FDA发布质量相关问答，稳定性试验、溶出度、微生物（内毒素）、分组法/矩阵法等专题！
近日，FDA发布了《行业指南：质量相关受控通信问答》（草案），该文件包含了 FDA 当前对在与药企沟通过程中频繁出现的质量有关主题的观点，从而让企业在药物开发活动中可以不需要提交受控通信给 FDA 就能向前推进其工作。
问答包含以下领域
分组法/矩阵法
容器密闭器变化
溶出度
微生物（内毒素）
批数
稳定性试验批数、摆放方向等
包装
刻痕与片剂分割测试
仿制固体口服制剂的尺寸与形状
问答部分翻译如下：
1. Bracketing/Matrixing
分组/矩阵
Question:
问
Is it acceptable to use a bracketingapproach for the manufacture of the exhibit batches of a generic drug productwith multiple strengths produced from common bulk granulations (or blends)? Doall of these exhibit batches need to be put into the stability program?
采用同一制粒工艺（或混合）得到的物料生产多个剂量规格仿制药展示批次时，是否可以使用分组法？是不是需要把所有这些展示批都放入稳定性试验计划？
Answer:
答
A bracketing approach is acceptable for adrug product with multiple strengths, as long as the active and inactiveingredients are in the same proportion between the different strengths (i.e.,the strengths are dose proportional). According to the FDA guidance forindustry ANDAs: Stability Testing of Drug Substances and Products Questions andAnswers (May 2014), for abbreviated new drug applications (ANDAs), threeseparate intermediate bulk granulations (or blends) should be manufactured. Onebatch of bulk granulation (or blend) should be used to manufacture all thestrengths proposed. The other two bulk granulations (or blends) can be used tomanufacture only the lowest and the highest strengths. Three bulk granulations(or blends) should be used to manufacture the strength(s) tested in thebioequivalence (BE) studies.
同一药品多个剂量规格时可以使用分组法，前提是不同规格的活性成分和非活性成分比例相同（即，各规格处方比例相同）。根据 FDA 行业指南：ANDA：原料药和制剂稳定性试验问答（201405），对于 ANDA，应生产 3 个单独的中间体制粒批次（或混合批次）。一个制粒批次（混合批次）用于生产所拟申报的所有规格，另 2 个制粒批次（混合批次）可只用于生产最低和最高规格。3 个制粒（或混合）批次应该用于生产 BE 研究中所用的受检规格。
Stability data should be provided for threebatches of the highest strength and three batches of the lowest strength, andthree batches of the strength(s) tested in the BE studies if the strength usedin the BE study was not the highest or lowest strength. Release data should beprovided for all the batches that were manufactured.
应提交 3 批最高剂量规格和 3 批最低剂量规格的稳定性数据，如果 BE 研究所用剂量规格不是最低或最低规格，则还要有 BE 研究中所测试的规格的 3 个批次的稳定性数据。应提交所生产的所有批次的放行数据。
2. Container-Closure Changes
容器密闭器变化
Question 1:
问 1
If the reference listed drug (RLD) is asterile injectable drug product packaged in an ampule, can the generic productbe packaged in a vial?
如果 RLD(参比制剂) 为安瓿瓶装无菌注射剂，仿制药可以装在西林瓶中吗？
Answer 1:
答 1
A proposed generic drug product is notrequired to have the same container closure system (CCS) as the RLD. However,the ANDA generally must contain information to show that the proposed genericdrug product has the same conditions of use and the same labeling, with certainpermissible differences, as the RLD2. Refer to FDA guidance for industry DeterminingWhether to Submit an ANDA or a 505(b)(2) Application (May 2019).
并不要求所拟仿制药采用与 RLD(参比制剂) 完全相同的容器密闭器系统（CCS）。但是 ANDA 一般必须包括有资料证明所拟仿制药具备相同的使用条件和相同的标签，允许与 RLD(参比制剂) 存在一定差异。参见 FDA 行业指南：确定是否按 ANDA提交还是按 505(b)(2)申报（201905）。
The proposed CCS will be evaluated duringthe review process3. In the assessment of an ANDA’s proposed CCS, the Agencywill, among other things, evaluate any differences in the proposed CCS relativeto the RLD CCS and determine whether these differences would result in theproposed generic drug product not having the same conditions of use and thesame labeling (with certain permissible differences) as the RLD.
