FDA關(guān)于廠房設(shè)施的法規(guī)條款及翻譯(與頭孢和青霉素相臨的廠房請(qǐng)注意

1、3.1 facility design and layout廠房設(shè)置及布置this page will address various regulatory issues related to this section of the gmp institute framework.click below to view the issues that are relevant to you.penicillin issues青霉素問題what do the cgmps mean by separate facilities? must the buildings be totally sepa

2、rated, or are the cgmps satisfied when the floors are physically separated with separate air filtration units installed? cgmp規(guī)定獨(dú)立的廠房是什么意思？廠房必須完全獨(dú)立嗎？在安裝有獨(dú)立的空氣過(guò)濾系統(tǒng)的情況下，樓層之間采取物理隔離可以嗎？is it acceptable to manufacture penicillin and non-penicillin products in the same facility on a campaign (i.e., the con

3、version of production facilities to a different product line on a routine basis) basis, with adequate cleaning validation procedures in place?在同一個(gè)廠房里生產(chǎn)青霉素和非青霉素產(chǎn)品，在有足夠清潔的前提下，可接受嗎？is it acceptable to manufacture penicillin products in the same facility as cephalosporin? 在同一個(gè)廠房?jī)?nèi)生產(chǎn)青霉素和頭孢產(chǎn)品可以接受嗎？can a fa

4、cility that produced penicillin dosage forms be decontaminated and renovated for production of non-penicillin solid dosage forms provided there is no further penicillin production in the renovated facility?一個(gè)生產(chǎn)制劑的廠房，如果在去除污染和改造的前提下且不會(huì)再被用于生產(chǎn)青霉素產(chǎn)品，可否用于生產(chǎn)非青霉素產(chǎn)品，is there an acceptable level of penicillin

5、 residue in non-penicillin drug products? 在非青霉素藥品中青霉素的殘留標(biāo)準(zhǔn)是多少？if a firms only operation is performing finished packaging operations for bulk tablet and capsule drug products, must it still maintain separate facilities and equipment for packaging penicillin products?如果一個(gè)公司的操作僅僅是片劑和膠囊的包裝，也必須是獨(dú)立的廠房及設(shè)備嗎

6、？what do the cgmps mean by separate facilities? must the buildings be totally separated, or are the cgmps satisfied when the floors are physically separated with separate air filtration units installed? cgmp規(guī)定獨(dú)立的廠房是什么意思？廠房必須完全獨(dú)立嗎？在安裝有獨(dú)立的空氣過(guò)濾系統(tǒng)的情況下，樓層之間采取物理隔離可以嗎？references: 21 cfr 211.42(d) design, a

7、nd construction features21 cfr 211.46(d) ventilation, air filtration, air heating and cooling21 cfr 211.176 penicillin contaminationfederal register, 9/29/78 (vol.43, no.190, book 2) preamble to the cgmps at comment 142cgmp regulations 21 cfr 211.42(d) and 211.46(d) require separation of penicillins

8、 from non-penicillins during processing. the discussion of the comments in the preamble to the regulations note that isolation of penicillin production operationscan be achieved by sealing offthe two operations. does not necessarily meanseparate buildings. thus, there can be a building within a buil

9、ding- i.e. two buildings are not required.however, there must be total separation of operations, meaning every aspect of the operations must be separate. adequate separation should include physical barriers and separate air handling systems. personnel and equipment from the penicillin facility shoul

10、d not enter the non-penicillin facility. these should operate with well established written procedures and controls. the separation should be audited, procedures validated, and where necessary monitored.cgmp 法規(guī) 21 cfr 211.42(d) and 211.46(d)要求青霉素與非青霉素產(chǎn)品在加工中獨(dú)立。 相關(guān)的討論觀點(diǎn)“青霉素產(chǎn)品操作的隔離可以通過(guò)將兩個(gè)操作完全分開而達(dá)到”，“并不

