FDA关于厂房的问答（谁翻译一下后半部分？）

石头968

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标准是多少？
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，可以设计成“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，厂房和设备的表面。
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方案/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分析标准，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, e- mail: rothmanb@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.
This same text is also reprinted in framework section 3.2.

3.2 Environmental Control Program
环境控制方案
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.
What is the purpose of an environmental monitoring program in aseptic processing? What are some major factors that ensure the environment does not contaminate product throughout a batch's manufacture?
在无菌生产中控制环境的目的是什么？在产品的整个生产过程中，保证产品不受污染的主要因素是什么？
Are firms required to use HEPA filters in the manufacture of tablets and capsules?
在片剂及胶囊剂的生产中，要求企业使用高效过滤器吗？
Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routine monitoring of aseptic processing areas?
在无菌生产区域，在净态下监测悬浮粒子而不用动态下监测可以接受吗？
Would FDA disapprove a pharmaceutical plant because it was located next to a landfill site?
如果一个制药厂房座落于垃圾厂附近FDA会接受吗？
Penicillin Issues
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?

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?
Is it acceptable to manufacture penicillin products in the same facility as cephalosporin?
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?
Is there an acceptable level of penicillin residue in non-penicillin drug products?
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?
What is the purpose of an environmental monitoring program in aseptic processing? What are some major factors that ensure the environment does not contaminate product throughout a batch's manufacture?
Reference:
21 CFR 211.42, Design and construction features [Subpart C-Buildings and Facilities];
211.113, Control of microbiological contamination;
211.22, Responsibilities of quality control unit;
211.46, Ventilation, air filtration, air heating and cooling;
1987 Guideline on Sterile Drug Products Produced by Aseptic Processing;
July 1994 Guide to Inspections of Sterile Drug Substance Manufacturers
The environmental monitoring program is a vital part of a quality control unit's CGMP responsibility to monitor and ensure ongoing control of an aseptic process. The CGMP regulations, at section 211.113 require firms to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. This section is particularly applicable to sterile drug products made by aseptic processing, and the aseptic guideline addressed at length various aspects of environmental monitoring.
An environmental monitoring program is vital for aseptic processing operations because it: 1) Provides crucial information on the quality of the aseptic processing environment during manufacturing; 2) prevents release of a potentially contaminated batch if appropriate quality standards (defined by a firm's written procedures) are not fulfilled; and, 3) prevents future contamination by detecting adverse trends.
In addressing the environmental monitoring program, the aseptic guideline discussed regular sampling and testing of the manufacturing environment, including air, floors, walls, and equipment surfaces. Evaluating the quality of air and surfaces in cleanrooms should start with a well-defined and specific written program, including validated test methods.
As explained in the guideline, among issues normally addressed by an environmental monitoring program are: sample location, appropriate sampling frequency, timing of sample collection, duration of sampling, size of sample, specific sampling equipment and techniques, limits, identification of microorganisms, trending systems, and procedures to promptly address out of limit results or adverse trends.
A number of major variables influence environmental control, all of which need to be addressed by appropriate written SOPs, in accordance with section 211.113.
It is important that a personnel qualification and monitoring program address operator practices, critical in maintaining environmental control of the aseptic processing area. In addition, the CGMPs at section 211.46 require equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product. In this context, the Heating, Ventilation, and Air Conditioning (HVAC) system design and controls play a key role in providing an adequate environment (e.g., particulate cleanliness, air pressure, and airflow) for aseptic processing.
Adequate cleaning and sanitizing procedures, facility design, equipment design, personnel flow, and material flow are among other key variables which significantly impact on the suitability of the environment in which aseptic processing operations are conducted.
Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999.
Are firms required to use HEPA filters in the manufacture of tablets and capsules?
References:
21 CFR 211.46, Ventilation, air filtration, air heating and cooling;
211.42, Design and construction features
No. The CGMP regulations do not specifically require tablet and capsule manufacturing facilities to maintain high-efficiency particulate air (HEPA) filtered air. The regulations, at 211.46, do require use of equipment for adequate control over air pressure, microorganism, dust, humidity and temperature when appropriate. In addition, this section calls for use of air filtration systems, including prefilters and particulate matter air filters on air supplies to production areas, as appropriate. These provisions speak to measures to prevent cross contamination, and the key phrase is "as appropriate".
Do not confuse the 211.46 provisions with 211.42(c)(10)(iii) which calls for aseptic processing areas to be equipped, as appropriate, with an air supply filtered through HEPA filters. Whereas such filtration is the norm for aseptic areas, tablet and capsule production rooms seldom need the same level of air filtration.
Despite the lack of an explicit CGMP requirement, some firms may elect to use HEPA filtered air systems as part of their dust control procedures. For example, firms may perform dust containment assessments and decide that such filters are warranted to prevent cross contamination of highly potent drugs that, even in small quantities, could pose a significant health hazard when carried over into other products.
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 3) September, 1997.
This text is also reprinted in framework section 3.3.
Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routine monitoring of aseptic processing areas?
References:
21 CFR 211.160(b), General requirements (Subpart I Laboratory Controls);
211.113, Control of microbiological contamination;
1987 Guideline on Sterile Drug Products Produced by Aseptic Processing.
No. Sampling an environment for particulates during static (at rest) times is of minimal utility in assessing actual processing conditions. On the other hand, operational (dynamic) monitoring performed throughout aseptic processing is needed. Here's why.
Aseptic processing operations are designed to exclude living microorganisms, endotoxins, and particulates from the finished product. It is generally accepted that monitoring of particulate concentration in classified (environmentally controlled) areas during operations serves as a direct indicator of changes in local air quality while indirectly indicating the increased potential for the introduction of microorganisms to the monitored area.
Occasional static monitoring during periods of no operation to ensure particulate levels remain well below an area's classification level would be useful as a facility maintenance parameter. However, firms should obtain data from dynamic monitoring (during operations) as a routine batch control. Firms should monitor frequently throughout manufacturing, and in proximity to the work surfaces and exposed product or container/closures. For example, in class 100 areas, samples should be taken about one foot away from the work surface. Many firms now have the capability to monitor nonviables continuously; however, failure to monitor continuously is not objectionable.
High levels of particulates generally represent a departure from processing norms, indicating, for example, unusual personnel activity which challenges the intended cleanroom design parameters. It is therefore important that the Quality Control unit investigate such "particulate excursions."
Finally, when qualifying a cleanroom, firms conduct studies to establish the room's air classification. Although the classification studies include assessment of particulate levels under static conditions, the final classification should be derived from data generated while equipment is in place and operations are ongoing.
Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov
Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 2), June, 1997.
This text is also reprinted in Framework section 3.3.
Would FDA disapprove a pharmaceutical plant because it was located next to a landfill site?
Reference:
21 CFR Part 211, Subpart C, Buildings and Facilities, generally.
Not necessarily. More important than a facility's proximity to sources of contamination is the adequacy of measures the firm takes to prevent such contamination from adversely affecting drug product quality. It would be far from prudent to locate a pharmaceutical establishment alongside a land reclamation facility (which conjures up visions of such potential sources of contamination as rodents, insects, birds, and ground water toxic leachates). The task of protecting the drug product and production environment from such contamination would be challenging, but not insurmountable. Field investigators who encounter such a situation should, of course, pay close attention to how the firm isolates production operations from potential contaminants. However, in the absence of demonstrated routes of contamination, we would not disapprove of the facility based solely on its proximity to the landfill.
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 3, Number 1) March, 1995.
This text is also reprinted in Framework section
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?
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.
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.
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).
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.
Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000.
This same text is also reprinted in framework section 3.1.
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?
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."
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.
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.  
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.
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.
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.
Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000.
This same text is also reprinted in framework sections 3.1 and 6.2.
Is it acceptable to manufacture penicillin products in the same facility as cephalosporin?
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.
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.  
Production of cephalosporin type products can be approached from two different regulatory/compliance perspectives:
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.
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.
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.  
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 3.1, 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?
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.
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.
In sum, while the CGMP regulations would not prohibit decontamination and conversion, the difficulty of cleaning up penicillin residues makes the chore daunting.
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 3.1.
Is there an acceptable level of penicillin residue in non-penicillin drug products?
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.
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.
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 3.1
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?
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.
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.
Contact for further info: Barry Rothman, HFD-325, 301-594-0098, e- mail: rothmanb@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.
This same text is also reprinted in framework section 3.1.

道路漫长黑暗

谢谢分享，这么多内容干嘛不弄个附件呢

野性之吻

Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routine monitoring of aseptic processing areas?
在无菌生产区域，在净态下监测悬浮粒子而不用动态下监测可以接受吗？                    净态 是啥态？？？？@石头968

石头968

道路漫长黑暗 发表于 2014-9-28 10:52
谢谢分享，这么多内容干嘛不弄个附件呢

省的下载

石头968

野性之吻 发表于 2014-9-28 10:56
Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routi ...

不懂，网上看到的

冰城

野性之吻 发表于 2014-9-28 10:56
Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routi ...