所拟 CCS 应在审评过程中进行评估。在对 ANDA 提出的 CCS 进行评估时，FDA 会评估所拟 CCS 与 RLD(参比制剂) 的 CCS之间的所有差异，确定这些差异是否会导致所拟仿制药不具备 RLD(参比制剂) 相同的使用条件和相同标签（允许一定程度差异）。
You should follow the recommendations inthe FDA guidance for industry Container Closure Systems for Packaging HumanDrugs and Biologics: Chemistry, Manufacturing, and Controls Documentation (July1999) for the chemistry, manufacturing, and controls (CMC) information thatshould be submitted in the ANDA.
应遵守 FDA 行业指南：人用药物和生物制品包装所用容器密闭系统：CMC 文件（199907）中关于应在 ANDA 中提交的 CMC 信息的建议。
Question 2:
问 2
Should a proposed generic ophthalmic drugproduct have the same cap color as the RLD when that color is not in line withthe American Academy of Ophthalmology (AAO) recommendation?
如果 RLD(参比制剂) 眼用药品的盖子颜色与美国眼科学会（AAO）建议不同，仿制药是否要采用与 RLD(参比制剂) 相同的盖子颜色？
Answer 2:
答 2
As described in the guidance for industry ContainerClosure Systems for Packaging Human Drugs and Biologics (July 1999), the capcolor of ophthalmic drug products should follow AAO color codes, or theapplicant should provide adequate justification for deviations from the AAOcolor coding system. For the proposed generic drug product, the Agencyrecommends that the color be in accordance with AAO recommendations.
正如行业指南：包装人药和生物制品所用容器密闭系统：CMC 文件（199907）中所述，眼科药的盖子颜色应遵守 AAO 的颜色代码，或者申报人应该提供足够的理由支持与 AAO 颜色代码系统的差异。对于所拟仿制药，FDA 建议根据 AAO 建议确定其颜色。
In this Q&A, the term review also meansassessment, which is the term that CDER’s Office of Pharmaceutical Quality andOffice of Generic Drugs will generally use in place of review. Assessment meansthe process of both evaluating and analyzing submitted data and information todetermine whether the application meets the requirements for approval anddocumenting that determination.
在本问答中，术语“审评 review”亦表示“评估 assessment”，CDER 的 OPQ 和 OGD 经常会用评估代替审评。评估表示评价和分析所提交的数据和资料，确定该申报资料是否满足批准要求并记录该决定的过程。
Dissolution
溶出度
Question:
问
If the dissolution method for a proposedgeneric drug product is not available in the FDA Dissolution Methods Databaseor in the United States Pharmacopeia (USP), can the Agency provide thedissolution method for the product?
如果所拟仿制药的溶出度检查方法在 FDA 的溶出方法数据库或 USP 中没有，FDA 是否可为该药品提供溶出度检查方法？
Answer:
答
When neither the USP dissolution method northe FDA’s Dissolution Methods Database provide a dissolution method for aproduct, the Agency recommends that applicants develop an appropriate anddiscriminating dissolution method for the proposed drug product, taking intoconsideration the method development and validation principles described in theUSP General Chapter <711> Dissolution or General Chapter <724> DrugRelease, and USP General Chapter <1092> The Dissolution Procedure: Developmentand Validation.
