（CGMP）美国药品生产质量管理规范(中英对照)

二○○三年十二月

目     录

 

 

210部分—人用及兽用药品

的生产、加工、包装或贮存的CGMP

Part 210 - CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL

   210.1  cGMP法规的地位

§ 210.1 Status of current good manufacturing practice regulations.

   (a) 在本部分及21CFR 211—226部分中陈述的法规是在药品生产、加工、包装或贮存中使用的现行生产质量管理规范及使用的设施或控制的最低标准，以保证该药品符合联邦食品、药品及化妆品法对安全性的要求，具有均一性和效价(或含量)并符合或代表其生产过程的质量及纯度等特征。

    (a) The regulations set forth in this part and in Parts 211 through 226 of this chapter contain the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess.

(b) 凡是在药品生产、加工、包装或贮存过程中存在任何不符合本部分及21CFR 211—226部分中陈述的法规的药品，依据联邦食品、药品及化妆品法501 (a)(2)-(B)，该药应被视为劣药，同时导致该事故发生的负责人应受相应的法规的制裁。

(b) The failure to comply with any regulation set forth in this part and in Parts 211 through 226 of this chapter in the manufacture, processing, packing, or holding of a drug shall render such drug to be adulterated under section 501(a)(2)(B) of the act and such drug, as well as the person who is responsible for the failure to comply, shall be subject to regulatory action.

   210.2  cGMP法规的适用性

§ 210.2 Applicability of current good manufacturing practice regulations.

(a) 本部分及21CFR 211—226适用于普通药品，21CFR 600—680适用于人用生物制品，除非另有明确规定，否则上述两者之间应该是相互补充而不是相互取代。如有上述两部分的法规不适用的药品，则可用特定的具体法规来替代。

(a) The regulations in this part and in Parts 211 through 226 of this chapter as they may pertain to a drug and in Parts 600 through 680 of this chapter as they may pertain to a biological product for human use, shall be considered to supplement, not supersede, each other, unless the regulations explicitly provide otherwise. In the event that it is impossible to comply with all applicable regulations in these parts, the regulations specifically applicable to the drug in question shall supersede the more general.

(b) If a person engages in only some operations subject to the regulations in this part and in Parts 211 through 226 and Parts 600 through 680 of this chapter, and not in others, that person need only comply with those regulations applicable to the operations in which he or she is engaged.

   210.3 定义

§ 210.3 Definitions.

(a) 在联邦食品、药品及化妆品法201部分中包含的定义和解释、说明适用于21CFR 211—226部分中的术语。

(a) The definitions and interpretations contained in section 201 of the act shall be applicable to such terms when used in this part and in Parts 211 through 226 of this chapter.

(b)  下面定义的术语适用于本部分及21CFR 211—226。

(b) The following definitions of terms apply to this part and to Parts 211 through 226 of this chapter.

    (1)法(Act)

   指联邦食品、药品及化妆品法，修订版(21 U.S.C  301 et seq.)。

(1)Actmeans the Federal Food, Drug, and Cosmetic Act, as amended (21 U.S.C. 301 et seq.).

(2)批(Batch)

指在规定限度内，按照某一生产指令在同一生产周期内生产出来的，具有同一性质和质量的一定数量的药品或其它物料。

(3)组分(Component)

指用于药品生产的所有成份，包括那些未在药品中出现的成份。

(4)药品(Drug Product)

指成品制剂(如：片剂、胶囊剂、口服液等)，通常含有一种活性成份并伴有非活性成份(但不是必需的)。本术语也包括不含有活性成份但作为安慰剂使用的成品制剂。

   (5)纤维(Fiber)

  指长度大于其宽度的3倍的任何微粒状污染物。

   (6)无纤维脱落的过滤器(Non-fiber-releasing filter)

   指任何经过适当的预处理(如清洗或冲洗)后，不会将纤维脱落到已过滤的组分或药品中的所有过滤器。所有含石棉过滤器均被认为是有纤维脱落的过滤器。

   (7)活性成份(Active Ingredient)

   是指所有用于保证药物活性或其他在疾病的诊断、治愈、缓解、治疗或预防中起直接作用，或影响人或其他动物身体结构或功能的组分。本术语包括那些能承受药品生产中的化学变化和为了保证其指定的活性或作用以一种经调整的形式存在于药品中的组分。

  (8)非活性成份(Inactive ingredient)

   指不同于“活性成份”的其他组分。

   (9)中间产品(In-process material)

   是指所有经制备、复合、混合或由化学反应得到的用于药品生产或制备的物料。

   (10)批（lot）

   指一批或是一批中特定的均一部分，在指定的范围内具有相同的性质和质量；或者若为由连续的生产过程制造出的药品，“批”指在单位时间或单位数量生产出的特定的、均一的部分，并且确保该部分在指定的范围内具有均一性质与质量。

   (11)批号(Lot number, control number，batch number)

   指由字母、数字、符号或他们的组合组成，由此可确定某批药品或物料的生产、加工、包装、贮存或销售的情况。

   (12)药品的生产、加工、包装或贮存(Manufacture, processing, packing, or holding of a drug product)

   包括药品的包装和标签操作、检验、质量控制。

   (13)药用物料(medicated feed)

   指在21CFR 558.3中定义的B型和C型药用物料。该物料含有联邦食品、药品及化妆品法201(g)部分中定义的一种或一种以上的药物，药用物料的生产应符合21CFR 226部分中的要求。

   (14)药用预混合料(medicated premix)

   指21CFR 558.3中定义的A型药用物质。该预混合料含有联邦食品、药品及化妆品法201(g)部分中定义的一种或一种以上的药物。药用预混合料生产应符合21CFR 226部分中的要求。

   (15)质量控制部门(Quality control unit)

   指由企业任命负责质量控制相关责任的任何人员或组织机构。

   (16)含量或效价（Strength）

  指：

   (Ⅰ) 原料药的浓度(如：以重量/重量、重量/体积、单位剂量/体积为基础)；和/(或)

   (Ⅱ) 活性(效价)也即由适当的实验室检测或由足够的临床数据得出的指定的药品治疗活性(如：可表达为对照于某标准的单位的术语)。

   (17)理论产量(Theoretical yield)

   指在生产、加工或包装某种药品的任一适当阶段中，并且基于所使用的组分的数量在实际生产中无任何损失或错误的情况下，应能生产的数量。

   (18)实际产量(Actual yield)

  指某种药品在生产、加工、包装的任一适当的阶段实际生产出的数量。

   (19)比率(Percentage of theoretical yield)

  实际产量(生产、加工或包装某种药品的适当阶段)与理论产量(在相同阶段)的比率，以百分数表示。

   (20)验收标准(Acceptance criteria)

   建立在相应的取样方法基础上的药品的质量检验标准和合格、不合格标准(如合格质量水平和不合格的质量水平)，是决定批准或拒收一批(或其他生产单元的小组)药品的必需因素。

   (21)代表性样品(Representative sample)

指一个样品按合理的标准抽取（如随机取样法），并包含若干单位（元），以能保证样品准确描绘被取样品的物料。

(2)Batchmeans a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture.

(3)Componentmeans any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product.

(4)Drug productmeans a finished dosage form, for example, tablet, capsule, solution, etc., that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredients. The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo.

(5)Fibermeans any particulate contaminant with a length at least three times greater than its width.

(6)Non-fiber-releasing filtermeans any filter, which after any appropriate pretreatment such as washing or flushing, will not release fibers into the component or drug product that is being filtered. All filters composed of asbestos are deemed to be fiber-releasing filters.

(7)Active ingredientmeans any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect.

(8)Inactive ingredientmeans any component other than an ``active ingredient.''

(9)In-process materialmeans any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product.

(10)Lotmeans a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits.

(11)Lotnumber, control number, or batch numbermeans any distinctive combination of letters, numbers, or symbols, or any combination of them, from which the complete history of the manufacture, processing, packing, holding, and distribution of a batch or lot of drug product or other material can be determined.

(12)Manufacture, processing, packing, or holding of a drug productincludes packaging and labeling operations, testing, and quality control of drug products.

(13) The termmedicated feedmeans any Type B or Type C medicated feed as defined in 558.3 of this chapter. The feed contains one or more drugs as defined in section 201(g) of the act. The manufacture of medicated feeds is subject to the requirements of Part 225 of this chapter.

(14) The termmedicated premixmeans a Type A medicated article as defined in 558.3 of this chapter. The article contains one or more drugs as defined in section 201(g) of the act. The manufacture of medicated premixes is subject to the requirements of Part 226 of this chapter.

(15)Quality control unitmeans any person or organizational element designated by the firm to be responsible for the duties relating to quality control.

(16)Strengthmeans:

(I) The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or

(ii) The potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard).

(17)Theoretical yieldmeans the quantity that would be produced at any appropriate phase of manufacture, processing, or packing of a particular drug product, based upon the quantity of components to be used, in the absence of any loss or error in actual production.

(18)Actual yieldmeans the quantity that is actually produced at any appropriate phase of manufacture, processing, or packing of a particular drug product.

(19)Percentage of theoretical yieldmeans the ratio of the actual yield (at any appropriate phase of manufacture, processing, or packing of a particular drug product) to the theoretical yield (at the same phase), stated as a percentage.

(20)Acceptance criteriameans the product specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan, that are necessary for making a decision to accept or reject a lot or batch (or any other convenient subgroups of manufactured units).

(21)Representative samplemeans a sample that consists of a number of units that are drawn based on rational criteria such as random sampling and intended to assure that the sample accurately portrays the material being sampled.

(22)Gang-printed labelingmeans labeling derived from a sheet of material on which more than one item of labeling is printed.

[43 FR 45076, Sept. 29, 1978, as amended at 51 FR 7389, Mar. 3, 1986; 58 FR 41353, Aug. 3, 1993]

EFFECTIVE DATE NOTE: At 58 FR 41353, Aug. 8, 1993, 210.3 was amended by adding paragraph (b)(22) effective Aug. 3, 1994.

 

 

A．总   则

Subpart A--General Provisions

211∙1范围

（a）   本部分的条例包含人用或兽用药品制备的现行最低限度的药品生产质量管理规范（GMP）

（b）   在本章里的这些针对药品的现行GMP条例和本章600至800的所有部分针对人用生物制品的现行GMP条例，除非明确另有说明者外，应认为是对本部分条例的补充，而是不代替。本章其他部分或本章600至680各部分和本部分均可适用的条例，前部分的条例可代替本部分条例。

（c）   在考虑经提议的，发表在1978年9月29日联邦注册表（FR）上一项免除时，若产品及其所有成份是以人用物品形式作一般销售和消费且这些产品根据其预期用途，亦可列入药品的范围内，则不应对这些非处方药（OTC）实施本部分条例，直至进一步的通知为止。本章110部分和113至119部分的条例用于鉴别这些变是食品的OTC药品是否按照GMP的要求生产、加工、包装和贮存。

Sec. 211.1 Scope.

(a) The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals.

(b) The current good manufacturing practice regulations in this chapter as they pertain to drug products; in parts 600 through 680 of this chapter, as they pertain to drugs that are also biological products for human use; and in part 1271 of this chapter, as they are applicable to drugs that are also human cells, tissues, and cellular and tissue-based products (HCT/Ps) and that are drugs (subject to review under an application submitted under section 505 of the act or under a biological product license application under section 351 of the Public Health Service Act); supplement and do not supersede the regulations in this part unless the regulations explicitly provide otherwise. In the event of a conflict between applicable regulations in this part and in other parts of this chapter, or in parts 600 through 680 of this chapter, or in part 1271 of this chapter, the regulation specifically applicable to the drug product in question shall supersede the more general.

