Guidance for Industry Changes to an Approved NDA or ANDA Q&A 中英

Guidance for

IndustryChanges to an ApprovedNDA or ANDAQuestions and Answers

目录REPORTING CATEGORIES报告类别..........................................................1GENERAL REQUIREMENTS一般要求........................................................2MANUFACTURING SITES生产地址...........................................................3MANUFACTURING PROCESS生产工艺.....................................................8SPECIFICATIONS规程..............................................................................12PACKAGE包装.........................................................................................13MISCELLANEOUS CHANGES多重变更....................................................15

Guidance for Industry1Changes to an Approved NDA or ANDAQuestions and AnswersThis guidance represents the Food and Drug Administration=s current thinking on this topic. It does

not create or confer any rights for or on any person and does not operate to bind FDA or the public.

An alternative approach may be used if such approach satisfies the requirements of the applicable

statutes and regulations.本指南代表FDA对此方面的最新定义，其并不对任何个人授权，也并不是为了约束个人和FDA而生效。如果您有其他方法能够满足现行法律、规程，您也可以采用。This document provides questions and answers relating to the guidance on Changes to

an Approved NDA or ANDA (the guidance).2

The questions are based on those posed

to CDER by applicants. The questions and answers are presented using subject

headings that correspond to the table of contents in the guidance.本文提供指南文件的常见问题及解答。常见问题来源于申请人向CDER提出的问题。常见问题及解答按照指南文件的目录顺序列表。REPORTING CATEGORIES报告类别Q1: For a change that is reported in a Supplement — Changes Being Effected in

30 Days, will CDER complete the review of the supplement within 30 Days?问1：对于按照30日内生效变更申请提交的报告，CDER是否能在30日内将增补文件审核完毕？A1: Within 30 days CDER will notify the applicant that prior approval is

required for the change (i.e., CDER has designated the supplement a prior

approval supplement) or that the FDA has determined appropriate information

is missing, including information that should have been developed by the

applicant in assessing the effects of the change. Supplement reviews will be

performed consistent with standard procedures. It is unlikely that a substantive

review and action letter will be completed within 30 days.答1:30日内，CDER确定增补应该按照批准前增补提交，将通知申请人该项事务；1

或者FDA判断应有的信息存在缺陷，包括申请人应当开展的变更影响评估报告，也会通知申请人。增补文件的审核时严格按照既定标准程序开展的，实质性的审核和通知函一般不可能在30日内就能完成。Q2: If information is missing from a Supplement — Changes Being Effected in 30

Days, will the reporting category be changed to a prior approval supplement?问2：若20日内生效变更信息缺失，该申请是否变更为优先批准变更增补？A2: No. If FDA informs the applicant within 30 days of receipt of the

Supplement — Changes Being Effected in 30 Days that information is missing,

the reporting category is not changed to a prior approval supplement. However,

distribution of the product made with the change must be delayed until the

supplement is amended with the missing information.答2：不会。即使FDA通知申请人该30日内生效变更申请信息有缺陷，也不会将其变更为优先批准变更增补文件类型。然而，变更后生产的产品必须在申请者将缺陷信息增补完毕后才能进行销售活动。Q3: A change (specified change) is planned. The guidance recommends that the

change be reported in a supplemental application. However, the data generated

indicate that this change does not adversely affect the identity, strength, quality,

purity, and potency of the product. Can this change be reported in an annual report?问3：企业做了变更计划。指南文件建议其变更用增补申请提交。而测试数据表明，该变更并不对产品性状、剂量、纯度及药效有不良影响。可否仅将该变更在年报中提交？A3: No. The recommended reporting category is based on the potential for the

change to adversely affect the identity, strength, quality, purity, or potency of

the drug product as these factors relate to the safety or effectiveness of the drug

product (see section 506A of the Federal Food, Drug, and Cosmetic Act (the

Act)). CDER expects that the majority of the data and information submitted to

support a supplemental change will, in the applicant’s judgment, demonstrate

that the change does not adversely affect the product. However, FDA will

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evaluate the completeness of the data and information and decide whether the

applicant’s conclusion (i.e., there is no adverse effect) is appropriate prior to

approving such a change.答3：不可以。指南文件对变更建议报告类型的分类，是建立在该变更是否对产品的性状、剂量、纯度及药效等与药物安全性、有效性相关的特性产生不良影响的可能性上的。CDER专家期待，从申请人的角度判断，所提供的支持变更的数据和信息是能够说明该变更对产品并无不良影响的。然而，FDA会评估数据的完整性，来判断申请人所提出的结论（即变更不造成不良影响）是否足够可靠，是否足够支持该变更申请。GENERAL REQUIREMENTS一般要求Q1: A manufacturing change is planned that can be reported in the annual report.

