201304 FDA行业指南-非青类β-内酰胺药品：防止交叉污染CGMP框架 - 药群论坛

This guidance describes the importance of implementing manufacturing controls to prevent cross-contamination of finished pharmaceuticals and active pharmaceutical ingredients (APIs) with non-penicillin beta-lactam drugs. This guidance also provides information regarding the relative health risk of, and the potential for, cross-reactivity in the classes of sensitizing beta-lactams (including both penicillins and non-penicillin beta-lactams). Finally, this guidance clarifies that manufacturers generally should utilize separate facilities for the manufacture of non-penicillin beta-lactams because those compounds pose health risks associated with cross-reactivity.

Drug cross-contamination is the contamination of one drug with one or more different drugs. Penicillin can be a sensitizing agent that triggers a hypersensitive exaggerated allergic immune response in some people. Accordingly, implementing methods for preventing cross-contamination of other drugs with penicillin is a key element of manufacturing penicillin and current good manufacturing practice (CGMP) regulations require the use of such methods. See, e.g., 21 CFR §§ 211.42(d), 211.46(d), and 211.176. Non-penicillin beta-lactam drugs also may be sensitizing agents and cross-contamination with non-penicillin beta-lactam drugs can initiate the same types of drug-induced hypersensitivity reactions that penicillins can trigger, including life-threatening allergic reactions. Therefore, manufacturers of non-penicillin beta-lactam drugs should employ similar control strategies to prevent cross-contamination, thereby reducing the potential for drug-induced, life-threatening allergic reactions.

本指南描述了实施生产控制防止制剂和活性原料药（API）与非青霉素β-内酰胺药品产生交叉污染的重要性。本指南还提供了关于相对健康风险的信息，以及不同类过敏性β-内酰胺（包括青类和非青类β-内酰胺）之间的交叉污染可能性。最后，本指南澄清了生产商通常应使用独立的设施生产非青类β-内酰胺，因为该类化合物具有交叉反应健康风险。药品交叉污染是指一种药品与另一种或多种不同药品产生污染。青霉素是一种高致敏药物，在有些人身上可能会引发超敏致死反应。相应地，采取措施来防止其它药品与青霉素类交叉污染是生产青霉素类产品的关键要求，CGMP法规要求使用这些方法，参见例如 21 CFR §§ 211.42(d), 211.46(d), and 211.176。非青β-内酰胺药品也可能是致敏性药品，与非青类β-内酰胺药品的交叉污染可能会引起与青霉素相似的同类型药品诱发性超敏反应，包括威胁生命的过敏反应。因此，非青类β-内酰胺药品生产商应采用相似的控制策略来防止交叉污染，从而降低药品诱发的威胁生命的过敏反应的可能性。

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidance documents describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA guidance means that something is suggested or recommended, but not required.

FDA的指南文件，包括本指南，并没有强制的法律效力。指南文件中所述的是当局现行的关于某一主题的想法，应仅作为建议来看待，除非其中引用了特定的法规或法定条款要求。SHOULD一词在FDA的指南中表示建议做某事，但并不是强制要求。

Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)) requires that, with few exceptions, all drugs be manufactured in compliance with current good manufacturing practices (CGMPs). Drugs that are not in compliance with CGMPs are considered to be adulterated. Furthermore, finished pharmaceuticals are required to comply with the CGMP regulations at 21 CFR parts 210 and 211.

联邦食品药品和化妆品法案(21 U.S.C. 351(a)(2)(B)) 的501(a)(2)(B)部分要求，除少数例外情况外，所有药品的生产均应符合CGMP的要求。不符合CGMP要求所生产的药品将被认为是假药。另外，制剂要求符合21CFR第210和211部分的CGMP法规。

Several CGMP regulations directly address facility and equipment controls and cleaning. For example, § 211.42(c) requires building and facility controls in general to prevent cross-contamination of drug products. Specifically, the regulation states, “[t]here shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mix-ups” during manufacturing, processing, packaging, storage, and holding.