11、需要獨(dú)立的廠房”。這樣，可以設(shè)計(jì)成“建筑物中之建筑物”，也就是說(shuō)，兩個(gè)建筑是沒有必要的。然而，操作上必須完全隔離，也就是說(shuō)，每一個(gè)方面都應(yīng)完全隔離。充足的隔離應(yīng)當(dāng)包括：物理上的屏障及通風(fēng)系統(tǒng)的隔離。青霉素廠房的人員及設(shè)備不應(yīng)進(jìn)行非青霉素的廠房。這些需要建立良好的書面程序并進(jìn)行控制。這種隔離應(yīng)進(jìn)行審計(jì)，程序應(yīng)經(jīng)驗(yàn)證，如果需要還應(yīng)進(jìn)行監(jiān)測(cè)。even with separation, if any possibility of contamination exists, the non-penicillin products must be tested (21 cfr 211.176). an e

12、xample of possible contamination could be inadequate controls over movement of equipment or personnel. section 211.176 requires non-penicillin products to be tested for traces of penicillin where the possibility of exposure exists, and not marketed if detectable levels of penicillin are found.即使在隔離狀

13、態(tài)下，如果存在任何被污染的可能，非青霉素產(chǎn)品應(yīng)該經(jīng)過(guò)檢驗(yàn)。一個(gè)可能污染的例子可能是人員及設(shè)備的不充分控制。section 211.176要求如果存在青霉素產(chǎn)品暴露的可能，非青霉素產(chǎn)品應(yīng)經(jīng)檢查，以追蹤是否存在青霉素，如果檢測(cè)到青霉素產(chǎn)品的殘留，產(chǎn)品不應(yīng)銷售。while this section prohibits marketing of products found to be contaminated with penicillin, it does not sanction marketing of non-penicillin products based only on test re

14、sults that show no detectable levels of such contamination. other cgmp requirements must still be met. for a discussion on this issue, please review the article is it acceptable under section 211.176 to release products to market as long as the products are tested and no penicillin is found? publish

15、ed in human drug cgmp notes (volume 6, issue 2, june 1998).當(dāng)這些禁止上市的產(chǎn)品里發(fā)現(xiàn)被青霉素污染時(shí)，并不僅僅是根據(jù)檢測(cè)結(jié)果證明在污染水平以下而不能流入市場(chǎng)。同時(shí)必須滿足其它c(diǎn)gmp要求也。關(guān)于此部分的討論，請(qǐng)參照is it acceptable under section 211.176 to release products to market as long as the products are tested and no penicillin is found? published in human drug cgmp not

16、es (volume 6, issue 2, june 1998).cross contamination issues have been a concern for a number of years, and continue to be problematic. in one penicillin cross-contamination case reviewed it was demonstrated how a non-penicillin facility was contaminated by a separate penicillin facility located in

17、the same manufacturing campus. this occurred due to lack of controls regarding movements of personnel, equipment and materials. in another case, cder concurred with a district recommendation to withhold approval on a sensitizing beta-lactam manufacturing facility that was adjacent to another drug pr

18、ocessing building, due to the lack of containment controls which ensured against cross contamination of the other drugs.交叉污染的問題多年來(lái)一直是個(gè)關(guān)注的問題，并且還會(huì)繼續(xù)是個(gè)問題。下面是一個(gè)青霉素污染的例子：在同一個(gè)廠區(qū)內(nèi)在獨(dú)立廠房生產(chǎn)的青霉素和非青霉素產(chǎn)品，由于人員和設(shè)備及物料控制不嚴(yán)格導(dǎo)致產(chǎn)品受到污染。另一個(gè)例子是一個(gè)臨近頭孢類產(chǎn)品的生產(chǎn)廠，由于缺乏足夠的控制，cder曾經(jīng)收回其批準(zhǔn)的證書。reprinted from human drug cgmp notes (vo

19、lume 8, number 1), march, 2000. this same text is also reprinted in framework section 3.2. is it acceptable to manufacture penicillin and non-penicillin products in the same facility on a campaign (i.e., the conversion of production facilities to a different product line on a routine basis) basis, w

20、ith adequate cleaning validation procedures in place? 在同一個(gè)廠房里生產(chǎn)青霉素和非青霉素產(chǎn)品，在有足夠清潔的前提下，可接受嗎？references:21 cfr 211.42(d) design, and construction features21 cfr 211.46(d) ventilation, air filtration, air heating and cooling21 cfr 211.176 penicillin contaminationfederal register, 9/29/78 (vol.43, no.190

