1、Second Supplement to USP 38-NF 33 Chemical Tests / Elemental ImpuritiesLimits)注：背景字体表示最新变化， 执行日期 2018.01.01 Page 1 of 9ELEMENTAL IMPURITIESLIMITSINTRODUCTIONThis general chapter specifies limits for the amounts of elemental impurities in drug products. Elemental impurities include catalysts and envi
2、ronmental 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
3、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, ca
4、dmium, lead, and mercuy, they (at the minimum) must be considered in the risk-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 thre
5、e 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
6、are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides.This chapter does not apply to radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, 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
7、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、
8、DNA 产品、过敏提取物、细胞、全血、Second Supplement to USP 38-NF 33 Chemical Tests / Elemental ImpuritiesLimits)注：背景字体表示最新变化， 执行日期 2018.01.01 Page 2 of 9cells, whole blood, cellular blood components or blood derivatives including plasma and plasma derivatives, dialysate solutions not intended for systemic circulat
9、ion, 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 substan
10、ces, 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 are no
11、t 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 Supplements .SP
12、ECIATIONThe 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 differing toxi
13、cities 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. 细胞血成份或血液制品，包括血浆和血浆制品、非系统
14、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）。可以用总砷测试法来测定砷，
15、即假设待测物料Second Supplement to USP 38-NF 33 Chemical Tests / Elemental ImpuritiesLimits)注：背景字体表示最新变化， 执行日期 2018.01.01 Page 3 of 9Where the limit is 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
16、specification.The mercury limits are based upon the inorganic (2+) oxidation state. The methyl mercury form (most toxic) is rarely an issue for pharmaceuticals. Thus, the limit was established assuming the most common (mercuric) inorganic form. Limits for articles that have the potential to contain
17、methyl mercury (e.g., materials derived from fish) are to be provided in the monograph.ROUTES OF EXPOSUREThe toxicity of an elemental impurity is related to its extent of exposure (bioavailability). The extent of exposure has been determined for each of the elemental impurities of interest for three
18、 routes of administration: oral, parenteral, and inhalational. These limits are based on chronic exposure. The other two routes of administration, 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 produ
19、cts. To account for the potential application of topical products to injured or broken skin, topical product permissible daily exposures (PDEs) 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 ind
20、ividual monograph. Consider the oral permissible daily exposures (PDEs) in Table 1, as a starting point in developing specific PDEs for other routes of administration except where otherwise stated in the individual monograph. NOTEThe routes of administration of drug products are defined in general c
21、hapter 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。用于受伤或破损皮
22、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。 ）Second Supplement to USP 38-NF 33 Chemical Tests / Elemental ImpuritiesLimits)注：背景字体表示最新变化， 执行日期 2018.01.01 Page 4 of 9Pharmaceutical Dosage Forms .