With respect to penicillin, § 211.42(d) requires that “[o]perations relating to the manufacture, processing, and packing of penicillin shall be performed in facilities separate from those used for other drug products for human use.” However, FDA has clarified that separate buildings may not be necessary, provided that the section of the manufacturing facility dedicated to manufacturing penicillin is isolated (i.e., completely and comprehensively separated) from the areas of the facility in which non-penicillin products are manufactured.[2] Under § 211.46(d), manufacturers must completely separate air handling systems for penicillin from those used for other drugs for human use. Additionally, § 211.176 requires manufacturers to test non-penicillin drug products for penicillin where the possibility of exposure to cross-contamination exists, and prohibits manufacturers from marketing such products if detectable levels of penicillin are found.[3]

有几个CGMP法规直接说明了设施和设备控制和清洁的要求。例如，§ 211.42(c) 是求建筑和设施控制通常应能防止药品的交叉污染。该法规特别申明在生产、加工、包装、存贮和持有过程中“公司的操作应有独立或指定的区域，或类似的其它必要的控制系统以防止污染或混淆”。关于青霉素， § 211.42(d)要求“青霉素的生产、加工和包装相关操作应在独立于其它人用药品的设施内进行”。但是，FDA已澄清如果专用于青霉素生产的设施部分与非青霉素类药品生产设施区域完全隔离（即完全综合隔离），可以不需要有独立的建筑。根据§ 211.46(d)，青霉素类产品与其它人用药品的空调净化系统必须完全分开，另外§ 211.176要求如果可能存在交叉污染时，生产商应在非青类药品中检测青霉素残留，一旦在这些产品中检出青霉素，则这些产品禁止上市销售。

Although FDA has not issued CGMP regulations specific to APIs, the Agency has provided guidance to API manufacturers in the guidance for industry, ICH[4] Q7, Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7 guidance).[5] Because some APIs are sensitizing compounds that may cause anaphylactic shock, preventing cross-contamination in APIs is as important as preventing cross-contamination in finished products. The ICH Q7 guidance recommends using dedicated production areas, which can include facilities, air handling equipment and processing equipment, in the production of highly sensitizing materials, such as penicillins and cephalosporins.[6]

尽管FDA还没有签发专门针对原料药的CGMP法规，但当局已向原料药生产商提供了行业指南，ICH Q7，原料药GMP（ICH Q7指南）。由于有些原料药为致敏性化合物，可能会引起过敏性休克，在原料药生产中防止原料药的交叉污染与在制剂中防止交叉污染一样的重要。ICH Q7指南推荐在生产高致敏性物料，如青霉素和头孢类药品时，采用专用生产区域，包括设施、空调净化系统和工艺设备。

Beta-lactam antibiotics, including penicillins and the non-penicillin classes, share a basic chemical structure that includes a three-carbon, one-nitrogen cyclic amine structure known as the beta-lactam ring. The side chain associated with the beta-lactam ring is a variable group attached to the core structure by a peptide bond; the side chain variability contributes to antibacterial activity. As of the date of this publication, FDA has approved over 34 beta-lactam compounds as active ingredients in drugs for human use.[7] Beta-lactam antibiotics include the following five classes[8]:

β-内酰胺抗生素，包括青霉素和非青霉素类，均具有相同的基本化学结构，包括一个三碳一氮环胺结构，通常称为β-内酰胺环。与β-内酰胺环相连的侧链则由不同基团组成，通过肽键与核心结构相连，侧链对抗菌活性产生不同作用。至本指南公布之日，FDA已批准了超过34个β-内酰胺类化合物作为人用药中的活性成分。β-内酰胺类抗生素包括以下五大类：

