作者：潘宪伟 来源：药研数据库

Pharmaceutical Technology; AUGUST 2010

Common Deficiencies in Abbreviated New Drug Applications

Part 1: Description, Composition, and Excipients

Aloka Srinivasan, Robert Iser, and Devinder S. Gill

仿制药申报常见缺陷信解读

第二部分：描述、组成和辅料

Chemistry reviewers in the US Food and Drug Administration’s Office of Generic Drugs provide an overview of common deficiences cited throughout the Chemistry, Manufacturing, and Controls section of abbreviated new drug applications (ANDAs).

The reviewers aim to assist ANDA sponsors in building quality into their submissions by clarifying components of the applications.

食品和药品管理局（FDA）仿制药办公室（Office of Generic Drugs）的化学审评员提供了一份概述，列举了简化新药/仿制药申请（ANDAs）中化学、制造和控制部分的常见缺陷

评审员的目标是通过澄清申请的组成部分来帮助ANDA发起者，提高其申报的质量

Aloka Srinivasan, PhD,* and Robert Iser, M.S., are team leaders, and Devinder S. Gill, PhD, is a deputy director, at the Office of Generic Drugs within the Office of Pharmaceutical Science, under the US Food and Drug Administration’s Center for Drug Evaluation and Research, [email protected].

*To whom all correspondence should be addressed.

Aloka Srinivasan 博士和医学硕士 Robert Iser 是食品和药品管理局（FDA）药物审评与研究中心下属的仿制药办公室（Office of Generic Drugs）的团队负责人，Devinder S. Gill 博士是副主任。

所有的信件都可以寄给：[email protected]。

As part of the US Food and Drug Administration’s Office of Generic Drugs (OGD) ongoing effort to streamline the review process and reduce the number of deficiencies cited for applications, a series of articles are being published to provide transparency and clarity to the sponsors submitting applications in the Question based Review (QbR) format. The articles highlight the need and significance of science-based justification in establishing drug substance (DS) and drug product (DP) specifications, in-process controls for both DS/DP, choice of formulation, selection of a product design, and selection of the manufacturing processes. Part 1 of this series, which dealt with the deficiencies cited in the drug substance section, was published in January 2010 (1).

作为美国食品和药物管理局（FDA）的一部分，仿制药办公室（OGD）正在努力简化审评流程和降低审评中缺陷的数量，目前正在发表一系列文章，为“以基于问题审查（QbR）格式”提交申请的申请人提供透明度和清晰度。在建立原料药（DS）和制剂（DP）质量标准、过程控制、处方选择、产品设计选择，和生产工艺选择中，这些文章强调了科学论证的必要性和重要性。ANDA申报常见缺陷系列第1部分发表于2010年1月，是关于原料药部分提到的缺陷。

本文是该系列（ANDA申报常见缺陷系列）文章的延续，重点是阐明，以通用技术文件（CTD）和基于问题审查的质量总体概述（QbR-QOS）格式为指南，在递交简化新药/仿制药申请（ANDAs）中，引用的描述和组成（3.2.P.1）和辅料（3.2.P.4）部分的，一些常见缺陷的意图和重要性。本文也包括P.1和P.4章节的其它问题，这些问题不是常规缺陷的一部分，但是对制剂的质量具有关键作用；如果不解决这些问题，可能会产生监管和质量影响。请参阅侧栏“常被引用的缺陷示例和注释”。这个列表不是包罗万象的，但确实包括经常被引用的注释和有关组成和辅料的缺陷。

Examples of commonly cited Description, Composition, and Excipient deficienciesand comments*常被引用的描述、组成、辅料缺陷 示例和注释*

1. The component and composition table for your drug product is incomplete. Please revise your components and composition table to include percent w/w of all ingredients present in each strength of the drug product.

   制剂中成份和组成表不完整，请修订成份和组成表以包括制剂的每种规格的所有成份的百分比（w/w）

2. The functionalities of hydrochloric acid or sodium hydroxide have been stated as buffers. Please clarify, as these two reagents usually do not constitute buffers. If needed, provide an updated component and composition table.

   在处方中盐酸或氢氧化钠的功能已规定表示为缓冲剂。请详加阐述，因为这两个试剂通常不作为缓冲剂。必要时，提供更新的成份和组成表。

3. Please justify the overage in your formulation by demonstration of similar or higher overage in the Reference Listed Drug (RLD). We recommend a comparison with multiple lots of RLD to justify the proposed overage.