Should the data to support the change be included in the annual report?问1：若指南文件建议某一可报告的生产变更在年报中报告，是否支持该变更的数据及信息也该包括在年报中？A2: Yes. After the change is implemented, the information should be included

in the next annual report. Moreover, the information to support the change

must be generated prior to distributing the product made with the change

(506A(b)). As stated in section 506A(b) of the Act, “a drug made with a

manufacturing change (whether a major manufacturing change or otherwise)

may be distributed only if, before distribution of the drug as so made, the

holder involved validated the effects of the change on the identity, strength,

quality, purity, and potency of the drug as the identity, strength, quality, purity,

and potency may relate to the safety or effectiveness of the drug.”答2：是的。实施变更后，该变更及其支持信息必须包括在下一年报中。并且，变更后的产品也必须在支持变更信息发布之后才能销售。按照联邦食品药品及化妆品法506A（b）部分所述：生产变更（无论是否是重大生产变更）后生产的产品必须在申请者能够完全验证该变更对产品性状、剂量、质量、纯度和药效及其他可能与药品安全性、有效性相关的特性3

的影响后，才能进行销售。MANUFACTURING SITES生产地址Q1: Can a change in the manufacturing site for a drug substance that involves a

different company (i.e., change in source) be reported in a Supplement — Changes

Being Effected in 30 Days?问1：若原料药生产地址变更包含另一个不同的公司（如物料来源），可否在30日内生效变更增补文件中报告？A1: As stated in section VI.A of the guidance, “A move to a different

manufacturing site that involves other changes (e.g., process, equipment)

should be evaluated as a multiple related change (see section XII) to determine

the appropriate reporting category.” Typically, a change from one drug

substance manufacturer to another involves more than simply a site change. In

most cases, there will be additional differences (e.g., route of synthesis,

process, solvents, equipment). Without extensive knowledge of the new and

old sources (e.g., access to the drug master file), an applicant cannot

adequately describe the differences between the sources or evaluate the

multiple change. Therefore, when the applicant does not have extensive

knowledge to provide the information and evaluation, the drug substance site

change should be reported in a prior approval supplement. When an applicant

has the extensive knowledge to describe the differences between the sources,

the applicant can report the change as appropriate after evaluation as a multiple

change. If the change is not reported in a prior approval supplement, the

applicant should include a statement in the submission that the change involves

no changes that should be reported in a prior approval supplement. In either

case, a move to a drug substance manufacturing site should be reported in a

prior approval supplement when the site does not have a satisfactory current

good manufacturing practice (CGMP)) inspection (see guidance for details) for

the type of operation.4

答1：指南VI.A部分陈述：若生产地址变更到另一生产地址且包含其他变更（工艺，设备），应当按照多重变更提交报告。典型的例子就是将原料药生产地址变更到另一地点，且只包含地址的变化。但是大多数情况下，可能都会包含别的变更（如合成路线、工艺、溶剂、设备等变更）。若没有对新旧两个物料来源公司广泛的信息掌握（如DMF情况），申请者是无法充分的评估该多重变更的。因此，若申请者无法提供广泛的信息和评估，则该原料药生产地址变更应该按照优先批准变更报告。若申请人有很广泛的信息来源，足够描述两个物料来源的区别，则申请人能在进行适当的评估后按照多重变更提交报告。若变更不安优先批准变更提交，则在报告中申请人应当做出声明，声明泵本报告中不包含必须在优先批准变更提交的变更。同样，若变更后的生产地址该类生产操作没有合格的CGMP条件，则该变更也必须按照优先批准变更提交（细节见指南）。Q2: Should a change to a different site be reported when the change is for

fabrication of packaging components?问2：若包装组件的加工地点变更，需要按照生产地址变更提交报告吗？A2: Section VI.A of the guidance identifies the site changes that should be

reported to CDER. A move to a different site to manufacture or process drug

products should be reported. The guidance defines sites used to manufacture or

process drug products to include sites used by the applicant (applicant owned

or contractors) to prepare (e.g., sterilize, depyrogenate, irradiate, wash)

container closure systems or packaging components. A change to a different

site for fabricating packaging components (e.g., bottles) or manufacturing

packaging materials (e.g., resins) need not be reported if there is no other

change (e.g., dimensions, composition, specification, processing aids). If other

changes occur, the reporting category should be based on the recommended

reporting categories for the changes (i.e., the manufacturing site change should

not be considered when determining the appropriate reporting category).5

答2：指南VI.A部分声明，地质变化必须通知CDER。即，生产和加工地址的变化必须报告。而指南定义，申请人使用的生产或加工的地址包括申请者拥有（自己持有或承包）用来准备（灭菌，去热源，辐照灭菌，清晰）容器密封系统或包装组件的地址。加工包装组件（如瓶）或生产包装物料（如树脂）的地址变更若无其他变更（包装规模，物料组成，规格，加工助剂）则不需要报告。若发生其他变更，要根据变更的建议报告类别提交报告（考虑报告类别时不用考虑生产地址变更）。Q3: The guidance states that a move to a different site that results in a restart at the

new manufacturing site of a type of operation that has been discontinued for more

than twoyears should be reported in a prior approval supplement (section VI.B.1).

