（CGMP）美國(guó)藥品生產(chǎn)質(zhì)量管理規(guī)范(中英對(duì)照)

二○○三年十二月

 

目?????錄

 

 

 

210部分—人用及獸用藥品

的生產(chǎn)、加工、包裝或貯存的CGMP

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

???210.1? cGMP法規(guī)的地位

§ 210.1 Status of current good manufacturing practice regulations.

(a)?在本部分及21CFR 211—226部分中陳述的法規(guī)是在藥品生產(chǎn)、加工、包裝或貯存中使用的現(xiàn)行生產(chǎn)質(zhì)量管理規(guī)范及使用的設(shè)施或控制的最低標(biāo)準(zhǔn)，以保證該藥品符合聯(lián)邦食品、藥品及化妝品法對(duì)安全性的要求，具有均一性和效價(jià)(或含量)并符合或代表其生產(chǎn)過(guò)程的質(zhì)量及純度等特征。

(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)?凡是在藥品生產(chǎn)、加工、包裝或貯存過(guò)程中存在任何不符合本部分及21CFR 211—226部分中陳述的法規(guī)的藥品，依據(jù)聯(lián)邦食品、藥品及化妝品法501 (a)(2)-(B)，該藥應(yīng)被視為劣藥，同時(shí)導(dǎo)致該事故發(fā)生的負(fù)責(zé)人應(yīng)受相應(yīng)的法規(guī)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法規(guī)的適用性

§ 210.2 Applicability of current good manufacturing practice regulations.

(a)?本部分及21CFR 211—226適用于普通藥品，21CFR 600—680適用于人用生物制品，除非另有明確規(guī)定，否則上述兩者之間應(yīng)該是相互補(bǔ)充而不是相互取代。如有上述兩部分的法規(guī)不適用的藥品，則可用特定的具體法規(guī)來(lái)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?定義

§ 210.3 Definitions.

(a)?在聯(lián)邦食品、藥品及化妝品法201部分中包含的定義和解釋、說(shuō)明適用于21CFR 211—226部分中的術(shù)語(yǔ)。

(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) ?下面定義的術(shù)語(yǔ)適用于本部分及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)

指聯(lián)邦食品、藥品及化妝品法，修訂版(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)

指在規(guī)定限度內(nèi)，按照某一生產(chǎn)指令在同一生產(chǎn)周期內(nèi)生產(chǎn)出來(lái)的，具有同一性質(zhì)和質(zhì)量的一定數(shù)量的藥品或其它物料。

(3)組分(Component)

指用于藥品生產(chǎn)的所有成份，包括那些未在藥品中出現(xiàn)的成份。

(4)藥品(Drug Product)

指成品制劑(如：片劑、膠囊劑、口服液等)，通常含有一種活性成份并伴有非活性成份(但不是必需的)。本術(shù)語(yǔ)也包括不含有活性成份但作為安慰劑使用的成品制劑。

(5)纖維(Fiber)

指長(zhǎng)度大于其寬度的3倍的任何微粒狀污染物。

(6)無(wú)纖維脫落的過(guò)濾器(Non-fiber-releasing filter)

指任何經(jīng)過(guò)適當(dāng)?shù)念A(yù)處理(如清洗或沖洗)后，不會(huì)將纖維脫落到已過(guò)濾的組分或藥品中的所有過(guò)濾器。所有含石棉過(guò)濾器均被認(rèn)為是有纖維脫落的過(guò)濾器。

(7)活性成份(Active Ingredient)

是指所有用于保證藥物活性或其他在疾病的診斷、治愈、緩解、治療或預(yù)防中起直接作用，或影響人或其他動(dòng)物身體結(jié)構(gòu)或功能的組分。本術(shù)語(yǔ)包括那些能承受藥品生產(chǎn)中的化學(xué)變化和為了保證其指定的活性或作用以一種經(jīng)調(diào)整的形式存在于藥品中的組分。

(8)非活性成份(Inactive ingredient)

指不同于“活性成份”的其他組分。

(9)中間產(chǎn)品(In-process material)

是指所有經(jīng)制備、復(fù)合、混合或由化學(xué)反應(yīng)得到的用于藥品生產(chǎn)或制備的物料。

(10)批（lot）

指一批或是一批中特定的均一部分，在指定的范圍內(nèi)具有相同的性質(zhì)和質(zhì)量；或者若為由連續(xù)的生產(chǎn)過(guò)程制造出的藥品，“批”指在單位時(shí)間或單位數(shù)量生產(chǎn)出的特定的、均一的部分，并且確保該部分在指定的范圍內(nèi)具有均一性質(zhì)與質(zhì)量。

(11)批號(hào)(Lot number, control number，batch number)

指由字母、數(shù)字、符號(hào)或他們的組合組成，由此可確定某批藥品或物料的生產(chǎn)、加工、包裝、貯存或銷售的情況。

(12)藥品的生產(chǎn)、加工、包裝或貯存(Manufacture, processing, packing, or holding of a drug product)

包括藥品的包裝和標(biāo)簽操作、檢驗(yàn)、質(zhì)量控制。

(13)藥用物料(medicated feed)

指在21CFR 558.3中定義的B型和C型藥用物料。該物料含有聯(lián)邦食品、藥品及化妝品法201(g)部分中定義的一種或一種以上的藥物，藥用物料的生產(chǎn)應(yīng)符合21CFR 226部分中的要求。

(14)藥用預(yù)混合料(medicated premix)

指21CFR 558.3中定義的A型藥用物質(zhì)。該預(yù)混合料含有聯(lián)邦食品、藥品及化妝品法201(g)部分中定義的一種或一種以上的藥物。藥用預(yù)混合料生產(chǎn)應(yīng)符合21CFR 226部分中的要求。

(15)質(zhì)量控制部門(Quality control unit)

指由企業(yè)任命負(fù)責(zé)質(zhì)量控制相關(guān)責(zé)任的任何人員或組織機(jī)構(gòu)。

(16)含量或效價(jià)（Strength）

指：

(Ⅰ)?原料藥的濃度(如：以重量/重量、重量/體積、單位劑量/體積為基礎(chǔ))；和/(或)

(Ⅱ)?活性(效價(jià))也即由適當(dāng)?shù)膶?shí)驗(yàn)室檢測(cè)或由足夠的臨床數(shù)據(jù)得出的指定的藥品治療活性(如：可表達(dá)為對(duì)照于某標(biāo)準(zhǔn)的單位的術(shù)語(yǔ))。

(17)理論產(chǎn)量(Theoretical yield)

指在生產(chǎn)、加工或包裝某種藥品的任一適當(dāng)階段中，并且基于所使用的組分的數(shù)量在實(shí)際生產(chǎn)中無(wú)任何損失或錯(cuò)誤的情況下，應(yīng)能生產(chǎn)的數(shù)量。

(18)實(shí)際產(chǎn)量(Actual yield)

指某種藥品在生產(chǎn)、加工、包裝的任一適當(dāng)?shù)碾A段實(shí)際生產(chǎn)出的數(shù)量。

(19)比率(Percentage of theoretical yield)

實(shí)際產(chǎn)量(生產(chǎn)、加工或包裝某種藥品的適當(dāng)階段)與理論產(chǎn)量(在相同階段)的比率，以百分?jǐn)?shù)表示。

(20)驗(yàn)收標(biāo)準(zhǔn)(Acceptance criteria)

建立在相應(yīng)的取樣方法基礎(chǔ)上的藥品的質(zhì)量檢驗(yàn)標(biāo)準(zhǔn)和合格、不合格標(biāo)準(zhǔn)(如合格質(zhì)量水平和不合格的質(zhì)量水平)，是決定批準(zhǔn)或拒收一批(或其他生產(chǎn)單元的小組)藥品的必需因素。

(21)代表性樣品(Representative sample)

指一個(gè)樣品按合理的標(biāo)準(zhǔn)抽取（如隨機(jī)取樣法），并包含若干單位（元），以能保證樣品準(zhǔn)確描繪被取樣品的物料。

(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．總???則

Subpart A–General Provisions

211?1范圍

（a）???本部分的條例包含人用或獸用藥品制備的現(xiàn)行最低限度的藥品生產(chǎn)質(zhì)量管理規(guī)范（GMP）

（b）???在本章里的這些針對(duì)藥品的現(xiàn)行GMP條例和本章600至800的所有部分針對(duì)人用生物制品的現(xiàn)行GMP條例，除非明確另有說(shuō)明者外，應(yīng)認(rèn)為是對(duì)本部分條例的補(bǔ)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適用的條例，前部分的條例可代替本部分條例。

（c）???在考慮經(jīng)提議的，發(fā)表在1978年9月29日聯(lián)邦注冊(cè)表（FR）上一項(xiàng)免除時(shí)，若產(chǎn)品及其所有成份是以人用物品形式作一般銷售和消費(fèi)且這些產(chǎn)品根據(jù)其預(yù)期用途，亦可列入藥品的范圍內(nèi)，則不應(yīng)對(duì)這些非處方藥（OTC）實(shí)施本部分條例，直至進(jìn)一步的通知為止。本章110部分和113至119部分的條例用于鑒別這些變是食品的OTC藥品是否按照GMP的要求生產(chǎn)、加工、包裝和貯存。

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定義

本章210?3中的定義適用于本部分。

Sec. 211.3 Definitions.