Allergic reactions associated with penicillins and non-penicillin beta-lactams range from rashes to life-threatening anaphylaxis. Immunoglobulin E (IgE) antibodies mediate the immediate hypersensitivity reactions that are responsible for the symptoms of hay fever, asthma, hives, and anaphylactic shock. IgE-mediated hypersensitivity reactions are of primary concern because they may be associated with significant morbidity and mortality. There is evidence that patients with a history of hypersensitivity to penicillin may also experience IgE-mediated reactions to other beta-lactams, such as cephalosporins and penems.[9]

与青霉素类和非青霉素类β-内酰胺相关的过敏反应包括从疹子至威胁生命的过敏反应。免疫球蛋白E（IgE）抗体作为媒介引发即刻超敏反应，症状表现为花粉过敏、哮喘、荨麻疹和过敏性休克。IgE媒体超敏反应引起高度重视是因为它可能会伴随很高的发病率和死亡率。有证据显示具有青霉素类超敏反应历史的患者可能也会对其它β-内酰胺类药物，如头孢菌素和青霉烯类产生IgE媒体超敏反应。

All non-penicillin beta-lactams also have the potential to sensitize individuals, and subsequent exposure to penicillin may result in severe allergic reactions in some patients. Although the frequency of hypersensitivity reactions due to cross-reactivity between beta-lactam classes can be lower than the risk within a class,[10] the hazard posed is present[11] and potentially life-threatening. The potential health hazard of non-penicillin beta-lactams therefore is similar to that of penicillins. Further similarities between non-penicillin beta-lactams and penicillins are as follows:

所有的非青类β-内酰胺也具有潜在的致敏性，有些患者在接触β-内酰胺后再接触青霉素可能会导致严重的过敏反应。尽管由于不同类别的β-内酰胺交叉反应的超敏反应概率可能低于同一类的风险，其所具有危害仍是存在的，且可能会导致生命威胁。非青类β-内酰胺的潜在健康危害因而与青霉素类的相似。非青β-内酰胺类和青霉素类的其它相似性如下：

While beta-lactam antibiotics are similar to one another in many ways, they may differ in pharmacokinetics, antibacterial activity, and potential to cause serious allergic reactions. Because allergy testing methods have not been well-validated,[15] it is clinically difficult to determine the occurrence and rate of cross-reactivity between beta-lactam antibiotics in humans. Therefore, undiagnosed or underreported cases of cross-reactivity likely exist. Some beta-lactam antibiotics have negligible potential for cross-reactivity with beta-lactams of other classes, whereas other beta-lactam compounds may exhibit sensitizing activity as derivatives before the incorporation of side chains that confer antibacterial activity.

由于β-内酰胺抗生素在很多方面相互相似，它们在药动学、抗菌活性和引起严重过敏反应的可能性方面还是有差异的。由于过敏反应测试方法还没有经过很好的验证，临床上很难决定β-内酰胺类抗生素在人身上的交叉反应发生情况和概率。因此，可能会存在交叉反应的案例无法确诊或未报道的情况。有些β-内酰胺抗生素与其它类别的β-内酰胺的交叉反应可能性可以忽略，而另一些β-内酰胺类化合物可能会在与调整抗菌活性的侧链结合前作为衍生物显示出过敏反应。

Regardless of the rate of cross-reactivity between beta-lactam drugs or the mechanism of action by which such cross-reactivity may occur, the potential health risk to patients indicates that drug manufacturers should take steps to control for the risk of cross-contamination for all beta-lactam products.[16]

Beta-lactam compounds such as clavulanic acid, tazobactam, and sulbactam have weak antibacterial activity but are irreversible inhibitors of many beta-lactamases. These compounds, which are potential sensitizing agents, are typically used in combination with specific beta-lactam agents to preserve antibacterial activity (e.g., amoxicillin-clavulanate, piperacillin-tazobactam). Because these compounds are almost always used in combination with specific beta-lactam agents, any clinical observations of hypersensitivity reactions likely would be attributed to the beta-lactam antibiotic component rather than the inhibitor. Although there have been no case reports confirming anaphylactic reactions to a beta-lactamase inhibitor that is also a beta-lactam, these compounds are potentially sensitizing agents, and manufacturers should implement controls to reduce the risk of cross-contamination with beta-lactamase inhibitors as with all other beta-lactam products.

