FDA关于厂房设施的法规条款及翻译(与头孢和青霉素相临的厂房请注意)

3 3.1 Facility Design and Layout 厂房设置及布置 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 青霉素问题 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规定独立的厂房是什么意思？厂房必须完全独立吗？在安装有独立的空气过滤系统的情况下，楼层之间采取物理隔离可以吗？ 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, with adequate cleaning validation procedures in place? 在同一个厂房里生产青霉素和非青霉素产品，在有足够清洁的前提下，可接受吗？ Is it acceptable to manufacture penicillin products in the same facility as cephalosporin? 在同一个厂房内生产青霉素和头孢产品可以接受吗？ Can a facility 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? 一个生产制剂的厂房，如果在去除污染和改造的前提下且不会再被用于生产青霉素产品，可否用于生产非青霉素产品， Is there an acceptable level of penicillin residue in non-penicillin drug products? 在非青霉素药品中青霉素的残留是多少？ If a firm's 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?   如果一个公司的操作仅仅是片剂和胶囊的包装，也必须是独立的厂房及设备吗？ 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规定独立的厂房是什么意思？厂房必须完全独立吗？在安装有独立的空气过滤系统的情况下，楼层之间采取物理隔离可以吗？ References: 21 CFR 211.42(d) Design, and construction features 21 CFR 211.46(d) Ventilation, air filtration, air heating and cooling 21 CFR 211.176 Penicillin contamination Federal Register, 9/29/78 (Vol.43, No.190, Book 2) Preamble to the CGMPs at comment 142 CGMP regulations [21 CFR 211.42(d) and 211.46(d)] require separation of penicillins from non-penicillins during processing. The discussion of the comments in the preamble to the regulations note that "…isolation of penicillin production operations…can be achieved by sealing off…the two operations." "…does not necessarily mean…separate buildings." Thus, there can be a "building within a building"- 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 should 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 法规 [21 CFR 211.42(d) and 211.46(d)]要求青霉素与非青霉素产品在加工中独立。 相关的讨论观点“青霉素产品操作的隔离可以通过将两个操作完全分开而达到”，“并不需要独立的厂房”。这样，可以成“建筑物中之建筑物”，也就是说，两个建筑是没有必要的。然而，操作上必须完全隔离，也就是说，每一个方面都应完全隔离。充足的隔离应当包括：物理上的屏障及通风系统的隔离。青霉素厂房的人员及设备不应进行非青霉素的厂房。这些需要建立良好的书面程序并进行控制。这种隔离应进行审计，程序应经验证，如果需要还应进行监测。 Even with separation, if any possibility of contamination exists, the non-penicillin products must be tested (21 CFR 211.176). An example 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. 即使在隔离状态下，如果存在任何被污染的可能，非青霉素产品应该经过检验。一个可能污染的例子可能是人员及设备的不充分控制。Section 211.176要求如果存在青霉素产品暴露的可能，非青霉素产品应经检查，以追踪是否存在青霉素，如果检测到青霉素产品的残留，产品不应销售。 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 results 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?" published in "Human Drug CGMP Notes" (Volume 6, Issue 2, June 1998). 当这些禁止上市的产品里发现被青霉素污染时，并不仅仅是根据检测结果证明在污染水平以下而不能流入市场。同时必须满足其它CGMP要求也。关于此部分的讨论，请参照"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 Notes" (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 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 processing building, due to the lack of containment controls which ensured against cross contamination of the other drugs. 交叉污染的问题多年来一直是个关注的问题，并且还会继续是个问题。下面是一个青霉素污染的例子：在同一个厂区内在独立厂房生产的青霉素和非青霉素产品，由于人员和设备及物料控制不严格导致产品受到污染。另一个例子是一个临近头孢类产品的生产厂，由于缺乏足够的控制，CDER曾经收回其批准的证书。 Reprinted from HUMAN DRUG CGMP NOTES (Volume 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, with adequate cleaning validation procedures in place? 在同一个厂房里生产青霉素和非青霉素产品，在有足够清洁的前提下，可接受吗？ References: 21 CFR 211.42(d) Design, and construction features 21 CFR 211.46(d) Ventilation, air filtration, air heating and cooling 21 CFR 211.176 Penicillin contamination Federal Register, 9/29/78 (Vol.43, No.190, 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 required.". 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。涉及到的法规条款是“很重要的一点需要指明：青霉素与非青霉素之间的隔离，绝对需要完全独立的空调系统” Campaign 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 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 to include the environment, as well as surfaces of the facility and equipment that are to be decontaminated. 