TestingandInspection(cGMP培训系列8)

1、Testing and Inspection on components, in-process material and finished productsGMP Training Module 71General Requirements基本要求Do you have written procedures to monitor each stage of components, containers and closures? Show me an example. How do you handle and store drug product containers and closur

2、es to prevent contamination? Are drug containers or closures stored off the floor and can be easily inspected? Do you have an identification code system to label and track the components? Does each lot have a status label, such as approved, rejected or quarantined? 2General Requirements基本要求(a) There

3、 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 c

4、losures 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

5、 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).3总要求 有

6、文字详细说明成份、药品容器、密封件的签收、鉴定、贮存、装运取样、检验和批准或拒收程序，并遵循。 成份、药品容器和密封件应专人管理和在防止污染的环境下贮存。 药品容器的包装袋或包装箱或密封件应离地面放置保持适当间隔，全球清洁和检查。 用明显的已接收的每装货量中的批号代码对成分、药品容器或密封件加以鉴别。此代码用于记录每批货的放置地方。对每批货的情况，如隔离、批准或拒收等作检查。4Receipt and storage of untested components, drug product containers, and closures接受未经测试原料 Do you perform visua

7、l check on received products?Before a component is approved, where do you store them? How do you prevent them being used before being tested and approved?5Receipt and storage of untested components, drug product containers, and closures原料接收 (a) Upon receipt and before acceptance, each container or g

8、rouping 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 be

9、en tested or examined, whichever is appropriate, and released. Storage within the area shall conform to the requirements of 211.80 (general requirements).6未检验的成份、药品容器和密封件的接收与贮存 接收时和验收前，对每个或编组的成份容器、药品容器和密封件进行目检，给内容物、容器损坏或拆封和污染等情况作适当的标志。 成份、药品容器各密封件应隔离贮存，直至经检验为止。合格，可发放。在符合21180要求的地区中贮存。7Testing and ap

10、proval or rejection of components, drug product containers, and closures测试Which department will sample, test and approve the component for use? What statistical method are you following in determining sample size for testing? What is the acceptance criteria? Do you keep reserve sample for active ing

11、redients? How long and how many do you keep them? 8Testing and approval or rejection of components, drug product containers, and closures测试(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,

12、 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 a

13、s 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 211.170.9成份、药品容器和封口物品的试验、批准或拒收 每批成份、药品容器和封口物品，在未经质量部门取样、检查合格前，不准使用。检验合格后发放使用。 收集每批的每一装货量的

14、代表性样品，供检验用。容器数目和每一容器里物质的取样量是有适当的标准的，例如，成份的变异性统计学标准、可信限、要求的精密度、供应商过去的质量历史、21170要求分析和留样所需的数量等。10(c) Samples shall be collected in accordance with the following procedures:(1) The containers of components selected shall be cleaned when necessary in a manner to prevent introduction of contaminants into

15、the component.(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) I

16、f 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 con

17、tainer 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.11How do you clean the containers of components? How

18、do you verify it is clean?During the operation, how do you control contamination ?Do you identify sample containers 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

19、, and the name of the person who collected the sample?12收集样品程序用适当的方法，清洁选出成份容器；打开容器，取样，重新封口，防止其内容物受污染和其他成分、药品容器或密封件的污染。必要时，使用灭菌设备和无菌取样技术。如果需要从容器顶部、中部和底部的成分中取样，样品须混合。鉴定样品容器，目的是确定如下资料：被取样的材料名称、批号、被取样的容器，取样日期及样品收集人的名字等。已取样的容器，应作标志，表示样品已取出。13Do you do identity test for each component for drug? Do you tes

20、t each component for conformity with all appropriate written specifications for purity, strength, and quality? If so, please show me the written specification for PVP-I and your test result in March, 2010. Do you also test containers and closures for conformity with all appropriate written specifica

21、tions? If so, please show me the written specification for PVP-I and your test result in June, 2010. 14(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, shal

22、l 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

23、test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the suppliers analyses through appropriate validation of the suppliers test results at appropriate intervals.(3) Containers and closures shall be tested for conformity with all

24、appropriate written specifications. 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

25、reliability of the suppliers test results through appropriate validation of the suppliers test results at appropriate intervals.15样品检验程序： 一个药品的每个成分，最少做一个特性试验。如有专一特性实验就应采用。 依照所有成文的规格标准检验每个成份的纯度、含量和质量。生产厂家代替上述试验。规定生产厂家最少要做个成份特别试验，可承认；这些成分的供应者扫提供的分析报告。规定隔一定时间，生产厂家定期验证供应午的试验结果，证明供应者的分析结果是正确的。 依照成文规程，检验容

26、器和密封件。生产厂家代替上述试验，规定生产厂家对这些容器或封口物品，最少做一次目检。可承认供应者的检验证书。规定生产厂家定期验证供应者的试验结果，证明其试验结果是正确的。16Do you microscopically examine your components? Do you have established specifications for drug component, product container and closure for contamination? How do you check for contamination before they are used?

