2023-05-06
收藏！法规 | 非无菌半固体剂型放大和批准后变更工业指南
GUIDANCE FOR INDUSTRY Nonsterile Semisolid Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence d0cumentation SUPAC-SS非无菌半固体剂型放大和批准后变更工业指南：化学、制造和控制；体外释放测试和体内生物等效性文件SUPAC-SS
This guidance provides recommendations to pharmaceutical sponsors of new drug applications (NDAs), abbreviated new drug applications (ANDAs), and abbreviated antibiotic drug applications (AADAs) who intend to change (1) the components or composition, (2) the manufacturing (process and equipment), (3) the scale-up/scale-down of manufacture, and/or (4) the site of manufacture of a semisolid formulation during the postapproval period. This guidance addresses nonsterile semisolid preparations (e.g., creams, gels, lotions, and ointments) intended for topical routes of administration. The guidance defines (1) the levels of change; (2) recommended chemistry, manufacturing, and controls (CMC) tests to support each level of change; (3) recommended in vitro release tests and/or in vivo bioequivalence tests to support each level of change; and (4) d0cumentation to support the change.本指南为新药申请（NDA）、仿制药申请（ANDA）和仿制抗生素药物申请（AADA）的制药发起人提供了建议，他们打算改变（1）成分或组成，（2）制造（工艺和设备），（3）制造批量的放大/缩小，和/或（4）批准后期间半固体制剂的生产地点。本指南涉及用于局部给药途径的非无菌半固体制剂（如乳膏、凝胶、乳液和软膏）。该指南定义了（1）变化的程度；（2） 推荐的化学、制造和控制（CMC）测试，以支持每个级别的变更；（3） 推荐的体外释放试验和/或体内生物等效性试验，以支持每一水平的变更；以及（4）支持变更所需提交的文件要求。
The guidance specifies the application information that should be provided to the Center for Drug eva1uation and Research (CDER) to ensure continuing product quality and performance chacteristics of the semisolid topical formulation for specified changes. The guidance does not comment on or otherwise affect compliance/inspection d0cumentation defined by the Office of Compliance in CDER or the Office of Regulatory Affairs at FDA.该指南规定了应向药物评估与研究中心（CDER）提供的申报信息，以确保在特定变化下，半固体局部制剂能维持其产品质量和性能特征。该指南不对CDER合规办公室或美国食品药品监督管理局监管事务办公室定义的合规/检查文件发表评论或产生其他影响。
The guidance provides recommendations on application d0cumentation for the following multiple changes, provided appropriate test and filing d0cuments are submitted (1) multiple level 1 changes with level 1 test and filing d0cumentation; (2) multiple level 1 changes; one level 2 change with level 2 test and filing d0cumentation; (3) multiple level 2 changes with level 2 test d0cumentation and a prior approval supplement (PAS) and (4) level 3 manufacturing site change and any other level 1 change with level 3 manufacturing site change test and filing d0cumentation. The d0cumentation to support the changes varies depending on the type and the complexity of the semisolid dosage form. For those changes filed in a Changes Being Effected (CBE) Supplement (21 CFR 314.70(c)), the FDA may review the supplemental information and decide that the changes are not approvable. Sponsors should contact the appropriate CDER review division and staff for information about tests and application d0cumentation for changes not addressed in this guidance, or for successive level 2 or 3 changes submitted over a short period.该指南为以下多项变更的申请文件提供了建议，前提是提交了适当的测试和备案文件（1）具有1级测试和备案文档的多项1级变更；（2） 多个1级变化；一个2级变更，带有2级测试和归档文件；（3） 具有2级测试文件和prior approval supplement (PAS)的多个2级变更，以及（4）具有3级生产现场变更和具有3级制造现场变更测试和归档文件的任何其他1级变更。支持变更的文件因半固体剂型的类型和复杂性而异。对于在《Changes Being Effected（CBE）补编》（21 CFR 314.70（c））中提交的变更，美国食品药品监督管理局可能会审查补充信息，并决定这些变更不可批准。发起人应联系相应的CDER审查部门和工作人员，以获取有关本指南中未提及的变更或短期内连续提交的2级或3级变更的测试和申请文件的信息。
The regulations provide that applicants may make changes to an approved application in accordance with a guidance, notice, or regulation published in the Federal Register that provides for a less burdensome notification of the change (e.g., by notification at the time a supplement is submitted or in the next annual report) (21 CFR 314.70(a)). This guidance permits less burdensome notice of certain postapproval changes within the meaning of § 314.70(a).条例规定，申请人可以根据指南、通知、或在《Federal Register》上发布的法规，该法规规定了较轻的变更通知（例如，在提交补充文件时或在下一份年度报告中发出通知）（《美国联邦法规汇编》第21卷第314.70（a）节）。本指南允许对§314.70第（a）条所指的某些批准后变更进行较轻的通知。
In general, semisolid dosage forms are complex formulations having complex structural elements. Often they are composed of two phases (oil and water), one of which is a continuous (external) phase, and the other of which is a dispersed (internal) phase. The active ingredient is often dissolved in one phase, although occasionally the drug is not fully soluble in the system and is dispersed in one or both phases, thus creating a three-phase system. The physical properties of the dosage form depend upon various factors, including the size of the dispersed particles, the interfacial tension between the phases, the partition coefficient of the active ingredient between the phases, and the product rheology. These factors combine to determine the release characteristics of the drug, as well as other characteristics, such as viscosity.
一般来说，半固体剂型是具有复杂结构元素的复杂制剂。它们通常由两相（油和水）组成，其中一个是连续（外部）相，另一个是分散（内部）相。活性成分通常溶解在一个相中，尽管有时药物不能完全溶解在系统中，而是分散在一个或两个相中，从而形成三相系统。剂型的物理特性取决于各种因素，包括分散颗粒的大小、相之间的界面张力、活性成分在相之间的分配系数以及产品流变性。这些因素结合起来决定了药物的释放特性，以及其他特性，例如粘度。
A.Critical Manufacturing Parameters关键制造参数
For a true solution, the order in which solutes are added to the solvent is usually unimportant. The same cannot be said for dispersed formulations, however, because dispersed matter can distribute differently depending on to which phase a particulate substance is added. In a typical manufacturing process, the critical points are generally the initial separation of a one-phase system into two phases and the point at which the active ingredient is added. Because the solubility of each added ingredient is important for determining whether a mixture is visually a single homogeneous phase, such data, possibly supported by optical microscopy, should usually be available for review. This is particularly important for solutes added to the formulation at a concentration near or exceeding that of their solubility at any temperature to which the product may be exposed.
