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1、III. COMPONENTS AND COMPOSITION NONRELEASE CONTROLLING EXCIPIENT组分和成分-非释放控制辅料This section of the guidance focuses on changes in nonrelease controlling excipients in the drug product. For modified release solid oral dosage forms, consideration should be given as to whether the excipient is critical o
2、r not critical to drug release. The sponsor should provide appropriate justifications for claiming any excipient(s) as a nonrelease controlling excipient in the formulation of the modified release solid oral dosage form. The functionality of each excipient should be identified. Changes in the amount
3、 of the drug substance are not addressed by this guidance. Changes in components or composition that have the effect of adding a new excipient or deleting an excipient are defined at level 3 (defined below), except as described below in Section III.A.1.a. Waiver of bioequivalence testing for a chang
4、e in composition which involves only a different color, flavor or preservative may be permissible as described in 21 CFR 320.22(d)(4). 本指南这部分主要针对药品非释放控制辅料的变更。对于缓控释固体口服制剂，应该对辅料是否为药物释放的关键辅料或非关键辅料进行考虑。发起人如果判定任何辅料为缓控释固体口服制剂中的非释放控制辅料，应该提供相应的理由。应该对每种辅料的功能进行识别。本指南未对药品中原料药量的变更进行规定。对组分或成分的变更中涉及到新增或删除辅料时，归类为3
5、级变更，第III.A.1.a中的情况除外。成分的变更如果只涉及到变更颜色、口味或防腐剂，按照21 CFR 320.22(d)(4) 的规定可能允许豁免生物等效性测试。A. Level 1 Change一级变更1. Definition of Level级别定义Level 1 changes are those that are unlikely to have any detectable impact on formulation quality and performance. 一级变更指那些不太可能对剂型的质量和功效有可检测的影响的变更。Examples:例如a. Deletion or
6、 partial deletion of an ingredient intended to affect the color or flavor of the drug product; or change in the ingredient of the printing ink to another approved ingredient. 删除或部分删除组分，这个组分会影响药品的颜色或口味；或者将印刷用油墨成分变更为另一种已批准成分。b. Changes in nonrelease controlling excipients, expressed as percentage (w/w
7、) of total formulation, less than or equal to the following percent ranges:非释放控制辅料的变更，以总配方的百分比表示，小于等于以下百分比范围：Nonrelease Controlling Excipient非释放控制辅料Percent Excipient (w/w)Out Of Total Target Dosage Form Weight辅料占总剂型重量的百分比Filler填充剂 5Disintegrant崩解剂Starch淀粉Other其他31Binder粘合剂 0.5Lubricant润滑剂Ca or Mg st
8、earate钙或镁硬脂酸盐Other其他0.251Glidant 助流剂Talc滑石粉Other其他Film Coat包衣10.11These percentages are based on the assumption that the drug substance in the product is formulated to 100% of label/potency. The total additive effect of all nonrelease controlling excipient changes should not be more than 5%.2 The to
9、tal weight of the dosage form should still be within the original approved application range. 以上的百分比是假设产品是100%按标签/效价配方制造的。所有非释放控制辅料变更的累加效应应该不超过5%。剂型总重量应该在原始批准申请的范围内。The components (active and excipients) in the formulation should have numerical targets that represent the nominal composition of the d
10、rug product on which any future changes in the composition of the product are to be based. Allowable changes in the composition should be based on the original approved target composition and not on previous level 1 changes in the composition. For products approved with only a range for excipients,
11、the target value may be assumed to be the midpoint of the original approved application range.剂型中的成分（活性成分和辅料）应该有数量化的投放范围，这个范围代表的是药品的公称成分，药品以后任何的变更都是基于这个范围的。成分中可允许的变更应该是基于原始批准的目标成分，并且不是基于成分中之前的一级变更。对于辅料的批准是在一个范围内的产品，目标值假设为原始批准范围的中值。2. Test Documentation检测文件a. Chemistry Documentation 化学文件Application/c
12、ompendial product release requirements and stability testing. 申请/注册产品放行要求和稳定性测试。Stability: First production batch on long-term stability data reported in annual report.稳定性测试：第一批生产的产品做长期稳定性测试，并在年报中进行报告。b. Dissolution documentation溶解文件None beyond application/compendial requirements. 除申请、注册要求外无其他要求。c.
13、Bioequivalence documentation生物等效性文件None.无3. Filing Documentation档案文件Annual report (all information including long-term stability data).年报（所有信息包括长期稳定性测试数据）B. Level 2 Change二级变更1. Definition of Level级别定义Level 2 changes are those that could have a significant impact on formulation quality and performan
14、ce.二级变更指的是那些可能会对剂型质量和功效有严重影响的变更。Examples:例如a. A change in the technical grade and/or specifications of a nonrelease controlling excipient.对技术等级和 /或非释放控制辅料的变更。b. Changes in nonrelease controlling excipients, expressed as percentage (w/w) of total formulation, greater than those listed above for a lev
15、el 1 change, but less than or equal to the following percent ranges (which represent a two-fold increase over level 1 changes):非 释放控制辅料的变更，以总配方的百分比表示，大于前面一级变更的百分比，但是小于等于以下百分比范围（以一级变更两倍的增长表示）：Nonrelease Controlling Excipient非释放控制辅料Percent Excipient (w/w)Out Of Total Target Dosage Form Weight辅料占总剂型重量的
16、百分比Filler填充剂 10Disintegrant崩解剂Starch淀粉Other其他62Binder粘合剂 1Lubricant润滑剂Ca or Mg stearate钙或镁硬脂酸盐Other其他0.52Glidant 助流剂Talc滑石粉Other其他Film Coat包衣20.22These percentages are based on the assumption that the drug substance in the drug product is formulated to 100% of label/potency. The total additive effect of all nonrelease controlling excipient changes should not change by more than 10%. The total weight of the dosage form could still be within or outside the original a