   请通过论证参比药物（RLD）有相似或更高的过量投料来证实你们处方中的过量投料的合理性。我们建议与多批RLD对比来证实所推荐的过量投料量。

4. We note that there are significant differences in the proposed formulation and that of the RLD. We request you to further comment why these differences do not affect performance and intended use of your drug product as per label claim.

   我们注意到申请人所推荐的处方与RLD有明显差别，我们要求你们做进一步的解释，以说明为什么这些差异不会影响你们制剂标签所声明的性能和既定用途。

5. We would like to point out that the premise of excipient compatibility studies is to ensure that there is no adverse chemical reaction between the API and excipients. Thus, we request that for your future applications, chemical changes and not just physical changes are studied during the pharmaceutical development.

   我们要指出辅料相容性研究的前提是确保原辅料间无不良的化学反应，因此，我们要求在你们以后的申请中，在药物开发中，要研究化学变化而不是仅研究物理变化。

6. Please provide a calculation to demonstrate that the amount of elemental iron complies with recommendations in 21 CFR 73.1200 based on maximum daily dose of the proposed product

   请提供计算证明铁元素的量符合21CFR 73.1200中的推荐值，该值根据建议的产品最大日剂量来计算。

7. Please justify the functionality related characteristics of the release controlling (excipient name) in your modified release product, for example, viscosity range. Please address what impact a lot with at the lower end and higher end of the range would have on the drug product critical quality attributes such as release profile.

   请证明你们的缓释制剂中释放控制（辅料名称）相关特性的功能合理性，比如：粘度范围。请叙述范围的最低点和最高点对制剂的关键质量属性（如释放分布情况）有何影响。

8. Due to the presence of carboxyl groups in the API there is a potential of interaction with the glycerin in the formulation. Please demonstrate that the proposed analytical methods are suitable to identify and quantify any ester product that may be formed.

   由于原料药有羧基存在，可能与处方中甘油有潜在的相互作用。请证实推荐采用的分析方法是适合于鉴别和定量任何可能形成的酯类产品。

9. It is reported in literature that lactose reacts with primary amines to form adduct “Amadori” complexes (Maillard Reaction) under pharmaceutical manufacturing processes conditions as well as during product shelf life. Your pharmaceutical development report has not addressed this topic though your API is an amine and lactose is the major excipient. Please provide information regarding any pharmaceutical development studies performed to rule out the formation of complex between API and lactose and to justify the use of lactose in this formulation.

   有文献报道在制药生产工艺条件和产品有效期内乳糖与伯胺反应形成加合物“Amadori”（Maillard反应），既然你们的原料药是胺类且乳糖是主要辅料，而你们的药物开发报告并未对此进行研究。请提供药物开发研究中进行的有关排除原料药和乳糖形成复合物的可能性，并证实处方中使用乳糖的合理性。

10. Please update your specification for (excipient name) to meet the current USP / NF monograph requirements.

    请更新你们（辅料名称）的标准以符合现行USP/NF专论的要求。

11. Please provide the retest date of the excipients with the assurance any ingredients which are prone to microbial growth are tested annually.

    请提供辅料的复验期，并确保对有滋生微生物倾向的任何成份每年进行检测。

12. You have used a certain grade of (excipient name) in your parenteral formulation, when the certificate of analysis from the supplier clearly indicates that this grade is not intended for use in parenteral dosage forms. Please provide a justification.

    你们在注射用制剂中使用了某一特定级别的（辅料名称），然而供应商的分析报告书明确表明该级别不适用于注射剂，请提供合理的理由。

13. Please clarify why you have set the acceptance criteria for impurities in (excipient name) at much higher level than that of vendor’s acceptance criteria.

    请阐明为什么你们设定（辅料名称）的杂质的可接受标准明显高于供应商的可接受标准。

14. We noted that your results of the analysis of impurities / physical attributes in (excipient name) differs significantly from that of the results found in the vendor’s certificate of analysis. Please clarify.

    我们注意到你们（辅料名称）的杂质/物理特性与供应商分析报告书中的结果有明显差异，请阐明原因。

Comments are usually not deficiencies and are found in section B of deficiency letters.评论通常不是缺陷，可以在缺陷信B部分找到

2.3.P.1 Description and composition of the drug product 药品的描述和处方组成

There are three sets of QbR-QOS questions with respect to composition of the drug product. They are as follows:

1. What are the components and composition of the final product? What is the function of each excipient?
2. Does any excipient exceed the Inactive Ingredients Database (IID or IIG) limit for this route of administration?
3. Do the differences between this formulation and the reference listed drug (RLD) present potential concerns with respect to therapeutic equivalence?

