Q3c杂质:残留溶剂的指导原则

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Q3C R2概念性指南

Q3C R2概念性指南

人用药品注册技术要求国际协调会
ICH三方协调指导原则
最终概念性指南
Q3C:杂质:残留溶剂指导原则
指导委员会于1994年3月10日批准发布
问题申明/目的
大体上,法规中并没有对药物制剂中残留溶剂(有机挥发性杂质)定性及定量及制剂中赋形剂的要求有全面的界定。

背景/现状
1993年10月在奥兰多的第二次国际协调会议上,对有关杂质的问题引起了广泛的兴趣和争论。

质量方面的专家工作组正努力建立药物制剂中杂质的指导原则以解决杂质的标准性问题。

毒理学家也参与了对与工艺相关的杂质的毒性研究。

对于有机会挥发性杂质,如残留溶剂的限度水平的界定问题仍亟待解决。

目前,不同的法规部门及药典对其限定不一,但普遍期望能对其建立一个单独的限度规定。

药典中已经对残留溶剂的控制方法进行了研究。

然而,ICH专家工作组和药典对残留溶剂各自的研究结果需要通过后期的协商达成一致,所以期待有其他的组织能参与到该项研究中。

影响
残留溶剂的限度列表及各地区对这些溶剂的限度要求有所不同(如注册申请中得出的结论、美国药典、欧洲药典、及日本药典中的不同建议值)。

这意味着不确定性及工业化生产的重复工作。

时间轴
目前对于杂质研究的ICH专家工作组由化学家和毒理学家组成,与来自药典委员会的专
家,如美国药典修正委员会、欧洲药典委员会及日本药典委员会等共同协作。

残留溶剂的指导原则

残留溶剂的指导原则

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)应限制使用,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。

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。

ichq3c溶剂残留指导原则

ichq3c溶剂残留指导原则

ichq3c溶剂残留指导原则?
答:ICH Q3C是国际药品注册协调委员会(International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use,简称ICH)发布的一系列指导原则之一。

ICH Q3C溶剂残留指导原则旨在提供关于制药产品中有机溶剂残留限量的建议和指导。

这些指导原则主要适用于药品开发和注册过程中的有
机溶剂残留问题,并帮助制药行业确保药品制造过程中使用的有机溶剂不对人体产生不良影响。

ICH Q3C溶剂残留指导原则分为三个部分:
1.ICH Q3C(R6):这个文档提供了关于食品和药品制品中有机溶剂残留限量的概述和指南。

它包含了各种有机溶剂的分类、评估方法和安全性评价。

2.ICH Q3C(R8):这个文档是对Q3C(R6)的更新版本,添加了关于新的有机溶剂的信息,包括氯仿和四氢呋喃等。

3.ICH Q3C(R7):这个文档是对Q3C(R6)的进一步更新版本,修订了关于有机溶剂分类和限量的一些内容。

根据ICH Q3C溶剂残留指导原则,制药企业需要进行有机溶剂残留评估,并确保其产品中的有机溶剂残留量在国际上接受的安全水平范围内。

这有助于确保药品的质量、安全性和有效性。

请注意,具体的有机溶剂残留限量要求可能因地区和国家而异,制药企业在制定和执行相关政策时应考虑当地法规和准则。

ICH Q C R 残留溶剂 培训

ICH Q C R 残留溶剂 培训

PDE(Permitted Daily Exposure)
每日允许暴露量 指药物中残留溶剂每日可接受的最大摄入量
• 认为这些限度适用于所有原料药、辅料和制剂。 •因此,若日摄入总量未知或未定,可采用这种方法。 •若处方中的所有辅料及原料药都符合限度,则这些组分可按任意比例使用。 •只要日摄入总量不超过 10g,就无须进一步计算。
• 对人体低潜在毒性的溶剂,无须制定基于健康的暴露限度。3类溶剂的PDE为每天50mg或 50mg以上
LIMITS 残留溶剂的限度
• ICH Q3C(R6)与《中国药典》(2015年)的对比
Ⅰ类溶剂限度
ICH Q3C(R6)与ChP 2015 四部 0861 中的Ⅰ类溶剂,种类与限度均一致 注意:1,1,1-三氯乙烷:限度高,但是属于Ⅰ类溶剂。
– 2、异丙基苯(Ⅲ类 → Ⅱ类)
CALCULATED 残留溶剂限度计算与检测 DETECTED
• ICH Q3C(R6)提供计算方法 • 采用气相色谱法或干燥失重测定法进行检测
残留溶剂限度计算
• 残留溶剂限度是如何计算的?


(ppm)
1000

PDE(mg / day) 量(g / day)
组分 原料药 辅料1 辅料2
制剂
在处方中的量 0.3g 0.9g 3.8g 5.0g
乙腈的含量 800ppm 400ppm 800ppm 728ppm
日暴露量 0.24mg 0.36mg 3.04mg 3.64mg
超限(410ppm)
超限(410ppm)
合格(低于4.1mg/day)
残留溶剂的检测方法
ICH Q3C 分享与交流 ICH Q3C(R6) 杂质:残留溶剂的指导原则 培训师:XR.Kong

残留溶剂的指导原则 q3c(r8)

残留溶剂的指导原则 q3c(r8)

残留溶剂的指导原则 q3c(r8)下载提示:该文档是本店铺精心编制而成的,希望大家下载后,能够帮助大家解决实际问题。

文档下载后可定制修改,请根据实际需要进行调整和使用,谢谢!本店铺为大家提供各种类型的实用资料,如教育随笔、日记赏析、句子摘抄、古诗大全、经典美文、话题作文、工作总结、词语解析、文案摘录、其他资料等等,想了解不同资料格式和写法,敬请关注!Download tips: This document is carefully compiled by this editor. I hope that after you download it, it can help you solve practical problems. The document can be customized and modified after downloading, please adjust and use it according to actual needs, thank you! In addition, this shop provides you with various types of practical materials, such as educational essays, diary appreciation, sentence excerpts, ancient poems, classic articles, topic composition, work summary, word parsing, copy excerpts, other materials and so on, want to know different data formats and writing methods, please pay attention!残留溶剂的指导原则 Q3C(R8)残留溶剂是指工艺过程中无法完全去除的有机化合物。

