20070523
PHARMACEUTICAL SCIENCES – 药物科学
QUESTIONS AND ANSWERS 问答
The Health Canada document PHARMACEUTICAL SCIENCES - QUESTIONS AND ANSWERS is intended to provide clarification on a number of issues that relate to Quality (e.g., Chemistry and Manufacturing) and Biopharmaceutics (e.g., Bioequivalence/Bioavailability) information of human drug submissions for pharmaceutical-type products. It is based on the current thinking on the topic. They are indented to briefly communicate in easily understood and comprehensible manner, requirements and practices or interpretations responding to the relevant questions in specific areas of Pharmaceutical Sciences.
加拿大卫生局文件“药物科学—问答”目的是针对人用药申报药品类型产品有关质量（例如化学和生产）和药物生物方面（例如生物等效性/生物利用度）的信息的一些问题进行澄清。这些回答都是基于目前对这些问题的讨论。文件想要采用易于理解的交流方法，对于一些药物科学特定领域的相关问题，解释一些相关要求、实践或说明。
To facilitate the review of this Q&A Document, the format and structure is based on ICH's Common Technical Document (CTD). It is acknowledged that not all modules of the CTD have been included (e.g., Module 4 has been omitted). The Q&A Document only includes those modules and sections that have questions related to Quality or Biopharmaceutics issues. It is our intent to update the Q&A Document on a quarterly basis.
为方便浏览本问答文件，本文格式和结构是基于ICH的CTD格式。但并未包括所有的CTD模块（例如模块四被略去）。问答文件仅包括那些与质量和药品生物问题相关的模块和部分。我们会每季对问答文件进行更新。
Sultan Ghani, Director
Bureau of Pharmaceutical Sciences
Therapeutic Products Directorate, HPFB, Health Canada
101 Tunney's Pasture Driveway, Tunney's Pasture
(A.L. 0201D)
Ottawa, Ontario
K1A 0K9
Telephone: (613) 941-3184
Facsimile: (613) 957-3989
This and other guidance documents are available on the Health Canada web site.
本指南和其它指南均可以在加拿大卫生局官网上获得。
TABLE OF CONTENTS 目录
MODULE 1: ADMINISTRATIVE INFORMATION AND PRESCRIBING INFORMATION
模块一：行政信息和处方信息
1.4 Health Canada Summaries 加拿大卫生局总结
1.4.1 Certified Product Information Document (CPID) 认证产品信息文件
MODULE 2: COMMON TECHNICAL DOCUMENT SUMMARIES
模块二：通用技术文件总结
2.3 Quality Overall Summary (QOS) 质量总结
MODULE 3: QUALITY
模块三：质量
3.2.S Drug Substance 原料药
3.2.S.2 Manufacture 生产
3.2.S.4 Control of Drug Substance 原料药控制
3.2.S.5 Reference Standards or Materials 标准对照品或标准物质
3.2.P Drug Product 制剂
3.2.P.2 Pharmaceutical Development 药品研发
3.2.P.3 Manufacture 生产
3.2.P.4 Control of Excipients 辅料控制
3.2.P.5 Control of Drug Product 制剂控制
3.2.P.8 Stability 稳定性
MODULE 5: CLINICAL STUDY REPORTS
模块五：临床研究报告
MODULE 1: ADMINISTRATIVE INFORMATION AND PRESCRIBING INFORMATION
模块一：行政信息和处方信息
1.4 Health Canada Summaries 加拿大卫生部概述
1.4.1 Certified Product Information Document (CPID) 认证产品信息文件（CPID）
Q): When filing a post-approval change (e.g., Supplement, NC), can previously fulfilled commitments (e.g., process validation, stability studies for a commitment batches) be removed from the CPID?
问：在提交批准后变更（例如增补、NC）时，是否可以将已实现的承诺（例如，工艺验证、承诺批次的稳定性研究）从CPID中移除？
A): Yes, in order to maintain a concise document, previously fulfilled commitments should be removed from the CPID. However, if a commitment for new stability studies is warranted by the proposed change a summary of the protocol for the commitment batches should be included in the CPID. A summary of the protocol for the ongoing stability studies should be retained. In addition, for process validation studies a protocol number or study report number (for a completed study) with a brief summary, should continue to be recorded in the CPID.
