USP29-1086药典药品中的杂质(中+英 已校).doc

USP29-1086 药典药品中的杂质 王璐译，陈玉霞校 IMPURITIES IN OFFICIAL ARTICLES 药典药品中的杂质药典药品中的杂质 Concepts about purity change with time and are inseparable from developments in analytical chemistry. If a material previously considered to be pure can be resolved into more than one component, that material can be redefined into new terms of purity and impurity. Inorganic, organic, biochemical, isomeric, or polymeric components can all be considered impurities. Microbiological species or strains are sometimes described in similar terms of resolving into more than one component. 关于纯度的概念随时间的改变而改变，并且与分析化学的发展息息相关。如果之前被认为是 纯净的物料可以被分解成不只一个组分，那么那个物料可重新定义为纯度和杂质的新术语。 无机的、有机的、生物化学的、同质异构或聚合组分可以全部看作是杂质。微生物种类或菌 种如果可以分解为不只一个组分时，用同样的术语来描述。 Communications about compendial articles may be improved by including in this Pharmacopeia the definitions of terms and the contexts in which these terms are used. (See Definitions below.) There has been much activity and discussion in recent years about term definition. Certain industry-wide concerns about terminology and context deserve widespread publication and ready retrievability and are included here. (See Industrial Concepts below.) See Foreign Substances and Impurities, in the section Tests and Assays, under General Notices and Requirements, as well as the recently adopted general chapter, Ordinary Impurities 466. Some other general chapters added over the years have also addressed topics of purity or impurity as these have come into focus or as analytical methodology has become available. Analytical aspects are enlarged upon in the chapter Validation of Compendial Methods 1225. 关于药典产品的交流，可以通过包括在该药典中的术语定义和使用这些术语的背景的方式 （参见以下的定义）得到改进。近些年，关于术语的定义已经展开了很多的活动和讨论。某 些行业范围内关于术语与背景的问题，值得广泛的发行并可以检索，而且被包括在此（参见 下面的企业概念）。参见凡例的检查与分析部分中的外来物质和杂质，以及近期被采用的通 用章节，一般杂质466。这几年里增加的其他的一些通用章节同样也论述过纯度和杂质 USP29-1086 药典药品中的杂质 15-2 的问题，因为这些问题已经成为了焦点性论题或是因为分析方法学已变得可以利用。药典方 法的验证1225一章中进一步论述了分析问题。 Monographs on bulk pharmaceutical chemicals usually cite one of three types of purity tests: (1) a chromatographic purity test coupled with a nonspecific assay; (2) a chromatographic purity-indicating method that serves as the assay; or (3) a specific test and limit for a known impurity, an approach that usually requires a reference standard for that impurity. Modern separation methods clearly play a dominant role in scientific research today because these methods simultaneously separate and measure components and fulfill the analytical ideal of making measurements only on purified specimens. Nevertheless, the more classical methods based on titrimetry, colorimetry, spectrophotometry, single or multiple partitions, or changes in physical constants (or any other tests or assays) lose none of their previous validities. The purity profile of a specimen that is constructed from the results of experiments using a number of analytical methods is the ultimate goal. 有关散装化学药品的正文通常引证三种纯度测试的其中一种：（1）具有非专属性分析的色 谱法纯度检查；（2）色谱指示纯度的方法，同时也作为含量分析的方法；或（3）对已知杂 质来说，是专属性的检查和限度，此方法通常需要该杂质的参考标准品。如今，很显然，现 代分离方法在科学研究领域里扮演着主导角色，因为这些方法可以同时分离组分并测量组分， 也实现了只测量净化后样品的分析目标。但无论怎样，以滴定法、比色法、分光光度法基础 的比较经典的方法，单个或多个分类、或物理常数方面的改变（或任何其他形式的检测或分 析），并未失去它们原有的有效性。用一系列的分析法获得的实验结果来构成一个样品的纯 度情况是最终的目标。 