【干货】FDA指南：仿制原料药和制剂稳定性试验问答（中英双语）

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？

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？

 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？

What is the Agencys 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？

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？

What will the recommendation for secondary packaging be?  

对外包装有什么建议？

What are the recommendations for stability testing of modified release products?

对于缓释产品的稳定性试验有什么建议？

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？

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？

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？

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))?  

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）？

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？

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？

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。 

Transdermal Patches ：经皮给药贴剂

Two of the three batch sizes for each strength should be at least 10 percent of the proposed commercial production batch or 25,000 units (for each strength), whichever is greater. The third batch can be smaller than 10 percent of the proposed commercial batch, but not less than 60 percent of the pilot scale batch. For transdermal matrix products, where different strengths are identified by the transdermal patch size (surface area), to comply with the three batch size recommendation, we recommend providing data on patches manufactured using three distinct matrix laminates at the time of submission. (Each laminate can be cut to support multiple strengths in the application, where applicable.) We recommend you contact the appropriate review division if you are manufacturing transdermal patches using other technologies (e.g., reservoir).[2]  

各不同剂量的3批中的2批批量应至少为申报商业批量的10%，或23000个最小单位（每个剂量），取其大者。第3批可以小于申报的商业批量的10%，但不能小于中试批量的60%。对于经皮给药支架产品，如果剂量差异与贴剂尺寸（表面积）差异相同，符合3个批量的推荐，我们建议在申报时提供采用3个明显区别的支架压板（适用时，每个压板可以剪切以支持申报中的不同剂量）。如果你采用了其它技术（例如膏药）来生产经皮给药贴剂，我们推荐你联系适当的审核部门， 

You should include a representative sample from all three batches using different components of backing, adhesives, release liner, and other critical excipients used in packaging a sufficient number of proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b).  

你应该包括所有3个批号采用不同基底成份、粘性材料、防粘衬里和其它用于包装的关键辅料的代表性样品，采用上市包装获得足够数量的样品，以满足21 CFR 211.166(a)(1-5) 和 211.166(b)的要求。 

Topicals 局部用药 

(a) Creams/Lotions/Gels：膏剂/洗液/胶

For nonsterile semi-solid dosage forms[3], the two pilot scale batches should be at least 100 Kg or 10 percent of the production batch, whichever is larger. The third batch can be smaller than 10 percent of the proposed commercial batch, but not less than 40 percent of the pilot scale batch. We recommend packaging representative samples from all the three batches in a sufficient number of proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b) .  

对于非无菌半固体剂型，应有2批中试批次，批量至少100kg或商业批量的10%，取其大者。第3批可以小于商业批量的10%，但不得小于中试批量的40%。我们推荐所有3个批次均有足够数据上市包装的代表性样品，以符合21 CFR 211.166(a)(1-5) 和 211.166(b)的要求。 

(b) Inhalation Solutions/Nasal Sprays (nasal nonmetered dose atomizer)：吸入溶液/鼻腔喷剂（鼻腔非定量喷雾器） 

Please refer to the following guidances for industry for information: Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products –Chemistry, Manufacturing, and Controls Documentation, and Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action.  

请参见以下行业指南：鼻腔喷雾剂和吸入溶液，混悬液，和喷雾药品------化学，生产，和控制文件，和鼻腔气雾剂和鼻腔喷剂的生物有效性和生物等效性研究 

Please contact OGD to discuss other dosage forms and/or routes of administration not covered in this document.  

如需讨论其它剂量形式和/或在本文件中未涵盖的给药方法，请联系OGD。

Is it acceptable to use a technical grade of the drug substance for the small scale batches or one of the two pilot scale batches of finished product?  

是否可以采用技术级的原料药用于小批量或两个中试批中的一批的药品生产？