USP30-1211翻譯-滅菌和無菌保證

1、學習文檔僅供參考1211sterilization and sterility assurance of compendial articles 滅菌和無菌保證綱要條款this informational chapter provides a general description of the concepts and principles involved in the quality control of articles that must be sterile. any modifications of or variations in sterility test procedur

2、es from those described under sterility tests 71should be validated in the context of the entire sterility assurance program and are not intended to be methods alternative to those described in that chapter. 報告章節(jié)規(guī)定涉及到條款質(zhì)量控制總的概念描述和原則是必須是無菌的.從無菌測試 的章節(jié)描述中 ,無菌保證程序的整個上下文中規(guī)定沒有可選擇的方法,任何有關(guān)無菌測試程序變更或修改應該得到驗證.

3、 within the strictest definition of sterility, a specimen would be deemed sterile only when there is complete absence of viable microorganisms from it. however, this absolute definition cannot currently be applied to an entire lot of finished compendial articles because of limitations in testing. ab

4、solute sterility cannot be practically demonstrated without complete destruction of every finished article. 在最嚴格的無菌定義里 ,僅當它不含有任何可存的微生物,樣品才被認為無菌 .然而, 因為測試的局限性，這個絕對的定義不能普遍應用到整個綱要條款中。實際上每個滅菌的物品沒有完全的破壞，絕對無菌性不能得到論證。the sterility of a lot purported to be sterile is therefore defined in probabilistic terms

5、, where the likelihood of a contaminated unit or article is acceptably remote. such a state of sterility assurance can be established only through the use of adequate sterilization cycles and subsequent aseptic processing, if any, under appropriate current good manufacturing practice, and not by rel

6、iance solely on sterility testing. the basic principles for validation and certification of a sterilizing process are enumerated as follows: 學習文檔僅供參考許多無菌狀態(tài)據(jù)說是消過毒的,因此是或然論的定義污染的個體和物品可能性是在可以接受的細小范圍的.這樣一個無菌狀態(tài)保證 ,僅能通過適當?shù)臏缇芷诤蜔o菌的后續(xù)加工 ,即便要 ,在當前合適的 gmp 程序下 ,無菌測試也不可靠 .一個無菌過程驗證的基本原理如下: 1. establish that the p

7、rocess equipment has capability of operating within the required parameters. 確定加工設(shè)備的操作性能處在正確的參數(shù). 2. demonstrate that the critical control equipment and instrumentation are capable of operating within the prescribed parameters for the process equipment. 證明關(guān)鍵控制設(shè)備和使用儀器是能夠在具有效力參數(shù)下操作 . 3. perform replica

8、te cycles representing the required operational range of the equipment and employing actual or simulated product. demonstrate that the processes have been carried out within the prescribed protocol limits and finally that the probability of microbial survival in the replicate processes completed is

9、not greater than the prescribed limits. 執(zhí)行可重復的循環(huán)表現(xiàn)在設(shè)備必需的操作范圍和使用真實或可模擬的產(chǎn)品 .證明加工是在給定協(xié)議范圍下執(zhí)行,而且最后在可重復的加工完成下微生物存活的可能性不能超過給定協(xié)議范圍. 4. monitor the validated process during routine operation. periodically as needed, requalify and recertify the equipment. 在常規(guī)的操作期間監(jiān)控驗證程序 .根據(jù)需要定期 ,重新證明和保證設(shè)備正常 . 5. complete the

10、 protocols, and document steps (1) through (4) above. 完善協(xié)議 ,證明以上步驟 1-4. the principles and implementation of a program to validate an aseptic processing procedure are similar to the validation of a sterilization process. in aseptic processing, the components of the final dosage form are sterilized s

11、eparately and the finished article is assembled in an aseptic manner. 學習文檔僅供參考驗證一個無菌處理程序的法則和執(zhí)行和滅菌過程確實認是相似的.在無菌處理中,最終劑量組成成分是分別滅菌的,最后物品的組裝是在無菌方式完成的. proper validation of the sterilization process or the aseptic process requires a high level of knowledge of the field of sterilization and clean room tec

12、hnology. in order to comply with currently acceptable and achievable limits in sterilization parameters, it is necessary to employ appropriate instrumentation and equipment to control the critical parameters such as temperature and time, humidity, and sterilizing gas concentration, or absorbed radia

13、tion. 滅菌過程或無菌程序正確確認要求較高的滅菌和絕對無塵室技術(shù)領(lǐng)域的知識水平 . an important aspect of the validation program in many sterilization procedures involves the employment of biological indicators (see biological indicators 1035).在許多滅菌程序一個重要確實認綱要方面包括生物指示劑的使用 (參見生物指示劑 -).the validated and certified process should be revalida