Purity or impurity measurements on finished preparations present a challenge to Pharmacopeial standard setting. Where degradation of a preparation over time is at issue, the same analytical methods that are stability-indicating are also purity-indicating. Resolution of the active ingredient(s) from the excipients necessary to the preparation presents the same qualitative problem. Thus, many monographs for Pharmacopeial preparations feature chromatographic assays. Where more significant impurities are known, some monographs set forth specific limit tests. In general, however, this Pharmacopeia does not repeat impurity tests in subsequent preparations where these appear in the monographs of bulk pharmaceutical chemicals and where these impurities USP29-1086 药典药品中的杂质 15-3 are not expected to increase. It is presumed that adequate retention specimens are in storage for the exact batch of bulk chemicals used in any specific lot of a preparation. Whenever analysis of an official preparation raises a question of the official attributes of any of the bulks used, subsequent analysis of retention specimens is in order. 成品制剂的纯度或杂质的测量对药典的标准品设置提出了挑战。制剂随着时间的流逝而发生 降解的现象成为讨论议题时，相同的分析方法(此方法具有稳定性显示)同样也具有纯度指示 的功能。因制剂的所必需辅料而造成的活性成分的分解呈现出相同的定性问题。因此，许多 有关药典制剂专论中特别说明了色谱分析。在了解比较明显的杂质后，一些专论阐述了专属 性的限度检查。然而，总的来说，如果那些出现在散装原料的专论中杂质检查并且这些杂质 并不会增加，那么该药典对随后的制剂产品没有重复该杂质检查。前提是用于任何特定制剂 批的原料药，已贮存了该批原料药适当的留样。只要法定制剂的分析引起了对所用的任何散 装化学药品的法定属性的怀疑，接下来应对保留的样品进行分析。 DEFINITIONS 定定 义义 Foreign Substances 外来物质 Foreign substances, which are introduced by contamination or adulteration, are not consequences of the synthesis or preparation of compendial articles and thus cannot be anticipated when monograph tests and assays are selected. The presence of objectionable foreign substances not revealed by monograph tests and assays constitutes a variance from the official standard. Examples of foreign substances include ephedrine in Ipecac or a pesticide in an oral liquid analgesic. Allowance is made in this Pharmacopeia for the detection of foreign substances by unofficial methods. (See Foreign Substances and Impurities, in the section Tests and Assays, under General Notices and Requirements.) 由污染或掺杂引入的外来物质，不是合成的结果或药典产品制备造成的结果，因此在选取正 文检查和含量测定时是无法预见的。不能通过正文检查和含量测定来显示的有害外来物质的 存在，造成了与法定标准的差异。外来物质的例子包括吐根中的麻黄素或口服液止痛剂里的 杀虫剂。该药典中允许通过非法定的方法检测外来物质。（参见凡例中，检查与含量分析部 分里的外来物质和杂质）。 USP29-1086 药典药品中的杂质 15-4 Residual Solvents 残留溶剂 Residual solvents are defined as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of a drug substance may enhance the yield or determine characteristics such as crystal form, purity, and solubility and, as such, may be a critical parameter in the synthetic process. Because there is no therapeutic benefit from residual solvents, they should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data. A classification of residual solvents by risk assessment is presented in the Residual Solvents Limits section of Organic Volatile Impurities 467. Class 1 solvents should be avoided in the production of drug substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment. 残留溶剂被定义为有机挥发性化学物，这些化学物质被用于原料药或辅料生产中，或在药物 制剂制备过程中产生。这些溶剂通过实际的生产技术不能被完全除去。对于原料药合成来说， 选择适当的溶剂可以增加产量或确定某些特性，如晶形，纯度，和溶解度，并且这些特性可 能是合成过程中的关键参数。因为残留溶剂没有治疗上的益处，所以它们应最大程度上得被 除去以符合药品规范，GMP，或其他质量要求。药物制剂中所含有残留溶剂的量，不应比 安全数据所支持的量更高。根据风险评估而评定的残留溶剂分类在有机挥发性杂质467 中的残留溶剂限度部分里有所陈述。级别 1 溶剂在原料药、辅料、或药物制剂的生产过程中 应被避免，除非在风险-利益评估中它们的用途被证明是非常正当的。 