Two manufacturing sites were approved in the original application. Production at

one of the sites has not occurred in 5 years but is going to be restarted. Should this

restart be reported in a prior approval supplement?指南声明，若变更的生产地址该类生产操作已终止了两年以上，测该变更需要按照批准前增补提交。而原申请通过了两个生产地址，其中一个生产地址五年之内没有发生生产操作但即将发生。这个变更也应该按照批准前增补提交吗？A3: A restart of manufacturing at a site already approved in the application

need not be reported in the application as long as the restart does not involve

any other , equipment, process) that should be reported. If the

restart involves a site that is not approved in the application, a prior approval

supplement should be submitted.答3：已经通过的申请中的生产地址重新开始生产时，若不包括其他需要报告的变更（设备，工艺等），则不需要报告。若重新生产设计一个未被批准的生产地址，则申请人必须按照批准前增补提交。Q4: A packaging site will be added that will enclose two sample cartons, along with

some promotional material, into a larger carton or box preprinted with the product

name:

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·Does the information about the tertiary packaging site need to be submitted to

the agency? If yes, can CDER be notified in an annual report?·Is the tertiary site held to the same CGMP requirements as a secondary site?

For example, if a tertiary site should be submitted to the agency, and this site has

not had any CGMP inspection within the last two years, is this change still

annual reportable?问4：计划增加一个包装地址，此地将两个标准纸箱装入一个大的印有产品名称的纸箱中，同时装入部分宣传资料。·这个三级包装地址需要向CDER报告吗？若需要，可否按年报方式报告？·这个三级包装地址是否也要向二级包装地址一样满足同等CGMP要求？例如，若一个三级包装地址必须报告，并且2年内并无任何CGMP检查，这个变更是否依然可以在年报中报告？A4: The guidance only distinguishes between primary and secondary

packaging sites. The site described would be considered a secondary packaging

site. CGMP requirements extend beyond packaging and repackaging

operations that involve direct product contact. For example, a site must register

with FDA (21 CFR Part 207) and is subject to CGMP inspection (21 CFR Part

211) when the site is used to attach inserts, or in the case of a cartoning site,

when cartons contain product labels. If registration and/or inspection are

required for the site of this secondary packaging operation, CDER should be

notified of the different site (via the application). The site should have a

satisfactory inspection relating to packaging operations for notification to

occur in the annual report. For the purposes of this guidance, in general, there

is no two-year limit on the CGMP inspection (see Manufacturing Sites Q10). If

registration and inspection are not required for the site of this secondary

packaging operation, the applicant need not notify CDER of the site. If you

have any questions on whether this packaging operation is subject to FDA

registration or inspection, you should contact the appropriate CDER inspection

and/or compliance staff for advice.7

答4：指南只定义了内包和外包。问题中描述的应属于外包。只要是直接与产品接触的操作，无论是内包还是外包，都应满足CGMP要求。例如，若一个生产地址用来给产品加入说明书，或在纸箱包装中加入说明书，就必须在FDA注册（21CFR,207）并通过CGMP检查(21CFR,211)。若这个外包地址需要在FDA注册和/或需要检查，申请者应通知CDER。在年报中报告该变更时应对该包装进行合格性检查。一般来说，指南并未对CGMP合格性限定两年的标准。若这个操作不需要注册、检查则不需要通知CDER这个变更。若您对该包装操作是否应该注册有任何疑问，请联系合适的CDER调查员或合规员征询意见。Q5: Certain changes relating to contract sterilization sites for packaging

components can be reported in an annual report (section VI.D.4). Does this also

apply to applicant owned sites?问5：承包的包装组件灭菌场地变更可以在年报中报告。申请人自己拥有的灭菌场地是否也适用该规定？A5: Yes. Whether the sterilization site is applicant- or contractor-owned, a

change to a different sterilization site for packaging components can be

reported in an annual report when the process is not materially different from

the process described in the approved application, and the facility has a

satisfactory CGMP inspection for the type of operation that is being performed.答5：是。无论该灭菌地址是承包的还是自有的，包装组件的灭菌场地变更都可以在年报中报告，只要该操作与已批准申请无实质上的差别，且该类操作符合该类操作的CGMP要求。Q6: Should a prior approval supplement be submitted for a change in the

