【转帖】【分享帖】制药技术精华帖汇总（四） - 经验共享

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标题:【转帖】【分享帖】制药技术精华帖汇总（四）

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不同规格、不同冻干参数、或延长工艺总时间的冻干设备的替换或添加
  Changes from bioburden-based terminal sterilization to the use of an overkill process, and vice versa.
  使用生物灭菌柜的终端灭菌方法改为使用过度杀伤工艺，反之亦然
  Changes to aseptic processing methods, including scale, that extend the total processing, including bulk storage time, by more than 50 percent beyond the validated limits in the approved application.
  改为无菌工艺方法，包括工艺能力放大，包括贮存时间超过申报资料的验证限度50％以上
  Changes in sterilizer load configurations that are outside the range of previously validated loads.
  灭菌器负荷超过预先验证的限度
Changes in materials or pore size rating of filters used in aseptic processing.
无菌工艺中物料或过滤器的孔径规格改变
3. The following changes for a natural product
下述产品变更
Changes in the virus or adventitious agent removal or inactivation methods.
病毒或外源性物质或去活方法的改变
This applies to any material where such procedures are necessary, including drug substance, drug product, reagents, and excipients.
适用于任何物料，包括原料药、制剂、试剂、辅料
  For drug substance and drug product, changes in the source material (e.g., microorganism, plant) or cell line.
  对于原料药和制剂，来源（如微生物、培养）或细胞链改变
  For drug substance and drug product, establishment of a new master cell bank or seed.
  对于原料药和制剂，建立新的细胞库或种子
4. Any fundamental change in the manufacturing process or technology from that currently used by the applicant. For example:
现行生产工艺或技术的基本变更，例如：
  a. Drug product 制剂
Dry to wet granulation or vice versa. 干法改为湿法或反之
Change from one type of drying process to another (e.g., oven tray, fluid bed, microwave).
由一种干燥工艺改为另一种（如烘箱、流化床、微波炉）
  b. Drug substance 原料药
Filtration to centrifugation or vice versa. 过滤改为离心或反之
Change in the route of synthesis of a drug substance 原料药合成途径改变
5. The following changes for drug substance 原料药下述变更
Any process change made after the final intermediate processing step in drug substance manufacture.
原料药生产过程中，最终中间体以后的工艺步骤的任何变更
Changes in the synthesis or manufacture of the drug substance that may affect its impurity profile and/or the physical, chemical, or biological properties.
可能影响原料药杂质和/或物理、化学或生物学特性的合成或生产的变更
6. Addition of an ink code imprint or change to or in the ink used for an existing imprint code for a solid oral dosage form drug product when the ink as changed is not currently used on CDER-approved drug products.17
加入或改变喷墨，如果当前使用的喷墨已不用于CDER批准的产品
7. Establishing a new procedure for reprocessing a batch of drug substance or drug product that fails to meet the approved specification.
制定不合格原料药或制剂的新的再加工规程
C. Moderate Changes (Supplement - Changes Being Effected) 中等变更
The following are examples of changes considered to have a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.
下面的例子是对药品特征、剂量、质量、纯度或药效有中等的潜在不良影响，可能与药品的安全性和有效性相关的变更
1. Supplement - Changes Being Effected in 30 Days  30天后进行的变更补充申请
  a. For drug products, any change in the process, process parameters, and/or equipment except as otherwise provided for in this guidance.
  本指南未提及的制剂产品的所有工艺、工艺参数和/或设备变更
  b. For drug substances, any change in process and/or process parameters except as otherwise provided for in this guidance.
  本指南未提及的原料药的工艺和/或工艺参数变更
  c. For natural protein drug substances and natural protein drug products:
  蛋白质原料药和制剂
  Any change in the process, process parameters, and/or equipment except as otherwise provided for in this guidance (e.g., section VII.B.5, VII.D.7).
  本指南未提及的任何工艺、工艺参数和/或设备变更
  An increase or decrease in production scale during finishing steps that involves different equipment.
  涉及不同设备的生产结束步骤的增加或减少
  Replacement of equipment with equipment of different design that does not affect the process methodology or process operating parameters.
  不同设计的设备变更，不影响工艺方法和工艺参数
  d. For sterile drug products, drug substances, and components, as appropriate:
  对于无菌制剂、原料药、成分
  Changes in dry heat depyrogenation processes for glass container systems for drug substances and drug products that are produced by terminal sterilization processes or aseptic processing.
  终端灭菌或无菌工艺生产的原料药或制剂的玻璃容器的干热除热原工艺的变更
  Changes to filtration parameters for aseptic processing (including flow rate, pressure, time, or volume, but not filter materials or pore size rating) when additional validation studies for the new parameters should be performed.
  无菌工艺（包括流速、压力、时间、体积、不包括过滤器材料或孔径）过滤参数的变更，新参数需进行额外验证
  Filtration process changes that provide for a change from single to dual sterilizing filters in series, or for repeated filtration of a bulk.
  过滤工艺变更，从单一过滤器变为双重过滤器或重复过滤
  Changes from one qualified sterilization chamber to another for in-process or terminal sterilization that result in changes to validated operating parameters (time, temperature, F0, and others).
  一个验证过的灭菌柜改为另一个中控或终端灭菌，导致验证参数改变（时间、温度、F0、其他）
  Changes in scale of manufacturing for terminally sterilized drug products that increase the bulk solution storage time by more than 50 percent beyond the validated limits in the approved application when bioburden limits are unchanged.
终端灭菌产品的生产规模改变，导致原液贮存时间增加50％以上，在生物负荷限度不变的情况下超过申报资料中的验证限度
e. For drug substances, redefinition of an intermediate, excluding the final intermediate, as a starting material.
对于原料药、中间体再定义、不包括最终中间体，作为起始物料