(c) Pending consideration of a proposed exemption, published in the Federal Register of September 29, 1978, the requirements in this part shall not be enforced for OTC drug products if the products and all their ingredients are ordinarily marketed and consumed as human foods, and which products may also fall within the legal definition of drugs by virtue of their intended use. Therefore, until further notice, regulations under part 110 of this chapter, and where applicable, parts 113 to 129 of this chapter, shall be applied in determining whether these OTC drug products that are also foods are manufactured, processed, packed, or held under current good manufacturing practice.

 

211∙3定义

本章210∙3中的定义适用于本部分。

Sec. 211.3 Definitions.

The definitions set forth in 210.3 of this chapter apply in this part.

 

B．组织与人员

 

211∙22质量控制部门的职责

（a）   本部门有批准和拒收所有成份、药品包装容器、密封件、中间体、包装材料、标签及药品的职责与权力。复查生产记录和权力，保证不产生差错，或若发生差错，保证他们充分调查这差错。本部门负责根据合同，批准或拒收由其它公司生产、加工、包装或贮存的药品。

（b）   适当的实验室检验设备、批准（或拒收）各种成份、药品容器、密封件、包装材料及药品，质量控制部门是可以获得的。

（c）   本部门有批准或驳回影响药品的均一性、效价或含量、质量及纯度的所有程序或规格标准的职责。

（d）   适用于本部门的职责与程序，应成文字材料，并应遵循。

211∙25人员资格

（a）   每位从事药品生产、加工、包装或仓贮工作人员，应接受培训、教育及有实践经验，完成委派的各项职务。培训是按照现行GMP（包括本章中的现行GMP条例和这些条例要求的成文程序）中涉及雇员的内容。邀请合格人员指导，并连续多次培训，保证雇员熟悉现行GMP对他们的要求。

（b）   负责监督药品的生产、加工、包装或仓贮工作的每一个工作人员，应受教育、培训及有经验，完成委派的各项职务。以此作为提供药品具有安全性、均一性、效价或含量、质量及纯度的保证。

（c）   有足够量招待和监督每种药品的生产、加工、包装或仓贮的合格人员。

211∙28人员职责

（a）   从事药品生产、加工、包装或仓贮的人员，应穿着适合于其履行职责的清洁衣服。按需要，头部、脸部、手部、臂部另外罩，防止药物受污染。

（b）   人员保持良好的个人卫生和健康。

（c）   未经监督人员允许，其他人员不能进入限制进入的建筑物和设施。

（d）   任何人，在任何时间，明显地表现出现有影响药品安全性和质量的疾病或开放性`损伤，应避免接触各种成份、药品容器、包装设备、密封件、中间体，直至监督人员结对药品有不利影响的健康情况。

211∙34顾问

为了对问题提出意见，聘请顾问。顾问应对药品生产、加工、包装或仓贮提出建议，他们受过足够的教育、培训，且有丰富的实践经验。保留他们的姓名、地址、任何的顾问资格及服务形式等履历资料。

Subpart B--Organization and Personnel

Sec. 211.22 Responsibilities of quality control unit.

(a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.

(b) Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit.

(c) The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.

(d) The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.

 

Sec. 211.25 Personnel qualifications.

(a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.

(b) Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess.

(c) There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product.

 

Sec. 211.28 Personnel responsibilities.

(a) Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform. Protective apparel, such as head, face, hand, and arm coverings, shall be worn as necessary to protect drug products from contamination.

(b) Personnel shall practice good sanitation and health habits.

(c) Only personnel authorized by supervisory personnel shall enter those areas of the buildings and facilities designated as limited-access areas.

(d) Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug products shall be excluded from direct contact with components, drug product containers, closures, in-process materials, and drug products until the condition is corrected or determined by competent medical personnel not to jeopardize the safety or quality of drug products. All personnel shall be instructed to report to supervisory personnel any health conditions that may have an adverse effect on drug products.

 

Sec. 211.34 Consultants.

Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained. Records shall be maintained stating the name, address, and qualifications of any consultants and the type of service they provide.

 

 

 

C．厂房和设施

 

211∙42设计与建造特征

（a）   任何用于某类药品生产、加工、包装或贮存的厂房或建筑群，大小适宜，结构与位置使其易于清洁、保养、适合操作。

（b）   建筑物有足够空间来有条理地安装设备和放置材料，避免不同类的成份、药品容器、密封件、标签、中间体或药品等相互混放，防止污染。通过厂房的上述物料其流向在设计时要防止污染。

（c）   操作应在明确规定的、大小适中的地区内进行。这些地区内进行。这些地区按规定各自分隔开，以防止污染。下列操作须在单独的地区内进行：

（1）   发放给生产或包装前，质量控制部门取样期间，成份、药品容器、密封件及标签的签收、鉴别、贮存及拒收。

（2）   在处理前，拒收的成份、药品容器、密封件及标签的贮存。

（3）   已发放的成份、药品容器、密封件及标签的贮存。

（4）   中间体的贮存。

（5）   生产与加工操作。

（6）   包装和贴标签操作。

（7）   药品发放前的隔离贮存。

（8）   发放后药品的贮存。

（9）   控制室与实验室操作。

（10）无菌操作及有关操作。

（Ⅰ）地板、墙壁和天花板平滑、坚硬、表面易清洁；

（Ⅱ）温度与湿度控制

（Ⅲ）空气经高效过滤器、在正压下过滤、层流或非层流均可；

（Ⅳ）环境监测系统；

（Ⅴ）创造无菌环境、房间和设备清洁、消毒系统；

（Ⅵ）控制无菌环境的设备维修系统。

（d）青霉素生产、加工及包装设备与生产其他人用药品的设备分开。

211∙44照明

所有地区均须提供充足的照明。

211∙46通风、空气过滤、空气加热与冷却

（a）   提供足够的通风。

（b）   提供足够能控制空气正压、微生物、尘土、温度和湿度的设备，适应药品生产、加工和贮存需要。

（c）   空气过滤系统，包括预过滤器和微粒物质空气过滤器。空气经过滤才送至生产区，如果空气是再循环到生产区，应测量尘埃含量，控制从生产区带来的尘埃。在生产区、生产中发生空气污染，应以排气系统或其他系统充分抽出空气，控制污染。

（d）   青霉素生产、加工和包装的空气输送系统应与其他人用药品的空气输送系统完全分开。

211∙48管件

（a）   在持续正压下，应对药品无污染的管道系统内供应饮用水。饮用水应符合环境保护机构制订的“基本饮用水条例”标准（40CFR141部分）。不符合该标准的水，不许进入水系统。

（b）   排水设备应有足够的大小，可直接连接排水管及安装防止虹吸倒流的空气破坏设备或其他机械设备。（43FR45077，1978年9月29日，修正于48FR11426，1983年3月18日）。

211∙50污水和废料

来自水厂和附近建筑物的污水、垃圾及其他废料，用安全、卫生的方法处理。

211∙52洗涤和盥洗设备

提供洗涤和盥洗设备，包括热、冷水、肥皂、清洁剂、空气干燥器或专用毛巾及进入厕所的清洁设备。

211∙56

（a）   所有用作药品生产、加工、包装及贮存的三房应保持清洁、卫生的环境，且不受啮齿动物、鸟类及其他害虫侵害扰（实验动物除外）。垃圾和有机废料，定时以卫生的方法控制处理。

（b）   填写分配卫生清洁任务的详细的清洁项目、方法、设备、用于清洁厂房和设施的材料的一览表。

（c）   填写适用的杀鼠剂、杀昆虫剂、杀真菌剂、熏蒸剂、去垢剂和消毒剂一览表。防止这些物品对设备、成份、药品容器密封件、包装材料、标签或药品污染。除依据联邦杀虫剂、杀真菌剂及杀鼠剂法规（7U.S.C135）已登记和使用的品种外，其他的不用。

211∙58保养

任何用于药品生产、加工、包装或贮存的厂保持良好状态。

 

Subpart C--Buildings and Facilities

Sec. 211.42 Design and construction features.

(a) Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.

(b) Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mixups between different components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The flow of components, drug product containers, closures, labeling, in-process materials, and drug products through the building or buildings shall be designed to prevent contamination.

(c) Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures:

(1) Receipt, identification, storage, and withholding from use of components, drug product containers, closures, and labeling, pending the appropriate sampling, testing, or examination by the quality control unit before release for manufacturing or packaging;

(2) Holding rejected components, drug product containers, closures, and labeling before disposition;

(3) Storage of released components, drug product containers, closures, and labeling;

(4) Storage of in-process materials;

(5) Manufacturing and processing operations;

(6) Packaging and labeling operations;

(7) Quarantine storage before release of drug products;

(8) Storage of drug products after release;

(9) Control and laboratory operations;

(10) Aseptic processing, which includes as appropriate:

(i) Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable;

(ii) Temperature and humidity controls;

(iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar;

(iv) A system for monitoring environmental conditions;

(v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions;

(vi) A system for maintaining any equipment used to control the aseptic conditions.

(d) Operations relating to the manufacture, processing, and packing of penicillin shall be performed in facilities separate from those used for other drug products for human use.

[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]

 

Sec. 211.44 Lighting.

Adequate lighting shall be provided in all areas.

 

Sec. 211.46 Ventilation, air filtration, air heating and cooling.

(a) Adequate ventilation shall be provided.

(b) Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product.

(c) Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas. If air is recirculated to production areas, measures shall be taken to control recirculation of dust from production. In areas where air contamination occurs during production, there shall be adequate exhaust systems or other systems adequate to control contaminants.

(d) Air-handling systems for the manufacture, processing, and packing of penicillin shall be completely separate from those for other drug products for human use.

 

Sec. 211.48 Plumbing.

(a) Potable water shall be supplied under continuous positive pressure in a plumbing system free of defects that could contribute contamination to any drug product. Potable water shall meet the standards prescribed in the Environmental Protection Agency's Primary Drinking Water Regulations set forth in 40 CFR part 141. Water not meeting such standards shall not be permitted in the potable water system.

(b) Drains shall be of adequate size and, where connected directly to a sewer, shall be provided with an air break or other mechanical device to prevent back-siphonage.

[43 FR 45077, Sept. 29, 1978, as amended at 48 FR 11426, Mar. 18, 1983]

 

Sec. 211.50 Sewage and refuse.

Sewage, trash, and other refuse in and from the building and immediate premises shall be disposed of in a safe and sanitary manner.

 

Sec. 211.52 Washing and toilet facilities.

Adequate washing facilities shall be provided, including hot and cold water, soap or detergent, air driers or single-service towels, and clean toilet facilities easily accesible to working areas.

 

Sec. 211.56 Sanitation.

(a) Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a clean and sanitary condition, Any such building shall be free of infestation by rodents, birds, insects, and other vermin (other than laboratory animals). Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner.

(b) There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed.

(c) There shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product containers, closures, packaging, labeling materials, or drug products and shall be followed. Rodenticides, insecticides, and fungicides shall not be used unless registered and used in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135).

(d) Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations.

 

Sec. 211.58 Maintenance.

Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a good state of repair.

 

 

 

D．设备Subpart D--Equipment

 

211∙63设备的设计、尺寸及位置

药品生产、加工、包装或贮存设备，设计合理，大小适当，布置合理，便于操作、清洁和保养。

Sec. 211.63 Equipment design, size, and location.

Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.

 

211∙65设备制造

（a）   设备表面与各种成人中间体或药品接触，不产生化学反应和作用。保证药品的安全性、均一性、效价或含量、质量或纯度改变。

（b）   操作所需之物质，如滂沱剂、冷却剂等不能进入设备里，与成人药品容器、封口物品、中间体或药品接触，保证药品的安全性、均一性、效价或含量、质量或纯度不变。

Sec. 211.65 Equipment construction.