sterilization site for a primary packaging component of a metered dose inhaler?问6：定量雾化吸入剂型的内包组件灭菌场地变更是否按照优先批准变更提交？A6: The change can be reported in an annual report as long as the process is

not materially different from that provided for in the approved application and

as long as the facility has a satisfactory CGMP inspection for the type of

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operation being performed (section VI.D.4)答6：只要该操作与已批准申请提供的操作并无实质上的差别，且该类操作符合该类操作的CGMP检查，即可仅在年报中报告。Q7: If an intermediate or starting material is also a drug substance, would the

recommendations on reporting site changes for intermediates or drug substances

apply?问7：若某一中间体或起始物料也是原料药，则其地址变更信息是按照中间体还是原料药提交？A7: If a drug substance is used as an intermediate in a drug substance

manufacturing process, the guidance on intermediates would apply. This

assumes that the material has been classified appropriately as an intermediate

(see relevant definitions in the glossary of the guidance). CDER traditionally

does not consider a drug substance to be a starting material.答7：若某原料药在生产工序中作为中间体使用，则有关中间体的指南文适用。即此时这个物料被认为是中间体。CDER一般不将原料药作为起始物料。Q8: Do the recommendations for manufacturing site changes apply to

manufacturing sites outside the United States as long as the site has a satisfactory

CGMP inspection for the type of operation that will be moved?问8：只要迁往的生产地符合CGMP检查，即使地址不在美国，对该类操作的地址变更建议报告类型依然适用吗？A8: Yes. The recommendations in the guidance apply to domestic and foreign

manufacturing sites.答8：是的。本指南在美国本土或其他国家都适用。Q9: The site where the certificates of analysis and regulatory documentation are

reviewed prior to commercial distribution of the product will be relocated. Should

this site change be reported in the application?

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问9：计划变更产品销售前审核化验证明书和监管文档的场所。该场所变更是否应在申请中报告？A9: A change in the site where GMP support paperwork operations occur need

not be reported in the application.答9：支持CGMP的文件操作场地变更无需报告。Q10: The guidance (section VI.B.2) states that a manufacturing site change should

be submitted in a prior approval supplement if the new manufacturing site does not

have a satisfactory CGMP inspection for the type of operation being moved. In

previous guidances it was stated that a satisfactory CGMP inspection within the last

two years was needed. Should a prior approval supplement be used if the new

facility has a satisfactory CGMP inspection for the type of operation being moved,

but the inspection occurred more than two years ago?问10：指南文件VI.B.2部分陈述，若变更的新生产场地对于该类生产操作并无合格的CGMP条件，则该变更应该按照优先批准变更提交报告。而之前的指南文件则声明需要2年之内的CGMP检查合格。若变更的生产场地2年之前该类生产操作经CGMP检查合格，变更报告是否应采用优先批准变更报告？A10: For the purposes of the guidance, there is no time limit on the satisfactory

CGMP inspection unless the type of operation was discontinued (section

VI.B.1).答10：只要该类生产操作未被中止，本指南并未对CGMP检查设定有效期限。Q11: What is the reporting category for a change to a different manufacturing site

for an excipient?问11：赋形剂的生产地址变更应按何种类型报告？A11: CDER need not be notified of this type of change.答11：不需向CDER报告此类变更。Q12: What is the recommended reporting category for the addition of a new aseptic

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filling line for sterile products?问12：若计划给无菌制剂增加一个添加防腐剂的生产线，该变更建议报告类型是什么？A12: The addition of a new aseptic filling line should be reported in a prior

approval supplement (section VI.B.4).答12：新的防腐剂添加生产线按照优先批准变更进行报告。Q13: Why does the guidance exclude drug substance intermediates when referring

to satisfactory CGMP inspections?问13：为什么在涉及到CGMP合格性检查时，指南文件将原料药中间体排除？A13: Section 510(a)(2)(B) of the Act requires that all drugs be manufactured,

processed, packed, and held in accordance with CGMPs. No distinction is

made between the manufacture of drug substance and drug product. Although

the CGMP regulations under 21 CFR Parts 210 and 211 apply only to drug

products, FDA expects appropriate CGMPs to be applied to all steps of a drug

substance manufacturing process beginning with the use of starting materials.