残留溶剂指导原则ICHQ3CR5

残留溶剂指导原则ICHQ3CR5

August 2011EMA/CHMP/ICH/82260/2006ICH guideline Q3C (R5) on impurities: guideline for residual solventsStep 5Part I (Parent guideline)Transmission to CHMP November 1996 Adoption by CHMP for release for consultation November 1996 End of consultation (deadline for comments) May 1997 Final adoption by CHMP September 1997 Date for coming into effect March 1998 Part II and part III (PDE for Tetrahydrofuran and N-Methylpyrrolidone)Transmission to CHMP July 2000 Adoption by CHMP for release for consultation July 2000 End of consultation (deadline for comments) September 2000 Final adoption by CHMP September 2002 Corrigendum to calculation formula for NMP November 2002 Transmission to CHMP March 2003February 2009 Update of table 2, table 3 and appendix 1 to reflect therevision of the PDEs for N-Methylpyrrolidone andTetrahydrofuran Q3C(R4)Part IV (PDE for cumene)Transmission to CHMP June 2010 Adoption by CHMP for release for consultation June 20107 Westferry Circus ● Canary Wharf ● London E14 4HB ● United KingdomEnd of consultation (deadline for comments) September 2010 Final adoption by CHMP March 2011 Date for coming into effect August 2011Q3C (R5) on impurities: guideline for residual solventsTable of contentsPart I (4)Impurities: Residual solvents - Parent guideline (4)1. Introduction (4)2. Scope of the guideline (4)3. General principles (5)3.1. Classification of residual solvents by risk assessment (5)3.2. Methods for establishing exposure limits (5)3.3. Options for describing limits of class 2 solvents (6)3.4. Analytical procedures (7)3.5. Reporting levels of residual solvents (7)4. Limits of residual solvents (8)4.1. Solvents to be avoided (8)4.2. Solvents to be limited (8)4.3. Solvents with low toxic potential (9)4.4. Solvents for which no adequate toxicological data was found (10)Glossary (11)Appendix 1: List of solvents included in the guideline (12)Appendix 2: Additional background (16)Appendix 3: Methods for establishing exposure limits (17)PART II: (20)PDE for Tetrahydrofuran (20)PART III: (22)PDE for N-Methylpyrrolidone (NMP) (22)PART IV (24)PDE for cumene (24)Part IImpurities: Residual solvents - Parent guideline1. IntroductionThe objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents. Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. 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, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical parameter in the synthetic process. This guideline does not address solvents deliberately used as excipients nor does it address solvates. However, the content of solvents in such products should be evaluated and justified.Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other 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 unacceptable toxicities (Class 1, Table 1) should be avoided in the production of drug substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment. Some solvents associated with less severe toxicity (Class 2, Table 2) should be limited in order to protect patients from potential adverse effects. Ideally, less toxic solvents (Class 3, Table 3) should be used where practical. The complete list of solvents included in this guideline is given in Appendix 1.The lists are not exhaustive and other solvents can be used and later added to the lists. Recommended limits of Class 1 and 2 solvents or classification of solvents may change as new safety data becomes available. Supporting safety data in a marketing application for a new drug product containing a new solvent may be based on concepts in this guideline or the concept of qualification of impurities as expressed in the guideline for drug substance (Q3A, Impurities in New Drug Substances) or drug product (Q3B, Impurities in New Drug Products), or all three guidelines.2. Scope of the guidelineResidual solvents in drug substances, excipients, and in drug products are within the scope of this guideline. 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 to test for solvents that are used or produced in the manufacture or purification of drug substances, excipients, or drug product. Although manufacturers may choose to test the drug product, a cumulative method may be used to calculate the residual solvent levels in the drug product from the levels in the ingredients used to produce the drug product. If the calculation results in a level equal to or below that recommended in this guideline, no testing of the drug product for residual solvents 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 a solvent is used during its manufacture.This guideline does not apply to potential new drug substances, excipients, or drug products used during the clinical research stages of development, nor does it apply to existing marketed drug products.The guideline applies to all dosage forms and routes of administration. Higher levels of residual solvents may be acceptable in certain cases such as short term (30 days or less) or topical application. Justification for these levels should be made on a case by case basis.See Appendix 2 for additional background information related to residual solvents.3. General principles3.1. Classification of residual solvents by risk assessmentThe term "tolerable daily intake" (TDI) is used by the International Program on Chemical Safety (IPCS) to describe exposure limits of toxic chemicals and "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 present guideline as a pharmaceutically acceptable intake of residual solvents to avoid confusion of differing values for ADI's of the same substance.Residual solvents assessed in this guideline are listed in Appendix 1 by common names and structures. They were evaluated for their possible risk to human health and placed into one of three classes as follows:Class 1 solvents: Solvents to be avoidedKnown human carcinogens, strongly suspected human carcinogens, and environmental hazards. Class 2 solvents: Solvents to be