静态？

毒手药王邓智先

学习一下

野性之吻

575231000 发表于 2014-9-28 11:11
静态？

静   净？？     

胜利者

这是啥时颁布的？

石头968

胜利者 发表于 2014-9-28 11:34
这是啥时颁布的？

不清楚啊，网上偶遇的

清歌一曲月如霜

青霉素的问题
什么的的cGMP意思不同的设施？必须在建筑物被完全分开，或者是的cGMP满足的时候，地板物理安装独立的空气过滤装置分离？

它是可以接受的制造青霉素和非青霉素产品在竞选同一设备（即生产设施转换到不同的产品线在常规的基础上）的基础上，以制定适当的清洁验证程序？
它是可以接受的青霉素生产的产品在同一个设备作为头孢菌素？
在生产青霉素剂型的设施，可以净化和改造生产非青霉素固体制剂提供没有进一步的青霉素生产中的装修设施？
有青霉素残基的非青霉素药物产品的可接受水平？
如果一个公司的唯一操作是执行成品包装作业散装片剂和胶囊剂药品，必须仍然保持独立的设施和设备，包装青霉素产品？
在无菌处理的环境监测计划的目的是什么？什么是保证整个环境的批量的生产不污染产品的一些主要因素是什么？
参考：
21 CFR211.42，设计及施工特点[C分部，建筑物和设施];
211.113，微生物污染的控制;
211.22，责任单位的质量控制;
211.46，通风，空气过滤，空气加热和冷却;
1987指引无菌药品无菌加工制作;
1994年7月指南的无菌原料药制造商检查
环境监测方案的质量控制部门的CGMP的责任监督和确保持续控制的无菌工艺的重要组成部分。 cGMP的规定，在第211.113要求企业建立并遵守旨在防止药品看来是无菌微生物污染的适当书面程序。本节特别适用于无菌加工制成的无菌药品，并在环境监测的长度各方面的无菌指引处理。
环境监测计划是无菌加工操作至关重要的，因为它：1）提供的无菌加工环境，生产过程中的质量是至关重要的信息; 2）防止潜在污染批次的释放，如果相应的质量标准（由公司的书面程序中定义）都没有实现;以及3）防止未来的污染检测不利的趋势。
在处理环境监测程序，无菌准则讨论定期取样和制造环境的测试中，包括空气，地板，墙壁，和设备的表面。评价空气和表面的洁净室质量应该以明确和具体的书面程序，包括验证的测试方法。
正如指引说明，除通常由环境监测程序解决的问题是：样品的位置，适当的采样频率，采样时机，采样时间，样本的大小，具体的采样设备和技术，范围，识别微生物，趋势分析系统和程序，及时解决了极限的结果或不利的趋势。
一些主要的变数影响环境控制，所有这些都需要通过适当的书面标准作业程序来解决，按照第211.113。
这是很重要的人员资格及监控程序地址运算符的做法，在保持无菌加工区的环境控制的关键。此外，的cGMP在部分211.46需要设备时适当的制造，加工，包装或贮存的药物产品的充分控制空气压力，微生物，灰尘，湿度和温度。在此背景下，加热，通风和空调（HVAC）系统的设计和控制，提供适当的环境中发挥关键作用（例如，微粒洁净度，气压和气流）进行无菌处理。
适当的清洁和消毒程序，设施设计，设备的设计，人员流动，和物料流是其他关键变量上，其中无菌处理操作的进行环境是否适合该显著影响之间。
联系以获取更多信息：理查德·弗里德曼，HFD-322，301-594-0095;电子邮件：friedmanr@cder.fda.gov
FDA的人用药品CGMP的注意事项（第7卷，第1号）1999年3月：转载自。
需要企业使用HEPA过滤器的片剂和胶囊的生产？
参考文献：
21 CFR211.46，通风，空气过滤，空气加热和冷却;
211.42，设计和施工特点
第cGMP的规定并没有特别要求片剂和胶囊的生产设施，以维持高效率微粒空气（HEPA）过滤空气。规定，于211.46，确实需要使用设备的充分控制气压，微生物，灰尘，湿度和适宜的温度时。此外，对于使用空气过滤系统，包括预过滤器和颗粒物的空气过滤器上的空气供应到生产区的这部分通话，如合适的。这些规定的措施，以防止交叉污染说话，和关键短语是“适当的”。
不要与211.42（三）（10）混淆211.46规定（三），这要求无菌加工区必须配备酌情通过HEPA过滤器过滤后的空气供应。而这种过滤是常态的无菌区，片剂和胶囊生产车间很少需要空气过滤相同的水平。
尽管缺乏明确的CGMP的要求，一些公司可能会选择使用HEPA过滤空气系统，其粉尘控制程序的一部分。例如，企业可以执行灰尘遏制评估和决定，这种过滤器是必要的，以防止强效药物的交叉污染，即使数量不多，当结转到其他产品中可能造成显著健康危害。
FDA的人用药品CGMP的注意事项（第5卷，第3期）1997年9月：来自转载。
本文还重印框架3.3节。
