usp232_233中文版

<232>ELEMENTALIMPURITIES—LIMITSINTRODUCTIONThis general chapter specifies limits for the amounts of elemental impurities in drug products. Elemental impurities include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment and the container closure system). When elemental impurities are known to be present, have been added, or have the potential for introduction, assurance of compliance to the specified levels is required.A risk-based control strategy may be appropriate when analysts determine how to assure compliance with this standard. Due to the ubiquitous nature of arsenic, cadmium, lead,assessment. Regardless of the approach used, compliance with the limits specified is required for all drug products unless otherwise specified in an individual monograph or excluded in paragraph three of this introduction.The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or non-recombinant origins), their derivatives, and products of which they are components (e.g., conjugates) are within the scope of this chapter, as are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides.This chapter does not apply to radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood derivatives including plasma and<232>元素杂质-限度介绍本通则规定了制剂中元素杂质的限度。

凡例改为：凡例标明解释和应用美国药典和国家药典的基础的假设、定义、和预设条件。

凡例里标明的要求适用于美国药典和国家药典（概略）和所有的一般章节除非另外有明确的规定。

各论要求和凡例或一般章节的要求不一样，各论要求取代凡例和一般章节的要求，不管各论中的不同之处是否明确。

1.标题和修订出版物的全称（包括三卷和其补充）是美国药典第32次修订版，和美国国家药典27版的，他们简称为美国药典，第32次修订版（或USP32），或称NF27和USP32-NF27。

美国药典32版和国家药典27版取代以前所有的修订版本。

在“USP”、“NF”、“USP-NF”使用期间，没有进一步的限定，美国药典就是官方要点，他们只包括美国药典32版、国家药典27版和任何补充意见。

同样的题目，没有进一步的区分，应用于印刷版和电子简化版的内容。

尽管美国药典和国家药典出版于同一个出版物内，但它们是彼此独立的两个出版物。

这次修订是官方从2009年5月1日开始的，但除去在文档中有指明的。

美国药典和国家药典的补充定期出版。

修订美国药典和国家药典的临时修订公告在药典论坛中发布。

临时修订公告包括官方修订和他们的生效日期，还有新美国药典参考标准的可用性公告。

试验和和操作方法公告暂时搁置待获得所需药典参照标准。

需要加快出版以正式文本或推迟的修订公告的修订。

他们一般立即出版在美国药典的官方网站上。

勘误表更正还没有收到理事会专家批准的错误出版项目。

并不反应官方的要求，勘误表经出版是有效的。

2.官方地位和法律上认可度2.10.正文内容正文内容含在美国药典和国家药典中，包括各论、一般章节和凡例。

对正文的修订内容包含在补充，临时修订公告和修订公告中。

一般章节编号首1900至99年被认为是诠释，其目的是为了提供信息的，给予的定义，或描述某一特定主题。

一般章节从编号100到1999.他们包括没有强制要求的，适用于任何官方文章，除去在凡例、各论或页码小于1000的一般章节中有特殊规定的。

氨基葡萄糖硫酸钠盐U S P32标准Glucosamine Sulfate Sodium Chloride(C6H14NO5)2SO4·2NaCl 573.31Bis(d-Glucose, 2-amino-2-deoxy-), sulfate sodium chloride complex.Bis(2-Amino-2-deoxy- -d-glucopyranose) sulfate sodium chloride complex (-,-) [38899-05-7].» Glucosamine Sulfate Sodium Chloride contains not less than 98.0 percent a nd not morethan 102.0 percent of (C6H14NO5)2SO4·2NaCl calculated on the dried basis. Packaging and storage— Preserve in tight, light-resistant containers.USP Reference standards 11—USP Glucosamine Hydrochloride RS .Identification—A: Infrared Absorption 197K.Test solution— Transfer about 50 mg of Glucosamine Sulfate Sodium Chlorid e to a centrifuge tube,and dissolve in 2 mL of water. Add about 0.5 mL of barium chloride TS, and c entrifuge.Evaporate the supernatant, and dry the residue at 105 for 2 hours. The IR spe ctrum correspondsto that of a similar preparation of USP Glucosamine Hydrochloride RS, except that the additionof barium chloride TS is omitted.B: It meets the requirements of the tests for Chloride 191 and Sodium 191. C: The retention time of the major peak in the chromatogram of the Assay pre paration correspondsto that in the chromatogram of the Standard preparation, as obtained in the As say.D: In the test for the Content of sulfate, after the addition of barium chloride T S, a whiteprecipitate is formed.Specific rotation 781S: between +50.0 and +55.0.Test solution: 35 mg per mL. Measure the specific rotation 3 hours after sampl e preparation.pH 791 : between 3.0 and 5.0, in a solution containing 20 mg per mL.Loss on drying 731 — Dry it at 105 for 2 hours: it loses not more than 1.0% of its weight.Residue on ignition 281 : between 22.5% and 26.0%.Potassium— Acidify 5 mL of a solution (1 in 20) with 6 N acetic acid, and add 5 drops ofsodium cobaltinitrite TS: no precipitate is formed.Arsenic, Method II 211 : 3 µg per g.Heavy metals, Method II 231 : 0.001%.Content of sulfate— Transfer about 1 g of Glucosamine Sulfate Sodium Chlori de, accurately weighed, to a 250-mL beaker, and dissolve in about 100 mL of water. Add 4 mL of 6 N hydrochloric acid. Heat the solutionto boiling, and add, with constant stirring, sufficient boiling barium chloride T S to completely precipitate the sulfate.Add an additional 2 mL of barium chloride TS, and digest on a steam bath for 1 hour. Pass the mixturethrough ashless filter paper, transferring the residue quantitatively to the filter, and wash the residue withhot water until no precipitate is obtained when 1 mL of silver nitrate TS is add ed to 5 mL of washing.Transfer the paper containing the residue to a tared crucible. Char the paper, without burning, and ignitethe crucible and its contents to constant weight. Calculate the content of sulfat e by multiplying the weightobtained by 0.4116. The content of sulfate is between 16.3% and 17.3%. Assay—Phosphate buffer, Mobile phase, Standard preparation, and Chromatographic system— Proceed asdirected in the Assay under Glucosamine Hydrochloride.Assay preparation— Transfer about 100 mg of Glucosamine Sulfate Sodium Chloride, accurately weighed, to a 100-mL volumetric flask. Dissolve in 30 mL of water, shake by mechanical means, dilute with water to volume,and mix.Procedure— Proceed as directed in the Assay under Glucosamine Hydrochlor ide. Calculate thepercentage of (C6H14NO5)2SO4·2NaCl in the portion of Glucosamine Sulfate Sodium Chloride takenby the formula:10,000(573.31/431.26)(C / W)(rU / rS)in which 573.31 is the molecular weight of the glucosamine sulfate sodium chl oride and 431.26 istwice the molecular weight of glucosamine HCl; W is the weight, in mg, of Glu cosamine SulfateSodium Chloride used to prepare the Assay preparation; and the others terms are as defined therein.Auxiliary Information— Please check for your question in the FAQs before conUSP32–NF27 Page 1031Pharmacopeial Forum: Volume No. 33(4) Page 692Chromatographic Column—GLUCOSAMINE SULFATE SODIUM CHLORIDEChromatographic columns text is not derived from, and not part of, USP 32 or NF 27项目标准（美国药典版）性状白色结晶性粉末比旋度+52°—+54°pH值 3.00—4.50铁离子≤10PPM重金属≤10PPM干燥失重≤1.00%含量98.0%-102.0%（以干基计）灼烧残渣23.5—25.0%氯化物≤14.00%硫酸盐16.3%-17.3%有机挥发杂质符合要求微生物检验细菌总数酵母、霉菌沙门氏菌大肠杆菌不大于500/g 不大于100/g 不得检出不得检出包装和储存保存在密封闭光的容器内有效期两年。

摘要美国药典 (USP) 组织正在开发有关药品和原料药中元素杂质测定的新通则。

USP<232> 规定了分析物的限量，而 USP<233> 则规定了样品制备选项（包括密闭容器微波消解）并推荐使用现代仪器，例如多元素 ICP-MS 和 ICP-OES 技术。

根据 USP<233> 的规定，分析仪器的检定须基于性能测试，包括需要论证仪器的准确性、重现性以及能够可靠鉴定分析物。

在本文中，我们列出的数据表明依照 USP<232>/<233> 成功验证了 Agilent 7700x ICP-MS 检测明胶胶囊样品中元素杂质的应用。

参照美国药典通则 <232>/<233> 草案验证 Agilent 7700x ICP-MS 在测定原料药元素杂质中的应用应用简报作者Samina Hussain Exova 美国Amir Liba and Ed McCurdy 安捷伦科技公司 美国制药所有规定的元素都通过了 USP<233> 的可接受标准，包括那些可能遭受基质干扰（比如 Cl 叠加在 V、Cr 和 As 上）的元素。

在 USP<232> 所要求的元素中，有些在氯化物基质中更易溶解或在化学上更加稳定，尤其是低浓度汞和铂族元素 (PGE)，因此可在所有水溶液和酸消化样品中加入低百分比浓度的 HCl 使它们稳定。

由于通过氦反应池气体（7700 的标准操作模式）能可靠地消除基于 Cl 的多原子干扰，因此，在常规操作中加入 HCl 来稳定样品对于 ICP-MS 方法来说已不再是问题。

引言美国药典 (USP) 组织目前正在开发药物中无机（元素性）杂质的新监测方法。

新通则 USP<232>（限量）和 <233> （规程）将在 2013 年实施。

USP<232> 为覆盖面更广的无机（元素）杂质（As、Cd、Hg、Pb、V、Cr、Ni、Mo、Mn、Cu、Pt、Pd、Ru、Rh、Os 和 Ir）规定了新的、更低的允许日接触量 (PDE) [1]。