有三套关于制剂组成的QbR-QOS问题。如下所示：

1. 最终产品的成分和组成是什么？每种辅料的功能是什么？
2. 是否有辅料超出了这种给药途径下的IID或IIG（非活性成分数据库）的限度。
3. 该处方与参比药品（RLD）之间的存在的差异是否有可能关系到治疗等效性？

The description and composition information is satisfactory in the majority of ANDAs submitted to OGD. Usually there is no need to issue deficiencies or comments to ANDA sponsors. However, when deficiencies are cited, they typically fall into four main categories. The first category is with respect to issues with the composition information. This information is typically presented in a tabular format in 2.3.P.1 and 3.2.P.1. When deficiencies are provided to sponsors they are, in many cases, related to insufficient clarity in the answers to the first set of QbR-QOS questions noted above. Second, there are common deficiencies cited with respect to proposed overages. The third category is related to the qualitative (Q1) or quantitative (Q2) formulation including the comparison to the reference listed drug (RLD) or the IIG (2). These are related to the second and third QbR-QOS questions above. The final category of composition related deficiencies is related to the make up of ingredients (e.g., iron oxide in coatings).

大多数提交到OGD的ANDAs，其描述和组成信息符合要求。通常就没必要向ANDA申报人提出缺陷或建议了。但是，一旦提出缺陷，可将其代表性的分为四大类。第一大类是关于成分信息的问题。这部分信息一般出现在2.3.P.1和3.2.P.1中以表格的形式体现。给申报人提出的缺陷，多数情况下，是关于上面提到的QbR-QOS中的第一套问题的答案不够明确。第二类，提出的常见缺陷是关于提议的过量投料。第三类是关于定性处方（Q1）或定量处方（Q2），包括与参比药品或IIG（非活性成分数据库）的对比。这些关系到上面提到的QbR-QOS中的第二和第三套问题。第四类有关组成的缺陷是关于成分的组成。（如，包衣中的氧化铁）。

Drug product composition information. 制剂组分信息

Very few deficiencies and comments are cited with regard to the information presented in the composition tables. If cited, these include not providing the percent of each excipient (e.g., w/w %) in the formulation. The intent of this question is to clearly provide the reviewer the intended function of the multifunctional excipients in the formulation at the proposed w/w % level. This information is critical to the assessment of the formulation as it is well documented that changing the w/w % of multifunctional excipient in the formulation can potentially change the function. In cases of multistrength products, it also provides the information on the dose proportionality over the range of strengths.

很少有缺陷和建议是关于出现在组分表中信息的。如果提到这方面的问题，包括处方中没有提供每种辅料的百分比（如w/w %）。这个问题的目的就是向审核者清楚提供处方中的多功能辅料在所提议的w/w% 水平的既定作用。这个信息对于评估处方很重要，因为它可以很完整的记录下处方中多功能辅料的百分比数w/w %的变化，而这些变化可能潜在的改变其功能。在多种规格的产品中，还要提供在多种规格范围内的剂量比例信息。

申请人应提供一个列表，对于每一种产品规格，要列出每种组成其成分的量、辅料的功能、级别（如Avicel PH 101等）、标准（如USP，NF，FCC等）以及适当的来源（如植物药或是来源于动物）。这个列表应包括整个工艺中用到的所有的物料，包括有机溶剂、水溶剂以及用于生产工艺中的工艺助剂和在工艺过程中的去除剂（如水、乙醇、氮等）。所有成分的信息包括标准和检验报告应在3.2.P.4中提供。单位剂量的定量信息必须详述包含在这个产品中一个单位内所有其它的组分。

另一个需要解决的问题可能是关于处方中辅料功能的理由解释。报告的功能应根据有证明文件的证据和产品的设计。对于多功能辅料，申报人应提供在提及的处方中预定功能的依据。根据预定的功能，辅料标准中应包括特定的控制。在原申报文件中指定的辅料的功能关于其批准后的变化会根据辅料的功能有官方的提示（即SUPAC-IR中可找到相关建议）。常见的多功能辅料的例子比如淀粉，它可用作多种用途（粘合剂，崩解剂等）。