23、DRUG PRODUCTSThe limits described in the second through fourth columns of Table 1 are the base daily dose PDEs 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
24、10 mL and not more than 100 mL must use the Summation Option.Large-Volume ParenteralsWhen the daily dose of 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
25、to produce the product component option. The amounts of elemental impurities present in each component used 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
26、calculate permissible concentrations from PDEs. For products whose daily volumes, as specified by labeling and/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.制剂表 1
27、 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
28、PDE 的允许浓度。Second Supplement to USP 38-NF 33 Chemical Tests / Elemental ImpuritiesLimits)注：背景字体表示最新变化， 执行日期 2018.01.01 Page 5 of 9Table 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 PDE
29、(g/day)吸入日服用 PDELVP Component Limit (g/g)LVP 组分限度Cadmium 镉 5.0 2.5 2 3.4 0.25Lead 铅 5.0 5.0 5.0 0.5Inorganic arsenica无 机 砷 15 15 2 1.9 1.5Inorganic mercurya无 机 汞 30 15 3 1.5 1.2 0.15Iridium 铱 100 10 1.5 1.0Osmium 锇 100 10 1.5 1.0Palladium 钯 100 10 1.0 1.0Platinum 铂 100 10 1 1.5 1.0Rhodium 铑 100 10 1
30、 1.5 1.0Ruthenium 钌 100 10 1 1.5 1.0Chromium 铬 11000 1100 3 2.9 cMolybdenum 钼 3000 180 1500 90 10 7.6 9.0Nickel 镍 200 600 20 60 5 6.0 6.0Vanadium 钒 100 120 10 12 1 1.2 1.2Copper 铜 3000 1300 300 130 30 13 13a See Speciation section. 见元素形态章节Second Supplement to USP 38-NF 33 Chemical Tests / Elemental
31、ImpuritiesLimits)注：背景字体表示最新变化， 执行日期 2018.01.01 Page 6 of 9a PDE = Permissible daily exposure based on a 50-kg person.The weight adjustment assumes an arbitrary adult human body weight for either sex of 50 kilograms (kg). This relatively low weight provides an additional safety factor against the sta
32、ndard weights of 60 or 70 kg that are often used in this type of calculation. It is recognized that some adult patients weigh less than 50 kg; these patients are considered to be accommodated by the built-in safety factors used to determine a PDE. If the metal was present in a formulation specifical
33、ly intended for pediatric use, an adjustment for a lower body weight would be appropriate.b See Speciation section.c Not a safety concern. Will be included in a future information chapter.Options for Demonstrating ComplianceDRUG PRODUCT ANALYSIS OPTIONThe results obtained from the analysis of a typi
34、cal dosage unit, scaled to a maximum daily dose, are compared to the Daily Dose PDE.Daily Dose PDE measured value (g/g) maximum daily dose (g/day)The measured amount of each impurity is NMT the Daily Dose PDE, unless otherwise stated in the individual monograph.SUMMATION OPTIONSeparately add the amo
35、unts of each elemental impurity (in g/g) present in each of the components of the drug product:Daily Dose PDE M1(CM WM) DDM = each ingredient used to manufacture a dosage unitCM = element concentration in component(drug substance or excipient) (g/g)a PDE = 以 50 kg 体重计算的允许日接触量。体重的调整是假设任一成年人体重为 50 kg。
36、同按照标准体重 60 或 70 kg 计算相比，该相对较轻的标准体重提供了额外的安全因素。众所周知有些成年患者的体重小于 50 kg；这些患者被认为是通过建立自身安全因素来确定 PDE。如果剂型中存在的金属杂质是专门给儿童使用的，要适当调整为较轻的体重值。b 见杂质形态章节。c 无安全性顾虑。会在以后的信息章节中包括。证明符合的方法制 剂 分 析 方 法测定标准剂量单位到最大日服用剂量所得的结果，与日服用 PDE 进行比较。日服用 PDE 测得值 (g/g) 最大日服用剂量 (g/day)除各论另行规定外，每一元素杂质的检测量不得过日服用 PDE。加和法分别加和制剂中各组分元素杂质（单位g/g
37、）的量：Daily Dose PDE M1(CM WM) DDM = 生产一个剂量单位所用的每个成份CM = 组分（原料药或辅料）中元素的浓度 (g/g)Second Supplement to USP 38-NF 33 Chemical Tests / Elemental ImpuritiesLimits)注：背景字体表示最新变化， 执行日期 2018.01.01 Page 7 of 9WM = weight of component in a dosage unit (g/dosage unit)DD = number of units in the maximum daily dose
