201308 FDA指南：ANDA：原料药和制剂稳定性试验问答（中英文） C. Drug Product Manufacturing and Packaging
Q1: Can the split bulk solution filled into different fill volumes be considered different batches?
将散装溶液装入不同分装体积应作为不同批号吗？
A1: No. Split filling one batch of bulk solution into different fill volume sizes does not constitute discrete batches.
不。分装一个批号散装溶液至不同分装体积不构成分批。
Q2: Can you clarify the packaging recommendations for the submission batches for blow-fill-seal containers?
可否说明一下对吹瓶/灌装/封口的包装形式申报批有什么包装方面的建议？ A2: Blow-fill-seal containers are not an exception from regular packaging and are usually packaged insi
de a secondary container or a carton. The secondary packaging should be included in all three batches. ICH Q1A(R2) addresses secondary packaging usefulness (see section II, B, 4, Drug Product
Container Closure System (2.2.4)).
吹瓶/灌装/封口的包装形式仍是常规包装的一种，通常还会有外包装或纸箱包装。三个批次均应进行外包装。ICH Q1A(R2)里说明了外包装是有用的。（参见第II部分，B，4，药品包装（2.2.4）） Q3: Should all three batches be stored in final proposed packaging?
所有三个批次均应以完整的包装形式存贮吗？
A3: Yes. You should package all three batches in the container closure system proposed for marketing. Q1A(R2) addresses this question (see section II, B, 4, Drug Product Container Closure System (2.2.4)).
是的。需要将三批产品以上市申请的包装形式进行包装。Q1A(R2)中说明了该问题（参见第II部分，B，4，药品包装（2.2.4））。
Q4: What is the Agency’s position on using different lots of APIs and/or packaging materials? How many API lots should be used in the
manufacture of finished product lots used to support the ANDA?
法规当局对于采用不同批次原料药和/或包装材料是什么态度？在药品生产中可以使用多少批次原料药来支持ANDA？
A4: A minimum of two lots of the drug substance[1] should be used to prepare the three primary batches of drug product. It is not necessary to use different lots
of packaging material, except in cases where the packaging material could affect drug product performance and/or delivery.
应至少使用2个批次的原料用于制备3个批次基本批的药品生产。不需要采用不同批次的包装材料，除非包装材料可能会对药品的性能和/或运输产生影响。
Q5: Should the small scale batches be packaged with commercial equipment, or is it acceptable to package using research equipment or by hand?
小批量的产品是否必须采用商业化设备进行包装，还是可以采用研发设备或手工包装？
A5: Small scale batches should be packaged with commercial equipment.
保定师范学校Packaging systems used should be the same as or similar to packaging
proposed for storage and market distribution. Please refer to ICH Q1A(R2) section II, B, 3, Selection of Batches (2.2.3) and the glossary definition for primary batches.
小批量应采用商业化设备进行包装。所采用的包装系统应与目标存贮和市售包装相同或相似。请参见ICH Q1A(R2)第II部分，B，3 批次的选择（2.2.3）和内包装的术语定义。
Q6: What will the recommendation for secondary packaging be?
对外包装有什么建议？
A6: We recommend following ICH Q1A(R2) section II, B, 4, Drug Product Container Closure System (2.2.4).
我们建议遵守ICH Q1A(R2)第II部分，B，4 药品包装密封系统（2.2.4）的要求。
Q7: What are the recommendations for stability testing of modified release products?
南澳1号
对于缓释产品的稳定性试验有什么建议？
A7: FDA recommends following the guidance for data on three batches per ICH Q1A(R2). ICH stability guidances do not distinguish among different dosage forms.
FDA对稳定性试验数据的推荐是依据ICH Q1A(R2)三批的要求。ICH稳定性指南并未对不同剂型进行区分。 Q8: What are the recommendations for the submission of oral solutions, ophthalmic solutions, oral and ophthalmic suspensions, transdermal patches, ointments, creams, granules for reconstitution, and
parenterals?
对于口服溶液、眼药水、口服和眼用悬混剂、透皮贴剂、软膏剂、擦剂、重塑颗粒剂和注射剂申报有什么建议？
A8: Our recommendations follow ICH Q1A(R2), and we recommend three discrete batches and 6 months of accelerated and long-term data at the time of submission for all dosage forms. Also, refer2 to other questions and
corresponding answers that specifically discuss other dosage forms included in this document.
我们的建议是遵守ICH Q1A(R2)要求，我们建议针对任何剂型均提交三个非连续批次，6个月加速和长期稳定性数据。同时，请参见本文件中针对其它剂型的其它问题和相关回答。
Q9: Are 6 months of stability data required on all three batches, or would one batch at 6 months and two lots at 3 months be acceptable?
是否申报中的三个批次均需要提交6个月稳定性试验数据，还是只要一批有6个月，其它2批可以只有3个月数据呢？
A9: Following ICH stability guidances, 6 months (accelerated) stability is recommended on all three submission batches.政治体制改革的必要性
根据ICH稳定性试验指南，建议所有申报批次均提交6个月（加速）稳定性试验数据。
Q10: Should the executed batch records for the three batches be included in the ANDA submission?
三批生产填写的批记录是否需要包括在ANDA申报中？
A10: Yes.
是的
Q11: Does all relevant CMC batch information for the three stability batches need to be included in the application (i.e., excipient Certificate of
Analysis (COA))?
核工业工程技术研究设计院是否所有与三个稳定性试验批次的相关CMC批次信息都需要包括在申报资料中（即辅料检验报告）？
A11: Yes. When more than one lot of API or excipients is used, the corresponding section in Module 3 should contain that information.
是的。如果使用了不止一个批号的原料药或辅料，则在模块3中，应包括所有的信息。
Q12: If you are an applicant submitting an ANDA with two API sources, are you required to perform stability on three batches of drug product for each API source?