正在静自生能力的颗粒物的监测，而不是动态的条件下接受常规监测的无菌加工区？
参考文献：
21 CFR211.160（b）中，一般要求（分部I实验室控制）;
211.113，微生物污染的控制;
1987指南上用无菌工艺生产无菌药品。
第采样静态（静止）过程中的颗粒物的环境时间是最少的效用评估实际加工条件。另一方面，在整个无菌工艺进行操作（动态）的监测是必要的。这里的原因。
无菌处理操作的目的是排除活的微生物，内毒素和微粒从最终产品中。人们普遍认为在操作期间监测粒子浓度的分类（环境控制）区作为改变当地的空气质量的直接指示，而间接地指示用于引入微生物于所监视的区域中的增加的潜力。
在没有操作的时间偶尔静态监控，确保颗粒水平仍远低于区域的分类级别将作为设备维护参数非常有用。然而，企业要获取数据的动态监测（在操作）作为常规的批量控制。企业应在整个生产经常监测，并在接近工作面和暴露的产品或容器/密封。例如，在100级区域，样品应采取大约一英尺远离工作表面。许多公司现在已经连续监测nonviables的能力;然而，未能持续监测并不反感。
高水平的微粒的一般表示从处理的规范，这表明，例如，异常的人员活动挑战了预期的洁净室设计参数的偏离。因此，重要的是质量控制部门调查这些“颗粒游览。”
最后，符合条件的洁净室时，企业进行研究，以确定室内空气分级。虽然分类研究包括静态条件下颗粒物水平进行评估，最终的分类应该从产生的数据可以得出，而设备的到位和操作正在进行中。
联系以获取更多信息：理查德·弗里德曼，HFD-322，301-594-0095;电子邮件：friedmanr@cder.fda.gov
从FDA的人用药品CGMP转载注意事项（第5卷第2期），1997年6月。
本文还重印框架3.3节。
美国FDA将不予药厂，因为它位于旁边的一个垃圾填埋场？
参考：
21 CFR第211，C部分，建筑物和设施，一般。
不一定。不是工厂的接近污染源更重要的是措施是否足够坚定以防止这种污染药品质量产生不利影响。这将是远远谨慎地寻找一种药物一起建立土地复垦基金（这让人想起了这种潜在的污染源为啮齿动物，昆虫，鸟类，水和地下水的有毒渗滤液愿景）。保护药品和生产环境的污染等的任务将是具有挑战性的，但并非不可克服。谁遇到这样的情况，当然要，密切关注企业如何分离生产业务从潜在的污染物实地调查。然而，在没有污染的展示路线，我们不会不赞成单凭它靠近垃圾填埋场的基础设施。
FDA的人用药品CGMP的注意事项（第3卷，第1号）1995年3月：转载自。
本文还重印框架节
什么的的cGMP意思不同的设施？必须在建筑物被完全分开，或者是的cGMP满足的时候，地板物理安装独立的空气过滤装置分离？
参考文献：
21 CFR211.42（D）的设计和施工特点
21 CFR211.46（四）通风，空气过滤，空气加热和冷却
21 CFR211.176青霉素污染
联邦注册，78年9月29日（第43卷，第190号，第2册）序言中的cGMP的评论142
CGMP法规[21 CFR211.42（d）和211.46（D）]需要从非青霉素青霉素类的加工过程中分离。在序言中规定的意见的讨论指出，“......青霉素生产经营的隔离...可以通过封锁......这两个操作来实现的。”“......并不一定意味着......独立的建筑。”因此，有可能是一个“楼中楼” - 即两幢大楼是不需要的。然而，必须有操作的总的分离，这意味着操作的各个方面，必须是分立的。足够的分离度应包括物理屏障和独立的空气处理系统。人员和设备从青霉素工厂不应该进入非青霉素设施。这些工作应以完善的书面程序和控制。分离应审核，程序验证，并在必要时进行监控。
即使使用分离，如果存在任何污染的可能性，所述非青霉素产品必须进行测试（21 CFR211.176）。可能污染的一个例子可以是在设备或人员移动控制不足。第211.176要求非青霉素产品为青霉素，其中曝光的可能性是存在的，而不是市售如果发现青霉素可检测水平的痕迹进行测试。
而这部分禁止销售的发现与青霉素被污染的产品，它不制裁营销仅基于该显示这种污染的没有可检测到的测试结果非青霉素产品。其他CGMP的要求仍必须得到满足。有关这个问题的讨论，请阅读文章“是根据第211.176发布的产品，只要产品进行测试，并没有青霉素被发现市场可以接受的？”发表在“人用药品的CGMP的注意事项”（第6卷，第2期，1998年6月）。
交叉污染的问题已为一些多年的关注，并不断有问题。在一个青霉素交叉污染的情况下审查已证明非青霉素设施是如何被污染由位于同一制造校园单独青霉素设施。出现这种情况是由于缺乏有关的人员，设备和材料的运动控制。在另一起案件中，CDER同意某区的建议不予批准的致敏β内酰胺制造工厂，这是相邻的另一种药物处理的建设，由于缺乏遏制的控制从而保证对其他药物的交叉污染。