The types of sites identified in the guidance are routinely subject to FDA

inspection with the exception of those facilities or establishments used to

manufacture or process drug substance intermediates. Drug substance

intermediate manufacturing or processing sites are not exempt from inspection,

but an inspection is generally discretionary. Moreover, this type of facility is

always subject to for cause inspection. Because drug substance intermediate

sites are not routinely inspected, a satisfactory CGMP inspection was not

included as a condition for submitting the change in a Supplement — Changes

Being Effected in 30 Days or annual report. However, when a drug substance

intermediate manufacturing or processing site has been inspected and the

CGMP inspection was not satisfactory, the change in site should be submitted

as a prior approval supplement.答13：法案5 10(a)(2)(B)部分要求，所有药物必须按照CGMP开展生产、11

加工、包装和贮藏操作。制剂和原料药的生产并无差别。尽管CGMP的21CFR210和211只适用于之际，FDA还是希望所有从使用起始物料开始的原料药生产过程满足合格的CGMP。指南文件的操作场地类型是以FDA的检查为基础，除了生产或加工原料药中间体的。原料药中间体的生产和加工场地并不能免除检查，但是基本上按照申请者自由安排。此外，此种设备通常是“因故”检查。因为原料药中间体的生产地址的CGMP并不进行例行检查，因此并不是必须在30日内生效变更申请的必要内容。MANUFACTURING PROCESS生产工艺Q1: An applicant intends to add a coarse screen to the opening of a blender,

through which all individual components of a granulation would pass prior to

granulation. The applicant asks whether this could be considered a change in a

control which would be reportable in a Supplement — Changes Being Effected

under section VII.C.2.a of the guidance.问1：申请者意图在混合机出料口增加一个粗孔筛，使所有物料在制粒前过筛。申请社询问，是否可以将该操作按照指南VII.C.2.a.所述，按照中控变更提交即将生效变更申请。A1: This change is not considered a change in control but an additional step in

the manufacturing process. However, it is not considered a fundamental

change in the manufacturing process. This type of change should be reported in

a Supplement — Changes Being Effected in 30 Days (section VII.C.1.a).A1：该操作不可能被认为是中控变更，但可以认为是增加了生产工序。然而该变更也不认为是生产工艺的基本变更。该变更可以以30日内生效变更提交。Q2: Can changes in mixing steps and elimination of a mixing step be reported in an

annual report if these changes are implemented prior to the manufacture of

validation batches?12

问2：若混合步骤变更或取消在验证批次生产之前实施，可否仅在年报中报告？A2: The timing of the postapproval change (i.e., pre- or post validation batches)

does not affect the recommended reporting category. The type of change

should be submitted in either a Supplement — Changes Being Effected in 30

Days (e.g., VIII.C.1.a.) or prior approval supplement (e.g., VII.B.1) depending

on the specifics of each situation such as the type of dosage form.答2：已批准变更的时间（例如，验证前或验证后的批次）不影响建议报告类别。应该按照不同的具体情况，例如剂型种类，来判断应该按优先批准变更提交还是30日内生效变更提交。Q3: What is the recommended reporting category for a drug product (immediate

release solid oral dosage form) scale change beyond 10 times the size of the

biobatch? If the change is annual reportable, should the information identified in

SUPAC-IR3

for an Level 1 scale change be submitted?问3：当一个制剂（如速释固体口服制剂）的生产规模超过了生物批次的十倍，建议报告类别是？若变更可以按照年报提交，SUPAC-IR3中所提及的Level 1

规模变更是否也要提交？A3: All changes in the scale of the nonprotein drug product manufacturing

batches can be reported in an annual report (see section VII.D.1.a).4

However,

if the scale change results in other changes (e.g., equipment, process), the

change would be considered a multiple change, and the recommended

reporting category should be the most restrictive of those for any of the indi

vidual changes (section XII). Recommendations on scale changes for protein

drug products are included in section VII.C.1.c and VII.D.1.a of the information and data recommendations in SUPAC-IR can be used to

support a change. However, the data and information that should be included

in the annual report to support the change depends on the extent of the scale

change. If the scale change is up to and including 10 times the size of the

biobatch, the data and information recommended in SUPAC-IR section V.A

(Level 1) should be submitted. If the scale up is greater than 10 times the size

13

of the biobatch, the data and information recommended in SUPAC-IR Section

V.B (Level 2) should be submitted.答3：非蛋白质制剂的生产批次规模变更都可按照年报提交。但是，若变更导致了其他的变更（如设备），则该变更应该被视为多重变更，且是所有单一变更中最具限制性的建议报告类型（见XII部分）。蛋白质类制剂的生产规模变更建议报告类型参见指南VII.C.1.c和VII.D.A.a部分。SUPAC-IR的建议信息和数据是可以用来支持变更的。然而，年报中所需要包括的支持变更的数据及信息取决于生产规模变更的程度。若规模变更在生物批次的十倍及以内，建议信息在SUPAC-IR的V.A.部分，一级变更提交。若是变更规模超过生物批的十倍，则建议信息在SUPAC-IR的V.B.部分，二级变更提交。Q4: Can changes in the drying process (i.e., tray dryer to cone dryer and associated