limitedNon-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity.Solvents suspected of other significant but reversible toxicities.Class 3 solvents: Solvents with low toxic potentialSolvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per day.3.2. Methods for establishing exposure limitsThe method used to establish permitted daily exposures for residual solvents is presented in Appendix 3. Summaries of the toxicity data that were used to establish limits are published in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997.3.3. Options for describing limits of class 2 solventsTwo options are available when setting limits for Class 2 solvents.Option 1: The concentration limits in ppm stated in Table 2 can be used. They were calculated using equation (1) below by assuming a product mass of 10 g administered daily. Concentration (ppm) = 1000 x PDE(1)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 this option may be applied if the daily dose is not known or fixed. If all excipients and drug substances in a formulation meet the limits given in Option 1, then these components may be used in any proportion. 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 under Option 2.Option 2: It is not considered necessary for each component of the drug product to comply with the limits given in Option 1. The PDE in terms of mg/day as stated in Table 2 can be used with the known maximum daily dose and equation (1) above to determine the 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 the practical minimum. The limits should be realistic in relation to analytical precision, manufacturing capability, reasonable variation in the manufacturing process, and the limits should reflect contemporary 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 that given 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 contains two excipients. The composition of the drug product and the calculated maximum content of residual acetonitrile are given in the following table.Acetonitrile content Daily exposure Component Amount informulationDrug substance 0.3 g 800 ppm 0.24 mgExcipient 1 0.9 g 400 ppm 0.36 mgExcipient 2 3.8 g 800 ppm 3.04 mgDrug Product 5.0 g 728 ppm 3.64 mgExcipient 1 meets the Option 1 limit, but the drug substance, excipient 2, and drug product do not meet the Option 1 limit. Nevertheless, the product meets the Option 2 limit of 4.1 mg per day and thus conforms to the recommendations in this guideline.Consider another example using acetonitrile as residual solvent. The maximum administered daily mass of a drug product is 5.0 g, and the drug product contains two excipients. The composition of the drug product and the calculated maximum content of residual acetonitrile is given in the following table.Acetonitrile content Daily exposure Component Amount informulationDrug substance 0.3 g 800 ppm 0.24 mgExcipient 1 0.9 g 2000 ppm 1.80 mgExcipient 2 3.8 g 800 ppm 3.04 mgDrug Product 5.0 g 1016 ppm 5.08 mgIn this example, the product meets neither the Option 1 nor the Option 2 limit according to this summation. The manufacturer could test the drug product to determine if the formulation process reduced the level of acetonitrile. If the level of acetonitrile was not reduced during formulation to the allowed limit, then the manufacturer of the drug product should take other steps to reduce the amount of acetonitrile in the drug product. If all of these steps fail to reduce the level of residual solvent, in exceptional cases the manufacturer could provide a summary of efforts made to reduce the solvent level to meet the guideline value, and provide a risk-benefit analysis to support allowing the product to be utilised with residual solvent at a higher level.3.4. Analytical proceduresResidual solvents are typically determined using chromatographic techniques such as gas chromatography. Any harmonised procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure for a particular application. If only Class 3 solvents are present, a non-specific method such as loss on drying may be used. Validation of methods for residual solvents should conform to ICH guidelines Text on Validation of Analytical Procedures and Extension of the ICH Text on Validation of Analytical Procedures.3.5. Reporting levels of residual solventsManufacturers of pharmaceutical products need certain information about the content of residual solvents in excipients or drug substances in order to meet the criteria of this guideline. The following statements are given as acceptable examples of the information that could be provided from a supplier of excipients or drug substances to a pharmaceutical manufacturer. The supplier might choose one of the following as appropriate:Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5%.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. Residual Class 2 solvents are below the Option 1 limit and residual Class 3 solvents are below 0.5%.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 that are 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%, respectively, they should be identified and quantified.4. Limits of residual solvents4.1. Solvents to be avoidedSolvents in Class 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 product with a significant therapeutic advance, then their levels should be restricted as shown in Table 1, unless otherwise justified. 1,1,1-Trichloroethane is included in Table 1 because it is an environmental hazard. The stated limit of 1500 ppm is based on a review of the safety data.TABLE 1. Class 1 solvents in pharmaceutical products (solvents that should be avoided).Solvent Concentration limitConcern(ppm)Benzene 2 CarcinogenCarbon tetrachloride 4 Toxic and environmental hazard1,2-Dichloroethane 5 Toxic1,1-Dichloroethene 8 Toxic1,1,1-Trichloroethane 1500 Environmental hazard4.2. Solvents to be limitedSolvents in Table 2 should be limited in pharmaceutical products because of their inherent toxicity. PDEs are given to the nearest 0.1 mg/day, and concentrations are given to the nearest 10 ppm. The stated values do not reflect the necessary analytical precision of determination. 