从人用药品CGMP的注意事项（第8卷，第1号），2000年3月再版。
同样的文字，也转载框架3.1节。
它是可以接受的制造青霉素和非青霉素产品在竞选同一设备（即生产设施转换到不同的产品线在常规的基础上）的基础上，以制定适当的清洁验证程序？
参考文献：
21 CFR211.42（D）的设计和施工特点
21 CFR211.46（四）通风，空气过滤，空气加热和冷却
21 CFR211.176青霉素污染
联邦注册，78年9月29日（第43卷，第190号，第2册）序言中的cGMP的评论148
不，这是不能接受的。在序言中规定的意见的讨论指出，“......它弄清楚这些法规完全独立的空气处理设施，青霉素和非青霉素生产需要是非常重要的。”和“...因为它有可能为青霉素和非青霉素生产区之间的空气处理系统，以进行互连，......处长认为有必要指出，任何这样的互连将是不可接受的。”
突击性生产青霉素和在同一个工厂，并使用相同的设备任何非青霉素类产品违反CGMP法规[211.42（d）和0.46（D）]。甲关注的是，在清洁验证过程并不包括在整个设施中的空气处理系统。这是重要的，因为运动的生产具有用于空气处理系统和设施的再次污染的可能性，并且可能导致非青霉素产品与青霉素交叉污染。去污的概念是比典型的清洁程序验证更广，在该取样被扩展到包括
环境，以及该设施和设备是表面进行净化。
污染的青霉素工厂不能开工的非青霉素生产到大量的净化和清理设施的完成按照既定程序，和有代表性的环境样本表明，该设备符合其去污协议/规范。
目前的技术使得空气处理系统的净化困难。这是因为，在净化/清洗程序将需要采样和的空气处理系统的其它部分的残留检测，包括管道系统。因为其整个长度上的空气处理系统具有这样创建的青霉素残渣积聚起来，用蜕断在未确定期间在非青霉素生产期间可能不均匀的区域和裂缝，这将是困难的。因此青霉素污染不会被均匀地分布在空气处理系统，以及“代表”样品（保留，表面和/或空气）可能不被污染的水平的准确描绘。
21 CFR211.176表明，在存在接触的可能性，非青霉素产品必须被测试为青霉素的痕迹，而不是市售如果检测的水平被发现。这意味着，从在每一个运动产生的非青霉素产品的所有批次的代表性样品必须以可接受的方法进行试验，结果发现不可探测的前启动非青霉素运动所产生的青霉素产物。
我们回顾一个案例展示了从重新包装空间的β-内酰胺残留物排油烟机的风扇叶片积极的环境表面采样，即使最近的β-内酰胺类分装操作已在采样前进行了半年多。
从人用药品CGMP的注意事项（第8卷，第1号），2000年3月再版。
同样的文字，也转载框架部分3.1和6.2。
它是可以接受的青霉素生产的产品在同一个设备作为头孢菌素？
参考文献：
21 CFR211.28人员的责任
21 CFR211.42（二），（三）及（四）设计和结构特点
21 CFR211.46（三）及（四）通风，空气过滤，空气加热和冷却
21 CFR211.67设备的清洁保养
21 CFR211.80（B）成分和药品容器和密封件的控制
21 CFR211.176青霉素污染
β-内酰胺产品包含的β-内酰胺环化学子。他们必须认识并引起人类过敏性反应的潜力。过敏症，由于公测内酰胺成分不耐受，可以引发反应，其范围从皮疹到危及生命的过敏反应。有证据表明，青霉素类和头孢菌素类之间存在交叉灵敏度。因此，患者谁不耐受青霉素的也可以是不耐受头孢菌素，和进一步，头孢菌素类可诱发过敏反应的患者青霉素过敏史。
免疫系统是极其敏感和化学成分十分微妙的变化可以区分。患者可容忍一个给定的药物，但不能容忍另一种药物有密切相关的化学结构。有证据表明，患者耐受青霉素可以是不耐头孢菌素。 CDER认识到相当大的潜力交叉灵敏度和意外暴露的可能危及生命的后果。因此，尽管部分211.42（d）所示，211.46（d）和211.176的不特定的要求，则建议制造用于头孢菌素类，青霉烯和头孢类的操作，可以从非-β-内酰胺产物和其它的β-内酰胺类药物的产品中分离。例如头孢菌素类产品会从青霉素类产品或非-β-内酰胺产物进行分离。
生产头孢类产品可以从两个不同的监管/合规的角度走近：
1）如头孢菌素类被认为是无青霉素药物，它们不能在一个设施缺乏从青霉素制品有足够的分离制备。 2）对头孢菌素的生产与其他非-β-内酰胺类药物的产品，类似的健康问题的患者对头孢菌素谁不应该在非-β-内酰胺产物暴露在它敏感的存在。
对于因在展示和验证适当的采样和测试方法用于测量交叉污染的困难，根本原因CGMP和青霉素的生产应在设施非beta-lactam类药物产品和其他的β-内酰胺类药物的产品，除非有足够的分离分开进行证明。我们不知道一个满意的共同基金作为今天。