β-内酰胺化合物如克拉维酸、他唑巴坦和舒巴坦均具有较弱的抗菌作用，但也是许多β-内酰胺产品的不可逆抑制剂。这些化合物是潜在的促敏剂，常与特定的β-内酰胺产品联用以避免产生耐药性（例如，阿莫西林-克拉维酸，派拉西林-他唑巴坦）。由于这些化合物几乎总是与特定的β-内酰胺产品联用，所有的超敏反应临床观察可能都作为β-内酰胺抗生类化合物的特性，而不是抑制剂的物性。尽管并没有确认β-内酰胺抑制剂的过敏性反应的病例报告，这些化合物可能会是潜在的致敏剂，生产商应进行控制以降低与β-内酰胺抑制剂交叉污染的风险，就和与所有其它β-内酰胺产品一样。

Some beta-lactam intermediate compounds and derivatives also possess similar sensitization and cross–reactivity properties. Beta-lactam intermediate compounds usually are API precursor materials that undergo molecular change or purification before use in the manufacture of beta-lactam antibiotic APIs. As a result of these changes, the intermediate compounds may develop antigenic characteristics that can produce allergic reactions. For example, 6-aminopenicillanic acid (6-APA) serves as the intermediate for the formation of all synthetic penicillins that are formed by attaching various side chains. The structure of 6-APA includes unbroken beta-lactam and thiazolidine rings. The beta-lactam ring is relatively unstable, and it commonly breaks open. In the case of 6-APA, this breakage leads to the formation of a penicilloyl moiety, which is the major antigenic determinant of penicillin. This moiety is thought to be a common cause of penicillin urticarial reaction.[17] Degradation of 6-APA can also result in the formation of minor antigenic determinants, including penicilloic acids, penaldic acid, and penicillamine. Anaphylactic reactions to penicillins usually are due to the presence of IgE antibodies to minor determinants in the body. Although 6-APA is not a true antibiotic, it still carries with it a potential to induce allergenicity.

有些β-内酰胺中间体化合物和衍生物也具有类似的致敏性和交叉反应特性。β-内酰胺中间体化合物通常是原料药前体物料，在制成β-内酰胺抗生素原料药前需要经过分子结构的变化或精制。这些变化可能会使得中间体化合物产生出抗原特性，从而导致过敏反应。例如，6-APA是所有合成青霉素类形成过程中的一个中间体，通过与不同侧链结合来形成青霉素原料药。6-APA的结构包括一个完整的β-内酰胺和四氢噻唑环。β-内酰胺环相对不稳定，通常会断裂打开，在这种情况下，这种环断裂会导致形成一种青霉噻唑基，它是青霉素过敏的主要因子。该基团被认为是青霉素导致荨麻疹反应的常规因素。6-APA的降解还可能形成少量的抗原决定簇，包括青霉噻唑酸、青霉醛酸以及青霉胺。对青霉素的过敏性反应通常是由于体内存在少量的IgE抗体决定簇。尽管6-APA还不是一个真实的抗生素，它还是会具有潜在的致敏诱发性。

Derivatives are unintended by-products that occur during the manufacturing process (i.e., an impurity or degradant). Like intermediates, beta-lactam derivatives could have sensitizing properties and may develop antigenic properties that can produce allergic reactions. Beta-lactam chemical manufacturing processes including, but not limited to, fermentation and synthesis, may create beta-lactam intermediates or derivatives with unknown health consequences. Although the health risk of sensitization and cross-reaction is difficult to predetermine for beta-lactam intermediates and derivatives and is not always well-defined, manufacturing controls intended to reduce the risk of cross-contamination should be considered for operations that produce beta-lactam intermediates or derivatives.