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)Acetonitrile 4.1 410Chlorobenzene 3.6 360Chloroform 0.6 60Cyclohexane 38.8 38801,2-Dichloroethene 18.7 1870Dichloromethane 6.0 6001,2-Dimethoxyethane 1.0 100N,N-Dimethylacetamide 10.9 1090N,N-Dimethylformamide 8.8 8801,4-Dioxane 3.8 3802-Ethoxyethanol 1.6 160Ethyleneglycol 6.2 620Formamide 2.2 220Hexane 2.9 290Methanol 30.0 30002-Methoxyethanol 0.5 50Methylbutyl ketone 0.5 50Methylcyclohexane 11.8 1180N-Methylpyrrolidone1 5.3 530Nitromethane 0.5 50Pyridine 2.0 200Sulfolane 1.6 160Tetrahydrofuran27.2 720Tetralin 1.0 100Toluene 8.9 8901,1,2-Trichloroethene 0.8 80Xylene* 21.7 2170*usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene4.3. Solvents with low toxic potentialSolvents in Class 3 (shown in 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 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 are less toxic in acute or short-term studies and negative in genotoxicity studies. It is considered that amounts of these residual solvents of 50 mg per day or less (corresponding to 5000 ppm or 0.5% under Option 1) would be acceptable without justification. Higher amounts may also be acceptable provided they are realistic in relation to manufacturing capability and good manufacturing practice.Table 3: Class 3 solvents which should be limited by GMP or other quality-based requirements. Acetic acid HeptaneAcetone Isobutyl acetateAnisole Isopropyl acetate1 The information included for N-Methylpyrrolidone reflects that included in the Revision of PDE Information for NMP which reached Step 4 in September 2002 (two mistyping corrections made in October 2002), and was incorporated into the core guideline in November 2005. See Part III (pages 20-21).2 The information included for Tetrahydrofuran reflects that included in the Revision of PDE Information for THF which reached Step 4 in September 2002, and was incorporated into the core guideline in November 2005. See Part II (pages 18-19).1-Butanol Methyl acetate2-Butanol 3-Methyl-1-butanolButyl acetate Methylethyl ketonetert-Butylmethyl ether Methylisobutyl ketoneCumene 2-Methyl-1-propanolDimethyl sulfoxide PentaneEthanol 1-PentanolEthyl acetate 1-PropanolEthyl ether 2-PropanolEthyl formate Propyl acetateFormic acid4.4. Solvents for which no adequate toxicological data was foundThe following solvents (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 PDE was found. Manufacturers should supply justification for residual levels of these solvents in pharmaceutical products.Table 4 Solvents for which no adequate toxicological data was found.1,1-Diethoxypropane Methylisopropyl ketone1,1-Dimethoxymethane Methyltetrahydrofuran2,2-Dimethoxypropane Petroleum etherIsooctane Trichloroacetic acidIsopropyl ether Trifluoroacetic acidGlossaryGenotoxic Carcinogens:Carcinogens which 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 that produces biologically significant increases in frequency or severity of any effects in the exposed humans or animals.Modifying Factor:A factor determined by professional judgment of a toxicologist and applied to bioassay 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 biologically significant 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 in pharmaceutical products. Reversible Toxicity:The occurrence of harmful effects that are caused by a substance and which disappear after exposure to the substance ends.Strongly Suspected Human Carcinogen:A substance for which there is no epidemiological evidence of carcinogenesis but there are positive genotoxicity data and clear evidence of carcinogenesis in rodents.Teratogenicity:The occurrence of structural malformations in a developing fetus when a substance is administered during pregnancy.Appendix 1: List of solvents included in the guideline Solvent Other Names Structure Class Acetic acid Ethanoic acid CH3COOH Class 3Acetone 2-PropanoneCH3COCH3 Class 3Propan-2-oneAcetonitrile CH3CN Class 2Anisole Methoxybenzene OCHClass 33Benzene Benzol Class 11-Butanol n-Butyl alcoholCH3(CH2)3OH Class 3Butan-1-olCH3CH2CH(OH)CH3 Class 3 2-Butanol sec-Butyl alcoholButan-2-olButyl acetate Acetic acid butyl ester CH3COO(CH2)3CH3 Class 3tert-Butylmethyl ether 2-Methoxy-2-methyl- propane (CH3)3COCH3 Class 3Carbon tetrachloride Tetrachloromethane CCl4 Class 1Chlorobenzene Cl Class 2Chloroform Trichloromethane CHCl3 Class 2Cumene IsopropylbenzeneCH(CH3)2Class 3(1-Methyl)ethylbenzeneCyclohexane Hexamethylene Class 2CH2ClCH2Cl Class 1 1,2-Dichloroethane sym-DichloroethaneEthylene dichlorideEthylene chloride1,1-Dichloroethene 1,1-DichloroethyleneH2C=CCl2 Class 1Vinylidene chloride1,2-Dichloroethene 1,2-DichloroethyleneClHC=CHCl Class 2Acetylene dichlorideDichloromethane Methylene chloride CH2Cl2 Class 2H3COCH2CH2OCH3 Class 2 1,2-Dimethoxyethane Ethyleneglycol dimethyl etherMonoglymeDimethyl CellosolveN,N-Dimethylacetamide DMA CH3CON(CH3)2 Class 2 N,N-Dimethylformamide DMF HCON(CH3)2 Class 2(CH3)2SO Class 3 Dimethyl sulfoxide MethylsulfinylmethaneMethyl sulfoxideDMSO1,4-Dioxane p-DioxaneO O Class 2[1,4]DioxaneEthanol Ethyl alcohol CH3CH2OH Class 3 2-Ethoxyethanol Cellosolve CH3CH2OCH2CH2OH Class 2 Ethyl acetate Acetic acid ethyl ester CH3COOCH2CH3 Class 3HOCH2CH2OH Class 2 Ethyleneglycol 1,2-Dihydroxyethane1,2-EthanediolCH3CH2OCH2CH3 Class 3 Ethyl ether Diethyl etherEthoxyethane1,1’-OxybisethaneEthyl formate Formic acid ethyl ester HCOOCH2CH3 Class 3 Formamide Methanamide HCONH2 Class 2 Formic acid HCOOH Class 3 Heptane n-Heptane CH3(CH2)5CH3 Class 3Hexane n-Hexane CH3(CH2)4CH3 Class 2Isobutyl acetate Acetic acid isobutyl ester CH3COOCH2CH(CH3)2 Class 3 Isopropyl acetate Acetic acid isopropyl ester CH3COOCH(CH3)2 Class 3 Methanol Methyl alcohol CH3OH Class 2 2-Methoxyethanol Methyl Cellosolve CH3OCH2CH2OH Class 2 Methyl acetate Acetic acid methyl ester CH3COOCH3 Class 33-Methyl-1-butanol Isoamyl alcoholIsopentyl