另外，对于有多重工艺步骤的复杂的产品（如缓释产品等），建议为了便于审核，将组分表中的中间产品的组分（如制粒、片心或微球）分隔开以反映出每一主要工艺步骤。另外，成分是颗粒内加还是外加也要明确。QbR的常见问答文件和关于提交药品生产和控制文件的工业指南提供了另外的见解。

也应说明关于选定剂型的论题。作为仿制药，剂型必须与批准的参比药品相同，除非经过适用性请愿批准，而且这很显然是主要的QTPP（目标产品质量概况）原则之一。按照所说的如果参比药品是一个胶囊，仿制药也必须为胶囊剂，而且还要符合CDER（Center for Drug Evaluation and Research医药评价和研究中心）数据标准手册中的定义。同样地，一个产品符合了数据标准手册中定义的乳膏的标准处方才可以称为乳膏。

Overages. 过量投料

One common deficiency is related to a proposed overage of the active. The firm should identify and justify any formulation overages that appear in the final product; and the overage should be further discussed with respect to the manufacturing process in 3.2.P.3. Note that, in general, the only acceptable justification for an overage in the final drug product formulation is if the ANDA sponsor demonstrates the same overage is also observed in the RLD. It is not acceptable to propose an overage to increase the shelf-life of the drug product. Generic sponsors should justify the proposed overage as compared to the RLD. Data that can be used to justify the overage may include comparative assay data on the test and reference products throughout shelf-life and comparative impurity/degradant levels demonstrating similar behavior. Other reported overages such as the use of excess coating solution in order to ensure uniform coating for product performance do require justification, and this information should be reported in the 3.2.P.1 and 3.2.P.3 sections, as applicable.

一个常见的缺陷是关于所提议的活性物质的过量投料。公司应对出现在终产品中的任何处方过量投料作出标识并证实其合理性；而且过量投料应在3.2.P.3中关于生产工艺方面予以进一步讨论。应注意一般来说，在最终产品处方中对于过量投料唯一可接受的理由就是，如果ANDA申报人证实了在参比药品中也出现了同样的过量投料。主张用过量投料来增加产品的有效期是不可接受的。仿制药申报人应与参比药品比较来证明提议的过多投量合理。可用于证明过多投料的资料可能包括自研制剂与参比制剂在整个有效期的含量对比数据以及比较杂质/降解水平来证实他们具有相似的性能。其它报告的过多投料如为了确保产品性能均匀地包衣而使用过多的包衣溶液，确实需要证明，这个信息应在3.2.P.1 和 3.2.P.3部分适当的报告。

Comparison to RLD. 与参比药品的比较

Although questions with respect to comparability of the formulation to the RLD in certain dosage form are often addressed during filing of the ANDA, with the justification for the allowed exceptions per the Code of Federal Regulations (CFR) is often times lacking. 21 CFR 314.94 (9) (iii through v) includes a list of “exception excipients” or inactive ingredient differences permitted in a generic product when compared to the RLD (7). These regulations must be followed by the applicant in order to meet the requirements of classification as a generic product. In cases where the applicant is using an exception excipient the sponsor must demonstrate that the differences do not affect the safety or efficacy of the proposed drug product, as required by the CFR.

特定剂型中关于处方与参比药品相比较的问题，虽然通常是在整理ANDA过程中提到，但是根据联邦法规（CFR）往往缺乏允许特例的依据。21CFR 314.94 (iii 到v) 包括一个“特例辅料”列表或与参比药品相比，在仿制产品中允许的非活性组分差异的一个列表。申请人必须遵循这些规定以满足归为仿制产品的要求。如果申请人使用特例辅料，申报人必须证明根据CFR的要求，之间的差异不会影响提议的产品的安全性或效能。

关于API与参比药品之间的比较，超出了本文的范围，但是，可以在“橙皮书”中找到关于药物等效性的很好的参考。

有一些常见的关于定性处方/定量处方（Q1/Q2）以及使用特例辅料的问题。例如，CRF允许在注射剂中替换或加入缓冲剂、防腐剂或抗氧化剂。但是，申报人需要认识到这些替换或加入对产品总体性能的影响。

QbR常见问题问答包括了一些另外的建议：是对于在溶液处方和生物等效性影响方面其它允许的差异。这些包括山梨醇或甘露醇在口服溶液中的量；在外用产品中渗透促进剂的量；在眼用溶液中任何定性（Q1）或定量（Q2）的差异，以及在吸入剂和鼻喷雾产品中任何定性或定量的差异。