衍生物是生产工艺中产生的无意的副产物（即杂质或降解物）。像中间体一样，β-内酰胺衍生物可能具有致敏特性，可能会发展出抗原特性，从而导致过敏反应。β-内酰胺化学生产过程包括，但不仅限于，发酵和合成，可能会产生出β-内酰胺中间体或衍生物，对健康产生未知后果。尽管β-内酰胺中间体和其衍生物对致敏性和交叉反应的健康风险是很难预测的，并且也从来都没有过很好的界定，但在生产β-内酰胺中间体或衍生物的操作中要考虑降低交叉污染风险的生产控制

Because of the potential health risks associated with cross-reactivity (cross-sensitivity) of beta-lactams, manufacturers should assess and establish stringent controls (including appropriate facility design provisions assuring separation) to prevent cross-contamination. Just as FDA considers the separation of production facilities for penicillins to be current good manufacturing practice, FDA expects manufacturers to treat sensitizing non-penicillin beta-lactam-based products similarly. Specifically, FDA recommends that manufacturers establish appropriate separation and control systems designed to prevent two types of contamination: (1) the contamination of a non-penicillin beta-lactam by any other non-penicillin beta-lactam, and (2) the contamination of any other type of product by a non-penicillin beta-lactam. Accordingly, FDA recommends that the area in which any class of sensitizing beta-lactam is manufactured be separated from areas in which any other products are manufactured, and have an independent air handling system.

由于β-内酰胺潜在的与交叉反应（交叉敏感）相关联的健康风险，生产商应评估并建立严格的控制（包括适当的厂房设计以保证隔离），以防止交叉污染。正如FDA考虑青霉素产品生产厂房隔离以符合现行GMP要求一样，FDA期望生产商以类似方式对待非青类致敏性β-内酰胺产品。FDA特别建议生产商建立适当的隔离和控制体系，设计为可以防止两种类型污染：（1）非青类β-内酰胺被其它非青类β-内酰胺污染；（2）其它类型产品被非青类β-内酰胺污染。相应地，FDA建议任一级别的致敏性β-内酰胺生产区域与其它任何产品生区域分开，并配备相互独立的空调系统。

As with penicillin, the section of a facility dedicated to manufacturing a sensitizing non-penicillin beta-lactam should be isolated (i.e., completely and comprehensively separated) from areas in the facility in which other products are manufactured. This control applies to each of the five classes of sensitizing beta-lactams; the area in which any class of sensitizing beta-lactam is manufactured should be separated from areas in which any other products are manufactured, including any other class of sensitizing beta-lactam. Manufacturing that is restricted to a specific class of beta-lactam compound (e.g., the cephalosporin family of products) generally would not mandate separate facilities and air handling systems, and could permit production campaigning and cleaning as sufficient control.

与青霉素一样，厂房中专用于生产致敏性非青类β-内酰胺的部分应进行隔离（即完全地综合隔离），与生产其它产品的厂房分开。该控制适用于五个级别致敏β-内酰胺，任一级别的致敏β-内酰胺生产区域均应与其它产品生产区域分开，并与其它级别致敏β-内酰胺生产区域分开。如果厂房限用于特定级别β-内酰胺化合物（例如头孢菌素系列产品），通常情况下可以不需要将厂房和空调系统分开，允许以不同产品生产之间的清场作为有效控制手段。

Finally, as discussed above, beta-lactam intermediates and derivatives may induce allergic reactions and therefore pose risks of cross-contamination. Accordingly, firms that manufacture beta-lactam intermediates or receive them for further processing, as well as firms whose manufacturing processes result in beta-lactam derivatives, should evaluate their manufacturing operations for the possibility of cross-contamination and implement appropriate controls to reduce or mitigate the potential for cross-contamination. As with penicillin and non-penicillin beta-lactam drugs, such controls could include, but are not limited to, isolation and separation of intermediate and derivative materials, facilities, equipment, and personnel.