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

 

B．組織與人員

 

211?22質(zhì)量控制部門的職責(zé)

（a）???本部門有批準(zhǔn)和拒收所有成份、藥品包裝容器、密封件、中間體、包裝材料、標(biāo)簽及藥品的職責(zé)與權(quán)力。復(fù)查生產(chǎn)記錄和權(quán)力，保證不產(chǎn)生差錯(cuò)，或若發(fā)生差錯(cuò)，保證他們充分調(diào)查這差錯(cuò)。本部門負(fù)責(zé)根據(jù)合同，批準(zhǔn)或拒收由其它公司生產(chǎn)、加工、包裝或貯存的藥品。

（b）???適當(dāng)?shù)膶?shí)驗(yàn)室檢驗(yàn)設(shè)備、批準(zhǔn)（或拒收）各種成份、藥品容器、密封件、包裝材料及藥品，質(zhì)量控制部門是可以獲得的。

（c）???本部門有批準(zhǔn)或駁回影響藥品的均一性、效價(jià)或含量、質(zhì)量及純度的所有程序或規(guī)格標(biāo)準(zhǔn)的職責(zé)。

（d）???適用于本部門的職責(zé)與程序，應(yīng)成文字材料，并應(yīng)遵循。

211?25人員資格

（a）???每位從事藥品生產(chǎn)、加工、包裝或倉(cāng)貯工作人員，應(yīng)接受培訓(xùn)、教育及有實(shí)踐經(jīng)驗(yàn)，完成委派的各項(xiàng)職務(wù)。培訓(xùn)是按照現(xiàn)行GMP（包括本章中的現(xiàn)行GMP條例和這些條例要求的成文程序）中涉及雇員的內(nèi)容。邀請(qǐng)合格人員指導(dǎo)，并連續(xù)多次培訓(xùn)，保證雇員熟悉現(xiàn)行GMP對(duì)他們的要求。

（b）???負(fù)責(zé)監(jiān)督藥品的生產(chǎn)、加工、包裝或倉(cāng)貯工作的每一個(gè)工作人員，應(yīng)受教育、培訓(xùn)及有經(jīng)驗(yàn)，完成委派的各項(xiàng)職務(wù)。以此作為提供藥品具有安全性、均一性、效價(jià)或含量、質(zhì)量及純度的保證。

（c）???有足夠量招待和監(jiān)督每種藥品的生產(chǎn)、加工、包裝或倉(cāng)貯的合格人員。

211?28人員職責(zé)

（a）???從事藥品生產(chǎn)、加工、包裝或倉(cāng)貯的人員，應(yīng)穿著適合于其履行職責(zé)的清潔衣服。按需要，頭部、臉部、手部、臂部另外罩，防止藥物受污染。

（b）???人員保持良好的個(gè)人衛(wèi)生和健康。

（c）???未經(jīng)監(jiān)督人員允許，其他人員不能進(jìn)入限制進(jìn)入的建筑物和設(shè)施。

（d）???任何人，在任何時(shí)間，明顯地表現(xiàn)出現(xiàn)有影響藥品安全性和質(zhì)量的疾病或開(kāi)放性`損傷，應(yīng)避免接觸各種成份、藥品容器、包裝設(shè)備、密封件、中間體，直至監(jiān)督人員結(jié)對(duì)藥品有不利影響的健康情況。

211?34顧問(wèn)

為了對(duì)問(wèn)題提出意見(jiàn)，聘請(qǐng)顧問(wèn)。顧問(wèn)應(yīng)對(duì)藥品生產(chǎn)、加工、包裝或倉(cāng)貯提出建議，他們受過(guò)足夠的教育、培訓(xùn)，且有豐富的實(shí)踐經(jīng)驗(yàn)。保留他們的姓名、地址、任何的顧問(wèn)資格及服務(wù)形式等履歷資料。

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．廠房和設(shè)施

 

211?42設(shè)計(jì)與建造特征

（a）???任何用于某類藥品生產(chǎn)、加工、包裝或貯存的廠房或建筑群，大小適宜，結(jié)構(gòu)與位置使其易于清潔、保養(yǎng)、適合操作。

（b）???建筑物有足夠空間來(lái)有條理地安裝設(shè)備和放置材料，避免不同類的成份、藥品容器、密封件、標(biāo)簽、中間體或藥品等相互混放，防止污染。通過(guò)廠房的上述物料其流向在設(shè)計(jì)時(shí)要防止污染。

（c）???操作應(yīng)在明確規(guī)定的、大小適中的地區(qū)內(nèi)進(jìn)行。這些地區(qū)內(nèi)進(jìn)行。這些地區(qū)按規(guī)定各自分隔開(kāi)，以防止污染。下列操作須在單獨(dú)的地區(qū)內(nèi)進(jìn)行：

（1）???發(fā)放給生產(chǎn)或包裝前，質(zhì)量控制部門取樣期間，成份、藥品容器、密封件及標(biāo)簽的簽收、鑒別、貯存及拒收。

（2）???在處理前，拒收的成份、藥品容器、密封件及標(biāo)簽的貯存。

（3）???已發(fā)放的成份、藥品容器、密封件及標(biāo)簽的貯存。

（4）???中間體的貯存。

（5）???生產(chǎn)與加工操作。

（6）???包裝和貼標(biāo)簽操作。

（7）???藥品發(fā)放前的隔離貯存。

（8）???發(fā)放后藥品的貯存。

（9）???控制室與實(shí)驗(yàn)室操作。

（10）無(wú)菌操作及有關(guān)操作。

（Ⅰ）地板、墻壁和天花板平滑、堅(jiān)硬、表面易清潔；

（Ⅱ）溫度與濕度控制

（Ⅲ）空氣經(jīng)高效過(guò)濾器、在正壓下過(guò)濾、層流或非層流均可；

（Ⅳ）環(huán)境監(jiān)測(cè)系統(tǒng)；

（Ⅴ）創(chuàng)造無(wú)菌環(huán)境、房間和設(shè)備清潔、消毒系統(tǒng)；

（Ⅵ）控制無(wú)菌環(huán)境的設(shè)備維修系統(tǒng)。

（d）青霉素生產(chǎn)、加工及包裝設(shè)備與生產(chǎn)其他人用藥品的設(shè)備分開(kāi)。

211?44照明

所有地區(qū)均須提供充足的照明。

211?46通風(fēng)、空氣過(guò)濾、空氣加熱與冷卻

（a）???提供足夠的通風(fēng)。

（b）???提供足夠能控制空氣正壓、微生物、塵土、溫度和濕度的設(shè)備，適應(yīng)藥品生產(chǎn)、加工和貯存需要。

（c）???空氣過(guò)濾系統(tǒng)，包括預(yù)過(guò)濾器和微粒物質(zhì)空氣過(guò)濾器。空氣經(jīng)過(guò)濾才送至生產(chǎn)區(qū)，如果空氣是再循環(huán)到生產(chǎn)區(qū)，應(yīng)測(cè)量塵埃含量，控制從生產(chǎn)區(qū)帶來(lái)的塵埃。在生產(chǎn)區(qū)、生產(chǎn)中發(fā)生空氣污染，應(yīng)以排氣系統(tǒng)或其他系統(tǒng)充分抽出空氣，控制污染。

（d）???青霉素生產(chǎn)、加工和包裝的空氣輸送系統(tǒng)應(yīng)與其他人用藥品的空氣輸送系統(tǒng)完全分開(kāi)。

211?48管件

（a）???在持續(xù)正壓下，應(yīng)對(duì)藥品無(wú)污染的管道系統(tǒng)內(nèi)供應(yīng)飲用水。飲用水應(yīng)符合環(huán)境保護(hù)機(jī)構(gòu)制訂的“基本飲用水條例”標(biāo)準(zhǔn)（40CFR141部分）。不符合該標(biāo)準(zhǔn)的水，不許進(jìn)入水系統(tǒng)。

（b）???排水設(shè)備應(yīng)有足夠的大小，可直接連接排水管及安裝防止虹吸倒流的空氣破壞設(shè)備或其他機(jī)械設(shè)備。（43FR45077，1978年9月29日，修正于48FR11426，1983年3月18日）。

211?50污水和廢料

來(lái)自水廠和附近建筑物的污水、垃圾及其他廢料，用安全、衛(wèi)生的方法處理。

211?52洗滌和盥洗設(shè)備

提供洗滌和盥洗設(shè)備，包括熱、冷水、肥皂、清潔劑、空氣干燥器或?qū)Ｓ妹砑斑M(jìn)入廁所的清潔設(shè)備。

211?56

（a）???所有用作藥品生產(chǎn)、加工、包裝及貯存的三房應(yīng)保持清潔、衛(wèi)生的環(huán)境，且不受嚙齒動(dòng)物、鳥(niǎo)類及其他害蟲侵害擾（實(shí)驗(yàn)動(dòng)物除外）。垃圾和有機(jī)廢料，定時(shí)以衛(wèi)生的方法控制處理。

（b）???填寫分配衛(wèi)生清潔任務(wù)的詳細(xì)的清潔項(xiàng)目、方法、設(shè)備、用于清潔廠房和設(shè)施的材料的一覽表。

（c）???填寫適用的殺鼠劑、殺昆蟲劑、殺真菌劑、熏蒸劑、去垢劑和消毒劑一覽表。防止這些物品對(duì)設(shè)備、成份、藥品容器密封件、包裝材料、標(biāo)簽或藥品污染。除依據(jù)聯(lián)邦殺蟲劑、殺真菌劑及殺鼠劑法規(guī)（7U.S.C135）已登記和使用的品種外，其他的不用。

211?58保養(yǎng)

任何用于藥品生產(chǎn)、加工、包裝或貯存的廠保持良好狀態(tài)。

 

