翻译(SUPAC-IR指导原则：速释口服固体制剂：放大生产和批准后变更)

Guidance for Industry

Immediate Release Solid Oral Dosage Forms

Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation

SUPAC-IR指导原则：速释口服固体制剂放大生产和批准后变更：化学、生产和控制，体外

溶出试验、体内生物等效性文件

Center for Drug Evaluation and Research (CDER)

November 1995

CMC 5

药品评价与研究中心

1995年11月

CMC 5

TABLE OF CONTENTS

目录

I. PURPOSE OF GUIDANCE （本指导原则的目的）. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 1 II. DEFINITION OF TERMS（术语定义）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3 https://www.360docs.net/doc/8113169610.html,PONENTS AND COMPOSITION（辅料成分或组成的变更）. . . . . . . . . . . . . . . . . . . . . . . . .. 6 IV. SITE CHANGES（地点变更）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 13 V. CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN)（批量大小（放大/缩小）的变更）. .. . . . 16 VI. MANUFACTURING（生产变更）. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 VII. IN VITRO DISSOLUTION （体外溶出试验）. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 VIII. IN VIVO BIOEQUIVALENCE STUDIES （体内生物等效性）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 IX. REFERENCES（参考文献）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 APPENDIX A: NARROW THERAPEUTIC RANGE DRUGS（附录A：治疗窗狭窄药物）. . . . . . . . . A-1

GUIDANCE FOR INDUSTRY 1

IMMEDIATE RELEASE SOLID ORAL DOSAGE FORMS SCALE-UP AND POSTAPPROVAL CHANGES: CHEMISTRY, MANUFACTURING, AND CONTROLS, IN VITRO DISSOLUTION TESTING, AND IN VIVO BIOEQUIVALENCE DOCUMENTATION

速释口服固体制剂放大生产和批准后变更：化学、生产和控制，体外溶出试验、体内生物等效性文件

I. PURPOSE OF GUIDANCE（本指导原则的目的）

This guidance provides recommendations to sponsors of new drug applications (NDA's), abbreviated new drug applications (ANDA's), and abbreviated antibiotic applications (AADA's) who intend, during the postapproval period, to change: 1) the components or composition; 2) the site of manufacture; 3) the scale-up/scale-down of manufacture; and/or 4) the manufacturing (process and equipment) of an immediate release oral formulation.

本指导原则所提供的的建议适用于新药申请（NDA's）、仿制药申请（ANDA's）和抗生素仿制药申请（AANA’S）的企业的批准后变更，内容包括：1）成分或组分的变更；2）生产地点的变更；3）放大/缩小生产规模的变更；和/或4）生产过程（工艺和设备）的变更This guidance is the result of: 1) a workshop on the scale-up of immediate release drug products conducted by the American Association of Pharmaceutical Scientists in conjunction with the United States Pharmacopoeial Convention and the Food and Drug Administration (FDA); 2) research conducted by the University of Maryland at Baltimore on the chemistry, manufacturing and controls of immediate release drug products under the FDA/University of Maryland Manufacturing Research Contract; 3) the drug categorization research conducted at the University of Michigan and the University of Uppsala on the permeability of drug substances; and 4) the Scale-Up and Post Approval Changes (SUPAC) Task Force which was established by the Center for Drug Evaluation and Research (CDER) Chemistry, Manufacturing and Controls Coordinating Committee to develop guidance on scale-up and other postapproval changes.

本指导原则是以下工作的成果：1）在美国药学科学家协会与美国药典委员会和FDA的指导下，进行速释药品放大生产的车间；2）在位于巴尔的摩的马里兰大学指导下，并在FDA/马里兰大学生产研究合同下的速释药品的化学、生产和控制的研究；3）在密歇根大学和乌普萨拉大学指导下的药品分类学研究中关于药物渗透性的研究；4）由药品评价和研究中心（CDER）化学、生产和控制协调委员会成立的放大生产和批准后变更（SUPAC）特别小组，来制定关于放大生产和其它的批准后变更的指导原则。

The guidance defines: 1) levels of change; 2) recommended chemistry, manufacturing, and controls tests for each level of change; 3) in vitro dissolution tests and/or in vivo bioequivalence tests for each level of change; and 4) documentation that should support the change. For those changes filed in a “changes being effected supplement” *21 CFR 314.70(c)+, the FDA may, after a review of the supplemental information, decide that the changes are not approvable. This guidance thus sets forth application information that should be provided to CDER to assure continuing product quality and performance characteristics of an immediate release solid oral dose formulation for specified postapproval changes. This guidance does not comment on or otherwise affect compliance/inspection documentation that has been def ined by CDER’s Office of Compliance or FDA’s Office of Regulatory Affairs. This guidance does not affect any

postapproval changes other than the ones specified. For changes not addressed in this guidance, or for multiple changes submitted at one time or over a short period of time, or where the number of batches needed for stability testing is not specified, sponsors should contact the appropriate CDER review division or consult other CDER guidances/guidelines to obtain information about tests and application documentation.