答：是的。为了保持文件的简洁，之前提交的承诺如果现在已实现，则应该从CPID中移除。但是，如果在提交的变更承诺了新的稳定性试验，则所承诺批次的试验方案的摘要需要包括在CPID中。需要保留正在进行的稳定性试验的方案摘要。另外，对于工艺验证，应在CPID中持续记录验证方案的编号或验证报告的编号（一个完整的工艺验证研究）以及一个简单的摘要。
MODULE 2: COMMON TECHNICAL DOCUMENT SUMMARIES
模块二：通用技术文件总结
2.3 Quality Overall Summary (QOS) 质量总结（QOS）
Q): Is the filing of Health Canada's Quality Overall Summary - Chemical Entities (QOS-CE) required?
问：是否需要按加拿大的指南要求提交化学实体质量总结（QOS-CE）？
A): A drug submission containing either Health Canada's QOS-CE or one prepared in accordance with ICH's CTD guideline for the Quality Overall Summary would be considered acceptable upon screening. However, due to anticipated benefits in promoting an efficient review of the submitted information, sponsors are encouraged to file Health Canada's QOS-CE.
答：申报文件中的质量总结可以是按照加拿大的QOS-CE的要求，也可以是按照ICH的CTD的要求编写，都可以接受。但是，为了提高对提交信息的审核效率，我们鼓励申报人按加拿大QOS-CE提交。
MODULE 3: QUALITY
模块三：质量
3.2.S Drug Substance 原料药
3.2.S.2 Manufacture 生产
Q): What level of detail for submission purposes is required on the starting material of an API prepared by chemical synthesis?
问：对化学合成的原料药，其起始物料的提交详细程度有什么要求？
A): It is acknowledged that ICH Q7A provides a definition for “API Starting Material”, which may be distinct from the concept of “starting material for synthesis” discussed in this Q&A document. These are considered complementary definitions, since Q7A defines the point at which GMP requirements apply to the synthetic process in some jurisdictions, while requirements for “starting material for synthesis” defines the starting point in the synthetic process for an API which should be provided to Health Canada to permit the evaluation of the safety and quality of the API. In many cases, the “starting material for synthesis” may precede the ICH “API Starting Material” by several steps in the synthetic process. The level of details required concerning reaction conditions and controls will increase as synthetic steps get closer to the final API. 我们都知道ICH Q7A对“原料药起始物料”进行了定义，该定义可能是针对本问答文件中讨论的“合成用起始物料”。这些定义都应作为是充分性定义，因为Q7A定义了在合成工艺中在一些官方判断中，从哪里开始需要实施GMP，但“合成用起始物料”的要求则定义了在原料药合成工艺中，需要向加拿大卫生局提供的工艺起始点，以使得加拿大卫生局可以对原料药的安全性和质量进行评估。在许多情况下，“合成用起始物料”可能比ICH中“原料药起始物料”要在合成工艺中提前几步。所要求的涉及反应条件和控制的详细程度随着与原料药的接近而增加。
In general, the starting material for synthesis in drug submissions should:
一般来说，申报资料中合成用起始物料应
l be a synthetic precursor one or more synthetic steps prior to the final API intermediate,
l 是原料药最后中间体之前一步或多步合成用的前体
l be a well characterised, isolated and purified substance with structure fully elucidated,
l 是很好定性，结构完全确认的分离出的并纯化的物质
l have well defined specifications which include one or more specific identity tests, and tests and limits for potency, specified and unspecified impurities and total impurities.
l 有完整的质量标准，其中包括一个或多个专属鉴别试验，检测和效价限度，已知和未知杂质和总杂
Acids, bases, salts, esters and similar derivatives of the API, and the racemate of a single enantiomeric API are not considered final intermediates.
原料药的酸、碱、盐、酯和类似的衍生物，单一光学结构原料药的混旋体不作为最后中间体。
The selection of a particular compound as the starting material for synthesis and its specifications should be justified.
需要对合成起始物料的选择和其质量标准进行论述。
In order to assess the presence of all potential impurities, including regioisomeric and stereoisomeric impurities, toxic impurities, residual solvents and residues of catalysts in the starting material, a brief narrative description of the synthesis including an outline leading to the starting material beginning with simpler molecules with all the reagents, solvents, and intermediates specified and the flow chart of the synthesis should be provided. Potential for the presence of adventitious agents, including viral and bacterial agents, residual proteins and TSE agents in the starting material selected should be discussed.