Toxic Impurities 有毒的杂质 Toxic impurities have significant undesirable biological activity, even as minor components, and require individual identification and quantitation by specific tests. These impurities may arise out of the synthesis, preparation, or degradation of compendial articles. Based on validation data, individualized tests and specifications are selected. These feature comparison to a Reference Standard of the impurity, if available. It is incumbent on the USP29-1086 药典药品中的杂质 15-5 manufacturer to provide data that would support the classification of such impurities as toxic impurities. 有毒的杂质具有显著的有害的生物反应，即使是很少的组分，并需要逐个的鉴定和通过专属 性检查进行定量分析。这些杂质可能是来自于药典物品的合成，制备，或降解。根据验证数 据，可选取个性化的检查和规范说明。如果可行，应将这些特性和杂质的参考标准品做比较。 提供支持这样的杂质为有毒杂质的数据，是生产商的责任。 Concomitant Components 伴随的组分 Concomitant components are characteristic of many bulk pharmaceutical chemicals and are not considered to be impurities in the Pharmacopeial sense. Limits on contents, or specified ranges, or defined mixtures are set forth for concomitant components in this Pharmacopeia. Examples of concomitant components are geometric and optical isomers (or racemates) and antibiotics that are mixtures. Any component that can be considered a toxic impurity because of significant undesirable biological effect is not considered to be a concomitant component. 伴随的组分是许多散装化学药品的特点，而且从药典意义上来说不被看作是杂质。对含量， 规定的范围，或定义的混合物的限度，在本药典中针对伴随组分而被阐述。伴随组分的例子 包括，几何学上的和旋光异构体（或外消旋化合物）和混合物的抗生素。因为其严重的不良 生物作用，任何可以被看作是有毒杂质的组分，不会认为是伴随的组分。 Signal Impurities 信号性的杂质 Signal impurities are distinct from ordinary impurities in that they require individual identification and quantitation by specific tests. Based on validation data, individualized tests and specifications are selected. These feature a comparison to a reference standard of the impurity, if available. 信号性的杂质不同于普通杂质，因为它们需要通过专属性检查进行单个鉴定和定量分析。根 据验证数据，可以选择个性化的检查和规范说明。如可行，这些特性应和杂质的参考标准品 做比较。 Signal impurities may include some process-related impurities or degradation products that provide key information about the process, such as diazotizable substances in USP29-1086 药典药品中的杂质 15-6 thiazides. It is incumbent on the manufacturer to provide data that would support the classification of such impurities as signal impurities rather than ordinary impurities. 信号性的杂质可能包括一些与过程相关的杂质或降解产品，而这些杂质或降解产品可以提供 过程的关键信息，例如，噻嗪类中的重氮化作用物质。生产商有义务去提供支持性的数据， 证明那些称为标志杂质的分类而不是普通杂质。 Ordinary Impurities 普通杂质 Ordinary impurities are those species in bulk pharmaceutical chemicals that are innocuous by virtue of having no significant, undesirable biological activity in the amounts present. These impurities may arise out of the synthesis, preparation, or degradation of compendial articles. Selections of tests and assays allow for anticipated amounts of impurities that are unobjectionable for the customary use of the article. The presence of ordinary impurities is controlled in monographs in this Pharmacopeia by including tests for Ordinary Impurities 466. Tests for related substances or chromatographic purity may also control the presence of ordinary impurities. 普通杂质是指散装化学药品中的种类，而这些杂质在所呈现的数量下，没有重大的、有害的 生物活性。这些杂质可能是由药典物质的合成、制备、或降解而引起的。检查和分析的选择 应考虑杂质预期的量对药品的正常使用不会造成有害的影响。普通杂质在该药典的正文中受 控，包括普通杂质466的检查。相关物质或色谱纯度的检测也可以控制普通杂质的存在。 Unless otherwise specified in an individual monograph, estimation of the amount and number of ordinary impurities is made by relative methods rather than by strict comparison to individual Reference Standards. Nonspecific detection of ordinary impurities is also consistent with this classification. 除非在个论中另有规定，通过比较法而不是和单个的参考标准品进行严格对比的方式评估普 通杂质的数量和数目。普通杂质的非专属性检测也是和该分类相一致的。 