本指导原则规定了以下内容：1）变更的类别；2）针对每一类变更建议进行的药物化学、药品生产以及生产和质量控制（CMC）研究内容；3）针对每一类变更建议进行的体外溶出试验和/或体内生物等效性试验；和4）变更用的支持性文件资料。对于那些在“起补充作用的变更”文件，FDA在对补充资料进行审查后，可以决定是否允许这些变更。本指导原则给出了需递交给药品评价和研究中心（CDER）的申请信息，以确保速释口服固体制剂在发生规定的变更后继续保持其质量和性能特点。本指导原则不评论也不更改由CDER法律管理办公室或FDA法规事务办公室颁布的法规/检查文件。本指导原则不涉及除了本文提到的变更情形外的其他情形的批准后变更。对于那些本指导原则未涉及的变更，以及同时或短时间内申请多个变更，或需进行稳定性实验的批次数量未规定的，申请人应与CDER相关审评部门沟通，或者参考CDER其他的指导原则/指南以获得有关研究和申报资料的信息。

21 CFR 314.70(a) provides that applicants may make changes to an approved application in accordance with a guideline, notice, or regulation published in the FEDERAL REGISTER that provides for a less burdensome notification of the change (for example, by notification at the time a supplement is submitted or in the next annual report). This guidance permits less burdensome notice of certain postapproval changes within the meaning of § 314.70(a).

FDA 的法规（21 CFR 314.70(a)）规定申请人可以根据发表在联邦登记（Federal Register）上的指导原则、通知或条例的规定，对所批准的申请内容实施变更，如此可以减轻繁重的变更通告量（举例而言，可以在递交补充申请时或在下一年年报中予以通告）。对于符合§314.70(a)的某些批准后变更，本指导原则允许减少通告量。

For postapproval changes for immediate release dosage forms that affect components and composition, scale-up, site change, and manufacturing process or equipment changes, this guidance supersedes the recommendations in section 4.G of the Office of Generic Drugs Policy and Procedure Guide 22-90 (September 11, 1990). For all other dosage forms and changes, this guidance does not affect the recommendations in Guide 22-90.

当速释制剂的批准后变更涉及成份和组成、生产规模放大、生产地点变化和生产工艺或设备改变时，本指导原则将代替仿制药办公室（OGD）制定的Policy and Procedure Guide 22-90 （September 11, 1990）章节4.G中提供的建议。但对于所有其他的剂型和变更，本指导原则不适用，仍应遵循Guide 22-90中的建议。

II. DEFINITION OF TERMS术语的定义

A.Batch 批

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)].

在同一个生产周期中，按照相同的生产规程制备的特定数量的药品或其它物料，并意图使其性质和质量在规定的限度内具有一致性。

B.Contiguous Campus 毗邻区域

Continuous or unbroken site or a set of buildings in adjacent city blocks.

连续的或未被隔断的地区，或者在毗邻街区内的一组建筑物。

C.Dissolution Testing溶出试验

Case A: Dissolution of Q = 85% in 15 minutes in 900 milliliters (mL) of 0.1N hydrochloride (HCl), using the United States Pharmacopeia (USP) <711> Apparatus 1 at 100 revolutions per minute (rpm) or Apparatus 2 at 50 rpm.

情况A：采用美国药典（USP）<711>装置1，转速为100rpm（转/分），或采用装置2，转速为50rpm，溶出介质为900mL 0.1N的HCl，药品15min内溶出限度达到85%。

Case B: Multi-point dissolution profile in the application/compendial medium at 15, 30, 45, 60, and 120 minutes or until an asymptote is reached for the proposed and currently accepted formulation.

情况B：对变更后的产品和现行产品绘制多点溶出曲线，采用申报资料/药典的规定的溶出介质，取样点为15，30，45，60和120min或至达到稳态。

Case C: Multi-point dissolution profiles performed in water, 0.1N HCl, and USP buffer media at pH 4.5, 6.5, and 7.5 (five separate profiles) for the proposed and currently accepted formulations. Adequate sampling should be performed at 15, 30, 45, 60, and 120 minutes until either 90% of drug from the drug product is dissolved or an asymptote is reached. A surfactant may be used with appropriate justification.

情况C：对变更后的产品和现行产品绘制多点溶出曲线，应选取水、0.1N的HCl，以及美国药典规定的3种pH分别为4.5，6.5和7.5的缓冲介质为溶出介质（5条独立的溶出曲线）。应采用充足的样品进行溶出度试验，取样点应选择15，30，45，60和120分钟直至药物累计溶出度达到90%或至稳态。在有恰当理由的情况下可使用表面活性剂。

D.Drug Product药品

A drug product is 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)]. A solid oral dosage form includes tablets, chewable tablets, capsules, and soft gelatin capsules.

药品是指已完工的剂型（比如片剂、胶囊或溶液），含有药物，一般还含有（但非必需）与其相关的一种或几种其它配料[21 CFR 314.3(b)]。固体口服剂型包括片剂、咀嚼片、胶囊和软胶囊。

E.Drug Substance原料药

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 of any function of the human body, but does not include intermediates used in the synthesis of such ingredient [21 CFR 314.3(b)].

在疾病的诊断，治疗，症状缓解，处理或疾病的预防中发挥药理活性或其他直接作用，或者能影响人体的功能或结构的一种活性成分，不包括其制备过程中产生的中间体[21 CFR 314.3(b)]。

F.Equipment设备

Automated or non-automated, mechanical or non-mechanical equipment used to produce the drug product, including equipment used to package the drug product.

用于生产药物制剂的自动化或非自动化、机械式或非机械式的设备，包括包装设备。

G.Formulation处方

A listing of the ingredients and composition of the dosage form.

