USP232中英对照USP38NF33.docx

1、USP232中英对照USP38NF33USP-232中英对照-USP-38-NF-33ELEMENTAL IMPURITIESLIMITSINTRODUCTIONThis 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, o

2、r 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

3、, 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 mercuy, they (at the minimum) must be considered in the ris

4、k-based control strategy 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 po

5、lypeptides (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, polynucleo

6、tides, 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 plasma derivatives, dialysate solutions not intended for systemic ci

7、rculation, and elements that are intentionally included in the drug product for therapeutic benefit. This chapter does not apply to products based on genes (gene therapy), cells (cell therapy), and tissue (tissue engineering).The limits presented in this chapter do not apply to excipients and drug s

8、ubstances, except where specified in this chapter or in the individual monographs. However, elemental impurity levels present in drug substances and excipients must be known, and reported documented, and made available upon request.This chapter does not apply to The limits indicated in this chapter

9、are not required for articles intended only for veterinary use and conventional vaccines. Requirements listed in this chapter also do not apply to total parenteral nutritions (TPNs) and dialysates. Dietary supplements and their ingredients are addressed in Elemental Contaminants in Dietary Supplemen

10、ts .SPECIATIONThe determination of the oxidation state, organic complex, or combination is termed speciation. Each of the elemental impurities has the potential to be present in differing oxidation or complexation states. However, arsenic and mercury are of particular concern because of the differin

11、g toxicities of their inorganic and complexed organic forms.The arsenic limits are based on the inorganic (most toxic) form. Arsenic can be measured using a total-arsenic procedure under the assumption that all arsenic contained in the material under test is in the inorganic form. Where the limit is

12、 exceeded using a total-arsenic procedure, it may be possible to show via a procedure that quantifies the different forms that the inorganic form meets the specification.The mercury limits are based upon the inorganic (2+) oxidation state. The methyl mercury form (most toxic) is rarely an issue for

13、pharmaceuticals. Thus, the limit was established assuming the most common (mercuric) inorganic form. Limits for articles that have the potential to contain methyl mercury (e.g., materials derived from fish) are to be provided in the monograph.ROUTES OF EXPOSUREThe toxicity of an elemental impurity i

14、s related to its extent of exposure (bioavailability). The extent of exposure has been determined for each of the elemental impurities of interest for three routes of administration: oral, parenteral, and inhalational. These limits are based on chronic exposure. The other two routes of administratio

15、n, mucosal and topical, are considered to be the same as oral for the purpose of this standard, and the PDEs described in Table 1 would apply to these products. To account for the potential application of topical products to injured or broken skin, topical product permissible daily exposures (PDEs)

16、will be the same as oral Table 1, except as indicated in the individual monograph. Mucosal will also use oral PDEs, except where otherwise stated in the individual monograph. Consider the oral permissible daily exposures (PDEs) in Table 1, as a starting point in developing specific PDEs for other ro

17、utes of administration except where otherwise stated in the individual monograph. NOTEThe routes of administration of drug products are defined in general chapter Pharmaceutical Dosage Forms .DRUG PRODUCTSThe limits described in the second through fourth columns of Table 1 are the base daily dose PD

18、Es of the elemental impurities of interest for a drug product taken by the a patient according to indicated routes of administration. Parenterals with an intended maximum dose of greater than 10 mL and not more than 100 mL must use the Summation Option.Large-Volume ParenteralsWhen the daily dose of

19、an injection is greater than 100 mL large volume parenteral (LVP), the amount of elemental impurities present in the drug product must may be controlled through the individual components used to produce the product component option. The amounts of elemental impurities present in each component used

20、in an LVP are less than the values included in the fifth column of Table 1.Parenteral ProductsParenteral drug products with maximum daily volumes up to 2 L may use the maximum daily volume to calculate permissible concentrations from PDEs. For products whose daily volumes, as specified by labeling a

21、nd/or established by clinical practice, may exceed 2 L (e.g., saline, dextrose, TPNs, solutions for irrigation), a 2-L volume may be used to calculate permissibleconcentrations from PDEs. 元素杂质-限度介绍本通则规定了制剂中元素杂质的限度。元素杂质包括催化剂和环境污染物，可能出现在原料药、辅料或制剂中。这些杂质可能本身就存在，也有可能是有意加入或无意引入的（如生产设备、密封容器系统间的相互作用）。当元素杂质已

22、知存在、已经加入或有可能引入时，必须保证杂质符合规定限度。当分析人员测定如何符合标准时，可以适当采用基于风险的控制策略。由于砷（As）、镉（Cd）、铅（Pb）和汞（Hg）是自然界普遍存在的元素，风险评估须至少要考虑这四种元素。无论采用何种方法，所有制剂产品必须符合规定限度，各论另行规定和本介绍章节第三段描述的产品除外。含有纯化蛋白和多肽（包括重组或非重组来源的蛋白质和多肽）的制剂，它们的衍生物及复方制剂（如偶合物）均在本通则范围内。本通则也适用于含有合成多肽、多核苷酸和低聚糖的制剂。本通则不适用于放射性药物、疫苗、细胞代谢物、DNA产品、过敏提取物、细胞、全血、细胞血成份或血液制品，包括血浆和