对于真正的溶液，溶质加入溶剂的顺序通常并不重要。然而，对于分散的制剂来说，情况并非如此，因为分散的物质可以根据颗粒物质添加到哪一相而分布不同。在典型的制造过程中，临界点通常是将一个相系统初始分离为两相，以及添加活性成分的点。由于每种添加成分的溶解度对于确定混合物在视觉上是否是单一的均相很重要，因此通常应该获得这些数据，这些数据可能可以从光学显微镜获取以供审查。这对于以接近或超过其在产品可能暴露的任何温度下的溶解度的浓度，并被添加到制剂中的溶质来说尤其重要。
Variations in the manufacturing procedure that occur after either of these events are likely to be critical to the characteristics of the finished product. This is especially true of any process intended to increase the degree of dispersion through reducing droplet or particle size (e.g., homogenization). Aging of the finished bulk formulation prior to packaging is critical and should be specifically addressed in process validation studies.
在这些事件中的任何一个发生之后，制造程序的变化可能对成品的特性影响至关重要。这对于任何旨在通过减小液滴或颗粒尺寸（例如均化）来增加分散度的工艺来说尤其如此。在确定包装方案前完成的主体配方的老化研究至关重要，应在工艺验证研究中着重解决。
B.General Stability Considerations稳定性研究
The effect that SUPAC changes may have on the stability of the drug product should be eva1uated. For general guidance on conducting stability studies, see the FDA Guideline for Submitting d0cumentation for the Stability of Human Drugs and Biologics. For SUPAC submissions, the following points should also be considered:
应评估SUPAC变化可能对药品稳定性产生的影响。有关进行稳定性研究的一般指导，请参阅美国食品药品监督管理局提交人类药物和生物制品稳定性文件的指南。对于SUPAC提交的文件，还应考虑以下几点：
1.In most cases, except those involving scale-up, stability data from pilot scale batches will be acceptable to support the proposed change.
在大多数情况下，除了涉及放大的情况外，中试批次的稳定性数据将是可接受的，以支持拟讨论的变更。
2.Where stability data show a trend towards potency loss or degradant increase under accelerated conditions, it is recommended that historical accelerated stability data from a representative prechange batch be submitted for comparison. It is also recommended that under these circumstances, all available long-term data on test batches from ongoing studies be provided in the supplement. Submission of historical accelerated and available long-term data would facilitate review and approval of the supplement.
如果稳定性数据显示在加速条件下有效力损失或降解物增加的趋势，建议提交代表性的变化发生前的批次的历史加速稳定性数据进行比较。还建议在这些情况下，在补充资料中提供正在进行的研究中的所有可用的测试批次的长期数据。提交历史加速和可用的长期数据将有助于审查和批准补充资料
3.A commitment should be included to conduct long-term stability studies through the expiration dating period, according to the approved protocol, on either the first or first three (see section III-VI for details) production batches, and to report the results in subsequent annual reports.应承诺根据批准的方案，在第一批或前三批（详见第III-VI节）生产批次的有效期内进行长期稳定性研究，并在随后的年度报告中报告结果。
C.The Role of In Vitro Release TestingIVRT测试的作用
The key parameter for any drug product is its efficacy as demonstrated in controlled clinical trials. The time and expense associated with such trials make them unsuitable as routine quality control methods. Therefore, in vitro surrogate tests are often used to assure that product quality and performance are maintained over time and in the presence of change. A variety of physical and chemical tests commonly performed on semisolid products and their components (e.g., solubility, particle size and crystalline form of the active component, viscosity, and homogeneity of the product) have historically provided reasonable evidence of consistent performance. More recently, in vitro release testing has shown promise as a means to comprehensively assure consistent delivery of the active component(s) from semisolid products.任何药品的关键参数都是其疗效，正如对照临床试验所证明的那样。与此类试验相关的时间和费用使其不适合作为常规质量控制方法。因此，通常使用体外替代测试来确保产品质量和性能在一段时间内保持不变。在历史角度看，通常对半固体产品及其组分进行的各种物理和化学测试（如活性组分的溶解度、粒度和结晶形式、产品的粘度和均匀性）提供了一致性能的合理证据。最近，体外释放测试（IVRT）已显示出作为一种全面确保半固体产品中活性成分递送一致性手段的前景。
An in vitro release rate can reflect the combined effect of several physical and chemical parameters, including solubility and particle size of the active ingredient and rheological properties of the dosage form. In most cases, in vitro release rate is a useful test to assess product sameness between prechange and postchange products. However, there may be instances where it is not suitable for this purpose. In such cases, other physical and chemical tests to be used as measures of sameness should be proposed and discussed with the Agency. With any test, the metrics and statistical approaches to d0cumentation of “sameness” in quality attributes should be considered.体外释放率可以反映几个物理和化学参数的综合影响，包括活性成分的溶解度和粒径以及剂型的流变学特性。在大多数情况下，体外释放率是评估变更前和变更后产品之间产品相同性的有用测试。然而，在某些情况下，它可能不适合用于此目的。在这种情况下，申请人应提出并与机构讨论其他用作确保相同性措施的物理和化学测试。对于任何测试，都应该考虑质量属性中“相同性”的度量和统计方法。
The evidence available at this time for the in vitro-in vivo correlation of release tests for semisolid dosage forms is not as convincing as that for in vitro dissolution as a surrogate for in vivo bioavailability of solid oral dosage forms. Therefore, the Center’s current position concerning in vitro release testing is as follows:目前，半固体剂型的体外-体内释放试验相关性的证据不如体外溶出作为固体口服剂型体内生物利用度的替代品的证据令人信服。因此，中心目前关于体外释放试验的立场如下：
1.In vitro release testing is a useful test to assess product “sameness” under certain scale-up and postapproval changes for semisolid products.体外释放测试是一种有用的测试，用于评估半固体产品在某些放大和批准后变化下的产品“相同性”
2.The development and validation of an in vitro release test are not required for approval of an NDA, ANDA or AADA nor is the in vitro release test required as a routine batch-to-batch quality control test.批准NDA、ANDA或AADA不需要体外释放试验的开发和验证，也不需要将体外释放试验作为常规的逐批质量控制试验。
3.In vitro release testing, alone, is not a surrogate test for in vivo bioavailability or bioequivalence.单独的体外释放试验不是体内生物利用度或生物等效性的替代试验
4.The in vitro release rate should not be used for comparing different formulations across manufacturers.体外释放率不应用于比较不同制造商的不同配方。
This section of the guidance focuses on changes in excipients in the drug product. Qualitative changes in excipients should include only those excipients which are present in approved drug products for the specific route of administration. Quantitative changes in excipients should not exceed the amount previously approved in products with the same specific route of administration. The chronology of changes in components and composition should be provided. 2 Changes in components or composition that have the effect of adding a new excipient or deleting an existing excipient are defined as level 3 changes (see section III.C below), except as described below. These changes generally result in the need to change the labeling.