最后，如果在提议的仿制药处方中带入任何其它的风险，可能会给公司提出建议要求证明这些辅料的使用不会对上市的产品带来较高的风险。例如包括使用天冬氨酰苯丙氨酸甲酯、蓖麻油、花生油、着色剂（如FD&C yellow #5）或苯甲醇，而这些东西不允许在新药申请（NDA）产品中出现。

Inactive Ingredients Database. 非活性成分数据库

The information on the IIG website provides the highest level of an ingredient approved for a single unit (2). As the information is for single unit, we highly recommend that the ANDA sponsor exercise caution in using this information in formulating their drug product. The scope of the information provided in the IIG database is limited to the use of an excipient in the Center for Drug Evaluation and Research (CDER) approved product and for this reason it is imperative the sponsor do the requisite due diligence to justify the use of the excipient in their product line. Citing the IIG may be sufficient is most cases but not in all drug products. Having this supportive information in the application will eliminate any question related to this critical concern. In cases, where citing IIG is found to be insufficient, the ANDA sponsor should follow the recommendations provided in the Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients in providing supportive data (9).

IIG网站上的信息提供了一种成分在单剂量中批准使用的最高限度。由于这些信息是针对单剂量的，我们强烈建议ANDA申报人在其产品处方中使用这些信息时应谨慎。IIG数据库中提供的信息范围仅限于在CDER（医药评价和研究中心）中批准的产品中辅料的使用，而且因为这个原因申报人必须加强注意来证实在他们的产品中使用该辅料的限度。IIG中所引用的可能是对于大多数产品的但是并不是对所有的制剂的。在申请中有了这个支持性信息，会忽略关于这个关键问题的任何一个问题。在实际中，如果发现引用的IIG是不够的，ANDA申报人应遵循以下工业指南中提出的建议：制药辅料安全性评估的非临床研究，其中可提供一些支持性数据。

Ingredient composition. 成分构成

Per 21 CFR 314.94 [(iii)(a)(9)(v)], the applicant is required to both identify and characterize the excipients in the proposed product demonstrating that they do not impact safety (7). This includes the composition or “make-up” of the ingredients. In many cases, complex coatings, colors, and flavors are proposed for use in the drug product. A composition should be provided in the ANDA or if the information is proprietary, a drug master file (DMF) reference or the composition of such components should be provided by the supplier directly to the Agency. This allows for a through evaluation of the composition of the materials proposed including iron oxides in coatings or other components from a quality and safety perspective. Certification from the manufacturer of coatings should be provided that the components of the coating either are found in the CDER approved products or applicable CFR citations should be provided for the use of these components in the coatings.

根据21 CFR 314.94 [(iii)(a)(9)(v)]，要求申请人要对提议产品中的辅料进行鉴别并描述其特性，证明他们不会影响安全性。这包括组分或成分的组成。在很多情况，制剂中提议用到复杂的包衣，着色剂和矫味剂。ANDA中应提供其组分或如果信息有专利，供应商应将DMF证明信或这种成分的组成直接提交给官方。这要求从质量和安全的角度对提议的物料成分（包括包衣中的氧化铁或其它的组成）做一个全面的评估。应提供包衣制造商的证明：包衣的成分要么是在CDER批准的产品中发现的，要么为包衣中使用这些组分提供适当的CFR引证。

关于氧化铁的使用，多次要求申报人证明其使用符合CFR的要求。ANDA申报人应表明他们的产品符合21 CFR 73.1200每天接触量不超过5mg 铁元素的要求。还建议申报人根据所用的处方列出铁每日摄入量的详细计算。另外，CFR中有一些关于所用的氧化铁质量的其它要求包括鉴别，添加的混合物，规格和杂质（如砷，铅，汞）。按照上面规定的，ANDA申报人应能提供支持性数据来证明他们的产品线中辅料的使用是合理的。

Compatibility of excipients with API. 辅料与API的相容性

With respect to design of the intended product, the lack of understanding of the chemistry and performance of excipients is one of common causes for production failures and recalls. Thus, it is important to study the compatibility of the excipients with the API and understand the critical material attributes prior to finalizing the drug product formulation. Performance characteristics will be discussed in a later section in this article.