制剂中的一系列的配料和组分。

H.Justification 合理性证明

Reports containing scientific data and expert professional judgment to substantiate decisions.

用以证明决策合理的报告，其内容由科学数据和专家的专业评判组成。

I.New Drug Substance新原料药

Any substance that, when used in the manufacture, processing, or packing of a drug, causes that drug to be a new drug, but does not include intermediates used in the synthesis of such substance [21 CFR 310.3(g)].

在药品生产、加工或包装过程中用到的使药品成为一种新药的物质。但不包括其合成中产生的中间体。

J.Operating Principle 工作原理

Rules or concepts governing the operation of the system.

用于指导系统运行的规则或理念。

K.Pilot Scale中试规模

The manufacture of either drug substance or drug product by a procedure fully representative of and simulating that used for full manufacturing scale.

For solid oral dosage forms this is generally taken to be, at a minimum, one-tenth that of full production, or 100,000 tablets or capsules, whichever is larger (see the FEDERAL REGISTER of Thursday, September 22, 1994, 59 FR 48754-59).

按照可完全代表和模拟全规模生产的过程生产的原料药或制剂。

对于口服固体制剂，中试规模一般至少是生产规模的十分之一或者100，000片或胶囊，取其中值较大者（见联邦公报1994年9月22日）。

L.Process 工艺

A series of operations and/or actions used to produce a desired result.

为产生期望的结果而进行的一系列的操作和/行动。

M.Ranges 范围

The extent to which or the limits between which acceptable variation exists.

可接受的变化程度或范围

N.Same 相同

Agreeing in kind, amount; unchanged in character or condition.

种类和数量上的一致性；性质或状态不变。

O.Scale-up放大

The process of increasing the batch size.

批量放大的过程。

P.Scale-down 缩小

The process of decreasing the batch size.

批量缩小的过程。

Q.Similar 相似

Having a general likeness.

具有总体上的相似性。

R.Significant body of information大量信息

A significant body of information on the stability of the drug 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.

对于新分子实体而言，制剂稳定性方面的大量信息可能会在上市后五年得到；对于新剂型而言，则可能为上市后三年。

S.Validation 验证

Establishing through documented evidence a high degree of assurance that a specific process will consistently produce a product that meets its predetermined specifications and quality attributes. A validated manufacturing process is one that has been proven to do what it purports or is represented to do. The proof of validation is obtained through collection and evaluation of data, preferably beginning from the process development phase and continuing through the production phase. Validation necessarily includes process qualification (the qualification of materials, equipment, systems, buildings, and personnel), but it also includes the control of the entire processes for repeated batches or runs.

通过文件证明的方式，高度确保某一具体生产工艺能始终如一地生产出符合预设标准和品质的产品。生产工艺经过验证指其生产的产品被证明与其所声称的一致。验证通过积累和评价数据来进行，这一过程最好从工艺开发就开始，并一直贯穿于实际生产。验证必然包括工艺确认（原材料确认、设备确认、系统确认、车间确认和人员确认），除此之外还应包括对整个工艺过程的控制以保证批次间具有重现性。

III. COMPONENTS AND COMPOSITION辅料的种类和组成的变更

This section of the guidance focuses on changes in excipients in the drug product. Changes in the amount of drug substance are not addressed by this guidance. Changes in components or composition that have the effect of adding a new excipient or deleting an excipient are defined at Level 3 (defined below), except as described below.

本章重点讨论药品辅料的变更。而原料药含量的变更不在本指导原则的讨论范围。对于辅料种类和组成的变更，涉及增加或减少辅料种类的变更被归入下述的第3类变更，其他的类型如下所述。

A.Level 1 Changes 1类变更

1.Definition of Level 定义

Level 1 changes are those that are unlikely to have any detectable impact on

formulation quality and performance.

1类变更是指不会对制剂质量和性能产生可查知的影响的变更。

Examples: 例如：

a.Deletion or partial deletion of an ingredient intended to affect the color or

flavor of the drug product; or change in the ingredient of the printing ink to

another approved ingredient.

去除或部分去除会影响药品颜色或味道的成分；或者将印字油墨的成分改

为另外一种已批准的成分。

b.Changes in excipients, expressed as percentage (w/w) of total formulation, less

than or equal to the following percent ranges:

辅料的变更，以其在处方中的百分比（w/w）表示，应小于或等于下表中的

百分比范围：

These percentages are based on the assumption that the drug substance in the product is formulated to 100% of label/potency. The total additive effect of all excipient changes should not be more than 5%. (Example: In a product consisting of active ingredient A, lactose, microcrystalline cellulose and magnesium stearate, the lactose and microcrystalline cellulose should not vary by more than an absolute total of 5% (e.g. lactose increases 2.5% and microcrystalline cellulose decreases by 2.5%) relative to the target dosage form weight if it is to stay within the Level 1 range).

该百分比是假设产品中的原料药按标签/效价的100%投料，所有辅料的变更累计应不大于5%。（例如：一个产品的处方包括活性成分A、乳糖、微晶纤维素和硬脂酸镁，那么乳糖和微晶纤维素变更的绝对总量不应超过5%（例如乳糖增加2.5%同时微晶纤维素减少2.5%））

The components (active and excipients) in the formulation should have numerical targets which represent the nominal composition of the drug product on which any future changes in the composition of the product are to be based. Allowable changes in the composition should be based on the approved target composition and not on previous Level 1 changes in the composition.