USP38通用章节目录中文剖析USP38-通用章节指导目录(附录)Guide to General Chapters 通用章节指导General Requirements for Test and Assays检查与含量分析的一般要求＜1＞INJECTIONS AND IMPLANTED DRUG PRODUCTS (PARENTERALS)—PRODUCT QUALITY TESTS 注射和植入药物产品(注射用) —产品质量测试＜1＞INJECTIONS注射剂＜2＞ORAL DRUG PRODUCTS—PRODUCT QUALITY TESTS 口服药物产品质量测试＜3＞TOPICAL AND TRANSDERMAL DRUG PRODUCTS—PRODUCT QUALITY TESTS 局部和透皮药物产品—产品质量测试＜4＞MUCOSAL DRUG PRODUCTS—PRODUCT QUALITY TESTS 粘膜药物产品质量测试＜5＞INHALATION AND NASAL DRUG PRODUCTS—GENERAL INFORMATION AND PRODUCT QUALITY TESTS 吸入剂产品—产品质量测试＜7＞LABELING 标签＜11＞USP REFERENCE STANDARDS USP标准品Apparatus for Test and Assays用于检查与含量分析的器具＜17＞PRESCRIPTION CONTAINER LABELING处方容器标签＜21＞THERMOMETERS温度计＜31＞VOLUMETRIC APPARATUS容量器具＜41＞BALANCES天平Microbiological Tests 微生物检查法＜51＞ANTIMICROBIAL EFFECTIVENESS TESTING抗菌剂有效性检查法＜55＞BIOLOGICAL INDICATORS—RESISTANCE PERFORMANCE TESTS生物指示剂－耐药性实验＜61＞MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: MICROBIAL ENUMERATION TESTS非无菌产品的微生物限度检查：微生物列举检查法＜62＞MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: TESTS FOR SPECIFIED MICROORGANISMS 非无菌产品的微生物限度检查：特定微生物检查法＜63＞MYCOPLASMA TESTS 支原体检查法＜71＞STERILITY TESTS无菌检查法Biological tests and assays生物检查法与测定法＜81＞ANTIBIOTICS—MICROBIAL ASSAYS抗生素－微生物测定＜85＞BACTERIAL ENDOTOXINS TEST细菌内毒素检查法＜87＞BIOLOGICAL REACTIVITY TESTS, IN VITRO体外的生物反应性检查法＜88＞BIOLOGICAL REACTIVITY TESTS, IN VIVO 体内的生物反应性检查法＜89＞ENZYMES USED AS ANCILLARY MATERIALS IN PHARMACEUTICAL MANUFACTURING 药品生产中酶作为辅料所使用＜90＞FETAL BOVINE SERUM—QUALITY ATTRIBUTES AND FUNCTIONALITY TESTS 牛胎儿血清-质量品质和功能检查法＜91＞CALCIUM PANTOTHENATE ASSAY泛酸钙测定法＜92＞GROWTH FACTORS AND CYTOKINES USED IN CELL THERAPY MANUFACTURING 在细胞疗法中使用生长因子和细胞因子＜111＞DESIGN AND ANALYSIS OF BIOLOGICAL ASSAYS 生物测定法的设计与分析＜115＞DEXPANTHENOL ASSAY右泛醇（拟胆碱药）测定法＜121＞INSULIN ASSAYS胰岛素测定法＜121.1＞PHYSICOCHEMICAL ANALYTICAL PROCEDURES FOR INSULINS胰岛素的物理化学分析程序＜123＞GLUCAGON BIOIDENTITY TESTS 高血糖素的生物鉴别检查法＜124＞ERYTHROPOIETIN BIOASSAYS 红细胞生成素的微生物测定＜126＞SOMATROPIN BIOIDENTITY TESTS 生长激素的生物鉴别检查法＜130＞PROTEIN A QUALITY ATTRIBUTES 蛋白质A的质量特征＜151＞PYROGEN TEST热原检查法＜161＞TRANSFUSION AND INFUSION ASSEMBLIES AND SIMILAR MEDICAL DEVICES 输血输液用具以及相类似的医疗器械＜171＞VITAMIN B12 ACTIVITY ASSAY……2548维生素B12活性测定法Chemical Tests and assays化学实验检查与测定法鉴别检查＜181＞IDENTIFICATION—ORGANIC NITROGENOUS BASES 鉴别－有机氮碱化合物＜191＞IDENTIFICATION TESTS—GENERAL鉴别实验－通用＜193＞IDENTIFICATION—TETRACYCLINES鉴别－四环素类＜197＞SPECTROPHOTOMETRIC IDENTIFICATION TESTS分光光度计鉴别实验＜201＞THIN-LAYER CHROMATOGRAPHIC IDENTIFICATION TEST薄层色谱鉴别实验Limit Tests 限度检查法＜206＞ALUMINUM铝＜207＞TEST FOR 1,6-ANHYDRO DERIV ATIVE FOR ENOXAPARIN SODIUM依诺肝素钠的酐类衍生物实验＜208＞ANTI-FACTOR Xa AND ANTI-FACTOR IIa ASSAYS FOR UNFRACTIONATED AND LOW MOLECULAR WEIGHT HEPARINS 普通肝素和低分子肝素产品中抗体Xa和抗体IIa测定＜209＞LOW MOLECULAR WEIGHT HEPARIN MOLECULAR WEIGHT DETERMINATIONS 低分子肝素钠分子量测定＜211＞ARSENIC砷＜221＞CHLORIDE AND SULFATE氯和硫＜223＞DIMETHYLANILINE二甲基苯胺＜226＞4-EPIANHYDRO-TETRACYCLINE4－？－四环素＜227＞4-AMINOPHENOL IN ACETAMINOPHEN-CONTAINING DRUG PRODUCTS 对乙酰氨酚药物产品中氨基酚＜228＞ETHYLENE OXIDE AND DIOXANE 环氧乙烷和二氧六环＜231＞HEA VY METALS重金属（删除）＜232＞ELEMENTAL IMPURITIES—LIMITS 元素杂质-限度＜233＞ELEMENTAL IMPURITIES—PROCEDURES 元素杂质-规程＜241＞IRON铁＜251＞LEAD铅＜261＞MERCURY汞＜267＞POROSIMETRY BY MERCURY INTRUSION 水银孔隙仪＜268＞POROSITY BY NITROGEN ADSORPTION–DESORPTION 氮吸附-解吸测定孔隙率＜271＞READILY CARBONIZABLE SUBSTANCES TEST易碳化物检查法＜281＞RESIDUE ON IGNITION炽灼残渣＜291＞SELENIUM硒Other Tests and Assays 其它检查法与测定法＜301＞ACID-NEUTRALIZING CAPACITY酸中和容量＜311＞ALGINATES ASSAY藻酸盐测定法＜341＞ANTIMICROBIAL AGENTS—CONTENT 抗菌剂－含量＜345＞Assay for Citric Acid/Citrate and Phosphate 柠檬酸/柠檬酸盐和磷酸盐的测定＜351＞ASSAY FOR STEROIDS类固醇（甾类化合物）测定法＜361> BARBITURATE ASSAY 巴比妥类药物测定法＜371＞COBALAMIN RADIOTRACER ASSAY钴铵素放射性跟踪剂测定法＜381＞ELASTOMERIC CLOSURES FOR INJECTIONS 注射剂的弹性密封件＜391＞EPINEPHRINE ASSAY肾上腺素测定法＜401＞FATS AND FIXED OILS脂肪与混合油＜411＞FOLIC ACID ASSAY叶酸测定法＜413＞IMPURITIES TESTING IN MEDICAL GASES 医用气体杂质检查＜415＞MEDICAL GASES ASSAY 医用气体含量检查＜425＞IODOMETRIC ASSAY—ANTIBIOTICS碘量检查法－抗生素＜429＞LIGHT DIFFRACTION MEASUREMENT OF PARTICLE SIZE粒径的光衍射测量法＜431＞METHOXY DETERMINATION甲氧基测定法＜441＞NIACIN OR NIACINAMIDE ASSAY 烟酰或烟酰胺测定法＜451＞NITRITE TITRATION亚硝酸盐滴定＜461＞NITROGEN DETERMINATION氮测定法＜466＞ORDINARY IMPURITIES一般杂质＜467＞RESIDUAL SOLVENTS残留溶剂＜469＞ETHYLENE GLYCOL, DIETHYLENE GLYCOL, AND TRIETHYLENE GLYCOL IN ETHOXYLATED SUBSTANCES乙氧基物质中乙二醇、二甘醇、三甘醇测定＜471＞OXYGEN FLASK COMBUSTION氧瓶燃烧法＜481＞RIBOFLAVIN ASSAY核黄素（维生素B2）测定法＜501＞SALTS OF ORGANIC NITROGENOUS BASES有机氮盐＜503＞ACETIC ACID IN PEPTIDES 多肽类中乙酸测定＜511＞SINGLE-STEROID ASSAY单一的类固醇测定法＜525＞SULFUR DIOXIDE 二氧化硫＜531＞THIAMINE ASSAY硫胺素测定法＜541＞TITRIMETRY滴定法＜551＞VITAMIN E ASSAY维生素E测定法＜561＞ARTICLES OF BOTANICAL ORIGIN植物起源的药品＜563＞IDENTIFICATION OF ARTICLES OF BOTANICAL ORIGIN植物药品的鉴别＜565＞BOTANICAL EXTRACTS植物提取＜571＞VITAMIN A ASSAY维生素A测定法＜581＞VITAMIN D ASSAY维生素D测定法＜591＞ZINC DETERMINATION锌的测定法Physical Test and Determinations物理检查与测定法＜601＞INHALATION AND NASAL DRUG PRODUCTS: AEROSOLS, SPRAYS, AND POWDERS—PERFORMANCE QUALITY TESTS吸入剂、鼻雾剂：气溶胶，喷雾，干粉-质量通则＜602＞PROPELLANTS 推进剂＜603＞TOPICAL AEROSOLS 局部喷雾剂＜604＞LEAK RATE 渗漏率＜610＞ALTERNATIVE MICROBIOLOGICAL SAMPLING METHODS FOR NONSTERILE INHALED AND NASAL PRODUCTS 非无菌吸入和鼻雾剂可供选择的微生物取样方法＜611＞ALCOHOL DETERMINATION乙醇测定法＜616＞BULK DENSITY AND TAPPED DENSITY堆密度与振实密度＜621＞CHROMATOGRAPHY色谱法＜631＞COLOR AND ACHROMICITY呈色与消色＜641＞COMPLETENESS OF SOLUTION溶解度＜643＞TOTAL ORGANIC CARBON总有机碳＜645＞W ATER CONDUCTIVITY水电导率＜651＞CONGEALING TEMPERATURE凝点温度＜659＞PACKAGING AND STORAGE REQUIREMENTS 包装和储藏要求＜660＞CONTAINERS—GLASS 容器-玻璃＜661＞CONTAINERS—PLASTICS容器-塑料＜670＞AUXILIARY PACKAGING COMPONENTS 辅助包装部件＜671＞CONTAINERS—PERFORMANCE TESTING容器－性能测试＜691＞COTTON棉花＜695＞CRYSTALLINITY结晶度＜696＞CHARACTERIZATION OF CRYSTALLINE SOLIDS BY MICROCALORIMETRY AND SOLUTION CALORIMETRY 通过溶液量热学测定结晶性＜697＞CONTAINER CONTENT FOR INJECTIONS 注射剂容器容积＜698＞DELIVERABLE VOLUME抽取体积＜699＞DENSITY OF SOLIDS固体密度＜701＞DISINTEGRATION崩解时限＜705＞QUALITY ATTRIBUTES OF TABLETS LABELED AS HA VING A FUNCTIONAL SCORE ？＜711＞DISSOLUTION 溶出度＜721＞DISTILLING RANGE馏程＜724＞DRUG RELEASE药物释放度＜729＞GLOBULE SIZE DISTRIBUTION IN LIPID INJECTABLEEMULSIONS脂类可注射的乳剂的粒径分布＜730＞Plasma Spectrochemistry 血浆光谱化学？＜731＞LOSS ON DRYING4干燥失重＜733＞LOSS ON IGNITION灼烧失重＜735＞X-RAY FLUORESCENCE SPECTROMETRY X射线光谱＜736＞MASS SPECTROMETRY 质谱＜741＞MELTING RANGE OR TEMPERATURE熔距或熔点＜751＞METAL PARTICLES IN OPHTHALMIC OINTMENTS眼用软膏中的金属粒子＜755＞MINIMUM FILL最低装量＜761＞NUCLEAR MAGNETIC RESONANCE核磁共振＜771＞OPHTHALMIC OINTMENTS眼用软膏＜776＞OPTICAL MICROSCOPY光学显微镜＜781＞OPTICAL ROTATION旋光度＜785＞OSMOLALITY AND OSMOLARITY渗透压＜786＞PARTICLE SIZE DISTRIBUTION ESTIMATION BY ANALYTICAL SIEVING 筛分法估算粒径分布＜787＞SUBVISIBLE PARTICULATE MATTER IN THERAPEUTIC PROTEIN INJECTIONS显微计数法在治疗性蛋白注射剂中应用＜788＞PARTICULATE MATTER IN INJECTIONS注射剂中的不溶性微粒＜789＞PARTICULATE MATTER IN OPHTHALMIC SOLUTIONS 眼用溶液中的不溶性微粒＜790＞VISIBLE PARTICULATES IN INJECTIONS 注射剂中可见异物＜791＞pH＜795＞PHARMACEUTICAL COMPOUNDING—NONSTERILE PREPARATIONS药物混合－非无菌制剂＜797＞PHARMACEUTICAL COMPOUNDING—STERILE PREPARATIONS药物混合－无菌制剂＜801＞POLAROGRAPHY极谱法＜811＞POWDER FINENESS粉剂细度＜821＞RADIOACTIVITY放射性＜823＞POSITRON EMISSION TOMOGRAPHY DRUGS FOR COMPOUNDING, INVESTIGATIONAL, AND RESEARCH USES用于正电子发射断层造影术的放射性药物＜831＞REFRACTIVE INDEX折光率＜841＞SPECIFIC GRAVITY比重＜846＞SPECIFIC SURFACE AREA 比表面积＜851＞SPECTROPHOTOMETRY AND LIGHT-SCATTERING分光光度计与光散射＜852＞ATOMIC ABSORPTION SPECTROSCOPY 原子吸收光谱＜853＞FLUORESCENCE SPECTROSCOPY 荧光光谱＜854＞MID-INFRARED SPECTROSCOPY 中红外光谱＜857＞ULTRAVIOLET-VISIBLE SPECTROSCOPY 紫外可见光谱＜861＞SUTURES—DIAMETER缝线－直径？