为了对起始物料中所有潜在杂质进行评估，包括手性和立体异构杂质、毒性杂质、残留溶剂和催化剂残留，申报资料中需要提供起始物料合成的简要描述，包括从简单分子开始直到起始物料的合成简要路线、所用试剂、溶剂、产生的中间体、合成流程图。外来试剂出现的可能性，包括在起始物料中选用的病毒、细菌试剂、残留蛋白质和TSE试剂需要进行讨论。
A more detailed description of the synthetic process should be provided for steps leading from the starting material to the final drug substance. The additional details should include quantities of raw materials, description of equipment, reaction conditions, in-process controls, percent yields, etc.
从起始物料开始至最后原料药的合成工艺应提供更详细的描述。详细内容应包括原料投料量、设备描述、反应条件、中控、百分比收率等。
3.2.S.4 Control of Drug Substance 原料药控制
Q): When qualifying a limit for an impurity in a generic product based on levels found in the Canadian Reference Product (CRP), what evidence should be submitted to show that it is the same impurity that is being analysed?
问：在基于采用加拿大对照药品（CRP）中测得的水平，对仿制药品中某一杂质拟定限度时，需要提交什么样的证据来说明所发现的是同一种杂质呢？
A): Generally, having the same retention time in an HPLC run using a single method, would not be considered sufficient to show the same impurity is being analysed. As such, it is recommended that samples of both the test and reference materials be spiked with the same impurity reference standard to show increased concentrations. For unidentified impurities, confirmation by another technique should be utilised, e.g., retention time comparison using a different chromatographic method, diode array spectroscopic detection.
一般来说，如果采用同一方法运行HPLC检测，具有相同的保留时间，不足以证明所分析的是同一种杂质。这种情况下，建议在所检测的样品和对照样品中加入同样的杂质对照品，使其显示出浓度增加。对于未鉴别的杂质，应采用另一技术进行确认，例如采用另一色谱方法对保留时间进行对比，采用DAD检测器进行检测。
Q): What is meant by the terms professed, house and compendial standards?
问：术语“宣称的标准”、“内部标准”和“药典标准”是什么意思？
A): Compendial standard claim is used for a drug substance and/or product claiming conformance to Schedule B compendial standards (e.g., USP, BP, Ph. Eur.). Health Canada may require additional tests, to ensure the quality, and safety of the drug substance and or product even for products claiming a compendial standard.
答：药典标准是指用于声称符合计划B药典标准（例如，USP，BP，Ph. Eur.）的原料药和/或制剂检测的标准。加拿大卫生局可能会要求附加测试，以保证原料药和/或制剂的质量和安全，即使是针对声称为药典标准的产品。
Professed standard claim is used for a drug substance and/or product where an official standard (i.e., Canadian Standard Drug (Part C, Division 6), Schedule B compendia) is not available.
“宣称的标准”用于没有官方标准（即，加拿大标准药品（C部分，6子部），计划B药典）提供时的原料药和/或药品检测。
House or Manufacturer’s standard claim is used for a drug substance and/or product that is listed in at least one of the Schedule B compendia, but the Sponsor chooses to use different standards and test methods. In accordance with C.01.011, drugs for which a manufacturer’s standard is claimed must meet the most stringent limits for potency and purity among any of the Schedule B monographs. This applies to assay, content uniformity, impurities (related and process) but does not include performance tests such as dissolution/drug release.
“内部或生产商的标准”是用于至少列于计划B药典其中之一的原料药和/或制剂检测，但申报人选择采用不同标准品和检测方法。根据C.01.011，采用生产商的标准品的药品必须满足计划B各论中最严格的效价和纯度限度，包括含量、含量均一性、杂质（有关物质和工艺杂质），但不包括性能测试，例如溶出度/药品释放性。
Q): Are signed and dated specifications and certificates of analyses for drug substance and drug product required?
问：申报资料中是否需要提交签名/日期的原料药和制剂的质量标准和分析报告？
A): Submissions are expected to have copies of the drug substance and drug product specifications signed and dated by the Quality Control manager or designate. Electronic signatures are also considered acceptable if certified in accordance with an acceptable standard (e.g., FDA’s 21CFR, Part 11). The specifications should include tests, acceptance criteria, and reference to analytical methods, and a version number.