使用同一厂房和同一设备生产青霉素和非青霉素产品违背了CGMP法规，[211.42(d) and .46(d)]。需注意的一点是清洁验证并不包括厂房的所有空调系统，这一点是非常重要的，因为这种生产方式可以造成潜在厂房和空调的再污染。去除污染的概念可能要比典型的清洁的概念要宽泛的多，取样可能扩大大环境，厂房和设备的面。 A facility contaminated with penicillin 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.   一个已经被青霉素污染的厂房不能再被用于生产非青霉素产品，除非依照已建立的程序进行最广泛的去除污染的清洁已经完成，有代表性的取样表明厂房按照清洁/程序的结果是符合的。 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 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 penicillin 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. 现在的技术要想去除空调系统的污染非常困难，这是因为去除污染而进行的残留检测需要对空气处理系统进行取样，包括管道。这是非常困难的，因为空气处理系统的不规则的面积，其内部的沟沟角角有可能使青霉素残留，而这些残留有可能在生产非青霉素产品时溶解出来。因为青霉素的污染在空气处理系统里的不均匀分布，而使得取样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 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指明当可能存在污染时，非青霉素产品必须被检测而跟踪是否存在青霉素，如果发现有残留，不能销售。 这就是说这一个生产阶段的所有批号应取样检测，这些取样应有代表性，方法应可接受，结果应为未检出，方可进行下一阶段的生产。 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 sampling. 我们遇到的一个例子是一个较好的例子，从包装室里的排风扇的翅子上擦试头孢残留，尽管在取样时包装操作已经超过6个月。 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? 在同一设施内生产青霉素和头孢是允许吗？ References: 21 CFR 211.28 Personnel responsibilities 21 CFR 211.42(b),(c)&(d) Design, and construction features 21 CFR 211.46(c)&(d) Ventilation, air filtration, air heating and cooling 21 CFR 211.67 Equipment cleaning and maintenance 21 CFR 211.80(b) Control of components and drug product containers and closures 21 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 trigger 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 anaphylaxis in patients with a history of penicillin anaphylaxis. β内酰胺类产品是一类具有β内酰胺环化学结构的产品，具有潜在过敏性可导致人过敏，由于对β内酰胺类的不耐受性，超敏性在此类产品性也可能存在而引起过敏，有例子表明在青霉素和头孢类之间存在交叉污染，因此，不能耐受青霉素的病人也可有耐受头孢产品，而且，头孢也可诱发有青霉素过敏史的人过敏。 The immune system is exquisitely sensitive and can distinguish between very subtle changes in chemical composition. 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-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 drug products. For example cephalosporin type products would be separated from penicillin type products or non-beta-lactam products.   免疫系统非常敏感，可以识别化学物质的细微变化，病人可以耐受一个给定的药物，而可能不能耐受化学物质非常相近的另一个物质，也有证据表面有的病人能耐受青霉素而不能耐受头孢。CDER认识到很大的可能存在交叉过敏现场，从而由于非预期的泄漏导致威协到人的生命安全，因此尽管在211.42 (d), 211.46(d) 和 211.176里对头孢的生产没有特殊的要求，但是推荐头孢、青霉烯及头孢烯的生产操作，也应与其它非β内酰胺类产品及其它β内酰胺类产品分开生产，例如，头孢类产品与青霉素类产品或非β内酰胺类产品隔离生产。 Production of cephalosporin type products can be approached from two different regulatory/compliance perspectives: 头孢类产品可以通过以下两种方法达到法规上的符合： 1) If cephalosporins are considered to be non-penicillin drugs, they could not be 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）如果头孢被理解为非青霉素药品，则不能在缺少足够隔离的生产青霉素的厂房内生产。 2）对头孢产品和其它非β内酰胺产品，出于类似的健康考虑，对那些对头孢过敏的人来说，当病人使用非头孢类产品时，也不能有头孢泄漏存在。 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 performed in facilities separated from non-beta-lactam drug products and other beta-lactam drug products unless adequate separation is demonstrated. We don’t know of a satisfactory shared facility as of today. 出于基本的CGMP考虑，在交叉污染方面取样及检测方法验证的困难性，青霉素产品的生产应在独立的设施内进行，与非青霉素产品和其它β内酰胺产品分开，除非有足够的隔离，我们至今为止为知道在同一个厂房内怎么做才能更充分。 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 facilities for sensitizing beta-lactam based products to be current good manufacturing practice.   此外，如果需要，其它CGMP的法规部分211.28; 211.42(b) & (c); 211.46(c); 211.67; and 211.80(b)可适用于控制β内酰胺和非β内酰胺产品之间的义叉污染，总之，本局是在基于CGMP的生产实践要求来考虑过敏性产品β内酰胺产品的生产问题的。 Contact for further information: Edwin Melendez, HFD-322; (301) 594-0095; e-mail: melendeze@cder.fda.gov 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-penicillin solid dosage forms provided there is no further penicillin production in the renovated facility? 