alcohol3-Methylbutan-1-ol(CH3)2CHCH2CH2OH Class 3Methylbutyl ketone 2-HexanoneHexan-2-oneCH3(CH2)3COCH3 Class 2Methylcyclohexane Cyclohexylmethane CH3Class 2 Methylethyl ketone 2-ButanoneMEKButan-2-oneCH3CH2COCH3 Class 3Methylisobutyl ketone 4-Methylpentan-2-one4-Methyl-2-pentanoneMIBKCH3COCH2CH(CH3)2 Class 32-Methyl-1-propanol Isobutyl alcohol2-Methylpropan-1-ol(CH3)2CHCH2OH Class 3 N-Methylpyrrolidone 1-Methylpyrrolidin-2-one1-Methyl-2-pyrrolidinone NCH3OClass 2Nitromethane CH3NO2 Class 2 Pentane n-Pentane CH3(CH2)3CH3 Class 3 1-Pentanol Amyl alcohol CH3(CH2)3CH2OH Class 3Pentan-1-olPentyl alcohol1-Propanol Propan-1-olPropyl alcoholCH3CH2CH2OH Class 32-Propanol Propan-2-olIsopropyl alcohol(CH3)2CHOH Class 3 Propyl acetate Acetic acid propyl ester CH3COOCH2CH2CH3 Class 3PyridineNClass 2Sulfolane Tetrahydrothiophene 1,1-dioxideSO OClass 2Tetrahydrofuran1Tetramethylene oxideOxacyclopentane OClass 2Tetralin 1,2,3,4-Tetrahydro-naphthalene Class 2Toluene Methylbenzene CH3Class 2 1,1,1-Trichloroethane Methylchloroform CH3CCl3 Class 1 1,1,2-Trichloroethene Trichloroethene HClC=CCl2 Class 2Xylene* DimethybenzeneXylolCH3CH3Class 2*usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene1 The information included for Tetrahydrofuran reflects that included in the Revision of PDE Information for THF which reached Step 4 in September 2002, and was incorporated into the core guideline in November 2005. See Part II (pages 18-19).Appendix 2: Additional backgroundA2.1 Environmental Regulation of Organic Volatile SolventsSeveral of the residual solvents frequently used in the production of pharmaceuticals are listed as toxic chemicals in Environmental Health Criteria (EHC) monographs and the Integrated Risk Information System (IRIS). The objectives of such groups as the International Programme on Chemical Safety (IPCS), the United States Environmental Protection Agency (USEPA), and the United States Food and Drug Administration (USFDA) include the determination of acceptable exposure levels. The goal is protection of human health and maintenance of environmental integrity against the possible deleterious effects of chemicals resulting from long-term environmental exposure. The methods involved 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 modification of the approach such as use of larger safety factors. The approach described therein relates primarily to long-term or life-time exposure of the general population in the ambient environment, i.e. ambient air, food, drinking water and other media.A2.2 Residual Solvents in PharmaceuticalsExposure limits in this guideline are established by referring to methodologies and toxicity data described in EHC and IRIS monographs. However, some specific assumptions about residual solvents to be used in the synthesis and formulation of pharmaceutical products should be taken into account in establishing exposure limits. They are:1) Patients (not the general population) use pharmaceuticals to treat their diseases or forprophylaxis to prevent infection or disease.2) The assumption of life-time patient exposure is not necessary for most pharmaceuticalproducts but may be appropriate as a working hypothesis to reduce risk to human health.3) Residual solvents are unavoidable components in pharmaceutical production and will oftenbe a part of drug products.4) Residual solvents should not exceed recommended levels except in exceptionalcircumstances.5) Data from toxicological studies that are used to determine acceptable levels for residualsolvents should have been generated using appropriate protocols such as those describedfor example by OECD, EPA, and the FDA Red Book.Appendix 3: Methods for establishing exposure limitsThe Gaylor-Kodell method of risk assessment (Gaylor, D. W. and Kodell, R. L.: Linear Interpolation algorithm for low dose assessment of toxic substance. J Environ. Pathology, 4, 305, 1980) is appropriate for Class 1 carcinogenic solvents. Only in cases where reliable carcinogenicity data are available should extrapolation by the use of mathematical models be applied to setting exposure limits. Exposure limits for Class 1 solvents could be determined with the use of a large safety factor (i.e., 10,000to 100,000) with respect to the no-observed-effect level (NOEL). Detection and quantitation of these solvents should be by state-of-the-art analytical techniques.Acceptable exposure levels in this guideline for Class 2 solvents were established by calculation of PDE values according to the procedures for setting exposure limits in pharmaceuticals (Pharmacopeial Forum, Nov-Dec 1989), and the method adopted by IPCS for Assessing Human Health Risk of Chemicals (Environmental Health Criteria 170, WHO, 1994). These methods are similar to those used by the USEPA (IRIS) and the USFDA (Red Book) and others. The method is outlined here to give a better understanding of the origin of the PDE values. It is not necessary to perform these calculations in order to use the PDE values tabulated in Section 4 of this document. PDE is derived from the no-observed-effect level (NOEL), or the lowest-observed effect level (LOEL) in the most relevant animal study as follows:PDE =NOEL x Weight Adjustment(1)F1 x F2 x F3 x F4 x F5The 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 "uncertainty factors" used in Environmental Health Criteria (Environmental Health Criteria 170, World Health Organization, Geneva, 1994), and "modifying factors" or "safety factors" in Pharmacopeial Forum. The assumption of 100% systemic exposure is used in all calculations regardless of route of administration.The modifying factors are as follows:F1 = A factor to account for extrapolation between speciesF1 = 5 for extrapolation from rats to humansF1 = 12 for extrapolation from mice to humansF1 = 2 for extrapolation from dogs to humansF1 = 2.5 for extrapolation from rabbits to humansF1 = 3 for extrapolation from monkeys to humansF1 = 10 for extrapolation from other animals to humans。

