SUPAC-IR 问答-1

beiwei5du

节选自CDE

COMPONENT AND COMPOSITION CHANGES

1.    Q: May one color be replaced with another by placing the batch on concurrent stability and reporting it in the annual report?

1.  问题： 能否通过将该批号放在当前的稳定性研究中，并在年度报告中报告

的做法将一种颜色以另一种颜色代替?

A: A change from one color to another should be submitted as a prior approval supplement.

回答：从一种颜色改为另一种颜色应当按Prior approval suppleme nt 申报

2.    Q: Can color be changed under SUPAC-IR?

2.  问题： 颜色能否按SUPAC-IR更改？

A: Yes. A change in color, either in amount or from one color to another, is a level 3 component and composition change which calls for a prior approval supplement. However, if the color is merely being removed, it is a level 1 change and can be reported in the next annual report.

回答： 可以。颜色的更改，不论是量的变化还是由一种颜色改为另一种颜色，都属于成分和组成的3 级变更，需要按Prior approval supplement 申报。但如果仅仅是去除颜色，则    属于1 级变更，可以在下一次年度报告中报告。

3.    Q: What is the full definition of a change in 'technical grade" of an excipient? Does this only mean a change in excipient specifications that may impact functionality or does it include a change in supplier even if all applicable specifications remain the same?

3.  问题：辅料“技术等级”变更的完整定义是什么？这是否仅仅指可影响功能的辅料的质量标准变更，或者所适用的质量标准都相同的情况下的供应商变更？

A: 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.

If a supplier of an excipient changes but its technical grade AND specifications remain the same, the agency should be notified in an annual report.

回答：辅料的技术等级因其质量标准和预定用途而异。不同技术等级在以下方面不同：

1)质量标准和/或功能;

2)杂质；

3)杂质谱。

如果辅料的供应商变更，而其技术等级和质量标准仍相同，则应当在年度报告中向FDA 通报。

4.    Q: How does one apply SUPAC-IR to multifunctional excipients, e.g., starch?

4.  问题： 多功能辅料（例如淀粉）怎样应用SUPAC-IR？

A: SUPAC-IR composition changes are based on being able to define the use or action of the particular excipient in the product. This rationale should be   included by the applicants as part of their original applications. Not all multifunctional excipients are listed in the guidance. However, if an excipient was utilized to provide multiple functions such as pregelatinized starch as a filler, starch as a disintegrant, starch paste as a binder, then the most conservative recommended change should be followed (e.g., for an excipient that is a filler, disintegrant and binder, the recommended limit for a Level 2 change is " 0.5 percent, see page 7, SUPAC-IR). An applicant may wish to add an explanation of how the change will affect other functions of the excipient in the product. If this information was not included in the original application, the review division should be consulted before filing such a SUPAC change, either through a CBE or annual report.

回答： SUPAC-IR 组成变更的依据是能够确定产品中特定辅料的使用或作用。初次申报资料中，申请人应当提供这一依据。指导原则中没有列出所有的多功能辅料。但如果一个辅料被用来提供多种功能，如预胶化淀粉作为充填剂，淀粉作为崩解剂，淀粉糊作为粘合剂，则应当按照最保守的推荐变更（例如对于作为充填剂、崩解剂和粘合剂的辅料，推荐的2 级变更的限度为0.5%，见SUPAC-IR第7页）。申请人可能希望增加说明材料，解释这些变更对产品中该辅料的其他功能有何影响。如果初次申报资料中不包含这一信息，在通过CBE 或年度报告申报这一SUPAC 变更前，应当先向评审部门咨询。

5.    Q: What is the reference source for defining the action of an inactive ingredient, for example, lubricant versus glidant? What if the action is defined differently in two sources?

5. 问题： 界定一个非活性成分的作用，例如是润滑剂还是助流剂作用的参考文

献是什么?如果两份参考文献中界定的作用不同应当怎么办?

A: An applicant should be able to justify the choice and the basis for the selection of a particular excipient, i.e., its expected function in the drug product. It may be useful to cite a source. The action may depend on the specific product.