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．設(shè)備Subpart D–Equipment

 

211?63設(shè)備的設(shè)計(jì)、尺寸及位置

藥品生產(chǎn)、加工、包裝或貯存設(shè)備，設(shè)計(jì)合理，大小適當(dāng)，布置合理，便于操作、清潔和保養(yǎng)。

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設(shè)備制造

（a）???設(shè)備表面與各種成人中間體或藥品接觸，不產(chǎn)生化學(xué)反應(yīng)和作用。保證藥品的安全性、均一性、效價(jià)或含量、質(zhì)量或純度改變。

（b）???操作所需之物質(zhì)，如滂沱劑、冷卻劑等不能進(jìn)入設(shè)備里，與成人藥品容器、封口物品、中間體或藥品接觸，保證藥品的安全性、均一性、效價(jià)或含量、質(zhì)量或純度不變。

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設(shè)備清潔與保養(yǎng)

（a）???相隔一定時(shí)間，對(duì)設(shè)備與工具進(jìn)行清潔、保養(yǎng)和消毒，防止出故障與污染，影響藥品的安全性、均一性、效價(jià)或含量、質(zhì)量或純度。

（b）???制訂藥品生產(chǎn)、加工包裝或貯存設(shè)備（包括用具）的清潔和保養(yǎng)文字程序，并執(zhí)行。這些程序包括，但不一定限于以下內(nèi)容；

（1）???分配清潔、保養(yǎng)任務(wù)。

（2）???保養(yǎng)和清潔細(xì)目一覽表。

（3）???詳細(xì)說(shuō)明用于清潔和保養(yǎng)的設(shè)備、物品和方法。拆卸和裝配設(shè)備的方法必須保證適合清潔和保養(yǎng)的要求。

（4）???除去或擦去前批遺留物的鑒定。

（5）???已清除了污染的清潔設(shè)備的保護(hù)。

（6）???使用前檢查清潔的設(shè)備。

（7）???保留保養(yǎng)、清潔、消毒的記錄。按211?180及211?182的說(shuō)明檢查。

211?68自動(dòng)化設(shè)備、機(jī)械化設(shè)備和電子設(shè)備

（a）???用于藥品生產(chǎn)、加工、包裝和貯存的自動(dòng)化、機(jī)械化或電子包括計(jì)算機(jī)或其它類型的設(shè)備。按慣例，對(duì)其設(shè)計(jì)之成文條款作標(biāo)定、檢查或核對(duì)，保證其工作性能良好。保留檢查、標(biāo)定、核對(duì)等文字記錄。

（b）???對(duì)保障重要生產(chǎn)變化的計(jì)算機(jī)或有關(guān)系統(tǒng)進(jìn)行操作培訓(xùn)。操作記錄或其他記錄只能由被認(rèn)可的人員制訂。向計(jì)算機(jī)或有關(guān)系統(tǒng)輸入或從中輸出的各種方案、其他記錄或資料，應(yīng)核查其準(zhǔn)確性。輸入計(jì)算機(jī)或關(guān)系統(tǒng)內(nèi)的檔案資料，除與實(shí)驗(yàn)室共同分析計(jì)算的結(jié)果可消除外，其他的應(yīng)保留。文字記錄與相應(yīng)的證明資料一起保存。事先設(shè)計(jì)好的硬件復(fù)制品或多各選擇系統(tǒng)，臺(tái)復(fù)印件、磁帶或微型膠卷等，保證其支持資料正確、可靠及完整。出現(xiàn)資料改動(dòng)、非人為消除或遺失時(shí)，應(yīng)維修。

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過(guò)濾器

用于生產(chǎn)、加工的液體過(guò)濾器或人用注射藥品的包裝材料不許釋放出纖維的進(jìn)入產(chǎn)品。除非不得以，不在生產(chǎn)、加工中使用釋放纖維的過(guò)濾器或注射藥品的包裝材料。若必須使用一種能釋放纖維素的過(guò)濾器，最后應(yīng)使用一非釋放紛紛物、平均最大孔徑為0.22μm(如實(shí)際生產(chǎn)條件限制，可用0.45μm)的附加過(guò)濾器過(guò)濾，降低注射劑內(nèi)微粒量。使用含石板的過(guò)濾器最后用或不用特殊非釋放纖維過(guò)濾器均可以，但要根據(jù)FDA有關(guān)部門提供的該非釋放纖維過(guò)濾器會(huì)或可能損害注射劑的安全性和有效性的證據(jù)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、藥品容器和密封件控制

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

 

211?80總要求

（a）????有文字詳細(xì)說(shuō)明成份、藥品容器、密封件的簽收、鑒定、貯存、裝運(yùn)取樣、檢驗(yàn)和批準(zhǔn)或拒收程序，并遵循。

（b）????成份、藥品容器和密封件應(yīng)專人管理和在防止污染的環(huán)境下貯存。

（c）????藥品容器的包裝袋或包裝箱或密封件應(yīng)離地面放置保持適當(dāng)間隔，全球清潔和檢查。

（d）????用明顯的已接收的每裝貨量中的批號(hào)代碼對(duì)成分、藥品容器或密封件加以鑒別。此代碼用于記錄每批貨的放置地方。對(duì)每批貨的情況，如隔離、批準(zhǔn)或拒收等作檢查。

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未檢驗(yàn)的成份、藥品容器和密封件的接收與貯存

（a）???接收時(shí)和驗(yàn)收前，對(duì)每個(gè)或編組的成份容器、藥品容器和密封件進(jìn)行目檢，給內(nèi)容物、容器損壞或拆封和污染等情況作適當(dāng)?shù)臉?biāo)志。

（b）???成份、藥品容器各密封件應(yīng)隔離貯存，直至經(jīng)檢驗(yàn)為止。合格，可發(fā)放。在符合211?80要求的地區(qū)中貯存。

211?84成份、藥品容器和封口物品的試驗(yàn)、批準(zhǔn)或拒收

（a）???????每批成份、藥品容器和封口物品，在未經(jīng)質(zhì)量部門取樣、檢查合格前，不準(zhǔn)使用。檢驗(yàn)合格后發(fā)放使用。

（b）???????收集每批的每一裝貨量的代表性樣品，供檢驗(yàn)用。

容數(shù)目和每一容器里物質(zhì)的取樣量是有適當(dāng)?shù)臉?biāo)準(zhǔn)的，例如，成份的變異性統(tǒng)計(jì)學(xué)標(biāo)準(zhǔn)、可信限、要求的精密度、供應(yīng)商過(guò)去的質(zhì)量歷史、21?170要求分析和留樣所需的數(shù)量等。

（c）???????收集樣品程序；

（1）???用適當(dāng)?shù)姆椒ǎ鍧嵾x出成份容器；

（2）???打開(kāi)容器，取樣，重新封口，防止其內(nèi)容物受污染和其他成分、藥品容器或密封件的污染。

（3）???必要時(shí)，使用滅菌設(shè)備和無(wú)菌取樣技術(shù)。

（4）???如果需要從容器頂部、中部和底部的成分中取樣，樣品須混合。

（5）???鑒定樣品容器，目的是確定如下資料：被取樣的材料名稱、批號(hào)、被取樣的容器，取樣日期及樣品收集人的名字等。

（6）???已取樣的容器，應(yīng)作標(biāo)志，表示樣品已取出。

（d）???????樣品檢驗(yàn)程序：

（1）???一個(gè)藥品的每個(gè)成分，最少做一個(gè)特性試驗(yàn)。如有專一特性實(shí)驗(yàn)就應(yīng)采用。

（2）???依照所有成文的規(guī)格標(biāo)準(zhǔn)檢驗(yàn)每個(gè)成份的純度、含量和質(zhì)量。生產(chǎn)廠家代替上述試驗(yàn)。規(guī)定生產(chǎn)廠家最少要做個(gè)成份特別試驗(yàn)，可承認(rèn)；這些成分的供應(yīng)者掃提供的分析報(bào)告。規(guī)定隔一定時(shí)間，生產(chǎn)廠家定期驗(yàn)證供應(yīng)午的試驗(yàn)結(jié)果，證明供應(yīng)者的分析結(jié)果是正確的。

（3）???依照成文規(guī)程，檢驗(yàn)容器和密封件。生產(chǎn)廠家代替上友誼賽試驗(yàn)，規(guī)定生產(chǎn)廠家對(duì)這些容器或封口物品，最少做一次目檢?？沙姓J(rèn)供應(yīng)者的檢驗(yàn)證書。規(guī)定生產(chǎn)廠家定期驗(yàn)證供應(yīng)者的試驗(yàn)結(jié)果，證明其試驗(yàn)結(jié)果是正確的。

（4）???必要時(shí)，用顯微鏡檢測(cè)成分。

（5）???每批易受污物、昆蟲或其他外來(lái)雜物污染的某一成份、藥品容器或密封件，鑒于其預(yù)期用途，在使用前，應(yīng)做微生物試驗(yàn)。

（e）任何批號(hào)的成份、藥品容器或密封件，若符合已成文的均一性、效價(jià)或含量、質(zhì)量、純度等的規(guī)格標(biāo)準(zhǔn)和本部分（d）的有關(guān)試驗(yàn)，可批準(zhǔn)使用。任何批號(hào)的上述材料，不符合這些規(guī)格，應(yīng)拒收。

