Testing and Inspection(cGMP培訓(xùn)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總要求 有

6、文字詳細(xì)說明成份、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。 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。 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。 用明顯的已接收的每裝貨量中的批號代碼對成分、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。對每批貨的情況，如隔離、批準(zhǔn)或拒收等作檢查。4Receipt and storage of untested components, drug product containers, and closures接受未經(jīng)測試原料 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未檢驗(yàn)的成份、藥品容器和密封件的接收與貯存 接收時(shí)和驗(yàn)收前，對每個(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。 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21180要求的地區(qū)中貯存。7Testing and ap

10、proval or rejection of components, drug product containers, and closures測試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測試(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、藥品容器和封口物品的試驗(yàn)、批準(zhǔn)或拒收 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。 收集每批的每一裝貨量的

14、代表性樣品，供檢驗(yàn)用。容器數(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)商過去的質(zhì)量歷史、21170要求分析和留樣所需的數(shù)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收集樣品程序用適當(dāng)?shù)姆椒?，清潔選出成份容器；打開容器，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。必要時(shí)，使用滅菌設(shè)備和無菌取樣技術(shù)。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。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、被取樣的容器，取樣日期及樣品收集人的名字等。已取樣的容器，應(yīng)作標(biāo)志，表示樣品已取出。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樣品檢驗(yàn)程序： 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。 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。 依照成文規(guī)程，檢驗(yàn)容

26、器和密封件。生產(chǎn)廠家代替上述試驗(yàn)，規(guī)定生產(chǎn)廠家對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。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 必要時(shí)，用顯微鏡檢測成分。 每批易受污物、昆蟲或其他外來雜物污染的某一成份、藥品容器或密

30、封件,應(yīng)檢測污染. 每批易受污物、昆蟲或其他外來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)。任何批號的成份、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。任何批號的上述材料，不符合這些規(guī)格，應(yīng)拒收。19Use of approved components, drug product containers, and closures使用順序 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. 獲準(zhǔn)作用的成份、藥品容器和密封件，先入庫者先用。若產(chǎn)生的偏差是暫時(shí)的和適當(dāng)，這種偏差是容許的。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. 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，若長期貯存或曝露在空氣、熱或其他可能對其產(chǎn)生不良影響的環(huán)境后，應(yīng)依照21184，對均一性、效價(jià)或含量、質(zhì)量、純度等復(fù)檢。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、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。24Drug product containers and closures藥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藥品密封容器和密封件 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、

41、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。 容器封口系統(tǒng)應(yīng)對貯藏和使用過程中可預(yù)見的能引起藥品變質(zhì)或污染的外部因素提供足夠的防護(hù)。 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。 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、除熱原過程）應(yīng)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中間體和藥品的取樣與檢驗(yàn)制訂和遵循說明每批的加工過程控制及對加工過程中材料的適當(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： 片劑或膠囊的重量變化。 崩解時(shí)間。 充分混和，保證均勻。 溶解時(shí)間和溶解速率。 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。樣品測試，保證藥品和中間體符合規(guī)格標(biāo)準(zhǔn)。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. 在生產(chǎn)加工期間，如在重要階段的開始、由質(zhì)量控制部門審定，決定取舍。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. 不合格的中間體，在隔離系統(tǒng)下鑒別及控制，防止其在加工及操作中使用。32Drug product inspection藥品檢查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藥品檢查 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)簽正確無誤。 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。 檢查結(jié)果記錄在謬論批的生產(chǎn)或控制記錄中。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測試批準(zhǔn)發(fā)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. 發(fā)放前每批藥品須經(jīng)實(shí)驗(yàn)室測定，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。對有效期短的，需無菌和/或熱原試驗(yàn)的放射藥物特殊批號，可在上述試驗(yàn)完成前發(fā)放，規(guī)定盡快完成試驗(yàn)。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