应明确处方中各组分（包括活性成分和辅料）的具体比例（目标比例），该目标比例代表药品的公称成分，后续的任何产品成分的变更都是基于该目标比例。

在评价药品成分变更能否被接受时，应以最初批准时的目标比例作为比较对象，而不是以前述的发生过1类变更后的处方比例作为比较对象。

2.Test Documentation试验资料

a.Chemistry Documentation化学资料

Application/compendial release requirements and stability testing.

Stability testing: one batch on long-term stability data reported in annual

report.

申报资料/药典要求的资料和在年报中提供的稳定性试验资料。

稳定性试验资料：在年报中提交一批长期稳定性数据

b.Dissolution Documentation溶出研究资料

None beyond application/compendial requirements.

申报资料/药典要求的资料，不需其他资料。

c.In Vivo Bioequivalence Documentation体内生物等效性资料

None.不需要

3.Filing Documentation归档文件

Annual report (all information including long-term stability data).

年报（记录所有信息，包括长期稳定性数据）

B.Level 2 Changes 2类变更

1.Definition of Level定义

2类变更是指对产品质量和性能可能产生显著影响的变更。

Level 2 changes are those that could have a significant impact on formulation quality and performance. Tests and filing documentation for a Level 2 change vary depending on three factors: therapeutic range, solubility, and permeability.

Therapeutic range is defined as either narrow or non-narrow. A list of narrow therapeutic range drugs is provided in Appendix A. Drug solubility and drug permeability are defined as either low or high. Solubility is calculated based on the minimum concentration of drug, milligram/milliliter (mg/mL), in the largest dosage strength, determined in the physiological pH range (pH 1 to 8) and temperature (37 + 0.5o C). High solubility drugs are those with a dose/solubility volume of less than or equal to 250 mL. (Example: Compound A has as its lowest solubility at 37 + 0.5 C, 1.0 mg/mL at pH 7, and is available in 100 mg, 200 mg and 400 mg strengths. This drug would be considered a low solubility drug as its dose/solubility volume is greater than 250mL (400 mg/1.0 mg/mL=400 mL).

Permeability (P e, centimeter per second) is e defined as the effective human jejunal wall permeability of a drug and includes an apparent resistance to mass transport to the intestinal membrane. High permeability drugs are generally those with an extent of absorption greater than 90% in the absence of documented instability in the gastrointestinal tract, or those whose permeability attributes have been determined experimentally).

2类变更的试验和归档文件的改变取决于3种因素：治疗范围，溶解性和渗透性。治疗范围被定义为治疗范围狭窄或非狭窄两类。治疗范围狭窄药物的列表见附录A。药物的溶解性和渗透性均被定义为低或高两类。溶解性是根据药物的最大应用剂量在生理pH范围（pH 1-8）和生理温度（37+ 0.5℃）条件下，计算得出的药物的最低浓度（mg/mL）。高溶解性药物是指溶解单位剂量药物体积小于等于250ml的药物。（例如化合物A，在37 + 0.5 C, pH 7条件下的最低溶解度为1.0 mg/mL，且其可应用的剂量为100mg，200 mg和400 mg。那么认为该药物为低溶解性药物，因为其剂量/溶解度的值大于250mL（400mg/1.0mg =

400mL））。渗透性（P，度每秒）定义为药物对正常人空肠壁的渗透性，包括对物质转运到肠膜的表观阻力。高渗透性药物一般是指吸收度超过90%且无此药物在胃肠道不稳定的记录，或者渗透性已通过实验确定的药物）。

Examples例如：

a.Change in the technical grade of an excipient. (Example: Avicel PH102 vs.

Avicel PH200.)

一种辅料技术等级的改变。（例如：Avicel PH102改为Avicel PH200.）

b.Changes in excipients, expressed as percent (w/w) of total formulation, greater

than those listed above for a Level 1 change but less than or equal to the following percent ranges (which represent a two fold increase over Level 1 changes):

辅料用量的改变，以处方总质量的百分比（w/w）计算，大于上述的1类变更，但小于或等于以下百分比范围（其代表超过1类变更2倍的增加）。

These percentages are based on the assumption that the drug substance in the drug product is formulated to 100% of label/potency. The total additive effect of all excipient changes should not change by more than 10%

该百分比是假设产品中的原料药按标签/效价的100%投料，所有辅料的变更累计应不大于10%。

The components (active and excipients) in the formulation should have numerical targets that represent the nominal composition of the product on which any future changes in the composition of the product are to be based. Allowable changes in

the composition should be based on the approved target composition and not on the composition based on previous Level 1 or Level 2 changes.

应明确处方中各组分（包括活性成分和辅料）的具体比例（目标比例），该目标比例代表药品的公称成分，后续的任何产品成分的变更都是基于该目标比例。

在评价药品成分变更能否被接受时，应以最初批准时的目标比例作为比较对象，而不是以前述的发生过1类或2类变更后的处方比例作为比较对象。

2.Test Documentation 实验资料

a.Chemistry Documentation 化学资料

Application/compendial release requirements and batch records.

Stability testing: 1 batch with 3 months accelerated stability data in

supplement and 1 batch on long-term stability.