21、, book 2) preamble to the cgmps at comment 148 no, it is not acceptable. the discussion of the comments in the preamble to the regulations state that it is important to make clear in these regulations that completely separate air-handling facilities for penicillin and non-penicillin production are r

22、equired. and because it is possible for air-handling systems between penicillin and non-penicillin production areas to be interconnected, .the commissioner finds it necessary to state that any such interconnection would be unacceptable. 不，不可接受。涉及到的法規(guī)條款是“很重要的一點(diǎn)需要指明：青霉素與非青霉素之間的隔離，絕對(duì)需要完全獨(dú)立的空調(diào)系統(tǒng)”campaig

23、n production of penicillin and any non-penicillin product in the same facility and with the same equipment violates the cgmp regulations 211.42(d) and .46(d). a concern is that the cleaning validation process does not include the air handling system throughout the facility. this is important because

24、 campaign production has the potential for recontamination of the air handling systems and facilities, and can lead to cross contamination of non-penicillin products with penicillin. the concept of decontamination is broader than a typical cleaning procedure validation, in that sampling is extended

25、to include the environment, as well as surfaces of the facility and equipment that are to be decontaminated. 使用同一廠房和同一設(shè)備生產(chǎn)青霉素和非青霉素產(chǎn)品違背了cgmp法規(guī)，211.42(d) and .46(d)。需注意的一點(diǎn)是清潔驗(yàn)證并不包括廠房的所有空調(diào)系統(tǒng)，這一點(diǎn)是非常重要的，因?yàn)檫@種生產(chǎn)方式可以造成潛在廠房和空調(diào)的再污染。去除污染的概念可能要比典型的清潔的概念要寬泛的多，取樣可能擴(kuò)大大環(huán)境，廠房和設(shè)備的表面。a facility contaminated with penic

26、illin could not begin non-penicillin production until extensive decontamination and clean-up of the facility is accomplished in accordance with the established procedures, and representative environmental samples demonstrate that the facility conforms with its decontamination protocol/specifications

27、.一個(gè)已經(jīng)被青霉素污染的廠房不能再被用于生產(chǎn)非青霉素產(chǎn)品，除非依照已建立的程序進(jìn)行最廣泛的去除污染的清潔已經(jīng)完成，有代表性的取樣表明廠房按照清潔方案/程序的結(jié)果是符合的。current technology makes decontamination of air handling systems difficult. this is because the decontamination/cleaning procedures would necessitate sampling and residual testing of other parts of the air handling

28、system, to include the ductwork. this would be difficult because the air handling system throughout its length has uneven areas and crevices that create the possibility of penicillin residue build-up, with slough-off at undetermined periods during the non-penicillin production period. thus penicilli

29、n contamination would not be uniformly distributed in the air handling system, and representative samples (retain, surface and/or air) may not be an accurate portrayal of the level of contamination. 現(xiàn)在的技術(shù)要想去除空調(diào)系統(tǒng)的污染非常困難，這是因?yàn)槿コ廴径M(jìn)行的殘留檢測(cè)需要對(duì)空氣處理系統(tǒng)進(jìn)行取樣，包括管道。這是非常困難的，因?yàn)榭諝馓幚硐到y(tǒng)的不規(guī)則的面積，其內(nèi)部的溝溝角角有可能使青霉素殘留，而這些

30、殘留有可能在生產(chǎn)非青霉素產(chǎn)品時(shí)溶解出來(lái)。因?yàn)榍嗝顾氐奈廴驹诳諝馓幚硐到y(tǒng)里的不均勻分布，而使得取樣的不能代表污染的水平。21 cfr 211.176 indicates that where the possibility of exposure exists, non-penicillin products must be tested for traces of penicillin and not marketed if detectable levels are found. this means that representative samples from all batches