如果我要提交的ANDA有两个原料药来源，是否需要对每个原料药来源制成的药品各取3批进行稳定性试验呢？
A12: If you propose to add a second or more than two sources of API for the same drug substance, we recommend you provide the following CMC information:
如果你需要增加一个或更多的原料药来生产同一种药品，我们建议你提供以下CMC信息
Comparison and justification of comparability (by the firm) of the physico-chemical properties and impurities of the drug substance from each source.
所有不同来源原料药的理化特性和杂质比较和判定
Appropriate stability data on three batches of drug product qualifying the first API source used in the bioequivalence (BE) studies as recommended by the
stability guidance.
在稳定性试验指南中，建议用于生物等效性（BE）研究的第一个原料药所生产的3批药品应有适当的稳定性数据。
A single pilot scale batch of the drug product bio-strength(s) manufactured using
2012年中央1号文件the second or each of the other proposed API source(s) used to support the ANDA application, along with comparative dissolution data.
第二个及其它来源的原料药生产一个中试批次药品的数据，用以支持ANDA申报，以及比较性溶出度数据。
Appropriate stability data (accelerated and long-term for 6 months at the time of filing) on the strength(s) manufactured for each API source. Appropriate
BASE MHGLLstability data may in some cases include intermediate condition stability data.
每个原料药来源生产的不同剂量下适当的稳定性数据（申报时有长期和加速6个月数据）。有些情况下，适当的稳定性数据需要包括中间条件稳定性数据。
Q13: What is meant by “small” scale? “Small” is not a defined word in ICH guidance. What are the packaging expectations from the small batch, as well as from the two pilot scale batches? Traditionally, ANDAs are
submitted with 100,000 units for solid oral dosage forms. Is this still
applicable?
“小”批量是什么意思？在ICH指南中“小”是没有定义的。小批量的包装期望是怎么样的，是要求与两个中试批准相同吗？传统意义上，ANDA固体口服制剂申报批要求是100，000个最小单位包装，现在还适用吗？
A13: The interpretation of what constitutes a small scale batch for the purpose of filing ANDAs is further elaborated below for various dosage forms and their packaging recommendations. Unless specifically noted below, one primary batch should be fully packaged.
在提交ANDA时所要求的小批量是什么，在下面对不同剂型及其包装情况进行了说明。如果以下未另加说明，则一个基本批的数据应全部进行包装。
Oral dosage forms 口服制剂
(a) Tablets/Capsules (e.g., immediate release, extended release, chewable,
orally disintegrating and delayed release tablets or capsules): 片剂、胶囊（例如中间释放、缓释、咀嚼、口腔崩解、延时释放片剂或胶囊）
Two of the three batches should be of at least 10 percent of the proposed production batch or 100,000 finished dosage units, whichever is greater (i.e., pilot scale batches). The third batch can be
smaller than the 10 percent of the proposed production batch, but not less than 25 percent of the pilot scale
batch. We recommend stability data be generated for the three ANDA
submission batches in the proposed marketing container. A minimum of
100,000 units in all proposed presentations is recommended. Representative samples from all three batches must be packaged in a sufficient number of proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b).
三批中的两批应达到目标批量的至少10%，或至少100,000最小制剂单位，取其中较大者（即中试批次）。第三批可以比目标批量的10%小，但不能低于中试批量的25%。我们建议稳定性数据由目标市售包装三批ANDA申报批产生。建议所有包装形式至少包括100,000个最小制剂单位。三批申报批中具有代表性的样品应有足够数量进行市售包装，满足21CFR211.166(a)（1-5）和
211.166（b）的要求。
(b) Powders/Solutions/Suspensions: 粉剂/溶液/混悬剂
Two of the three batches should be at least 10 percent of the proposed maximum size commercial batch. The third batch can be smaller than 10 percent of the proposed commercial batch, but not less than 25 percent of the pilot scale batch. To capture variability introduced by packaging, the product from all the batches should be used in the packaging process. We recommend packaging representative samples from all three batches of a sufficient number of
proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b) .
3批中的2批要求是商业最小批量10%的批量。第3批可以小于提出的商业批量的10%，但不小于中试批准的25%批量。为了发现包装引起的差异，所有批次产品均应采用申报的包装工艺进行包装。
我们建议根据21 CFR 211.166(a)(1-5) 和211.166(b)中的要求，对所有3批中均按申请的上市包装对足够数据样品进行包装获得代表性样品。
Parenterals Solutions/Powders for Solutions (lyophilized
cakes)/Suspensions/Sterile Topicals (Ophthalmic and Otic drug
products):
注射液/溶液用粉剂（冻干粉）/混悬剂/无菌局部（眼用和耳用剂）
Two of the three batches should be at least 10 percent of the proposed maximum size commercial batch (i.e., pilot scale size) or 50 L (per batch), whichever is larger. The third batch can be smaller than 10 percent of the proposed
commercial batch, but not less than 25 percent of the pilot scale batch. To capture variability introduced by packaging, the product from all the batches should be used in the packaging process. Representative samples from all the three batches should be packaged in a sufficient number of proposed
marketing presentations to comply with 21 CFR 211.166(a)(1-5) and
211.166(b). We recommend manufacturing all the batches to meet sterility requirements.
3批中的2批应是申报的商业批量至少10%批量（即中试批量）或50L（每批），取大者。第3批可以小于申请的商业批次的10%，但不小于中试批量的25%。应根据21 CFR 211.166(a)(1-5) 和211.166(b)中的要求，对所有3批中均按申请的上市包装对足够数据样品进行包装获得代表性样品。我们建议所有批准生产均满足无菌要求。
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