预期产品的设计方面，缺少对辅料化学和性能方面的理解是造成生产失败和召回的主要原因之一。因此，研究辅料与API的相容性并且在确定制剂处方之前了解关键物料的属性非常重要。性能特征会在本文后面的部分加以讨论。

• What evidence supports compatibility between the excipients and the drug substance?

  什么证据支持辅料和原料药之间的相容性呢？

Thus, justifying excipient compatibility based on end product testing or monitoring changes in physical appearance are not acceptable.

这个问题的回复在2.3.P.2.1.2关于API与辅料相容性中，申报人经常根据一些事实提出不执行这些研究的理由：比如辅料对于给定的剂型很“普通”，而且展示批的稳定性数据是可以接受的。发现一些申报人仅监控API与提及的辅料混合后物理性质的变化。需要理解的是辅料与API相容性研究的前提是根据原料药和辅料以及生产工艺的化学相互作用的机械论的理解的提出证实合理性的依据。

因此，根据终产品测试或监控物理性质的变化来证实辅料相容性的合理性是不能接受的。

An example of a so called “common” excipient significantly affecting the formulation, is lactose, when used in conjunction with APIs which are primary or secondary amines. The formation of “Amadori” complexes has been found to be detrimental to the stability of many drug products. Polacrillin potassium is another excipient which may form complexes with APIs containing amines based on the manufacturing process (high heat) or pH of the formulation and result in low assay of the active ingredient over shelf life (11). Another relevant interaction that is frequently observed is that of polyols with free carboxylic group containing APIs.

有一个实例，一种所谓称作很“普通”的辅料，对处方产生了显著的影响，那就是乳糖用于与第一胺和第二胺的APIs结合时。已发现生成的“Amadori”复合物对多种产品的稳定性不利。Polacrillin钾是另外一种辅料，根据生产工艺（高热）或处方 的pH值它可与含胺的APIs生成复合物，而且导致活性成分在有效期内含量下降。另外经常观察到就是多羟基化合物与含游离的羧基基团的APIs之间的相互作用。

• Levels of methacrylic acid and divinyl benzene in polacrillin potassium
• Residual peroxides in povidone, crospovidone and/or polyethylene glycol
• Heavy metals or other metal reagents in talc.

根据这一事实，即处方与参比药品处方相似作为不进行辅料-API相容性研究的理由也有它的缺陷。通常发现根据级别和供应商，辅料的杂质和残留溶剂谱可能显著的不同。鼓励申报人对可能潜在的影响制剂质量的辅料的杂质和残留溶剂进行鉴别。辅料中杂质可能影响产品稳定性的例子如下：

• 甲基丙烯酸和联乙烯苯在polacrillin钾中的限度
• 聚乙烯吡啶酮、交联聚乙烯吡啶酮和/或聚氧乙烯中残留的过氧化氢
• 滑石粉中重金属或其它金属试剂

Control of excipients 辅料控制

There is only a single question in the QbR-QOS pertaining to control of excipients: “What are the specifications for the inactive ingredients and are they suitable for their intended function?” However, despite its apparent simplicity, the question is a poignant one and relates to a critical question in the pharmaceutical development section, 2.3.P.2.2, which plays a role in ensuring the quality of the drug product and its performance based on label claim over the shelf life.

• How were the excipients and their grades selected?

在QbR-QOS中仅有一个问题是关于辅料控制的：“非活性成分的标准是什么，以及它们适用于设定的功能吗？”。然而，尽管其表面上简单，问题却非常深刻，而且涉及到制药开发2.3.P.2.2部分一个关键的问题，它关乎根据标签中的声明在整个有效期内确保制剂的质量以及其性能。

• 如何选择辅料以及其级别？

Performance characteristics of excipients. 辅料的性能特征

One of the least understood questions in QbR-QOS is perhaps the one in 2.3.P.2.2, where the sponsor is asked to justify the selection of the “grade” of the excipients. Overwhelmingly, the response to this question is that the excipients are USP/NF grade. Another common response is the verbatim information as found in the Handbook of Pharmaceutical Excipients (12) with no specificity to the intended use in the proposed drug product. This question in the QbR-QOS is intended to demonstrate the understanding of the performance characteristics (i.e., excipient performance or functionality related characteristics) of the excipients which may affect the manufacturability of the drug product. The performance characteristics of excipient are based on their form and their physical properties. For example, for a solid excipient that is to be used in dry blending and direct compaction processes, the impact of changing physical parameters such as bulk density, surface area, particle shape and size distribution need to be evaluated and justified. Similarly, liquid excipients may be evaluated for variation in viscosity and pH; and polymeric excipients need to be evaluated for the impact of changes in molecular weight distribution or viscosity, as applicable.