(a) Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

(b) Any substances required for operation, such as lubricants or coolants, shall not come into contact with components, drug product containers, closures, in-process materials, or drug products so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

 

211∙67设备清洁与保养

（a）   相隔一定时间，对设备与工具进行清洁、保养和消毒，防止出故障与污染，影响药品的安全性、均一性、效价或含量、质量或纯度。

（b）   制订药品生产、加工包装或贮存设备（包括用具）的清洁和保养文字程序，并执行。这些程序包括，但不一定限于以下内容；

（1）   分配清洁、保养任务。

（2）   保养和清洁细目一览表。

（3）   详细说明用于清洁和保养的设备、物品和方法。拆卸和装配设备的方法必须保证适合清洁和保养的要求。

（4）   除去或擦去前批遗留物的鉴定。

（5）   已清除了污染的清洁设备的保护。

（6）   使用前检查清洁的设备。

（7）   保留保养、清洁、消毒的记录。按211∙180及211∙182的说明检查。

211∙68自动化设备、机械化设备和电子设备

（a）   用于药品生产、加工、包装和贮存的自动化、机械化或电子包括计算机或其它类型的设备。按惯例，对其设计之成文条款作标定、检查或核对，保证其工作性能良好。保留检查、标定、核对等文字记录。

（b）   对保障重要生产变化的计算机或有关系统进行操作培训。操作记录或其他记录只能由被认可的人员制订。向计算机或有关系统输入或从中输出的各种方案、其他记录或资料，应核查其准确性。输入计算机或关系统内的档案资料，除与实验室共同分析计算的结果可消除外，其他的应保留。文字记录与相应的证明资料一起保存。事先设计好的硬件复制品或多各选择系统，台复印件、磁带或微型胶卷等，保证其支持资料正确、可靠及完整。出现资料改动、非人为消除或遗失时，应维修。

Sec. 211.67 Equipment cleaning and maintenance.

(a) Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

(b) Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following:

(1) Assignment of responsibility for cleaning and maintaining equipment;

(2) Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules;

(3) A description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance operations, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance;

(4) Removal or obliteration of previous batch identification;

(5) Protection of clean equipment from contamination prior to use;

(6) Inspection of equipment for cleanliness immediately before use.

(c) Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified in 211.180 and 211.182.

 

Sec. 211.68 Automatic, mechanical, and electronic equipment.

(a) Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.

(b) Appropriate controls shall be exercised over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel. Input to and output from the computer or related system of formulas or other records or data shall be checked for accuracy. The degree and frequency of input/output verification shall be based on the complexity and reliability of the computer or related system. A backup file of data entered into the computer or related system shall be maintained except where certain data, such as calculations performed in connection with laboratory analysis, are eliminated by computerization or other automated processes. In such instances a written record of the program shall be maintained along with appropriate validation data. Hard copy or alternative systems, such as duplicates, tapes, or microfilm, designed to assure that backup data are exact and complete and that it is secure from alteration, inadvertent erasures, or loss shall be maintained.

[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]

211∙72过滤器

用于生产、加工的液体过滤器或人用注射药品的包装材料不许释放出纤维的进入产品。除非不得以，不在生产、加工中使用释放纤维的过滤器或注射药品的包装材料。若必须使用一种能释放纤维素的过滤器，最后应使用一非释放纷纷物、平均最大孔径为0.22μm(如实际生产条件限制，可用0.45μm)的附加过滤器过滤，降低注射剂内微粒量。使用含石板的过滤器最后用或不用特殊非释放纤维过滤器均可以，但要根据FDA有关部门提供的该非释放纤维过滤器会或可能损害注射剂的安全性和有效性的证据而定。

Sec. 211.72 Filters.

Filters for liquid filtration used in the manufacture, processing, or packing of injectable drug products intended for human use shall not release fibers into such products. Fiber-releasing filters may not be used in the manufacture, processing, or packing of these injectable drug products unless it is not possible to manufacture such drug products without the use of such filters. If use of a fiber-releasing filter is necessary, an additional non-fiber-releasing filter of 0.22 micron maximum mean porosity (0.45 micron if the manufacturing conditions so dictate) shall subsequently be used to reduce the content of particles in the injectable drug product. Use of an asbestos-containing filter, with or without subsequent use of a specific non-fiber-releasing filter, is permissible only upon submission of proof to the appropriate bureau of the Food and Drug Administration that use of a non-fiber-releasing filter will, or is likely to, compromise the safety or effectiveness of the injectable drug product.

E．成分、药品容器和密封件控制

Subpart E--Control of Components and Drug Product Containers and Closures

 

211∙80总要求

（a）    有文字详细说明成份、药品容器、密封件的签收、鉴定、贮存、装运取样、检验和批准或拒收程序，并遵循。

（b）    成份、药品容器和密封件应专人管理和在防止污染的环境下贮存。

（c）    药品容器的包装袋或包装箱或密封件应离地面放置保持适当间隔，全球清洁和检查。

（d）    用明显的已接收的每装货量中的批号代码对成分、药品容器或密封件加以鉴别。此代码用于记录每批货的放置地方。对每批货的情况，如隔离、批准或拒收等作检查。

Sec. 211.80 General requirements.

(a) There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures; such written procedures shall be followed.

(b) Components and drug product containers and closures shall at all times be handled and stored in a manner to prevent contamination.

(c) Bagged or boxed components of drug product containers, or closures shall be stored off the floor and suitably spaced to permit cleaning and inspection.

(d) Each container or grouping of containers for components or drug product containers, or closures shall be identified with a distinctive code for each lot in each shipment received. This code shall be used in recording the disposition of each lot. Each lot shall be appropriately identified as to its status (i.e., quarantined, approved, or rejected).

211∙82未检验的成份、药品容器和密封件的接收与贮存

（a）   接收时和验收前，对每个或编组的成份容器、药品容器和密封件进行目检，给内容物、容器损坏或拆封和污染等情况作适当的标志。

（b）   成份、药品容器各密封件应隔离贮存，直至经检验为止。合格，可发放。在符合211∙80要求的地区中贮存。

211∙84成份、药品容器和封口物品的试验、批准或拒收

（a）       每批成份、药品容器和封口物品，在未经质量部门取样、检查合格前，不准使用。检验合格后发放使用。

（b）       收集每批的每一装货量的代表性样品，供检验用。

容数目和每一容器里物质的取样量是有适当的标准的，例如，成份的变异性统计学标准、可信限、要求的精密度、供应商过去的质量历史、21∙170要求分析和留样所需的数量等。

（c）       收集样品程序；

（1）   用适当的方法，清洁选出成份容器；

（2）   打开容器，取样，重新封口，防止其内容物受污染和其他成分、药品容器或密封件的污染。

（3）   必要时，使用灭菌设备和无菌取样技术。

（4）   如果需要从容器顶部、中部和底部的成分中取样，样品须混合。

（5）   鉴定样品容器，目的是确定如下资料：被取样的材料名称、批号、被取样的容器，取样日期及样品收集人的名字等。

（6）   已取样的容器，应作标志，表示样品已取出。

（d）       样品检验程序：

（1）   一个药品的每个成分，最少做一个特性试验。如有专一特性实验就应采用。

（2）   依照所有成文的规格标准检验每个成份的纯度、含量和质量。生产厂家代替上述试验。规定生产厂家最少要做个成份特别试验，可承认；这些成分的供应者扫提供的分析报告。规定隔一定时间，生产厂家定期验证供应午的试验结果，证明供应者的分析结果是正确的。

（3）   依照成文规程，检验容器和密封件。生产厂家代替上友谊赛试验，规定生产厂家对这些容器或封口物品，最少做一次目检。可承认供应者的检验证书。规定生产厂家定期验证供应者的试验结果，证明其试验结果是正确的。

（4）   必要时，用显微镜检测成分。

（5）   每批易受污物、昆虫或其他外来杂物污染的某一成份、药品容器或密封件，鉴于其预期用途，在使用前，应做微生物试验。

（e）任何批号的成份、药品容器或密封件，若符合已成文的均一性、效价或含量、质量、纯度等的规格标准和本部分（d）的有关试验，可批准使用。任何批号的上述材料，不符合这些规格，应拒收。

211∙86获准作用的成份、药品容器和密封件，先入库者先用。若产生的偏差是暂时的和适当，这种偏差是容许的。

211∙87获准的成份、药品容器和密封件的复检

经质量控制部门批准或拒收的成份、药品容器密封件，若长期贮存或曝露在空气、热或其他可能对其产生不良影响的环境后，应依照211∙84，对均一性、效价或含量、质量、纯度等复检。

211∙89拒收的成份、药品容器和封口物品

拒收的成份、药品容器和封口物品应经鉴定和在隔离系统下加以控制，防止在生产和加工使用。

211∙94药品密封容器和密封件

（a）   药品包装容器和密封件应不起反应、不吸着、不吸附、不致改变药品的安全性、均一性、含量或效价、质量和纯度而超出制定的或其它颁布的规定要求。

（b）   容器封口系统应对贮藏和使用过程中可预见的能引起药品变质或污染的外部因素提供足够的防护。

（c）   药品容器和密封件应清洁、灭菌和除热原，保证其适用于预期目的。

（d）   药品容器和密封件的标准或规格、检验方法（指清洁和消毒方法、除热原过程）应成文并遵循。

 

F  .生产和加工控制

 

211∙100成文的规程、偏差

（a）   编写为保证药品的均一性、含量或效价、质量及纯度而设计的生产和加工控制程序，这些程序包括本部内全部要求。这些成文程序（包括变化）须经有关部门起草、复查和批准，然后再经质量控制部门复查与批准。

（b）   在实施各种生产和加工控制功能中，遵循已制定的生产和加工控制程序，并在招待时以文件加以证明。程序中出现的任何偏差，应作记录，并提出证据。

211∙101成分的进料

成文的生产和控制程序包括下面的内容，其设计应保证所生产的药品具有核武器原有的均一性、含量和效价、质量和纯度。

（a）  按处方配制的药品，保证其活性成份含量不低于100%标示量或规定量。

（b）  生产药品用的成份应称量、测量或适当粉碎。若一种成份从原来容器转移到另一容器内，用下列资料以鉴别：

(1)     成份名称或项目代码。

(2)     接收或控制号。

(3)     在新容器中的重量或份量。

(4)     使用此成分2配制的一批药品，包含其产品名称、含量和批号。

（c）成份的称重、测量或粉碎操作，应受到严密的监督。所盛成份已用于生产的每一容器，须经第二人检查，保证：

（1）   此成份是由质量控制人员发放的。

（2）   重量或份量正确，批生产记录一致。

（3）   容器经严格鉴别。

（d）每一成份投料时，一人操作，另一人核对。

211∙103产量计算

在药品生产、加工或贮存的每一适当阶段结束时，测算实际产量与理论产量的百分比。

211∙105设备鉴别

（a）   在整个生产周期内，同批药品生产使用的全部混合和贮存容器、生产线和主要设备应严格识别，标示出药品的成份，需要时，不须标出所处的加工阶段。

（b）   一种药品每批生产使用的主要设备，以一鉴别性识别号或代号加以识别。此鉴别号或代号记录在该批号产品的记录本。若生产中只使用一种特殊型号的设备，可用该设备名字代替鉴别性识别或代号。

211∙110中间体和药品的取样与检验

（a）   制订和遵循说明每批的加工过程控制及对加工过程中材料的适当样品实行检验或检查的成文程序，保证药品的一致性和完整性。上述控制程序包括，但不限于如下内容：

（1）   片剂或胶囊的重量变化。

（2）   崩解时间。

（3）   充分混和，保证均匀。

（4）   溶解时间和溶解速率。

（5）   溶液的澄明度、溶解完全性及PH值。

（b）   考虑上述特性而制定的有效中间加工规格与药品最终规格一致。此中间加工规格应在以前可靠的加工方法稳定性评估和经应用统计学程序断定认为合适的基础上制定的。样品测试，保证药品和中间体符合规格标准。