申报资料/药典要求的资料和批记录。

稳定性试验资料：1批样品的3个月的加速稳定性试验数据（在补充申请中

提供），以及1批样品的长期稳定性试验数据。

b.Dissolution Documentation 溶出研究资料

Case A: High Permeability, High Solubility Drugs情况A：高渗透性、高溶解

性药物

Dissolution of 85% in 15 minutes in 900 mL of 0.1N HCl. If a drug

product fails to meet this criterion, the applicant should perform the

tests described for Case B or C (below).

以900mL 0.1N的HCl溶液为溶出介质，药物的溶出度可在15min

内达到85%。如果药物未达到此标准，那么该药的申报应执行如情

况B或C（下文）所述的试验。

Case B: Low Permeability, High Solubility Drugs 情况B：低渗透性、高溶解

性药物

Multi-point dissolution profile should be performed in the

application/compendial medium at 15, 30, 45, 60 and 120 minutes or

until an asymptote is reached. The dissolution profile of the proposed

and currently used product formulations should be similar.

多点溶出曲线的绘制，应选取申报资料/药典中规定的溶出介质，

取样点应为15，30，45，60和120分钟或直至达到稳态。变更后

的产品应与现行产品的溶出曲线相似。

Case C: High Permeability, Low Solubility Drugs 情况C：高渗透性，低溶解

性药物

Multi-point dissolution profiles should be performed in water, 0.1 N

HCl, and USP buffer media at pH 4.5, 6.5, and 7.5 (five separate

profiles) for the proposed and currently accepted formulations.

Adequate sampling should be performed at 15, 30, 45, 60, and 120

minutes until either 90% of drug from the drug product is dissolved or

an asymptote is reached. A surfactant may be used, but only with

appropriate justification. The dissolution profile of the proposed and

currently used product formulations should be similar.

多点溶出曲线的绘制，应选取水、0.1N的HCl，以及美国药典规定

的3种pH分别为4.5，6.5和7.5的缓冲介质（5条独立的溶出曲线）。

应采用充足的样品进行溶出度试验，取样点应选择15，30，45，

60和120分钟直至药物累计溶出度达到90%或至稳态。可使用表

面活性剂，但其使用只能在有恰当理由的情况下。变更后的产品应

与现行产品的溶出曲线相似。

c.In Vivo Bioequivalence Documentation 体内生物等效性资料

None: if the situation does not meet the description in Case A, Case B or Case

C, refer to Level 3 changes.

不需要：如果变更不满足情况A、B或情况C所描述的情形，请参考第3类

变更。

3.Filing Documentation 归档文件

Prior approval supplement (all information including accelerated stability data);

annual report (long-term stability data).

此前批准的补充文件（所有信息，包括加速稳定性试验数据）；年报（长期稳定

性试验数据）

C.Level 3 Changes 3类变更

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类变更是指可能对制剂质量和性能产生显著影响的变更。

Tests and filing documentation vary depending on the following three factors: therapeutic range, solubility, and permeability.

试验和归档文件根据因三个因素而不同：治疗窗、溶解度、渗透性。

Examples: 例如

a.Any qualitative and quantitative excipient changes to a narrow therapeutic drug

beyond the ranges noted in Section III.A.1.b.

治疗窗狭窄药物处方中辅料的质和量的改变超出章节III.A.1.b.规定的范围。

b.All other drugs not meeting the dissolution criteria under Section III.B.2.b.

其它所有未达到章节III.A.2.b.规定的溶出度标准的药品。

c.Changes in the excipient ranges of low solubility, low permeability drugs

beyond those listed in Section III.A.1.b.

低溶解性、低渗透性药物处方辅料的变更超出了章节III.A.1.b.规定的范围。

d.Changes in the excipient ranges of all drugs beyond those listed in Section

III.B.1.b.

所有药物处方中辅料的变更超出了章节III.B.2.b规定的范围。

2.Test Documentation 试验资料

a.Chemistry Documentation 化学资料

Application/compendial release requirements and batch records.

申报资料/药典要求的资料和批记录。

Significant body of information available: （已积累大量信息的情况）

One batch with three months accelerated stability data reported in

supplement; one batch on long-term stability data reported in annual

report.

在补充申请资料中应提供一批3个月的加速稳定性试验数据；在年

报中提供的一批长期稳定性试验数据。

Significant body of information not available: （未积累大量信息的情况）

Up to three batches with three months accelerated stability data

reported in supplement; one batch on long-term stability data

reported in annual report.

在补充申请资料中应提供3批3个月的加速稳定性试验数据；在年

报中提供一批的长期稳定性试验数据。

b.Dissolution Documentation 溶出研究资料

Case B dissolution profile as described in Section III.B.2.b.

在章节III.B.2.b中规定的情况B的溶出曲线。

c.In Vivo Bioequivalence Documentation 体内生物等效性试验资料

Full bioequivalence study. The bioequivalence study may be waived with an

acceptable in vivo/in vitro correlation has been verified.

完整的生物等效性研究资料。当该药品被证明具有可接受的体内外相关性

时，可以免除生物等效性研究。

3.Filing Documentation 归档文件

Prior approval supplement (all information including accelerated stability data);

annual report (long-term stability data).