The value of 2.0% was selected as the general limit on ordinary impurities in monographs where documentation did not support adoption of other values. This value represents the maximum allowable impact from this source of variation, when taken with the variation allowed by the composite of other Pharmacopeial tests and assays for both the bulk pharmaceutical chemical and the preparations. USP29-1086 药典药品中的杂质 15-7 选定 2.0%的数值作为正文中普通杂质的一般限度，在正文中的文件不支持采用其他数值。 该数值代表该变异来源允许的最大值，此时考虑了其他散装化学药品和制剂的药典检查和分 析一起允许的差异。 Where a monograph sets limits on concomitant components, signal impurities, and/or toxic impurities, these species are not to be included in the estimation of ordinary impurities unless so stated in the individual monograph. 如果正文限定伴随的组分、信号性杂质、和/或有毒杂质，这些种类并不包括在普通杂质的 评估中，除非个论中有说明。 Related Substances 相关的物质 Related substances are structurally related to a drug substance. These substances may be identified or unidentified degradation products or impurities arising from a manufacturing process or during storage of a material. 相关的物质是结构上与原料药相有关。这些物质也许是经确认的或未经确认的降解产品或来 源于生产过程中或物料储存期间的杂质。 Process Contaminants 过程中的污染物 Process contaminants are identified or unidentified substances (excluding related substances and water), including reagents, inorganics (e.g., heavy metals, chloride, or sulfate), raw materials, and solvents. These substances may be introduced during manufacturing or handling procedures. 过程中的污染物是经确定的或未经确定的物质（除相关的物质和水），包括试剂、无机物 （如，重金属、氯化物、或硫酸盐）、原材料、和溶剂。这些物质有可能是生产或处理过程 中引进来的。 INDUSTRIAL CONCEPTS 企业概念企业概念 Pharmaceutical manufacturers interact with regulatory agencies in developing new drug substances and new drug products, and cooperate with the compendia in writing official monographs for the compendial articles the manufacturers produce. Establishment of impurity limits in drug substances should proceed on a rational basis so that everyone USP29-1086 药典药品中的杂质 15-8 involved in the development and approval phases can carry on their work in a predictable fashion. Although drug development in the United States is the primary focus of this section of the chapter, the subject also has broad applicability across national boundaries. 制药生产商和法规管理部门在开发新原料药和新药物制剂方面相互交流，并在编写由生产商 生产的药典物品的官方专论方面通力合作。原料药纯度限度的制定应根据理论基础来进行， 这样在开发和批准阶段的每个人都可以按预期的方式进行他们的工作。尽管美国药品的研究 是本章节部分的主要焦点性话题，但是内容也可宽泛得适用于国家范围内。 Manufacturers share with regulatory agencies and with the compendia the goal of making available to the public high-quality products that are both safe and efficacious. This goal continues to be achieved through rational approaches to the complex process of drug development. Tests used at all stages of drug development and marketing should not be interpreted individually but as a whole. Controls on raw materials and on manufacturing as well as those on drug substances, along with toxicological and clinical studies performed, ensure the safety and efficacy of drug products. It has been suggested that impurities should be identified when they exceed some set amount, e.g., 0.1, 0.3, or 0.5%. It is more rational to identify impurities and to set limits based on the factors detailed here, relying on the scientific judgments of manufacturers, the compendia, and regulators to arrive at sets of acceptable limits for identified and unidentified impurities. 生产商、法规管理部门、和药典编撰人员有着共同的理想，即让公众得到既安全又有效的高 质量药品。这个目标可通过针对药品研究的复杂过程的合理的途径得到持续的实现。在药品 研发和销售的各个阶段所用到的试验都不应进行单独的解释说明而是将它们看作一个整体对 待。