14、ted periodically; however, the revalidation program need not necessarily be as extensive as the original program.驗證和鑒定的程序應當定時性地重新生效 ,然而,重新生效程序不必像原始文件那樣廣泛. a typical validation program, as outlined below, is one designed for the steam autoclave, but the principles are applicable to the other steriliz

15、ation procedures discussed in this informational chapter. the program comprises several stages.一個典型確實認程序如以下大綱,一個蒸汽高壓滅菌鍋設(shè)計而作,但原理也是適用于其它的滅菌程序 ,將在報告章節(jié)討論 . the installation qualification stage is intended to establish that controls and other instrumentation are properly designed and calibrated. document

16、ation should be on file demonstrating the quality of the required utilities such as steam, water, and air. 限定時期安裝目的建立調(diào)節(jié)裝置和其它的使用儀器能夠得到適當設(shè)計和校準 .文件能夠記錄下來備查證明要求效用的質(zhì)量像蒸汽,水,空氣.the operational qualification stage is intended to confirm that the empty chamber functions within the parameters of temperature a

17、t all of the key chamber locations prescribed in the protocol.可操作資格的時期是打算確認在學習文檔僅供參考協(xié)議規(guī)定的所有關(guān)鍵鍋室區(qū)域在溫度參數(shù)以內(nèi)的鍋室功能.it is usually appropriate to develop heat profile records, i.e., simultaneous temperatures in the chamber employing multiple temperature-sensing devices.它通常適用于顯示壓力剖面的記錄也就是在鍋室使用多種溫度敏感裝置a typi

18、cal acceptable range of temperature in the empty chamber is 1when the chamber temperature is not less than 121. 當鍋室溫度不少于 121 ,一個典型的可接受的鍋室溫度幅度范圍是 1 .the confirmatory stage of the validation program is the actual sterilization of materials or articles. 確認程序確實認時期是原料或物品實際滅菌期 .this determination requires

19、 the employment of temperature-sensing devices inserted into samples of the articles, as well as either samples of the articles to which appropriate concentrations of suitable test microorganisms have been added, or separate bis in operationally fully loaded autoclave configurations. 決定要求溫度敏感裝置嵌入到物品

20、樣本中,除了添加微生物測試需要的適當?shù)奈锲窛舛?或在操作上二度單獨的裝滿物品的高壓滅菌鍋裝置 . the effectiveness of heat delivery or penetration into the actual articles and the time of the exposure are the two main factors that determine the lethality of the sterilization process. the final stage of the validation program requires the document

21、ation of the supporting data developed in executing the program. 熱傳遞或穿透實際物品的效力和曝光時間是兩個主要的因素決定滅菌程序的破壞性.確認的最終階段需要執(zhí)行程序的數(shù)據(jù)支持文件發(fā)展更新. it is generally accepted that terminally sterilized injectable articles or critical devices purporting to be sterile, when processed in the autoclave, attain a 10 6microbia

22、l survivor probability, i.e., assurance of less than 1 chance in 1 million that viable microorganisms are present in the sterilized article or dosage form. 一般公認的是末尾已滅菌的可注射的商品或關(guān)鍵設(shè)備聲明是無菌的.在高壓滅菌鍋程序到達 10 6細菌存活率也就是說保證在已滅菌的物品或配藥形式上可存活的微生物一百萬個不超過一個的幾率.with heat-stable articles, the approach often is to con

23、siderably exceed the critical time necessary to achieve the 10 6學習文檔僅供參考microbial survivor probability (overkill). 隨著熱穩(wěn)定的物品 ,方法通常是相當超越需要的臨界溫度到達10 6細菌存活率 (過度殺滅 ).however, with an article where extensive heat exposure may have a damaging effect, it may not be feasible to employ this overkill approach.

24、然而隨著物品曝露在過度壓力下可能有一個破壞性的作用 . in this latter instance, the development of the sterilization cycle depends heavily on knowledge of the microbial burden of the product, based on examination, over a suitable time period, of a substantial number of lots of the presterilized product.在后面的例子 ,滅菌周期的發(fā)展很大程度上依靠基

25、于檢驗 ,適當?shù)臅r間周期 ,許多實質(zhì)預先消毒的產(chǎn)品微生物負擔的知識. the d value is the time (in minutes) required to reduce the microbial population by 90% or 1 log cycle (i.e., to a surviving fraction of 1/10), at a specific temperature. d- 值是在特效的溫度下需要的時間(分鐘)減少微生物群體 ,或大約90% or log1 周期(也就是 1/10 存活部分 ) .therefore, where the d value

26、of a bi preparation of, for example, bacillus stearothermophilus spores is 1.5 minutes under the total process parameters, e.g., at 121, if it is treated for 12 minutes under the same conditions, it can be stated that the lethality input is 8d. 然而一個 bi,d 值的地方 ,例如 嗜熱脂肪桿菌孢子在總的程序參數(shù)下為1.5 分鐘,舉例來說,在 121 .