此前批准的补充申请文件（所有信息，包括加速稳定性试验数据）；年报（长期

稳定性试验数据）

IV. SITE CHANGES 生产地点变更

Site changes consist of changes in location of the site of manufacture for both company-owned and contract manufacturing facilities and do not include any scale-up changes, changes in manufacturing (including process and/or equipment), or changes in components or composition. Scale-up is addressed in Section V of this guidance. New manufacturing locations should have a satisfactory current Good Manufacturing Practice (CGMP) inspection.

地点的变更包括企业自有的和合同制造企业的生产地点变更，不包括生产规模放大的变更，生产的变更（包括工艺和/或设备），或者药品成分或组成的变更。对于生产规模放大的变更的规定见本指导原则的章节V。新的生产地点应通过CGMP认证。

A.Level 1 Changes 1类变更

1.Definition of Level 定义

Level 1 changes consist of site changes within a single facility where the same equipment, standard operating procedures (SOP's), 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

1类变更是指同一企业内的生产地点改变，但变更前后的生产设备、标准操作规范（SOP’s）、环境条件（比如温度和湿度）、质量控制和人员素质等方面完全一致，批记录中除管理信息和生产地点外，其它内容不得改变。相同的人员素质是指已在该生产地点工作一段时间，且对生产工艺具备足够经验的人员。

2.Test Documentation 试验资料

a.Chemistry Documentation 化学资料

None beyond application/compendial release requirements.

申报资料/药典要求的资料，不需要其它资料。

b.Dissolution Documentation 溶出研究资料

None beyond application/compendial release requirements.

申报资料/药典要求的资料，不需要其它资料

c.In Vivo Bioequivalence Documentation 体内生物等效性资料

None. 不需要

3.Filing Documentation 归档文件

Annual report. 年报

B.Level 2 Changes 2类变更

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 the same equipment, SOP's, 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类变更是指变更前后的生产地点位于毗邻区域，或在毗邻的街区，且变更前后的生产设备，标准操作规范，环境条件（比如温度和湿度）、质量控制和人员素质应完全一致，生产记录中除了管理信息和生产地点外，其它内容不得改变。

2.Test Documentation 试验资料

a.Chemistry Documentation 化学资料

Location of new site and updated batch records. None beyond

application/compendial release requirements.

One batch on long-term stability data reported in annual report.

生产地点的变更声明和最新的批记录。申报资料/药典要求的资料，不需要其它

资料。

在年报中提供一批的长期稳定性试验数据。

b.Dissolution Documentation 溶出研究资料

None beyond application/compendial release requirements.

申报资料/药典要求的资料，不需要其它资料。

c.In Vivo Bioequivalence Documentation 体内生物等效性资料

None. 不需要

3.Filing Documentation 归档文件

Changes being effected supplement; annual report (long- term stability test data).

实施变更的补充申请资料；年报（长期稳定性试验数据）。

C.Level 3 Changes 3类变更

1.Definition of Level 定义

Level 3 changes consist of a 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, the same equipment, SOP's, environmental conditions, and controls should be used in the

manufacturing process at the new site, and no changes may be made to the manufacturing batch records except for administrative information, location and language translation, where needed.

3类变更是指变更前后的生产地点位于不同的区域。不同区域是指位于变更前生产地点的非毗连的地点或非毗邻的街区。达到3类变更的要求，变更前后的生产设备、标准操作规范、环境条件和质量控制应一致，批记录中除了管理信息、生产地点和翻译的语言（如果需要的话）外，其它内容不得改变。

2.Test Documentation 试验资料

a.Chemistry Documentation 化学资料

Location of new site and updated batch records.

Application/compendial release requirements.

生产地点变更声明和最新的批记录。

申报资料/药典要求的资料。

Stability: 稳定性研究资料

Significant body of data available: （已积累大量信息的情况）

One batch with three months accelerated stability data reported in

supplement; one batch on long-term stability data reported in annual

report.

在补充申请资料中应提供一批3个月的加速稳定性试验数据；在年

报中提供的一批长期稳定性试验数据。

Significant body of data not available: （未积累大量信息的情况）

Up to three batches with three months accelerated stability data

reported in supplement; up to three batches on long- term stability data

reported in annual report.

在补充申请资料中应提供3批3个月的加速稳定性试验数据；在年

报中提供3批长期稳定性试验数据。

b.Dissolution Documentation 溶出试验资料

Case B: 情况B：

Multi-point dissolution profile should be performed in the

application/compendial medium at 15, 30, 45, 60 and 120 minutes or

until an asymptote is reached. The dissolution profile of the drug product

at the current and proposed site should be similar.

多点溶出曲线的绘制，应选取申报资料/药典中规定的溶出介质，取样

点应为15，30，45，60和120分钟或直至达到稳态。变更生产地点前

后的产品溶出曲线应相似。

c.In Vivo Bioequivalence Documentation 体内生物等效性试验资料

None. 不需要

3.Filing Documentation 归档文件

Changes being effected supplement; annual report (long-term stability data).

实施变更的补充申请资料；年报（长期稳定性试验数据）。

V. CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN) 批量变更（生产规模的放大/缩小）Postapproval changes in the size of a batch from the pivotal/pilot scale biobatch material to larger or smaller production batches call for submission of additional information in the

application. Scale-down below 100,000 dosage units is not covered by this guidance. All scale-up changes should be properly validated and, where needed, inspected by appropriate agency personnel.