一个生产制剂的厂房，如果在去除污染和改造的前提下且不会再被用于生产青霉素产品，可否用于生产非青霉素产品， Reference: 21 CFR 211.42(d), Design and construction features; 211.46(d), Ventilation, air filtration, air heating and cooling; 211.176, Penicillin contamination; 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 any firm that has successfully decontaminated a penicillin facility and converted it to production of non-penicillin products. 可以。但是，去除污染是极为困难的，我们至今还没有了解到任何一个公司成功的去除了青霉素厂房的污染，转而生产非青霉素产品。 Note that at section 211.176 the CGMP regulations require that if a reasonable possibility exists that a non-penicillin 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 been 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法规的211.176部分要求：如果非青霉素产品可能存在与青霉素产品交叉污染问题，必须检测非青霉素产品中的青霉素含量，如果用合法的方法检测到青霉素，则产品不能销售。如果不能有效的去除污染，则青霉素是可能存在的，这就使得企业有责任检测每一个批号的非青霉素产品。 In sum, while the CGMP regulations would not prohibit decontamination and conversion, the difficulty of cleaning up penicillin residues makes the chore daunting. 总之，尽管CGMP并不禁止这种做法的转产，青霉素的清洁残留也会使人望而却步。 Contact for further info: Edwin Melendez, HFD-322, 301-594-0095; e-mail; melendeze@cder.fda.gov Reprinted from: FDA's 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? 在非青霉素产品中青霉素产品的残留有可接受标准吗？ Reference: 21 CFR 211.176, Penicillin contamination; 21 CFR 436.104 Penicillin Activity; FDA By-Lines No.3, Nov.77, A Review 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 detectable levels of penicillin are found when tested according to procedures specified in The Procedures for Detecting and Measuring Penicillin Contamination in Drugs. 任何可检查水平都是不可接受的，因为21 CFR 211.176指明：依据特定的检测被污染产品中的程序检测，如果在非青霉素产品中发现任何水平的青霉素污染，则此产品不能销售。 The current analytical standard for demonstrating 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 latter amount reflects the method's 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 firm's responsibility to develop, validate, and use other methodology with similar sensitivity. 现在证明厂房能被足够去除污染的标准，同一个建筑物内的隔离，或者交叉污染的检测在21 CFR 211.176 和436.104中作了规定，LOD为0.006 ppm，不可接受的检测数为0.03 ppm.。注意后都的数据反应了方法的可信度及再现性，但不代表而耐受水平。这种分析方法仅适用于青霉素G及氨苄青霉素在列出的限定的产品中的参照方法，不包括其它beta-内酰胺类抗生素。如果此方法不适用，企业有责任开发，验证，使用其它类似灵敏度的方法来检测产品中的头孢。 Contact for further info: Edwin Melendez, HFD-322, 301-594-0095; e-mail: melendeze@cder.fda.gov ; Dr. Richard Adams, HFD-643, 301-827-5849; e-mail: adamsr@cder.fda.gov . Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999. This same text is also reprinted in Framework section 3.2. If a firm's 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? 如果一个公司的操作仅仅是片剂和胶囊的包装，也必须是独立的厂房及设备吗？ Reference: 21 CFR Sections 211.42.(d), Design and construction features [Buildings and Facilities], 211.46(d), Ventilation, air filtration, air heating and cooling, and 211.176, Penicillin contamination Yes. The CGMP regulations explicitly require that operations relating to the manufacture, processing and packaging of penicillin be performed in facilities that are separate from those facilities used for other drugs. The regulations also require separate air-handling systems in facilities used for penicillin products. Furthermore, if a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, CGMPs require that the non-penicillin drug be tested for the presence of penicillin. The CGMPs make no exceptions from the foregoing for operations that are limited to repackaging solid oral dosage forms. 是的，CGMP法规明确要求有关青霉素的生产，加工及包装的厂房应与其它的药品的厂房分开，法规也要求在生产青霉素的厂房内有独立的空气处理系统。而且，如果存在非青霉素产品被青霉素产品污染的可能，CGMP要求应检测非青霉素产品中的青霉素含量，CGMP没有将固体制剂的包装排除在外。 It should be noted that the requirement for separate facilities does not necessarily mean that operations relating to penicillin products must be conducted in separate buildings from other drugs. A separate area dedicated to penicillin products within a larger facility may be acceptable if penicillin containment can be established and validated. 应当指出青霉素生产需要隔离的设施并不意味着需要独立的建筑，如果青霉素的污染可以程度可能确定且经过验斑点，在一个较大的设施内青霉素有专用的隔离的面积是可以接受的。 Contact for further info: Barry Rothman, HFD-325, 301-594-0098