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#227
Guidance for Industry Two-Phased Chemistry, Manufacturing, and Controls (CMC) Technical Sections
行业指南：CMC技术部分分期申报
DRAFT GUIDANCE
This draft guidance document is for comment purposes only. Submit comments on this draft guidance by the date provided in the Federal Register notice announcing the availability of the draft guidance. Submit electronic comments tohttp://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. You should identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register. For further information regarding this document, contact Heather Longstaff, Center for Veterinary Medicine (HFV-145), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 240-402-0651, e-mail: heather.longstaff@fda.hhs.gov Additional copies of this draft guidance document may be requested from the Communications Staff (HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Place, Rockville, MD 20855, and may be viewed on the Internet at eitherhttp://www.fda.gov/AnimalVeterinary/default.htm or http://www.regulations.gov. U.S. Department of Health and Human Services Food and Drug Administration
Center for Veterinary Medicine
October 2014
Table of Contents 目录
I.INTRODUCTION 概念
II.WHAT IS A TWO-PHASED CMC TECHNICAL SECTION 什么是CMC技术部分分期申报
III.PROCESS FOR THE TWO-PHASED CMC TECHNICAL SECTION CMC技术部分分期申报程序
A. Recommended Meetings 推荐的会议
B. How to Submit Two-Phased Submissions in eSubmitter 如何使用电子申报提交分期申报
IV. FIRST PHASED SUBMISSION 第一期申报
A. What to Include 要包括什么
B. How Information from First Phase Relates to Second Phase
C. Review Outcomes 审核结果
D. Review Clock 审核时限
V. SECOND PHASED SUBMISSION 第二期申报
A. What to Include 要包括什么
B. Review Outcomes 审核结果
C. Review Clock 审核时限. Q7 g% G! E/ h( y) ?
Guidance for Industry
Two-Phased Chemistry, Manufacturing, and Controls (CMC) Technical Sections
( {. A8 V; E6 c, uThis draft guidance represents the Food and Drug Administration’s (FDAor Agency) current thinking on this topic.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. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this draft guidance using the contact information on the title page of this guidance. |
, [2 m4 V& G9 i# QI. INTRODUCTION 概述
This draft guidance provides recommendations to sponsors submitting chemistry, manufacturing, and controls (CMC) data submissions. For review efficiency, the Center for Veterinary Medicine (CVM) prefers that CMC information be submitted in a single technical section. However, there may be instances when a two-phased technical submission process is more beneficial to improve the overall time to drug approval. Sponsors may submit the phased CMC technical section as a single technical section or a two-phased technical section. This draft guidance describes the use of the two-phased technical section submission process.
本指南草案给提交CMC数据申报的申报人提供建议。为了提高审阅效率，兽药中心（CVM）倾向于申报人将CMC资料放在一个单独的技术部分提交。实际上，如果采用两期技术提交方式，可能会有效提高药品批准的整体时间。申报人可以分期提交CMC技术部分，一次性提交或分为两期提交。本指南草案描述了使用两期提交技术部分的流程。
This draft guidance does not provide recommendations on the specific CMC information that should be submitted to comply with 21 CFR §§ 514.1(b)(4) and (5). A sponsor should consider all relevant FDA guidance documents for recommendations on the information that should be submitted to support drug approval.[1] 本指南草案并不提供CMC技术方面的建议，所有CMC资料应按 21 CFR §§ 514.1(b)(4) 和(5)的要求提交。申报人应考虑所有相关的FDA指南文件，其中列出了需要提交来支持药品批准的资料。
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required.