（c）   在生产加工期间，如在重要阶段的开始、由质量控制部门审定，决定联取舍。

（d）   不合格的中间体，在隔离系统下鉴别及控制，防止其在征税或加工操作中使用。

211∙111生产时间限制

在适当时候，制定完成每一生产阶段的时间限制，保证药品质量。制定的时间限制产生偏差，如这些偏差不损害药品质量，是可以接受的。这些偏差应有文字文件证明是正当的。

211∙113微生物污染的控制

（a）   制订和遵循预防不需消毒药品有害微生物的适当程序。

（b）   制订和遵循预防已消毒药品微生物污染的适当程序。这些程序包括所有消毒过程的验证。

211∙115返工

（a）   制订和遵循指导人合格批号返工及保证返工批号达标的程序。

（b）   没有质量控制部门复检与批准，不许进行返工。

 

G.包装和标签控制

 

211∙122材料的检查和使用标准

（a）   制订详细标签和包装材料的接收、鉴别、贮存、半年取样检验的程序，并遵循这些成文程序。在接收、用于药品包装和贴标签前，有代表性地对其取样与检验。

（b）   符合成文规格标准的标签和包装材料，可批准发放使用。不符合规格者，不得用于生产。

（c）   接收每批不同标签和包装材料，无须签收、测试。无论是接收或拒收，须保留其记录。

（d）   用于不同药品、含量、剂型及成份数量的标签和标示材料分别贮存，并持上适当牌证，只限经核准人员接近贮存地区。

（e）   作废和陈旧的标签、标示材料及其他包装材料应销毁。

（f）   排字印刷在不同药品或同一药品不同规格的品种上`使用排字印刷，考虑在印刷期间和印刷后，印刷品的设置、切裁和管理等，应制订包装和标签工作专门控制程序。

（g）   在药品印标签的生产线，其上的或与其有关的印刷设备应受到临近，保证所有印痕与本批产品记录中说明的印痕一致。

211∙125标签的发放

（a）   严格控制已发放的，用于药品的标签。

（b）   已发放的一批标签材料，须认真检查其无一性，应与一批或单批生产记录中说明的标签一致。

（c）   核对发放的，已使用的及回收的标签，若发现成品数量与发出的标签数量不符，差额超出根据历史水平先前定下的数量范围，则需对这些偏差作出评估，按照211∙192要求调查原因。

（d）   超出有关批号或控制号标签，全部应销毁。

（e）   回收的标签，如保留应加上证明标志贮存，防止混淆。

（f）   制订发放标签的详细控制程序，并遵循。

211∙130包装和标签操作

设计保证标签、标示及包装材料正确用于药品的程序，并遵循。这些程序结合下列

（a）   预防混合和由物理的或其他操作空间物质引起的交叉

（b）   带批号或控制呈药品的鉴别，检查该药品的制造和控制历史。

（c）   包装工作开展前，检查包装和标签材料的适用性和正确性，且这些检验所提供的证明文件应符合批生产记录。

（d）   使用前，立即检查包装和贴标签设备，保证 所有药品离开先前的操作，同时移开不适用于随后操作的包装材料。检查结果以批生产记录形式提供证明文件。

211∙132人用百处方药（OTC）保险包装的要求

（a）   一般来说，在联邦食品、药物和化妆品法规下，FDA有权制定非处方药保险包装的统一国家要求。提高非处方药包装的可靠性和有助保证非自主药的安全与效果。一种零售OTC药品（皮肤科药、牙粉、胰岛素、喉片除外）没有包装在保险包装内或或没有适当的标签，根据联邦法规501部分，属掺假药；根据502部分或两者，飞行属错贴标签。

（b）   保险包装每个生产者和包装者，应将零售OTC药品装入保险包装内，若此药易受公众影响，该药应在内保持至售出。

保险包装是内有一个或多个批示物或障碍物的药品包装。若缺损或失落，能适当地给顾客提供已发生破损的明显证据如果因缺损而使产品受损，则要求此包装在设计上应有特色（例如喷雾产品容器）或使用一个或多个有鉴别性性批示物或障碍物加进包装内（例如图案、名称、注册商标、标识或图画等）。上述“在设计上有特色”之意，即此包装不能用一般的通用材料和加工工艺来复制。术语“喷雾产品”即用液化气体或压缩气体交容器中成份喷出。一具保险包装可以是能提供目视其中包装完整性的密闭容器、第二容器 、封闭系统或任何联合系统。这些保险装置被设计成在生产、分装和销售陈列期间，以适当方法搬运，保持不致受损坏。

（1）   两段式明胶硬胶囊产品，除非包装工艺密封的外，最少需二个保险装置。

（2）   所有其他产品，包括经保险工艺密封的二段式明胶硬胶囊，最少需要一个保险装置。

（c）   标签。除在易拆安瓿中氨吸入物、本部分的（b）节规定的喷雾产品或压缩医用氧容器外，本部分涉及的非处方药的每个零售包装，要求带有一“声明”放置在一明显的地方，使顾客对包装的特殊保险装置有所警觉。此标签“声明”不要求放置于适当的地方，当包装的保险装置破损或失落时，不受影响。如果选择符合本部分（b）节要求的保险装置是使用鉴别我的话，那要参考标签“声明”。例如，在带有一皱缩套的瓶上的标签“声明”应写“为了此瓶周围印有标志”。

（d）   申请免除对包装和标签的要求。生产者和馐者可申请免除本部分对包装和标签的要求。一个免除申请，要求按本章10∙30，以公民申请形式提交，且根据“免除保险包装申请条例”加以鉴别。申请所需之内容如下：

（1）   药品名称。若申请的是某一类药，需列出类名，并列出该类药中的产品表。

（2）   药品没必要实施或不能达到本部门的保险包装或标签的要求的理由。

（3）   选择的措施的可行性报告；申请者已采取的措施的可行性报告；减少产品或药品种类掺假的可能性的报告。

（4）   证明免除是合理的其他资料。

（e）   非处方药受已被批准的新药申请管辖。要求非处方药原被批准的新药申请持有人，根据本章314∙70（c）提供的那样，可在FDA批准前实施。根据本章314∙70（b），胶囊密封的生产改进需FDA先批准。

（f）   1970年毒物预防包装条例。本部分不影响本章310∙3（L）规定的特殊包装的任何要求和1970年毒物保护包装条例的要求（经管理和预算处批准，控制号091 0149）[54联邦注册5228，1989年2月2日]。

211∙134药品检查

（a）   已包装和贴标签的产品，在结束工作时，应检查，保证本批容器和包装的标签正确无误。

（b）   操作结束时，每组收集一个代表性样品，同时检查标签。

（c）   检查结果记录在谬论批的生产或控制记录中。

211∙137有效期

（a）   保证一个产品在使用时符合均一性、效价或含量、质量和纯度等标准，应提供一个有效期。有效期按211∙166所友谊赛的稳定性试验测定。

（b）   有效期是在符合标签上规定的贮存条件下，按211∙166所述的稳定性试验测定。

（c）   基药品在配制时要重新配伍，那重新配伍好的和未重新配伍的两种药品标签上均须提供有效日期。

（d）   根据本章201∙17的要求，有效日期标在标签上。

（e）   顺势治疗（homeopathic）药品免除本部分的要求。

（f）   标“没有美国效价标准”的变应原撮物免除本部分要求。

（g）   若人用非处方药品标签没有提供剂量范围，同时，经至少三年稳定性资料证明其是稳定的，可不实施本部分的要求。[43联邦注册45077，1978年9月29日，修正，在46联邦56412，1981年11月17日]。

 

H．贮存和销售

 

211∙142入库程序

制订和遵循药品入库程序，包括：

（a）   药品发放前，由质量控制部门待验。

（b）   药品在适当的温度、湿度和光线下贮存，不影响药品的均一性、效价或含量、质量及纯度。

211∙150销售程序

制订和遵循药品销售程序，包括：

（a）   最早批准库存的药品，应先销售。若违背本要求的地方是暂时和适可的，这是允许的。

（b）   通过每批药品的销售系统，能迅速检查药品，若有必要，便于撤回。

 

I∙实验室控制

 

211∙160总要求

（a）   按本部分的要求，制订规格、标准、取样方法、试验程序或其他实验室控制机制，包括上述内容的修改，由有关部门起草和复查，并经质量控制部门批准。遵守本部分中各要求，在实施时，提供证明文件。任何对成文的规格、标准、取样方法、试验程序或其他实验室控制机制的改动，应作记录，并提供证明这些改动是正确的。

（b）   实验室控制内容，包括科学地制订完善、合理的规格、标准、取样方法及为保证各种成份、药品容器、密封件、中间体、标签和药品符合均一性、效价和含量、质量与纯度标准而设计的检验程序。实验室控制包括：

（1）   根据接收的规格、测定用于药品生产、加工包装及贮存的每装货量中的每批的成份、药品容器、密封件和标签。保证它们符合制定的规格标准。此规格包括使用的取样和检验程序说明。样品有代表性及经适当鉴别。这些程序亦要求对任何变质的成份、药品容器或密封件作重复检验。

（2）   根据中间体的成文规格和取样及检验程序，测定中间体。样品应有代表性和经适当鉴定。

（3）   若仪器设备、量具和记录装置的准确度和/或精密度范围不符，按照制订的成文方案，包括具体说明书，一览表，准确度和精确度范围及作用条款，在适当时间间隔内，对这些仪器设备进行标定。不符合已制定规格的仪器、设备不能使用。

211∙165销售要求检验与发放

（a）   发放前每批药品须经实验室测定，保证其符合药品的最终规格标准，包括特性和活性成份的含量。对有效期短的，需无菌和/或热原试验的放射药物特殊批号，可在上述试验完成前发放，规定尽快完成试验。

（b）   要求无有害微生物的药品，根据需要，每批药品应有适当的实验室检验。

（c）   任何取样和检验计划，应在成文程序中说明。此程序包括取样方法和每批检验的联合批号。

（d）   对质量控制部门的取样和检验的接收标准是满足保证那些药品符合各自的规格标准和统计学的质量控制标准。；这些标准是批准和发放药品的条件。此统计学质量控制标准包括适当的接收水平和/或适当的拒收水平。

（e）   证实和提供文件证明经严格使用的检验方法的准确性、灵敏性、特异性和重复性。此验证和证明，可按照211∙194（a）(2)项完成。

（f）   不符合制订的标准、规格和其他有关质量控制标准的药品，应拒收，但可返工。被 返工的药品。在接收和应用前，须符合标准、规格和其他有关标准。

211∙166稳定性试验

（a）   有一个设计确定药品稳定性的成文试验方案。此试验用于测定合适的贮存条件和有效期。成文方案包括：

（1）   样品量和试验时间间隔。此间隔是基于各自的检查特征的统计学标准而定，保障稳定性评价的正确性。

（2）   保留样品的贮存条件。

（3）   可靠的、有意义的各具体的试验方法。

（4）   同一容器-密闭系统内正在销售药品的检验。

（5）   配制时，配伍的药品（按标签指出的）和配制后的药品的检验。

（b）   每个药品有足够批号受检，测定一个适当的有效期，保留这些资料的记录。结合成份，药品及容器-封闭系统的基本稳定性资料的“加速研究”，用于支持提供足够的货架寿命的实验性有效期是不合适的，而且，这种研究正在实行。使用“加速研究”提供的资料，设计一实验性有效期，此有效期是后于由实际货架研究支持的日期。必须有实施的稳定性试验，包括适当的时间间隔的药品检验，直至此实验性有效期被证实或被确定为止。