27、下相同的條件下如果加熱12 分鐘,規(guī)定的致命性的輸入是8d. the effect of applying this input to the product would depend on the initial microbial burden. 應用這個輸入產(chǎn)品的效果依靠最初的微生物耐熱負荷.assuming that its resistance to sterilization is equivalent to that of the bi, if the microbial burden of the product in question is 102 microorganism

28、s, a lethality input of 2d yields a microbial burden of 1 (10theoretical), and a further 6d yields a calculated microbial survivor probability of 10 6. 假設(shè)它抵抗滅菌等同bi 耐熱能力,如果產(chǎn)品的微生物負擔bi 可商榷的是 102微生物 ,一個 2d 產(chǎn)量致命輸入一個微生物 1擔子(理論上是 10 ),進一步的 6d 產(chǎn)量一個計算出的存活幾率是10 6. (under the same conditions, a lethality input

29、 of 12d may be used in a typical “overkill” approach.) (在相同的條件下 ,一個 12d 致死輸入量可能是在一個典型學習文檔僅供參考的過度殺傷方法 )generally, the survivor probability achieved for the article under the validated sterilization cycle is not completely correlated with what may occur with the bi. for valid use, therefore, it is ess

30、ential that the resistance of the bi be greater than that of the natural microbial burden of the article sterilized. 通常,有效的滅菌時間對物品而言存活概率取得，不能完全和bi 聯(lián)系起來。為有效利用，因此bi 的抗性是比已滅菌物品上的自然界微生物大。it is then appropriate to make a worst-case assumption and treat the microbial burden as though its heat resistance w

31、ere equivalent to that of the bi, although it is not likely that the most resistant of a typical microbial burden isolates will demonstrate a heat resistance of the magnitude shown by this species, frequently employed as a bi for steam sterilization. 于是進行最差的假設(shè)和測試微生物負擔是合適的好象它的熱抵抗力等同于bi ，盡管不是類似于大多數(shù)典型微

32、生物擔子隔離證明一個物種顯示的巨大熱抵抗。對蒸汽滅菌而言， 經(jīng)常作為一個 bi 。in the above example, a 12-minute cycle is considered adequate for sterilization if the product had a microbial burden of 102 microorganisms. 在上面的例子如果產(chǎn)品有一個102微生物擔子，12 分鐘的時間被認為是合適的滅菌時間。 however, if the indicator originally had 106 microorganisms content, actua

33、lly a 10 2 probability of survival could be expected; i.e., 1 in 100 bis may yield positive results. 然而，如果最初的指示劑有106微生物含量，實際上，預期 10 2存活率，也就是說 100 bis 有 1 個，產(chǎn)生陽性結(jié)果。this type of situation may be avoided by selection of the appropriate bi. alternatively, high content indicators may be used on the basis

34、 of a predetermined acceptable count reduction. 通過適當?shù)?bi 選擇，這個典型情況可以防止。擇二為一，高容量的指示劑可用于以預定的可接受的數(shù)量減少為基礎(chǔ)。the d value for the bacillus stearothermophilus preparation determined or verified for these conditions should be reestablished when a specific program of validation is changed. determination of sur

35、vival curves (see biological indicators 1035), or what has been called the fractional cycle approach, may be employed to determine the d value of the biological indicator preferred 學習文檔僅供參考for the specific sterilization procedure. 當確認的特效程序改變時為這些條件決定或校驗對嗜熱脂肪桿菌預備的d 值應當是重建 .the fractional cycle approac

36、h, may also be used to evaluate the resistance of the microbial burden. fractional cycles are studied either for microbial count-reduction or for fraction negative achievement. 部分時間方法也可以用來估計微生物擔子抵抗力.these numbers may be used to determine the lethality of the process under production conditions. 在產(chǎn)品到

37、達要求的情況下這些數(shù)字可以用來確定程序的致死量 . the data can be used in qualified production equipment to establish appropriate sterilization cycles. a suitable biological indicator such as the bacillus stearothermophilus preparation may be employed also during routine sterilization. 在具有資格的產(chǎn)品設(shè)備這數(shù)據(jù)能用來確定合適的滅菌時間.一個適當?shù)奈⑸镏甘緞?/p>