此外，如果的CGMP法规必要的，其他部分[即211.28; 211.42（二）及（三）; 211.46（C）; 211.67;和211.80（B）]可以被应用到控制的β-内酰胺类和非-β-内酰胺类药物的产品之间的污染。总之该机构认为，生产设施敏β内酰胺类产品是目前良好生产规范的分离。
联系以获取更多信息：埃德温·梅伦德斯，HFD-322; （301）594-0095;电子邮件：melendeze@cder.fda.gov
从人用药品CGMP的注意事项（第8卷，第1号），2000年3月再版。
同样的文字，也转载框架部分3.1，4.3，和6.2。
在生产青霉素剂型的设施，可以净化和改造生产非青霉素固体制剂提供没有进一步的青霉素生产中的装修设施？
参考：
21 CFR211.42（D），设计和施工的特点;
211.46（d）所示，通风，空气过滤，空气的加热和冷却;
211.176，青霉素污染;
美国FDA通过线＃3，Nov.77，对青霉素类残留药物中的检测程序;
21 CFR436.104青霉素活动;和
FDA的指南，以确认清洗过程中，1993年7月的检查。
是的。然而，在净化过程是非常困难的，我们不知道已经成功净化青霉素设施，并把它转换为生产非青霉素产品的任何公司的。
注意，在第211.176的CGMP法规要求，如果在合理可能性是存在的非青霉素药物产品已经暴露于交叉污染与青霉素，非青霉素产品必须进行测试青霉素的存在下，如果检测到不销售水平使用的编纂方法发现。这种合理的可能性可能存在的地方去污还没有得到有效执行。这将使该公司负责在其为青霉素的存在测试每一个不少非青霉素类产品的位置。
总之，虽然CGMP法规不禁止净化和转换，清理青霉素残留的难度，使繁琐艰巨。
联系作进一步的信息：埃德温·梅伦德斯，HFD-322，301-594-0095;电子邮件; melendeze@cder.fda.gov
FDA的人用药品CGMP的注意事项（第7卷，第1号）1999年3月：转载自。
同样的文字，也转载框架3.1节。
有青霉素残基的非青霉素药物产品的可接受水平？
参考：
21 CFR211.176，青霉素污染;
21 CFR436.104青霉素活动;
美国FDA通过，3号线，Nov.77，A
审查的残留青霉素的药品检测程序。
青霉素残留任何可检测的水平被认为是违规，因为21 CFR211.176表明，非青霉素类药品不得如果发现青霉素的检测水平时，按照程序检测和测量药物青霉素污染规定的程序进行测试销售。
用于演示的设施充分净化，在同一建筑物内分离或交叉污染的测量电流的分析标准法典21 CFR211.176和436.104，并拥有0.006 ppm的检测能力的限制（如青霉素G采用南黄体）和0.03百万分之违规的检测量。需要注意的是，后者价值反映了法的限制相对于信心和重现性，并不代表公差等级。此分析方法被限制的青霉素G的检测和氨苄青霉素中的在所引用的方法中列出，但不包括其它的β-内酰胺类抗生素产品的数量有限。在情况下，这种方法是行不通的，这是公司的责任，开发，验证，并使用其他方法有类似的敏感性。
联系作进一步的信息：埃德温·梅伦德斯，HFD-322，301-594-0095;电子邮件：melendeze@cder.fda.gov;博士理查德·亚当斯，HFD-643，301-827-5849;电子邮件：adamsr@cder.fda.gov。
FDA的人用药品CGMP的注意事项（第7卷，第1号）1999年3月：转载自。
同样的文字，也转载框架3.1节
如果一个公司的唯一操作是执行成品包装作业散装片剂和胶囊剂药品，必须仍然保持独立的设施和设备，包装青霉素产品？
参考：
21 CFR第211.42（D），设计和施工特点[建筑物和设施]
211.46（d）所示，通风，空气过滤，空气加热和冷却，并
211.176，青霉素污染
是的。的CGMP法规明确要求，有关的制造，加工和青霉素的包装操作中设备相分离的那些用于其他药物的设施进行。该法规还要求独立的空气处理系统用于对青霉素产品的设施。此外，如果在合理可能性是存在的非青霉素药物产品已经暴露于交叉污染与青霉素，的cGMP要求该非青霉素药物对青霉素的存在下进行测试。的的cGMP使从上述的操作被限制为重新包装的固体口服剂型没有例外。
但是应当注意的是，对于不同的设施的要求并不一定意味着与青霉素产品的操作必须在从其它药物分开的建筑物中进行。在一个更大的工厂，致力于青霉素产品的一个单独的区域是可以接受的，如果遏制青霉素可以建立和验证。
联系作进一步的信息：巴里·罗斯曼，HFD-325，301-594-0098，电子邮件：rothmanb@cder.fda.gov
FDA的人用药品CGMP的注意事项（第6卷，第2号）1998年6月：转载自。
同样的文字，也转载框架3.1节。