FDA的指南文件，包括本指南并不建立法定的强制责任。相反，指南描述了当局目前对该问题的思考，应仅被看作是一种推荐，除非其中内容被法规或立法要求所引用。指南中的“应该”一词表示建议或推荐的事情，并不要求强制执行。
II. WHAT IS A TWO-PHASED CMC TECHNICAL SECTION 什么是CMC技术部分分期申报
A complete New Animal Drug Application (NADA) or Abbreviated New Animal Drug Application (ANADA) must include information identified in 21 CFR §§ 514.1(b)(4) and (5). In order to facilitate the approval of NADAs or ANADAs, CVM now accepts major data submissions for individual sections of an NADA or ANADA (technical sections) under the Investigational New Animal Drug (INAD) or Generic Investigational New Animal Drug (JINAD) file. The CMC technical section is considered one of the major data submissions.[2] 一份完整的新兽药申报（NADA）或简略新兽药申报（ANADA）必须包括 21 CFR §§ 514.1(b)(4) 和(5)中要求的资料。为了便于NADA或ANADA的批准，CVM现在接受临床新兽药（INAD）或仿制临床新兽药（JINAD）期间的NADA或ANADA（技术部分）单个部分主要数据申报。
Traditionally, sponsors submit complete CMC information in one submission, under either the (J)INAD or the (A)NADA process. Some CMC information, as described below, may be available for review prior to submitting a single traditional CMC technical section. In such instances and with CVM’s concurrence, sponsors may submit the CMC data using a two-phased submission process.
以前，申报人根据(J)INAD或(A)NADA程序在一份申报材料中提交完整的CMC资料。有些CMC资料，如下所述，在提交单独的传统CMC技术部分前，申报人其实可以获得CMC资料。在这种情况下，由CVM同意，申报人可以采用分期提交程序来提交CMC数据。
The two-phased process allows the submission of two separate CMC submissions, each with its own review clock, and each including complete appropriate CMC information that is available for review at the time of submission. The two submissions may both be submitted to the (J)INAD, or the first submission may be submitted to the (J)INAD and the second to the (A)NADA after transition of the (J)INAD to the (A)NADA.
两期程序允许提交两份独立的CMC申报，每份申报的审阅计时相互独立，每份申报均包括在申报时可以获得的完整适当的CMC资料。两次申报可以都交给（J）INAD，也可以将第一期申报资料提交给(J)INAD，在(J)INAD将资料转给(A)NADA后，将第二期提交给(A)NADA。 III. PROCESS FOR THE TWO-PHASED CMC TECHNICAL SECTION CMC技术部分分期申报程序
A. Recommended Meetings 推荐的会议
CVM recommends that sponsors schedule a meeting with the Division of Manufacturing Technologies (HFV-140) prior to using the two-phased submission process in order to obtain concurrence of the sponsor's approach to submitting the CMC technical section(s). A sponsor may schedule another meeting with CVM after receiving correspondence from CVM regarding the first phase and prior to submitting the second phase.
CVM建议申报人在采用分期申报程序前，安排与生产技术中心（HFV-140）开一次会议，以获得其对申报人提交CMC技术部分的同意。在收到CVM的通信后，申报人可以安排与CVM再开一次会，讨论关于第一期申报和第二期申报前的问题。
B. How to Submit Two-Phased Submissions in eSubmitter 电子提交中如何按分期方式提交
Sponsors may submit two-phased submissions in paper or preferably through eSubmitter.[3] If sponsors elect to use eSubmitter, all of the questions in the CMC template must be answered in both phases. When submitting the first phase, any questions in the eSubmitter templates that ask for information that will be submitted in the second phase may be answered with "To be submitted in Phase II." When submitting the second phase, any questions that were addressed in the first phase may be answered with a reference to the first phased submission. 分期申报可以是纸质的，当然最好通过电子提交。如果申报人选择采用电子申报，则两期申报中都必须回答CMC模板里的所有问题。在提交第一期申报资料时，电子提交模板中与将在第二期申报中提交的资料相关的所有问题都可以回答“将在第二期提交”。在提交第二期申报资料时，所有在第一期申报中已回答的问题则可以引用第一期申报资料。
IV. FIRST PHASED SUBMISSION 第一期提交
CVM has identified several components of the CMC technical section that sponsors may complete early in the development process and therefore are available to submit to CVM in the first phase of the two-phased submission process. For example, a second-party or master file holder often prepares a master file containing CMC information for the drug substance, which may be available for review prior to the submission of a referencing data submission. If a sponsor references the master file in the first phase, the master file holder may have time to address any deficiencies and CVM may schedule cGMP inspections without significantly impacting the overall time to approval for the (A)NADA.