本节指南的重点是药品中辅料的变化。辅料的定性变化应仅包括特定给药途径的批准药品中存在的辅料。辅料的定量变化不应超过具有相同特定给药途径的产品中先前批准的量。应提供成分和组成变化的时间顺序。2具有添加新辅料或删除现有辅料效果的成分或组成的变化被定义为3级变化（见下文第III.C节），以下所述情况除外。这些变化通常导致需要更改标签。
Compositional changes in preservatives are considered separately and are not included as part of the total additive effect under sections III.A, B and C.防腐剂的成分变化是单独考虑的，不包括在第III.A、B和C节的总添加效应中。
A.Level 1 Change一级变更
1.Definition of Level定义
Level 1 changes are those that are unlikely to have any detectable impact on formulation quality and performance1级变化是指不太可能对配方质量和性能产生任何可检测影响的变化
Examples例如:
Deletion or partial deletion of an ingredient intended to affect the color, fragrance, or flavor of the drug product.删除或部分删除旨在影响药品颜色、香味或风味的成分
Any change in an excipient up to 5% of approved amount of that excipient. The total additive effect of all excipient changes should not be more than 5%. Changes in the composition should be based on the approved target composition and not on previous level 1 changes in the composition. A change in diluent (q.s. excipient) due to component and composition changes in excipient may be made and is excluded from the 5% change limit辅料的任何变化，最高可达该辅料批准量的5%。所有辅料变化的总添加效应不应超过5%。成分的变化应基于已批准的目标成分，而不是之前的1级成分变化。由于辅料的成分和组成变化，可能会导致稀释剂发生变化，且不包括在5%的变化范围内
Change in a supplier of a structure forming excipient that is primarily a single chemical entity (purity$95%) or change in a supplier or technical grade of any other excipient.主要为单一化学实体的结构形成辅料供应商的变更（纯度为95%），或任何其他辅料的供应商或技术等级的变更
2.Test d0cumentation测试文件
a.Chemistry d0cumentation化学文件
Application/compendial product release requirements and stability testing.符合申报资料/药典标准的放行要求和稳定性测试
Stability testing: First production batch on long-term stability reported in annual report.稳定性测试：年度报告中报告的第一批生产批的长期稳定性。
b.In Vitro Release d0cumentation体外释放文件
None.不需要
c.In Vivo Bioequivalence d0cumentation体内生物等效文件
None.不需要
3.Filing d0cumentation灌装文件
Annual report (all information including long-term stability data).年度报告（包括长期稳定性数据在内的所有信息）。
B.Level 2 Change二级变更
1.Definition of Level定义
Level 2 changes are those that could have a significant impact on formulation quality and performance.2级变化是指潜在可能对配方质量和性能产生重大影响的变化。
Examples:例如
Changes of >5% and≤10% of approved amount of an individual excipient. The total additive effect of all excipient changes should not be more than 10%. Changes in the composition should be based on the approved target composition and not on previous level 1 or level 2 changes in the composition. Changes in diluent (q.s. excipient) due to component and composition changes in excipients are acceptable and are excluded from the 10% change limit.单个辅料批准量的变化>5%和≤10%。所有辅料变化的总添加效应不应超过10%。成分的变化应基于已批准的目标成分，而不是之前的1级或2级成分变化。由于辅料的成分和组成变化而引起的稀释剂的变化是可以接受的，并且不在10%的变化限制范围内。
Change in supplier of a structure forming excipient not covered under level 1.1级未涵盖的结构形成赋形剂的供应商变更。
Change in the technical grade of structure forming excipient.结构形成赋形剂技术等级的变化。
Change in particle size distribution of the drug substance, if the drug is in suspension.如果药物处于混悬状态，则原料药粒度分布的变化。
2.Test d0cumentation测试文件
a.Chemistry d0cumentation化学文件
Application/compendial product release requirements and executed batch records.符合申报资料/药典标准的放行要求和执行的批次记录。
Stability testing: One batch with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first production batch reported in annual report.稳定性测试：在CBE补充中报告一批三个月的加速稳定性数据，在年度报告中报告的第一批生产的长期稳定性数据。
b.In Vitro Release d0cumentation体外释放文件
The in vitro release rate of a lot of the new/modified formulation should be compared with that of a recent lot of comparable age of the pre-change formulation of the product. The median in vitro release rates (as estimated by the estimated slope from each cell, see section VII) of the two formulations should be demonstrated to be within acceptable limits using the testing procedure described in section VII (IN VITRO RELEASE TEST) below.一批新的/改良的制剂的体外释放率应与最近一批变化前产品的制剂的可比效期的产品的体外释放速率进行比较。应使用以下第VII节（体外释放试验）中所述的试验程序，证明两种制剂的中位体外释放率（通过每个扩散池的的斜率评估，见第VII节）在可接受的限度内。
c.In Vivo Bioequivalence d0cumentation体内生物等效性文件
None.不需要
3.Filing d0cumentation灌装文件
Changes being effected supplement (all information including accelerated stability data); annual report (long-term stability data).CBE补充资料（包括加速稳定性数据在内的所有信息）；年度报告（长期稳定性数据）。
C.Level 3 Change三级变更
1.Definition of Level定义
Level 3 changes are those that are likely to have a significant impact on formulation quality and performance.3级变化是指极可能对配方质量和性能产生重大影响的变化。
Examples:例如
Any qualitative and quantitative changes in an excipient beyond the ranges noted in level 2 change.辅料的任何定性和定量变化超出2级变化中注明的范围。
Change in crystalline form of the drug substance, if the drug is in suspension.如果药物处于混悬状态，则药物结晶形式的变化。
2.Test d0cumentation测试文件
a.Chemistry d0cumentation化学文件
Application/compendial product release requirements and executed batch records.符合申报资料/药典标准的放行要求和执行的批次记录。
Significant body of information available: One batch with three months accelerated stability data reported in prior approval supplement and long-term stability data of first three production batches reported in annual report可获取Significant body of information（见名词解释，下同）：prior approval supplemen中报告的一个批次的三个月加速稳定性数据和年度报告中报告的前三个生产批次的长期稳定性数据