＜871＞SUTURES—NEEDLE ATTACHMENT缝线－穿孔实验＜881＞TENSILE STRENGTH张力＜891＞THERMAL ANALYSIS热分析＜905＞UNIFORMITY OF DOSAGE UNITS制剂单位的含量均匀度＜911＞VISCOSITY—CAPILLARY METHODS黏度-毛细管法＜912＞VISCOSITY—ROTATIONAL METHODS 黏度-旋转法＜913＞VISCOSITY—ROLLING BALL METHOD 黏度-球法＜921＞W ATER DETERMINATION水分测定＜941＞CHARACTERIZATION OF CRYSTALLINE ANDPARTIALLY CRYSTALLINE SOLIDS BY X-RAY POWDER DIFFRACTION (XRPD)X光衍射General Information通用信息＜1005＞ACOUSTIC EMISSION 声频发射＜1010＞ANALYTICAL DATA—INTERPRETATION AND TREATMENT分析数据－解释与处理＜1015＞AUTOMATED RADIOCHEMICAL SYNTHESIS APPARATUS放射性自动合成装置＜1024＞BOVINE SERUM 牛血清＜1027＞FLOW CYTOMETRY 流式细胞仪＜1030＞BIOLOGICAL ASSAY CHAPTERS—OVERVIEW AND GLOSSARY生物测定章节-综述和术语＜1031＞THE BIOCOMPATIBILITY OF MATERIALS USED IN DRUG CONTAINERS, MEDICAL DEVICES, AND IMPLANTS 用于药物容器、医疗设施和植入剂的材料的生物相容性＜1034＞ANALYSIS OF BIOLOGICAL ASSAYS 生物测定分析＜1035＞BIOLOGICAL INDICATORS FOR STERILIZATION灭菌用生物指示剂＜1041＞BIOLOGICS生物制剂＜1043＞Ancillary Material for Cell, Gene, and Tissue-Engineered Products细胞，基因与组织设计产品的辅助材料＜1044＞CRYOPRESERV ATION OF CELLS 细胞低温保存＜1045＞BIOTECHNOLOGY-DERIVED ARTICLES生物技术提取产品＜1046＞CELLULAR AND TISSUE-BASED PRODUCTS细胞与组织产品＜1047＞GENE THERAPY PRODUCTS 基因治疗产品＜1048＞QUALITY OF BIOTECHNOLOGICAL PRODUCTS: ANALYSIS OF THE EXPRESSION CONSTRUCT IN CELLS USED FOR PRODUCTION OF r-DNA DERIVED PROTEIN PRODUCTS 生物技术产品的质量：从蛋白质产品中提取的r-DNA产品在细胞中表达结构的分析＜1049＞QUALITY OF BIOTECHNOLOGICAL PRODUCTS: STABILITY TESTING OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS生物技术产品的质量：生物技术/生物产品的稳定性实验＜1050＞VIRAL SAFETY EV ALUATION OF BIOTECHNOLOGY PRODUCTS DERIVED FROM CELL LINES OF HUMAN OR ANIMAL ORIGIN从人或动物细胞中提取的生物技术产品的病毒安全性评估＜1051＞CLEANING GLASS APPARATUS玻璃容器的清洗＜1052＞BIOTECHNOLOGY-DERIVED ARTICLES—AMINO ACID ANALYSIS生物技术提取法-氨基酸测定＜1053＞CAPILLARY ELECTROPHORESIS 毛细管电泳法＜1054＞BIOTECHNOLOGY-DERIVED ARTICLES—ISOELECTRIC FOCUSING生物技术提取法-等电点聚集＜1055＞BIOTECHNOLOGY-DERIVED ARTICLES—PEPTIDE MAPPING生物技术提取法-肽谱＜1056＞BIOTECHNOLOGY-DERIVED ARTICLES—POLYACRYLAMIDE GEL ELECTROPHORESIS 生物技术提取法-凝胶电泳＜1057＞BIOTECHNOLOGY-DERIVED ARTICLES—TOTAL PROTEIN ASSAY生物技术提取法-总蛋白测定＜1058＞ANALYTICAL INSTRUMENT QUALIFICATION 分析仪器要求＜1059＞EXCIPIENT PERFORMANCE 赋形剂＜1061＞COLOR—INSTRUMENTAL MEASUREMENT显色－仪器测量＜1065＞Ion Chromatography 离子色谱法＜1066＞PHYSICAL ENVIRONMENTS THAT PROMOTE SAFE MEDICATION USE物理环境促使安全使用药物＜1072＞DISINFECTANTS AND ANTISEPTICS 消毒剂和防腐剂＜1074＞EXCIPIENT BIOLOGICAL SAFETY EV ALUATION GUIDELINES赋形剂（辅料）生物安全性评估指导＜1078＞GOOD MANUFACTURING PRACTICES FOR BULK PHARMACEUTICAL EXCIPIENTS 批药品赋形剂的生产管理规范＜1079＞Good Storage and Shipping Practices 良好的贮存与运输规范＜1080＞BULK PHARMACEUTICAL EXCIPIENTS—CERTIFICATE OF ANALYSIS批药品赋形剂-COA＜1084＞GLYCOPROTEIN AND GLYCAN ANALYSIS—GENERAL CONSIDERATIONS 糖蛋白和多糖分析-一般通则＜1086＞IMPURITIES IN DRUG SUBSTANCES AND DRUG PRODUCTS药物和药物产品中的杂质＜1087＞APPARENT INTRINSIC DISSOLUTION—DISSOLUTION TESTING PROCEDURES FOR ROTATING DISK AND STATIONARY DISK内部的溶出度-旋转和静止溶出检测程序？＜1088＞IN VITRO AND IN VIVO EV ALUATION OF DOSAGEFORMS体内与体外的剂型的评估＜1090＞ASSESSMENT OF DRUG PRODUCT PERFORMANCE-BIOAV AILABILITY, BIOEQUIV ALENCE, AND DISSOLUTION药物产品性能评估：生物利用度、生物等效性和溶出＜1091＞LABELING OF INACTIVE INGREDIENTS非活性成分的标示＜1092＞THE DISSOLUTION PROCEDURE: DEVELOPMENT AND V ALIDATION溶出程序：开发与验证＜1094＞CAPSULES—DISSOLUTION TESTING AND RELATED QUALITY ATTRIBUTES 胶囊-关于产品质量的溶出测定＜1097＞BULK POWDER SAMPLING PROCEDURES：粉末样品取样程序＜1102＞IMMUNOLOGICAL TEST METHODS—GENERAL CONSIDERATIONS免疫测试方法-总则＜1103＞IMMUNOLOGICAL TEST METHODS—ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) 免疫学测试方法-酶联免疫吸附测定＜1104＞IMMUNOLOGICAL TEST METHODS—IMMUNOBLOT ANALYSIS免疫测试方法-免疫印迹法＜1105＞IMMUNOLOGICAL TEST METHODS—SURFACE PLASMON RESONANCE 免疫测试方法-表面等离子体共振＜1106＞IMMUNOGENICITY ASSAYS—DESIGN AND VALIDATION OF IMMUNOASSAYS TO DETECT ANTI-DRUG ANTIBODIES＜1111＞MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: ACCEPTANCE CRITERIA FORPHARMACEUTICAL PREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL USE非无菌产品的微生物学检查：药用制剂和制药过程使用的物质接受标准＜1112＞MICROBIAL CHARACTERIZATION, IDENTIFICATION, AND STRAIN TYPING 非无菌药物产品水活性测定应用＜1113＞MICROBIOLOGICAL ATTRIBUTES OF NONSTERILE PHARMACEUTICAL PRODUCTS 非无菌药品中的微生物分布＜1115＞BIOBURDEN CONTROL OF NONSTERILE DRUG SUBSTANCES AND PRODUCTS 非无菌药物和产品的生物负载控制＜1116＞MICROBIOLOGICAL CONTROL AND MONITORING OF ASEPTIC PROCESSING ENVIRONMENTS洁净的房间与其它可控环境的微生物评估＜1117＞MICROBIOLOGICAL BEST LABORATORY PRACTICES 微生物最优实验室规范＜1118＞MONITORING DEVICES—TIME, TEMPERATURE, AND HUMIDITY监控装置－时间、温度与湿度＜1119＞NEAR-INFRARED SPECTROPHOTOMETRY近红外分光光度测定法＜1120＞Raman Spectrophotometry 拉曼分光光度测定法＜1121＞NOMENCLATURE命名＜1125＞NUCLEIC ACID-BASED TECHNIQUES—GENERAL 核酸技术-通则＜1126＞NUCLEIC ACID-BASED TECHNIQUES—EXTRACTION, DETECTION, AND SEQUENCING 核酸技术-提取、检测、测序＜1127＞NUCLEIC ACID-BASED TECHNIQUES—AMPLIFICATION 核酸技术-扩增＜1128＞NUCLEIC ACID-BASED TECHNIQUES—MICROARRAY 核酸技术-微阵列＜1129＞NUCLEIC ACID-BASED TECHNIQUES—GENOTYPING 核酸技术-基因分型＜1130＞NUCLEIC ACID-BASED TECHNIQUES—APPROACHES FOR DETECTING TRACE NUCLEIC ACIDS (RESIDUAL DNA TESTING)核酸技术-探测微量核酸的应用（残留DNA测试）＜1136＞PACKAGING AND REPACKAGING—SINGLE-UNIT CONTAINERS包装和再包装－单一容器＜1151＞PHARMACEUTICAL DOSAGE FORMS药物剂型＜1152＞ANIMAL DRUGS FOR USE IN ANIMAL FEEDS兽药在动物饲料中的使用＜1160＞PHARMACEUTICAL CALCULATIONS IN PRESCRIPTION COMPOUNDING 按处方混合的药物的计算＜1163＞QUALITY ASSURANCE IN PHARMACEUTICAL COMPOUNDING按处方混合的药物的质量保证＜1171＞PHASE-SOLUBILITY ANALYSIS相溶解分析＜1174＞Powder Flow 粉末流动性＜1176＞PRESCRIPTION BALANCES AND VOLUMETRIC APPARATUS 处方天平与容量器具＜1177＞Good Packaging Practices 良好的包装操作＜1178＞Good Repackaging Practices 良好的再包装操作＜1180＞HUMAN PLASMA 人血浆＜1181＞SCANNING ELECTRON MICROSCOPY扫描电子显微镜＜1184＞SENSITIZATION TESTING 致敏测试＜1191＞STABILITY CONSIDERATIONS IN DISPENSING PRACTICE分装操作中稳定性考察＜1195＞SIGNIFICANT CHANGE GUIDE FOR BULK PHARMACEUTICAL EXCIPIENTS 散装药用辅料更换指导原则＜1197＞GOOD DISTRIBUTION PRACTICES FOR BULK PHARMACEUTICAL EXCIPIENTS 散装药用辅料良好的分装操作＜1207＞STERILE PRODUCT PACKAGING—INTEGRITY EV ALUATION无菌产品包装－完整性评估＜1208＞STERILITY TESTING—V ALIDATION OF ISOLATOR SYSTEMS无菌实验－隔离系统的验证＜1209＞STERILIZATION—CHEMICAL AND PHYSICOCHEMICAL INDICATORS AND INTEGRATORS灭菌－化学与物理化学的指示剂以及二者的综合＜1211＞STERILIZATION AND STERILITY ASSURANCE OF COMPENDIAL ARTICLES 药典物品中的灭菌与灭菌保证＜1216＞TABLET FRIABILITY片剂的脆碎度＜1217＞TABLET BREAKING FORCE 片剂断裂力＜1222＞TERMINALLY STERILIZED PHARMACEUTICAL PRODUCTS—PARAMETRIC RELEASE 药品终端灭菌－放行参数＜1223＞V ALIDATION OF ALTERNATIVE MICROBIOLOGICAL METHODS可供选择的微生物学方法的验证＜1224＞TRANSFER OF ANALYTICAL PROCEDURES 分析方法转移＜1225＞V ALIDATION OF COMPENDIAL PROCEDURES药典方法的验证＜1226＞VERIFICATION OF COMPENDIAL PROCEDURES 药典方法的确认＜1227＞V ALIDATION OF MICROBIAL RECOVERY FROM PHARMACOPEIAL ARTICLES从药物中回收微生物的验证＜1229＞STERILIZATION OF COMPENDIAL ARTICLES 药典灭菌过程＜1229.1＞STEAM STERILIZATION BY DIRECT CONTACT 直接蒸汽灭菌＜1229.2＞MOIST HEAT STERILIZATION OF AQUEOUS LIQUIDS 水溶液的湿热灭菌＜1229.3＞MONITORING OF BIOBURDEN 生物负载监控＜1229.4＞STERILIZING FILTRATION OF LIQUIDS 溶液的无菌过滤器＜1229.6＞LIQUID-PHASE STERILIZATION 液态灭菌＜1229.7＞GASEOUS STERILIZATION 气态灭菌＜1229.8＞DRY HEAT STERILIZATION 干热灭菌＜1229.10＞RADIATION STERILIZATION 辐射灭菌＜1230＞W ATER FOR HEMODIALYSIS APPLICATIONS 血液透析过程用水＜1231＞W ATER FOR PHARMACEUTICAL PURPOSES制药用水＜1234＞VACCINES FOR HUMAN USE—POLYSACCHARIDE AND GLYCOCONJUGATE VACCINES 人用疫苗-多糖和糖复合物疫苗＜1235＞V ACCINES FOR HUMAN USE—GENERAL CONSIDERATIONS 人用疫苗-通则＜1237＞VIROLOGY TEST METHODS 病毒测试方法＜1238＞V ACCINES FOR HUMAN USE—BACTERIAL V ACCINES 人用疫苗-细菌疫苗＜1240＞VIRUS TESTING OF HUMAN PLASMA FOR FURTHER MANUFACTURE下一步使用人血浆的病毒测试＜1241＞W ATER–SOLID INTERACTIONS IN PHARMACEUTICAL SYSTEMS在药物系统中水与固体的相互作用＜1251＞WEIGHING ON AN ANALYTICAL BALANCE关于分析天平的称重＜1265＞Written Prescription Drug Information－Guidelines 书面的处方药信息－指南＜1285＞PREPARATION OF BIOLOGICAL SPECIMENS FOR HISTOLOGIC AND IMMUNOHISTOCHEMICAL ANALYSIS 为了组织和免疫组织分析的生物标本制备＜1285.1＞HEMATOXYLIN AND EOSIN STAINING OF SECTIONED TISSUE FOR MICROSCOPIC EXAMINATION显微镜观察用苏木精和伊红染色的切片＜1601＞PRODUCTS FOR NEBULIZATION—CHARACTERIZATION TESTS 产品雾化状态-性状描述＜1644＞THEORY AND PRACTICE OF ELECTRICAL CONDUCTIVITY MEASUREMENTS OF SOLUTIONS溶液电导值测量方法的理论与实践＜1660＞EV ALUATION OF THE INNER SURFACE DURABILITY OF GLASS CONTAINERS 玻璃容器内表面耐久性评估＜1724＞SEMISOLID DRUG PRODUCTS—PERFORMANCE TESTS 半固态药物产品-性能测试＜1736＞APPLICATIONS OF MASS SPECTROMETRY 质谱应用＜1761＞APPLICATIONS OF NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY核磁共振光谱应用＜1787＞MEASUREMENT OF SUBVISIBLE PARTICULATE MATTER IN THERAPEUTIC PROTEIN INJECTIONS用显微镜测量方法测量治疗性蛋白注射剂的不溶性微粒＜1788＞METHODS FOR THE DETERMINATION OF PARTICULATE MATTER IN INJECTIONS AND OPHTHALMIC SOLUTIONS注射剂和眼用溶液的不溶性微粒测定的方法选择＜1852＞ATOMIC ABSORPTION SPECTROSCOPY—THEORY AND PRACTICE原子吸收光谱-理论与实践＜1853＞FLUORESCENCE SPECTROSCOPY—THEORY AND PRACTICE荧光光谱-理论与实践＜1854＞MID-INFRARED SPECTROSCOPY—THEORY AND PRACTICE中红外光谱-理论与实践＜1857＞ULTRA VIOLET-VISIBLE SPECTROSCOPY—THEORY AND PRACTICE紫外可见光谱-理论与实践＜1911＞RHEOMETRY 流变测定Dietary Supplements营养补充剂General Tests and Assays 一般检查法与测定法＜2021＞MICROBIAL ENUMERATION TESTS—NUTRITIONAL AND DIETARY SUPPLEMENTS…3080微生物数量实验－营养与食品添加剂＜2022＞MICROBIOLOGICAL PROCEDURES FOR ABSENCE OF SPECIFIED MICROORGANISMS—NUTRITIONAL AND DIETARY SUPPLEMENTS (3083)不得检出特定微生物的程序－营养与营养补充剂＜2023>MICROBIOLOGICAL ATTRIBUTES OF NONSTERILE NUTRITIONAL AND DIETARY SUPPLEMENTS……3087非无菌的营养与食品添加剂中的微生物分布<2040>DISINTEGRATION AND DISSOLUTION OF DIETARY SUPPLEMENTS (3089)食品添加剂的崩解与溶出<2091>WEIGHT V ARIATION OF DIETARYSUPPLEMENTS……3092食品添加剂的重量差异<2750>MANUFACTURING PRACTICES FOR DIETARY SUPPLEMENTS (3093)食品添加剂的生产操作。