如果 USP 溶出度方法和 FDA 的溶出度方法数据库均没有为该产品提供溶出度检测方法，FDA 建议申报人为所拟药品开发具有识别力的适当溶出度检查方法，同时考虑 USP 通则<711>溶出度或通则<724>药物放行，以及 USP 通则<1092>溶出度方法：开发和验证中所述的方法开发和验证原则。
Please note that the Agency considers thatdissolution should be product-specific and therefore the selection of thedissolution method and setting of the acceptance criterion/criteria should bebased on the dissolution data generated for the proposed drug product.Therefore, for the in vitro dissolution method to be used for quality control(QC) of your proposed drug product, the Agency recommends that irrespective ofthe source of the proposed dissolution method (USP, FDA, or in-house),additional dissolution studies be conducted to demonstrate the suitability ofthe selected method for the proposed drug product. For this purpose, the Agencyrecommends that the report for the development and validation of an in-housemethod or verification of a USP method being proposed for dissolution QCtesting be provided in the drug product’s ANDA submission, specifically inModule 3.2.P.54. The report should include complete information/data on: i)solubility of the drug substance(s); ii) adequacy of the selected dissolutiontesting conditions (i.e., apparatus, rotation speed, medium, volume, samplingtimes, etc.); iii) validation/verification of the robustness of the selecteddissolution method; iv) validation/verification of the analytical method usedto assay the dissolution samples; and v) demonstration of the discriminatingability of the dissolution method [for modified release products and immediaterelease drug products containing low soluble drug substance(s)].
请注意，FDA 认为溶出度方法应该是产品专用的，因此溶出度方法的选择和可接受标准的设定应该根据所拟药品中得到的溶出度数据。因此，对于你所拟药品 QC 所用体外溶出度方法，FDA 建议无论所拟溶出度方法来自何处（USP、FDA 或自建），均应进行更多溶出度研究，证明为所拟药品选择的方法的适用性。为此，FDA 建议在产品 ANDA 申报资料中放入准备用于 QC 溶出度检测的自建议方法的开发和验证报告或 USP 方法的确认，具体是放在模块 3.2.P.5 中。报告应包括有完整的资料/数据：（1）药物成分的溶解度，（2）所选择溶出度检测条件的充分性（即仪器、旋转速度、介质、体积、取样时间等），（3）所选择溶出度方法耐用性的验证/确认，（4）用于溶出度检测样品分析的分析方法验证/确认，以及（5）证明溶出方法具有识别能力的证据【含有低溶解度药物成分的改释药品和速释药品】。
Additionally, for generic immediate releasesolid oral drug products including a highly soluble drug substance (per theBiopharmaceutics Classification System (BCS) definition5), the Agencyrecommends that dissolution QC testing be conducted as described in FDA’sguidance for industry Dissolution Testing and Acceptance Criteria forImmediate-Release Solid Oral Dosage Form Drug Products Containing HighSolubility Drug Substances (August 2018). The information/data supporting thehigh solubility of the drug substance(s), as described in the BCS guidance (ICHguidance for industry M9 Biopharmaceutics Classification System-BasedBiowaivers (May 2021)) should be included in the ANDA submission (Module3.2.P.5 or Module 3.2.S.1.3), in addition to the proposed drug product’sdissolution data.
另外，对于含有高溶解度药物成分（依据 BCS 定义）的仿制速释固体口服制剂，FDA 建议按 FDA行业指南：含高溶解度药物成分的速释固体口服固体制剂的溶出度检测和可接受标准（201808）执行溶出度 QC 检测。除了所拟制剂的溶出度数据外，还应在 ANDA 申报资料（模块 e3.2.P.5 或模块 3.2.S.1.3）包括如 BCS 指南所述（ICH 行业指南 M9 基于 BCS 的生物豁免（202105））的支持原料药高溶解度的资料/数据。
Please note that the acceptability of theproposed dissolution method and acceptance criterion(a) will be determinedduring the ANDA review process based on the totality of the provideddissolution data/information and additional data/information may be requestedduring the submission review process.
请注意，在 ANDA 审核流程中，将根据所提交的全部溶出度数据/资料确定所拟溶出度方法和可接受标准的可接受度，在申报资料审评过程中，可能会要求提交其它数据/资料。
Microbiology (Endotoxin testing):
微生物（内毒素检测）
Question 1
问 1
How should a bacterial endotoxins testacceptance criterion be determined for the finished drug product?