Q3C(R6)-20191004-S-Step 4杂质:残留溶剂指导原则

Q3C(R6)-20191004-S-Step 4杂质:残留溶剂指导原则

人用药品注册技术要求国际协调会ICH H ARMONISED G UIDELINEICH 协调指导原则杂质:残留溶剂的指导原则 Q3C(R6)最终版本2016年 10 月 20日本指导原则由相应的ICH 专家工作组制定,并根据ICH 进程已提交给管理当局征询意见。

在ICH 进程的第四阶段,最后的草案被推荐给欧盟、日本、美国、加拿大和瑞士的管理机构采纳。

Q3C(R6)文件历史母指导原则:杂质:残留溶剂的指导原则对母指导原则所含THF的PDE信息的修订修订母指导原则所含NMP的PDE信息母指导原则:杂质:残留溶剂的指导原则对母指导原则所含异丙基苯的PDE信息的修订修订母指导原则所含甲基异丁基酮的PDE信息,并纳入三乙胺的PDE乙二醇PDE修正I MPURITIES: G UIDELINE FOR R ESIDUAL S OLVENTS杂质:残留溶剂的指导原则TABLE OF CONTENTS目录PART I:IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS (4)第一部分:杂质:残留溶剂的指导原则 (4)1.INTRODUCTION引言 (4)2.SCOPE OF THE GUIDELINE 指导原则的适用范围 (5)3.GENERAL PRINCIPLES通则 (6)3.1Classification of Residual Solvents by Risk Assessment基于风险评估的残留溶剂的分类 (6)3.2 Methods for Establishing Exposure Limits 建立暴露限度的方法 (6)3.3 Options for Describing Limits of Class 2 Solvents 2 类溶剂限度的表示方法 (7)3.4 Analytical Procedures分析方法 (9)3.5 Reporting levels of residual solvents残留溶剂的报告水平 (9)4.LIMITS OF RESIDUAL SOLVENTS 残留溶剂的限度 (10)4.1 Solvents to Be Avoided应避免的溶剂 (10)4.2 Solvents to Be Limited应限制的溶剂 (10)4.3 Solvents with Low Toxic Potential低潜在毒性的溶剂 (12)4.4 Solvents for which No Adequate Toxicological Data was Found 没有足够毒理学数据的溶剂 (13)GLOSSARY术语 (14)APPENDIX 1. LIST OF SOLVENTS INCLUDED IN THE GUIDELINE附录 1:指导原则中包括的溶剂列表 (15)APPENDIX 2. ADDITIONAL BACKGROUND附录 2:其他背景 (18)APPENDIX 3. METHODS FOR ESTABLISHING EXPOSURE LIMITS附录 3:建立暴露限度的方法 (19)PART II:IMPURITIES: RESIDUAL SOLVENTS (MAINTENANCE)PDE FOR TETRAHYDROFURAN第二部分:杂质:残留溶剂(修订)四氢呋喃的 PDE (23)PART III:IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE) PDE FOR N-METHYLPYRROLIDONE (NMP) 第三部分:杂质:残留溶剂(修订)N-甲基吡咯烷酮(NMP)的 PDE25 PART IV:IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE) PDE FOR CUMENEICH Harmonised Tripartite Guideline第四部分:杂质:残留溶剂(修订)异丙基苯的 PDE (27)PART V:IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE)PDE FOR TRIETHYLAMINE AND PDE OF METHYLISOBUTYLKETONE第五部分:杂质:残留溶剂(修订)三乙胺的 PDE 和甲基异丁基酮的 PDE (31)PART I:IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS第一部分:杂质:残留溶剂的指导原则Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 17 July 1997, this Guideline is recommended for adoption to the three regulatory parties to ICH在 1997 年 7 月 17 日的 ICH 指导委员会会议上进入 ICH 进程第四阶段,并建议 ICH 的三方监管机构采纳该指导原则1.INTRODUCTION引言The objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.本指导原则旨在建议为保证患者安全而应规定的药物中残留溶剂的可接受量。

杂质:残留溶剂的指导原则

杂质:残留溶剂的指导原则

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)应限制使用,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。

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。

残留溶剂的指导原则

残留溶剂的指导原则

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)应限制使用,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。

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。

Q3C 溶剂残留和分类

Q3C 溶剂残留和分类

摘自Q3C-残留溶剂的指导选择一类溶剂:应避免致癌物;备受怀疑的致癌物;环境危害物二类溶剂:设定残余量,限量使用非基因性动物致癌物;可能导致不可逆中毒,比如神经性中毒,畸形;可能导致其他可逆性中毒三类溶剂: 低毒对人体有潜在毒性,可以接触,但不超过50mg/day。

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 that are used in earlier manufacturing steps and not removed consistently by a validated process.ICH规定3类只要干失小于0.5, 但1,2类并不是不能出现。

按照毒性大小和对环境的危害程度,该指导原则将溶剂分成三类(所列举的溶剂并不完全,应对合成和生产过程所有可能的残留溶剂进行评估):第一类溶剂是指已知可以致癌并被强烈怀疑对人和环境有害的溶剂。

在可能的情况下,应避免使用这类溶剂。

如果在生产治疗价值较大的药品时不可避免地使用了这类溶剂,除非能证明其合理性,残留量必须控制在规定的范围内,如:苯(2ppm)、四氯化碳(4ppm)、1,2-二氯乙烷(5ppm)、1,1-二氯乙烷(8ppm)、1,1,1-三氯乙烷(1500ppm)。

第二类溶剂是指无基因毒性但有动物致癌性的溶剂。

按每日用药10克计算的每日允许接触量如下:2-甲氧基乙醇(50ppm)、氯仿(60ppm)、1,1,2-三氯乙烯(80ppm)、1,2-二甲氧基乙烷(100ppm)、1,2,3,4-四氢化萘(100ppm)、2-乙氧基乙醇(160ppm)、环丁砜(160ppm)、嘧啶(200ppm)、甲酰胺(220ppm)、正己烷(290ppm)、氯苯(360ppm)、二氧杂环己烷(380ppm)、乙腈(410ppm)、二氯甲烷(600ppm)、乙烯基乙二醇(620ppm)、N,N-二甲基甲酰胺(880ppm)、甲苯(890ppm)、N,N-二甲基乙酰胺(1090ppm)、甲基环己烷(1180ppm)、1,2-二氯乙烯(1870ppm)、二甲苯(2170ppm)、甲醇(3000ppm)、环己烷(3880ppm)、N-甲基吡咯烷酮(4840ppm)、。