（c）   本部分对顺势治疗药品的要求如下：

（1）   对各成份间的可配伍性，有一个基于药品的检验或测定的稳定性文字评价。同时，根据药品销售经验，指出政党的或预期的服用期内，药品没有变质。

（2）   稳定性评价应建立在正点销售的同一容器-封闭系统药品的基础上。

（d）   标有“没有美国效价标准”变应原提取物，免除本部分要求[43联邦注册4507，1978年9月29日，修正，在46联邦56412，1981年11月17日]

211∙167特别检验要求

（a）   标明无菌和/或无热原的每批药品，应有检查符合此要求的实验室检验。检验程序应成文遵循。

（b）   每批眼膏，应有测定符合有关外部微粒，粗糙或磨蚀物质存在的规格检验。检验程序应成文并遵循。

（c）   每批控释制剂都有一实验室检验，测定每一活性成份药品的最后一批的有效期满后三个月。

211∙170样品保存

（a）   每一装货量的活性成份经鉴别后，留样。留样最少二倍于满足全部测定所需样品数量为准，无菌和热原检验所需量除外。测定活性成份量否符合其制订的规格。

（1）   药品中的活性成份。除本忍气吞声（a）（1）和（3）友谊赛及的外，留样按该药量后一批有效期后计，保留一年。

（2）   放射性药品中的活性成份（非放射活性试剂盒除外）的留样保留：

Ⅰ）如果药品注明有效期是三十天或以内，保留期是含此活性成份药品的最后一批的有效期满后三个月。

Ⅱ）如果药品注明有效期是三十天或以上，保留期是含此活性成份药品的最后一批的有效期满后六个月。

（3）   根据211∙137免除有效期的非处方药，其活性成分留样，是含此活性成份药品的最后一批药品销售后三年。

（b）经鉴别，代表每批药品的留样，地药品标签指定的条件贮存。留样贮存在盛销售药品的同样容器封闭系统内或基本上有相同我的容器系统内。留样最少二总倍于数应满足检验需要量，无菌和热原检验的留样除外。每年至少目检留样（除（b）（2）中述及的药品外）一次，检查其变质发问，除非目检会影响留样的完整性。对留样变质迹象，根据211∙192加以研究。检查结果的记录和该药品的稳定性资料一起保留。医用压缩不保留。药品留样保留时间如下：

（1）除本部分（b）（2）和（3）中述及的药品外的药品，留样保留时间是该药有效期满后一年。

（2）除非放射性试剂盒外，放射活性药品的留样保留。

Ⅰ）如药品有效期为三十天或以内，则该药品有效期满后保留三个月；

Ⅱ）如有效期超过三十天，则药品有效期满后保留六个月。

（3）非处方药品，根据211∙137，免除有效期，留样从销售最后一批药品计，保留三年[48联邦注册130251983年3月29日]。

211∙173实验动物

饲养和控制用于检测成份、加工过程中材料或药品规格的动物，保证其适合预期的用途。鉴定动物，并保留表明其应用情况的记录。

211∙176青霉素污染

若一非青霉素药品有可能被青霉素交叉感染，此非青霉素药品应检查青霉素的存在。按药品中青霉素污染和测量程序（通过参考文献具体化）中指出的方法检验，如达到可检出水平，该药品不许销售。文件可从研究和检测部门（HFD470）药品评价和研究中心、FDA、200C St.Sw.Washington DC 2024,或从联邦注册处（1100L St.Nw.,Washington,DC2048）得到。

[43FR45077，1978年9月29日，增补在；47FR9396，1982年3月5日；50FR8996，1985年3月6日；55FR11577，1990年3月29日]。

 

J．记录和报告

 

211∙180总要求

（a）任何生产、控制或销售记录，须依照本部分要求特别是与一批药品有关的上述记录，在该批药品有效期满后，保留一年以上。一些无有效期的非处方药品，由于它们符合211∙137的标准，在该批药品销售后，保留三年。

（b）全部成份，药品容器、密封件及标签的记录，在有效期满后，保留一年以上。一些无有效期的非处方药品，由于它们符合211∙137规定的免除的标准，故从销售最后一批药品计，上述记录保留三年。

（c）本部分要求的全部记录或它们的复印品，应便于在保存期内对活性成份的复核检验。因此，人微言轻检验的部分，这些记录应以光电复印或其他方法复制。直接从电子计算机或其它设备中提出的记录，符合本段的要求。

（d）本部分要求的记录，可用原始记录或复印件，如光电复印、缩微胶卷，应适合阅读器和光电复印设备的使用。

（e）保留本部分所要求的文字记录，其中的资料可用作评价至少一个年度每个药品的质量标准，决定药品的规格、生产或控制程序中需要屐的地方。制订文字程序、遵循这些评价，并包括下列条款：

（1）每一批复查一次，是否批准或拒收，与此有关的记录。

（2）投诉、撤销、退回或报废药品的复查，按211∙192对每个药品进行调查。

（f）应建立程序以保证企业负责人责任。如果他们没注意或不知道上述的要求，以书面形式，将按211∙198、211∙204或211∙208等条款实施的任何调查结果、任何撤销、FDA发出的检测报告或与FDA通过的GMP有关的，受规章限制的任何活动等通知他们。

211∙182设备清洁和使用记录

主要设备的清洁、维修（常规维修，如润滑、调整等除外）和使用文字记录，包括在单独的设备记录内。此记录列有日期、时间、产品和加工批号等内容。若设备用于生产一种药品，那么，不要求单独设备记录。药品批号（单批或整批）应按号码排列，且按号顺生产。使用的设备，其清洁、维修和使用记录是整批记录的一部分。实施和双查清洁和维修的人员，填写日期、签名和填写工作记录。记录同伯登记，按年月顺序进行。

211∙184成份、药品容器、密封件及标签记录

这些记录包括如下内容：

（a）每批成份、药品容器、密封件和标签的每一装货量的鉴别与数量，供应商名称；供应商的批号（如知道）、按21∙80指定的接收代码、接收日期。主要生产商的名称和地址，若有不同的供应商，造表列出（如知道）。

（b）任何检验结果（包括按211∙82（a）211∙84(d)或211∙122（a）的要求进行的检验结果）和从那里得到的结论。

（c）每个成份、药品容器、密封件的单独存货记录和每批使用的成份核对表（对各成份来说）。此存货记录应有使用各成份、药品容器和密封件的各批（整批或小批）药品的详细测定资料。

（d）按211∙122（c）和211∙130（c）制订的规定，检查或复查标签和贴标签所提供的文件。

（e）拒收的成份、药品容 器、密封件和标签的处理。

211∙186主要生产和控制的记录

（a）保障批与批间的一致性，制备各批药品的主要生产和控制记录（包括各批的量），由一人填写日期和签名（全名、手签）。由另一个单独核实，填写日期和签名。此主要生产和控制记录的制备，由一文字程序加以说明，并要遵循。

（b）主要生产和控制记录包括：

（1）产品名称、会计师和剂型的说明。

（2）药品各活性成份的名称和每剂量单位或每重量单位的重量或容量。任何剂量单位的总重量或容量的说明。

（3）一个完整的，以名字或代码表示的成份表格，充分、显示具体的质量特性。

（4）准确表明各成份的重量或容量，各成份使用同一计量系统（公制、常衡或药衡制）。由于制备而不可避免地造成该剂型中杨份量的改变，如果它们在该主要生产和控制记录中被证明是正确的，这种合理的变动是允许的。

（5）有关任何成份的计算超过量的说明。

（6）在适当加工阶段，理论重量或容量的说明。

（7）理论产量的说明，包括根据211∙192要求，对超过理论产量最大和最小百分率的调查说明。

（8）药品容器、密封件和包装材料的说明，包括标签和全部其它标签的样本或复制件的说明。这些样本或复制件经对此负责的人员签名和注明日期。

（9）完善的生产和控制指令，取样和检验程序、各种规格标准，各种特殊的注解和各种预防方法均需遵照执行。

211∙188批生产和控制记录

每批生产的药品有批的生产和控制记录，包括每批有关生产和控制的完整资料。这些记录包括：

（a）适当的主要生产或控制记录、复查、注明的日期及签名的准确复制件。

（b）完成本批的生产、加工、包装、贮存中各项重要措施须提供的资料，包括：

（1）日期。

（2）使用的重要设备和生产线的特性。

（3）每批使用的成份或中间体的具体

（4）加工过程中使用的成份的重量和容量。

（5）加工过程和实验室控制结果。

（6）使用前、后，包装和贴标签地区的检查。

（7）在适当加工阶段，实际产量的说明和理论百分数的说明。

（8）完整的标签控制记录，包括全部使用的标签样本或复制件。

（9）药品容器和密封件的说明。

（10） 已经完成的取样。

（11） 生产中，招待和直接监督或复查各个重要过程的人员身份证明。

（12） 任何的调查，按211∙192进行。

（13） 检查结果，211∙134处理。

211∙192产品记录复查

所有药品生产和控制记录，包括包装和标签记录，须按全部已制订通过的程序复查和认可。此复查和认可应在该批药品发放或销售前完成。一些非解释性差异（包括超过在主要生产和控制记录中制订的最大或最小百分数的理论产量的百分数）或一批或任何一个成份不符合其规格中任一项，则应作彻底调查，不管这批药品是否已销售。这种调查应提高扩展到该同一药品的其他批号和与此具体的不合格或差异相联系的其它药品。应写成文字记录，包括结论和继续跟踪。

211∙194实验室记录

（a）实验室记录包括保证符合已制订的规格和标准的全部完整的检验（包括检查和分析）资料。

（1）与接收的检验用样品有关的资料：来源（取样地方）、数量、批号或其他的特性代码，定期样品的取样日期及检验用样品的接收日期。

（2）样品检验方法的说明。此说明应指出制订样品检验方法的资料出处，通过这些检验方法，确保样品符合现行准确标准（若使用的方法是在最新修订版美国药典、国家处方集、官方的分析化学协会（ABABC）、分析方法类书籍或在其它公认的标准文献或在一已批准的新药申请中详述，此文献方法不修改。应用的试验方法，在实际使用条件下考证是否适用（从Association of Official Analytical Chemists 2200 Wilson Blvd，Suite 400,Arlington,VA22201 3301）。

（3）相应的各个检验用样品的重量或容量的说明。

（4）各检验过程中获得的全部资料的完整记录，包括：实验仪器测定成份、药品容器、密封件、中间体或药品的全部图表、曲线和光谱及检验的批量。

（5）与检验有关的全部计算记录，包括测量单位、换算系数和相量系数。

（6）说明为何交检验结果与被检的成份、药品容器、密封件、中间体或药品的已制订的特性、含量或效价、质量和纯度标准作比较的过程。

（7）每个检验人员签名及完成日期。

（8）依照制订的标准，由另一人员复查原始记录的准确性和完整性。复查人签名。

（b）保留检验过程中任何修改已制订、应用的检验方法的完整记录。此记录包括修改的原因和证明检验结果同修改前方法的结果同样准确的可靠资料。

（c）保留任何检验和实验室参考标准、试剂和标准溶液的完整记录。

（d）保留按211∙160（b）(4)的要求，定期校正实验室仪器器具和量具、记录装置的完整记录。

（e）保留按21∙166要求实施的全部稳定性试验的完整记录。[43FR45077，1978年9月29日，修正，55FR11577，1990年3月29日]

211∙196销售记录

销售记录包括产品名称和含量与效价及该剂型的说明、收货人的姓名和地址、装运日期和数量、药品批号或控制号。对压缩医用气体产品，销售记录不要求包括批号或控制号。（经管理和预算处根据控制号0910 0139批准）[49FR45077，1978年9月29日]