如何确定制剂成品的细菌内毒素检测可接受标准？
Answer 1:
答 1
The finished drug product bacterialendotoxins test acceptance criterion should be determined based on the maximumdose that can be delivered within one hour as interpreted from the packageinsert. Special considerations can include:
制剂成品的细菌内毒素检测可接受标准应该根据包装说明书中所述的一个小时内可给药的最大剂量计算而得。特别注意事项包括：
Additional doses that may be administeredafter the initial dose,
在初始剂量之后给药的增加剂量
Maintenance doses administered after an initialbolus dose,
在初始小量单次给药之后摄入的维持剂量
Incremental dose increases, and
递增剂量增加，以及
For anesthetics or other drugs for whichrepeat doses are administered until a desired clinical outcome is achieved, themaximum number of potential doses at the minimum specified time intervalbetween doses that could be administered in a one-hour period.
对于麻醉药和其它重复给药直至达到所需临床结果的药品，以最短指定时间给药间歇时间计算一个小时内可能最大潜在给药数量
The USP General Chapter <85> BacterialEndotoxins Test recommended maximum endotoxin exposure is NMT 5 EU/kg(interpreted as within 1 hour) for most drugs based on an average patientweight of 70 kg. For drugs administered to pediatric patients, consult theWHO-CDC growth charts6 for average weight at the youngest patient age for theproposed generic drug.
USP 通则<85>细菌内毒性检测基于平均患者体重 70kg 建议大多数药品最大内毒素暴露值为 NMT 5EU/kg（解释为 1 小时内）。对于儿科患者给药，参见 WHO-CDC 生长曲线得到所拟仿制药最年轻患者的平均体重。
For drug products administered topically ona body surface area basis, the recommended maximum endotoxins exposure is 100EU per square meter.
对于以人体表面积为基础的局部给药药品，建议最大内毒素暴露值为 100EU/m2。
For drug products administeredintrathecally (or epidurally due to risk of inadvertent intrathecaladministration), the maximum recommended exposure is 0.2 EU/kg (in 1 hour).
对于鞘内注射药品（或因疏忽鞘内给药风险而采用硬膜给药），最大建议暴露值为0.2EU/kg（1 小时内）。
Please note that USP monographs may containhistorical bacterial endotoxins test acceptance criteria that may not reflectthe maximum dose that can be interpreted from the current drug package insertof the RLD. The proposed endotoxin limit for a proposed generic product shouldbe based on dosing in the current RLD package insert. If the calculated limitis higher than the USP monograph limit, we recommend that applicants submit acontrolled correspondence to confirm acceptability with the Agency prior tosubmission of the ANDA.
请注意 USP 各论可能有些历史的细菌内毒素检测可接受标准，未反映出 RLD(参比制剂) 当前药品包装说明书中可诠释的最大剂量。为一个所拟仿制药提议的内毒素限度应该是基于当前的 RLD(参比制剂) 包装说明书。如果所计算的限度高于 USP 各论限度，我们建议申报人在提交ANDA 之前提交一份受控通信，确认 FDA 是否可接受。
Question 2:
问 2
Is it acceptable to omit bacterialendotoxin limits in the proposed specification for a topical ophthalmic drugproduct?
是否可接受删除局部膏剂所拟质量标准中的细菌内毒素限度？
Answer 2:
答 2
Topical ophthalmic drug products aregenerally not required to be tested for bacterial endotoxins. Therefore, thefinished product release and stability specifications for topical ophthalmicproducts are not required to include testing for bacterial endotoxins unlessthe labeling indicates that the product is nonpyrogenic. However, if thelabeling for a topical ophthalmic product includes directions for use on anabraded eye and/or use during surgery, a bacterial endotoxin specification forthe drug product may be appropriate.7
外用眼膏制剂一般不需要检测细菌内毒素。因此，局部眼用制剂放行和稳定性质量标准不要求有细菌内毒素项目，标签显示产品为无热源产品者除外。但是如果局部眼用制剂的标签中使用指导有包括在外科手术期间使用或用于受损眼部，则可能需要订有细菌内毒素标准。
Please note that this answer is specific tothis question and does not address other ophthalmic drug products, dosageforms, or combination products that include an ophthalmic drug productcomponent.