重磅!CDE公开征求ICH《Q3C(R8):杂质:残留溶剂的指导原则》指导原则草案意见

重磅!CDE公开征求ICH《Q3C(R8):杂质:残留溶剂的指导原则》指导原则草案意见

重磅!CDE公开征求ICH《Q3C(R8):杂质:残留溶剂的
指导原则》指导原则草案意见
ICH《Q3C(R8):杂质:残留溶剂的指导原则》指导原则草案现进入第3阶段区域公开征求意见阶段。

按照ICH相关章程要求,ICH 的监管机构成员需收集本地区关于第2b阶段指导原则草案的意见并反馈ICH。

上述指导原则草案的原文和译文见附件,现向社会公开征求意见(反馈意见用中英文均可)。

为与ICH工作组统一,建议反馈意见时主要针对ICH英文原文,可具体标明原文行号,中文翻译稿可作为参考。

因时间仓促,译文质量难免存在不足之处,若对译文提出意见也可同步反馈。

社会各界如有意见,请于2020年6月10日前通过电子邮箱反馈。

联系人:何伍任连杰。

Q3C(R7)杂质:残留溶剂指导原则(中文翻译公开征求意见稿)

Q3C(R7)杂质:残留溶剂指导原则(中文翻译公开征求意见稿)

注:2005 年 11 月 机构采纳。
修订前本版本命
名为 Q3C(M):
THF
对母指导原则所含 NMP 的 PDE 信息的修订
Q3C(R2)
N-甲基吡咯烷酮(NMP)的每日允许暴露量(PDE):根据2000 年 7 月 20 日
注:2005 年 11 月新的毒理学数据修订 PDE。
修 订 前 本 版 本 命指导委员会经第二阶段后批准修订版,并发布以便向公众征
药物中的残留溶剂在此定义为在原料药或辅料的生产中以及制剂制备过程中使用 或产生的有机挥发性化合物。这些溶剂在实际生产技术中不能完全除去。选择适当的溶 剂合成原料药可提高收率或决定药物的性质,如晶型、纯度和溶解度。因此,溶剂有时 可能是合成工艺的关键因素。本指导原则并不针对特意用作辅料的溶剂,也不针对溶剂 化物。然而这些制剂中的溶剂也应进行评价,并论证其合理性。
异丙基苯文档的 PDE 已经作为第 IV 部分整合在核心 Q3C (R4)指导原则中,指导原则更名为 Q3C(R5)。
已对表 2、表 3 和附录 1 进行更新,以反映对异丙基苯的 PDE 进行的修订。
修订母指导原则所含甲基异丁基酮的 PDE 信息,并纳入三乙胺的 PDE
Q3C(R6) Q3C(ห้องสมุดไป่ตู้6)
名为 Q3C(M):求意见。
NMP
Q3C(R2)
指导委员会经第四阶段后批准,并建议 ICH 的 3 个监管机2002 年 9 月 12 日
注:2005 年 11 月 构采纳。
修订前本版本命
名为 Q3C(M):
NMP
Q3C(R3)
指导委员会批准的计算公式勘误。
注:2005 年 11 月
修订前本版本命
2002 年 10 月 28 日

ICHQ3C(R6)残留溶剂培训教材

ICHQ3C(R6)残留溶剂培训教材

• 将制剂各成分所含的残留溶剂超限累〔41加0ppm ,每天的溶剂总量应低于PDE给定的值.
组分 原料药 辅料1 辅料2
制剂
在处方中的量 0.3g 0.9g 3.8g 5.0g
乙腈的含量 800ppm 400ppm 800ppm 728ppm
日暴露量 0.24mg 0.36mg 3.04mg 3.64mg
•"可能存在"系指用于工艺最后一步,以及用于较前几步生产工艺、用经验证的 工艺不能一致地除尽的溶剂.
谢谢
THANK YOU
天50mg或50mg以上
LIMITS 残留溶剂的限度
• ICH Q3C〔R6与《中国药典》〔2015年的对比
Ⅰ类溶剂限度
ICH Q3C〔R6与ChP 2015 四部 0861 中的Ⅰ类溶剂,种类与限度均一致 注意ห้องสมุดไป่ตู้1,1,1-三氯乙烷:限度高,但是属于Ⅰ类溶剂.
Ⅱ类溶剂限度
• 关注点 • 1、异丙基苯〔5000ppm → 70 ppm,Ⅲ类 → Ⅱ类 • 2、甲基异丁基酮〔5000ppm → 4500 ppm,Ⅲ类 → Ⅱ类
• ICH Q3C〔R6提供计算方法 • 采用气相色谱法或干燥失重测定法进行检测
残留溶剂限度计算
• 残留溶剂限度是如何计算的?


(ppm)
1000

PDE(mg / day) 量(g / day)
PDE〔Permitted
Daily Exposure 每日允许暴露量 指药物中残留溶剂每
• 认为这些限度适用于所有原料药、辅料和制剂日. 可接受的最大摄入
• 因此,若日摄入总量未知或未定,可采用这种方法.

• 若处方中的所有辅料及原料药都符合限度,则这些组分可按任意比例使用.