211∙198投诉档案

（a）    制订和遵循说明处理麦收药品有关的全部文字和口头投诉的成文程序。此程序包括经质量控制部门复查这一条款。任一投诉中，药品有任一项不符合其规格的可能性，则根据211∙192，对该药品进行测定，作一调查。这些程序不应应包括复查条款，检查此投诉是否再出现严重的和意外的不良反应。根据本章310∙305，不良反应须向FDA报告。

（b）    每个投诉的文字记录保存在药品专用档案内。与该药品投诉有关的档案，保存在生产、加工或包装该药品的企业中，若存放于别的地方会更有利于检查，可在那里保存。涉及一药品的文字记录，从该品的有效期满计，保存一年以上或从收到投诉日期计，保存一年不管哪个长，由时间较长者决定。在某些缺少有效期的非处方药品的情况下，由于它们符合211∙137中免除条例，故这些文字记录的保存时间应是从该药品销售后三年。

（1）   投诉文字记录包括如下资料：发现地方、药品名称、含量或效价、批号、投诉者姓名、投诉性质及答复投诉等。

（2）    执行211∙192中的调查，包括此调查和跟踪中的发现。调查报告记录或其复印件，根据211∙180（c），保存在作该调查的企业中。

（3）    若没有执行211∙192中的调查，此文字报告应包括没必要调查的原因和负责此检查的负责人姓名。[43FR 45077，1978年9月29日，修正51FR 24479，1986年7月3日]。

 

K．退回的药品和回收处理

 

211∙204退回的药品

退回的药品按原样作鉴定和保存。应考虑退回药品在退回前或退回期间的贮存、装运条件或原药品容器、纸板盒或标签是否有问题由于贮存或装运的原因，令人怀疑药品的安全性、均一性、含量或效价、质量或纯度有问题，除非经检验、检查或调查，证明此药品符合其安全、均一性、含量或效价、质量或纯度标准，否则，应将退回药品毁坏。但药品可返工，保证其符合标准、规格和特性。退回药品的记录应保存，记录包括退回药品的名称、制剂的功效、批号（控制号或整批批号）、退货原因及数量、销售日期及最终销售日期。若退货原因牵涉到多批产品，应依照211∙192药品的加收处理。

遭受不良贮存条件（包括极高的温度、湿度、烟薰蒸气、压力、贮存期过长、天灾造成的辐射、为灾或仪器失灵等）影响的药品，不必回收和不准销售。每当有药品是否受上述条件影响的问题存在时，只有当下列情况时才可进行回收药品工作。

（a）    实验室检验和鉴别（包括那里可提供的动物饲养研究）证明完全符合均一性、含量或效价、质量或纯度标准。

（b）    检查药品及其有关包装，证明其没有遭到天灾或事故等不适当贮存条件的影响。可接受特殊感观的检查，但仅作药品符合均一性、含量或效价、质量或纯度标准的补充证据记录包括药品名称、批号、销售等，且须保存。

Sec. 211.82 Receipt and storage of untested components, drug product containers, and closures.

(a) Upon receipt and before acceptance, each container or grouping of containers of components, drug product containers, and closures shall be examined visually for appropriate labeling as to contents, container damage or broken seals, and contamination.

(b) Components, drug product containers, and closures shall be stored under quarantine until they have been tested or examined, as appropriate, and released. Storage within the area shall conform to the requirements of 211.80.

 

Sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures.

(a) Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit.

(b) Representative samples of each shipment of each lot shall be collected for testing or examination. The number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon appropriate criteria such as statistical criteria for component variability, confidence levels, and degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve where required by 211.170.

(c) Samples shall be collected in accordance with the following procedures:

(1) The containers of components selected shall be cleaned where necessary, by appropriate means.

(2) The containers shall be opened, sampled, and resealed in a manner designed to prevent contamination of their contents and contamination of other components, drug product containers, or closures.

(3) Sterile equipment and aseptic sampling techniques shall be used when necessary.

(4) If it is necessary to sample a component from the top, middle, and bottom of its container, such sample subdivisions shall not be composited for testing.

(5) Sample containers shall be identified so that the following information can be determined: name of the material sampled, the lot number, the container from which the sample was taken, the date on which the sample was taken, and the name of the person who collected the sample.

(6) Containers from which samples have been taken shall be marked to show that samples have been removed from them.

(d) Samples shall be examined and tested as follows:

(1) At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.

(2) Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.

(3) Containers and closures shall be tested for conformance with all appropriate written procedures. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/closures by the manufacturer and provided that the manufacturer establishes the reliability of the supplier's test results through appropriate validation of the supplier's test results at appropriate intervals.

(4) When appropriate, components shall be microscopically examined.

(5) Each lot of a component, drug product container, or closure that is liable to contamination with filth, insect infestation, or other extraneous adulterant shall be examined against established specifications for such contamination.

(6) Each lot of a component, drug product container, or closure that is liable to microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.

(e) Any lot of components, drug product containers, or closures that meets the appropriate written specifications of identity, strength, quality, and purity and related tests under paragraph (d) of this section may be approved and released for use. Any lot of such material that does not meet such specifications shall be rejected.

[43 FR 45077, Sept. 29, 1978, as amended at 63 FR 14356, Mar. 25, 1998]

 

Sec. 211.86 Use of approved components, drug product containers, and closures.

Components, drug product containers, and closures approved for use shall be rotated so that the oldest approved stock is used first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.

 

Sec. 211.87 Retesting of approved components, drug product containers, and closures.

Components, drug product containers, and closures shall be retested or reexamined, as appropriate, for identity, strength, quality, and purity and approved or rejected by the quality control unit in accordance with 211.84 as necessary, e.g., after storage for long periods or after exposure to air, heat or other conditions that might adversely affect the component, drug product container, or closure.

 

Sec. 211.89 Rejected components, drug product containers, and closures.

Rejected components, drug product containers, and closures shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.

 

Sec. 211.94 Drug product containers and closures.

(a) Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.

(b) Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.

(c) Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.

(d) Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.

 

Subpart F--Production and Process Controls

Sec. 211.100 Written procedures; deviations.

(a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.

(b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.

 

Sec. 211.101 Charge-in of components.

Written production and control procedures shall include the following, which are designed to assure that the drug products produced have the identity, strength, quality, and purity they purport or are represented to possess:

(a) The batch shall be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient.

(b) Components for drug product manufacturing shall be weighed, measured, or subdivided as appropriate. If a component is removed from the original container to another, the new container shall be identified with the following information:

(1) Component name or item code;

(2) Receiving or control number;

(3) Weight or measure in new container;

(4) Batch for which component was dispensed, including its product name, strength, and lot number.

(c) Weighing, measuring, or subdividing operations for components shall be adequately supervised. Each container of component dispensed to manufacturing shall be examined by a second person to assure that:

(1) The component was released by the quality control unit;

(2) The weight or measure is correct as stated in the batch production records;

(3) The containers are properly identified.

(d) Each component shall be added to the batch by one person and verified by a second person.

 

Sec. 211.103 Calculation of yield.

Actual yields and percentages of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product. Such calculations shall be performed by one person and independently verified by a second person.

 

Sec. 211.105 Equipment identification.

(a) All compounding and storage containers, processing lines, and major equipment used during the production of a batch of a drug product shall be properly identified at all times to indicate their contents and, when necessary, the phase of processing of the batch.

(b) Major equipment shall be identified by a distinctive identification number or code that shall be recorded in the batch production record to show the specific equipment used in the manufacture of each batch of a drug product. In cases where only one of a particular type of equipment exists in a manufacturing facility, the name of the equipment may be used in lieu of a distinctive identification number or code.

 

Sec. 211.110 Sampling and testing of in-process materials and drug products.

(a) To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited to, the following, where appropriate:

(1) Tablet or capsule weight variation;

(2) Disintegration time;

(3) Adequacy of mixing to assure uniformity and homogeneity;

(4) Dissolution time and rate;

(5) Clarity, completeness, or pH of solutions.

(b) Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. Examination and testing of samples shall assure that the drug product and in-process material conform to specifications.

(c) In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g., at commencement or completion of significant phases or after storage for long periods.

(d) Rejected in-process materials shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.

 

Sec. 211.111 Time limitations on production.

When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented.

 

Sec. 211.113 Control of microbiological contamination.

(a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.

(b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.

 

Sec. 211.115 Reprocessing.

(a) Written procedures shall be established and followed prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to insure that the reprocessed batches will conform with all established standards, specifications, and characteristics.

(b) Reprocessing shall not be performed without the review and approval of the quality control unit.

 

Subpart G--Packaging and Labeling Control

Sec. 211.122 Materials examination and usage criteria.

(a) There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials; such written procedures shall be followed. Labeling and packaging materials shall be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a drug product.

(b) Any labeling or packaging materials meeting appropriate written specifications may be approved and released for use. Any labeling or packaging materials that do not meet such specifications shall be rejected to prevent their use in operations for which they are unsuitable.

(c) Records shall be maintained for each shipment received of each different labeling and packaging material indicating receipt, examination or testing, and whether accepted or rejected.

(d) Labels and other labeling materials for each different drug product, strength, dosage form, or quantity of contents shall be stored separately with suitable identification. Access to the storage area shall be limited to authorized personnel.

(e) Obsolete and outdated labels, labeling, and other packaging materials shall be destroyed.

(f) Use of gang-printed labeling for different drug products, or different strengths or net contents of the same drug product, is prohibited unless the labeling from gang-printed sheets is adequately differentiated by size, shape, or color.

(g) If cut labeling is used, packaging and labeling operations shall include one of the following special control procedures:

(1) Dedication of labeling and packaging lines to each different strength of each different drug product;

(2) Use of appropriate electronic or electromechanical equipment to conduct a 100-percent examination for correct labeling during or after completion of finishing operations; or

(3) Use of visual inspection to conduct a 100-percent examination for correct labeling during or after completion of finishing operations for hand-applied labeling. Such examination shall be performed by one person and independently verified by a second person.

(h) Printing devices on, or associated with, manufacturing lines used to imprint labeling upon the drug product unit label or case shall be monitored to assure that all imprinting conforms to the print specified in the batch production record.

[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41353, Aug. 3, 1993]

 

Sec. 211.125 Labeling issuance.

(a) Strict control shall be exercised over labeling issued for use in drug product labeling operations.

(b) Labeling materials issued for a batch shall be carefully examined for identity and conformity to the labeling specified in the master or batch production records.

(c) Procedures shall be used to reconcile the quantities of labeling issued, used, and returned, and shall require evaluation of discrepancies found between the quantity of drug product finished and the quantity of labeling issued when such discrepancies are outside narrow preset limits based on historical operating data. Such discrepancies shall be investigated in accordance with 211.192. Labeling reconciliation is waived for cut or roll labeling if a 100-percent examination for correct labeling is performed in accordance with 211.122(g)(2).

(d) All excess labeling bearing lot or control numbers shall be destroyed.

(e) Returned labeling shall be maintained and stored in a manner to prevent mixups and provide proper identification.

(f) Procedures shall be written describing in sufficient detail the control procedures employed for the issuance of labeling; such written procedures shall be followed.

[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354, Aug. 3, 1993]

 

Sec. 211.130 Packaging and labeling operations.

There shall be written procedures designed to assure that correct labels, labeling, and packaging materials are used for drug products; such written procedures shall be followed. These procedures shall incorporate the following features:

(a) Prevention of mixups and cross-contamination by physical or spatial separation from operations on other drug products.

