USP-232中英对照-USP-38-NF-33

<232>ELEMENTAL
IMPURITIES—LIMITS
INTRODUCTION
This 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。

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
plasma derivatives, dialysate solutions not intended for systemic circulation, 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 substances, 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.
supplements and their ingredients are addressed in Elemental Contaminants in Dietary Supplements <2232>.
SPECIATION
The 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 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 exceeded using a
total-arsenic procedure, it may be possible to show via a procedure that quantifies the （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 <2232>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，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。

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 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 EXPOSURE
The 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 routes of administration: oral, parenteral,
[NOTE—The routes of administration of drug products are defined in general chapter Pharmaceutical Dosage Forms <1151>.]
DRUG PRODUCTS
The limits described in the second through fourth columns of T able 1 are the base daily dose 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<1151>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
Parenteral Products Parenteral 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 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 permissible concentrations from PDEs.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PDE的允许浓度。

Table 1. Elemental Impurities for Drug Products
Options for Demonstrating Compliance
DRUG PRODUCT ANALYSIS OPTION
The results obtained from the analysis of a typical dosage unit, scaled to a maximum daily dose, are compared to the Daily Dose PDE.
Daily Dose PDE ≥ measured value (μg/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 OPTION
Separately add the amounts of each elemental impurity (in μg/g) present in each of the components of the drug product:
Daily Dose PDE ≥ [ΣM1(C M × W M)] × D D
M = each ingredient used to manufacture a dosage unit
C M = element concentration in component (drug substance or excipient) (μg/g)
W M= weight of component in a dosage unit 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。

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(μg/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μg/g）的量：
Daily Dose PDE ≥ [ΣM1(C M × W M)] × D D
M = 生产一个剂量单位所用的每个成份
C M= 组分（原料药或辅料）中元素的浓度(μg/g)
W M = 一个剂量单位中组分的重量(g/单位剂
(g/dosage unit)
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 ensure that additional elemental impurities cannot be inadvertently added through the manufacturing process or via the container closure system over the shelf life of the product.
INDIVIDUAL COMPONENT OPTION
For drug products with a daily dose of NMT 10 g, if all drug substances and excipients 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 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 量)
D D = 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。

impurities.
DRUG SUBSTANCE AND EXCIPIENTS
documented. The acceptable levels for these impurities depend on the material's 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
example concentration limits for components (drug substances and excipients) of drug
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.
[NOTE —Individual components may need to be limited at levels different from those in the table depending on monograph -specific mitigating factors.]
ANALYTICAL TESTING
to demonstrate compliance, proceed as directed in general chapter Elemental
Impurities-Procedures <233> a nd 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，如果存在，必须记录。

这些杂质的可接受限度取决于物料的最终用途。

因此，制剂生产商必须确定生产制剂所用原料药和辅料中的元素杂质的可接受限度。

表2中提供的数据是最大日服用剂量为10g/天的制剂组分（原料药和辅料）的浓度限度。

这些数据作为默认浓度限度，为制剂生产商和制剂组分供应商之间提供讨论帮助。

（注：单组分的限度可能需要根据各论特定的缓解因素制定不同于表格中的限度。

）
分析测试
如果生产商通过工艺监测和供应链控制就可以证明符合，则可能不需要进一步的测试。

当测试证明符合时，按照药典通则<233>元素杂质-检测方法进行，并在目标元素评估中至少要包含砷、镉、铅、汞。

Table 2. Default Concentration Limits for Drug Substances and Excipients Example Concentration Limits for Components of Drug Products with a 10-g Maximum Daily Dose。