回答：申请人应当能提供选择某一特定辅料的理由和依据，例如其在药品中的预期功能。引用参考文献可能有帮助。其作用可能取决于具体的产品。

6.    Q: Does SUPAC-IR cover changes in granulating solution volume outside the range in an application?

6. 问题： SUPAC-IR 是否适用于制粒溶液体积超过申报范围的变更?

A: Changes in granulating solution volume are not covered under SUPAC-IR. Minor changes are considered as normal operating procedure and should be included in the executed batch record. However, if this represents a permanent change, such a change may be described in the annual report along with the data to justify that the formulation quality and performance (i.e., drug product is within the approved specifications) was not altered.

回答： SUPAC-IR不适用于制粒溶液体积的变更。微小变化可认为是正常的操作步骤，应当包括在实际批记录中。但如果这代表着永久的变更，则这一变更应当在年度报告中加以说明，并提供相应数据，证明该配方的质量和性能没有变化（即药品在批准的质量标准范围内）

7.    Q: To what category does a change in granulation solvent in a wet granulation process belong?

7.问题：湿法制粒工艺中制粒溶剂的变更属于哪一类?

A: A change in granulating solvent (e.g., alcohol to water) would alter the composition of the drug product, both qualitatively and quantitatively, even though it may be removed during manufacture of the drug product. Because such a change may have significant impact on formulation quality and performance, it is a level 3 composition change that needs a prior approval supplement.

回答：制粒溶剂的变更（例如将酒精改为水），即使在药品生产过程中可能会将其去除，也会从质和量上改变药品的组成。由于这一变更可能对配方的质量和性能有显著影响，因此属于3 级成分变更，即Prior approval supplement。

8.    Q: The NDA includes validated/approved ranges for excipients in the formulation. We would like to move the target formula amount of one of the fillers to the upper value in the range. Will this be a level 1 change in composition?

8.问题：NDA包含了该配方中辅料经过验证的/批准的范围。我们想把一种填充剂的目标配方量改为范围中的上限值。这是否属于药品成分的1级变更？

A: All changes are predicated on the target approved in the original application or through a prior approval supplement for a formulation change. For products approved with only a range for an excipient, the target may be assumed to be the mid-point of the approved range. If the new target is within the validated range, the change will be a level 1 or 2 change depending on the specific excipient changed and the percent change (see the SUPAC-IR guidance document). The target originally approved remains the target of record; i.e., Level 1 or Level 2 component changes made under SUPAC- IR do not change the target. If the new target is not within the validated range, the proposed target will need a prior approval supplement.

回答： 所有变更是根据初次申报批准的目标来预测，或通过Prior approval supplement 申报该配方变更。对于辅料只批准在某个范围内的产品，可以将目标假定为批准范围的中值。如果新的目标在经过验证的范围内，则这一变更为1 级或2 级变更，具体取决于变更的特定辅料和其百分比变化（见SUPAC-IR指导原则文件）。最初批准的目标仍为备案的目标，即按SUPAC- IR进行的 1级或2 级成分变更不改变目标值。如果新的目标不在已验证的范围内，则新提出的目标要通过Prior approval supplement 申报。

9.    Q: When microcrystalline cellulose is increased by 5%, the tablet weight increases. Can this still be a level 1 change?

9.问题：当微晶纤维素增加5%时，片剂的重量增加。这是否仍属于1 级变更?

A: After the SUPAC-IR change, if the new target weight is still within the range in the approved original application, it is a level 1 change. Otherwise, it is a Level 2 or 3 change, both of which are to be submitted as a prior approval supplement.

回答： SUPAC-IR 变更后，如果新的目标重量仍在批准的最初申报的范围内，则它属于1 级变更。否则，属于2 级或3 级变更，二者均为Prior approval supplement。

10. Q: If one component in a formulation is decreased, must another be increased so that the final weight can remain the same?

10.问题：如果配方中一种成分减少，另一种成分是否必须增加以保持最终的重量仍不变?

