【分享】usp 29 1086 中英对照

楼主自己翻译的吗

DEFINITIONS
定 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）。

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 á467ñ. 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 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 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 á466ñ. 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.
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
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 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:
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 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 application (ANDA) is another activity in which limits are set on impurities. Since the approach may vary from that of filing an NDA, it is addressed as a separate issue. The underlying assumption is that the analytical methods used to evaluate impurities in a drug substance are suitable for their intended purpose at each stage in the development.
对原料药里的杂质限度的设定是一个演化过程。在调研性新药（IND）文件被归档之前开始于美国，并一直持续直到新药申请（NDA）批准之后。因此，在对药品研究过程中的不同阶段做分别说明，把它们看作是分开的问题较合适。在药品研究过程中有三点需要特别注意，它们限度的设定可能会出现很大的差别：（1）在最初IND申请阶段；（2）NDA文件起草阶段；和（3）NDA批准之后。简略新药申请（ANDA）的文件编写又是另外一回事，其中需设定杂质的限度。因为ANDA文件的起草方式可能和NDA文件的编写方式存在不同，所以建议作为一个单独的问题加以说明。下面的假设是，用于评估原料药中杂质的分析方法适用于研发过程的各个阶段中原料药的预期用途。
An impurity is any component of a drug substance (excluding water) that is not the chemical entity defined as the drug substance. The impurity profile of a drug substance is a description of the impurities present in a typical lot of a drug substance produced by a given manufacturing process. The description includes the identity or some qualitative analytical designation (if unidentified), the range of each impurity observed, and the classification of each identified impurity.
杂质是原料药（水除外）中任何一种不被定义为原料药化学实体的成分。原料药中的杂质的情况存在于原料药的特定批中的杂质描述，此而批原料药是由给定工艺而生产的。描述包括鉴定或一些定性分析（如果是未经确认的杂质），观察到的每种杂质的范围，以及每种经过确认的杂质的分类。
Following are two more terms that enlarge upon those given under Definitions.
以下还有另外两个术语，这两个术语扩大了在定义中给出的范围。
Related Substances— 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.
相关物质---相关的物质在结构上与原料药有关。这些物质可以是经过确定的或未经确定的降解产品或生产过程或原料贮藏时产生的杂质。
Process Contaminants— 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.
过程污染物---过程污染物是经确定的或未经确定的物质（相关物质和水除外），包括试剂、无机物（如，重金属、氯化物、或硫酸盐）、原料、和溶剂。这些物质可能是生产或处理过程中引入的。

INITIAL IND FILING
最初的IND文件编写
At the initial IND filing, the chemical nature of a bulk substance has generally been defined. The manufacturing process normally is in an early stage of development, and materials may be produced on a laboratory scale. Usually few batches have been made and, therefore, little historical data are available. The reference materials of a drug substance may be relatively impure. Limits for the purity of a drug substance are set to indicate drug quality. The setting of limits on related substances and process contaminants can be characterized as follows.
在最初的IND文件起草阶段，原料药的化学性质已经可以大致上确定下来。通常地，生产过程是研究的早期阶段，此时原料的生产还只是实验室规模。通常情况下已被生产的原料药只有少数的几批，因此，可以获得为数有限的历史数据。原料药的参照物可能相对来说是不纯的。设定原料药纯度的限度以此确定药品的质量。对相关物质和过程污染物的限度设定具体如下：
(1) Limits are set on total impurities, and an upper limit may be set on any single impurity. The limit for total impurities should maintain, if possible, a nominal composition material balance.
根据总杂质设定限度，而且对任何一单一杂质可设定上限。如可能，总杂质限度应确保近似的各种组分物料的平衡。
(2) Impurity profiles are documented. These are profiles of the lots of drug substances used in clinical studies and in toxicological studies that establish the safety of drug substances. The lots used in these studies should be typical products of the manufacturing process in use at that time.
记录杂质的情况。这些是有关用在临床和毒理研究中的原料药批次的杂质情况，而临床研究和毒理研究用来确立原料药的安全性。用于这些研究的批次应是当时采用生产工艺下的具有代表性的药品。
(3) Limits for residual solvents are based on the known toxicology of the solvents and on the manufacturing capabilities and dosing regimens.
根据溶剂的已知毒理性和生产能力以及给药方案设定残留溶剂的限度。
(4) General inorganic contaminants are monitored by appropriate tests such as a heavy metals limit test and/or a test for residue on ignition. Traditional compendial limits are applied unless otherwise indicated. Specific metal contaminants that appear during manufacturing should be monitored by appropriate analytical techniques, and limits should be set based on the toxicological properties of these metals.
一般的无机污染物通过适当的检查法来监测，如重金属限度检查法和/或炽灼残渣检查。除非另有说明，可应用传统的药典上的限度。在生产过程中产生的特殊金属污染物应通过适当的分析技术进行监测，并根据这些金属的毒理特性来制订限度。
(5) Appropriate limits are set for impurities known to be toxic.
为已知的有毒杂质制订适当限度。
(6) If appropriate, enantiomeric purity is controlled.
如合适，控制对映体的纯度。
Although water is not classified as an impurity, limits for water content may be needed to ensure the stability or ease of processing a drug substance.
尽管水未被划分为杂质，但需要限定含水量，以确保稳定性和易于原料药的加工。