答：申报中需要提交原料药和制剂由QC经理或相应职务人员签名、日期的质量标准复印件。如果根据可接受标准（例如 FDA21CFR，第11部分）经过认证，电子签名也可以接受。质量标准应包括检测项目、可接受标准和采用的分析方法，版本编号。
Signed and dated Certificates of Analyses should also be provided for batches used in pivotal clinical and bioavailability studies or those used to establish the pharmaceutical equivalence where a request for a biowaiver has been included in the submission. However, in situations where a significant number of batches have been used in pivotal clinical studies, a tabulated summary of the testing results would be considered acceptable if accompanied by copies of representative CofA’s of batches used in pivotal clinical studies.
如果在申报中已包括了生物试验免除的申请，则需要提供用于关键临床试验和生物利用度研究，或其它用于建立药学等效性的批次的签名、日期的分析报告。但是，如果在关键临床试验中使用了很多的批次，则可以只提供表格形式的检测结果，同时附入用于关键临床试验的代表性批次的分析报告。
3.2.S.5 Reference Standards or Materials 标准对照品或标准物质
Q): What information should be submitted to validate primary and secondary reference standards?
问：需要提交什么信息来对一级标准品和二级标准品来进行验证？
A): A primary reference standard other than a compendial standard should be highly purified and fully characterized. All data supporting structure elucidation, strength and purity should be submitted. A certificate of analysis should also be submitted with purity assigned based on mass balance.
答：非药典标准的一级标准品必须具有高纯度，全面定性。所有支持性数据，包括结构确证、剂量和纯度均应提交。分析报告也应该提交，其中纯度赋值应基于质量守衡。
Secondary reference standards [working standards, house standards] should be prepared similarly to the primary reference material and standardized against the compendial reference standard or primary reference standard. Secondary reference standard should be fully characterized as to identity (IR and UV spectra should be submitted for both the primary and secondary reference standards run concomitantly) and purity, and copies of CofA should be provided.
二级标准品【工作标准品、内部标准品】确认方法与一级标准品类似，应采用药典标准品或一级标准品进行标化。二级标准品定性应包括所有鉴别（应提交一级标准品与二级标准品同条件测试的红外、紫外光谱），和纯度，还需要提交检验报告复印件。
In all cases, all purification steps used to further purify samples taken from a pilot or commercial batch for the purpose of generating a reference standard should be described.
在所有情况下，都需要描述对中试批次或商业批次中取得的样品进行纯化的所有步骤。
3.2.P Drug Product 药品
3.2.P.2 Pharmaceutical Development 药物研发
Q): What are the requirements for a scored tablet with respect to uniformity of fractions resulting from breaking it?
问：对于刻痕片剂的掰开后的碎片均一性有什么要求？
A): For immediate-release, uncoated and coated tablets manufactured with a score (e.g., bisected or quadrisected), data is required to ensure that the divided portions provide uniform dosing for the patients. In other words, split tablets are considered dosage units and their uniformity needs to be established. This is applicable irrespective of the labelled dosage regimen due to the possibility of the tablets being broken for lower dosing by the user by virtue of the tablet design with a score line. The requirements for scored modified-release tablets will be evaluated on a case-by-case basis, and additional tests, e.g., comparative dissolution (release) test results of split halves may be required.
答：对于即释、无包衣和包衣片，如果生产的是刻痕片（例如，一半刻度或四分刻度），数据应能保证掰开后的部分能给病人提供均一的剂量。换句话说，掰开后的药片被认为是一个制剂剂量，其均一性需要保证。这适用于，不论标示的剂量是多少，可以由使用者利用其刻痕线掰开而服用低剂量的所有片剂。刻痕缓释片剂的要求需要依个案逐个评估，可能会需要附加测试，例如，掰开后的半片的比较性溶出度（释放）检测结果。
The data provided should include uniformity of dosage units on each split portion from a minimum of 10 randomly selected whole tablets. At least one lot of each proposed strength should be tested, performed in a manner that would be representative of that used by the consumer (e.g., manually split by hand). The uniformity test on split portions should be demonstrated with the results reported in the submission. The data should include a description of the test method, individual values, mean, and standard deviation. The acceptance criteria (range and variation) for the split portions should be as described in the USP General Chapter <905> Uniformity of Dosage Units for whole tablets.
提供的数据应包括至少10片随机选取的整片，掰开后的所有部分的剂量均一性数据。每个申报的剂量至少测试一批，所选取的方式应能代表被消费者所使用的方式（例如，用手掰开）。在申报文件中的结果应与掰开部分的均一性测试一起论述。数据应包括方法描述、单一测试值、平均值、标准偏差。掰开部分的可接受标准（范围和变异性）应与用于整片的USP通论<905>“制剂单位的均一性”所述一致。
The scoring configuration for a subsequent entry product (e.g., generic) should match that of the innovator’s product.