A: No. The amount of a single component in the formulation may be changed independent of any other changes. (See 9 above)

回答：否。配方中单个成分的量可以独立变化，而不受其他变化的影响(见问题9)

11. Q: It is my understanding that the development report should cover ranges of processing parameters. Further, the validation report should cover the target parameters for production. If this is true, when level 1 changes are made, how can the validation cover ranges? For future validation reports, is it acceptable to vary processing parameters to prepare for future SUPAC changes?

11.问题： 我的理解是研发报告应当包含工艺参数的范围。而且，验证报告应当包含生产的目标参数。如果是这样，当进行1 级变更时，如何使验证能涵盖各参数的范围？对于将来的验证报告，能否改变工艺参数以备将来的SUPAC 变更？

A: The validation report should cover the target production parameters; however, it is not restricted to these only. If a range is specific, it needs to be validated. This can involve manufacturing batches of product at the extremes of the desired range(s), with appropriate testing to assure that the extreme range batches continue to meet all quality attributes, including dissolution and possibly in vivo bioequivalence tests. For future validation reports, it is acceptable to vary processing parameters. However, it should be understood that the Center's chemists do not review validation data collected by applicants, post-approval, on the first three production batches, because such information is checked by the Field investigators as part of the cGMP requirements. Thus, a summary of validation data on the test (bioavailability/bioequivalence) batch(es) submitted in the original application for approval is the basis for setting acceptable ranges of processing parameters for manufacture of the IR dosage form. These data may include parameters such as mixing time, mixing speed, and blend assays. Thus, for future level 1 SUPAC-IR changes, applicants should use the approved validation ranges as described in the application.

回答：验证报告应涵盖目标生产参数；但它不仅仅限于这些。如果是一个特定的范围，则它需要验证。如果有合适的检验确保范围极端值的生产批次仍符合所有的质量属性，包括溶出度及可能的体内生物等效性试验，在理想范围的极端值时的产品生产批次也可以包含。对于将来的验证报告，改变工艺参数是可以接受的。但需要意识到CDER的化学家们不会审查由申办者在批准后收集的最初3 个生产批次的验证数据，因为这些信息由现场检查者作为 cGMP要求的一部分进行审查。因此，最初申请中申报的检验（生物利用度/生物等效性）批次的验证数据总结，是设定普通剂型的生产工艺参数可接受范围的基础。这些数据可以包括混合时间、混合速度和混合含量测定等参数。因此对于将来的1 级SUPAC-IR变更，申请人应当使用申报中所述的经批准的验证范围。

12. Q: What is the guidance to determine if a new drug falls into the category of narrow therapeutic range?

12.问题：确定一种新药是否属于治疗窗窄的药物类别，其指导原则是什么?

A: Appendix A of the SUPAC-IR guidance lists a number of such drugs. In addition, 21 CFR 320.33 describes how to determine if a drug falls into this category.

回答： SUPAC-IR 指导原则的附录A 列出了许多这样的药物。此外，21 CFR 320.338描述了如何确定一种药物是否属于这一类别。

13. Q: Is a change in gelatin capsule size considered a SUPAC-IR component and composition change?

13.问题：明胶胶囊大小的变更是否为SUPAC-IR成分和组成的变更?

A: Issues related to empty gelatin capsules are not covered in the SUPAC-IR guidance. Only the component categories discussed in the document are covered. Changes for other components should be submitted in accordance with the provisions of 21 CFR 314.70.

回答：SUPAC-IR指导原则不适用于空明胶胶囊相关的问题，仅涉及该文件中讨论的成分分类。其他成分的变更应当按照21 CFR 314.70.的规定申报。

14. Q: When making a component or composition change according to SUPAC-IR, and the approved application has a range and target for a specific component, does the range move when the target changes?

14.问题：当按照SUPAC-IR进行成分或组成变更且批准的申请中有具体成分的范围和目标时，如果目标发生变化，范围是否移动？

A: No. The range remains the same even when the target changes. Such changes are predicated on the target approved in the original application or through prior approval supplement for a formulation change. Changes to the approved range should be made by prior approval supplements in accordance with the provisions of 21 CFR 314.70.