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2. Supplement - Changes Being Effected  已进行的变更补充申请
  a. A change in methods or controls that provides increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess.
  方法或控制变更，提高原料药或制剂成分、剂量、质量、纯度、药效的保证
  b. For sterile drug products, elimination of in-process filtration performed as part of the manufacture of a terminally sterilized drug product.
  无菌制剂，取消终端灭菌生产的中控过滤步骤

D. Minor Changes (Annual Report) 小变更（年报）
The following are examples of changes considered to have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.
下面的例子是对药品特征、剂量、质量、纯度或药效有最小的潜在不良影响，可能与药品的安全性和有效性相关的变更。
1 For drug products, changes to equipment of the same design and operating principle and/or changes in scale except as otherwise provided for in this guidance (e.g., section VII.C.1.c, VII.D.7).
本指南未涉及的制剂产品设备设计和操作原理和/或规模变更
2 A minor change in an existing code imprint for a dosage form.  For example, changing from a numeric to alphanumeric code.
制剂刻字喷墨的变更，如由数字改为文字数字
3 Addition of an ink code imprint or a change in the ink used in an existing code imprint for a solid oral dosage form drug product when the ink is currently used on CDER-approved drug products.
加入喷墨或改变喷墨
4 Addition or deletion of a code imprint by embossing, debossing, or engraving on a solid dosage form drug product other than a modified-release dosage form.
非控制制剂的口服固体制剂加入或取消刻字代码
5 A change in the order of addition of ingredients for solution dosage forms or solutions used in unit operations (e.g., granulation solutions).
单剂量使用的液体制剂或溶液剂成分加入次序改变
1 Changes in scale of manufacturing for terminally sterilized drug products that increase the bulk solution storage time by no more than 50 percent beyond the validated limits in the approved application when bioburden limits are unchanged.
终端灭菌的制剂产品生产规模改变，延长原液贮存时间50％以上，在生物负荷限度不变的情况下超过申报资料中的验证限度
  7. For natural protein drug products and natural protein drug substances:
对于蛋白质制品和天然蛋白质原料药
  An increase or decrease in production scale during finishing steps that does not involve an equipment change.
  生产末期增加或降低生产规模，没有设备变更
  Replacement of equipment with equipment of the same design, operating principle, and capacity with no change in production scale.
  设备变更，变更前后的设备的设计、操作原理、产能、生产规模相同
VIII. SPECIFICATIONS 质量标准
A. General Considerations
All changes in specifications from those in the approved application must be submitted in a prior approval supplement unless otherwise exempted by regulation or guidance (§ 314.70(b)(2)(i)). Specifications (i.e., tests, analytical procedures, and acceptance criteria) are the quality standards provided in an approved application to confirm the quality of drug substances, drug products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a drug substance or drug product. For the purpose of defining specifications, acceptance criteria are numerical limits, ranges, or other criteria for the tests described. Examples of a test, an analytical procedure, and an acceptance criterion are, respectively, an assay, a specific, fully described high pressure liquid chromatography (HPLC) procedure, and a range of 98.0–102.0 percent.  The recommendations in this section also apply to specifications associated with sterility assurance that are included in NDA and ANDA submissions.18
从那些已批准申请的质量标准里的所有变更必须提交在“批准前变更补充申请”，除非另有被规章或指导原则豁免的(§ 314.70(b)(2)(i))。规程（例如，检测、分析步骤、可接受标准）是在已批准的申请里提供证实原料药、制剂、中间体、原材料、反应物、成分、中控物料、包装，和原料药或制剂生产过程中使用的其它物质的质量标准。质量标准和可接受标准的目的是明确数值界限，范围，或为检验所描述的其他标准。实例检验，一个分析规程和一个可接受标准为各自检测、完全特定的高效液相步骤、范围98.0%-102.0%。本条中的建议也适用于和无菌保证有联系的质量标准，包括在NDA和ANDA。
A regulatory analytical procedure is the procedure in the approved application that is designated for use in evaluating a defined characteristic of the drug substance or drug product. Section 501(b) of the Act recognizes the analytical procedures in the U.S. Pharmacopeia/National Formulary (USP/NF) as the regulatory analytical procedures for compendial items. Tests and associated acceptance criteria and regulatory analytical procedures in addition to those specified in the USP/NF may be required for approving compendial items (section 505 of the Act).
获批准的法定分析规程是能被指定用于评估原料药或制剂的确定性质的规程。美国药典/国家处方集的法定分析规程是根据法案的第501(b)确定的分析规程。对正在批准的简明条款除了那些在USP/NF中详细说明的，还有检测和有联系的可接受标准，法定分析规程，可能都被要求在其中。(section 505 of the Act)
The applicant may include in its application alternatives to the approved regulatory analytical procedures for testing the drug substance and drug product. However, for purposes of determining compliance with the Act, regulatory analytical procedures are used.
申请人可以在其申请书中包括其可实施的用于检验原料药和制剂的不同于法定分析规程的替代方法。不过，为了和法案相一致，使用法定分析规程来判断决定。
In sections B through D below, the use of the term analytical procedure without a qualifier such as regulatory or alternative refers to an analytical procedure used to test materials other than the drug substance or drug product.
在B部分到以下D，没有限定分析规程的使用范围，例如法定或可替代的指的是被用于检测物料而不是原料药或制剂的分析规程。