之后进入的产品（例如仿制药）的刻痕参数应与新药创始人的产品参数一致。
Q): What is the significance of f2 while comparing dissolution test results?
问：在比较溶出度检测结果时，f2有什么重要意义？
A): Calculation of similarity factor, f2, is recommended to compare dissolution profiles from solid dosage forms (e.g., tablets, capsules) to establish in vitro similarity between different test samples of the same product. This comparison could be used to support a request for waiver of performing bioequivalence study.
答：计算相似度因子f2，是用于比较固体剂型（例如，片剂、胶囊）的溶出度概况，以建立不同同一产品不同样品间体内代谢相似性。这种比较可以用支持申请豁免生物等效性研究。
An f2 value between 50 and 100 suggests the two dissolution profiles are considered similar. If the f2 values are below 50, an investigation should be initiated to determine the cause of apparent dissimilarity. Scientific explanation and alternative data may be considered on a case by case basis.
f2值在50-100之间表示两个溶出度概况认为类似。如果f2值低于50，则需要启动调查以确认明显不相似的原因。不同的案例应考虑不同的科学解释和相应的代替数据。
3.2.P.3 Manufacture 生产
Q): Is it necessary for analytical testing facilities to meet GMP requirements?
问：分析检测的场所是否需要符合GMP要求？
A): Yes. Analytical tests performed by any facility must be compliant with Good Manufacturing Practices (GMP) requirements of Division 2 under the Food and Drug Regulations. This requirement is applicable to all Canadian distributors and importers engaged in the sale of a drug (as described in C.02.003) who either have their own testing facility or rely upon the services of another testing facility for evaluation of raw material (C.02.009), packaging material (C.02.016) finished product (C.02.018), and stability (C.02.028).
答：是的。任何实施分析检测的场所均必须符合《食品药品法规》GMP要求，第二部分。该要求适用于所有从事药品销售的加拿大分销商和进口商（在C.01.003中描述），他们要么需要有自己的检测场所，要么依赖其它检测场所的服务来对原料（C.02.009），包装材料（C.02.016）和制剂（C.02.018）及稳定性（C.02.028）进行评估
Q): What is the requirement in the pre-approval stage, in the way of data to support transportation of drug product intermediates and bulk dosage forms from one facility to another for final processing and/or packaging in the market container?
问：在批准前阶段的要求是怎样的？我是说如果制剂中间体和散装制剂需要从一个场所运输至另一个场所进行最终的加工和/或市售包装，这些数据收集应符合什么要求？
A): It should be noted that the HPFB Inspectorate’s GMP Guideline and Guidelines for Temperature Control of Drug Products during Storage and Transportation provides guidance for transportation requirements for drug product in its final market container. However, at the pre-approval stage an assessment is needed of the transportation conditions of drug product intermediates (e.g., granules, coated pellets) and bulk dosage forms (e.g., bulk tablets, bulk solutions), which are transported from one manufacturing facility to another for additional processing and/or packaging in the final market containers.
答：需要注意在HPFB检查的“GMP指南和药品在存贮和运输过程中的温度控制指南”中，提供了关于制剂已完成市售包装的制剂的运输要求。但是，在批准前的阶段，需要对制剂中间体（例如颗粒、包衣片），以及散装制剂（例如散装片剂、散装溶液）的运输条件进行评估，这些产品从一个生产场所运输至另一个生产场所进行另外的加工和/或市售包装。
Data required to support transportation of finished product intermediates and bulk dosage forms will vary, depending on the nature of the intermediate or bulk product and the mode of transportation. Transportation studies should consider conditions likely to be encountered during transportation, including exposure to elevated and depressed temperature and humidity, and reduced atmospheric pressure (such as might be encountered during air transportation), and physical stresses associated with vibration and impact. The pre-market submission should include results of, or a detailed protocol for, transportation studies, and may include tests conducted on actual shipped samples, or on samples subjected to simulated transportation conditions. Product characteristics which should be considered include, but are not limited to the following:
用于支持制剂中间体和散装制剂运输条件的数据可能会有差异，这取决于中间体或散装制剂的特性，以及运输的模式。运输研究应考虑运输过程中可能会遇到的条件，包括暴露于高温和低温，高湿度和低湿度，低气压（可能会在空运中遇到），物理挤压伴随震动和冲击。上市前申报应包括以下结果或详细方案，运输研究，可能包括对实际运输样品的检测，或对于模拟运输条件下样品的检测。应考虑的产品特性包括，但不限于以下：
l assay and degradation products (all intermediates and bulk drug products)
l 含量和降解产品（所有中间体和散装制剂）
l precipitation of dissolved solutes for solutions
l 溶液中已溶解的物质沉淀
l phase separation of multi-phase (disperse) systems
l 多相（分散）系统的相分离
l settling of fines in powders and granules
l 粉末和颗粒中细粉下沉
l friability of tablets or granules
l 片剂或颗粒的脆碎度
l container/closure integrity (e.g., liquid preparations subjected to reduced pressure).