Significant body of information not available: Three batches with three months accelerated stability data reported in prior approval supplement and long-term stability data of first three production batches reported in annual report.不可获取Significant body of information：prior approval supplement中报告三个批次的三个月加速稳定性数据和年度报告中报告的前三个生产批次的长期稳定性数据。
b.In Vitro Release d0cumentation体外释放数据
The in vitro release rate of the new/modified formulation should be established as a point of reference. Under this level 3 change, in vitro release d0cumentation is not required, but sponsors are encouraged to develop this information for use in subsequent changes under this guidance.
新配方/改良配方的体外释放率应作为参考点。根据这一3级变更，不需要体外释放文件，但鼓励申请人开发这些信息，以便在本指南下的后续变更中使用。
c.In Vivo Bioequivalence d0cumentation体内生物等效性文件
Full bioequivalence study on the highest strength, with in vitro release/other approach on the lower strength(s).最高剂量的完全生物等效性研究，较低剂量的体外释放/其他方法。
3.Filing d0cumentation灌装文件
Prior approval supplement (all information including accelerated stability data); annual report (long-term stability data).Prior Approval Supplement (PAS)（包括加速稳定性数据在内的所有信息）；年度报告（长期稳定性数据）。
D.Preservative防腐剂
For semisolid products, any change in the preservative may affect the quality of the product. If any quantitative or qualitative changes are made in the formulation, additional testing should be performed. No in vitro release d0cumentation or in vivo bioequivalence d0cumentation is needed for preservative changes.对于半固体产品，防腐剂的任何变化都可能影响产品的质量。如果配方发生任何定量或定性变化，则应进行额外的测试。防腐剂变更不需要体外释放文件或体内生物等效性文件。
1.Level 1 Change一级变更
a.Definition of Level定义
Quantitatively 10% or less change in the approved amount of preservative.
防腐剂批准量的定量变化为10%或更少。
b.Test d0cumentation测试文件
Application/compendial product release requirements.符合申报资料/药典标准的放行要求
Preservative Effectiveness Test carried out at lowest specified preservative level.在最低规定防腐剂水平下进行的防腐剂有效性测试。
c.Filing d0cumentation灌装文件
Annual report年度报告
2.Level 2 Change二级变更
a.Definition of Level定义
Quantitatively greater than 10% and up to 20% change in the approved amount of preservative.防腐剂批准量的定量变化大于10%，最高可达20%。
b.Test d0cumentation测试文件
Application/compendial product release requirements符合申报资料/药典标准的放行要求
Preservative Effectiveness Test at lowest specified preservative level.最低规定防腐剂水平下的防腐剂有效性测试。
c.Filing d0cumentation灌装文件
Changes being effected supplement.CBE补充。
3.Level 3 change三级变更
a.Definition of Level定义
Quantitatively greater than 20% change in the approved amount of preservative (including deletion) or use of a different preservative.防腐剂批准量（包括删除）或使用不同防腐剂的定量变化超过20%。
b.Test d0cumentation
Application/compendial product release requirements.符合申报资料/药典标准的放行要求。
Preservative Effectiveness Test at lowest specified preservative level.最低规定防腐剂水平下的防腐剂有效性测试。
Analytical method for identification and assay for new preservative.新防腐剂的鉴别和分析方法。
Validation studies to show that the new preservative does not interfere with application/compendial test.验证研究表明，新防腐剂不会干扰申报资料/药典标准测试。
Executed batch records执行的批次记录
Stability testing: One batch with three months accelerated stability data reported in prior approval supplement and long-term stability data of first production batch reported in annual report.稳定性测试：prior approval supplement中报告的一批三个月加速稳定性数据和年度报告中报告的第一批生产的长期稳定性数据。
c.Filing d0cumentation灌装文件
Prior approval supplement (all information including accelerated stability data); annual report (long-term stability data).Prior approval supplement（包括加速稳定性数据在内的所有信息）；年度报告（长期稳定性数据）。
Manufacturing changes may affect both equipment used in the manufacturing process and the process itself.制造变更可能会影响制造过程中使用的设备和过程本身。
A.Equipment设备
1.Level 1 Change一级变更
a.Definition of Level定义
Change from nonautomated or nonmechanical equipment to automated or mechanical equipment to transfer ingredients. Change to alternative equipment of the same design and operating principles.将非自动化或非机械设备改为自动化或机械设备以转移配料。更改为具有相同设计和操作原理的替代设备。
b.Test d0cumentation测试文件
i.Chemistry d0cumentation化学文件
Application/compendial product release requirements. Notification of change and submission of updated executed batch records.符合申报资料/药典标准的放行要求。变更通知和更新的已执行批次记录的提交。
Stability testing: First production batch on long-term stability reported in annual report.稳定性测试：年度报告中报告的第一批长期稳定性生产。
ii.In Vitro Release d0cumentation体外释放文件
None.不需要
iii.In Vivo Bioequivalence d0cumentation体内生物等效文件
None.不需要
c.Filing d0cumentation
Annual report (all information including long-term stability data).年度报告（包括长期稳定性数据在内的所有信息）。
2.Level 2 Change二级变更
a.Definition of Level定义
Change in equipment to a different design or different operating principles. Change in type of mixing equipment, such as high shear to low shear and vice versa.将设备变更为不同的设计或不同的操作原理。混合设备类型变化，如高剪切到低剪切，反之亦然。
b.Test d0cumentation测试文件
i.Chemistry d0cumentation化学文件
Application/compendial product release requirements. Notification of change and submission of updated executed batch records符合申报资料/药典标准的放行要求。变更通知和提交更新的已执行批次记录
Significant body of information available: One batch with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first production batch reported in annual report.可获得Significant body of information：在CBE报告补充一批三个月的加速稳定性数据，在年度报告中报告第一批生产批的长期稳定性数据。
Significant body of information not available: Three batches with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first three production batches reported in annual report.不可获得Significant body of information：年度报告中报告三个月加速稳定性数据的三个批次的CBE补充和前三个生产批次的长期稳定性数据。