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B. Major Changes (Prior Approval Supplement) 大变更
The following are examples of changes in specifications considered to have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.
下面的例子是对药品特征、剂量、质量、纯度或药效重大的潜在不良影响，可能与药品的安全性和有效性相关的变更。
1 Relaxing an acceptance criterion except as otherwise provided for in this guidance (e.g., section VIII.C.1.b, VIII.C.1.e).
本指南未提及的可接受限度变宽
2 Deleting any part of a specification except as otherwise provided for in this guidance (e.g., section VIII.D.2).
本指南未提及的质量标准项目的删除
3 Establishing a new regulatory analytical procedure including designation of an alternative analytical procedure as a regulatory procedure.
制定新的法定分析规程，包括替代规程
4 A change in a regulatory analytical procedure that does not provide the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the regulatory analytical procedure described in the approved application.
对申报资料中的法定分析规程的变更，但是不能等效或更好地保证被测物的特征、剂量、质量、纯度或药效
5 A change in an analytical procedure used for testing components, packaging components, the final intermediate, in-process materials after the final intermediate, or starting materials introduced after the final intermediate that does not provide the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application except as otherwise noted. For example, a change from an HPLC procedure that distinguishes impurities to (1) an HPLC procedure that does not, (2) another type of analytical procedure (e.g., titrimetric) that does not, or (3) an HPLC procedure that distinguishes