process changes) of the crude drug substance be reported in an annual report?问4：计划发生天然原料药的干燥过程中的变更（如盘式干燥器变更为锥桶干燥器），可否仅在年报中报告？A4: Section VII.B.5 of the guidance recommends a prior approval supplement

when any change is made after the final intermediate processing step in the

drug substance manufacture. Changes that occur after the final intermediate for

synthetic or semisynthetic drug substances will be addressed in the guidance

on Bulk Active Chemicals – Postapproval Changes II (BACPAC II). Until the

BACPAC II guidance is finalized, the appropriate chemistry review division(s)

can be consulted for advice if an applicant believes a change made after the

final intermediate processing step is not a major change.答4：指南的VII.B.5.部分建议，原料药生产工艺中，在最后中间体加工工序之后所发生的任何变更都按照优先批准变更提交。在合成或半合成原料药最后中间体后发生的任何变更，可以参考BACPAC指南。直到指南完成，若申请人认为最后中间体加工工艺后的变更不是重大变更，可以向化学审核部门征询意见。14

Q5: For nonprotein drug substances, how should scale changes be reported when

there are no other changes?问5：对非蛋白质原料药来说，若无其他附加变更，只有生产规模变更，应如何报告？A5: Changes in the manufacturing scale for a nonprotein drug substance prior

to the final intermediate need not be reported to CDER unless the change

adversely affects the identity, strength, quality, purity, or potency of the drug

product as these factors relate to the safety and effectiveness of the drug

product. Changes in scale for synthetic or semisynthetic drug substances after

the final intermediate will be addressed in the BACPAC II guidance. Until the

BACPAC II guidance is finalized, the appropriate chemistry review division(s)

can be consulted for advice if an applicant believes a change made after the

final intermediate processing step is not a major change.答5：非蛋白质原料药发生在最后中间体加工工序之前的生产规模变更无需向CDER报告，除非该变更对药品的性状，剂量，质量，纯度有效性或其他与药品安全性有效性相关的特性有不良影响。在合成或半合成原料药最后中间体后发生的任何变更，可以参考BACPAC指南。直到指南完成，若申请人认为最后中间体加工工艺后的变更不是重大变更，可以向化学审核部门征询意见。Q6: Section VII.B.2 of the guidance recommends a prior approval supplement for

changes in sterilizer and load configurations that are outside the range of

previously validated loads. How should changes in load configuration for

manufacturing process equipment (e.g., forceps, stopper bowl) be reported?问6：指南VII.B.2部分建议，超过原批准验证范围的灭菌及负载变更应提交优先批准变更，那么生产工序的设备负载变更应该如何报告（如镊子，塞碗等）？A6: A Supplement — Changes Being Effected in 30 Days is recommended if

the load change is large enough so that the cycle has to be adjusted beyond the

previously validated range. If the cycle does not have to be adjusted, an annual

15

report is recommended.答6：若负载变更过大，导致生产将在批准的验证范围外进行调整，则将提交30日内生效变更增补。若其他部分不用调整，则在年报中报告即可。Q7: Can CDER be notified in an annual report when the filling speed line for a

sterile product is increased by changing the speed of filling through the fill heads or

adding filling heads.问7：若计划通过加快灌装头灌装速度或增加灌装头数目来增加某无菌制剂的灌装生产速度，可否仅在年报中向CDER提交报告？A7: Changing the speed of filling through the fill heads or adding fill heads

can be reported in an annual report as long as the total processing time is not

extended beyond the validated limits in the approved application.答7：只要整个生产时间并未超过已通过申请的验证范围，则通过增加灌装头的灌装速度或灌装头数目来加快生产速度的变更可以仅在年报中报告。Q8: A prior approval supplement is recommended for changes in the source

material of drug substances or drug products derived from plants, animals, or

microorganisms (section VII.B.3). Does this recommendation apply to a substance

derived from a natural source that is used as the starting material for the synthetic

part of a semisynthetic process?问8：原料药的起始物料来源变更，或者源自植物、动物或微生物的制剂产品的来源变更都应按照优先批准变更报告。这个建议是否对衍生自天然产物的原料药、而该天然产物又是某合成路线或半合成路线的起始物料的情况也适用？A8: Yes. This recommendation applies to the starting materials for the

synthetic part of a semi-synthetic process as well as a drug substance or drug

product derived directly from these sources with no further synthetic

modification. For example, the recommendation applies to changes in the

source material for: (1) a plant extract that undergoes synthetic modification to