元素杂质232INTRODUCTIONThis chapter specifies limits for the amounts of elemental impurities in drug products. Regardless of the approach used, compliance with the limits specified is required for all drug products unless otherwise specified in an individual monograph or specifically excluded in this Introduction. 1S ( USP40 )Elemental impurities include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment and the container–closure system). When elemental impurities are known to be present, have been added, or have the potential for introduction, assurance of compliance to the specified levels is required. A risk-based control strategy may be appropriate when analysts determine how to assure compliance with this standard. Due to the ubiquitous nature of arsenic, cadmium, lead, and mercury, they (at the minimum) must be considered in the risk assessment.介绍本章规定了药物产品中元素杂质含量的限制。

232元素杂质—限度介绍本通则明确了药品中各元素杂质的限度。

元素杂质包括催化剂、环境污染物，可能存在于原料药、赋形剂、制剂中。

这些杂质或自然产生，或有意添加，或由于不注意而引入（例如，与处理设备相互作用）。

当知道元素杂质存在，或有意添加，或有引入的可能性，应当保证这些杂质符合限度要求。

可以采用基于风险的控制策略来确保产品满足限度标准。

由于砷、镉、铅和汞普遍存在的特性，风险控制策略至少应考虑这四种元素。

不管采用什么分析方法，所有药品均应满足元素杂质限度标准。

本章提出的限度标准不适用于赋形剂与原料药，除非本章或各论中明确说明。

然而赋形剂与原料药中元素杂质水平必须报告。

本章提出的限度标准同样不适用于兽用产品和常规疫苗。

饮食补充剂和它们的成份的相关规定见于《饮食补充剂中的元素杂质》2232 .1形态分析对于元素氧化态、有机络合态、化合态的测定，称为形态分析。

每种元素可能存在不同的氧化态或络合态。

然而，砷和汞应特别关注，因为它们的无机态和络合有机态具有不同的毒性。

砷的限度标准是基于无机态（毒性最大）。

假定样品中所有砷都是无机态，可用总砷测定法检测。

当总砷法结果超过限度标准，应当使用能够对不同形态砷定量的分析方法，以确定无机态砷是否满足法定要求。

汞的限度标准是基于无机（2+）氧化态。

甲基汞（毒性最强），但对于药品，通常不是问题。

这样，汞限度标准的确定是基于汞最常见的无机形态。

对于可能含有甲基汞的产品（例如，从鱼中得到的物质），相应的汞限度标准将在各论中提及。

接触途径元素杂质的毒性跟接触程度（生物利用度）有关。

对于每一种元素杂质接触程度取决于给药途径：口服、肠外注射、吸入。

这些限度确定是基于慢性接触。

为建立标准需要，另两种给药途径，黏膜和局部接触可认为跟口服相同，而表1中的PDE值也适用于这些产品[注意—药品的给药途径在制剂通则中介绍制剂通则1151. ]Change to read:药品表1的第二至第四栏给出的限度值是一些元素杂质的基本日剂量PDE值（病人按指定给药途径服用）。