ii.In Vitro Release d0cumentation体外释放文件
The in vitro release rate of a lot of the dosage form prepared in new equipment should be compared with the release rate of a recent lot of comparable age of the product prepared using original equipment. The median in vitro release rates (as estimated by the estimated slope from each cell, see section VII) of the two formulations should be demonstrated to be within acceptable limits, using the testing procedure described in section VII (IN VITRO RELEASE TEST) below.在新设备中制备的批次的体外释放率应与使用原始设备制备的最近一批可比效期的产品的释放率进行比较。应使用以下第VII节（体外释放试验）中所述的试验程序，证明两种制剂的中位体外释放率（通过每个扩散池的斜率估计，见第VII节）在可接受的限度内。
iii.In Vivo Bioequivalence d0cumentation体内生物等效文件
None.不需要
c.Filing d0cumentation灌装文件
Changes being effected supplement (all information including accelerated stability data); annual report (long-term stability data).
CBE补充（包括加速稳定性数据在内的所有信息）；年度报告（长期稳定性数据）。
3.Level 3 Change
No level 3 changes are anticipated in this category.预计这一类别不会发生3级变化。
B.Process工艺
1.Level 1 Change一级变更
a.Definition of Level定义
Process changes, including changes such as rate of mixing, mixing times, operating speeds, and holding times within approved application ranges. Also, order of addition of components (excluding actives) to either oil or water phase.工艺变化，包括在批准的应用范围内的混合速率、混合时间、操作速度和保持时间等变化。此外，也包括油相或水相中成分（不包括活性物质）的添加顺序。
b.Test d0cumentation测试文件
i.Chemistry d0cumentation化学文件
None beyond application/compendial product release requirements.没有超出符合申报资料/药典标准的放行要求。
ii.In Vitro Release d0cumentation体外释放文件
None.不需要
iii.In Vivo Bioequivalence d0cumentation体内生物等效文件
None.不需要
c.Filing d0cumentation灌装文件
Annual report年度报告
2.Level 2 Change二级变更
a.Definition of Level定义
Process changes, including changes such as rate of mixing, mixing times, rate of cooling, operating speeds, and holding times outside approved application ranges for all dosage forms. Also, any changes in the process of combining the phases.工艺变化，包括混合速率、混合时间、冷却速率、操作速度和保持时间等超出所有剂型批准应用范围的变化。此外，合并阶段过程中的任何变化。
b.Test d0cumentation测试文件
i.Chemistry d0cumentation化学文件
Application/compendial product release requirements. Notification of change and submission of updated executed batch records.符合申报资料/药典标准的放行要求。变更通知和提交更新的已执行批次记录。
Significant body of information available: One batch with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first production batch reported in annual report.可获得Significant body of information：在CBE补充中报告一批三个月的加速稳定性数据，在年度报告中报告第一批生产批的长期稳定性数据。
Significant body of information not available: Three batches with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first three production batches reported in annual report.不可获得Significant body of information：年度报告中报告了三个月加速稳定性数据的三个批次的CBE补充和前三个生产批次的长期稳定性数据。
ii.In Vitro Release d0cumentation体外释放文件
The in vitro release rate of a lot of the dosage form prepared by the new/modified process should be compared with the in vitro release rate of a recent lot of comparable age of the dosage form prepared by the prechange process. The median in vitro release rates (as estimated by the estimated slope from each cell, see VII) of the lots prepared by the two processes should be demonstrated to be within acceptable limits, using the testing procedure described in section VII (IN VITRO RELEASE TEST) below.通过新的/改良的工艺制备的批次剂型的体外释放率应与变更前工艺制备的最近生产的可比效期的批次的体外释放速率进行比较。应使用以下第VII节（体外释放试验）中所述的试验程序，证明通过两种工艺制备的批次的体外释放率中位数（通过每个扩散池的斜率估计，见VII）在可接受的限度内。
iii.In Vivo Bioequivalence d0cumentation体内生物等效性文件
None.不需要
c.Filing d0cumentation灌装文件
Changes being effected supplement (all information including accelerated stability data); annual report (long-term stability data).CBE补充（包括加速稳定性数据在内的所有信息）；年度报告（长期稳定性数据）。
3.Level 3 Change三级变更
No level 3 changes are anticipated in this category.预计这一类别不会发生3级变化。
This guidance recommends that the minimum batch size for the NDA pivotal clinical trial batch or the ANDA/AADA biobatch be at least 100 kg or 10% of a production batch, whichever is larger. Deviations from this recommendation should be discussed with the appropriate agency review division. All scale changes should be properly validated and may be inspected by appropriate agency personnel.本指南建议NDA关键临床试验批次或ANDA/AADA生物批次的最小批量至少为100 kg或生产批次的10%，以较大者为准。与本建议的偏差应与相应的机构审查部门进行讨论。所有规模变化都应经过适当验证，并可由适当的机构人员进行检查。
A.Level 1 Change一级变更
1.Definition of Level定义
Change in batch size, up to and including a factor of ten times the size of the pivotal clinical trial/biobatch, where: (1) the equipment used to produce the test batch(es) are of the same design and operating principles; (2) the batch(es) is manufactured in full compliance with cGMPs; and (3) the same standard operating procedures (SOPs) and controls, as well as the same formulation and manufacturing procedures, are used on the test batch(es) and on the full-scale production batch(es).批次大小的变化，最大为关键临床试验/生物批次大小的十倍，其中：（1）用于生产试验批次的设备具有相同的设计和操作原理；（2） 该批次的生产完全符合cGMP；以及（3）在试验批次和全量生产批次上使用相同的标准操作程序和控制，以及相同的配方和制造程序。
2.Test d0cumentation
a.Chemistry d0cumentation化学文件
Application/compendial product release requirements. Notification of change and submission of updated executed batch records in annual report. Stability testing: First production batch on long-term stability reported in annual report.符合申报资料/药典标准的放行要求。变更通知和年度报告中提交更新的已执行批次记录。稳定性测试：年度报告中报告的第一批长期稳定性生产。