CVM已确定了几个CMC技术部分中的构成要素，申报人可以在研发过程中完成，从而获取资料在第一期提交。例如，一个第二方或主文件持有人通常会次血一份主文件，其中包括原料药的CMC信息，这些资料可以在对照数据提交前获得，以供审核。如果申报人在第一期提交中引用了主文件，主文件的持有人可以有时间来回复所有缺陷，CVM可以安排现场CGMP审计，而不会因此对(A)NADA的整体批准时间造成重大影响。
A. What to Include 包括什么
The following items may be appropriate for inclusion in the first phased submission:
以下项目适合包括在第一期的申报资料中
? all master file references, e.g., Type II for drug substances and Type V for sterile process validation information,
? 所有主文件参考文献，例如，原料药二类和无菌工艺五类
? drug substance CMC information,
? 原料药CMC资料
? analytical methods and validations, and
? 分析方法和验证，以及
? other items as discussed and agreed upon in a meeting with CVM.
? 在与CVM的会议中讨论并达成共识的其它项目
CVM recommends a reference to one drug or veterinary master file (DMF or VMF) for each active pharmaceutical ingredient (API). CVM may not accept multiple master file references for an API in the first phase and, therefore, may refuse to file or review.[4] A sponsor can submit multiple references in a technical section; however CVM usually discourages this practice since it decreases the likelihood of a single cycle review. CVM建议每个原料药引用一个人药或兽药主文件（DMF或VMF）。CVM不会接受第一期申报中一个原料药参照多个主文件，可能会拒收申报资料或拒绝审阅。申报人可以在技术部分提交多个参照药品，但是CVM一般不鼓励这种做法，因为这样会降低单次循环审阅的可能性。
Each component submitted in the first phase should be complete; however, if a sponsor would like to use an alternate strategy this should be discussed with CVM prior to submission of the first phase. With respect to analytical controls, each individual analytical method and its corresponding validation package is considered to be a complete component, such that any or all of the methods may be submitted for review in the first phase (e.g., the assay method/validation could be submitted in the first phase and the impurity method/validation could be submitted in the second phase, or both methods/validations could be submitted together in either the first or second phase).
在第一期提交的各成分均应完整，但是，如果申报人愿意使用中车种策略，则应在第一期提交前与CVM进行讨论。在分析控制方面，每个分析方法及其对应的验证包会被作为一个完整的组成部分，这样在第一期可以提交任何或所有方法（例如，含量方法验证可以在和一期提交，杂质方法/验证可以在第二期提交，也可以在第一期或第二期同时提交两个方法）。
B. How Information from First Phase Relates to Second Phase 第一期资料如何与第二期资料相关
Upon review of the second phase, CVM assesses information received in the first phase in the context of the information in the second phase. This may result in comments on information previously found acceptable based on new or additional information provided in the second phase. For example, an impurity method/validation provided in the first phase may be re-evaluated during the second phase to ensure that the validation data support the proposed finished product specification for impurities that is provided in the second submission.
在对第二期审核时，CVM会基于第二期申报资料对第一期申报资料进行评估。这时可能会发现之前认为是可接受的资料，在对第二期申报资料审核时提出意见。例如，在第一期申报资料中包括的一个杂质方法/验证可能会在第二期评审时被重新评估，以保证验证数据支持第二期申报资料中所拟的制剂质量标准中杂质测试。
C. Review Outcomes 审阅结果
The sponsor receives a technical section incomplete letter following review of the first phased submission. There are two possible versions of the letter. The information in the first phased submission may be found acceptable, in which case a letter will be issued indicating that the submitted information is acceptable but the technical section remains incomplete. If the information in the first phased submission is found incomplete, the incomplete letter will contain CVM’s comments. A sponsor should address any deficiency comments from the first phased submission in the second phased submission, along with any remaining information to complete the CMC technical section.