批准后，将生产规模从制备生物批的中试规模（pivotal/pilot scale）进行放大或缩小需要提交补充申请资料。生产规模缩小到10万剂量单位以下的变更不属于本指导原则范畴。对所有生产规模放大的变更均应进行合理的验证，并且必要时应由合适的代理人进行核查。

A.Level 1 Changes 1类变更

1.Definition of Level 定义

Change in batch size, up to and including a factor of 10 times the size of the pilot/biobatch, where: 1) the equipment used to produce the test batch(es) is of the same design and operating principles; 2) the batch(es) is (are) manufactured in full compliance with CGMP's; and 3) the same standard operating procedures (SOP's) 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).

生产规模的变更在原中试规模/生物批的10倍以内，并且与中试规模相比，1）

试验批所用生产设备应具有相同的设计和工作原理；2）生产过程应完全符合

cGMP的要求；3）试验批和全规模生产批应采用相同的标准操作规范、质量控制

方法，以及相同的处方和生产步骤。

2.Test Documentation 试验资料

a.Chemistry Documentation 化学资料

Application/compendial release requirements. Notification of change and

submission of updated batch records in annual report.

One batch on long-term stability reported in annual report.

申报资料/药典要求的资料。批量变更声明和在年报中提交的新的批记录。

b.Dissolution Documentation 溶出研究资料

None beyond application/compendial release requirements.

申报资料/药典要求的资料，不需要其他资料。

c.In Vivo Bioequivalence 体内生物等效性资料

None. 不需要

3.Filing Documentation 归档文件

Annual report (long-term stability data).

年报（长期稳定性试验数据）

B.Level 2 Changes 2类变更

1.Definition of Level 定义

Changes in batch size beyond a factor of ten times the size of the pilot/biobatch, where: 1) the equipment used to produce the test batch(es) is of the same design and operating principles; 2) the batch(es) is (are) manufactured in full compliance with CGMP'S; and 3) the same SOP's 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).

生产规模的变更在中试规模/生物批的10倍以上，并且与中试规模相比，1）试

验批所用生产设备应具有相同的设计和工作原理；2）生产过程应完全符合cGMP

的要求；3）试验批和全规模生产批应采用相同的标准操作规范、质量控制方法，

以及相同的处方和生产步骤。

2.Test Documentation 试验资料

a.Chemistry Documentation 化学资料

Application/compendial release requirements. Notification of change and

submission of updated batch records.

申报资料/药典要求的资料。批量变更声明和在年报中提交的新的批记录。

Stability testing: One batch with three months accelerated stability data and

one batch on long-term stability.

稳定性试验：一批3个月的加速稳定性试验和一批长期稳定性试验。

b.Dissolution Documentation 溶出研究资料

Case B testing. 按情况B进行溶出试验研究。

c.In Vivo Bioequivalence 体内生物等效性资料

None. 不需要

3.Filing Documentation 归档文件

Changes being effected supplement; annual report (long-term stability data).

实施变更的补充申请资料；年报（长期稳定性试验数据）。

VI. MANUFACTURING 生产变更

Manufacturing changes may affect both equipment used in the manufacturing process and the process itself.

生产变更可能造成两方面的影响，即生产过程中使用的设备以及生产工艺本身。

A.Equipment 生产设备的变更

1.Level 1 Changes 1类变更

a.Definition of Change 定义

This category consists of: 1) change from non-automated or non-mechanical

equipment to automated or mechanical equipment to move ingredients; and 2)

change to alternative equipment of the same design and operating principles of

the same or of a different capacity.

设备变更包括：1）将运送物料的非自动化或非机械化的设备改为自动化或

机械化的设备；2）设计和工作原理的相同，但容量相同或不同的设备的变

更。

b.Test Documentation 试验资料

i.Chemistry Documentation 化学资料

Application/compendial release requirements. Notification of change

and submission of updated batch records.

Stability testing: One batch on long-term stability.

申报资料/药典要求的资料。批量变更声明和在年报中提交的新的批

记录。

稳定性试验：一批长期稳定性试验。

ii.Dissolution Documentation 溶出研究资料

None beyond application/compendial release requirements.

申报资料/药典要求的资料，不需要其他资料。

iii.In Vivo Bioequivalence Documentation 体内生物等效性资料

None. 不需要

c.Filing Documentation 归档文件

Annual report (long-term stability data).

年报（长期稳定性试验数据）

2.Level 2 Changes 2类变更

a.Definition of Level 定义

Change in equipment to a different design and different operating principles.

设备的设计和工作原理的改变。

b.Test Documentation 化学资料

i.Chemistry Documentation

Application/compendial release requirements. Notification of change

and submission of updated batch records.

申报资料/药典要求的资料。批量变更声明和在年报中提交的新的批

记录。

Stability testing: 稳定性试验：

Significant body of data available:（已积累大量信息的情况）

One batch with three months accelerated stability data

reported in supplement; one batch on long-term stability

data reported in annual report.

补充申请资料中应提供一批3个月的加速稳定性试验

数据；在年报中提供一批长期稳定性试验数据。

Significant body of data not available:（未积累大量信息的情况）

Up to three batches with three months accelerated

stability data reported in supplement; up to three

batches on long-term stability data reported in annual

report.