请注意本回答针对的是本问题，并不是解决其它眼用制剂、其它剂型，或包括有眼用制剂组份的组合产品。
Number of Batches
批数
Question 1:
问 1
If an applicant intends to have more thanone drug product manufacturing site in an abbreviated new drug application(ANDA), how many exhibit batches should be provided for each site?
如果申报人想要在 ANDA 中放进多个制剂生产场所，每个场所要提供多少展示批？
Answer 1:
答 1
Stability data from three exhibit batchesmanufactured at each drug product manufacturing site for each strength shouldbe submitted in the ANDA, or a bracketing approach as described in Section 2above should be used. The applicant should submit data from at least threebatches of drug product that can include any one of the following batch sizes:
在 ANDA 中应提交每个规格在每个制剂生产场所生产的 3 个展示批次的稳定性数据，或者如上面第 2 部分所述采用分组方法。申报人应按以下批量之一提交至少 3 批数据：
Three pilot scale batches, three batchesthat meet the minimum dosage form batch recommendations, whichever is larger, orthree commercial scale batches
3 批中试规模，或 3 个满足最小剂型批次建议的批次，取其大者，或 3 批商业规模
Twopilot scale batches or two batches that meet the minimum dosage form batch
recommendations, whichever is larger, andone small scale batch
2 批中试规模，或 2 个满足最小剂型批次建议的批次，取其大者，加 1 批小规模
Twocommercial scale batches and one small scale batch
2 批商业规模和 1 批小规模
This data should be submitted from eachdrug product manufacturing site.
各制剂生产场所分别提交上述数据。
Orientation
方向
Question 1:
问 1
If the generic drug product is a “forinjection” (sterile lyophilized powder), can stability data for exhibit batchesbe generated using only one orientation?
如果仿制药是“注射用 ”（无菌冻干粉），展示批的稳定性数据是否可以仅使用一个摆放方向？
Answer 1:
答 1
According to the FDA guidance for industry ANDAs:Stability Testing of Drug Substances and Products Questions and Answers (May2014), “For primary batches of liquids, solutions, semi-solids, andsuspensions, the product should be placed into an inverted (or horizontal)position and an upright (or vertical) position.” Since lyophilized powders donot fall under one of these categories, exhibit batches for drug products thatare sterile lyophilized powders may be placed on stability in one orientationalone, provided that the ANDA submission includes an adequate justification forthe orientation selected.
根据 FDA 行业指南：ANDA：原料药和制剂稳定性测试问答（201405），“对于液体、溶液、半固体和混悬液内包产品，要采用正向（或水平）方向和倒置（或垂直）方向放置。”由于冻干粉不属于上述类别，因此无菌冻干粉制剂的展示批稳定性测试可以只放置一个方向，前提是 ANDA 申报资料中有足够的理由支持所选的方向。
Question 2:
问 2
If a product is packaged usingblow-fill-seal technology and the container is composed of a single material,can stability data for exhibit batches be generated using only horizontal orupright orientation?
如果产品使用吹灌封技术，且容器使用的是一次性材料，展示批的稳定性数据是否可以仅为使用水平或正向放置产生的数据？
Answer 2:
答 2
For products packaged using blow-fill-sealtechnology, stability studies on exhibit batches may be performed in oneorientation alone, as long as the orientation provides maximal contact for thedrug product with container closure system components, including the seal andneck. See guidance for industry Nasal Spray and Inhalation Solution,Suspension, and Spray Drug Products — Chemistry, Manufacturing, and ControlsDocumentation (July 2002).
对于使用吹灌封技术的产品，展示批的稳定性测试可仅采用一种方向，前提是该放置方向能让药品接触最多的容器密闭器系统部件。参见行业指南：鼻喷雾剂和吸入溶液、混悬液和喷雾制剂—CMC 文件（200207）。
Therefore, stability testing conducted inthe horizontal position would be acceptable if adequate justification is providedin the submission to demonstrate that the position selected represents themaximum contact of the drug product and container closure system components.Stability testing conducted only in the upright or vertical position wouldgenerally be unacceptable due to the lack of exposure of the drug product tothe seal and the twist-off neck area.