211?86獲準(zhǔn)作用的成份、藥品容器和密封件，先入庫(kù)者先用。若產(chǎn)生的偏差是暫時(shí)的和適當(dāng)，這種偏差是容許的。

211?87獲準(zhǔn)的成份、藥品容器和密封件的復(fù)檢

經(jīng)質(zhì)量控制部門批準(zhǔn)或拒收的成份、藥品容器密封件，若長(zhǎng)期貯存或曝露在空氣、熱或其他可能對(duì)其產(chǎn)生不良影響的環(huán)境后，應(yīng)依照211?84，對(duì)均一性、效價(jià)或含量、質(zhì)量、純度等復(fù)檢。

211?89拒收的成份、藥品容器和封口物品

拒收的成份、藥品容器和封口物品應(yīng)經(jīng)鑒定和在隔離系統(tǒng)下加以控制，防止在生產(chǎn)和加工使用。

211?94藥品密封容器和密封件

（a）???藥品包裝容器和密封件應(yīng)不起反應(yīng)、不吸著、不吸附、不致改變藥品的安全性、均一性、含量或效價(jià)、質(zhì)量和純度而超出制定的或其它頒布的規(guī)定要求。

（b）???容器封口系統(tǒng)應(yīng)對(duì)貯藏和使用過(guò)程中可預(yù)見(jiàn)的能引起藥品變質(zhì)或污染的外部因素提供足夠的防護(hù)。

（c）???藥品容器和密封件應(yīng)清潔、滅菌和除熱原，保證其適用于預(yù)期目的。

（d）???藥品容器和密封件的標(biāo)準(zhǔn)或規(guī)格、檢驗(yàn)方法（指清潔和消毒方法、除熱原過(guò)程）應(yīng)成文并遵循。

 

F? .生產(chǎn)和加工控制

 

211?100成文的規(guī)程、偏差

（a）???編寫為保證藥品的均一性、含量或效價(jià)、質(zhì)量及純度而設(shè)計(jì)的生產(chǎn)和加工控制程序，這些程序包括本部?jī)?nèi)全部要求。這些成文程序（包括變化）須經(jīng)有關(guān)部門起草、復(fù)查和批準(zhǔn)，然后再經(jīng)質(zhì)量控制部門復(fù)查與批準(zhǔn)。

（b）???在實(shí)施各種生產(chǎn)和加工控制功能中，遵循已制定的生產(chǎn)和加工控制程序，并在招待時(shí)以文件加以證明。程序中出現(xiàn)的任何偏差，應(yīng)作記錄，并提出證據(jù)。

211?101成分的進(jìn)料

成文的生產(chǎn)和控制程序包括下面的內(nèi)容，其設(shè)計(jì)應(yīng)保證所生產(chǎn)的藥品具有核武器原有的均一性、含量和效價(jià)、質(zhì)量和純度。

（a）??按處方配制的藥品，保證其活性成份含量不低于100%標(biāo)示量或規(guī)定量。

（b）??生產(chǎn)藥品用的成份應(yīng)稱量、測(cè)量或適當(dāng)粉碎。若一種成份從原來(lái)容器轉(zhuǎn)移到另一容器內(nèi)，用下列資料以鑒別：

(1)?????成份名稱或項(xiàng)目代碼。

(2)?????接收或控制號(hào)。

(3)?????在新容器中的重量或份量。

(4)?????使用此成分2配制的一批藥品，包含其產(chǎn)品名稱、含量和批號(hào)。

（c）成份的稱重、測(cè)量或粉碎操作，應(yīng)受到嚴(yán)密的監(jiān)督。所盛成份已用于生產(chǎn)的每一容器，須經(jīng)第二人檢查，保證：

（1）???此成份是由質(zhì)量控制人員發(fā)放的。

（2）???重量或份量正確，批生產(chǎn)記錄一致。

（3）???容器經(jīng)嚴(yán)格鑒別。

（d）每一成份投料時(shí)，一人操作，另一人核對(duì)。

211?103產(chǎn)量計(jì)算

在藥品生產(chǎn)、加工或貯存的每一適當(dāng)階段結(jié)束時(shí)，測(cè)算實(shí)際產(chǎn)量與理論產(chǎn)量的百分比。

211?105設(shè)備鑒別

（a）???在整個(gè)生產(chǎn)周期內(nèi)，同批藥品生產(chǎn)使用的全部混合和貯存容器、生產(chǎn)線和主要設(shè)備應(yīng)嚴(yán)格識(shí)別，標(biāo)示出藥品的成份，需要時(shí)，不須標(biāo)出所處的加工階段。

（b）???一種藥品每批生產(chǎn)使用的主要設(shè)備，以一鑒別性識(shí)別號(hào)或代號(hào)加以識(shí)別。此鑒別號(hào)或代號(hào)記錄在該批號(hào)產(chǎn)品的記錄本。若生產(chǎn)中只使用一種特殊型號(hào)的設(shè)備，可用該設(shè)備名字代替鑒別性識(shí)別或代號(hào)。

211?110中間體和藥品的取樣與檢驗(yàn)

（a）???制訂和遵循說(shuō)明每批的加工過(guò)程控制及對(duì)加工過(guò)程中材料的適當(dāng)樣品實(shí)行檢驗(yàn)或檢查的成文程序，保證藥品的一致性和完整性。上述控制程序包括，但不限于如下內(nèi)容：

（1）???片劑或膠囊的重量變化。

（2）???崩解時(shí)間。

（3）???充分混和，保證均勻。

（4）???溶解時(shí)間和溶解速率。

（5）???溶液的澄明度、溶解完全性及PH值。

（b）???考慮上述特性而制定的有效中間加工規(guī)格與藥品最終規(guī)格一致。此中間加工規(guī)格應(yīng)在以前可靠的加工方法穩(wěn)定性評(píng)估和經(jīng)應(yīng)用統(tǒng)計(jì)學(xué)程序斷定認(rèn)為合適的基礎(chǔ)上制定的。樣品測(cè)試，保證藥品和中間體符合規(guī)格標(biāo)準(zhǔn)。

（c）???在生產(chǎn)加工期間，如在重要階段的開(kāi)始、由質(zhì)量控制部門審定，決定聯(lián)取舍。

（d）???不合格的中間體，在隔離系統(tǒng)下鑒別及控制，防止其在征稅或加工操作中使用。

211?111生產(chǎn)時(shí)間限制

在適當(dāng)時(shí)候，制定完成每一生產(chǎn)階段的時(shí)間限制，保證藥品質(zhì)量。制定的時(shí)間限制產(chǎn)生偏差，如這些偏差不損害藥品質(zhì)量，是可以接受的。這些偏差應(yīng)有文字文件證明是正當(dāng)?shù)摹?/p>

211?113微生物污染的控制

（a）???制訂和遵循預(yù)防不需消毒藥品有害微生物的適當(dāng)程序。

（b）???制訂和遵循預(yù)防已消毒藥品微生物污染的適當(dāng)程序。這些程序包括所有消毒過(guò)程的驗(yàn)證。

211?115返工

（a）???制訂和遵循指導(dǎo)人合格批號(hào)返工及保證返工批號(hào)達(dá)標(biāo)的程序。

（b）???沒(méi)有質(zhì)量控制部門復(fù)檢與批準(zhǔn)，不許進(jìn)行返工。

 

G.包裝和標(biāo)簽控制

 

211?122材料的檢查和使用標(biāo)準(zhǔn)

（a）???制訂詳細(xì)標(biāo)簽和包裝材料的接收、鑒別、貯存、半年取樣檢驗(yàn)的程序，并遵循這些成文程序。在接收、用于藥品包裝和貼標(biāo)簽前，有代表性地對(duì)其取樣與檢驗(yàn)。

（b）???符合成文規(guī)格標(biāo)準(zhǔn)的標(biāo)簽和包裝材料，可批準(zhǔn)發(fā)放使用。不符合規(guī)格者，不得用于生產(chǎn)。

（c）???接收每批不同標(biāo)簽和包裝材料，無(wú)須簽收、測(cè)試。無(wú)論是接收或拒收，須保留其記錄。

（d）???用于不同藥品、含量、劑型及成份數(shù)量的標(biāo)簽和標(biāo)示材料分別貯存，并持上適當(dāng)牌證，只限經(jīng)核準(zhǔn)人員接近貯存地區(qū)。

（e）???作廢和陳舊的標(biāo)簽、標(biāo)示材料及其他包裝材料應(yīng)銷毀。

（f）???排字印刷在不同藥品或同一藥品不同規(guī)格的品種上`使用排字印刷，考慮在印刷期間和印刷后，印刷品的設(shè)置、切裁和管理等，應(yīng)制訂包裝和標(biāo)簽工作專門控制程序。

（g）???在藥品印標(biāo)簽的生產(chǎn)線，其上的或與其有關(guān)的印刷設(shè)備應(yīng)受到臨近，保證所有印痕與本批產(chǎn)品記錄中說(shuō)明的印痕一致。

211?125標(biāo)簽的發(fā)放

（a）???嚴(yán)格控制已發(fā)放的，用于藥品的標(biāo)簽。

（b）???已發(fā)放的一批標(biāo)簽材料，須認(rèn)真檢查其無(wú)一性，應(yīng)與一批或單批生產(chǎn)記錄中說(shuō)明的標(biāo)簽一致。

（c）???核對(duì)發(fā)放的，已使用的及回收的標(biāo)簽，若發(fā)現(xiàn)成品數(shù)量與發(fā)出的標(biāo)簽數(shù)量不符，差額超出根據(jù)歷史水平先前定下的數(shù)量范圍，則需對(duì)這些偏差作出評(píng)估，按照211?192要求調(diào)查原因。