Penicillin Issues
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?

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?
Is it acceptable to manufacture penicillin products in the same facility as cephalosporin?
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?
Is there an acceptable level of penicillin residue in non-penicillin drug products?
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?
What is the purpose of an environmental monitoring program in aseptic processing? What are some major factors that ensure the environment does not contaminate product throughout a batch's manufacture?
Reference:
21 CFR 211.42, Design and construction features [Subpart C-Buildings and Facilities];
211.113, Control of microbiological contamination;
211.22, Responsibilities of quality control unit;
211.46, Ventilation, air filtration, air heating and cooling;
1987 Guideline on Sterile Drug Products Produced by Aseptic Processing;
July 1994 Guide to Inspections of Sterile Drug Substance Manufacturers
The environmental monitoring program is a vital part of a quality control unit's CGMP responsibility to monitor and ensure ongoing control of an aseptic process. The CGMP regulations, at section 211.113 require firms to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. This section is particularly applicable to sterile drug products made by aseptic processing, and the aseptic guideline addressed at length various aspects of environmental monitoring.
An environmental monitoring program is vital for aseptic processing operations because it: 1) Provides crucial information on the quality of the aseptic processing environment during manufacturing; 2) prevents release of a potentially contaminated batch if appropriate quality standards (defined by a firm's written procedures) are not fulfilled; and, 3) prevents future contamination by detecting adverse trends.
In addressing the environmental monitoring program, the aseptic guideline discussed regular sampling and testing of the manufacturing environment, including air, floors, walls, and equipment surfaces. Evaluating the quality of air and surfaces in cleanrooms should start with a well-defined and specific written program, including validated test methods.
As explained in the guideline, among issues normally addressed by an environmental monitoring program are: sample location, appropriate sampling frequency, timing of sample collection, duration of sampling, size of sample, specific sampling equipment and techniques, limits, identification of microorganisms, trending systems, and procedures to promptly address out of limit results or adverse trends.
A number of major variables influence environmental control, all of which need to be addressed by appropriate written SOPs, in accordance with section 211.113.
It is important that a personnel qualification and monitoring program address operator practices, critical in maintaining environmental control of the aseptic processing area. In addition, the CGMPs at section 211.46 require equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product. In this context, the Heating, Ventilation, and Air Conditioning (HVAC) system design and controls play a key role in providing an adequate environment (e.g., particulate cleanliness, air pressure, and airflow) for aseptic processing.
Adequate cleaning and sanitizing procedures, facility design, equipment design, personnel flow, and material flow are among other key variables which significantly impact on the suitability of the environment in which aseptic processing operations are conducted.
Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999.
Are firms required to use HEPA filters in the manufacture of tablets and capsules?
References:
21 CFR 211.46, Ventilation, air filtration, air heating and cooling;
211.42, Design and construction features
No. The CGMP regulations do not specifically require tablet and capsule manufacturing facilities to maintain high-efficiency particulate air (HEPA) filtered air. The regulations, at 211.46, do require use of equipment for adequate control over air pressure, microorganism, dust, humidity and temperature when appropriate. In addition, this section calls for use of air filtration systems, including prefilters and particulate matter air filters on air supplies to production areas, as appropriate. These provisions speak to measures to prevent cross contamination, and the key phrase is "as appropriate".
Do not confuse the 211.46 provisions with 211.42(c)(10)(iii) which calls for aseptic processing areas to be equipped, as appropriate, with an air supply filtered through HEPA filters. Whereas such filtration is the norm for aseptic areas, tablet and capsule production rooms seldom need the same level of air filtration.
Despite the lack of an explicit CGMP requirement, some firms may elect to use HEPA filtered air systems as part of their dust control procedures. For example, firms may perform dust containment assessments and decide that such filters are warranted to prevent cross contamination of highly potent drugs that, even in small quantities, could pose a significant health hazard when carried over into other products.
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 3) September, 1997.
This text is also reprinted in framework section 3.3.
Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routine monitoring of aseptic processing areas?
References:
21 CFR 211.160(b), General requirements (Subpart I Laboratory Controls);
211.113, Control of microbiological contamination;
1987 Guideline on Sterile Drug Products Produced by Aseptic Processing.
No. Sampling an environment for particulates during static (at rest) times is of minimal utility in assessing actual processing conditions. On the other hand, operational (dynamic) monitoring performed throughout aseptic processing is needed. Here's why.