QbR-QOS中最易理解的问题大概就是在2.3.P.2.2，要求申报人给出选择辅料级别的正当的理由。这个问题不可辩驳的回复就是辅料为USP/NF级别。另一个常见的回复就是按照在制药辅料手册中发现的信息逐字逐句的搬来，对提议的制剂的既定用途没有特异性。QbR-QOS中这个问题的旨在表明对可能影响制剂质量的辅料的性能特性的理解（即辅料的性能或与特征相关的功能性）。辅料的功能特性是根据其结构和物理属性。例如，一种固体辅料要用于干粉混合和直接压片工艺中，物理参数变化的影响如容积密度、表面积、颗粒形状和粒径分布需要评估而且要合理。同样的，液体辅料可能要评估其粘性和pH的变化。而聚合物辅料，如适用，需要评估分子量分布或粘性变化的影响。

如果辅料的制造商都不鼓励使用，可能需要申报人在一定的处方中避免使用这种特定级别的辅料。据观察，已有辅料用于一种处方中，而供应商的检验报告明确标明这种级别不适用于这种特定的剂型。这是一种很严重的缺陷而且需要清楚的论证其合理性。有一个这样的样子，就是根据生产商的信息，避免一定级别的甘露醇用于注射剂处方中。另外一个例子就是根据USP-NF专论，卡波姆934不适用于内服。

Control of excipients (specifications). 辅料的控制（质量标准）

The QBR-QOS question in 2.3.P.4 regarding the specifications of the excipients may be regarded as a summing up of the understanding based on the response to the two questions in the pharmaceutical development section, discussed above.

在2.3.P.4关于辅料标准的问题可以看作是根据上面讨论的在制药开发部分的两个问题回复的理解的总结。

Compendial excipients. 收入药典的辅料

The primary requirement for a compendial excipient is that it meets all the USP–NF requirements (13). The sponsors need to continuously monitor the USP–NF for monograph updates to ensure excipient compliance. As part of the USP–NF monographs for excipients there are performance related tests based on the intended use in a dosage form. The sponsors are encouraged to refer the individual monographs, as applicable (e.g., lactose and microcrystalline cellulose).

收载进入药典的辅料首要的要求就是要符合USP-NF的要求。申报人需要不断的追踪USP-NF的更新情况以确保辅料的符合性。辅料作为USP-NF专论的一部分，有根据剂型的特定用途相关的性能测试。如适用，鼓励申报人参考个论（如乳糖和微晶纤维素）

我们经常会看到在可接受标准方面，对于一定的控制，辅料供应商的检验报告与ANDA申报人所提供的标准之间有差异。在这种情况下，申报人需要清楚的提供，他们提议的可接受标准的正当的理由以及对产品的稳定性和安全性任何可能的影响。

Noncompendial excipients. 未收入药典的辅料

For non-compendial excipients which are comprised of definite mixtures of compendial excipients, the mixture composition and ingredient identifications are requested. Specifications should include all meaningful controls for quality and purity (e.g., identity, assay, impurities, heavy metals etc.) that are found in the individual USP–NF monographs. Additionally, other sources of tests and criteria for non-compendial excipients may include the manufacturer’s information, the CFR and the FCC (14, 15). It is often observed that the compendial methods of analysis for the individual components in the mixture may not be suitable in these cases due to interference from the other components. Thus, information regarding the validation of non-compendial test methods for these excipients needs to be provided.

对于那些由一定的收入药典的辅料组成的混合物构成的未收入药典辅料，需要混合的成分和组成成分的鉴别。标准应包括对质量和杂质的所有有意义的控制（如鉴别，含量，杂质，重金属等），这些控制在USP-NF各论中都可找到。另外，对于未收入药典的辅料，测试和标准的其它来源可能包括制造商的信息，CFR和FCC的要求。经常观察到，混合物中单个成分的药典分析方法可能由于与其它组分的互相干扰不适合于这些情况。因此，需要提供对于这些辅料有关非药典测试方法验证的信息。

一种新型的辅料定义为以前未被官方批准的辅料。这些辅料一般是作为新药批准工艺的一部分被批准的。在一定的情况下，对于批准的辅料最低标准要求是一份DMF以及临床和安全性评估。辅料主文件指南形式的好的参考就是美国国际制药辅料委员会。