（d）???超出有關(guān)批號(hào)或控制號(hào)標(biāo)簽，全部應(yīng)銷毀。

（e）???回收的標(biāo)簽，如保留應(yīng)加上證明標(biāo)志貯存，防止混淆。

（f）???制訂發(fā)放標(biāo)簽的詳細(xì)控制程序，并遵循。

211?130包裝和標(biāo)簽操作

設(shè)計(jì)保證標(biāo)簽、標(biāo)示及包裝材料正確用于藥品的程序，并遵循。這些程序結(jié)合下列

（a）???預(yù)防混合和由物理的或其他操作空間物質(zhì)引起的交叉

（b）???帶批號(hào)或控制呈藥品的鑒別，檢查該藥品的制造和控制歷史。

（c）???包裝工作開(kāi)展前，檢查包裝和標(biāo)簽材料的適用性和正確性，且這些檢驗(yàn)所提供的證明文件應(yīng)符合批生產(chǎn)記錄。

（d）???使用前，立即檢查包裝和貼標(biāo)簽設(shè)備，保證 所有藥品離開(kāi)先前的操作，同時(shí)移開(kāi)不適用于隨后操作的包裝材料。檢查結(jié)果以批生產(chǎn)記錄形式提供證明文件。

211?132人用百處方藥（OTC）保險(xiǎn)包裝的要求

（a）???一般來(lái)說(shuō)，在聯(lián)邦食品、藥物和化妝品法規(guī)下，F(xiàn)DA有權(quán)制定非處方藥保險(xiǎn)包裝的統(tǒng)一國(guó)家要求。提高非處方藥包裝的可靠性和有助保證非自主藥的安全與效果。一種零售OTC藥品（皮膚科藥、牙粉、胰島素、喉片除外）沒(méi)有包裝在保險(xiǎn)包裝內(nèi)或或沒(méi)有適當(dāng)?shù)臉?biāo)簽，根據(jù)聯(lián)邦法規(guī)501部分，屬摻假藥；根據(jù)502部分或兩者，飛行屬錯(cuò)貼標(biāo)簽。

（b）???保險(xiǎn)包裝每個(gè)生產(chǎn)者和包裝者，應(yīng)將零售OTC藥品裝入保險(xiǎn)包裝內(nèi)，若此藥易受公眾影響，該藥應(yīng)在內(nèi)保持至售出。

保險(xiǎn)包裝是內(nèi)有一個(gè)或多個(gè)批示物或障礙物的藥品包裝。若缺損或失落，能適當(dāng)?shù)亟o顧客提供已發(fā)生破損的明顯證據(jù)如果因缺損而使產(chǎn)品受損，則要求此包裝在設(shè)計(jì)上應(yīng)有特色（例如噴霧產(chǎn)品容器）或使用一個(gè)或多個(gè)有鑒別性性批示物或障礙物加進(jìn)包裝內(nèi)（例如圖案、名稱、注冊(cè)商標(biāo)、標(biāo)識(shí)或圖畫等）。上述“在設(shè)計(jì)上有特色”之意，即此包裝不能用一般的通用材料和加工工藝來(lái)復(fù)制。術(shù)語(yǔ)“噴霧產(chǎn)品”即用液化氣體或壓縮氣體交容器中成份噴出。一具保險(xiǎn)包裝可以是能提供目視其中包裝完整性的密閉容器、第二容器 、封閉系統(tǒng)或任何聯(lián)合系統(tǒng)。這些保險(xiǎn)裝置被設(shè)計(jì)成在生產(chǎn)、分裝和銷售陳列期間，以適當(dāng)方法搬運(yùn)，保持不致受損壞。

（1）???兩段式明膠硬膠囊產(chǎn)品，除非包裝工藝密封的外，最少需二個(gè)保險(xiǎn)裝置。

（2）???所有其他產(chǎn)品，包括經(jīng)保險(xiǎn)工藝密封的二段式明膠硬膠囊，最少需要一個(gè)保險(xiǎn)裝置。

（c）???標(biāo)簽。除在易拆安瓿中氨吸入物、本部分的（b）節(jié)規(guī)定的噴霧產(chǎn)品或壓縮醫(yī)用氧容器外，本部分涉及的非處方藥的每個(gè)零售包裝，要求帶有一“聲明”放置在一明顯的地方，使顧客對(duì)包裝的特殊保險(xiǎn)裝置有所警覺(jué)。此標(biāo)簽“聲明”不要求放置于適當(dāng)?shù)牡胤?，?dāng)包裝的保險(xiǎn)裝置破損或失落時(shí)，不受影響。如果選擇符合本部分（b）節(jié)要求的保險(xiǎn)裝置是使用鑒別我的話，那要參考標(biāo)簽“聲明”。例如，在帶有一皺縮套的瓶上的標(biāo)簽“聲明”應(yīng)寫“為了此瓶周圍印有標(biāo)志”。

（d）???申請(qǐng)免除對(duì)包裝和標(biāo)簽的要求。生產(chǎn)者和饈者可申請(qǐng)免除本部分對(duì)包裝和標(biāo)簽的要求。一個(gè)免除申請(qǐng)，要求按本章10?30，以公民申請(qǐng)形式提交，且根據(jù)“免除保險(xiǎn)包裝申請(qǐng)條例”加以鑒別。申請(qǐng)所需之內(nèi)容如下：

（1）???藥品名稱。若申請(qǐng)的是某一類藥，需列出類名，并列出該類藥中的產(chǎn)品表。

（2）???藥品沒(méi)必要實(shí)施或不能達(dá)到本部門的保險(xiǎn)包裝或標(biāo)簽的要求的理由。

（3）???選擇的措施的可行性報(bào)告；申請(qǐng)者已采取的措施的可行性報(bào)告；減少產(chǎn)品或藥品種類摻假的可能性的報(bào)告。

（4）???證明免除是合理的其他資料。

（e）???非處方藥受已被批準(zhǔn)的新藥申請(qǐng)管轄。要求非處方藥原被批準(zhǔn)的新藥申請(qǐng)持有人，根據(jù)本章314?70（c）提供的那樣，可在FDA批準(zhǔn)前實(shí)施。根據(jù)本章314?70（b），膠囊密封的生產(chǎn)改進(jìn)需FDA先批準(zhǔn)。

（f）???1970年毒物預(yù)防包裝條例。本部分不影響本章310?3（L）規(guī)定的特殊包裝的任何要求和1970年毒物保護(hù)包裝條例的要求（經(jīng)管理和預(yù)算處批準(zhǔn)，控制號(hào)091 0149）[54聯(lián)邦注冊(cè)5228，1989年2月2日]。

211?134藥品檢查

（a）???已包裝和貼標(biāo)簽的產(chǎn)品，在結(jié)束工作時(shí)，應(yīng)檢查，保證本批容器和包裝的標(biāo)簽正確無(wú)誤。

（b）???操作結(jié)束時(shí)，每組收集一個(gè)代表性樣品，同時(shí)檢查標(biāo)簽。

（c）???檢查結(jié)果記錄在謬論批的生產(chǎn)或控制記錄中。

211?137有效期

（a）???保證一個(gè)產(chǎn)品在使用時(shí)符合均一性、效價(jià)或含量、質(zhì)量和純度等標(biāo)準(zhǔn)，應(yīng)提供一個(gè)有效期。有效期按211?166所友誼賽的穩(wěn)定性試驗(yàn)測(cè)定。

（b）???有效期是在符合標(biāo)簽上規(guī)定的貯存條件下，按211?166所述的穩(wěn)定性試驗(yàn)測(cè)定。

（c）???基藥品在配制時(shí)要重新配伍，那重新配伍好的和未重新配伍的兩種藥品標(biāo)簽上均須提供有效日期。

（d）???根據(jù)本章201?17的要求，有效日期標(biāo)在標(biāo)簽上。

（e）???順勢(shì)治療（homeopathic）藥品免除本部分的要求。

（f）???標(biāo)“沒(méi)有美國(guó)效價(jià)標(biāo)準(zhǔn)”的變應(yīng)原撮物免除本部分要求。

（g）???若人用非處方藥品標(biāo)簽沒(méi)有提供劑量范圍，同時(shí)，經(jīng)至少三年穩(wěn)定性資料證明其是穩(wěn)定的，可不實(shí)施本部分的要求。[43聯(lián)邦注冊(cè)45077，1978年9月29日，修正，在46聯(lián)邦56412，1981年11月17日]。

 

H．貯存和銷售

 

211?142入庫(kù)程序

制訂和遵循藥品入庫(kù)程序，包括：

（a）???藥品發(fā)放前，由質(zhì)量控制部門待驗(yàn)。

（b）???藥品在適當(dāng)?shù)臏囟取穸群凸饩€下貯存，不影響藥品的均一性、效價(jià)或含量、質(zhì)量及純度。

211?150銷售程序

制訂和遵循藥品銷售程序，包括：

（a）???最早批準(zhǔn)庫(kù)存的藥品，應(yīng)先銷售。若違背本要求的地方是暫時(shí)和適可的，這是允許的。

（b）???通過(guò)每批藥品的銷售系統(tǒng)，能迅速檢查藥品，若有必要，便于撤回。

 

I?實(shí)驗(yàn)室控制

 