制药行业常用英语词汇（缩写、中英文对照）制药行业常用英语词汇（缩写、中英文对照）序号中文英文及缩写 1 药品生产质量管理规范 GMP：GoodManufacturingPractice 2 国家食品与药品监督管理局 State Food and Drug Administration 3 总则 GeneralProvisions 4 《中华人民共和国药品管理法》 the DrugAdministration Law of the People"s Republic of China 5 制剂Preparation 6 原料药 API: Active PharmaceuticalIngredient 7 成品finished goods 8 工序 process 9 机构与人员 organization and personnel 10 专业知识 professional knowledge 11 生产经验 production e_perience 12 组织能力 organizational skill 13 技术人员 technical staff 14 实施implementation 15 药品生产 pharmaceutical manufacturing 16 质量管理quality management 17 质量检验 quality inspection 18 专业技术培训professional and technicaltraining 19 基础理论知识 basic theoreticalknowledge 20 实际操作技能 practical operationskills 21 高生物活性 highly potent 22 高毒性 high to_icity 23 污染 contamination 24 考核评估 assessment25 厂房与设施 buildings and facilities 26 生产环境 production environment 27 空气洁净级别 clean air level 28 昆虫 insect 29 洁净室（区）clean room(area) 30 光滑 smooth 31 无裂缝 no cracks 32 无颗粒物脱落no particle shedding 33 耐受 endure 34 消毒 disinfection 35 无菌 sterile 36 交界处 junction, joint 37 弧形 arc 38 灰尘积聚 dues accumulation 39 储存区 store area 40 生产规模 production scale 41 设备 equipment 42 物料material 43 中间产品 intermediate product 44 待验品 quarantined material 45 交叉污染 cross-contamination 46 管道 pipeline, ductwork 47 风口 tuber 48 公用设施, 公用工程 utilities of publicservice 49 照明 lighting 50 照度 illumination 51 应急紧急情况 emergency 52 净化 purification, clean 53 微生物, 微生物学, 微生物 micro-organism,microbiology,microbiologic的 54 监测 monitoring 55 记录 record 56 天棚天花板 ceiling, roof 57 密封 seal 58 静压差 Static DifferentialPressure 59 温度 temperature 60 相对湿度 RH: Relative Humidity 61 低漏地漏 floor drainer 62 青霉素penicillin 63 分装室 separating room, fillingroom 64 相对负压 relative negativepressure 65 废气 waste gas,e_hausted air 66 &beta;－内酰胺结构类药品 &beta;-Lactasestructure drug, drugs of &beta;-Lactic group 67 避孕药品 contraceptives 68 激素类 hormone 69 抗肿瘤类 anti-tumor, oncology 70 放射性药品 Radiopharmaceuticals 71 包装 packing, package 72 循环使用recycling 73 微粒 particles 74 辐射 radiation, irradiation 75 细菌bacteria 76 病毒 virus 77 细胞 cell 78 脱毒前后 pre and postdeto_ification 79 活疫苗与灭活疫苗 activevaccine/inactivatedvaccine 80 人血液制品 blood products 81 预防制品prevention products82 灌装 filling 83 中药 Chinesetraditional medicines 84 前处理pretreatment 85 提取 e_traction 86 浓缩 concentration 87 动物脏器viscera of animal,organ ofanimal 88 蒸、炒、炙、煅 ing, frying,sunburn, testing 89 炮制concocted 90 通风 ventilation 91 除烟 smoke removal 92 除尘 dust removal 93 降温设施 temperature-reducingestablishment,cooling 94 筛选 screening, sift 95 切片 slicing 96 粉碎 grinding 97 压缩空气 pressed air 98 惰性气体 noble gas 99 取样 Sling 100 称量室weighing room, dispensingroom 中药标本 Chinese herbalsle,e_emplar of TCM 102 检定鉴定 verification, identification 103 同位素 Isoe 104 设备 equipment 105 选型 model/type selection 106 耐腐蚀anticorrosion 107 吸附 adsorption, absorption 108 润滑剂, 润滑 lubricant, lubricate 109 冷却剂 coolant 110 流向 flow direction111 纯化水 PW: Purified Water 112 注射用水 WFI: Water for Injection 113 滋生 breeding 114 储罐 tank 115 死角 neglected portion 116 盲管blind pipe 117 纤维 fiber 118 疏水性 hydrophobicity 119 仪表instrumentation 120 量具 measuring tool 121 衡器 weighing instrument 122 精密度 precision 123 维修 maintenance 124 不合格 disqualified reject 125 物料 material 126 购买 purchasing 127 发放 releasing 128 产地 origin 129 入库 loading 130 固体 solid 131 液体 liquid 132 挥发性 volatile 133 净药材 medicine, TCM 134 麻醉药品 narcotics 135 精神药品 psychotropic drug 136 易燃 bustible 137 易爆 e_plosive 138 验收 acceptance 139 使用说明书instruction140 标签 label 141 卫生, 清洁/消毒 sanitation 142 车间, 辅房workshop 143 间隔时间 time interval 144 清洁剂 detergent 145 消毒剂disinfectant 146 废弃物 wastes 147 更衣室 changing room 148 工作服, work clothes 149 颗粒性物质, 颗粒剂 granules 150 耐药菌株 drug-resistantstrain 151 传染病 infectiousdisease 152 皮肤病 dermatitis 153 验证verification, validation 154 确认 qualification 155 安装 installation156 运行 running operation 157 性能 performance 158 原辅料 raw material and incipient 159 文件 document 160 投诉 plaint 161 报废 reject 162 品名product name 163 处方 preion, formula 164 技术参数 technicalparameter165 容器 container 166 半成品 semi-finished product,intermediate 167 申请 lication 168 稳定性 stability169 起草 draft 170 生产管理 production management,manufacturing control.171 事故 accident 172 混淆 mi_-up 173 喷雾 spray 174 合格证certificate 175 清场 clearance 176 质量管理 quality management 177 内控internal control,on-line test 178 滴定液 tartan 179 培养基 medium 180 有效期 validity, e_piry date,shelf life 181 产品销售与收回 product sales andrecovery/recall 182 投诉与不良反应报告 plaints and adversereaction 自检self-inspection 184 附则 schedule endi_ 185 平衡 balance 186 饮用水drinking water, potablewater 187 蒸馏法 distillation 188 离子交换法 ion e_change 189 反渗透法 RO: Reverse Osmosis 190 附加剂添加剂 additives 191 滞留 stranded resort 192 批 batch, lot 193 组分, 组成 ponent 194 无纤维脱落的过滤器 non-fiber-releasingfilter 195 活性成份 Active Ingredient 196 非活性成份 Inactive ingredient 197 中间产品 in-processproduct,intermediate product198 批号 batch number 199 药用物料 medicated feed 20__药用预混合料 medicated premi_ 201 质量控制部门 Quality control department 202 理论产量 Theoretical yield 203 实际产量 Actual yield 204 比率 Percentage, rate 205 验收标准可接受标准 Acceptance criteria 206 代表性样品 Representative sle 207 微粒状的 particulate 208 污染物contaminant 209 石棉 asbestos 210 诊断 diagnosis 211 缓解 mitigation 212 化学变化 chemical change 213 组分 ingredient, ponent 214 制备 fabricate preparation 215 复合 pound 216 混合 blend 217 加工 processing 218 浓度concentration 219 单位剂量 unit dose 220 药品包装容器 drug product containers 221 密封件, 封盖 closure 222 效价 Titer 223 纯度 purity 224 规格 strength 225 监督 supervise, monitor 226 实验室 laboratory 227 无菌操作 aseptic operation,sterileoperation 228 层流 laminar flow 229 湍流 turbulent air flow 230 空气过滤 air filtration 231 空气加热 air heating 232 预过滤器 profiler 233 排气系统 e_haust system 234 管件 plumbing 235 虹吸倒流 back-siphon age 236 污水 sewage 237 废料 refuse 238 盥洗设备 toilet facilities 239 空气干燥器 air drier 240 垃圾 trash 241 有机废料 organic waste 242 杀鼠剂rodenticides 243 杀昆虫剂 insecticides 244 杀真菌剂 fungicides 245 熏蒸剂 fumigating reagents 246 去垢剂 cleaning agents 247 消毒剂 sanitizing agents 248 滂沱剂 lubricant 249 自动化设备 automatic, mechanical,or electronic equipment 250 微型胶卷 microfilm 251 注射剂 injection 252 灭菌设备 sterilization equipment 253 无菌取样技术 aseptic sling techniques 254 显微镜 microscope 255 热, 内毒素 pyrogen, endoto_in 256 偏差 deviation 257 变更 change control 258 进料 charge-in 259 项目代码 item code 260 鉴别 identify 261 片剂 tablet 262 胶囊 capsule 263 颗粒剂 granule 264 溶解时间溶出时间 dissolution time 265 澄明度clarity 266 隔离系统 quarantinesystem, isolation system 267 返工reprocessing 268 发放 issuance, release 269 非处方药 OTC:over-the-counter 270 处方药 preed medicine 271 皮肤科药、牙粉、胰岛素、喉片dermatological,dentifrice,insulin, or throat lozenge product 272 保险包装 ter-resistant package 273 明胶硬胶囊 hard gelatin capsule 274 顺势治疗homeopathic 275 入库 warehousing 276 变质 deteriorate 277 准确性accuracy 278 灵敏性 sensitivity 279 特异性 specificity 280 重复性reproducibility, repeatability 281 变应原提取物 allergenic e_tracts 282 眼膏 ophthalmic ointment 283 粗糙或磨蚀物质 harsh or abrasivesubstances 284 控释制剂 controlled-releasedosage form 285 实验动物 laboratory animals 286 供应商 Supplier 287 光谱 spectrum 288 测量单位 units of measure 289 换算系数 conversion factors 290 试剂 reagent 291 安慰剂placebo 292 明确地 e_plicitly 293 取代 supersede 294 溶液 solution 295 批准 roval 296 (美国)食品药品监督管理局 FDA: Food and DrugAdministration 297 标准操作程序 SOP: StandardOperatingProcedure 298 质量保证 QA: Quality Assurance 299 质量控制QC:Quality Control 300 批生产记录 BPR: Batch ProductionRecord 301 批检验记录 BAR: Batch AnalysisRecord 302 工艺规程 PP: Process Procedure 303 健康,安全,环保 EHS: Environment,Health andSafe 304 美国联邦法规 CFR: Code of FederalRegulation 305 美国药典USP: The UnitedStatesPharmacopeia 306 欧洲药典 EP: European pharmacopeia 307 英国药典 BP: British pharmacopeia 308 药物主文件 DMF: Drug Master File 309 验证主计划 VMP: Validation MasterPlan 310 验证方案 VP: Validation Protocol 311 验证报告 : Validation Report 312 安装确认 IQ: Installation Qualification313 运行确认 OQ: Operation Qualification 314 性能确认 PQ: Performance Qualification 315 超出标准(限度) OOS: Out of Specification 316 冻干产品 freeze-dry product,lyophilizated product 317 工厂主述文件SMF: Site Master File。

GOOD MANUFACTURE PRACTICE 美国药品生产质量管理规范（CGMP）二○○三年十二月目 录210.1 cGMP法规的地位 (2)210.2 cGMP法规的适用性 (2)210.3 定义 (2)211-A- 总则 (4)211-B- 组织与人员 (4)211-C- 厂房和设施 (5)211-D- 设备 (7)211-E- 成份、药品容器和密封件的控制 (8)211-F- 生产和加工控制 (10)211-G- 包装和标签控制 (11)211-H- 贮存和销售 (13)211-I- 实验室控制 (14)211-J- 记录和报告 (16)211-K- 退回的药品和回收处理 (20)210部分—人用及兽用药品的生产、加工、包装或贮存的CGMP210.1 cGMP法规的地位(a) 在本部分及21CFR 211—226部分中陈述的法规是在药品生产、加工、包装或贮存中使用的现行生产质量管理规范及使用的设施或控制的最低标准，以保证该药品符合联邦食品、药品及化妆品法对安全性的要求，具有均一性和效价(或含量)并符合或代表其生产过程的质量及纯度等特征。

(b) 凡是在药品生产、加工、包装或贮存过程中存在任何不符合本部分及21CFR 211—226部分中陈述的法规的药品，依据联邦食品、药品及化妆品法501 (a)(2)-(B)，该药应被视为劣药，同时导致该事故发生的负责人应受相应的法规的制裁。

210.2 cGMP法规的适用性(a) 本部分及21CFR 211—226适用于普通药品，21CFR 600—680适用于人用生物制品，除非另有明确规定，否则上述两者之间应该是相互补充而不是相互取代。

如有上述两部分的法规不适用的药品，则可用特定的具体法规来替代。

210.3 定义(a) 在联邦食品、药品及化妆品法201部分中包含的定义和解释、说明适用于21CFR 211—226部分中的术语。

(b) 下面定义的术语适用于本部分及21CFR 211—226。

232元素杂质—限度123介绍4本通则明确了药品中各元素杂质的限度。

元素杂质包括催化剂、环境污染物，5可能存在于原料药、赋形剂、制剂中。

这些杂质或自然产生，或有意添加，或6由于不注意而引入（例如，与处理设备相互作用）。

当知道元素杂质存在，或7有意添加，或有引入的可能性，应当保证这些杂质符合限度要求。

可以采用基8于风险的控制策略来确保产品满足限度标准。

由于砷、镉、铅和汞普遍存在的9特性，风险控制策略至少应考虑这四种元素。

不管采用什么分析方法，所有药10品均应满足元素杂质限度标准。

11本章提出的限度标准不适用于赋形剂与原料药，除非本章或各论中明确说12明。

然而赋形剂与原料药中元素杂质水平必须报告。

13本章提出的限度标准同样不适用于兽用产品和常规疫苗。

饮食补充剂和它们14的成份的相关规定见于《饮食补充剂中的元素杂质》2232 .11516形态分析17对于元素氧化态、有机络合态、化合态的测定，称为形态分析。

每种元素可能存在不同的氧化态或络合态。

然而，砷和汞应特别关注，因为它们的无机态1819和络合有机态具有不同的毒性。

20砷的限度标准是基于无机态（毒性最大）。

假定样品中所有砷都是无机态，可用总砷测定法检测。

当总砷法结果超过限度标准，应当使用能够对不同形态2122砷定量的分析方法，以确定无机态砷是否满足法定要求。

23汞的限度标准是基于无机（2+）氧化态。

甲基汞（毒性最强），但对于药品，24通常不是问题。

这样，汞限度标准的确定是基于汞最常见的无机形态。

对于可25能含有甲基汞的产品（例如，从鱼中得到的物质），相应的汞限度标准将在各26论中提及。

27282930接触途径31元素杂质的毒性跟接触程度（生物利用度）有关。

对于每一种元素杂质接触程度取决于给药途径：口服、肠外注射、吸入。

这些限度确定是基于慢性接触。

3233为建立标准需要，另两种给药途径，黏膜和局部接触可认为跟口服相同，而表1中的PDE值也适用于这些产品[注意—药品的给药途径在制剂通则中介绍制剂通34则1151. ]35Change to read:363738药品39表1的第二至第四栏给出的限度值是一些元素杂质的基本日剂量PDE值（病40人按指定给药途径服用）。