31、of non-penicillin products produced in each campaign must be tested with an acceptable method and found non-detectable for the penicillin product produced prior to the start-up of the non-penicillin campaign. 21 cfr 211.176指明當(dāng)可能存在污染時(shí)，非青霉素產(chǎn)品必須被檢測(cè)而跟蹤是否存在青霉素，如果發(fā)現(xiàn)有殘留，不能銷售。 這就是說(shuō)這一個(gè)生產(chǎn)階段的所有批號(hào)應(yīng)取樣檢測(cè)，這些取樣應(yīng)有代表

32、性，方法應(yīng)可接受，結(jié)果應(yīng)為未檢出，方可進(jìn)行下一階段的生產(chǎn)。one case we reviewed demonstrated a positive environmental surface sample from the fan blade of an exhaust hood in the repack room for beta-lactam residue, even though the most recent beta-lactam repackaging operation had been performed more than six months prior to samp

33、ling. 我們遇到的一個(gè)例子是一個(gè)較好的例子，從包裝室里的排風(fēng)扇的翅子上擦試頭孢殘留，盡管在取樣時(shí)包裝操作已經(jīng)超過(guò)6個(gè)月。reprinted from human drug cgmp notes (volume 8, number 1), march, 2000. this same text is also reprinted in framework sections 3.2 and 6.2. is it acceptable to manufacture penicillin products in the same facility as cephalosporin? 在同一設(shè)施內(nèi)生

34、產(chǎn)青霉素和頭孢是允許嗎？references: 21 cfr 211.28 personnel responsibilities 21 cfr 211.42(b),(c)&(d) design, and construction features21 cfr 211.46(c)&(d) ventilation, air filtration, air heating and cooling21 cfr 211.67 equipment cleaning and maintenance21 cfr 211.80(b) control of components and drug product

35、containers and closures21 cfr 211.176 penicillin contamination beta-lactams are products with a chemical substructure that contains the beta-lactam ring. they have the potential to sensitize and cause allergic response in humans. hypersensitivity, due to intolerance of beta lactam ingredients, can t

36、rigger reactions which range from a rash to life-threatening anaphylaxis. there is evidence that cross-sensitivity exists between penicillins and cephalosporins. thus, patients who are intolerant of penicillin may also be intolerant of cephalosporins, and further, cephalosporins may induce anaphylax

37、is in patients with a history of penicillin anaphylaxis. 內(nèi)酰胺類產(chǎn)品是一類具有內(nèi)酰胺環(huán)化學(xué)結(jié)構(gòu)的產(chǎn)品，具有潛在過(guò)敏性可導(dǎo)致人過(guò)敏，由于對(duì)內(nèi)酰胺類的不耐受性，超敏性在此類產(chǎn)品性也可能存在而引起過(guò)敏，有例子表明在青霉素和頭孢類之間存在交叉污染，因此，不能耐受青霉素的病人也可有耐受頭孢產(chǎn)品，而且，頭孢也可誘發(fā)有青霉素過(guò)敏史的人過(guò)敏。the immune system is exquisitely sensitive and can distinguish between very subtle changes in chemical comp

38、osition. patients may be tolerant of a given drug but intolerant of another drug with closely related chemical structures. there is evidence that patients tolerant of penicillin may be intolerant of cephalosporins.cder recognizes the considerable potential for cross-sensitivity and the possible life

39、-threatening consequences of unintended exposure. therefore, although not a specific requirement of sections 211.42 (d), 211.46(d) and 211.176, it is recommended that manufacturing operations for cephalosporins, penems and cephems, be separated from non-beta-lactam products and other beta-lactam dru

40、g products. for example cephalosporin type products would be separated from penicillin type products or non-beta-lactam products.免疫系統(tǒng)非常敏感，可以識(shí)別化學(xué)物質(zhì)的細(xì)微變化，病人可以耐受一個(gè)給定的藥物，而可能不能耐受化學(xué)物質(zhì)非常相近的另一個(gè)物質(zhì)，也有證據(jù)表面有的病人能耐受青霉素而不能耐受頭孢。cder認(rèn)識(shí)到很大的可能存在交叉過(guò)敏現(xiàn)場(chǎng)，從而由于非預(yù)期的泄漏導(dǎo)致威協(xié)到人的生命安全，因此盡管在211.42 (d), 211.46(d) 和 211.176里對(duì)頭孢的生產(chǎn)沒有