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FDA有关术语大全

FDA（FOOD AND DRUG ADMINISTRATION）：（美国）食品药品管理局
IND（INVESTIGATIONAL NEW DRUG）：临床研究申请（指申报阶段,相对于NDA而言）；研究中的新药（指新药开发阶段，相对于新药而言，即临床前研究结束）
NDA（NEW DRUG APPLICATION）：新药申请
ANDA（ABBREVIATED NEW DRUG APPLICATION）：简化新药申请
EP诉（EXPORT APPLICATION）：出口药申请（申请出口不被批准在美国销售的药品）
TREATMENT IND：研究中的新药用于治疗
ABBREVIATED（NEW）DRUG：简化申请的新药
DMF（DRUG MASTER FILE）：药物主文件（持有者为谨慎起见而准备的保密资料，可以包括一个或多个人用药物在制备、加工、包装和贮存过程中所涉及的设备、生产过程或物品。只有在DMF持有者或授权代表以授权书的形式授权给FDA，FDA在审查IND、 NDA、ANDA时才能参考其内容）
HOLDER：DMF持有者
CFR（CODE OF FEDERAL REGULATION）：（美国）联邦法规
PANEL：专家小组
BATCH PRODUCTION：批量生产；分批生产
BATCH PRODUCTION RECORDS：生产批号记录
POST-OR PRE- MARKET SURVEILLANCE：销售前或销售后监督
INFORMED CONSENT：知情同意（患者对治疗或受试者对医疗试验了解后表示同意接受治疗或试验） PRESCRIPTION DRUG：处方药
OTC DRUG（OVER—THE—COUNTER DRUG）：非处方药
U．S．PUBLIC HEALTH SERVICE：美国卫生福利部
NIH（NATIONAL INSTITUTE OF HEALTH）：（美国）全国卫生研究所
CLINICAL TRIAL：临床试验
ANIMAL TRIAL：动物试验
ACCELERATED APPROVAL：加速批准
STANDARD DRUG：标准药物
INVESTIGATOR：研究人员；调研人员
PREPARING AND SUBMITTING：起草和申报
SUBMISSION：申报；递交
BENIFIT（S）：受益
RISK（S）：受害
DRUG PRODUCT：药物产品
DRUG SUBSTANCE：原料药
ESTABLISHED NAME：确定的名称
GENERIC NAME：非专利名称
PROPRIETARY NAME：专有名称；
INN（INTERNATIONAL NONPROPRIETARY NAME）：国际非专有名称
NARRATIVE SUMMARY记叙体概要
ADVERSE EFFECT：副作用
ADVERSE REACTION：不良反应
PROTOCOL：方案
ARCHIVAL COPY：存档用副本
REVIEW COPY：审查用副本
OFFICIAL COMPENDIUM：法定药典（主要指USP、 NF）．
USP（THE UNITED STATES PHARMACOPEIA）：美国药典（现已和NF合并一起出版）
NF（NATIONAL FORMULARY）：（美国）国家药品集
OFFICIAL＝PHARMACOPEIAL= COMPENDIAL：药典的；法定的；官方的
AGENCY：审理部门（指FDA）
SPONSOR：主办者（指负责并着手临床研究者）
IDENTITY：真伪；鉴别；特性
STRENGTH：规格；规格含量（每一剂量单位所含有效成分的量）
LABELED AMOUNT：标示量
REGULATORY SPECIFICATION：质量管理规格标准（NDA提供）
REGULATORY METHODOLOGY：质量管理方法（FDA用于考核原料药或药物产品是否符合批准了的质量管理规格标准的整套步骤）
REGULATORY METHODS VALIDATION：管理用分析方法的验证（FDA对NDA提供的方法进行验证）
Dietary supplement：食用补充品

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[font=黑体

]CFR210/211原文件及中文翻译

Part 210 - Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General
Part 211 - Current Good Manufacturing Practice for Finished Pharmaceuticals
210部分—人用及兽用药品的生产、加工、包装或贮存的cGMP（概述）
211部分—制剂药品的cGMP
Part 210 -Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General
210.1 Status of current good manufacturing practice regulations.
210.2 Applicability of current good manufacturing practice regulations.
210.3 Definitions.
AUTHORITY: Secs. 201, 501, 502, 505, 506, 507, 512, 701, 704 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 355, 356, 357, 360b, 371, 374).
SOURCE: 43 FR 45076, Sept. 29, 1978, unless otherwise noted.
§ 210.1 Status of current good manufacturing practice regulations.
(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) 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 Applicability of current good manufacturing practice regulations.
(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 Definitions.
(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) The following definitions of terms apply to this part and to Parts 211 through 226 of this chapter.
(1) Act means the Federal Food, Drug, and Cosmetic Act, as amended (21 U.S.C. 301 et seq.).
(2) Batch means 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) Component means any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product.
(4) Drug product means 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) Fiber means any particulate contaminant with a length at least three times greater than its width.
(6)Non-fiber-releasing filter means 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 ingredient means 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 ingredient means any component other than an ``active ingredient.''
(9) In-process material means any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product.