211?160總要求

（a）???按本部分的要求，制訂規(guī)格、標(biāo)準(zhǔn)、取樣方法、試驗(yàn)程序或其他實(shí)驗(yàn)室控制機(jī)制，包括上述內(nèi)容的修改，由有關(guān)部門起草和復(fù)查，并經(jīng)質(zhì)量控制部門批準(zhǔn)。遵守本部分中各要求，在實(shí)施時(shí)，提供證明文件。任何對(duì)成文的規(guī)格、標(biāo)準(zhǔn)、取樣方法、試驗(yàn)程序或其他實(shí)驗(yàn)室控制機(jī)制的改動(dòng)，應(yīng)作記錄，并提供證明這些改動(dòng)是正確的。

（b）???實(shí)驗(yàn)室控制內(nèi)容，包括科學(xué)地制訂完善、合理的規(guī)格、標(biāo)準(zhǔn)、取樣方法及為保證各種成份、藥品容器、密封件、中間體、標(biāo)簽和藥品符合均一性、效價(jià)和含量、質(zhì)量與純度標(biāo)準(zhǔn)而設(shè)計(jì)的檢驗(yàn)程序。實(shí)驗(yàn)室控制包括：

（1）???根據(jù)接收的規(guī)格、測(cè)定用于藥品生產(chǎn)、加工包裝及貯存的每裝貨量中的每批的成份、藥品容器、密封件和標(biāo)簽。保證它們符合制定的規(guī)格標(biāo)準(zhǔn)。此規(guī)格包括使用的取樣和檢驗(yàn)程序說(shuō)明。樣品有代表性及經(jīng)適當(dāng)鑒別。這些程序亦要求對(duì)任何變質(zhì)的成份、藥品容器或密封件作重復(fù)檢驗(yàn)。

（2）???根據(jù)中間體的成文規(guī)格和取樣及檢驗(yàn)程序，測(cè)定中間體。樣品應(yīng)有代表性和經(jīng)適當(dāng)鑒定。

（3）???若儀器設(shè)備、量具和記錄裝置的準(zhǔn)確度和/或精密度范圍不符，按照制訂的成文方案，包括具體說(shuō)明書，一覽表，準(zhǔn)確度和精確度范圍及作用條款，在適當(dāng)時(shí)間間隔內(nèi)，對(duì)這些儀器設(shè)備進(jìn)行標(biāo)定。不符合已制定規(guī)格的儀器、設(shè)備不能使用。

211?165銷售要求檢驗(yàn)與發(fā)放

（a）???發(fā)放前每批藥品須經(jīng)實(shí)驗(yàn)室測(cè)定，保證其符合藥品的最終規(guī)格標(biāo)準(zhǔn)，包括特性和活性成份的含量。對(duì)有效期短的，需無(wú)菌和/或熱原試驗(yàn)的放射藥物特殊批號(hào)，可在上述試驗(yàn)完成前發(fā)放，規(guī)定盡快完成試驗(yàn)。

（b）???要求無(wú)有害微生物的藥品，根據(jù)需要，每批藥品應(yīng)有適當(dāng)?shù)膶?shí)驗(yàn)室檢驗(yàn)。

（c）???任何取樣和檢驗(yàn)計(jì)劃，應(yīng)在成文程序中說(shuō)明。此程序包括取樣方法和每批檢驗(yàn)的聯(lián)合批號(hào)。

（d）???對(duì)質(zhì)量控制部門的取樣和檢驗(yàn)的接收標(biāo)準(zhǔn)是滿足保證那些藥品符合各自的規(guī)格標(biāo)準(zhǔn)和統(tǒng)計(jì)學(xué)的質(zhì)量控制標(biāo)準(zhǔn)。；這些標(biāo)準(zhǔn)是批準(zhǔn)和發(fā)放藥品的條件。此統(tǒng)計(jì)學(xué)質(zhì)量控制標(biāo)準(zhǔn)包括適當(dāng)?shù)慕邮账胶?或適當(dāng)?shù)木苁账健?/p>

（e）???證實(shí)和提供文件證明經(jīng)嚴(yán)格使用的檢驗(yàn)方法的準(zhǔn)確性、靈敏性、特異性和重復(fù)性。此驗(yàn)證和證明，可按照211?194（a）(2)項(xiàng)完成。

（f）???不符合制訂的標(biāo)準(zhǔn)、規(guī)格和其他有關(guān)質(zhì)量控制標(biāo)準(zhǔn)的藥品，應(yīng)拒收，但可返工。被 返工的藥品。在接收和應(yīng)用前，須符合標(biāo)準(zhǔn)、規(guī)格和其他有關(guān)標(biāo)準(zhǔn)。

211?166穩(wěn)定性試驗(yàn)

（a）???有一個(gè)設(shè)計(jì)確定藥品穩(wěn)定性的成文試驗(yàn)方案。此試驗(yàn)用于測(cè)定合適的貯存條件和有效期。成文方案包括：

（1）???樣品量和試驗(yàn)時(shí)間間隔。此間隔是基于各自的檢查特征的統(tǒng)計(jì)學(xué)標(biāo)準(zhǔn)而定，保障穩(wěn)定性評(píng)價(jià)的正確性。

（2）???保留樣品的貯存條件。

（3）???可靠的、有意義的各具體的試驗(yàn)方法。

（4）???同一容器-密閉系統(tǒng)內(nèi)正在銷售藥品的檢驗(yàn)。

（5）???配制時(shí)，配伍的藥品（按標(biāo)簽指出的）和配制后的藥品的檢驗(yàn)。

（b）???每個(gè)藥品有足夠批號(hào)受檢，測(cè)定一個(gè)適當(dāng)?shù)挠行?，保留這些資料的記錄。結(jié)合成份，藥品及容器-封閉系統(tǒng)的基本穩(wěn)定性資料的“加速研究”，用于支持提供足夠的貨架壽命的實(shí)驗(yàn)性有效期是不合適的，而且，這種研究正在實(shí)行。使用“加速研究”提供的資料，設(shè)計(jì)一實(shí)驗(yàn)性有效期，此有效期是后于由實(shí)際貨架研究支持的日期。必須有實(shí)施的穩(wěn)定性試驗(yàn)，包括適當(dāng)?shù)臅r(shí)間間隔的藥品檢驗(yàn)，直至此實(shí)驗(yàn)性有效期被證實(shí)或被確定為止。

（c）???本部分對(duì)順勢(shì)治療藥品的要求如下：

（1）???對(duì)各成份間的可配伍性，有一個(gè)基于藥品的檢驗(yàn)或測(cè)定的穩(wěn)定性文字評(píng)價(jià)。同時(shí)，根據(jù)藥品銷售經(jīng)驗(yàn)，指出政黨的或預(yù)期的服用期內(nèi)，藥品沒(méi)有變質(zhì)。

（2）???穩(wěn)定性評(píng)價(jià)應(yīng)建立在正點(diǎn)銷售的同一容器-封閉系統(tǒng)藥品的基礎(chǔ)上。

（d）???標(biāo)有“沒(méi)有美國(guó)效價(jià)標(biāo)準(zhǔn)”變應(yīng)原提取物，免除本部分要求[43聯(lián)邦注冊(cè)4507，1978年9月29日，修正，在46聯(lián)邦56412，1981年11月17日]

211?167特別檢驗(yàn)要求

（a）???標(biāo)明無(wú)菌和/或無(wú)熱原的每批藥品，應(yīng)有檢查符合此要求的實(shí)驗(yàn)室檢驗(yàn)。檢驗(yàn)程序應(yīng)成文遵循。

（b）???每批眼膏，應(yīng)有測(cè)定符合有關(guān)外部微粒，粗糙或磨蝕物質(zhì)存在的規(guī)格檢驗(yàn)。檢驗(yàn)程序應(yīng)成文并遵循。

（c）???每批控釋制劑都有一實(shí)驗(yàn)室檢驗(yàn)，測(cè)定每一活性成份藥品的最后一批的有效期滿后三個(gè)月。

211?170樣品保存

（a）???每一裝貨量的活性成份經(jīng)鑒別后，留樣。留樣最少二倍于滿足全部測(cè)定所需樣品數(shù)量為準(zhǔn)，無(wú)菌和熱原檢驗(yàn)所需量除外。測(cè)定活性成份量否符合其制訂的規(guī)格。

（1）???藥品中的活性成份。除本忍氣吞聲（a）（1）和（3）友誼賽及的外，留樣按該藥量后一批有效期后計(jì)，保留一年。

（2）???放射性藥品中的活性成份（非放射活性試劑盒除外）的留樣保留：

Ⅰ）如果藥品注明有效期是三十天或以內(nèi)，保留期是含此活性成份藥品的最后一批的有效期滿后三個(gè)月。

Ⅱ）如果藥品注明有效期是三十天或以上，保留期是含此活性成份藥品的最后一批的有效期滿后六個(gè)月。

（3）???根據(jù)211?137免除有效期的非處方藥，其活性成分留樣，是含此活性成份藥品的最后一批藥品銷售后三年。

（b）經(jīng)鑒別，代表每批藥品的留樣，地藥品標(biāo)簽指定的條件貯存。留樣貯存在盛銷售藥品的同樣容器封閉系統(tǒng)內(nèi)或基本上有相同我的容器系統(tǒng)內(nèi)。留樣最少二總倍于數(shù)應(yīng)滿足檢驗(yàn)需要量，無(wú)菌和熱原檢驗(yàn)的留樣除外。每年至少目檢留樣（除（b）（2）中述及的藥品外）一次，檢查其變質(zhì)發(fā)問(wèn)，除非目檢會(huì)影響留樣的完整性。對(duì)留樣變質(zhì)跡象，根據(jù)211?192加以研究。檢查結(jié)果的記錄和該藥品的穩(wěn)定性資料一起保留。醫(yī)用壓縮不保留。藥品留樣保留時(shí)間如下：