因此，如果在申报资料中提交了足够的论证证明所选择的方向代表了药品最大程度接触容器密闭系统部件，则可以接受水平方向放置的稳定性检测。仅采用垂直方向执行的稳定性测试一般来说不能接受，因为缺少制剂暴露于密封区域和瓶颈拧断区域的情况。
Packaging
包装
Question 1:
问 1
Should the three exhibit batches for ageneric product be fully packaged in the proposed marketed packaging?
仿制药的 3 个展示批次是否要全部包装在所拟上市包装中？
Answer 1:
答 1
In accordance with FDA guidances forindustry on Q1A(R2): Stability Testing of New Drug Substances and Products (November2003) and ANDAs: Stability Testing of Drug Substances and Products Questionsand Answers (May 2014), one of the three exhibit batches should be completelypackaged using all the proposed marketed configurations. This batch could beeither a pilot scale or a small scale batch. The other two exhibit batchesshould be packaged in sufficient quantity to comply with 21 CFR 211.166(a)(1-5)and 211.166(b). All batches, including the small scale batch, should bepackaged using commercial packaging equipment or similar equipment. Differentbatches of packaging material should be used where the packaging material couldaffect drug product performance and/or delivery.
根据 FDA 行业指南 Q1A(R2)：新原料药和制剂的稳定性测试（200311）和 ANDA：原料药和制剂稳定性测试问答（201405），3 个展示批次中有一批应该使用所有所拟上市参数完整包装。该批次应是中试规模或小规模批量，另 2 个展示批应该按 21 CFR 211.166(a)(1-5) 和 211.166(b)包装足够数量。所有批次，包括小规模批次，均应使用商业化包装设备或类似设备包装。如果包装材料会影响药品性能和/或给药情况，则要使用不同批次包装材料包装。
Question 2:
问 2
For a combination product consisting of apen injector device with an injectable drug product filled in a cartridge, isit acceptable to package only the amount required for stability into thecartridges and pen injector device for the three exhibit batches submitted inthe ANDA?
对于含有笔式注射器，将注射药品灌装在笔筒中的组合产品，是否可以接受 ANDA 中提交的 3 个展示批次只包装稳定性检测所需数量到笔筒中和笔式注射器中？
Answer 2:
答 2
For a pen injector device used with aninjectable drug product filled in a cartridge and other similar products, werecommend that all three of the exhibit batches be completely filled intocartridges. As described in FDA guidances for industry Q1A(R2): StabilityTesting of New Drug Substances and Products (November 2003) and ANDAs:Stability Testing of Drug Substances and Products Questions and Answers (May2014), one of the three batches should be entirely assembled into the peninjector devices. The other two primary stability batches should have asufficient number of samples packaged and assembled into the pen injectordevices for stability and reserve samples, in accordance with 21 CFR211.166(a)(1-5), 211.166(b), and 211.170.
对于将注射用药品灌装在笔筒同的笔式注射装置和其它类似产品，我们建议所有 3 个展示批次均完整灌装到笔筒中。如 FDA 行业指南 Q1A（R2）：新原料药和制剂的稳定性测试（200311）和 ANDA：原料药和制剂稳定性测试问答（201405）所述，3 批中应该有 1 批完整装配到笔式注射器中，另 2 批基本稳定性批次应该包装有足够数量的样品并装配至笔式注射器中用于稳定性留样和法定留样，满足 21 CFR 211.166(a)(1-5), 211.166(b)和 211.170 要求。
Question 1:
问 1
Is the reference listed drug (RLD)considered to have functional scoring when it is not mentioned in the labelingand half the tablet does not match the lowest labeled dose?
