylpyrrolidoneNitromethanePentane1-Pentanol1-Propanol2-PropanolPropyl acetatePyridineSulfolaneTetrahydrofuranTetralinToluene1,1,1-TrichloroethaneIsoamyl alcoholIsopentyl alcohol3-Methylbutan-1-ol2-HexanoneHexan-2-oneCyclohexylmethane2-ButanoneMEKButan-2-one4-Methylpentan-2-one4-Methyl-2-pentanoneMIBKIsobutyl alcohol2-Methylpropan-1-ol1-Methylpyrrolidin-2-one1-Methyl-2-pyrrolidinonen-PentaneAmyl alcoholPentan-1-olPentyl alcoholPropan-1-olPropyl alcoholPropan-2-olIsopropyl alcoholAcetic acid propyl esterTetrahydrothiophene 1,1-dioxideTetramethylene oxideOxacyclopentane1,2,3,4-Tetrahydro-naphthaleneMethylbenzeneMethylchloroform4

(CH3)2CHCH2CH2OHCH3(CH2)3COCH3CH3CH2COCH3CH3COCH2CH(CH3)2(CH3)2CHCH2OHCH3NO2CH3(CH2)3CH3CH3(CH2)3CH2OHCH3CH2CH2OH(CH3)2CHOHCH3COOCH2CH2CH3CH3CCl3Class 3Class 2Class 2Class 3Class 3Class 3Class 2Class 2Class 3Class 3Class 3Class 3Class 3Class 2Class 2Class 2Class 2Class 2Class 1Contains Nonbinding Recommendations

1,1,2-TrichloroetheneXylene11TrichloroetheneDimethybenzeneXylolHClC=CCl2Class 2Class 2Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.III.SOLVENTS GROUPED BY CLASS

Solvents in Class 1 (Table 1) should not be employed in the manufacture of drug substances,excipients, and drug products because of their unacceptable toxicity or their deleterious

environmental effect. However, if their use is unavoidable in order to produce a drug productwith a significant therapeutic advance, then their levels should be restricted as shown in Table 1,unless otherwise justified. The solvent 1,1,1-Trichloroethane is included in Table 1 because it isan environmental hazard. The stated limit of 1,500 ppm is based on a review of the safety data.

Table 1. – Class 1 Solvents in Pharmaceutical Products (Solvents That Should Be Avoided)

SolventConcentration Limit(ppm) 2 4 5 81,500ConcernBenzeneCarbon tetrachloride1,2-Dichloroethane1,1-Dichloroethene1,1,1-TrichloroethaneCarcinogenToxic and environmental hazardToxicToxicEnvironmental hazard5

Contains Nonbinding Recommendations

Solvents in Class 2 (Table 2) should be limited in pharmaceutical products because of theirinherent toxicity. PDEs are given to the nearest 0.1 mg/day, and concentrations are given to thenearest 10 ppm. The stated values do not reflect the necessary analytical precision ofdetermination. Precision should be determined as part of the validation of the method.

Table 2. – Class 2 Solvents in Pharmaceutical Products

Solvent

PDE (mg/day) Concentration Limit (ppm)Acetonitrile4.1

Chlorobenzene3.6Chloroform0.6Cyclohexane38.81,2-Dichloroethene18.7Dichloromethane6.01,2-Dimethoxyethane1.0N,N-Dimethylacetamide10.9N,N-Dimethylformamide8.81,4-Dioxane3.82-Ethoxyethanol1.6Ethyleneglycol6.2Formamide2.2Hexane2.9Methanol30.02-Methoxyethanol0.5Methylbutyl ketone0.5Methylcyclohexane11.8N-Methylpyrrolidone5.3Nitromethane0.5Pyridine2.0Sulfolane1.6

Tetrahydrofuran 7.2

720

Tetralin1.0Toluene

8.91,1,2-Trichloroethene0.8Xylene1

21.7

1

Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.

6

410

360

60

3,8801,8706001001,0908803801606202202903,00050501,18053050200160

1000802,170

Contains Nonbinding Recommendations

Solvents in Class 3 (Table 3) may be regarded as less toxic and of lower risk to human health.Class 3 includes no solvent known as a human health hazard at levels normally accepted inpharmaceuticals. However, there are no long-term toxicity or carcinogenicity studies for manyof the solvents in Class 3. Available data indicate that they are less toxic in acute or short-termstudies and negative in genotoxicity studies. It is considered that amounts of these residualsolvents of 50 mg per day or less (corresponding to 5,000 ppm or 0.5 percent under Option 1)would be acceptable without justification. Higher amounts may also be acceptable provided theyare realistic in relation to manufacturing capability and good manufacturing practice (GMP).

Table 3. – Class 3 Solvents Which Should Be Limited by GMP or Other Quality-Based

Requirements

Acetic acidAcetoneAnisole1-Butanol2-ButanolButyl acetatetert-Butylmethyl etherCumene

Dimethyl sulfoxideEthanolEthyl acetateEthyl etherEthyl formateFormic acid

HeptaneIsobutyl acetateIsopropyl acetateMethyl acetate3-Methyl-1-butanolMethylethyl ketoneMethylisobutyl ketone2-Methyl-1-propanolPentane1-Pentanol1-Propanol2-PropanolPropyl acetate

7

Contains Nonbinding Recommendations

The solvents listed in Table 4 may also be of interest to manufacturers of excipients, drug

substances, or drug products. However, no adequate toxicological data on which to base a PDEwere found. Manufacturers should supply justification for residual levels of these solvents inpharmaceutical products.

Table 4. – Solvents for Which No Adequate Toxicological Data Were Found

1,1-Diethoxypropane1,1-Dimethoxymethane2,2-DimethoxypropaneIsooctaneIsopropyl ether

Methylisopropyl ketoneMethyltetrahydrofuranPetroleum etherTrichloroacetic acidTrifluoroacetic acid

8