Excipients of animal origin. 动物来源的辅料

Bovine or transmissible spongiform encephalopathy (BSE/TSE) statement and country of origin should be provided for excipients of animal origin. For excipients which may be of both animal and vegetable origin, if the firm proposes to switch from one to another in near future, the effect of the switching on the manufacturability of the product should be addressed. Common excipients in this category are Magnesium Stearate, Calcium Stearate and Stearic Acid. Submitting merely the COAs for both grades of the excipient is usually not enough. Sponsors are requested to provide information regarding pharmaceutical development studies which may have been performed to evaluate the product manufactured using both the grades, for appearance (sticking and picking), content uniformity, tablet friability, tablet dissolution (at target hardness) and manufacturing yield, to assure the equivalence.

对于动物来源的辅料应提供疯牛病声明以及原产国。对于既可能是动物来源也可能是植物来源的辅料，如果公司主张不久后从一种转换为另一种，那么应考虑转换后产品的可制造性的影响。这一类型常见的辅料为硬脂酸镁，硬脂酸钙和硬脂酸。仅仅提交辅料每个级别的检验报告通常是不够的。要求申报人提供关于制药开发研究的信息，这些信息可能已用于评估使用各种级别生产的产品以确保其等价，如外观（粘性和吸附性）、含量均匀度、片剂易脆性、片剂溶出度（在目标硬度）以及产量。

Retest dates of excipients. 辅料的复验期

This rather simple information is often missing from the submissions. Although this is covered under cGMPs (21 CFR 211), one of the reasons for requesting this information is to confirm that excipients which support microbial grown are tested frequently, preferably once a year.

这个相对简单的信息在提交时通常被遗漏。尽管这是cGMPs （21CFR 211）要求的，要求这一信息的一个原因是为了确保对支持微生物生长的辅料经常要进行测试，最好是一年一次。

Reduced testing based on vendor validation. 根据供应商验证减少测试项目

Firms often provide information in their application regarding proposed reduced testing of the excipients, once the vendor has been validated. As valuable as this information is a firm may be reminded in these cases that vendor validation is a field function based on 21 CFR 211.84(d)(2) and not reviewed or approved by OGD (17). The firm is advised to consult with the district office regarding the appropriateness of their vendor validation policy. Acknowledging this in the original ANDA submission is recommended.

企业经常在他们的申请中提供这样的信息：一旦他们的供应商经过了验证，就主张减少辅料测试项目。同样有用的是这一信息可能提醒公司在这些情况下供应商验证是根据21CFR 211.84 (d)(2) 的一个领域职责，而不是由OGD审核和批准的。建议公司咨询区域办公室关于他们供应商验证合适的政策。建议在ANDA最初提交时就告知这一点。

Conclusion 结论

This concludes our discussion on the commonly cited deficiencies for sections 3.2.P.1, Description and Composition of the Drug Product and 3.2.P.4, Control of Excipients. It is noted that the deficiencies and comments cited in these sections of the ANDA are not as numerous as in other sections. However, appropriate information in these two sections are crucial in demonstrating that the sponsor has adequate understanding of the QTPP of their drug product and has strived to manufacture a robust formulation with desired performance over shelf life.

我们对3.2.P.1部分描述和制剂的组分以及 3.2.P.4辅料的控制中常见的一些缺陷进行讨论得出结论。据悉，ANDA在这些章节中的缺陷和建议并不象其它章节中的那么多。然而，在这两部分中适当的信息很关键：表明申报人足够理解其制剂的QTPP（目标产品质量概况），而且一直致力于制造一个稳定的处方，在整个有效期内有良好的性能 。

Numbering in section heads correspond to those in the Common Technical Document (CTD).

分段编号与通用技术文件（CTD）中的编号相对应

Acknowledgments致谢

The authors wish to acknowledge Lawrence Yu, PhD, OGD Deputy Director for Science, and Vilayat A. Sayeed, PhD, OGD Director of Chemistry Division III, for their encouragement and invaluable insight.

感谢仿制药办公室（OGD）科学副主任Lawrence Yu博士和 仿制药办公室第三部门主任Vilayat A. Sayeed博士的鼓励和宝贵建议

The views and opinions in this article are only those of the authors and do not necessarily reflect the views of policies of FDA.

本文所表达的观点仅代表作者个人观点，并不代表FDA的观点或政策

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