38、例如嗜熱脂肪桿菌預備在常規(guī)的滅菌期間也可以使用.any microbial burden method for sterility assurance requires adequate surveillance of the microbial resistance of the article to detect any changes, in addition to periodic surveillance of other attributes.除了定期監(jiān)督其它品質(zhì) ,為無菌保證任何微生物擔子方法要求適當物品微生物抗性監(jiān)督探測任何改變. methods of sterilizatio

39、n 滅菌方法in this informational chapter, five methods of terminal sterilization, including removal of microorganisms by filtration and guidelines for aseptic processing, are described. 在這報告的章節(jié)描述 ,終端滅菌的五種方法 ,包括微生物清除 ,通過過濾和無菌處理的指導.modern technological developments, however, have led to the use of addition

40、al procedures. these include blow-molding (at high temperatures), forms of moist heat other than saturated steam and uv irradiation, as well as on-line continuous filling in aseptic processing. 然而,現(xiàn)代科技的發(fā)展已經(jīng)引導附加程序的運用.這些包括吹塑法 (在高溫 ) the choice of the appropriate process for a given dosage form or comp

41、onent requires a high level of knowledge of sterilization techniques and information concerning any 學習文檔僅供參考effects of the process on the material being sterilized.1對一個給定的配藥形式或成份的合適的程序選擇要求滅菌技術(shù)和有關(guān)影響原料滅菌程序的信息的較高的知識水平。steam sterilization 蒸汽滅菌the process of thermal sterilization employing saturated stea

42、m under pressure is carried out in a chamber called an autoclave利用飽和水蒸汽在鍋室下由壓力攜帶的熱滅菌方法叫高壓滅菌鍋。it is probably the most widely employed sterilization process.2它是利用最廣泛的滅菌程序。the basic principle of operation is that the air in the sterilizing chamber is displaced by the saturated steam, achieved by employ

43、ing vents or traps. 工作的基本原理是在滅菌室通過通風孔和攜帶物由飽和水蒸汽取代空氣。in order to displace air more effectively from the chamber and from within articles, the sterilization cycle may include air and steam evacuation stages. 為了更加有效率從鍋室和物品里置換出空氣，滅菌時間可以包括空氣和水蒸汽排開時間。the design or choice of a cycle for given products or c

44、omponents depends on a number of factors, including the heat lability of the material, knowledge of heat penetration into the articles, and other factors described under the validation program (see above). 給定的產(chǎn)品或成分的滅菌時間的設(shè)計或選擇取決于很多因素，包括材料的熱不穩(wěn)定性， 熱滲透物品的知識，和在確認程序下描述的其它因素參見上述。apart from that description

45、 of sterilization cycle parameters, using a temperature of 121, the f0 concept may be appropriate. 除了滅菌時間參數(shù)描述外，使用溫度為121 ，f0的概念可能是適合的。 the f0 , at a particular temperature other than 121, is the time (in minutes) required to provide the lethality equivalent to that provided at 121for a stated time. 除

46、了 121 ,在特殊溫度 f0，是時間分鐘要求在 121 適合即定時間提供使微生物帶來致命性等同條件。modern autoclaves g 比 enerally operate with a control system that is significantly more 學習文檔僅供參考responsive than the steam reduction valve of older units that have been in service for many years. 現(xiàn)代化高壓滅菌鍋通常帶有控制系統(tǒng)操作，比服務很多年的舊式蒸汽降低閥是引起值得注目地反響。in order f

47、or these older units to achieve the precision and level of control of the cycle discussed in this chapter, it may be necessary to upgrade or modify the control equipment and instrumentation on these units. 為了這些舊的單元到達精確和這章節(jié)討論的時間控制水平，升級和修改控制裝備以及這些單元的使用設(shè)備是必要的。this modification is warranted only if the

48、chamber and steam jacket are intact for continued safe use and if deposits that interfere with heat distribution can be removed. 僅如果為了持續(xù)地安全利用和驅(qū)除存放物干擾熱分配，鍋室和蒸汽套是完整無缺，修改被批準。dry-heat sterilization 干熱滅菌the process of thermal sterilization of pharmacopeial articles by dry heat is usually carried out by a

49、 batch process in an oven designed expressly for that purpose. 藥典條款熱滅菌程序通常通過在一個特別設(shè)計的烤爐進行干熱來實現(xiàn)到達滅菌的目的。a modern oven is supplied with heated, filtered air, distributed uniformly throughout the chamber by convection or radiation and employing a blower system with devices for sensing, monitoring, and co