41、特殊的要求，但是推薦頭孢、青霉烯及頭孢烯的生產(chǎn)操作，也應(yīng)與其它非內(nèi)酰胺類產(chǎn)品及其它內(nèi)酰胺類產(chǎn)品分開生產(chǎn)，例如，頭孢類產(chǎn)品與青霉素類產(chǎn)品或非內(nèi)酰胺類產(chǎn)品隔離生產(chǎn)。production of cephalosporin type products can be approached from two different regulatory/compliance perspectives: 頭孢類產(chǎn)品可以通過(guò)以下兩種方法達(dá)到法規(guī)上的符合：1) if cephalosporins are considered to be non-penicillin drugs, they could not be

42、 manufactured in a facility lacking adequate separation from penicillin products. 2) for cephalosporin production with other non-beta-lactam drug products, similar health concerns exist for patients sensitive to cephalosporins who should not be exposed to it in a non-beta-lactam product. 1）如果頭孢被理解為非

43、青霉素藥品，則不能在缺少足夠隔離的生產(chǎn)青霉素的廠房?jī)?nèi)生產(chǎn)。 2）對(duì)頭孢產(chǎn)品和其它非內(nèi)酰胺產(chǎn)品，出于類似的健康考慮，對(duì)那些對(duì)頭孢過(guò)敏的人來(lái)說(shuō)，當(dāng)病人使用非頭孢類產(chǎn)品時(shí)，也不能有頭孢泄漏存在。for fundamental cgmp reasons and because of the difficulties in demonstrating and validating appropriate sampling and testing methodology for measuring cross-contamination, penicillin production should be p

44、erformed in facilities separated from non-beta-lactam drug products and other beta-lactam drug products unless adequate separation is demonstrated. we dont know of a satisfactory shared facility as of today. 出于基本的cgmp考慮，在交叉污染方面取樣及檢測(cè)方法驗(yàn)證的困難性，青霉素產(chǎn)品的生產(chǎn)應(yīng)在獨(dú)立的設(shè)施內(nèi)進(jìn)行，與非青霉素產(chǎn)品和其它內(nèi)酰胺產(chǎn)品分開，除非有足夠的隔離，我們至今為止為知道在同一個(gè)

45、廠房?jī)?nèi)怎么做才能更充分。furthermore, if necessary, other sections of the cgmp regulations i.e., 211.28; 211.42(b) & (c); 211.46(c); 211.67; and 211.80(b) could be applied to control contamination between beta-lactam and non-beta-lactam drug products. in summary the agency considers the separation of production

46、facilities for sensitizing beta-lactam based products to be current good manufacturing practice.此外，如果需要，其它c(diǎn)gmp的法規(guī)部分211.28; 211.42(b) & (c); 211.46(c); 211.67; and 211.80(b)可適用于控制內(nèi)酰胺和非內(nèi)酰胺產(chǎn)品之間的義叉污染，總之，本局是在基于cgmp的生產(chǎn)實(shí)踐要求來(lái)考慮過(guò)敏性產(chǎn)品內(nèi)酰胺產(chǎn)品的生產(chǎn)問題的。contact for further information: edwin melendez, hfd-322; (301)

47、594-0095; e-mail: reprinted from human drug cgmp notes (volume 8, number 1), march, 2000.this same text is also reprinted in framework sections 3.2, 4.3, and 6.2.can a facility that produced penicillin dosage forms be decontaminated and renovated for production of non-penicilli

48、n solid dosage forms provided there is no further penicillin production in the renovated facility?一個(gè)生產(chǎn)制劑的廠房，如果在去除污染和改造的前提下且不會(huì)再被用于生產(chǎn)青霉素產(chǎn)品，可否用于生產(chǎn)非青霉素產(chǎn)品，reference: 21 cfr 211.42(d), design and construction features; 211.46(d), ventilation, air filtration, air heating and cooling;211.176, penicillin con