l 容器/密闭系统完整性（例如，液体制剂压力会降低）
l any other stability/performance indicating test specific to the particular drug product type
l 任何特殊剂型专用的其它稳定性/性能指示检测
The transportation studies should be adequate to support conclusions regarding selection of appropriate bulk packaging materials, mode(s) of transportation, necessary controls on shipping conditions, and maximum hold times.
运输研究应足以支持对散装物料的包装、运输模式、在运输条件下必要的控制、最大的间隔时间的选择结论，
Q): What are the criteria for using matrix or family approach for product process validation of tablets?
问：片剂工艺验证如果采用矩阵或家庭方式，标准是什么？
A): Use of matrix or family approach may be possible and acceptable in particular circumstances for a manufacturer that uses the same process for several related products to develop a scientifically sound validation plan.
答：采用矩阵或家庭方式在一些特殊情况下，即该生产商采用了同样的工艺用于几个相关产品的科学合理验证计划的拟定，是可能并可以接受的，
For tablets use of matrix approach is limited to certain process steps, depending on the composition and manufacturing process. It is recognized that the matrix approach has limitations when there are concerns with respect to physical characteristics such as flow properties, particle size distribution, homogeneity that could influence the quality and performance of the tablet.
对于片剂，采用矩阵方式仅限于某些工艺步骤，并取决于成份和生产工艺。我们已经认识到如果涉及到如流动性、粒径分布、均一性等可能会影响片剂的质量和性能的物理特性时，矩阵方式具有局限性，
Generally speaking, for common granules of different tablet strengths (i.e., same composition of granules for all strengths), the granulation steps could be validated using a matrix approach.
一般来说，对于不同片剂剂量的普通颗粒（即，所有剂量颗粒采用相同组分），制粒步骤可能需要采用矩阵方式来验证。
However, discrete manufacturing steps such as compression, and coating that involve different tools, equipment, and process conditions for the different strengths can not be validated using the matrix approach. For these steps the manufacturing process for each tablet strength has to be validated individually. The Sponsor may submit data from pharmaceutical development based on design of experiment (DOE) to establish design space for manufacturing steps such as compression, in which case matrixing approach of process validation would be considered.
但，不连续生产步骤，例如压延和包衣可能会用到不同的工具、设备，不同剂量的工艺条件无法采用矩阵方法进行验证。对于每个片剂剂量，这种生产工艺步骤必须单独验证。申请者可能会提交基于实验设计的药物研发数据，以建立生产步骤，如压延，的设计空间，这种情况下可以考虑采用矩阵方法进行工艺验证。
3.2.P.4 Control of Excipients 辅料的控制
Q): What are the requirements for use of gelatin from animal origin?
问：使用动物来源的明胶有什么要求？
A): The following are the requirements for acceptance of gelatin manufactured from animal origin materials from countries which are classified either as low- or high-risk for Transmissible Spongiform Encephalopathy (TSE) disease such as Bovine Spongiform Encephalopathy (BSE).
答：以下是一些对采用来自于低或高TSE风险，例如疯牛病（BSE），国家的动物来源原料生产的明胶的接受要求，
l information on the country of origin is provided,
l 需要提供产地国家信息
l all Specified Risk Materials and the vertebral column are removed from bones used for the production of gelatin,
l 用于明胶生产的所有特定风险材料和从骨头中移除的脊椎
l appropriate production methods are used to ensure TSE inactivation,
l 采用了合适的生产方法以保证TSE去活
l information on the manufacturer of gelatin product (e.g., capsule shells) is provided,
l 提供明胶产品（例如，胶囊壳）的生产商信息
l the gelatin used for production has a recent EDQM Certificate of Suitability for TSE risk products.
l 用于生产的明胶应有近期的EDQM颁发的TSE风险产品CEP证书
The above information could also be provided in the form of a Drug Master File.