Aseptic processing operations are designed to exclude living microorganisms, endotoxins, and particulates from the finished product. It is generally accepted that monitoring of particulate concentration in classified (environmentally controlled) areas during operations serves as a direct indicator of changes in local air quality while indirectly indicating the increased potential for the introduction of microorganisms to the monitored area.
Occasional static monitoring during periods of no operation to ensure particulate levels remain well below an area's classification level would be useful as a facility maintenance parameter. However, firms should obtain data from dynamic monitoring (during operations) as a routine batch control. Firms should monitor frequently throughout manufacturing, and in proximity to the work surfaces and exposed product or container/closures. For example, in class 100 areas, samples should be taken about one foot away from the work surface. Many firms now have the capability to monitor nonviables continuously; however, failure to monitor continuously is not objectionable.
High levels of particulates generally represent a departure from processing norms, indicating, for example, unusual personnel activity which challenges the intended cleanroom design parameters. It is therefore important that the Quality Control unit investigate such "particulate excursions."
Finally, when qualifying a cleanroom, firms conduct studies to establish the room's air classification. Although the classification studies include assessment of particulate levels under static conditions, the final classification should be derived from data generated while equipment is in place and operations are ongoing.
Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov
Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 2), June, 1997.
This text is also reprinted in Framework section 3.3.
Would FDA disapprove a pharmaceutical plant because it was located next to a landfill site?
Reference:
21 CFR Part 211, Subpart C, Buildings and Facilities, generally.
Not necessarily. More important than a facility's proximity to sources of contamination is the adequacy of measures the firm takes to prevent such contamination from adversely affecting drug product quality. It would be far from prudent to locate a pharmaceutical establishment alongside a land reclamation facility (which conjures up visions of such potential sources of contamination as rodents, insects, birds, and ground water toxic leachates). The task of protecting the drug product and production environment from such contamination would be challenging, but not insurmountable. Field investigators who encounter such a situation should, of course, pay close attention to how the firm isolates production operations from potential contaminants. However, in the absence of demonstrated routes of contamination, we would not disapprove of the facility based solely on its proximity to the landfill.
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 3, Number 1) March, 1995.
This text is also reprinted in Framework section
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?
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.
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.
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).
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.
Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000.
This same text is also reprinted in framework section 3.1.
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?
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."
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.
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.  
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.
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.
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.
Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000.
This same text is also reprinted in framework sections 3.1 and 6.2.
Is it acceptable to manufacture penicillin products in the same facility as cephalosporin?
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.
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.  
Production of cephalosporin type products can be approached from two different regulatory/compliance perspectives:
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.
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.
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.  
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 3.1, 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?
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.
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.
In sum, while the CGMP regulations would not prohibit decontamination and conversion, the difficulty of cleaning up penicillin residues makes the chore daunting.
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 3.1.
Is there an acceptable level of penicillin residue in non-penicillin drug products?
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.
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.
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 3.1
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?
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.
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.
Contact for further info: Barry Rothman, HFD-325, 301-594-0098, e- mail: rothmanb@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.
This same text is also reprinted in framework section 3.1.

石头968

清歌一曲月如霜 发表于 2014-9-28 11:41
青霉素的问题
什么的的cGMP意思不同的设施？必须在建筑物被完全分开，或者是的cGMP满足的时候，地板物理安 ...

感谢!

xhf123456

谢谢分享，学习一下。

Chris

575231000 发表于 2014-9-28 11:11
静态？

static condition静态