27、17(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 contaminat

28、ion.(6) Each lot of a component, drug product container, or closure with potential for 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

29、 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.18 必要时，用显微镜检测成分。 每批易受污物、昆虫或其他外来杂物污染的某一成份、药品容器或密

30、封件,应检测污染. 每批易受污物、昆虫或其他外来杂物污染的某一成份、药品容器或密封件，鉴于其预期用途，在使用前，应做微生物试验。任何批号的成份、药品容器或密封件，若符合已成文的均一性、效价或含量、质量、纯度等的规格标准和本部分（d）的有关试验，可批准使用。任何批号的上述材料，不符合这些规格，应拒收。19Use of approved components, drug product containers, and closures使用顺序 When using components, drug containers and closures, do you follow FIFO (first

31、 in, first out) rule for approved samples? Do you accept any deviations? If so, why? Show me a situation where some deviations are acceptable. 20Use of approved components, drug product containers, and closures Components, drug product containers, and closures approved for use shall be rotated so th

32、at the oldest approved stock is used first. Deviation from this requirement is permitted if such deviation is temporary and appropriate. 获准作用的成份、药品容器和密封件，先入库者先用。若产生的偏差是暂时的和适当，这种偏差是容许的。21Retesting of approved components, drug product containers, and closures Components, drug product containers, and c

33、losures 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 adverse

34、ly affect the component, drug product container, or closure. 经质量控制部门批准或拒收的成份、药品容器密封件，若长期贮存或曝露在空气、热或其他可能对其产生不良影响的环境后，应依照21184，对均一性、效价或含量、质量、纯度等复检。22Rejected components, drug product containers, and closures 次品控制 How do you control rejected components, drug product containers, and closures from being

35、used? What is your identification system for rejected components, drug containers and closures? Where do you store them and who has access to them?23Rejected components, drug product containers, and closures Rejected components, drug product containers, and closures shall be identified and controlle

36、d under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable. 拒收的成份、药品容器和封口物品应经鉴定和在隔离系统下加以控制，防止在生产和加工使用。24Drug product containers and closures药品密封容器和密封件 Are your drug product containers and closures reactive, additive, or absorptiv

37、e so as to alter the safety, identity, strength, quality, or purity of the drug? How do you determine them? How do you know your container closure systems can protect the drug product from foreseeable external factors?25Drug product containers and closures (a) Drug product containers and closures sh

38、all 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

39、 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. Such depyrogenation proc

40、esses shall be validated. (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.26药品密封容器和密封件 药品包装容器和密封件应不起反应、不吸着、不吸附、不致改变药品的安全性、

41、均一性、含量或效价、质量和纯度而超出制定的或其它颁布的规定要求。 容器封口系统应对贮藏和使用过程中可预见的能引起药品变质或污染的外部因素提供足够的防护。 药品容器和密封件应清洁、灭菌和除热原，保证其适用于预期目的。 药品容器和密封件的标准或规格、检验方法（指清洁和消毒方法、除热原过程）应成文并遵循。27Sampling and testing of in-process materials and drug products. To assure batch uniformity and integrity of drug products, written procedures shall

42、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 proces

43、ses 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 mixin

44、g to assure uniformity and homogeneity;(4) Dissolution time and rate;(5) Clarity, completeness, or pH of solutions.(6) Bioburden testing.28中间体和药品的取样与检验制订和遵循说明每批的加工过程控制及对加工过程中材料的适当样品实行检验或检查的成文程序，保证药品的一致性和完整性。上述控制程序包括，但不限于如下内容： 片剂或胶囊的重量变化。 崩解时间。 充分混和，保证均匀。 溶解时间和溶解速率。 溶液的澄明度、溶解完全性及PH值。29 Valid in-proce

45、ss 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.

46、 Examination and testing of samples shall assure that the drug product and in-process material conform to specifications. 考虑上述特性而制定的有效中间加工规格与药品最终规格一致。此中间加工规格应在以前可靠的加工方法稳定性评估和经应用统计学程序断定认为合适的基础上制定的。样品测试，保证药品和中间体符合规格标准。30 In-process materials shall be tested for identity, strength, quality, and purity

47、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. 在生产加工期间，如在重要阶段的开始、由质量控制部门审定，决定取舍。31 Rejected in-process materials shall be identified and controlled under

48、 a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable. 不合格的中间体，在隔离系统下鉴别及控制，防止其在加工及操作中使用。32Drug product inspection药品检查Do you check the products and packages having the right label? How many do you checked? Show me the procedure and

49、records of your label verification last week.33Drug 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 com

50、pletion 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.34药品检查 已包装和贴标签的产品，在结束工作时，应检查，保证本批容器和包装的标签正确无误。 操作结束时，每组收集一个代表性样品，同时检查标签。 检查结果记录在谬论批的生产或控制记录中。35Testing and release for di

51、stributionDo you have final specifications for the drug product, including the identity and strength of each active ingredient, prior to release?Show me an example each that finish product did or did not meet the final specifications. Do you do bioburden test/microbial test on the finished product？

52、What is your spec? Show me an example. Do you have written procedures/sampling plan/sampling method for above testing?36Testing and release for distribution测试批准发放(a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specification

53、s 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,

54、provided such testing is completed as soon as possible. 发放前每批药品须经实验室测定，保证其符合药品的最终规格标准，包括特性和活性成份的含量。对有效期短的，需无菌和/或热原试验的放射药物特殊批号，可在上述试验完成前发放，规定尽快完成试验。37(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 unit