b.In Vitro Release d0cumentation体外释放文件
None.不需要
c.In Vivo Bioequivalence d0cumentation体内生物等效文件
None.不需要
3.Filing d0cumentation灌装文件
Annual report (all information including long-term stability data)年度报告（包括长期稳定性数据在内的所有信息）
B.Level 2 Change二级变更
1.Definition of Level定义
Changes in batch size from beyond a factor of ten times the size of the pivotal clinical trial/biobatch, where: (1) the equipment used to produce the test batch(es) are of the same design and operating principles; (2) the batch(es) is manufactured in full compliance with cGMPs; and (3) the same standard operating procedures (SOPs) and controls, as well as the same formulation and manufacturing procedures, are used on the test batch(es) and on the full-scale production batch(es).批次大小的变化超过关键临床试验/生物批次大小的十倍，其中：（1）用于生产试验批次的设备具有相同的设计和操作原理；（2） 该批次的生产完全符合cGMP；以及（3）在试验批次和全量生产批次上使用相同的标准操作程序和控制，以及相同的配方和制造程序。
2.Test d0cumentation测试文件
a.Chemistry d0cumentation化学文件
Application/compendial product release requirements. Notification of change and submission of updated executed batch records.符合申报资料/药典标准的放行要求。变更通知和提交更新的已执行批次的记录。
Stability testing: One batch with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first production batch reported in annual report稳定性测试：在CBE补充中报告一批三个月的加速稳定性数据，在年度报告中报告第一批生产的长期稳定性数据
b.In Vitro Release d0cumentation体外释放文件
The in vitro release rate of a lot of the scaled-up batch should be compared with the in vitro release rate of a recent lot, of comparable age, of the prechange scale. The median in vitro release rates (as estimated by the estimated slope from each cell, see section VII) of the lots of the two scales should be demonstrated to be within acceptable limits, using the testing procedure described in section VII (IN VITRO RELEASE TEST) below.应将一批放大批次的体外释放率与最近一批具有可比效期的变化前的产品的体外释放速率进行比较。应使用以下第VII节（体外释放试验）中所述的试验程序，证明两种量表批次的体外释放率中位数（通过每个扩散池的斜率评估，见第VII节）在可接受的范围内。
c.In Vivo Bioequivalence d0cumentation体内生物等效文件
None.不需要
3.Filing d0cumentation
Changes being effected supplement (all information including accelerated stability data); annual report (long-term stability data)CBE补充（包括加速稳定性数据在内的所有信息）；年度报告（长期稳定性数据）
C.Level 3 Change三级变更
No level 3 changes are anticipated in this category.预计这一类别不会发生3级变化。
I.MANUFACTURING SITE制造场所
Manufacturing site changes consist of changes in location in the site of manufacture, packaging/filling operations, and/or testing for both company owned and contract manufacturing facilities and do not include any other level 2 or 3 changes, e.g., changes in scale, manufacturing (including process and/or equipment), and components or composition. New manufacturing locations should have had a satisfactory cGMP inspection within the past two years.制造现场变更包括公司自身和协议制造商的制造现场位置、包装/灌装操作和/或测试的变更，不包括任何其他2级或3级变更，例如规模、制造（包括工艺和/或设备）以及组件或组成的变更。新的生产地点应该在过去两年内通过了令人满意的cGMP检查。
A stand-alone analytical testing laboratory site change may be submitted as a changes being effected supplement if the new facility has a current and satisfactory cGMP compliance profile with FDA for the type of testing operation in question. The supplement should contain a commitment to use the same test methods employed in the approved application, written certification from the testing laboratory stating that they are in conformance with cGMPs, and a full descr1ption of the testing to be performed by the testing lab. If the facility has not received a satisfactory cGMP inspection for the type of testing involved, a prior approval supplement is recommended. No stability data are needed for a change in a stand alone analytical facility.如果新检测实验相关检测操作具有令人满意的cGMP合规性，达到FDA要求，则可提交独立分析检测实验室场地变更，作为CBE补充。补充文件应包含使用批准申请中使用的相同测试方法的承诺、测试实验室的书面证明，说明这些方法符合cGMP，以及测试实验室将进行的测试的完整描述。如果实验室未收到令人满意的cGMP检查，建议进行prior approval supplement。独立分析设施的变化不需要稳定性数据。
A.Level 1 Change一级变更
1.Definition of Level定义
Level 1 changes consist of site changes within a single facility where the same equipment, standard operating procedures (SOPs), environmental conditions (e.g., temperature and humidity) and controls, and personnel common to both manufacturing sites are used, and where no changes are made to the manufacturing batch records, except for administrative information and the location of the facility. Common is defined as employees already working on the campus who have suitable experience with the manufacturing process.一级变更包括单个设施内的现场变更，其中使用了相同的设备、标准操作程序（SOP）、环境条件（如温度和湿度）和控制装置，以及两个制造现场共用的人员，并且除了管理信息和设施位置外，不对制造批次记录进行任何变更。通常被定义为已经在工厂工作的员工，他们在制造过程中有适当的经验。
2.Test d0cumentation测试文件
a.Chemistry d0cumentation化学文件
None beyond application/compendial product release requirements.没有超出符合申报资料/药典标准的放行要求。
b.In Vitro Release d0cumentation体外释放文件
None.不需要
c.In Vivo Bioequivalence d0cumentation体内生物等效文件
None.不需要
3.Filing d0cumentation灌装文件
Annual report.年度报告
B.Level 2 Change二级变更
1.Definition of Level定义
Level 2 changes consist of site changes within a contiguous campus, or between facilities in adjacent city blocks, where similar equipment, standard operating procedures, (SOPs), environmental conditions (e.g., temperature and humidity) and controls, and personnel common to both manufacturing sites are used, and where no changes are made to the manufacturing batch records, except for administrative information and the location of the facility.