50、ntrolling the critical parameters. 一個現(xiàn)代烤箱提供熱，過濾過的空氣，均一分布在鍋室，通過利用一個吹風機系統(tǒng)裝置傳送或發(fā)散適用于感知，監(jiān)測和控制臨界參數(shù)。the validation of a dry-heat sterilization facility is carried out in a manner similar to that for a steam sterilizer described earlier. where the unit is employed for sterilizing components such as contain

51、ers intended for intravenous solutions, care should be taken to avoid accumulation of particulate matter in the chamber. 干熱滅菌設(shè)備確實認通過與早期的蒸汽滅菌器相似的方式實現(xiàn)。為這滅菌成分例如用來盛裝注射靜脈內(nèi)溶液的容器，應當注意防止鍋室顆粒物質(zhì)的積聚。a typical acceptable range in temperature in the empty chamber is 15學習文檔僅供參考when the unit is operating at not le

52、ss than 250.在空的鍋室，一個典型可接受的溫度范圍是 15 ，當它工作時，溫度不小于250 。in addition to the batch process described above, a continuous process is frequently employed to sterilize and depyrogenate glassware as part of an integrated continuous aseptic filling and sealing system. 除了以上描述的一爐程序外，一個連續(xù)的程序是頻繁地使用滅菌和熱原的玻璃器具作為一個綜合

53、的持續(xù)的無菌的添充物和密封系統(tǒng)的一部分。heat distribution may be by convection or by direct transfer of heat from an open flame. 熱發(fā)送通過傳送或從一個明火直接熱傳遞。 the continuous system usually requires a much higher temperature than cited above for the batch process because of a much shorter dwell time. 因為一個較短的保壓時間，連續(xù)的系統(tǒng)對鍋爐程序通常要求比以上

54、引證的更高的溫度。however, the total temperature input during the passage of the product should be equivalent to that achieved during the chamber process. 然而，在產(chǎn)品通過期間總的溫度輸入應當與鍋室程序取得等效。the continuous process also usually necessitates a rapid cooling stage prior to the aseptic filling operation. 持續(xù)的程序通常也是使一個快速冷

55、卻階段先于無菌填充物實成為必要。in the qualification and validation program, in view of the short dwell time, parameters for uniformity of the temperature, and particularly the dwell time, should be established.在資格和確認程序，考慮到短的保壓時間，溫度的同樣參數(shù)，特別是保壓時間，應當確定。a microbial survival probability of 10 12 is considered achievabl

56、e for heat-stable articles or components. an example of a biological indicator for validating and monitoring dry-heat sterilization is a preparation of bacillus subtilis spores. since dry heat is frequently employed to render glassware or containers free from pyrogens as well as viable microbes, a p

57、yrogen challenge, where necessary, should be an integral part of the validation program, e.g., by inoculating one or more of the articles to be treated with 1000 or more usp units of bacterial endotoxin. the test with limulus lysate could be used to demonstrate that the endotoxic substance has been

58、inactivated to not more 學習文檔僅供參考than 1/1000 of the original amount (3 log cycle reduction). for the test to be valid, both the original amount and, after acceptable inactivation, the remaining amount of endotoxin should be measured. for additional information on the endotoxin assay, see bacterial en

59、dotoxins test 85 . 對熱穩(wěn)定物品或者成分， 10 12的微生物的存活概率被認為可以實現(xiàn)。對于干熱滅菌確實認和監(jiān)測，一個生物指示劑的例子就是枯草芽孢桿菌孢子 的制備。自從干熱滅菌頻繁地用于玻璃器具以及容器的的熱原以及可活化的微生物的清除，除去熱原是必要的，應當成為確認程序的主要部分，例如通過接種用1000或者更大 usp 單位的細菌內(nèi)毒素處理過的一種或更多物品。鱟試劑測試可以用于證明內(nèi)毒素物質(zhì)已經(jīng)活性喪失到不超過原來總量的1/1000降低了 3 log 數(shù)量級。由于該測試被證明有效，不管是原始量還是可接受的失活量，內(nèi)毒素的殘留量都應該測量。關(guān)于內(nèi)毒素分析的更多信息，參見細菌內(nèi)毒

60、素測試85 . gas sterilization 氣體滅菌法the choice of gas sterilization as an alternative to heat is frequently made when the material to be sterilized cannot withstand the high temperatures obtained in the steam sterilization or dry-heat sterilization processes. the active agent generally employed in gaseou