231 HEAVY METALSThis test is provided to demonstrate that the content of metallic impurities that are colored by sulfide ion, under the specified test conditions, does not exceed the Heavy metals limit specified in the individual monograph in percentage (by weight) of lead in the test substance, as determined by concomitant visual comparison (see Visual Comparison in the section Procedure under Spectrophotometry and Light-Scattering 851) with a control prepared from a Standard Lead Solution. [NOTE—Substances that typically will respond to this test are lead, mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper, and molybdenum.]Determine the amount of heavy metals by Method I, unless otherwise specified in the individual monograph. Method I is used for substances that yield clear, colorless preparations under the specified test conditions. Method II is used for substances that do not yield clear, colorless preparations under the test conditions specified for Method I, or for substances that, by virtue of their complex nature, interfere with the precipitation of metals by sulfide ion, or for fixed and volatile oils. Method III, a wet-digestion method, is used only in those cases where neither Method I nor Method II can be usedSpecial ReagentsLead Nitrate Stock Solution— Dissolve 159.8 mg of lead nitrate in 100 mL of water to which has been added 1 mL of nitric acid, then dilute with water to 1000 mL. Prepare and store this solution in glass containers free from soluble lead salts.Standard Lead Solution— On the day of use, dilute 10.0 mL of Lead Nitrate Stock Solution with water to 100.0 mL. Each mL of Standard Lead Solution contains the equivalent of 10 µg of lead. A comparison solution prepared on the basis of 100 µL of Standard Lead Solution per g of substance being tested contains the equivalent of 1 part of lead per million parts of substance being tested.Method IpH 3.5 Acetate Buffer— Dissolve 25.0 g of ammonium acetate in 25 mL of water, and add 38.0 mL of 6 N hydrochloric acid. Adjust, if necessary, with 6 N ammonium hydroxide or 6 N hydrochloric acid to a pH of 3.5, dilute with water to 100 mL, and mix.Standard Preparation— Into a 50-mL color-comparison tube pipet 2 mL of Standard LeadSolution (20 µg of Pb), and dilute with water to 25 mL. Using a pH meter or short-range pH indicator paper as external indicator, adjust with 1 N acetic acid or 6 N ammonium hydroxide to a pH between 3.0 and 4.0, dilute with water to 40 mL, and mix.Test Preparation— Into a 50-mL color-comparison tube place 25 mL of the solution prepared for the test as directed in the individual monograph; or, using the designated volume of acid where specified in the individual monograph, dissolve in and dilute with water to 25 mL the quantity, in g, of the substance to be tested, as calculated by the formula:2.0/(1000L),in which L is the Heavy metals limit, as a percentage. Using a pH meter orshort-range pH indicator paper as external indicator, adjust with 1 N acetic acid or 6 N ammonium hydroxide to a pH between 3.0 and 4.0, dilute with water to 40 mL, and mix. Monitor Preparation— Into a third 50-mL color-comparison tube place 25 mL of a solution prepared as directed for Test Preparation, and add 2.0 mL of Standard Lead Solution. Using a pH meter or short-range pH indicator paper as external indicator, adjust with 1 N acetic acid or 6 N ammonium hydroxide to a pH between 3.0 and 4.0, dilute with water to 40 mL, and mix.Procedure— To each of the three tubes containing the Standard Preparation, the Test Preparation, and the Monitor Preparation, add 2 mL of pH 3.5 Acetate Buffer, then add 1.2 mL of thioacetamide–glycerin base TS, dilute with water to 50 mL, mix, allow to stand for 2 minutes, and view downward over a white surface *: the color of the solution from the Test Preparation is not darker than that of the solution from the Standard Preparation, and the color of the solution from the Monitor Preparation is equal to or darker than that of the solution from the Standard Preparation. [NOTE—If the color of the Monitor Preparation is lighter than that of the Standard Preparation, use Method II instead of Method I for the substance being tested.]Method IINOTE—This method does not recover mercury.pH 3.5 Acetate Buffer— Prepare as directed under Method I.Standard Preparation— Pipet 4 mL of the Standard Lead Solution into a suitable test tube, and add 10 mL of 6 N hydrochloric acid.Test Preparation— Use a quantity, in g, of the substance to be tested as calculated by the formula:4.0/(1000L),in which L is the Heavy metals limit, as a percentage. Transfer the weighed quantity of the substance to a suitable crucible, add sufficient sulfuric acid to wet the substance, and carefully ignite at a low temperature until thoroughly charred. (The crucible may be loosely covered with a suitable lid during the charring.) Add to the carbonized mass 2 mL of nitric acid and 5 drops of sulfuric acid, and heat cautiously until white fumes no longer are evolved. Ignite, preferably in a muffle furnace, at 500 to 600, until the carbon is completely burned off (no longer than 2 hours). If carbon remains, allow the residue to cool, add a few drops of sulfuric acid, evaporate, and ignite again. Cool, add 5 mL of 6 N hydrochloric acid, cover, and digest on a steam bath for 10 minutes. Cool, and quantitatively transfer the solution to a test tube. Rinse the crucible with a second 5-mL portion of 6 N hydrochloric acid, and transfer the rinsing to the test tube.Monitor Preparation— Pipet 4 mL of the Standard Lead Solution into a crucible identical to that used for the Test Preparation and containing a quantity of the substance under test that is equal to 10% of the amount required for the Test Preparation. Evaporate on a steam bath to dryness. Ignite at the same time, in the same muffle furnace, and under the same conditions used for the Test Preparation. Cool, add 5 mL of 6 N hydrochloric acid, cover, and digest on a steam bath for 10 minutes. Cool, and quantitatively transfer to a test tube. Rinse the crucible with a second 5-mL portion of 6 N hydrochloric acid, and transfer the rinsing to the test tube.Procedure— Adjust the solution in each of the tubes containing the Standard Preparation, the Test Preparation, and the Monitor Preparation with ammonium hydroxide, added cautiously and dropwise, to a pH of 9. Cool, and adjust with glacial acetic acid, added dropwise, to a pH of 8, then add 0.5 mL in excess. Using a pH meter or short-range pH indicator paper as external indicator, check the pH, and adjust, if necessary, with 1 N acetic acid or 6 N ammonium hydroxide to a pH between 3.0 and 4.0. Filter, if necessary,washing the filter with a few mL of water, into a 50-mL color-comparison tube, and then dilute with water to 40 mL. Add 2 mL of pH 3.5 Acetate Buffer, then add 1.2 mL of thioacetamide–glycerin base TS, dilute with water to 50 mL, mix, allow to stand for 2 minutes, and view downward over a white surface*: the color of the solution from the Test Preparation is not darker than that of the solution from the Standard Preparation, and the color of the solution from the Monitor Preparation is equal to or darker than that of the solution from the Standard Preparation. [NOTE—If the color of the solution from the Monitor Preparation is lighter than that of the solution from the Standard Preparation, proceed as directed for Method III for the substance being tested.]Method IIIpH 3.5 Acetate Buffer— Prepare as directed under Method I.Standard Preparation— Transfer a mixture of 8 mL of sulfuric acid and 10 mL of nitric acid to a clean, dry, 100-mL Kjeldahl flask, and add a further volume of nitric acid equal to the incremental volume of nitric acid added to the Test Preparation. Heat the solution to the production of dense, white fumes; cool; cautiously add 10 mL of water; and, if hydrogen peroxide was used in treating the Test Preparation, add a volume of 30 percent hydrogen peroxide equal to that used for the substance being tested. Boil gently to the production of dense, white fumes. Again cool, cautiously add 5 mL of water, mix, and boil gently to the production of dense, white fumes and to a volume of 2 to 3 mL. Cool, dilute cautiously with a few mL of water, add 2.0 mL of Standard Lead Solution (20 µg of Pb), and mix. Transfer to a 50-mL color-comparison tube, rinse the flask with water, adding the rinsing to the tube until the volume is 25 mL, and mix.Test Preparation— Unless otherwise indicated in the individual monograph, use a quantity, in g, of the substance to be tested as calculated by the formula:2.0/(1000L),in which L is the Heavy metals limit, as a percentage.If the substance is a solid— Transfer the weighed quantity of the test substance to a clean, dry, 100-mL Kjeldahl flask. [NOTE—A 300-mL flask may be used if the reaction foams excessively.] Clamp the flask at an angle of 45, and add a sufficient quantity of a mixtureof 8 mL of sulfuric acid and 10 mL of nitric acid to moisten the substance thoroughly. Warm gently until the reaction commences, allow the reaction to subside, and add portions of the same acid mixture, heating after each addition, until a total of 18 mL of the acid mixture has been added. Increase the amount of heat, and boil gently until the solution darkens. Cool, add 2 mL of nitric acid, and heat again until the solution darkens. Continue the heating, followed by addition of nitric acid until no further darkening occurs, then heat strongly to the production of dense, white fumes. Cool, cautiously add 5 mL of water, boil gently to the production of dense, white fumes, and continue heating until the volume is reduced to a few mL. Cool, cautiously add 5 mL of water, and examine the color of the solution. If the color is yellow, cautiously add 1 mL of 30 percent hydrogen peroxide, and again evaporate to the production of dense, white fumes and a volume of 2 to 3 mL. If the solution is still yellow, repeat the addition of 5 mL of water and the peroxide treatment. Cool, dilute cautiously with a few mL of water, and rinse into a 50-mL color-comparison tube, taking care that the combined volume does not exceed 25 mL.If the substance is a liquid— Transfer the weighed quantity of the test substance to a clean, dry, 100-mL Kjeldahl flask. [NOTE—A 300-mL flask may be used if the reaction foams excessively.] Clamp the flask at an angle of 45, and cautiously add a few mL of a mixture of 8 mL of sulfuric acid and 10 mL of nitric acid. Warm gently until the reaction commences, allow the reaction to subside, and proceed as directed for If the substance is a solid, beginning with “add portions of the same acid mixture.”Monitor Preparation— Proceed with the digestion, using the same amount of sample and the same procedure as directed in the subsection If the substance is a solid in the section Test Preparation, until the step “Cool, dilute cautiously with a few mL of water.” Add 2.0 mL of Lead Standard Solution (20 µg of lead), and mix. Transfer to a 50-mL color comparison tube, rinse the flask with water, adding the rinsing to the tube until the volume is 25 mL,Procedure— Treat the Test Preparation, the Standard Preparation, and the Monitor Preparation as follows. Using a pH meter or short-range pH indicator paper as external indicator, adjust the solution to a pH between 3.0 and 4.0 with ammonium hydroxide (a dilute ammonia solution may be used, if desired, as the specified range is approached),dilute with water to 40 mL,To each tube add 2 mL of pH 3.5 Acetate Buffer, then add 1.2 mL ofthioacetamide–glycerin base TS, dilute with water to 50 mL, mix, allow to stand for 2 minutes, and view downward over a white surface*: the color of the Test Preparation is not darker than that of the Standard Preparation, and the color of the Monitor Preparation is equal to or darker than that of the Standard Preparation.<231> 重金属本试验系在规定的试验条件下，金属离子与硫化物离子反应显色，通过制备的标准铅溶液目视比较测定，以确证供试品中重金属杂质含量不超过各论项下规定的限度（以供试品中铅的百分比表示，以重量计）。

美国药典USP1231制药用水中文翻译USP33-制药用水<1231>制药用水<1231>引言在药品、原料药和中间体，药典产品以及分析试剂的加工、制备和生产过程中，水被广泛用作一原料，组分和溶剂。

此通用章节的信息提供了有关水的其它信息：未被包括在的水的专论中的属性，可以用以提高水质量的处理技术，以及在选择水源时应考虑最低水质量标准的描述。

此信息章节并未打算替代现有的条例或指导，现有的这些条例或指导涉及USA和国际的（ICH或WHO）的GMP问题，工程指导或其它关于水的条例（FDA、EPA或WHO）指导。