49、tamination; fda by-lines #3, nov.77, procedures for the detection of residual penicillins in drugs;21 cfr 436.104 penicillin activity; and fda guide to inspections of validation of cleaning processes, july 1993. yes. however, the decontamination process is extremely difficult and we are unaware of a

50、ny firm that has successfully decontaminated a penicillin facility and converted it to production of non-penicillin products. 可以。但是，去除污染是極為困難的，我們至今還沒有了解到任何一個(gè)公司成功的去除了青霉素廠房的污染，轉(zhuǎn)而生產(chǎn)非青霉素產(chǎn)品。note that at section 211.176 the cgmp regulations require that if a reasonable possibility exists that a non-penici

51、llin drug product has been exposed to cross-contamination with penicillin, the non-penicillin product must be tested for the presence of penicillin and not marketed if detectable levels are found using the codified method. such a reasonable possibility may be present where decontamination has not be

52、en conducted effectively. that would put the responsible firm in a position of having to test each and every lot of non-penicillin product for the presence of penicillin. 注意到cgmp法規(guī)的211.176部分要求：如果非青霉素產(chǎn)品可能存在與青霉素產(chǎn)品交叉污染問題，必須檢測(cè)非青霉素產(chǎn)品中的青霉素含量，如果用合法的方法檢測(cè)到青霉素，則產(chǎn)品不能銷售。如果不能有效的去除污染，則青霉素是可能存在的，這就使得企業(yè)有責(zé)任檢測(cè)每一個(gè)批號(hào)的非

53、青霉素產(chǎn)品。in sum, while the cgmp regulations would not prohibit decontamination and conversion, the difficulty of cleaning up penicillin residues makes the chore daunting. 總之，盡管cgmp并不禁止這種做法的轉(zhuǎn)產(chǎn)，青霉素的清潔殘留也會(huì)使人望而卻步。contact for further info: edwin melendez, hfd-322, 301-594-0095; e-mail;

54、 reprinted from: fdas human drug cgmp notes (volume 7, number 1) march, 1999.this same text is also reprinted in framework section 3.2. is there an acceptable level of penicillin residue in non-penicillin drug products? 在非青霉素產(chǎn)品中青霉素產(chǎn)品的殘留有可接受標(biāo)準(zhǔn)嗎？reference: 21 cfr 211.176, penicillin contamination; 21

55、cfr 436.104 penicillin activity; fda by-lines no.3, nov.77, areview of procedures for the detection of residual penicillins in drugs. any detectable levels of penicillin residue are considered violative because 21 cfr 211.176 indicates that a non-penicillin drug product must not be marketed if detec

56、table levels of penicillin are found when tested according to procedures specified in the procedures for detecting and measuring penicillin contamination in drugs. 任何可檢查水平都是不可接受的，因?yàn)?1 cfr 211.176指明：依據(jù)特定的檢測(cè)被污染產(chǎn)品中的程序檢測(cè)，如果在非青霉素產(chǎn)品中發(fā)現(xiàn)任何水平的青霉素污染，則此產(chǎn)品不能銷售。 the current analytical standard for demonstrating

57、adequate decontamination of facilities, separation within the same building, or measurement of cross-contamination is codified at 21 cfr 211.176 and 436.104 and has a limit of detectability of 0.006 ppm (as penicillin g using s. lutea) and a violative detection amount of 0.03 ppm. note that the latt

58、er amount reflects the methods limits with respect to confidence and reproducibility and does not represent a tolerance level. this analytical methodology is limited to the detection of penicillin g and ampicillin in a limited number of products listed in the referenced method, not including other beta-lactam antibiotics. in situations where this methodology is not workable, it is the firms responsibility to develop, validate, and use other methodology with similar sensitivity. 現(xiàn)在證明廠房能被足夠去除污染的分析標(biāo)準(zhǔn)，同一個(gè)建筑物內(nèi)的隔離，或者交叉污染的檢測(cè)在21 cfr 211.176 和436.104中作了規(guī)定，lod為0.006 ppm，不可接受的檢測(cè)數(shù)為0.03 ppm.。注意后都的數(shù)據(jù)反應(yīng)了方法