(b) Identification and handling of filled drug product containers that are set aside and held in unlabeled condition for future labeling operations to preclude mislabeling of individual containers, lots, or portions of lots. Identification need not be applied to each individual container but shall be sufficient to determine name, strength, quantity of contents, and lot or control number of each container.

(c) Identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch.

(d) Examination of packaging and labeling materials for suitability and correctness before packaging operations, and documentation of such examination in the batch production record.

(e) Inspection of the packaging and labeling facilities immediately before use to assure that all drug products have been removed from previous operations. Inspection shall also be made to assure that packaging and labeling materials not suitable for subsequent operations have been removed. Results of inspection shall be documented in the batch production records.

[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354, Aug. 3, 1993]

 

Sec. 211.132 Tamper-evident packaging requirements for over-the-counter (OTC) human drug products.

(a)General.The Food and Drug Administration has the authority under the Federal Food, Drug, and Cosmetic Act (the act) to establish a uniform national requirement for tamper-evident packaging of OTC drug products that will improve the security of OTC drug packaging and help assure the safety and effectiveness of OTC drug products. An OTC drug product (except a dermatological, dentifrice, insulin, or lozenge product) for retail sale that is not packaged in a tamper-resistant package or that is not properly labeled under this section is adulterated under section 501 of the act or misbranded under section 502 of the act, or both.

(b)Requirements for tamper-evident package.(1) Each manufacturer and packer who packages an OTC drug product (except a dermatological, dentifrice, insulin, or lozenge product) for retail sale shall package the product in a tamper-evident package, if this product is accessible to the public while held for sale. A tamper-evident package is one having one or more indicators or barriers to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. To reduce the likelihood of successful tampering and to increase the likelihood that consumers will discover if a product has been tampered with, the package is required to be distinctive by design or by the use of one or more indicators or barriers to entry that employ an identifying characteristic (e.g., a pattern, name, registered trademark, logo, or picture). For purposes of this section, the term "distinctive by design" means the packaging cannot be duplicated with commonly available materials or through commonly available processes. A tamper-evident package may involve an immediate-container and closure system or secondary-container or carton system or any combination of systems intended to provide a visual indication of package integrity. The tamper-evident feature shall be designed to and shall remain intact when handled in a reasonable manner during manufacture, distribution, and retail display.

(2) In addition to the tamper-evident packaging feature described in paragraph (b)(1) of this section, any two-piece, hard gelatin capsule covered by this section must be sealed using an acceptable tamper-evident technology.

(c)Labeling.(1) In order to alert consumers to the specific tamper-evident feature(s) used, each retail package of an OTC drug product covered by this section (except ammonia inhalant in crushable glass ampules, containers of compressed medical oxygen, or aerosol products that depend upon the power of a liquefied or compressed gas to expel the contents from the container) is required to bear a statement that:

(i) Identifies all tamper-evident feature(s) and any capsule sealing technologies used to comply with paragraph (b) of this section;

(ii) Is prominently placed on the package; and

(iii) Is so placed that it will be unaffected if the tamper-evident feature of the package is breached or missing.

(2) If the tamper-evident feature chosen to meet the requirements in paragraph (b) of this section uses an identifying characteristic, that characteristic is required to be referred to in the labeling statement. For example, the labeling statement on a bottle with a shrink band could say "For your protection, this bottle has an imprinted seal around the neck."

(d)Request for exemptions from packaging and labeling requirements.A manufacturer or packer may request an exemption from the packaging and labeling requirements of this section. A request for an exemption is required to be submitted in the form of a citizen petition under 10.30 of this chapter and should be clearly identified on the envelope as a "Request for Exemption from the Tamper-Evident Packaging Rule." The petition is required to contain the following:

(1) The name of the drug product or, if the petition seeks an exemption for a drug class, the name of the drug class, and a list of products within that class.

(2) The reasons that the drug product's compliance with the tamper-evident packaging or labeling requirements of this section is unnecessary or cannot be achieved.

(3) A description of alternative steps that are available, or that the petitioner has already taken, to reduce the likelihood that the product or drug class will be the subject of malicious adulteration.

(4) Other information justifying an exemption.

(e)OTC drug products subject to approved new drug applications.Holders of approved new drug applications for OTC drug products are required under 314.70 of this chapter to provide the agency with notification of changes in packaging and labeling to comply with the requirements of this section. Changes in packaging and labeling required by this regulation may be made before FDA approval, as provided under 314.70(c) of this chapter. Manufacturing changes by which capsules are to be sealed require prior FDA approval under 314.70(b) of this chapter.

(f)Poison Prevention Packaging Act of 1970.This section does not affect any requirements for "special packaging" as defined under 310.3(l) of this chapter and required under the Poison Prevention Packaging Act of 1970.

(f)Poison Prevention Packaging Act of 1970.This section does not affect any requirements for "special packaging" as defined under 310.3(l) of this chapter and required under the Poison Prevention Packaging Act of 1970.

[54 FR 5228, Feb. 2, 1989, as amended at 63 FR 59470, Nov. 4, 1998]

 

Sec. 211.134 Drug product inspection.

(a) Packaged and labeled products shall be examined during finishing operations to provide assurance that containers and packages in the lot have the correct label.

(b) A representative sample of units shall be collected at the completion of finishing operations and shall be visually examined for correct labeling.

(c) Results of these examinations shall be recorded in the batch production or control records.

 

Sec. 211.137 Expiration dating.

(a) To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing described in 211.166.

(b) Expiration dates shall be related to any storage conditions stated on the labeling, as determined by stability studies described in 211.166.

(c) If the drug product is to be reconstituted at the time of dispensing, its labeling shall bear expiration information for both the reconstituted and unreconstituted drug products.

(d) Expiration dates shall appear on labeling in accordance with the requirements of 201.17 of this chapter.

(e) Homeopathic drug products shall be exempt from the requirements of this section.

(f) Allergenic extracts that are labeled "No U.S. Standard of Potency" are exempt from the requirements of this section.

(g) New drug products for investigational use are exempt from the requirements of this section, provided that they meet appropriate standards or specifications as demonstrated by stability studies during their use in clinical investigations. Where new drug products for investigational use are to be reconstituted at the time of dispensing, their labeling shall bear expiration information for the reconstituted drug product.

(h) Pending consideration of a proposed exemption, published in the Federal Register of September 29, 1978, the requirements in this section shall not be enforced for human OTC drug products if their labeling does not bear dosage limitations and they are stable for at least 3 years as supported by appropriate stability data.

[43 FR 45077, Sept. 29, 1978, as amended at 46 FR 56412, Nov. 17, 1981; 60 FR 4091, Jan. 20, 1995]

 

Subpart H--Holding and Distribution

Sec. 211.142 Warehousing procedures.

Written procedures describing the warehousing of drug products shall be established and followed. They shall include:

(a) Quarantine of drug products before release by the quality control unit.

(b) Storage of drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity of the drug products are not affected.

 

Sec. 211.150 Distribution procedures.

Written procedures shall be established, and followed, describing the distribution of drug products. They shall include:

(a) A procedure whereby the oldest approved stock of a drug product is distributed first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.

(b) A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary.

 

Subpart I--Laboratory Controls

Sec. 211.160 General requirements.

(a) The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit. The requirements in this subpart shall be followed and shall be documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified.

(b) Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall include:

(1) Determination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products. The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified. Such procedures shall also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration.

(2) Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. Such samples shall be representative and properly identified.

(3) Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products. Such samples shall be representative and properly identified.

(4) The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.

 

Sec. 211.165 Testing and release for distribution.

(a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on specific batches of shortlived radiopharmaceuticals, such batches may be released prior to completion of sterility and/or pyrogen testing, provided such testing is completed as soon as possible.

(b) There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms.

(c) Any sampling and testing plans shall be described in written procedures that shall include the method of sampling and the number of units per batch to be tested; such written procedure shall be followed.

(d) Acceptance criteria for the sampling and testing conducted by the quality control unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release. The statistical quality control criteria shall include appropriate acceptance levels and/or appropriate rejection levels.

(e) The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with 211.194(a)(2).

(f) Drug products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant critieria.

 

Sec. 211.166 Stability testing.

(a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include:

(1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability;

(2) Storage conditions for samples retained for testing;

(3) Reliable, meaningful, and specific test methods;

(4) Testing of the drug product in the same container-closure system as that in which the drug product is marketed;

(5) Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted.

(b) An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained. Accelerated studies, combined with basic stability information on the components, drug products, and container-closure system, may be used to support tentative expiration dates provided full shelf life studies are not available and are being conducted. Where data from accelerated studies are used to project a tentative expiration date that is beyond a date supported by actual shelf life studies, there must be stability studies conducted, including drug product testing at appropriate intervals, until the tentative expiration date is verified or the appropriate expiration date determined.

(c) For homeopathic drug products, the requirements of this section are as follows:

(1) There shall be a written assessment of stability based at least on testing or examination of the drug product for compatibility of the ingredients, and based on marketing experience with the drug product to indicate that there is no degradation of the product for the normal or expected period of use.

(2) Evaluation of stability shall be based on the same container-closure system in which the drug product is being marketed.

(d) Allergenic extracts that are labeled "No U.S. Standard of Potency" are exempt from the requirements of this section.

[43 FR 45077, Sept. 29, 1978, as amended at 46 FR 56412, Nov. 17, 1981]

 

Sec. 211.167 Special testing requirements.

(a) For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements. The test procedures shall be in writing and shall be followed.

(b) For each batch of ophthalmic ointment, there shall be appropriate testing to determine conformance to specifications regarding the presence of foreign particles and harsh or abrasive substances. The test procedures shall be in writing and shall be followed.

(c) For each batch of controlled-release dosage form, there shall be appropriate laboratory testing to determine conformance to the specifications for the rate of release of each active ingredient. The test procedures shall be in writing and shall be followed.

 

Sec. 211.170 Reserve samples.

(a) An appropriately identified reserve sample that is representative of each lot in each shipment of each active ingredient shall be retained. The reserve sample consists of at least twice the quantity necessary for all tests required to determine whether the active ingredient meets its established specifications, except for sterility and pyrogen testing. The retention time is as follows:

(1) For an active ingredient in a drug product other than those described in paragraphs (a) (2) and (3) of this section, the reserve sample shall be retained for 1 year after the expiration date of the last lot of the drug product containing the active ingredient.

(2) For an active ingredient in a radioactive drug product, except for nonradioactive reagent kits, the reserve sample shall be retained for:

(i) Three months after the expiration date of the last lot of the drug product containing the active ingredient if the expiration dating period of the drug product is 30 days or less; or

(ii) Six months after the expiration date of the last lot of the drug product containing the active ingredient if the expiration dating period of the drug product is more than 30 days.

(3) For an active ingredient in an OTC drug product that is exempt from bearing an expiration date under 211.137, the reserve sample shall be retained for 3 years after distribution of the last lot of the drug product containing the active ingredient.

(b) An appropriately identified reserve sample that is representative of each lot or batch of drug product shall be retained and stored under conditions consistent with product labeling. The reserve sample shall be stored in the same immediate container-closure system in which the drug product is marketed or in one that has essentially the same characteristics. The reserve sample consists of at least twice the quantity necessary to perform all the required tests, except those for sterility and pyrogens. Except for those for drug products described in paragraph (b)(2) of this section, reserve samples from representative sample lots or batches selected by acceptable statistical procedures shall be examined visually at least once a year for evidence of deterioration unless visual examination would affect the integrity of the reserve sample. Any evidence of reserve sample deterioration shall be investigated in accordance with 211.192. The results of the examination shall be recorded and maintained with other stability data on the drug product. Reserve samples of compressed medical gases need not be retained. The retention time is as follows:

(1) For a drug product other than those described in paragraphs (b) (2) and (3) of this section, the reserve sample shall be retained for 1 year after the expiration date of the drug product.