2级变更包括相邻园区内或相邻城市街区设施之间的现场变更，使用类似的设备、标准操作程序（SOP）、环境条件（如温度和湿度）和控制措施，以及两个制造现场共用的人员，并且不更改制造批记录，除了管理信息和设施的位置。
2.Test d0cumentation测试文件
a.Chemistry d0cumentation化学文件
Location of new site and updated executed batch records. None beyond application/compendial product release requirements.新设施的位置和更新的已执行批次记录。没有超出符合申报资料/药典标准的放行要求。
Stability testing: First production batch on long-term stability reported in annual report.稳定性测试：年度报告中报告的第一批长期稳定性生产。
b.In Vitro Release d0cumentation体外释放文件
None.不需要
c.In Vivo Bioequivalence d0cumentation体内生物等效文件
None.不需要
3.Filing d0cumentation灌装文件
Changes being effected supplement; annual report (long-term stability data).CBE补充；年度报告（长期稳定性数据）。
C.Level 3 Change三级变更
1.Definition of Level定义
Level 3 changes consist of a site change in manufacturing site to a different campus. A different campus is defined as one that is not on the same original contiguous site or where the facilities are not in adjacent city blocks. To qualify as a Level 3 change, similar equipment, SOPs, environmental conditions, and controls should be used in the manufacturing process at the new site. Changes should not be made to the manufacturing batch records except when consistent with other level 1 changes. Administrative information, location, and language translation may be revised as needed.
第3级变更包括将生产现场变更为不同的园区。不同的园区被定义为不在同一原始相邻场地上，或者设施不在相邻的城市街区。为了符合3级变更的资格，在新工厂的制造过程中应使用类似的设备、SOP、环境条件和控制措施。除非与其他1级更改一致，否则不应对生产批次记录进行更改。行政信息、地点和语言翻译可能会根据需要进行修订。
Any change to a new contract manufacturer also constitutes a level 3 change.对新协议制造商的任何变更也构成3级变更。
2.Test d0cumentation测试文件
a.Chemistry d0cumentation化学文件
Location of new site and updated executed batch records.新设施的位置和更新的已执行批次记录。
Application/compendial product release requirements.符合申报资料/药典标准的放行要求。
Significant body of information available: One batch with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first three production batches reported in annual report可获得Significant body of information：年度报告中报告的一批具有三个月加速稳定性数据的CBE补充和前三个生产批次的长期稳定性数据
Significant body of information not available: Three batches with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first three production batches reported in annual report.不可获得Significant body of information：年度报告中报告三个月加速稳定性数据的三个批次的CBE补充和前三个生产批次的长期稳定性数据。
b.In Vitro Release d0cumentation体外释放文件
The in vitro release rate of a lot of the dosage form from the new manufacturing site should be compared with the in vitro release rate of a recent lot of comparable age of the dosage form manufactured at the prior site. The median in vitro release rates (as estimated by the estimated slope from each cell, see section VII) of the lots from the two sites should be demonstrated to be within acceptable limits, using the testing procedure described in section VII (IN VITRO RELEASE TEST) below.从新的生产地点的批次体外释放速率应与在先前生产地点最近生产的可比效期的批次的体外释放率进行比较。应使用以下第VII节（体外释放试验）中所述的试验程序，证明两个部位批次的体外释放率中位数（通过每个扩散池的斜率评估，见第VII节）在可接受的范围内。
c.In Vivo Bioequivalence d0cumentation体内生物等效文件
None.不需要
3.Filing d0cumentation灌装文件
Changes being effected supplement (all information including accelerated stability data); annual report (long-term stability data).CBE补充（包括加速稳定性数据在内的所有信息）；年度报告（长期稳定性数据）。
原文内容已经过时，建议参考最新的《In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs Guidance for Industry》（超链接）
The design of in vivo bioequivalence studies for semisolid dosage forms varies depending on the pharmacological activity of the drug and dosage form. A brief general discussion of such tests follows.半固体剂型的体内生物等效性研究的设计因药物和剂型的药理活性而异。以下是对此类试验的简要概述。
Objective:目标
To d0cument the bioequivalence of the drug product for which the manufacture has been changed, as defined in this guidance, compared to the drug product manufactured prior to the change or compared to the reference listed drug (RLD).记录本指南中定义的变更生产的药品与变更前生产的药品相比或与参比药物（RLD）相比的生物等效性。
Design:设计
The study design is dependent on the nature of the active drug. The bioequivalence study can be a comparative skin blanching study as in glucocorticoids (FDA, Topical Dermatological Corticosteroids: In Vivo Bioequivalence, June 2, 1995.) or a comparative clinical trial or any other appropriate validated bioequivalence study (e.g., dermatopharmacokinetic study) for the topical dermatological drug product.研究设计取决于活性药物的性质。生物等效性研究可以是与糖皮质激素类似的比较性皮肤漂白研究（美国食品药品监督管理局，局部皮肤科皮质类固醇：体内生物等效性，1995年6月2日）。
Analytical Method:分析方法
The assay methodology selected should ensure specificity, accuracy, interday and intraday precision, linearity of standard curves, and adequate sensitivity, recovery, and stability of the samples under the storage and handling conditions associated with the analytical method.