23、血浆制品、非系统循环用透析液，和药品用于治疗用途有意加入的元素。本通则不适用于基于基因（基因治疗）、细胞（细胞治疗）和组织（组织工程）的药品。本通则所列限度不适用于辅料和原料药，本通则或各论另行规定除外。但是原料药和辅料中的元素杂质水平必须已知、记录、需要时提供。本通则不适用于兽药产品。本通则所列要求也不适用于全胃肠外营养液和透析液。膳食补充剂及其成份参见USP 膳食补充剂中的污染元素。元素形态测定氧化态、有机络合物或复合态称为元素形态。每种元素杂质都可能以不同的氧化态或络合态存在。但是，砷和汞因其无机形态和络合形态均具有不同毒性，故需特别关注。砷的限度基于其无机形态（毒性最大）。可以用总砷测

24、试法来测定砷，即假设待测物料中的砷均为无机形态。如果用总砷测试法，结果超出限度，可通过其它方法定量检测不同形态的砷，证明无机形态的砷符合质量标准。汞的限度基于其无机（2+）氧化态。甲基汞形态（毒性最大）在药物中十分罕见，因此，汞的限度是假设其为最常见的无机形态（二价汞）制定的。可能含有甲基汞的产品（如鱼制品），其限度在各论中有规定。接触途径元素杂质的毒性与其接触程度（生物利用度）有关。根据三种给药途径：口服、注射和吸入，每种目标元素杂质的接触程度已经确定。限度是基于长期接触而制定的。另外两种给药途径：粘膜给药和局部用药，其限度同口服药品，表1中描述的日接触量（PDE）也适用于这些产品。用于受伤

25、或破损皮肤的局部给药，其允许的日接触量（PDE）同表1中的口服制剂，各论另行规定除外。除各论另行规定外，粘膜给药PDE也可参考表1中的口服制剂。各论另行规定除外，表1中口服制剂的PDE可以作为开发其他给药途径PDE的起始点。（注意： USP通则药物剂型中规定了药品的给药途径。）制剂表1中2-4列所列限度是根据病人指定的用药途径，按照基本日服用量计算出的目标元素杂质允许的日接触量。最大剂量在10 mL到100 mL之间的注射剂必须使用下述加和法计算。大容量注射剂当注射剂的日剂量超过100 mL大容量注射剂(LVP)时，药品中元素杂质的量可能会通过下述单组分法控制。LVP中每个组分所含元素杂质的量

26、要小于表1中第五列的数值。注射用药注射用药如果最大日给药体积达到2 L，则可以使用最大日给药体积来计算PDE的允许浓度。对于日剂量在标签上注明和/或临床确定的药品，可以超过2 L的（如生理盐水、葡萄糖、全胃肠外营养液、冲洗剂），2 L的体积可以用于计算PDE的允许浓度。Table 1. Elemental Impurities for Drug Products制剂元素杂质Element元素Oral Daily Dose PDEa (g /day)口服日服用PDEParenteral Daily Dose PDE (g/day)注射日服用PDEInhalational Daily Dose P

27、DE (g/day)吸入日服用PDELVP Component Limit (g/g)LVP组分限度Cadmium镉5.02.52 3.40.25Lead铅5.05.05.00.5Inorganic arsenica无机砷15152 1.91.5Inorganic mercurya无机汞30 153 1.51.20.15Iridium铱100101.51.0Osmium锇100101.51.0Palladium钯100101.01.0Platinum铂100101 1.51.0Rhodium铑100101 1.51.0Ruthenium钌100101 1.51.0Chromium铬110001

28、1003 2.9cMolybdenum钼3000 1801500 9010 7.69.0Nickel镍200 60020 605 6.06.0Vanadium钒100 12010 121 1.21.2Copper铜3000 1300300 13030 1313a See Speciation section. 见元素形态章节Table 2. Default Concentration Limits for Drug Substances and Excipients Example Concentration Limits for Components of Drug Products wit

29、h a 10-g Maximum Daily Dose表2 最大日服用剂量为10 g的制剂组分浓度限度举例Element元素Concentration Limits(g/g) for Components Used in Oral Drug Products口服制剂中组分的浓度限度(g/g)Concentration Limits (g/g) for Components Used in Parenteral Drug Products注射剂中组分的浓度限度(g/g)Concentration Limits(g/g) for Components Used in Inhalational Dr

30、ug Products吸入剂中组分的浓度限度(g/g)Cadmium镉0.50.250.2 0.34Lead铅0.50.50.5Inorganic arsenica无机砷1.51.50.2 0.19Inorganic mercurya无机汞3 1.50.3 0.150.1 0.12Iridium铱101.00.15Osmium锇101.00.15Palladium钯101.00.15Platinum铂101.00.15Rhodium铑101.00.15Ruthenium钌101.00.15Chromium铬11001100.3 0.29Molybdenum钼300 18150 9.01 0.76Nickel镍20 602 6.00.5 0.60Vanadium钒10 121 1.20.1 0.12Copper铜300 13030 133 1.3a See Speciation section. 见元素形态章节