（1）除本部分（b）（2）和（3）中述及的藥品外的藥品，留樣保留時(shí)間是該藥有效期滿后一年。

（2）除非放射性試劑盒外，放射活性藥品的留樣保留。

Ⅰ）如藥品有效期為三十天或以內(nèi)，則該藥品有效期滿后保留三個(gè)月；

Ⅱ）如有效期超過(guò)三十天，則藥品有效期滿后保留六個(gè)月。

（3）非處方藥品，根據(jù)211?137，免除有效期，留樣從銷售最后一批藥品計(jì)，保留三年[48聯(lián)邦注冊(cè)130251983年3月29日]。

211?173實(shí)驗(yàn)動(dòng)物

飼養(yǎng)和控制用于檢測(cè)成份、加工過(guò)程中材料或藥品規(guī)格的動(dòng)物，保證其適合預(yù)期的用途。鑒定動(dòng)物，并保留表明其應(yīng)用情況的記錄。

211?176青霉素污染

若一非青霉素藥品有可能被青霉素交叉感染，此非青霉素藥品應(yīng)檢查青霉素的存在。按藥品中青霉素污染和測(cè)量程序（通過(guò)參考文獻(xiàn)具體化）中指出的方法檢驗(yàn)，如達(dá)到可檢出水平，該藥品不許銷售。文件可從研究和檢測(cè)部門（HFD470）藥品評(píng)價(jià)和研究中心、FDA、200C St.Sw.Washington DC 2024,或從聯(lián)邦注冊(cè)處（1100L St.Nw.,Washington,DC2048）得到。

[43FR45077，1978年9月29日，增補(bǔ)在；47FR9396，1982年3月5日；50FR8996，1985年3月6日；55FR11577，1990年3月29日]。

 

J．記錄和報(bào)告

 

211?180總要求

（a）任何生產(chǎn)、控制或銷售記錄，須依照本部分要求特別是與一批藥品有關(guān)的上述記錄，在該批藥品有效期滿后，保留一年以上。一些無(wú)有效期的非處方藥品，由于它們符合211?137的標(biāo)準(zhǔn)，在該批藥品銷售后，保留三年。

（b）全部成份，藥品容器、密封件及標(biāo)簽的記錄，在有效期滿后，保留一年以上。一些無(wú)有效期的非處方藥品，由于它們符合211?137規(guī)定的免除的標(biāo)準(zhǔn)，故從銷售最后一批藥品計(jì)，上述記錄保留三年。

（c）本部分要求的全部記錄或它們的復(fù)印品，應(yīng)便于在保存期內(nèi)對(duì)活性成份的復(fù)核檢驗(yàn)。因此，人微言輕檢驗(yàn)的部分，這些記錄應(yīng)以光電復(fù)印或其他方法復(fù)制。直接從電子計(jì)算機(jī)或其它設(shè)備中提出的記錄，符合本段的要求。

（d）本部分要求的記錄，可用原始記錄或復(fù)印件，如光電復(fù)印、縮微膠卷，應(yīng)適合閱讀器和光電復(fù)印設(shè)備的使用。

（e）保留本部分所要求的文字記錄，其中的資料可用作評(píng)價(jià)至少一個(gè)年度每個(gè)藥品的質(zhì)量標(biāo)準(zhǔn)，決定藥品的規(guī)格、生產(chǎn)或控制程序中需要屐的地方。制訂文字程序、遵循這些評(píng)價(jià)，并包括下列條款：

（1）每一批復(fù)查一次，是否批準(zhǔn)或拒收，與此有關(guān)的記錄。

（2）投訴、撤銷、退回或報(bào)廢藥品的復(fù)查，按211?192對(duì)每個(gè)藥品進(jìn)行調(diào)查。

（f）應(yīng)建立程序以保證企業(yè)負(fù)責(zé)人責(zé)任。如果他們沒(méi)注意或不知道上述的要求，以書面形式，將按211?198、211?204或211?208等條款實(shí)施的任何調(diào)查結(jié)果、任何撤銷、FDA發(fā)出的檢測(cè)報(bào)告或與FDA通過(guò)的GMP有關(guān)的，受規(guī)章限制的任何活動(dòng)等通知他們。

211?182設(shè)備清潔和使用記錄

主要設(shè)備的清潔、維修（常規(guī)維修，如潤(rùn)滑、調(diào)整等除外）和使用文字記錄，包括在單獨(dú)的設(shè)備記錄內(nèi)。此記錄列有日期、時(shí)間、產(chǎn)品和加工批號(hào)等內(nèi)容。若設(shè)備用于生產(chǎn)一種藥品，那么，不要求單獨(dú)設(shè)備記錄。藥品批號(hào)（單批或整批）應(yīng)按號(hào)碼排列，且按號(hào)順生產(chǎn)。使用的設(shè)備，其清潔、維修和使用記錄是整批記錄的一部分。實(shí)施和雙查清潔和維修的人員，填寫日期、簽名和填寫工作記錄。記錄同伯登記，按年月順序進(jìn)行。

211?184成份、藥品容器、密封件及標(biāo)簽記錄

這些記錄包括如下內(nèi)容：

（a）每批成份、藥品容器、密封件和標(biāo)簽的每一裝貨量的鑒別與數(shù)量，供應(yīng)商名稱；供應(yīng)商的批號(hào)（如知道）、按21?80指定的接收代碼、接收日期。主要生產(chǎn)商的名稱和地址，若有不同的供應(yīng)商，造表列出（如知道）。

（b）任何檢驗(yàn)結(jié)果（包括按211?82（a）211?84(d)或211?122（a）的要求進(jìn)行的檢驗(yàn)結(jié)果）和從那里得到的結(jié)論。

（c）每個(gè)成份、藥品容器、密封件的單獨(dú)存貨記錄和每批使用的成份核對(duì)表（對(duì)各成份來(lái)說(shuō)）。此存貨記錄應(yīng)有使用各成份、藥品容器和密封件的各批（整批或小批）藥品的詳細(xì)測(cè)定資料。

（d）按211?122（c）和211?130（c）制訂的規(guī)定，檢查或復(fù)查標(biāo)簽和貼標(biāo)簽所提供的文件。

（e）拒收的成份、藥品容 器、密封件和標(biāo)簽的處理。

211?186主要生產(chǎn)和控制的記錄

（a）保障批與批間的一致性，制備各批藥品的主要生產(chǎn)和控制記錄（包括各批的量），由一人填寫日期和簽名（全名、手簽）。由另一個(gè)單獨(dú)核實(shí)，填寫日期和簽名。此主要生產(chǎn)和控制記錄的制備，由一文字程序加以說(shuō)明，并要遵循。

（b）主要生產(chǎn)和控制記錄包括：

（1）產(chǎn)品名稱、會(huì)計(jì)師和劑型的說(shuō)明。

（2）藥品各活性成份的名稱和每劑量單位或每重量單位的重量或容量。任何劑量單位的總重量或容量的說(shuō)明。

（3）一個(gè)完整的，以名字或代碼表示的成份表格，充分、顯示具體的質(zhì)量特性。

（4）準(zhǔn)確表明各成份的重量或容量，各成份使用同一計(jì)量系統(tǒng)（公制、常衡或藥衡制）。由于制備而不可避免地造成該劑型中楊份量的改變，如果它們?cè)谠撝饕a(chǎn)和控制記錄中被證明是正確的，這種合理的變動(dòng)是允許的。

（5）有關(guān)任何成份的計(jì)算超過(guò)量的說(shuō)明。

（6）在適當(dāng)加工階段，理論重量或容量的說(shuō)明。

（7）理論產(chǎn)量的說(shuō)明，包括根據(jù)211?192要求，對(duì)超過(guò)理論產(chǎn)量最大和最小百分率的調(diào)查說(shuō)明。

（8）藥品容器、密封件和包裝材料的說(shuō)明，包括標(biāo)簽和全部其它標(biāo)簽的樣本或復(fù)制件的說(shuō)明。這些樣本或復(fù)制件經(jīng)對(duì)此負(fù)責(zé)的人員簽名和注明日期。

（9）完善的生產(chǎn)和控制指令，取樣和檢驗(yàn)程序、各種規(guī)格標(biāo)準(zhǔn)，各種特殊的注解和各種預(yù)防方法均需遵照?qǐng)?zhí)行。