所选的分析方法应确保样品在与分析方法相关的储存和处理条件下的特异性、准确性、日间和日间精密度、标准曲线的线性以及足够的灵敏度、回收率和稳定性。
GLOSSARY OF TERMS术语表
Approved Target Composition: The components and amount of each ingredient for a drug product used in an approved pivotal clinical study or bioequivalence study.
Batch: A specific quantity of a drug or other material produced according to a single manufacturing order during the same cycle of manufacture and intended to have uniform character and quality, within specified limits. (21 CFR 210.3(b)(2)).
Contiguous Campus: Contiguous or unbroken site or a set of buildings in adjacent city blocks.
Creams/Lotions: Semisolid emulsions that contain fully dissolved or suspended drug substances for external application. Lotions are generally of lower viscosity.
Diluent: A vehicle in a pharmaceutical formulation commonly used for making up volume and/or weight (e.g., water, paraffin base).
Drug Product: A drug product is a finished dosage form (e.g., cream, gel, or ointment) in its marketed package. It also can be a finished dosage form (e.g., tablet, capsule, or solution) that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3(b)).
Drug Release: The disassociation of a drug from its formulation thereby allowing the drug to be distributed into the skin or be absorbed into the body where it may exert its pharmacological effect
Drug Substance: An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient (21 CFR 314.3(b))
Emulsion: Emulsions are two phase systems in which an immiscible liquid (dispersed phase) is dispersed throughout another liquid (continuous phase or external phase) as small droplets. Where oil is the dispersed phase and an aqueous solution is the continuous phase, the system is designated as an oil-in-water emulsion. Conversely, where water or an aqueous solution is the dispersed phase and oil or oleaginous material is the continuous phase, the system is designated as a water-in-oil emulsion. Emulsions are stabilized by emulsifying agents that prevent coalescence, the merging of small droplets into larger droplets and, ultimately, into a single separated phase. Emulsifying agents (surfactants) do this by concentration in the interface between the droplet and external phase and by providing a physical barrier around the particle to coalesce. Surfactants also reduce the interfacial tension between the phases, thus increasing the ease of emulsification upon mixing. Emulsifying agents substantially prevent or delay the time needed for emulsion droplets to coalesce. Emulsification is the act of forming an emulsion. Emulsification can involve the incorporation of a liquid within another liquid to form an emulsion or a gas in a liquid to form a foam
Formulation: A listing of the ingredients and quantitative composition of the dosage form.
Gel: A semisolid system in which a liquid phase is constrained within a three dimensional, crosslinked matrix. The drug substance may be either dissolved or suspended within the liquid phase
Homogenization: A method of atomization and thereby emulsification of one liquid in another in which the liquids are pressed between a finely ground valve and seat under high pressure (e.g., up to 5,000 psi).
Internal phase: The internal phase or the dispersed phase of an emulsion comprises the droplets that are found in the emulsion.
In Vitro Release Rate: Rate of release of the active drug from its formulation, generally expressed as amount/unit area/time 0.5.
Ointment: An unctuous semisolid for topical application. Typical ointments are based on petrolatum. An ointment does not contain sufficient water to separate into a second phase at room temperature. Water soluble ointments may be formulated with polyethylene glycol.
Pilot Scale Batch: The manufacture of drug product by a procedure fully representative of and simulating that intended to be used for full manufacturing scale.
Preservative: An agent that prevents or inhibits microbial growth in a formulation to which it has been added.
Process: A series of operations, actions and controls used to manufacture a drug product.
Scale-up: The process of increasing the batch size
Scale-down: The process of decreasing the batch size.
Shear: A strain resulting from applied forces that cause or tend to cause contiguous parts of a body to slide relative to one another in direction parallel to their plane of contact. In emulsification and suspensions, the strain produced upon passing a system through a homogenizer or other milling device.
Low shear: Processing in which the strain produced through mixing and/or emulsifying shear is modest.
High shear: Forceful processes which, at point of mixing or emulsification place a great strain on the product. Homogenization, by its very nature, is a high shear process which leads to a small and relatively uniform emulsion droplet size. Depending on their operation, mills and mixers are categorized as either high shear or low shear devices.
Significant Body of Information: A significant body of information on the stability of the product is likely to exist after five years of commercial experience for new molecular entities , or three years of commercial experience for new dosage forms.
Structure Forming Excipient: An excipient which participates in the formation of the structural matrix which gives an ointment, cream or gel etc., its semisolid character. Examples are gel forming polymers, petrolatum, certain colloidal inorganic solids (e.g., bentonite), waxy solids (e.g., cetyl alcohol, stearic acid), and emulsifiers used in creams.
Strength: Strength is the concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or the potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard) (21 CFR 210.3(b)(16)). For semisolid dosage forms the strength is usually stated as a weight/weight (w/w) or weight/volume (w/v) percentage.
Suspending agent: An excipient added to a suspension to control the rate of sedimentation of the active ingredients.
Technical grade: Technical grades of excipients differ in their specifications and intended use. Technical grades may differ in: (1) specifications and/or functionality, (2) impurities, and (3) impurity profiles.
Validation: A procedure to establish d0cumented evidence that provides a high degree of assurance that a specific process or test will consistently produce a product or test outcome meeting its predetermined specifications and quality attributes. A validated manufacturing process or test is one that has been proven to do what it purports or is represented to do. The proof of process validation is obtained through collection and eva1uation of data, preferably beginning with the process development phase and continuing through the production phase. Process validation necessarily includes process qualification (the qualification of materials, equipment, systems, building, personnel), but it also includes the control of the entire processes for repeated batches or runs.
参考文献：《GUIDANCE FOR INDUSTRY Nonsterile Semisolid Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence d0cumentation SUPAC-SS》
GuidanceforIndustry NonsterileSemisolidDosageForms Scale UpandPostapprovalChanges Chemistry,Manufacturing,andControls InVitroReleaseTestingandInVivo Bioequivalenced0cumentation.pdf
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