补充申请资料中应提供3批3个月的加速稳定性试验

数据；在年报中提供3批长期稳定性试验数据ii.Dissolution Documentation 溶出研究资料

Case C dissolution profile. 情况C的溶出曲线图。

iii.In Vivo Bioequivalence Documentation 体内生物等效性资料

None. 不需要

c.Filing Documentation 归档文件

Prior approval supplement with justification for change; annual report (long-term

stability data).

此前批准的补充申请资料及变更的验证资料；年报（长期稳定性试验数据）

B.Process 生产工艺的变更

1.Level 1 Changes 1类变更

a.Definition of Level 定义

This category includes process changes including changes such as mixing times

and operating speeds within application/validation ranges.

此类所指的工艺变更为在申报/验证范围内的变更，如混合时间和运行速度。

b.Test Documentation 试验资料

i.Chemistry Documentation 化学资料

None beyond application/compendial release requirements.

申报资料/药典要求的资料，不需要其他资料。

ii.Dissolution Documentation

None beyond application/compendial release requirements.

申报资料/药典要求的资料，不需要其他资料。

iii.in Vivo Bioequivalence Documentation 体内生物等效性资料

None. 不需要

c.Filing Documentation 归档文件

Annual report. 年报

2.Level 2 Changes 2类变更

a.Definition of Level 定义

This category includes process changes including changes such as mixing times

and operating speeds outside of application/validation ranges.

此类所指的工艺变更为超出申报/验证范围的变更，如混合时间和运行速度。

b.Test Documentation 试验资料

i.Chemistry Documentation 化学资料

Application/compendial release requirements. Notification of change

and submission of updated batch records.

Stability testing: One batch on long-term stability.

申报资料/药典要求的资料。批量变更声明和在年报中提交的新的批

记录。

稳定性试验：1批长期稳定性试验。

ii.Dissolution Documentation 溶出研究资料

Case B dissolution profile. 情况B的溶出曲线图。

iii.In Vivo Bioequivalence Documentation 体内生物等效性资料

None. 不需要

c.Filing Documentation 归档文件

Changes being effected supplement; annual report (long-term stability data).

此前批准的补充申请资料及变更的验证资料；年报（长期稳定性试验数据）。

3.Level 3 Changes 3类变更

a.Definition of Level 定义

This category includes change in the type of process used in the manufacture of

the product, such as a change from wet granulation to direct compression of dry

powder.

此类所指的变更为用于加工产品的工艺类型的改变，比如由湿法制粒改为粉

末直接压片的变更。

b.Test Documentation 试验资料

i.Chemistry Documentation 化学资料

Application/compendial release requirements. Notification of change

and submission of updated batch records.

申报资料/药典要求的资料。批量变更声明和在年报中提交的新的批

记录。

Stability testing: 稳定性试验

Significant body of data available: （已积累大量信息的情况）

One batch with three months accelerated stability data

reported in supplement; one batch on long-term stability data

reported in annual report.

补充申请资料中应提供一批3个月的加速稳定性试验数据；

在年报中提供一批长期稳定性试验数据。

Significant body of data not available: （未积累大量信息的情况）

Up to three batches with three months accelerated stability

data reported in supplement; up to three batches on

long-term stability data reported in annual report.

补充申请资料中应提供3批3个月的加速稳定性试验数据；

在年报中提供3批长期稳定性试验数据。

ii.Dissolution Documentation 溶出研究资料

Case B dissolution. 按情况B进行溶出研究。

iii.In Vivo Bioequivalence Documentation 体内生物等效性资料

In vivo bioequivalence study. The bioequivalence study may be waived if

a suitable in vivo/in vitro correlation has been verified.

体内生物等效性研究。如果已合理地证明了体内外相关性，可免除生

物等效性研究。

c.Filing Documentation 归档文件

Prior approval supplement with justification; annual report (long-term stability

data).

此前批准的补充申请资料及变更的验证资料；年报（长期稳定性试验数据）。

VII. IN VITRO DISSOLUTION 体外溶出度的研究

See current United States Pharmacopeia/National Formulary, section <711>, for general dissolution specifications. All profiles should be conducted on at least 12individual dosage units.

参见现行版的美国药典/国家处方集，第<711>章。所有溶出曲线都应采用至少12个剂量单位进行试验。

Dissolution profiles may be compared using the following equation that defines a similarity factor (f2): 溶出曲线的相似性可用以下方程进行比较，其中相似性以相似因子f2表示：f2 = 50 LOG {[1+1/n ∑n t=1 (R t -T t )2 ] -0.5 x 100}

where R t and T t are the percent dissolved at each time point. An f2 value between 50 and 100 suggests the two dissolution profiles are similar.

其中R t和T t为各取样点的累计溶出度。f2值在50和100之间时，认为两条溶出曲线相似。

VIII. IN VIVO BIOEQUIVALENCE STUDIES 体内生物等效性研究

Below is a general outline of an in vivo bioequivalence study. It is intended as a guide and the design of the actual study may vary depending on the drug and dosage form.

下文是一个体内生物等效性研究大纲。可将其作为一个研究指南，在实际研究中，可根据药物或剂型改变试验设计。

A.Objective: 目的

To compare the rate and extent of absorption of the drug product for which the

manufacture has been changed, as defined in this guidance, to the drug product

manufactured prior to the change.

为了比较生产变更前后药品的吸收比率和程度。