38、(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 ensure that additional elemental impurities cannot be inadvertently added through the manuf
39、acturing process or via the container closure system over the shelf life of the product.INDIVIDUAL COMPONENT OPTIONThe Individual Component Option is available to LVP products only. An LVP may meet the requirements when each drug substance and excipient meets the limits provided in the LVP Component
40、 Limit column (Table 1). If all drug substances and excipients in a formulation meet the limits shown, then these components may be used in any proportion. No further calculation is necessary. While elemental impurities derived from the manufacturing process or the container closure system are not s
41、pecifically provided for in the Individual Component Option, it is expected that the drug product manufacturer will ensure that these sources do not contribute significantly to the total content of elemental impurities.For drug products with a daily dose of NMT 10 g, if all drug substances and excip
42、ients in a formulation meet the concentration limits shown in Table 2, then these components may be used in any proportion. No further calculation is necessary. While elemental impurities derived from the manufacturing process or the container closure system are not specifically provided for in the
43、Individual Component Option, it is expected that the drug product manufacturer will WM = 一个剂量单位中组分的重量(g/单位剂量)DD = 最大日服用剂量的制剂单位数(单位/天)除各论另行规定外，每一元素杂质的加和结果不得过日服用 PDE。在使用此方法进行药品评估前，生产商必须确保生产过程中不会引入元素杂质，或药品贮存期间不会通过密封容器系统引入元素杂质。单 组 分 法单 组 分 法 仅 适 用 于 LVP。 当 每 个 原 料 药 和 辅料 均 符 合 表 1 中 LVP 组 分 限 度 列 的 限 度
44、时 ，LVP 有 可 能 符 合 要 求 。 如 果 制 剂 中 所 有 原 料药 和 辅 料 均 符 所 列 限 度 ， 那 么 这 些 组 分 可 以按 任 一 比 例 使 用 。 不 再 需 要 进 一 步 计 算 。 但单 组 分 法 中 未 明 确 说 明 生 产 工 艺 或 密 封 容 器系 统 引 入 元 素 杂 质 的 情 况 ， 期 望 的 是 制 剂 生产 商 能 够 确 保 这 些 情 况 不 会 严 重 影 响 元 素 杂质 的 总 量 。对 于 日 服 用 剂 量 不 大 于 10 g 的 药 品 ， 如 果 原料 药 和 辅 料 在 处 方 中 符 合 表 2 中
45、的 浓 度 限 度 ，那 么 这 些 组 分 可 以 以 任 意 比 例 使 用 。 不 再 需要 进 一 步 计 算 。 但 是 从 生 产 工 艺 或 密 封 容 器系 统 引 入 的 元 素 杂 质 在 单 组 分 法 中 没 有 特 别说 明 ， 希 望 制 剂 生 产 商 可 以 确 保 这 些 因 素 不会 严 重 影 响 元 素 杂 质 的 总 体 含 量 。Second Supplement to USP 38-NF 33 Chemical Tests / Elemental ImpuritiesLimits)注：背景字体表示最新变化， 执行日期 2018.01.01 Page
46、 8 of 9ensure that these sources do not contribute significantly to the total content of elemental impurities.DRUG SUBSTANCE AND EXCIPIENTSThe presence concentration of elemental impurities in drug substances and excipients must be controlled and, where present, reported documented. The acceptable l
47、evels for these impurities depend on the materials ultimate use. Therefore, drug product manufacturers must determine the acceptable level of elemental impurities in the drug substances and excipients used to produce their products.The values provided in Table 2 represent are example concentration l
48、imits for components (drug substances and excipients) of drug products dosed at a maximum daily dose of 10 g/day. These values serve as default concentration limits to aid discussions between drug product manufacturers and the suppliers of the components of their drug products. NOTEIndividual compon
49、ents may need to be limited at levels different from those in the table depending on monograph-specific mitigating factors.ANALYTICAL TESTINGIf, by processes monitoring and supply-chain control, manufacturers can demonstrate the absence of impurities compliance, then further testing is may not needed. When testing is done to demonstrate compliance, proceed as directed in general chapter Elemental Impurities-Procedures and minimally include arsenic, cadmium, lead, and mercurt in the Target Element evaluation.原 料 药 和 辅 料原料药和辅料中的元素杂质浓度必须控制