回答：否。即使目标发生变化，范围仍保持不变。这些变更由最初申请中批准的目标预测，对于处方变更，通过Prior approval supplement 申报。已批准范围的变更，应当按照21 CFR 314.70.的规定按Prior approval supplement 申报。

15. Q: Are wetting agents covered under SUPAC-IR?

15.问题： SUPAC-IR是否适用于润湿剂?

A: No. Only components included in categories spelled out in the guidance qualify as SUPAC-IR changes. Thus, wetting agents are not covered.

回答：否。仅指导原则中指出的类别中包含的成分才可属于SUPAC-IR变更。因此润湿剂不在此列。

16. Q: Can inks be changed under SUPAC-IR? If so, how?

16. 问题：按照 SUPAC-IR油墨能否更改?如果能，应当如何更改?

A: If the new ink has been used in other approved products the change is allowed under SUPAC-IR as a level 1 change. Alternatively, if all of the components of the ink have been used in approved drug products, the switch also can be made under SUPAC-IR. A justification should be given; reference should be made to the approved product(s) where the ink and/or the components are already used.

回答： 如果新的油墨在其他批准的产品中使用过，允许根据SUPAC-IR 按1 级变更处理。或者，如果油墨的所有成分已经用于已批准的药品，则也可以按照SUPAC-IR进行转换。应当说明理由；应当指出有哪些批准的产品已经使用这些油墨和/或成分。回答：如果新的油墨在其他批准的产品中使用过，允许根据SUPAC-IR 按1 级变更处理。

17. Q: Can inks be eliminated under SUPAC-IR?

17. 问题： 能否按SUPAC-IR去除油墨?

A: Ink can be eliminated as a level 1 change.

回答： 去除油墨可以按照1 级变更处理。

beiwei5du

1、为什么颜色的变化以及着色剂的量的变化被定义level3并做prior approval supplement???level 3的举例中并未提及颜色变化的变更，同时level 1中有如下举例：
“a. Deletion or partial deletion of an ingredient intended to affectthe color or flavor of the drug product; or change in the ingredient of the printing ink to another approved ingredient.”；同时为什么删除着色剂（去除颜色）则被定义为level 1并在年报中体现即可？？？
2、第四个问题中“ the recommended limit for a Level 2 change is " 0.5 percent, see page 7, SUPAC-IR)”应该修改为“ the recommended limit for a Level 1 change is " 0.5 percent, see page 7, SUPAC-IR)”吧？？？
3、第八个问题中“All changes are predicated on the target approved in the original application”的翻译“所有变更是根据初次申报批准的目标来预测”是否修改为“所有的变更应基于初次申请中批准的目标值”？？？
4、第十一个问题如何理解？？？“因此，最初申请中申报的检验（生物利用度/生物等效性）批次的验证数据总结，是设定普通剂型的生产工艺参数可接受范围的基础。这些数据可以包括混合时间、混合速度和混合含量测定等参数。”
5、第十二个问题中“In addition, 21 CFR 320.338 describes how to determine if a drug falls into this category.”的21 CFR 320.338是否应修改为“21 CFR 320.33”
@hongwei2000

syhorchid

谢谢分享

工作QQ

supac是个什么鬼？

beiwei5du

工作QQ 发表于 2017-8-13 09:46
supac是个什么鬼？

放大和批准后变更

xqliu

学习一下啦，谢谢提供分享。

hongwei2000

beiwei5du 发表于 2017-8-12 06:29
1、为什么颜色的变化以及着色剂的量的变化被定义level3并做prior approval supplement???level 3的举例中并 ...

个人看法：
1、着色剂减少，危害不会增加；颜色变更，一般意味着变更了着色剂品种，安全性不好说，所以需要批准。
2、看Supac-IR原文吧
3、U R right，但更好的翻译应该是，所有变更的目标值，应基于首次批准的初始值。
4、IR的生产工艺参数应来源于首次批准时的检验和验证结果

小金库

感谢分享。