其内容有有助于使用者更好地理解制药用水问题以及一些仅针对水的微生物和化学问题。

此章节并不是关于制药用水的一个全面综合性的文件。

它包括在水的处理、贮存和使用时需要考虑的基本信息点。

保证制药用水以及生产符合相适用的政府条例、指南和各种类型的水的药典标准是使用者的职责。

这些水的化学纯度的控制是很重要的，并且是本药典中各论的主要目的。

与其它药典产品不同，大批量水专论（纯化水和注射用水）也限制此产品是如何被生产的，因为认为纯化过程的本质与完善程度与（水）最终的纯度直接相关。

在这些个论中所列的化学属性应被看作为一组最低的规范要求。

对于某些应用来说，可能需要更加严格的规范以保证适合其特定的用途。

关于这些水的适当应用的基本指导可以在正文中找到，并且在本章节中给出更进一步的解释。

对于很多水的用途来说，控制其微生物质量是很重要的。

由于健康与安全的原因，所有具有药典标准的包装形式的水要求是无菌的，因为这些水的一些预期用途有此要求。

USP认为大批量专论水的微生物规范是不适当的，并且未被包括在这些水的专论中。

这些水可以被用于不同的用途，一些要求严格的微生物控制，而一些却未要求。

对于一给定大批量水来说，所需的微生物规范取决于其用途。

对于一些没有相关规范和检测的使用者来说，将不必需负担此难于控制的（水的微生物）属性的单个规范。

USP 36-233 修订公告20130128 （中英文）<232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures<232>元素杂质---限度和<233>元素杂质—检测方法Pursuant to a Revision Bulletin posted on November 15, 2012 and updated on November 21, 2012, and in accordance with the Rules and Procedures of the 2010–2015 Council of Experts, the Executive Committee of the Council of Experts (CoE EC) postponed the official dates of <232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures. The purpose for the postponement was to allow adequate time for the CoE EC to adjudicate and render a decision on three appeals related to the two general chapters. Due to the similarity of issues raised, these appeals were consolidated and considered simultaneously as a single appeal. As noted in the prior Revision Bulletin, the portion of the appeal that was allowed to proceed and was considered by the CoE EC was that related to the content of the general chapters and their official dates. The portion of the appeal that related to the planned implementation of these chapters effective May 2014 through a proposed General Notices provision was denied as untimely, as the General Notices proposal at issue had not yet appeared in Pharmacopeial Forum (PF) forpublic notice and comment.在2012年11月15日修订公告贴出，在2012年11月21日更新后，根据2010-2015专家委员会规则和程序，专家执行委员会推迟了<232>【元素杂质—限度】和<233>【元素杂质---方法】的公布时间。

5634〈232〉 Elemental Impurities—Limits / Chemical TestsSecond Supplement to USP 35–NF 30Table 1. Elemental Impurities for Drug Products (Continued)Individual components may need to be limited at levels dif-ferent from those in the table depending on monograph-Paren-Inhala-specific mitigating factors.]Oral teral tional LVP Daily Daily Daily Compo-Table 2. Default Concentration Limits for Drug Substances andDose Dose Dose nent ExcipientsPDE a PDE PDE LimitElement (µg/day)(µg/day)(µg/day)(µg/g)Concentra-Concentra-Concentra-Nickel 50050 1.5 5.0tion Limits tion Limits tion Limits Vanadium 1001030 1.0(µg/g) for (µg/g) for (µg/g) for Oral Drug Parenteral Inhalational Copper 10001007025Products Drug Prod-Drug Prod-a PDE = Permissible daily exposure based on a 50-kg person.with a ucts with a ucts with a b See Speciation section.Maximum Maximum Maximum *Not a safety concern.Daily Dose Daily Dose Daily Dose Element of ≤10 g/dayof ≤10 g/dayof ≤10 g/dayOptions for Demonstrating ComplianceCadmium 2.50.250.15Lead0.50.50.5Inorganic DRUG PRODUCT ANALYSIS OPTIONarsenic 0.150.150.15Inorganic The results obtained from the analysis of a typical dosage mercury 1.50.150.15unit, scaled to a maximum daily dose, are compared to the Iridium 10 1.00.15Daily Dose PDE .Osmium 10 1.00.15Daily Dose PDE ≥ measured value (µg/g) × maximum dailyPalladium 10 1.00.15dose (g/day)Platinum 10 1.00.15Rhodium 10 1.00.15The measured amount of each impurity is NMT the Daily Ruthenium 10010 1.5Dose PDE , unless otherwise stated in the individual monograph.Chromium ** 2.5Molybdenum 10 1.025Nickel 50 5.00.15SUMMATION OPTIONVanadium 1001030Copper 100107Separately add the amounts of each elemental impurity (in µg/g) present in each of the components of the drug *Not a safety concern.product using the following equation:ANALYTICAL TESTINGDaily Dose PDE ≥ [ΣM 1(C M × W M )] × D DIf, by validated processes and supply-chain control, manu-wherefacturers can demonstrate the absence of impurities, then M = each ingredient used to manufacture a dosage unit further testing is not needed. When testing is done to C M = element concentration in component (drug sub-demonstrate compliance, proceed as directed in general stance or excipient) (µg/g)chapter Elemental Impurities—Procedures 〈233〉, and mini-W M = weight of component in a dosage unit (g/dosage mally include As, Cd, Pd, and Hg in the Target Element eval-unit)uation.s 2S (USP35)D D = number of units in the maximum daily dose (unit/day)The result of the summation of each impurity is NMT the Daily Dose PDE , unless otherwise stated in the individual monograph. Before products can be evaluated using this option, the manufacturer must validate that additional ele-mental impurities cannot be inadvertently added through Add the following:the manufacturing process.DRUG SUBSTANCE AND EXCIPIENTSs〈233〉 ELEMENTAL IMPURITIES—The presence of elemental impurities in drug substances PROCEDURESand excipients must be controlled and, where present, re-ported. The acceptable levels for these impurities depend on the material’s ultimate use. Therefore, drug product manu-facturers must determine the acceptable level of elemental impurities in the drug substances and excipients used to INTRODUCTIONproduce their products.This chapter describes two analytical procedures (Proce-The values provided in Table 2 represent concentration dures 1 and 2) for the evaluation of the levels of the ele-limits for components (drug substances and excipients) of mental impurities. The chapter also describes criteria for ac-drug products dosed at a maximum daily dose of ≤10 g/ceptable alternative procedures. Alternative procedures that day. These values serve as default concentration limits to aid meet the validation requirements described herein may be discussions between drug product manufacturers and the considered equivalent to Procedures 1 and 2 for the pur-suppliers of the components of their drug products. [N OTE —poses of this test. In addition, system standardization andSecond Supplement to USP 35–NF 30Chemical Tests / 〈233〉 Elemental Impurities—Procedures5635suitability evaluation using applicable reference materials COMPENDIAL PROCEDURES 1 AND 2 should be performed on the day of analysis. The require-ment for an elemental impurity test is specified in GeneralNotices and Requirements or in the individual monograph. Bymeans of verification studies, analysts will confirm that the Procedure and Detection Technique analytical procedures described herein, as well as alternativeanalytical procedures, are suitable for use on specified Procedure 1 can be used for elemental impurities generally material.amenable to detection by inductively coupled plas-ma–atomic (optical) emission spectroscopy (ICP–AES orICP–OES). Procedure 2 can be used for elemental impurities Speciation generally amenable to detection by ICP–MS. Before initialuse, the analyst should verify that the procedure is appropri-The determination of the oxidation state, organic complex ate for the instrument and sample used (procedural verifica-or combination is termed speciation. Analytical procedures tion) by meeting the Alternative Procedure Validation require-for speciation are not included in this chapter but examples ments below.may be found elsewhere in the USP–NF and in the literature.Sample PreparationDefinitionsForms of sample preparation include Neat, Direct Aqueous Concentrated Acid:Concentrated ultra-pure nitric, sulfu-Solution, Direct Organic Solution, and Indirect Solution. The ric, hydrochloric, or hydrofluoric acids or Aqua Regia.selection of the appropriate sample preparation depends onthe material under test and is the responsibility of the ana-Aqua Regia:Aqua regia is a mixture of concentrated hy-lyst. When a sample preparation is not indicated in the drochloric and nitric acids, typically at ratios of 3:1 or 4:1,monograph, an analyst may use any of the following appro-respectively.priately verified preparation procedures. In cases where spik-Matched Matrix:Solutions having the same solvent com-ing of a material under test is necessary to provide an ac-position as the Sample solution. In the case of an aqueous ceptable signal intensity, the blank should be spiked with solution, Matched Matrix would indicate that the same acids,the same Target Elements, and where possible, using the acid concentrations, and mercury stabilizer are used in both same spiking solution. Standard solutions may contain mul-preparations.tiple Target Elements. [NOTE—All liquid samples should be Target Elements:Elements with the potential of being weighed.]present in the material under test. Include As, Cd, Pd, and Neat:Used for liquids or alternative procedures that allows Hg in the target element evaluation when testing is done to the examination of unsolvated samples.demonstrate compliance. Target elements should also in-Direct Aqueous Solution:Used when the sample is solu-clude any elements that may be added through materialble in an aqueous solvent.processing or storage, and any elements whose presencemay interfere with the operation of the analytical proce-Direct Organic Solution:Used where the sample is solu-dures.ble in an organic solvent.Target Limit or Target Concentration:The acceptance Indirect Solution:Used when a material is not directly sol-value for the elemental impurity being evaluated. Exceeding uble in aqueous or organic solvents. Digest the sample us-the target limit indicates that a material under test exceeds ing a closed-vessel digestion procedure, similar to the proce-the acceptable value. The determination of compliance is dure provided below. The sample preparation scheme addressed in other chapters. [N OTE—When applying this should yield sufficient sample to allow quantification of each chapter to Elemental Impurities—Limits 〈232〉 and Elemental element at the limit specified in the corresponding mono-Contaminants in Dietary Supplements 〈2232〉,1Target Limits graph or chapter.can be approximated by dividing the Daily Dose PDEs by the Closed Vessel Digestion:This sample-preparation proce-maximum daily dose for the Drug Product Analysis Option in dure is designed for samples that must be digested in a〈232〉 or the Daily Serving PDE divided by the maximum Concentrated Acid using a closed-vessel digestion apparatus. daily serving size in 〈2232〉]Closed-vessel digestion minimizes the loss of volatile impuri-J:The concentration (w/w) of the element(s) of interest at ties. The choice of a Concentrated Acid depends on the sam-the Target Limit, appropriately diluted to the working range ple matrix. The use of any of the Concentrated Acids may be of the instrument. For example, if the target elements are appropriate, but each introduces inherent safety risks. There-Pb and As for an analysis of an oral solid drug product with fore, appropriate safety precautions should be used at alla daily dose of 10g/day using an inductively coupled plas-times. [N OTE—Weights and volumes provided may be ad-ma–mass spectrometry (ICP-MS). The target limit for these justed to meet the requirements of the digestion apparatus elements would be 0.5 µg/g and 0.15 µg/g (see Table 2 in used.]chapter 〈232〉). However, in this case, the linear dynamic An example procedure that has been shown to have range of the ICP-MS is known to extend from 0.01 ng/mL broad applicability is the following. Dehydrate and predigest to 0.1 µg/mL for these elements. Therefore, a dilution factor0.5 g of primary sample in 5 mL of freshly prepared Concen-of at least 1:10 is required to ensure that the analysis occurs trated Acid. Allow to sit loosely covered for 30 minutes in a in the linear dynamic range of the instrument. J would thus fume hood. Add an additional 10 mL of Concentrated Acid, equal 0.05 µg/mL and 0.015 µg/mL for Pb and As, respec-and digest, using a closed vessel technique, until digestion tively, when the dilution factor is added.or extraction is complete. Repeat if necessary by adding anadditional 5 mL of Concentrated Acid. [N OTE—Where closed Appropriate Reference Materials:Where Appropriate Ref-vessel digestion is necessary, follow the manufacturer’s rec-erence Materials are specified in the chapter, certified refer-ommended procedures to ensure safe use.]ence materials (CRM) from a national metrology institute(NMI), or reference materials that are traceable to the CRM Reagents:All reagents used for the preparation of sample of a NMI should be used. An example of a NMI in the and standard solutions should be free of elemental impuri-United States is the National Institute of Standards and ties, in accordance with Plasma Spectrochemistry 〈730〉. Technology.1This dietary supplement chapter is still under revision and will appear onlinein PF 38(3) [May–June 2012].5636〈233〉 Elemental Impurities—Procedures / Chemical Tests Second Supplement to USP 35–NF 30system well (60 seconds) before introducing the Sample in Procedure 1: ICP-AESorder to minimize carryover.]Analysis:Analyze according to the manufacturer’s sugges-Standardization solution 1:2J of the Target Element(s) intions for program and m/z. Calculate and report resultsa Matched Matrixbased on the original sample size. [N OTE—Appropriate Standardization solution 2:0.5J of the Target Element(s)measures must be taken to correct for matrix-induced inter-in a Matched Matrix ferences (e.g., argon chloride interference with arsenic Sample stock solution:Proceed as directed in Sample determinations.]Preparation above. Allow the sample to cool, if necessary.For mercury determination, add an appropriate stabilizer.ALTERNATE PROCEDURE VALIDATION Sample solution:Dilute the Sample Stock Solution with anappropriate solvent to obtain a final concentration of theIf a specified compendial procedure does not meet the Target Elements at NMT 2J.needs of a specific application, an alternative procedure may Blank:Matched Matrixbe used (see General Notices 6.30). Alternative procedures Elemental spectrometric system must be validated and must be acceptable and therefore (See Plasma Spectrochemistry 〈730〉.)equivalent to the compendial procedures for the purposes Mode:ICP of the test. The principles of validation are provided in gen-Detector:Optical detection system eral chapter Validation of Compendial Procedures 〈1225〉. Thelevel of validation necessary to ensure that an alternative Rinse:Diluent usedprocedure is acceptable depends on whether a limit test or Standardization:Standardization solution 1, Standardi- a quantitative determination is necessary. The requirementszation solution 2, and Blank for validation of an elemental impurities procedure for either System suitability type of determination are described below. Where this infor-Sample:Standardization solution 1mation differs from that presented in Validation of Com-pendial Procedures 〈1225〉, the parameters and acceptance Suitability requirementscriteria presented in this chapter take precedence. Any alter-Drift:Compare results obtained from Standardizationnative procedure that has been validated and meets the ac-solution 1 before and after the analyis of the Sampleceptance criteria that follow is considered to be equivalent solutions.to the compendial procedures for the purposes of this test.Suitability criteria:NMT 20% for each Target Element.[N OTE—If samples are high in mineral content, rinse systemwell (60 seconds) before introducing the Sample in order to LIMIT PROCEDURESminimize carryover.]The following section defines the validation parameters Analysis:Analyze according to the manufacturer’s sugges-for the acceptability of alternative limit procedures. Meeting tions for program and wavelength. Calculate and report re-these requirements must be demonstrated experimentally sults on the basis of the original sample size. [N OTE—Appro-using an appropriate system suitability procedure and refer-priate measures must be taken to correct for matrix-inducedence material. Meeting these requirements demonstrates interferences (e.g., Wavelength overlaps).]that the procedure is equivalent to the compendial proce-dure as a limit procedure for the Target Element.Procedure 2: ICP-MS The suitability of the method must be determined byconducting studies with material or mixture under test sup-plemented with known concentrations of each Target Ele-Standardization solution 1:2J of the Target Element(s) inment of interest at the appropriate acceptance limit concen-a Matched Matrixtration. The material or mixture under test must be spiked Standardization solution 2:0.5J of the Target Element(s)before any sample preparation steps are performed.in a Matched MatrixSample stock solution:Proceed as directed for SamplePreparation above. Allow the sample to cool, if necessary. DetectabilityFor mercury determination, add an appropriate stabilizer.Sample solution:Dilute the Sample stock solution with an Standard solution: A preparation of reference materials for appropriate solvent to obtain a final concentration of the the Target Element(s) at the Target Concentrations.Target Elements at NMT 2J.Spiked sample solution 1:Prepare a solution of sample Blank:Matched Matrix under test, spiked with appropriate reference materials forthe Target Elements at the Target Concentration, solubilized Elemental spectrometric systemor digested as described in Sample Preparation.(See Plasma Spectrochemistry 〈730〉.)Spiked sample solution 2:Prepare a solution of the sam-Mode:ICP. [N OTE—An instrument with a cooled sprayple under test, spiked with appropriate reference materials chamber is recommended. (A collision cell or reaction cellat 80% of the Target Concentration for the Target Elements, may also be beneficial.)]solubilized or digested as described in Sample Preparation.Detector:Mass spectrometerUnspiked sample solution: A sample of material under Rinse:Diluent usedtest, solubilized or digested in the same manner as the Sam-Standardization:Standardization solution 1, Standardi-ple solutions.zation solution 2, and BlankAcceptance criteriaSystem suitabilityNon-instrumental procedures:Spiked sample solution 1 Sample:Standardization solution 1provides a signal or intensity equivalent to or greater thanSuitability requirements that of the Standard Solution. Spiked sample solution 2 must Drift:Compare results obtained from Standardization provide a signal or intensity less than that of the Spiked solution 1 before and after the analysis of the Sample sample solution 1. [N OTE—The signal from each Spiked sam-solutions.ple solution is NLT the Unspiked sample solutiondetermination.]Suitability criteria:Drift NMT 20% for each Target Ele-ment. [N OTE—If samples are high in mineral content, rinse Instrumental procedures:The average value of thethree replicate measurements of Spiked sample solution 1 isSecond Supplement to USP 35–NF 30Physical Tests / 〈616〉 Bulk Density and Tapped Density of Powders 5637within (±15%) of the average value obtained for the repli-RUGGEDNESScate measurements of the Standard solution . The average value of the replicate measurements of Spiked sample solu-Perform the Repeatability analysis over three independent tion 2 must provide a signal intensity or value less than that events using the following events or combinations thereof:of the Standard solution . [N OTE —Correct the values obtained 1.on different days, orfor each of the spiked solutions using the Unspiked sample 2.with different instrumentation, or solution .]3.with different analysts.Acceptance criteriaRelative standard deviation:NMT 25% for each Target Precision for Instrumental MethodsElement(Repeatability)[N OTE —Non-instrumental precision is demonstrated by Specificitymeeting the Detectability requirement above.]Sample solutions:Six independent samples of the mate-The procedure must be able to unequivocally assess (see rial under test, spiked with appropriate reference materials Validation of Compendial Procedures 〈1225〉) each Target Ele-for the Target Elements at the Target Concentration .ment in the presence of components that may be expected Acceptance criteriato be present, including other Target Elements , and matrix components.Relative standard deviation:NMT 20% for each Target Element .Limit of Quantitation, Range, and LinearitySpecificityDemonstrated by meeting the Accuracy requirement.s 2S (USP35)The procedure must be able to unequivocally assess (see Validation of Compendial Procedures 〈1225〉) each Target Ele-ment in the presence of components that may be expected to be present, including other Target Elements , and matrix components.Physical Tests and QUANTITATIVE PROCEDURESDeterminationsThe following section defines the validation parameters for the acceptability of alternative quantitative procedures.Meeting these requirements must be demonstrated experi-mentally, using an appropriate system suitability procedure 〈616〉 BULK DENSITY AND and reference materials. Meeting these requirements dem-onstrates that the procedure is equivalent to the compendial TAPPED DENSITY OF POWDERSprocedure for the purpose of quantifying the Target Elements .AccuracyChange to read:Standard solutions:Prepare solutions containing the Tar-get Elements at concentrations ranging from 50% to 150%of J , using appropriate reference materials.BULK DENSITYTest samples:Prepare samples of the material under test spiked with appropriate reference materials before any sam-This general chapter has been harmonized with the corre-ple preparation steps (digestion or solubilization) at concen-sponding texts of the European Pharmacopoeia and/or the trations ranging from 50% to 150% of J for each Target Japanese Pharmacopoeia . 3The portion that is not harmo-Element .nized is marked with symbols (33) to specify this fact.3Acceptance criteriaThe bulk density of a powder is the ratio of the mass of Spike recovery:70%–150% for the mean of three rep-an untapped powder sample and its volume including the licate preparations at each concentrationcontribution of the interparticulate void volume. Hence, the bulk density depends on both the density of powder parti-cles and the spatial arrangement of particles in the powder Precisionbed. The bulk density is expressed in grams per mL (g/mL)although the international unit is kilograms per cubic meter (1g/mL = 1000kg/m 3) because the measurements aremade using cylinders. It may also be expressed in grams per REPEATABILITYcubic centimeter (g/cm 3). The bulking properties of a pow-der are dependent upon the preparation, treatment, and Test samples:Six independent samples of material understorage of the sample, i.e., how it was handled. The parti-test (taken from the same lot) spiked with appropriate refer-cles can be packed to have a range of bulk densities; how-ence materials for the Target Element(s) at the indicated ever, the slightest disturbance of the powder bed may result level.in a changed bulk density. Thus, the bulk density of a pow-Acceptance criteriader is often very difficult to measure with good reproducibil-ity and, in reporting the results, it is essential to specify how Relative standard deviation:NMT 20% for each Target the determination was made. The bulk density of a powder Elementis determined by measuring the volume of a known weight of powder sample, that may have been passed through a s sieve s 2S (USP35), into a graduated cylinder (Method I ), or by。