NDA FILING
NDA文件编写
During the IND phases of drug development, the manufacturing process for a drug substance may undergo a number of revisions. Generally, the scale will have changed from laboratory size and will approach or reach full production batch size. A number of batches will normally have been produced, and a historical data base of the results of testing for impurities will exist. When significant changes in a manufacturing process are made, the impurity profile should be reviewed to determine if the toxicological studies are still supportive.
在药品研发的IND阶段，原料药的生产过程可能会经历几次修订。一般地，生产规模会发生改变，从最初的实验室规模逐渐接近或达到全面的批生产规模。正常情况下将会生产很多批，也将会有杂质检测结果的历史性数据。当生产过程发生重大变化时，应检查杂质的情况，从而决定毒理性实验是否仍然具有支持性。
At the NDA stage a reference standard of defined purity is available, analytical methods have been validated, impurity and degradation profiles are known, and enantiomeric purity has been evaluated. The setting of limits on related substances and process contaminants can be characterized as follows.
在NDA阶段，可以获得确定纯度的参考标准品，分析方法已被验证，知道了杂质和降解情况，而且也已评估了对映体的纯度。对相关物质和过程污染物限度的设定具体如下：
(1) Consistency of the impurity profile of a drug substance has been established.
已经制定了原料药杂质情况的一致性。
(2) IND limits for total and individual impurities (identified and unidentified) are reviewed and adjusted based on manufacturing experience and toxicological data.
根据生产经验和毒理数据检查并调整总杂质和单个杂质（经确定的和未经确定的）的IND限度。
(3) Impurities present in significant amounts are identified and individual limits are set. However, it is not always possible to identify and/or prepare authentic substances for impurities. The labile nature of some impurities precludes this possibility. Limits may be set on these substances based on comparison of lots produced and used in toxicological and clinical studies.
以较大数量存在的杂质已被鉴定，并制定了单个杂质的限度。然而，不一定总是可以鉴定和/或制备杂质的真正物质。有些杂质的不稳定特性排除了这种可能性。可以根据比较所生产的批次和用在毒理性和临床研究的批次来制订这些物质的限度。
(4) The impurity profiles of the lots designated for marketing should not be significantly different from those of the lot(s) used for toxicological and clinical studies.
指定用做销售的批次的杂质情况不应和用于毒理性和临床研究的批次的杂质情况存在明显的差异。
(5) The composition material balance should be used, if possible, to evaluate the adequacy of the controls.
如可能，应采用物料平衡，以评估控制的充分性。
(6) Limits for residual solvents are based on the known toxicology of the solvents and on the manufacturing capabilities and dosing regimens.
根据溶剂的已知毒理性和生产能力以及给药方法制订残留溶剂的限度。
(7) Limits are set for inorganic contaminants by appropriate tests such as a heavy metals limit test and/or by a test for residue on ignition. Traditional compendial limits are applied unless otherwise indicated. Based on toxicological properties, limits may be set for specific metal contaminants that appear during manufacturing.
通过适当的检查法来设定无机污染物的限度，如，重金属限度检查法和/或炽灼残渣检查。除非另有说明，可应用传统的药典上的限度。在生产过程中产生的特殊金属污染物应通过适当的分析技术进行监测，并根据这些金属的毒理特性来制订限度。