如果 RLD(参比制剂) 的标签里没有说明其是刻痕药片，片剂的一半并不符合最低标示剂量，是否还认为 RLD(参比制剂) 有功能性刻痕？
Answer 1:
答 1
Any scoring on the RLD should be consideredfunctional scoring, and therefore, the generic product should have similarscoring. According to FDA guidance for industry Tablet Scoring:
Nomenclature, Labeling, and Data forEvaluation (March 2013), “scoring configuration of generic drug products shouldbe the same as the RLD.” We recommend that split tablet testing be performedand the data submitted in the ANDA; otherwise, the Agency may refuse to receivethe ANDA due to inconsistent scoring configuration between the RLD and the testproduct. (FDA guidance for industry ANDA Submissions – Refuse-to-ReceiveStandards, Rev. 2 (December 2016)).
RLD(参比制剂) 上所有刻痕均认为是功能性刻痕，因此仿制药应该有类似的刻痕。根据 FDA 行业指南：片剂刻痕：命名法、标签和评估用数据（201303），“仿制药的刻痕参数应该与 RLD(参比制剂) 相同”。我们建议进行药片分割测试并在 ANDA 中提交数据，否则，FDA 会因为其刻痕参数与 RLD(参比制剂) 不同而拒收该 ANDA。（FDA 行业指南：ANDA 申报—拒收标准，R2，201612）
Question 2:
问 2
If the RLD has partial score lines, can theproposed generic product have a full score line(s)?
如果 RLD(参比制剂) 有局部分刻线，所拟仿制药是否要有全部分刻线？
Answer 2:
答 2
When the RLD has partial score lines, thegeneric can have a full score line(s) to produce partial doses equivalent tothat of the RLD as indicated in the approved labeling. Scoring between the RLDand generic products should be consistent to ensure that the patient is able toadjust the dose by breaking the tablet in the same manner, such that thepatient can switch from the RLD to the generic product without encounteringproblems related to the dose. Additionally, consistent scoring assures thatneither the generic product nor the RLD has an advantage in the marketplacebecause one is scored and one is not. For additional information, see FDAguidance for industry Tablet Scoring: Nomenclature, Labeling, and Data forEvaluation (March 2013).
如果 RLD(参比制剂) 有局部分刻线，则仿制药可以有全部分刻线得到等同于RLD(参比制剂) 已批准标签中所指的那部分剂量。RLD(参比制剂) 和仿制药之间的分刻应该一致，确保患者可以通过相同方式掰开药片调整剂量，这样患者就可以从 RLD(参比制剂) 切换到仿制药而不会面临与剂量有关的问题。另外，刻痕一致也确保仿制药或 RLD(参比制剂) 都不会因为一个有刻痕另一个没有而在市场上占有优势。更多信息参见 FDA 行业指南：片剂刻痕：命名法、标签和评估用数据（201303）。
Size and Shape of Generic Solid Oral DosageForms
固体口服仿制制剂的尺寸和形状
Question:
问
If the reference listed drug (RLD) has beendiscontinued and there is no information on its shape and size, is itacceptable to use the shape and size of the FDA designated reference standardto design the generic product?
如果 RLD(参比制剂) 已退市，并且没有其形状和尺寸信息，是否可接受使用 FDA 指定参比制剂的形状和尺寸来设计仿制药品？
Answer:
答
In cases where the RLD is not availablebecause it has been discontinued for reasons not associated with safety andefficacy, FDA may have designated a reference standard. The FDA designatedreference standard is recommended to be used in in-vivo bioequivalence studiesas well as comparative in-vitro studies. In this situation, if information onthe size and shape of the RLD are not available, it is acceptable to use thesize and shape of the FDA designated reference standard to develop the genericproduct provided it meets the recommendations in the size and shape guidance.
如果 RLD(参比制剂) 已因为与安全性和有效性无关的原因退市而无法获得，FDA 可能指定了另一个参比制剂。FDA 建议在体内 BE 研究和体外比较研究时使用指定的参比制剂。在此情况下，如果无法获得 RLD(参比制剂) 的尺寸和形状信息，可以接受使用 FDA 指定参比制剂的尺寸和形状开发仿制药品，前提是其满足尺寸和形状指南中的建议。