在对第一期申报资料进行审核后，申报人会收到一份技术部分不完整通知。该通知函会有两种可能的版本。如果第一期申报资料被认为是可以接受的，则该信函会说明所提交的申报资料已被接受，但技术部分仍不完整。如果第一期申报中的资料被认为是不完整的，则不完整信函会包括CVM的评价。申报人要在第二期申报资料中说明第一期申报资料中的所有缺陷，以及提交所有余下信息，使得CMC技术部分完整。
D. Review Clock 审核时限
The review clock for a first phased submission is 180 days for an INAD, and 270 days for a JINAD.[5] 第一期申报审核时限INAD为180天，JINAD为270天。
V. SECOND PHASED SUBMISSION 第二期提交
The second phased submission should not be submitted to the (J)INAD or the (A)NADA until the sponsor receives correspondence from CVM regarding the first phased submission.
只有在申报人收到CVM关于第一期提交的信函后，申报人才可以将第二期申报资料提交给(J)INAD或(A)NADA。
A. What to Include 要包括什么
The second phased submission includes the remainder of the information necessary for a complete technical section that was not included in the first phased submission. If the second phased submission is missing information required for a complete technical section, CVM may refuse to file it in the (J)INAD or refuse to review the (A)NADA.[6] 第二期申报资料包括第一期资料中未包括的完整技术部分所必须的余下所有资料。如果第二期申报资料中缺失了完整技术部分所需的资料，则CVM可能会在(J)INAD拒收文件或拒绝审核(A)NADA。
Any responses to incomplete comments from the first phased submission are also included in this phase. All master files should also be referenced, regardless of whether master file references were provided in the first phased submission.
第二期申报资料中还要包括对第一期申报资料中所有不完整评估的回复。不管在第一期申报资料中是否已提供引用主文件，在第二期申报资料中要引用所有主文件。
If the sponsor chooses to transition from the investigational phase to the application phase (file an (A)NADA) at the time of submission of the second phase, the technical section incomplete letter from the first phase should be included in the submission.
如果申报人选择在提交第二期申报资料时，从临床阶期过渡到申报阶期（提交(A)NADA），则在第二期申报资料中要包括对第一期不完整技术部分的信函。
B. Review Outcomes 审核结果
There are two possible outcomes following review of the second phased submission. The information in the second phased submission may be found acceptable, and a letter is issued indicating that the information is acceptable and the technical section is complete, or that the (A)NADA is complete with regards to CMC information. If the information in the second phased submission is incomplete, CVM will issue an incomplete letter. Sponsors should then submit responses to CVM comments as part of the reactivation to the second phased submission. As per the AGDUFA II/ADUFA III goals letter, this reactivation may be eligible for an abbreviated review clock at the discretion of CVM. [7] 第二期申报资料的审核结果有两种。如果第二期申报资料被认为是可以接受的，则会签发一封信函说明资料被受理，技术部分已完整，或(A)NADA中CMC资料完整。如果第二期申报资料中的信息不完整，CVM会签发一封不完整信函。申报人应针对CVM的评价作出回复，以重新激活第二期申报资料。根据AGDUFA II/ADUFA III目标函，CVM可以自由裁定该重新激活对于简略审核来说是可以接受的。
C. Review Clock 审核时限
The review clock for a second phased submission is 180 days for an INAD, and 270 days for a JINAD.[8] 第二期申报的审核时限INAD为180天，JINAD为270天。
联邦快讯（包括相关信息：草案征求意见截止时间等）
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2014–D–1492]
Two-Phased Chemistry, Manufacturing, and Controls Technical Sections; Draft Guidance for Industry;
Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of a draft guidance for industry (GFI #227) entitled ‘‘Two-Phased Chemistry, Manufacturing, and Controls (CMC) Technical Sections.’’