16

produce the drug substance, or (2) a cellular metabolite that undergoes

synthetic modification to produce an antibiotic drug substance. This

recommendation does not apply to starting materials derived from natural

sources that are widely available (i.e., used more than just to produce

pharmaceuticals), such as glucose or tartaric acid, that can be used in a

synthetic process.答8：是的。该建议对半合成工艺合成部分的起始物料，或有他们直接衍生不经过其他合成修饰的原料药和制剂都适用。例如，该建议对以下物料来源的变更适用：（1）：经过合成修饰后生产原料药的植物提取物；（2）：经过合成修饰后生产抗菌素原料药的细胞代谢物。本指南不使用天然来源、广泛使用的起始物料（即不止在制剂过程中使用的物料），如葡萄糖或酒石酸，因其可能在合成工艺中用到。SPECIFICATIONS规程Q1: How should a revision of an analytical procedure be reported to allow for the

use of a company (i.e., secondary) standard in addition to the U. S. Pharmacopeia

(USP) standard?问1：如何提交报告才能在USP标准之外给分析规程增加一个公司规程（第二标准）？A1: The revision of an analytical procedure to allow the option to use a

secondary standard should be reported in an annual report. Also, the laboratory

reference standards used must comply with CGMP regulations (e.g., 21 CFR

211.194(c)).答1：允许使用第二标准的修正分析规程应在年报中报告。同时，实验室参考标准也必须符合CGMP规程。Q2: How should a decrease in the fill volume be reported?问2：填充体积的减少应该如何上报？A2: A change in the fill volume of a drug product involves a change to the

specification and must be submitted in a prior approval supplement unless

17

exempted by regulation or guidance (506A(c)(2)(A) of the Act). There is no

exemption for this type of specification change; therefore, a prior approval

supplement should be submitted.答2：填充体积的减少包括了规格的变化，并必须提交优先批准变更，除非有法规或指南豁免。而这类规格变更并无豁免。因此必须按照优先批准变更提交。Q3: What reporting category should be used if a USP HPLC assay procedure

replaces, or is used in addition to, a microbiological assay that is listed in the

approved specification as the regulatory analytical procedure?问3：若计划增加一个USP标准的HPLC分析规程来辅助或替代原批准申请中作为常规分析程序的微生物鉴定，应怎样报告变更？A3: The addition of the HPLC analytical procedure to comply with an official

compendium can be submitted in an annual report (section VIII.D.1). However,

if the microbiological assay will also be deleted, the deletion of a test should be

reported in a prior approval supplement (section VIII.B.2 and 3).答3：添加符合药典标准的HPLC分析程序可以在年报中报告。然而，若微生物鉴定被取消，则该检测手段被取消的变更应按优先批准变更递交增补。Q4: In the approved application, it is specified that full product testing will be

performed before bulk material is sent to a contract packager and when the

packaged material is received from the contractor. Can notification in an annual

report be used to replace the full testing of the product after it is received from the

contractor with an identity test?问4：在已批准的申请中规定，在生产厂家向包装承包公司发货之前和从该承包公司接受包装好的产品之后都应该进行完整的产品检测。若计划将接受包装后的完整检测变更为鉴定试验，该如何进行报告？A4: This change involves a deletion of tests and should be reported in a prior

approval supplement (section VIII.B.2).18

答4：该变更包括检测的取消，应在优先批准变更中上报。PACKAGE包装Q1: The plastic used in a desiccant canister is being changed. When the desiccant is

used for bottles of solid oral dosage form products, should it be reported as a

Supplement —Changes Being Effected under section IX.C.2.b of the guidance?问1：计划变更干燥罐上使用的塑料。该干燥罐是用来干燥固体口服试剂瓶，是否应该按照IX.C.2.b提交到即将生效变更？A1: Section IX.C.2 b. states that a change in or addition to or deletion of a

desiccant should be reported in a Supplement — Changes Being Effected. A

change in desiccant refers to the type of desiccant used (e.g., silica gel, calcium

chloride) or amount. Changes in the plastic canister of a desiccant used in a

solid oral dosage form product should be reported as recommended for

changes in the plastic for the container closure system. Under certain

circumstances these changes can be reported in an annual report (e.g., section

IX.D.3).答1：该部分声明，干燥剂的增加或取消都应该按照即将生效变更申请。干燥剂的变更指干燥剂类型（硅胶或氯化钙）和数量的变更。固体口服制剂中干燥剂的塑料罐的变更可以认为是容器密封系统的塑料材料变更。某些情况下可以按照年报报告。Q2: How should deletion of cotton filler from the bottles of a solid oral dosage formproduct be reported?问2：计划取消固体口服制剂瓶中的棉花赛，该变更需要报告吗？A2: The deletion of a cotton filler is considered similar to the deletion of a

desiccant and should be reported in a Supplement — Changes Being Effected.答2：棉花塞的取消被认为和干燥剂的取消类似，按照即将生效变更报告。Q3: The guidance recommends notification in an annual report for a change in the