原料药中元素杂质的法规要求及控制方法张再奇元素杂质又称重金属，重金属原义指比重大于5的金属，元素杂质包括可能存在于原料、辅料或制剂中，来源于合成中催化剂残留、药品生产制备过程中引入或辅料中存在的、生产设备引入、或容器密闭系统引入。

某些元素杂质不仅对药品的稳定性、保质期产生不利影响，还可能因为潜在的毒性引发药物副反应。

因此欧盟、美国对杂质的控制越来越严格，对此项不断修订，中国在加入ICH后对此项检测应该也会向国际靠拢，因此了解法规对元素杂质的要求、建立有效的检测方法变得尤为重要。

一、各国法规变更史（1）EMA、EP关于元素杂质的修订EP最新版为9.0版，其中保留了2.4.8金属测试方法A-H；2.4.20章节金属催化剂和金属试剂残留检测；5.20金属催化剂或金属试剂残留。

但在9.3增补版（2018年1月1日实施）中5.20项下规定，元素杂质限度遵循ICH要求。

EMA对元素杂质的修订如下表1。

（2）ICH对元素杂质的修订历程ICH于2009年10月批准了Q3D，经多方讨论后，修订版本的Q3D step4于2014年12月16日生效，其中列出了24种元素杂质的三种给药途径的PDE 值，确定实施日期为：新上市许可为2016年6月生效，已上市品种为2017年12月生效。

（3）USP对元素杂质的修订历程FDA规定在2018年1月1日之后，针对USP药典品种，提交新的NDA、ANDA 应该符合USP<232>、<233>。

针对非USP药典品种，申请人提交新的NDA、ANDA时，应该遵循Q3D。

美国对元素杂质的规定与ICH规定在不同时期，内容不一致，但从2017年12月之后，USP对元素种类和限量均与ICH保持一致。

修订历程详见下表2。

（4）中国药典对重金属检测的修订中国药典对重金属检测的修订主要体现在表3中，名称仍然为重金属，方法仍采用比色法，2017年中国成为了ICH成员国，未来中国的药政监管将遵循ICH指南规定，元素杂质与国际接轨也是大势所趋。

<232>ELEMENTALIMPURITIES—LIMITSINTRODUCTIONThis general chapter specifies limits for the amounts of elemental impurities in drug products. Elemental impurities include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment and the container closure system). When elemental impurities are known to be present, have been added, or have the potential for introduction, assurance of compliance to the specified levels is required.A risk-based control strategy may be appropriate when analysts determine how to assure compliance with this standard. Due to the ubiquitous nature of arsenic, cadmium, lead,assessment. Regardless of the approach used, compliance with the limits specified is required for all drug products unless otherwise specified in an individual monograph or excluded in paragraph three of this introduction.The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or non-recombinant origins), their derivatives, and products of which they are components (e.g., conjugates) are within the scope of this chapter, as are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides.This chapter does not apply to radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood derivatives including plasma and<232>元素杂质-限度介绍本通则规定了制剂中元素杂质的限度。