(2) For a radioactive drug product, except for nonradioactive reagent kits, the reserve sample shall be retained for:

(i) Three months after the expiration date of the drug product if the expiration dating period of the drug product is 30 days or less; or

(ii) Six months after the expiration date of the drug product if the expiration dating period of the drug product is more than 30 days.

(3) For an OTC drug product that is exempt for bearing an expiration date under 211.137, the reserve sample must be retained for 3 years after the lot or batch of drug product is distributed.

[48 FR 13025, Mar. 29, 1983, as amended at 60 FR 4091, Jan. 20, 1995]

 

Sec. 211.173 Laboratory animals.

Animals used in testing components, in-process materials, or drug products for compliance with established specifications shall be maintained and controlled in a manner that assures their suitability for their intended use. They shall be identified, and adequate records shall be maintained showing the history of their use.

 

Sec. 211.176 Penicillin contamination.

If a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-penicillin drug product shall be tested for the presence of penicillin. Such drug product shall not be marketed if detectable levels are found when tested according to procedures specified in `Procedures for Detecting and Measuring Penicillin Contamination in Drugs,' which is incorporated by reference. Copies are available from the Division of Research and Testing (HFD-470), Center for Drug Evaluation and Research, Food and Drug Administration, 5100 Paint Branch Pkwy., College Park, MD 20740, or available for inspection at the National Archives and Records Administration (NARA). For information on the availability of this material atNARA, call 202-741-6030, or go to:http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.

[43 FR 45077, Sept. 29, 1978, as amended at 47 FR 9396, Mar. 5, 1982; 50 FR 8996, Mar. 6, 1985; 55 FR 11577, Mar. 29, 1990; 66 FR 56035, Nov. 6, 2001; 69 FR 18803, Apr. 9, 2004]

 

Subpart J--Records and Reports

Sec. 211.180 General requirements.

(a) Any production, control, or distribution record that is required to be maintained in compliance with this part and is specifically associated with a batch of a drug product shall be retained for at least 1 year after the expiration date of the batch or, in the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption under 211.137, 3 years after distribution of the batch.

(b) Records shall be maintained for all components, drug product containers, closures, and labeling for at least 1 year after the expiration date or, in the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption under 211.137, 3 years after distribution of the last lot of drug product incorporating the component or using the container, closure, or labeling.

(c) All records required under this part, or copies of such records, shall be readily available for authorized inspection during the retention period at the establishment where the activities described in such records occurred. These records or copies thereof shall be subject to photocopying or other means of reproduction as part of such inspection. Records that can be immediately retrieved from another location by computer or other electronic means shall be considered as meeting the requirements of this paragraph.

(d) Records required under this part may be retained either as original records or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques, such as microfilming, are used, suitable reader and photocopying equipment shall be readily available.

(e) Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. Written procedures shall be established and followed for such evaluations and shall include provisions for:

(1) A review of a representative number of batches, whether approved or rejected, and, where applicable, records associated with the batch.

(2) A review of complaints, recalls, returned or salvaged drug products, and investigations conducted under 211.192 for each drug product.

(f) Procedures shall be established to assure that the responsible officials of the firm, if they are not personally involved in or immediately aware of such actions, are notified in writing of any investigations conducted under 211.198, 211.204, or 211.208 of these regulations, any recalls, reports of inspectional observations issued by the Food and Drug Administration, or any regulatory actions relating to good manufacturing practices brought by the Food and Drug Administration.

[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]

 

Sec. 211.182 Equipment cleaning and use log.

A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed. If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record. The persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.

 

Sec. 211.184 Component, drug product container, closure, and labeling records.

These records shall include the following:

(a) The identity and quantity of each shipment of each lot of components, drug product containers, closures, and labeling; the name of the supplier; the supplier's lot number(s) if known; the receiving code as specified in 211.80; and the date of receipt. The name and location of the prime manufacturer, if different from the supplier, shall be listed if known.

(b) The results of any test or examination performed (including those performed as required by 211.82(a), 211.84(d), or 211.122(a)) and the conclusions derived therefrom.

(c) An individual inventory record of each component, drug product container, and closure and, for each component, a reconciliation of the use of each lot of such component. The inventory record shall contain sufficient information to allow determination of any batch or lot of drug product associated with the use of each component, drug product container, and closure.

(d) Documentation of the examination and review of labels and labeling for conformity with established specifications in accord with 211.122(c) and 211.130(c).

(e) The disposition of rejected components, drug product containers, closure, and labeling.

 

Sec. 211.186 Master production and control records.

(a) To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person. The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed.

(b) Master production and control records shall include:

(1) The name and strength of the product and a description of the dosage form;

(2) The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product, and a statement of the total weight or measure of any dosage unit;

(3) A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic;

(4) An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component. Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the master production and control records;

(5) A statement concerning any calculated excess of component;

(6) A statement of theoretical weight or measure at appropriate phases of processing;

(7) A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation according to 211.192 is required;

(8) A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling;

(9) Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed.

 

Sec. 211.188 Batch production and control records.

Batch production and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch. These records shall include:

(a) An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed;

(b) Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including:

(1) Dates;

(2) Identity of individual major equipment and lines used;

(3) Specific identification of each batch of component or in-process material used;

(4) Weights and measures of components used in the course of processing;

(5) In-process and laboratory control results;

(6) Inspection of the packaging and labeling area before and after use;

(7) A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing;

(8) Complete labeling control records, including specimens or copies of all labeling used;

(9) Description of drug product containers and closures;

(10) Any sampling performed;

(11) Identification of the persons performing and directly supervising or checking each significant step in the operation;

(12) Any investigation made according to 211.192.

(13) Results of examinations made in accordance with 211.134.

 

Sec. 211.192 Production record review.

All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup.

 

Sec. 211.194 Laboratory records.

(a) Laboratory records shall include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays, as follows:

(1) A description of the sample received for testing with identification of source (that is, location from where sample was obtained), quantity, lot number or other distinctive code, date sample was taken, and date sample was received for testing.

(2) A statement of each method used in the testing of the sample. The statement shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested. (If the method employed is in the current revision of the United States Pharmacopeia, National Formulary, Association of Official Analytical Chemists International, Book of Methods,1or in other recognized standard references, or is detailed in an approved new drug application and the referenced method is not modified, a statement indicating the method and reference will suffice). The suitability of all testing methods used shall be verified under actual conditions of use.

1Copies may be obtained from: Association of Official Analytical Chemists International,481 North Frederick Ave., suite 500,Gaithersburg,MD20877.

(3) A statement of the weight or measure of sample used for each test, where appropriate.

(4) A complete record of all data secured in the course of each test, including all graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific component, drug product container, closure, in-process material, or drug product, and lot tested.

(5) A record of all calculations performed in connection with the test, including units of measure, conversion factors, and equivalency factors.

(6) A statement of the results of tests and how the results compare with established standards of identity, strength, quality, and purity for the component, drug product container, closure, in-process material, or drug product tested.

(7) The initials or signature of the person who performs each test and the date(s) the tests were performed.

(8) The initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

(b) Complete records shall be maintained of any modification of an established method employed in testing. Such records shall include the reason for the modification and data to verify that the modification produced results that are at least as accurate and reliable for the material being tested as the established method.

(c) Complete records shall be maintained of any testing and standardization of laboratory reference standards, reagents, and standard solutions.

(d) Complete records shall be maintained of the periodic calibration of laboratory instruments, apparatus, gauges, and recording devices required by 211.160(b)(4).

(e) Complete records shall be maintained of all stability testing performed in accordance with 211.166.

[43 FR 45077, Sept. 29, 1978, as amended at 55 FR 11577, Mar. 29, 1990; 65 FR 18889, Apr. 10, 2000; 70 FR 40880, July 15, 2005]

 

Sec. 211.196 Distribution records.

Distribution records shall contain the name and strength of the product and description of the dosage form, name and address of the consignee, date and quantity shipped, and lot or control number of the drug product. For compressed medical gas products, distribution records are not required to contain lot or control numbers.

Distribution records shall contain the name and strength of the product and description of the dosage form, name and address of the consignee, date and quantity shipped, and lot or control number of the drug product. For compressed medical gas products, distribution records are not required to contain lot or control numbers.

[49 FR 9865, Mar. 16, 1984]

 

Sec. 211.198 Complaint files.

(a) Written procedures describing the handling of all written and oral complaints regarding a drug product shall be established and followed. Such procedures shall include provisions for review by the quality control unit, of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with 211.192. Such procedures shall include provisions for review to determine whether the complaint represents a serious and unexpected adverse drug experience which is required to be reported to the Food and Drug Administration in accordance with 310.305 and 514.80 of this chapter.

(b) A written record of each complaint shall be maintained in a file designated for drug product complaints. The file regarding such drug product complaints shall be maintained at the establishment where the drug product involved was manufactured, processed, or packed, or such file may be maintained at another facility if the written records in such files are readily available for inspection at that other facility. Written records involving a drug product shall be maintained until at least 1 year after the expiration date of the drug product, or 1 year after the date that the complaint was received, whichever is longer. In the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption under 211.137, such written records shall be maintained for 3 years after distribution of the drug product.

(1) The written record shall include the following information, where known: the name and strength of the drug product, lot number, name of complainant, nature of complaint, and reply to complainant.

(2) Where an investigation under 211.192 is conducted, the written record shall include the findings of the investigation and followup. The record or copy of the record of the investigation shall be maintained at the establishment where the investigation occurred in accordance with 211.180(c).

(3) Where an investigation under 211.192 is not conducted, the written record shall include the reason that an investigation was found not to be necessary and the name of the responsible person making such a determination.

[43 FR 45077, Sept. 29, 1978, as amended at 51 FR 24479, July 3, 1986; 68 FR 15364, Mar. 31, 2003]

 

Subpart K--Returned and Salvaged Drug Products

Sec. 211.204 Returned drug products.

Returned drug products shall be identified as such and held. If the conditions under which returned drug products have been held, stored, or shipped before or during their return, or if the condition of the drug product, its container, carton, or labeling, as a result of storage or shipping, casts doubt on the safety, identity, strength, quality or purity of the drug product, the returned drug product shall be destroyed unless examination, testing, or other investigations prove the drug product meets appropriate standards of safety, identity, strength, quality, or purity. A drug product may be reprocessed provided the subsequent drug product meets appropriate standards, specifications, and characteristics. Records of returned drug products shall be maintained and shall include the name and label potency of the drug product dosage form, lot number (or control number or batch number), reason for the return, quantity returned, date of disposition, and ultimate disposition of the returned drug product. If the reason for a drug product being returned implicates associated batches, an appropriate investigation shall be conducted in accordance with the requirements of 211.192. Procedures for the holding, testing, and reprocessing of returned drug products shall be in writing and shall be followed.

 

Sec. 211.208 Drug product salvaging.

Drug products that have been subjected to improper storage conditions including extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures shall not be salvaged and returned to the marketplace. Whenever there is a question whether drug products have been subjected to such conditions, salvaging operations may be conducted only if there is (a) evidence from laboratory tests and assays (including animal feeding studies where applicable) that the drug products meet all applicable standards of identity, strength, quality, and purity and (b) evidence from inspection of the premises that the drug products and their associated packaging were not subjected to improper storage conditions as a result of the disaster or accident. Organoleptic examinations shall be acceptable only as supplemental evidence that the drug products meet appropriate standards of identity, strength, quality, and purity. Records including name, lot number, and disposition shall be maintained for drug products subject to this section.

 

Authority:21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264.
Source:43 FR 45077, Sept. 29, 1978, unless otherwise noted.