以上信息均应包括在DMF表格中。
3.2.P.5 Control of Drug Product 制剂控制
Q): What is the requirement with respect to the assay limit of drug substance in the drug product specifications?
问：关于制剂质量标准中原料药含量限度有什么要求？
A): The assay limit of ±10.0% (90.0-110.0%) described in the regulations and some Schedule B compendia indicates the minimum and maximum potencies of the medicinal ingredient in a drug product until the end of its shelf life. This would mean at release a more stringent limit, e.g., ±5.0%, needs to be maintained to ensure the above expectation of ±10.0% is met until the end of shelf life. Typically, an assay limit of 95.0-105.0% at release and 90.0-110.0% at the end of shelf life of the medicinal ingredient in the drug product is considered acceptable. It is acknowledged that there are exceptions to this recommendation (e.g., vitamins, some antibiotics).
答：法规中要求含量限度为±10.0% (90.0-110.0%)，一些B计划药典中要求了货架期结束时制剂中药性成分的最低和最高效价。这就是说，需要有更严格的放行限度，例如±5.0%，以保证的货架期结束时仍满足上述的±10.0%的要求。通常，放行时采用含量限度95.0-105.0%，货架期结束时采用90.0-110.0%认为是可以接受的。当然也有一些产品是例外的（例如，维生素、一些抗生素）。
Q): What are the recommendations for developing a discriminatory dissolution/drug release method?
问：对于差异溶出度/药品释放方法的研发有什么建议？
A): The proposed dissolution/drug release method is intended to ensure the entire drug present in the dosage form is available for release, and that quality and/or manufacturing anomalies can be detected.
答：所拟的溶出度/药品释放方法应能保证制剂中的整个药品可以被释放，且其质量和/或生产异常可以被发现。
To demonstrate the discriminatory power, the Sponsor may use formulations prepared during the pharmaceutical development that have differences. Examples include qualitative and/or quantitative difference in excipients, drug substance particle size, process parameters or have different in-process test specifications for hardness, coating thickness etc.
为了模拟差异能力，申报人可以在药品研发期间，采用不同的制备处方。例如，可以采用质和/或量不同的辅料、原料药粒径、工艺参数，或不同的硬度、包衣厚度等中控检测质量标准。
Inability to demonstrate the discriminatory power for the dissolution/drug release would mean the proposed test method has limited utility as a quality control test to verify lot-to-lot similarity, and would be of minimal value for supporting significant post-approval changes.
如果无法证明溶出度/药物释放差异能力，则说明所拟的检测方法很难用于质量控制检测来确认批间相似性，对支持重大的批准后变更基本没有价值。
Q): What is the recommended development data for a dissolution/drug release method?
问：对溶出度/药品释放方法的研发数据有什么建议？
A): The method development information should include a rationale for choosing the particular apparatus type (paddle, basket, peak vessel etc.), dissolution medium (volume, temperature, pH), operating conditions (rotation speed), and should establish sink condition (i.e. dissolves > 3 times the amount of drug). When a surfactant is used in the dissolution medium a rationale should be provided to justify the choice of the surfactant and its concentration. Evidence that the method is discriminatory (refer to the Q&A on discriminatory method) could also be included in the method validation section. The RSD at time points beyond the initial time point should be less than 10%.
答：方法研发信息应包括选择特殊的分析仪器类型（桨式、篮式、peak杯）、溶出度介质（体积、温度、pH值）、操作条件（搅拌速度）的合理性，应建立漏槽状态（即，溶解性>3倍药品数量）。如果在溶中度介质中使用了表面活性剂，则需要提供论述其表面活性选择及浓度合理性。方法验证部分还应包括方法差异的证据（参见本问答文件中差异方法）。不在初始时间点的数据的RSD应小于10%。
The general chapters of the USP and Ph. Eur. provide additional information on this subject.
USP和EP的通论章节中对此论题提供了更多信息。
3.2.P.8 Stability 稳定性
Q): An NDS is proposed which is a combination of two previously approved drug substances. Which stability guideline would apply (i.e., Stability Testing for New Drug Substances and Products or Stability Testing for Existing Drug Substances and Products)?