ICH Q3c 中文版)

ICH Q3c 中文版)
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。
杂质:残留溶剂的指导原则
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。
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 1,1-二甲基甲烷 2,2-二甲丙烷 异辛烷 异丙醚
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

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
1,1-二氯乙烯
8
毒性

化学药物残留溶剂研究的技术指导原则

化学药物残留溶剂研究的技术指导原则

化学药物残留溶剂研究的技术指导原则一、概述药物中的残留溶剂系指在原料药或辅料的生产中、以及在制剂制备过程中使用或产生而又未能完全去除的有机溶剂。

根据国际化学品安全性纲要,以及美国环境保护机构、世界卫生组织等公布的研究结果,很多有机溶剂对环境、人体都有一定的危害,因此,为保障药物的质量和用药安全,以及保护环境,需要对残留溶剂进行研究和控制。

本指导原则是在参考人用药物注册技术要求国际协调会(International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use,ICH)颁布的残留溶剂研究指导原则,美国药典(the United States Pharmacopoeia,USP)、英国药典(British Pharmacopoeia, BP)、欧洲药典(European Pharmacopoeia,EP)、中国药典(Chinese Pharmacopoeia, ChP)相关内容的基础上,结合我国药物研发的特点,通过分析、研究残留溶剂问题与药物的安全性、有效性及质量可控性之间的内在关系而制定的。

本指导原则总结了对残留溶剂问题的一般认识,旨在帮助药物研发者科学合理的进行残留溶剂方面的研究,也为药物评价者提供参考。

考虑到残留溶剂研究涉及的范围比较广泛,本指导原则主要对原料药的残留溶剂问题进行讨论,并以此为基础,探讨和总结药物研究过程中对残留溶剂问题的一般性原则。

药物研发者可参考本指导原则对制剂和辅料的残留溶剂问题进行研究。

考虑到药物研究开发的阶段性,本指导原则适用于药物研发的整个过程。

二、基本内容(一)残留溶剂研究的基本原则1、确定残留溶剂的研究对象从理论上讲,药物制备过程中所使用的有机溶剂均有残留的可能,均应进行残留量的研究。

但是,药物研发者可以通过对有机溶剂的性质、药物制备工艺等进行分析,提出科学合理的依据,有选择性的对某些溶剂进行残留量研究,这样,既可以合理有效的控制产品质量,又有利于降低药物研究的成本,避免不必要的浪费。

Q3C(M) 残留溶剂(修订):NMP和THF的日允许接触剂量(PDE)

Q3C(M) 残留溶剂(修订):NMP和THF的日允许接触剂量(PDE)

杂质:残留溶剂(修订)N-甲基吡咯烷酮(NMP)的日允许接触剂量(PDE)ICH协议指南本指导原则于2002年9月12日ICH指导委员会上进入ICH进程的第四阶段,被推荐给三方管理当局采纳。

在1997年12月,ICH Q3C指南进入第5阶段。

专家工作组的成员达成一致意见:如果有可靠的和更确切的毒理资料作为参考,可以对相关品种的PDE作修改。

1999年形成了一个修订协议并组成一个专家修定工作组。

该协议提出对各种溶剂的PCE进行再审议并允许对指南的相关条例进行调整,包括对各种溶剂的PDE数据进行调整。

此外,协议还允许在有足够的毒性资料的前提下,可增加新的溶剂及其PDE数据。

去年下半年EWG收到有关N-甲基吡咯烷酮(NMP)新的毒性资料。

此内容已由NMP 产业集团上报给FDA。

这是一个由E.I.DUPONT DE Nemours和Co进行的为期二年的大鼠长期喂食实验(未公开发表)。

有关资料已呈送给EWA的成员们进行分析。

在当时看来,这些实验结果足以向指导委员会提出更改NMP毒性类别的建议。

在2002年2月28日至3月2日的ICH会议上,作者向指导委员会汇报了EWG分析的结论和达成的一致意见,即报NMP从第2类溶剂(PDE为48.4mg/天)改为第3类溶剂(PDE为207mg/天)。

但不久,EWG的成员又提供了能够得出更低PDE的进一步的资料和评价。

以下的章节包含如何计算新的PDE的合理的和更灵敏的方法。

动物毒性以下论文是用于计算NMP的PDE:“大鼠出生前接触NMP对其出生后成长和发育的影响”Hass U. 等,《神经毒理》致畸1994,16(3)241~249。

取怀孕Wistar大鼠,在孕期的7~20天的周期内通过吸入给药的方法给予NMP150ppm ×6小时/每日,孕期满后允许孕鼠产仔,结果未检测到对母鼠的毒性,幼仔的尺寸大小也未受给药的影响,同时未观察到机体异常。

出生后5周内,幼仔的体重下降(有显著意义)。

Q3C:杂质残留溶剂的指导原则

Q3C:杂质残留溶剂的指导原则

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)应限制使用,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。

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。

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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 )应限制使用,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。

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 。

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。

应限制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,Vo l . 9 ,No . l,Suplement,April 1997.3.3 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。

方程(1) C(ppm)= 1000XPile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。

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 3.64mg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。

残留溶剂的方法论证应遵循ICH 指导原则:“分析方法论证:定义和术语”及“分析方法论证: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 应限制的溶剂列于表2 的溶剂,由于其具毒性,在制剂中应予限制,规定PDE杂质:残留溶剂的指导原则第8 页共18 页约0.1mg/天,浓度约10ppm 。

所列值不能反映测定所必需的分析精度,精度应为方法论证的一部分。

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 38801,2-二氯乙烯18.7 1870二氯甲烷 6.0 6001,2-二甲亚砜 1.0 100N,N-二甲乙酰胺10.9 1090N,N-二甲基甲酰胺8.8 8801,4-二恶烷 3.8 3802-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 30002-甲氧基乙醇0.5 50甲基丁酮0.5 50甲基环己烷11.8 1180N-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 8901,1,2-三氯乙烯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限制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。

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