211?188批生產(chǎn)和控制記錄

每批生產(chǎn)的藥品有批的生產(chǎn)和控制記錄，包括每批有關(guān)生產(chǎn)和控制的完整資料。這些記錄包括：

（a）適當(dāng)?shù)闹饕a(chǎn)或控制記錄、復(fù)查、注明的日期及簽名的準(zhǔn)確復(fù)制件。

（b）完成本批的生產(chǎn)、加工、包裝、貯存中各項(xiàng)重要措施須提供的資料，包括：

（1）日期。

（2）使用的重要設(shè)備和生產(chǎn)線的特性。

（3）每批使用的成份或中間體的具體

（4）加工過(guò)程中使用的成份的重量和容量。

（5）加工過(guò)程和實(shí)驗(yàn)室控制結(jié)果。

（6）使用前、后，包裝和貼標(biāo)簽地區(qū)的檢查。

（7）在適當(dāng)加工階段，實(shí)際產(chǎn)量的說(shuō)明和理論百分?jǐn)?shù)的說(shuō)明。

（8）完整的標(biāo)簽控制記錄，包括全部使用的標(biāo)簽樣本或復(fù)制件。

（9）藥品容器和密封件的說(shuō)明。

（10）?已經(jīng)完成的取樣。

（11）?生產(chǎn)中，招待和直接監(jiān)督或復(fù)查各個(gè)重要過(guò)程的人員身份證明。

（12）?任何的調(diào)查，按211?192進(jìn)行。

（13）?檢查結(jié)果，211?134處理。

211?192產(chǎn)品記錄復(fù)查

所有藥品生產(chǎn)和控制記錄，包括包裝和標(biāo)簽記錄，須按全部已制訂通過(guò)的程序復(fù)查和認(rèn)可。此復(fù)查和認(rèn)可應(yīng)在該批藥品發(fā)放或銷售前完成。一些非解釋性差異（包括超過(guò)在主要生產(chǎn)和控制記錄中制訂的最大或最小百分?jǐn)?shù)的理論產(chǎn)量的百分?jǐn)?shù)）或一批或任何一個(gè)成份不符合其規(guī)格中任一項(xiàng)，則應(yīng)作徹底調(diào)查，不管這批藥品是否已銷售。這種調(diào)查應(yīng)提高擴(kuò)展到該同一藥品的其他批號(hào)和與此具體的不合格或差異相聯(lián)系的其它藥品。應(yīng)寫成文字記錄，包括結(jié)論和繼續(xù)跟蹤。

211?194實(shí)驗(yàn)室記錄

（a）實(shí)驗(yàn)室記錄包括保證符合已制訂的規(guī)格和標(biāo)準(zhǔn)的全部完整的檢驗(yàn)（包括檢查和分析）資料。

（1）與接收的檢驗(yàn)用樣品有關(guān)的資料：來(lái)源（取樣地方）、數(shù)量、批號(hào)或其他的特性代碼，定期樣品的取樣日期及檢驗(yàn)用樣品的接收日期。

（2）樣品檢驗(yàn)方法的說(shuō)明。此說(shuō)明應(yīng)指出制訂樣品檢驗(yàn)方法的資料出處，通過(guò)這些檢驗(yàn)方法，確保樣品符合現(xiàn)行準(zhǔn)確標(biāo)準(zhǔn)（若使用的方法是在最新修訂版美國(guó)藥典、國(guó)家處方集、官方的分析化學(xué)協(xié)會(huì)（ABABC）、分析方法類書籍或在其它公認(rèn)的標(biāo)準(zhǔn)文獻(xiàn)或在一已批準(zhǔn)的新藥申請(qǐng)中詳述，此文獻(xiàn)方法不修改。應(yīng)用的試驗(yàn)方法，在實(shí)際使用條件下考證是否適用（從Association of Official Analytical Chemists 2200 Wilson Blvd，Suite 400,Arlington,VA22201 3301）。

（3）相應(yīng)的各個(gè)檢驗(yàn)用樣品的重量或容量的說(shuō)明。

（4）各檢驗(yàn)過(guò)程中獲得的全部資料的完整記錄，包括：實(shí)驗(yàn)儀器測(cè)定成份、藥品容器、密封件、中間體或藥品的全部圖表、曲線和光譜及檢驗(yàn)的批量。

（5）與檢驗(yàn)有關(guān)的全部計(jì)算記錄，包括測(cè)量單位、換算系數(shù)和相量系數(shù)。

（6）說(shuō)明為何交檢驗(yàn)結(jié)果與被檢的成份、藥品容器、密封件、中間體或藥品的已制訂的特性、含量或效價(jià)、質(zhì)量和純度標(biāo)準(zhǔn)作比較的過(guò)程。

（7）每個(gè)檢驗(yàn)人員簽名及完成日期。

（8）依照制訂的標(biāo)準(zhǔn)，由另一人員復(fù)查原始記錄的準(zhǔn)確性和完整性。復(fù)查人簽名。

（b）保留檢驗(yàn)過(guò)程中任何修改已制訂、應(yīng)用的檢驗(yàn)方法的完整記錄。此記錄包括修改的原因和證明檢驗(yàn)結(jié)果同修改前方法的結(jié)果同樣準(zhǔn)確的可靠資料。

（c）保留任何檢驗(yàn)和實(shí)驗(yàn)室參考標(biāo)準(zhǔn)、試劑和標(biāo)準(zhǔn)溶液的完整記錄。

（d）保留按211?160（b）(4)的要求，定期校正實(shí)驗(yàn)室儀器器具和量具、記錄裝置的完整記錄。

（e）保留按21?166要求實(shí)施的全部穩(wěn)定性試驗(yàn)的完整記錄。[43FR45077，1978年9月29日，修正，55FR11577，1990年3月29日]

211?196銷售記錄

銷售記錄包括產(chǎn)品名稱和含量與效價(jià)及該劑型的說(shuō)明、收貨人的姓名和地址、裝運(yùn)日期和數(shù)量、藥品批號(hào)或控制號(hào)。對(duì)壓縮醫(yī)用氣體產(chǎn)品，銷售記錄不要求包括批號(hào)或控制號(hào)。（經(jīng)管理和預(yù)算處根據(jù)控制號(hào)0910 0139批準(zhǔn)）[49FR45077，1978年9月29日]

211?198投訴檔案

（a）????制訂和遵循說(shuō)明處理麥?zhǔn)账幤酚嘘P(guān)的全部文字和口頭投訴的成文程序。此程序包括經(jīng)質(zhì)量控制部門復(fù)查這一條款。任一投訴中，藥品有任一項(xiàng)不符合其規(guī)格的可能性，則根據(jù)211?192，對(duì)該藥品進(jìn)行測(cè)定，作一調(diào)查。這些程序不應(yīng)應(yīng)包括復(fù)查條款，檢查此投訴是否再出現(xiàn)嚴(yán)重的和意外的不良反應(yīng)。根據(jù)本章310?305，不良反應(yīng)須向FDA報(bào)告。

（b）????每個(gè)投訴的文字記錄保存在藥品專用檔案內(nèi)。與該藥品投訴有關(guān)的檔案，保存在生產(chǎn)、加工或包裝該藥品的企業(yè)中，若存放于別的地方會(huì)更有利于檢查，可在那里保存。涉及一藥品的文字記錄，從該品的有效期滿計(jì)，保存一年以上或從收到投訴日期計(jì)，保存一年不管哪個(gè)長(zhǎng)，由時(shí)間較長(zhǎng)者決定。在某些缺少有效期的非處方藥品的情況下，由于它們符合211?137中免除條例，故這些文字記錄的保存時(shí)間應(yīng)是從該藥品銷售后三年。

（1）???投訴文字記錄包括如下資料：發(fā)現(xiàn)地方、藥品名稱、含量或效價(jià)、批號(hào)、投訴者姓名、投訴性質(zhì)及答復(fù)投訴等。

（2）????執(zhí)行211?192中的調(diào)查，包括此調(diào)查和跟蹤中的發(fā)現(xiàn)。調(diào)查報(bào)告記錄或其復(fù)印件，根據(jù)211?180（c），保存在作該調(diào)查的企業(yè)中。

（3）????若沒(méi)有執(zhí)行211?192中的調(diào)查，此文字報(bào)告應(yīng)包括沒(méi)必要調(diào)查的原因和負(fù)責(zé)此檢查的負(fù)責(zé)人姓名。[43FR 45077，1978年9月29日，修正51FR 24479，1986年7月3日]。

 

K．退回的藥品和回收處理

 

211?204退回的藥品

退回的藥品按原樣作鑒定和保存。應(yīng)考慮退回藥品在退回前或退回期間的貯存、裝運(yùn)條件或原藥品容器、紙板盒或標(biāo)簽是否有問(wèn)題由于貯存或裝運(yùn)的原因，令人懷疑藥品的安全性、均一性、含量或效價(jià)、質(zhì)量或純度有問(wèn)題，除非經(jīng)檢驗(yàn)、檢查或調(diào)查，證明此藥品符合其安全、均一性、含量或效價(jià)、質(zhì)量或純度標(biāo)準(zhǔn)，否則，應(yīng)將退回藥品毀壞。但藥品可返工，保證其符合標(biāo)準(zhǔn)、規(guī)格和特性。退回藥品的記錄應(yīng)保存，記錄包括退回藥品的名稱、制劑的功效、批號(hào)（控制號(hào)或整批批號(hào)）、退貨原因及數(shù)量、銷售日期及最終銷售日期。若退貨原因牽涉到多批產(chǎn)品，應(yīng)依照211?192藥品的加收處理。

遭受不良貯存條件（包括極高的溫度、濕度、煙薰蒸氣、壓力、貯存期過(guò)長(zhǎng)、天災(zāi)造成的輻射、為災(zāi)或儀器失靈等）影響的藥品，不必回收和不準(zhǔn)銷售。每當(dāng)有藥品是否受上述條件影響的問(wèn)題存在時(shí)，只有當(dāng)下列情況時(shí)才可進(jìn)行回收藥品工作。

（a）????實(shí)驗(yàn)室檢驗(yàn)和鑒別（包括那里可提供的動(dòng)物飼養(yǎng)研究）證明完全符合均一性、含量或效價(jià)、質(zhì)量或純度標(biāo)準(zhǔn)。

（b）????檢查藥品及其有關(guān)包裝，證明其沒(méi)有遭到天災(zāi)或事故等不適當(dāng)貯存條件的影響?？山邮芴厥飧杏^的檢查，但僅作藥品符合均一性、含量或效價(jià)、質(zhì)量或純度標(biāo)準(zhǔn)的補(bǔ)充證據(jù)記錄包括藥品名稱、批號(hào)、銷售等，且須保存。

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.