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(10) Lot means 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) Lot number, control number, or batch number means 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 product includes packaging and labeling operations, testing, and quality control of drug products.
(13) The term medicated feed means 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 term medicated premix means 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 unit means any person or organizational element designated by the firm to be responsible for the duties relating to quality control.
(16) Strength means:
(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 yield means 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 yield means 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 criteria means 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 sample means 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 labeling means 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) effectiveAug. 3, 1994.
Part 211 - Current Good Manufacturing Practice for Finished Pharmaceuticals
(21 CFR Part 211 As of April, 1996)
Authority: Secs. 201, 501, 502, 505, 506, 507, 512, 701, 704 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 355, 356, 357, 360b, 371, 374).
Source: 43 FR 45077, Sept. 29, 1978, unless otherwise noted.
Subpart A--General Provisions
§211.1 - Scope.
§211.3 - Definitions.

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Subpart B--Organization and Personnel
§211.22 - Responsibilities of quality control unit.
§211.25 - Personnel qualifications.
§211.28 - Personnel responsibilities.
§211.34 - Consultants.
Subpart C--Buildings and Facilities
§211.42 - Design and construction features.
§211.44 - Lighting.
§211.46 - Ventilation, air filtration, air heating and cooling.
§211.48 - Plumbing.
§211.50 - Sewage and refuse.
§211.52 - Washing and toilet facilities.
§211.56 - Sanitation.
§211.58 - Maintenance.
Subpart D--Equipment
§211.63 - Equipment design, size, and location.
§211.65 - Equipment construction.
§211.67 - Equipment cleaning and maintenance.
§211.68 - Automatic, mechanical, and electronic equipment.
§211.72 - Filters.
Subpart E--Control of Components and Drug Product Containers and Closures
§211.80 - General requirements.
§211.82 - Receipt and storage of untested components, drug product containers, and closures.
§211.84 - Testing and approval or rejection of components, drug product containers, and closures.
§211.86 - Use of approved components, drug product containers, and closures.
§211.87 - Retesting of approved components, drug product containers, and closures.
§ 211.89 - Rejected components, drug product containers, and closures.
§ 211.94 - Drug product containers and closures.
Subpart F--Production and Process Controls
§211.100 - Written procedures; deviations.
§211.101 - Charge-in of components.
§211.103 - Calculation of yield.
§211.105 - Equipment identification.
§211.110 - Sampling and testing of in-process materials and drug products.
§211.111 - Time limitations on production.
§211.113 - Control of microbiological contamination.
§211.115 - Reprocessing.
Subpart G--Packaging and Labeling Control
§211.122 - Materials examination and usage criteria.
§211.125 - Labeling issuance.
§211.130 - Packaging and labeling operations.
§211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug products.
§211.134 - Drug product inspection.
§ 211.137 - Expiration dating.

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Subpart H--Holding and Distribution
§ 211.142 - Warehousing procedures.
§ 211.150 - Distribution procedures.
Subpart I--Laboratory Controls
§ 211.160 - General requirements.
§ 211.165 - Testing and release for distribution.
§ 211.166 - Stability testing.
§211.167 - Special testing requirements.
§ 211.170 - Reserve samples.
§ 211.173 - Laboratory animals.
§ 211.176 - Penicillin contamination.
Subpart J--Records and Reports
§ 211.180 - General requirements.
§ 211.182 - Equipment cleaning and use log.
§ 211.184 - Component, drug product container, closure, and labeling records.
§ 211.186 - Master production and control records.
§ 211.188 - Batch production and control records.
§ 211.192 - Production record review.
§ 211.194 - Laboratory records.
§ 211.196 - Distribution records.
§ 211.198 - Complaint files.
Subpart K--Returned and Salvaged Drug Products
§ 211.204 - Returned drug products.
§ 211.208 - Drug product salvaging.
Subpart A-General Provisions
§ 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, and in parts 600 through 680 of this chapter, as they pertain to biological products for human use, shall be considered to supplement, not supersede, the regulations in this part unless the regulations explicitly provide otherwise. In the event it is impossible to comply with applicable regulations both in this part and in other parts of this chapter or in parts 600 through 680 of this chapter, the regulation specifically applicable to the drug product in question shall supersede the regulation in this part.
(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.

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§ 211.3 Definitions.
The definitions set forth in § 210.3 of this chapter apply in this part.
Subpart B-Organization and Personnel
§ 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.
§ 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.
§ 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.
§ 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.
Subpart C-Buildings and Facilities
§ 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 for the firm's operations to prevent contamination or mixups as follows:
(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;

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(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]
§ 211.44 Lighting.
Adequate lighting shall be provided in all areas.
§ 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.
§ 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]
§ 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.
§ 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 accessible to working areas.

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