翻译(SUPACIR指导原则：速释口服固体制剂：放大生产与批准后变更).docx

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 DocumentationSUPAC-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 1995CMC 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）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1II. DEFINITION OF TERMS（术语定义）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3III.COMPONENTS AND COMPOSITION（辅料成分或组成的变更）. . . . . . . . . . . . . . . . . . . . . . . . . 6IV. SITE CHANGES（地点变更） . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13V. CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN)（批量大小（放大/缩小）的变更）. . . . . 16VI. MANUFACTURING（生产变更） . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18VII. IN VITRO DISSOLUTION （体外溶出试验）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23VIII. IN VIVO BIOEQUIVALENCE STUDIES （体内生物等效性）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23IX. REFERENCES（参考文献） . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25APPENDIX A: NARROW THERAPEUTIC RANGE DRUGS（附录A：治疗窗狭窄药物）. . . . . . . . . A-1GUIDANCE FOR INDUSTRY 1IMMEDIATE 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 (NDAs), abbreviated new drug applications (ANDAs), and abbreviated antibiotic applications (AADAs) 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（NDAs）、仿制药申请（ANDAs）和抗生素仿制药申请（AANAS）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 defined by CDERs Office of Compliance or FDAs 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) Apparatus 1 at 100 revolutions per minute (rpm) or Apparatus 2 at 50 rpm.情况A：采用美国药典（USP）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：EXCIPIENT辅料PERCENT EXCIPIENT (w/w) OUT OF TOTAL TARGET DOSAGE FORM WEIGHT辅料与整个片剂重量的百分比（w/w）Filler填充剂5Disintegrant崩解剂Starch淀粉3Other其他1Binder粘合剂0.5Lubricant润滑剂Calcium(Ca) or Magnesium(Mg) Stearate硬脂酸钙或硬脂酸镁0.25Other其他1Glidant助流剂Talc滑石粉1Other其他0.1Film Coat薄膜衣1These 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 + 0.5oC). 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 (Pe, 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）。EXCIPIENT辅料PERCENT EXCIPIENT (w/w) OUT OF TOTAL TARGET DOSAGE FORM WEIGHT辅料与整个片剂重量的百分比（w/w）Filler填