19

container closure system for a nonsterile drug product, based on a showing of

equivalency to the approved system under a protocol approved in the application or

published in an official compendium. Does “protocol” refer to a comparability

protocol or the approved stability protocol?问3：指南建议，若能通过已批准申请或药典公布的既定规程，证明非无菌制剂的容器密封系统变更后和已通过批准的系统的等效性，就可以在年报中报告该变更。既定规程指可比性方案还是稳定性方案？A3: With respect to the guidance, the term protocol refers to tests, validation

studies, and acceptable limits to be achieved to demonstrate the absence of

adverse effect on the identity, strength, quality, purity, and potency of the drug

from specific types of changes. This type of protocol is often referred to as an

equivalency protocol or comparability protocol. The approved stability

protocol may be one part of the comparability/equivalency protocol to help

demonstrate the absence of an adverse effect.答3：对于指南，规程是指能说明发生的特定变更对药物性状、剂量、质量、纯度和效力并无不良影响的检测，验证，研究和合格范围。这一类规程通常指等效性规程或等效性规程。已批准的稳定性规程可以作为可比性/等效性规程的一部分来说明变更不造成不良影响。Q4: Can a change from tri-layer to a bi-layer blister package for a solid oral dosage

form be reported in an annual report when:· The product contact surface will remain the same.· The available data shows that the new package provides the same protective

properties as the currently approved container closure system.· The new primary packaging component materials have been used in and been

in contact with CDER-approved solid oral dosage form products.问4：哭啼口服制剂的三层泡罩变更为二层泡罩包装，发生下列情况按何种方式报告：·

与制剂接触的表面材料不变更20

·

有可靠数据表明，变更后的包装能提供和批准的包装密封系统等效的保护性能。·新的包装组件材料曾经或正在CDER批准的固体口服制剂中使用过或接触过A4: Based on the information provided, the change can be reported in an

annual report (section IX.D.5). The annual report should include the necessary

documentation that confirms the statements that the product contact surface

remains the same and that the bi-layer blister package has the same or better

protective properties as the tri-layer blister (e.g., light or moisture transmission,

stability data).答4：从可提供的信息来看，该变更可以从年报中报告。年报中应包括足够的信息，来确切说明产品预包装的接触部分保持不变，且双层和三层泡罩相比能提供等同或更好的保护功能（透光性，透湿性和稳定性数据）。Q5: The guidance recommends notification in an annual report when there is a

change to a new container closure system, and the container closure system is

already approved in the NDA or ANDA for other strengths of the product (section

IX.D.3). Is the word product intended to mean the same formulation of the product,

and can the products be approved in different NDAs or ANDAs?问5：指南建议，将容器密封系统变更为NDA或ANDA已批准的该产品另一种剂量规格已使用过的密封系统，变更可以在年报中上报。此处的产品是否指和该产品剂型一样的产品，能否在不同的ANDA或NDA通过？A5: The word product as used in this example is intended to mean products

that have the same basic formulation. These formulations may be

proportionally different due to a difference in strength. When different

strengths of the same product are approved in different applications from the

same applicant, the changes can still be reported in an annual report.答5：产品一次此处代表有相同基本配方的制剂。配方可能按照剂量不同21

成比例变化。当同一个申请人同一产品不同剂量在不同申请中被批准，该变更同样可以用年报来报告。MISCELLANEOUS CHANGES多重变更Q1: The guidance recommends an annual report for the addition of time points to

the stability protocol or deletion of time points beyond the approved expiration

dating period. If these changes are made in an annual report, is the protocol still

considered approved?问1：指南文件建议，在稳定性规程中加入时间点，或者在已批准终止时间之外删除时间点，这类变更可以在年报中提交。按年报提交后该规程是否仍被认可？A1: Yes. If changes such as these are made in an annual report, the stability

protocol is still considered approved.答1：是的。在年报中报告该变更后该规程仍然被认可。Q2: How should the addition of a test to an approved stability protocol be reported?问2：计划向认可的稳定性规程中增加试验，应如何报告变更？A2: When a test is added, whether it is added to a release specification or a

stability protocol, the change should be reported in a Supplement — Changes

Being Effected under section VIII.C.2.a of the guidance, which states "An

addition to a specification that provides increased assurance that the drug

substance or drug product will have the characteristics of identity, strength,

purity, or potency that it purports or is represented to possess. For example,

adding a new test and associated analytical procedure and acceptance

criterion."答2：只要是增加试验，无论是增加稳定性试验还是放行标准，都可以按照即将生效变更增补提交。指南VIII.C.2所述：质量标准中加入项目以加强原料药或制剂的特性、剂量、质量、纯度或应有药效的质量保证。例如，添加新的检测项目及其相关的分析规程、可接受标准。22

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