INITIAL IND FILING
最初的IND文件编写
At the initial IND filing, the chemical nature of a bulk substance has generally been defined. The manufacturing process normally is in an early stage of development, and materials may be produced on a laboratory scale. Usually few batches have been made and, therefore, little historical data are available. The reference materials of a drug substance may be relatively impure. Limits for the purity of a drug substance are set to indicate drug quality. The setting of limits on related substances and process contaminants can be characterized as follows.
在最初的IND文件起草阶段，原料药的化学性质已经可以大致上确定下来。通常地，生产过程是研究的早期阶段，此时原料的生产还只是实验室规模。通常情况下已被生产的原料药只有少数的几批，因此，可以获得为数有限的历史数据。原料药的参照物可能相对来说是不纯的。设定原料药纯度的限度以此确定药品的质量。对相关物质和过程污染物的限度设定具体如下：
(1) Limits are set on total impurities, and an upper limit may be set on any single impurity. The limit for total impurities should maintain, if possible, a nominal composition material balance.
根据总杂质设定限度，而且对任何一单一杂质可设定上限。如可能，总杂质限度应确保近似的各种组分物料的平衡。
(2) Impurity profiles are documented. These are profiles of the lots of drug substances used in clinical studies and in toxicological studies that establish the safety of drug substances. The lots used in these studies should be typical products of the manufacturing process in use at that time.
记录杂质的情况。这些是有关用在临床和毒理研究中的原料药批次的杂质情况，而临床研究和毒理研究用来确立原料药的安全性。用于这些研究的批次应是当时采用生产工艺下的具有代表性的药品。
(3) Limits for residual solvents are based on the known toxicology of the solvents and on the manufacturing capabilities and dosing regimens.
根据溶剂的已知毒理性和生产能力以及给药方案设定残留溶剂的限度。
(4) General inorganic contaminants are monitored by appropriate tests such as a heavy metals limit test and/or a test for residue on ignition. Traditional compendial limits are applied unless otherwise indicated. Specific metal contaminants that appear during manufacturing should be monitored by appropriate analytical techniques, and limits should be set based on the toxicological properties of these metals.
一般的无机污染物通过适当的检查法来监测，如重金属限度检查法和/或炽灼残渣检查。除非另有说明，可应用传统的药典上的限度。在生产过程中产生的特殊金属污染物应通过适当的分析技术进行监测，并根据这些金属的毒理特性来制订限度。
(5) Appropriate limits are set for impurities known to be toxic.
为已知的有毒杂质制订适当限度。
(6) If appropriate, enantiomeric purity is controlled.
如合适，控制对映体的纯度。
Although water is not classified as an impurity, limits for water content may be needed to ensure the stability or ease of processing a drug substance.
尽管水未被划分为杂质，但需要限定含水量，以确保稳定性和易于原料药的加工。

NDA FILING
NDA文件编写
During the IND phases of drug development, the manufacturing process for a drug substance may undergo a number of revisions. Generally, the scale will have changed from laboratory size and will approach or reach full production batch size. A number of batches will normally have been produced, and a historical data base of the results of testing for impurities will exist. When significant changes in a manufacturing process are made, the impurity profile should be reviewed to determine if the toxicological studies are still supportive.
在药品研发的IND阶段，原料药的生产过程可能会经历几次修订。一般地，生产规模会发生改变，从最初的实验室规模逐渐接近或达到全面的批生产规模。正常情况下将会生产很多批，也将会有杂质检测结果的历史性数据。当生产过程发生重大变化时，应检查杂质的情况，从而决定毒理性实验是否仍然具有支持性。
At the NDA stage a reference standard of defined purity is available, analytical methods have been validated, impurity and degradation profiles are known, and enantiomeric purity has been evaluated. The setting of limits on related substances and process contaminants can be characterized as follows.
在NDA阶段，可以获得确定纯度的参考标准品，分析方法已被验证，知道了杂质和降解情况，而且也已评估了对映体的纯度。对相关物质和过程污染物限度的设定具体如下：
(1) Consistency of the impurity profile of a drug substance has been established.
已经制定了原料药杂质情况的一致性。
(2) IND limits for total and individual impurities (identified and unidentified) are reviewed and adjusted based on manufacturing experience and toxicological data.
根据生产经验和毒理数据检查并调整总杂质和单个杂质（经确定的和未经确定的）的IND限度。
(3) Impurities present in significant amounts are identified and individual limits are set. However, it is not always possible to identify and/or prepare authentic substances for impurities. The labile nature of some impurities precludes this possibility. Limits may be set on these substances based on comparison of lots produced and used in toxicological and clinical studies.
以较大数量存在的杂质已被鉴定，并制定了单个杂质的限度。然而，不一定总是可以鉴定和/或制备杂质的真正物质。有些杂质的不稳定特性排除了这种可能性。可以根据比较所生产的批次和用在毒理性和临床研究的批次来制订这些物质的限度。
(4) The impurity profiles of the lots designated for marketing should not be significantly different from those of the lot(s) used for toxicological and clinical studies.
指定用做销售的批次的杂质情况不应和用于毒理性和临床研究的批次的杂质情况存在明显的差异。
(5) The composition material balance should be used, if possible, to evaluate the adequacy of the controls.
如可能，应采用物料平衡，以评估控制的充分性。
(6) Limits for residual solvents are based on the known toxicology of the solvents and on the manufacturing capabilities and dosing regimens.
根据溶剂的已知毒理性和生产能力以及给药方法制订残留溶剂的限度。
(7) Limits are set for inorganic contaminants by appropriate tests such as a heavy metals limit test and/or by a test for residue on ignition. Traditional compendial limits are applied unless otherwise indicated. Based on toxicological properties, limits may be set for specific metal contaminants that appear during manufacturing.
通过适当的检查法来设定无机污染物的限度，如，重金属限度检查法和/或炽灼残渣检查。除非另有说明，可应用传统的药典上的限度。在生产过程中产生的特殊金属污染物应通过适当的分析技术进行监测，并根据这些金属的毒理特性来制订限度。