The purpose of this document is to provide recommendations to sponsors submitting CMC data submissions. For review efficiency, the Center for Veterinary Medicine (CVM) prefers that CMC information be submitted in a single technical section. However, there may be instances when a two-phased technical submission process is more beneficial to improve the overall time to drug approval. Sponsors may submit the phased CMC technical section as a single technical section or a two-phased technical section. This guidance describes the use of the two-phased technical section submission process.
DATES: Although you can comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance, submit either electronic or written comments on the draft guidance by December 19, 2014.
ADDRESSES: Submit written requests for single copies of the guidance to the Communications Staff (HFV–12), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Pl., Rockville, MD 20855. Send one selfaddressed adhesive label to assist that office in processing your requests. See the SUPPLEMENTARY INFORMATION section for electronic access to the draft guidance document.
Submit electronic comments on the draft guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA–305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:
Heather Longstaff, Center for Veterinary Medicine (HFV–145), Food and Drug Administration, 7500 Standish Pl.,
Rockville, MD 20855, 240–402–0651, email: heather.longstaff@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a draft guidance for industry (GFI #227) entitled ‘‘Two-Phased Chemistry, Manufacturing, and Controls (CMC) Technical Sections.’’ It is intended to provide recommendations to industry regarding CMC data submitted to CVM to support approval of a new animal drug or abbreviated new animal drug.
As specified in the Animal Drug User Fee Amendments of 2013 (ADUFA III) and Animal Generic Drug User Fee Amendments of 2013 (AGDUFA II) respective goals letters, the Agency agreed to develop guidance for a twophased CMC technical section submission and review process by the end of fiscal year 2014.
The two-phased process allows for two separate CMC submissions, each with its own review clock, and each including complete appropriate CMC information that is available for review at the time of submission. The draft guidance specifies the technical details of how the process works, the review clocks, the information that is appropriate for each technical section submission, and the possible review outcomes. The guidance also includes CVM’s recommendations for meetings between the Division of Manufacturing Technologies and the sponsor during this process to ensure concurrence with the approach used for the CMC technical section.
II. Significance of Guidance
This level 1 draft guidance is being issued consistent with FDA’s good guidance practices regulation (21 CFR 10.115). The draft guidance, when finalized, will represent the Agency’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.
III. Paperwork Reduction Act of 1995
This draft guidance refers to previously approved collections of information found in FDA regulations.
These collections of information are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501–3520). The collections of information in this guidance have been approved under 0910–0032 and 0910–0669.
IV. Comments
Interested persons may submit either electronic comments regarding this document to http://www.regulations.gov or written comments to the Division of Dockets Management (see ADDRESSES). It is only necessary to send one set of comments. Identify comments with the docket number found in brackets in the heading of this document. Received comments may be seen in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov. V. Electronic Access
Persons with access to the Internet may obtain the draft guidance at eitherhttp://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm orhttp://www.regulations.gov.
Dated: October 15, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014–24796 Filed 10–17–14; 8:45 am]
BILLING CODE 4164–01–P
: u X: J+ k( N* F6 J" j[2] For details of the administrative (A)NADA process, refer to GFI #132: The Administrative New Animal Drug Application Process. , |) g0 V( e6 v2 G4 c ~& t2 ^
+ |- B$ } l; i5 k[4] 21 CFR § 514.110 Reasons for refusing to file applications, see also, ADUFA III/AGDUFA II goals letters.
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[6] 21 CFR § 514.110 Reasons for refusing to file applications, see also, ADUFA III/AGDUFA II goals letters. 9 c( F7 d5 D A' ?# s5 Z$ P
[7] The ADUFA III goals letter stipulates that in order for INAD submissions/NADAs to be eligible for shorter reactivation times for the phased submissions, they must be submitted through the eSubmitter tool. ; Q! o2 M( g' v, `# V' p! L3 C
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