对原材料、生产、以及原料药的控制，还有所进行的毒理学和临床实验，都保证了药物 制剂的安全性和有效性。建议当杂质超过制订的某一数量时，如，0.1, 0.3, 或 0.5%，就应 对它们进行鉴定。根据这里详细描述的因素来鉴定杂质并制订限度是更加合理的，依赖于生 产商、药典内容、和法规管理人员对经确认和未经确认杂质所制定的可接受性限度的科学判 断。 Limits are set for impurity levels as one of the steps in ensuring the identity, strength, quality, and chemical purity of drug substances. The ultimate goal is to produce a final drug product of high quality and at a reasonable cost that is safe and efficacious and remains so throughout its shelf life. The setting of limits for impurities in bulk drug substances is a complex process that considers a number of factors: USP29-1086 药典药品中的杂质 15-9 为杂质量制订一限度是确保原料药的同一性、浓度、质量和化学纯度步骤之一。最终的目标 是生产出质量高、成本合理的制剂成品，并且这些制剂成品在整个货架期内始终保持安全性 和有效性。对散装化学药品中杂质限度的制订是一个复杂的过程，需要考虑以下几点因素： (1) the toxicology of a drug substance containing typical levels of impurities and/or the toxicology of impurities relative to a drug substance; 含有代表性杂质水平的原料药的毒理特性和/或与原料药相关的杂质的毒理特性； (2) the route of administration, e.g., oral, topical, parenteral, or intrathecal; 给药途径，如，口服、局部用药、注射用药或膜内用药； (3) the daily dose, i.e., frequency and amount (micrograms or grams) administered of a drug substance; 每日剂量，如，次数和服用的原料药的数量（微克或克）； (4) the target population (age and disease state), e.g., neonates, children, or senior citizens; 目标人群（年龄和病症），如，新生儿、儿童、或老年人； (5) the pharmacology of an impurity, when appropriate; 如可行，杂质的药理学； (6) the source of a drug substance, e.g., synthetic, natural product, or biotechnology; 原料药的来源，如，人工合成品、天然药物、还是生物技术加工品； (7) the duration of therapy, i.e., administration over a long period (treatment of chronic conditions) versus administration intended for a short duration (treatment of acute conditions); and 治疗所持续的时间，如，服药周期长（对慢性疾病的治疗）与短期性服药（对急性疾病 的治疗）； (8) the capability of a manufacturer to produce high-quality material at a reasonable cost to consumers. 生产商以合理的成本为消费者生产高质量的药品的能力。 Concepts for setting impurity limits in bulk drug substances are the concerns of the regulatory and compendial agencies as well as the pharmaceutical industry. The basic tenet for setting limits is that levels of impurities in a drug substance must be controlled to ensure its safety and quality throughout its development into and use as a drug product. The concepts are derived from issues and experiences with drug substances from USP29-1086 药典药品中的杂质 15-10 traditional sources and technologies. Issues arising from biotechnologically produced drug substances, e.g., recombinant DNA and hybridomas, are still being defined and so are not necessarily covered by these concepts. However, the concepts can serve as a general foundation to address specific issues arising from biotechnology. 制订散装化学药品中的杂质限度是法规管理部门、药典机构和制药企业共同关心的课题。制 订限度的基本理念是原料药中的杂质含量必须受到控制，以确保在药物制剂的研究和使用时 的安全性和质量。此观念源于使用传统材料和技术生产的原料药的问题和经验。来自于使用 生物技术生产的原料药(如，DNA 重组和杂交瘤)的问题仍被定义，因此没有必要囊括在这些 观念中。但是，观念可视作阐述生物技术引发的具体问题的一般基础。 The setting of limits on impurities in drug substances is an evolutionary process, beginning in the United States before an investigational new drug (IND) is filed and continuing until well after the approval of a new drug application (NDA). Therefore, it is appropriate to address different stages in drug development as separate issues. There are three points in the drug development process where the setting of limits may be significantly different: (1) at the initial IND application, (2) at the filing of the NDA, and (3) after NDA approval. The filing of an abbreviated new drug applica