问：如果提交了一个NDS，其中的原料药中之前已批准的两种原料药的复合。那么应适用哪个稳定性指南（即，“新原料药和制剂稳定性试验”还是“已有原料药和制剂稳定性试验”？
A): If the new drug submission contains active ingredients that have been previously approved by Health Canada, they would be considered existing drugs and therefore the recommendations outlined in the Stability Testing for Existing Drug Substances and Products guideline would apply.
答：如果新的申报中包括的活性成分在之前已经由加拿大卫生局批准，则作为“已有药品”，因此适用“已有原料药和制剂稳定性试验指南”中的建议。
Q): In deleting a test or time point from the approved stability protocol, does the revised protocol have to be submitted via a Level 2 - NC?
问：从已批准的稳定性试验方案中删除一个检测项目或检测时间点，修订后的方案是否需要通过二级NC进行提交？
A): Yes, a relaxation in previously approved information (e.g., deletion of a test or time point in an approved stability protocol) would generally be filed as a Level 2 - NC. The deletion of certain tests (e.g., deleting a sterility test and replacing it with process parametric release) would be filed as a Level 1 - Supplement.
答：是的。对已批准信息放宽要求（例如，从已批准的稳定性试验方案中删除一项检测或一个时间点）一般作为二级NC提交。删除一些特定检测（例如，删除无菌检测，采用工艺参数放行来代替）则应作为一级增补提交。
MODULE 5: CLINICAL STUDY REPORTS
模块5：临床研究报告
Q): With respect to filing an Abbreviated New Drug Submission (ANDS) do the criteria for comparative bioavailability/bioequivalence outlined in the Therapeutic Products Directorate guideline Conduct and Analysis of Bioavailability and Bioequivalence Studies Part B: Oral Modified Release Formulations, 1996(Guideline B) apply for a drug product that displays complicated pharmacokinetic characteristics (e.g. critical dose drug, etc.) and is an oral modified release dosage form.
问：在提交简约新药申请（ANDS）时，在治疗用产品指南“生物利用度和生物等效性研究的实施和分析，B部分：口服缓释制剂，1996”（指南B）中列出的生物利用度/生物等效性比较标准，是否适用于显示出复杂药物动力学特征（例如，临界剂量药品，等）的药品，该药品为口服缓释剂型？
A): Yes, the criteria outlined in the Therapeutic Products Directorate Guideline B applies to oral modified releasedrug products filed as an ANDS, in addition to the criteria outlined in other applicable guidelines and policies (e.g., TPD guideline Bioequivalence Requirements: Critical Dose Drugs, 2006).
答：适用。除了其它适用的指南和方针外（例如，TPD指南，生物等效性要求：临界剂量药品，2006），在治疗用产品指南B中列出的标准也适用于提交ANDS的口服缓释药品。
Q): With respect to filing an Abbreviated New Drug Submission (ANDS) do the criteria for comparative bioavailability/bioequivalence outlined in the Therapeutic Products Directorate guideline Conduct and Analysis of Bioavailability and Bioequivalence Studies Part A: Oral Dosage Forms Used for Systemic Effects, 1992 (Guideline A) apply for a drug product that displays complicated pharmacokinetic characteristics (e.g., drug for which an early time to onset of action is important) and is an oral immediate release dosage form?
问：在提交简约新药申报（ANDS）时，在治疗用产品指南“生物利用度和生物等效性研究的实施和分析，A部分：用于系统性影响的口服制剂，1992”（指南A）中列出的生物利用度/生物等效性比较标准，是否适用于显示出复杂药物动力学特征（例如，用于发病初期的药，其措施较为重要，等）的药品，该药品为口服即释剂型？
A): Yes, the criteria outlined in the Therapeutic Products Directorate Guideline A applies to oral immediate releasedrug products filed as an ANDS, in addition to the criteria outlined in other applicable guidelines, policies and notices to industry (e.g., Notice to Industry: Bioequivalence Requirements for Drugs for Which an Early Time of Onset or Rapid Rate of Absorption is Important (rapid onset drugs), 2005).
答：适用。除了其它适用的指南、方针和行业通知外（例如，行业通知：用于发病初期药品，或快速吸收较为重要的药品的生物等效性要求（快速发病用药品），2006），在治疗用产品指南B中列出的标准也适用于提交ANDS的口服即释药品。
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发表于 2014-10-15 16:14:34
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