最后，如上所讨论，β-内酰胺中间体及其衍生物可能会导致过敏反应，因此具有交叉污染的风险。相应地，生产β-内酰胺中间体或接收这类产品进行下一步加工的公司，以及生产中会产生β-内酰胺衍生物的公司，应评估其生产操作中会导致交叉污染的风险，并采取适当控制以降低或消除可能的交叉污染。对于青霉素类和非青霉素类β-内酰胺药品，这类控制可能包括，但不限于，将中间体或衍生物料、厂房、设备和人员进行隔离。

[3] See “A Review of Procedures for the Detection of Residual Penicillins in Drugs” (Appendix I, Procedures for Detecting and Measuring Penicillin Contamination in Drugs, FDA By-Lines No. 8 (November 1977)), available athttp://www.fda.gov/downloads/Abo ... CDER/UCM095812.pdf. NB: This link works as of 5/18/2012. 参见“药品中青霉素残留检测方法回顾”，1977年11月，FDA By-lines 第8期，药品中检出和测量青霉素污染的方法附录1，可以在上述网站找到。链接截至2012年5月18日仍有效。

[5] We update guidance documents periodically. To make sure you have the most recent version of a guidance, check the Guidance Page at 我们会定期更新指南文件，为保证你所获得的是最新版本，请核查以下网址http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

[7] Approved beta-lactam antibiotics are listed in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, generally known as the Orange Book (available on the Internet at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm). The Orange Book is searchable by active ingredient and updated as newer drug products are added.

[9] Saxon, A, DC Adelman, A Patel, R Hajdu, and GB Calandra, 1988, Imipenem cross-reactivity with penicillin in humans, J Allergy Clin Immunol, 82:213-217; Saxon, A, GN Beall, AS Rohr, and DC Adelman, 1987, Immediate hypersensitivity reactions to beta-lactam antibiotics, Ann Intern Med, 107(2):204-215; Prescott, Jr., WA, DD DePestel, JJ Ellis, and RE Regal, 2004, Incidence of carbapenem-associated allergic-type reactions among patients with versus patients without a reported penicillin allergy, Clin Infect Dis, 38:1102-1107.

[12] Dayan, AD, 1993, Allergy to antimicrobial residues in food: assessment of the risk to man, Vet Microbiol, 35:213-226; Blanca, M, J Garcia, JM Vega, A Miranda, MJ Carmona et al., 1996, Anaphylaxis to penicillins after non-therapeutic exposure: an immunological investigation, Clin Exp Allergy, 26:335-340.

[14] Perez Pimiento, A, M Gomez Martinez, A Minguez Mena, A Trampal Gonzalez, S de Paz Arranz, and M Rodriguez Mosquera, 1998, Aztreonam and ceftazidime: evidence of in vivo cross-allergenicity, Allergy, 53:624-625; Shepard, GM, 1991, Allergy to B-lactam antibiotics, Immunol Allergy Clin North Am, 11(3):611-633.

[16] Following publication of the draft version of this guidance (76 FR 14024), several commenters suggested that monobactams, specifically aztreonam, have a lower risk profile than other beta-lactam products and therefore should be exempted from the separation and control recommendations set forth in this guidance. We have reviewed relevant scientific and medical literature and determined that the relative risk of cross-reactivity associated with aztreonam, when compared to other beta-lactams, is a matter of scientific uncertainty. Accordingly, at this time, FDA does not recommend manufacturing controls that treat aztreonam differently from other beta-lactam products. As with any non-binding recommendations offered in guidance to industry, manufacturers can use an alternative approach if the alternative approach satisfies the requirements of the applicable statutes and regulations. Manufacturers who wish to discuss an alternative separation and control strategy for a non-penicillin beta-lactam such as aztreonam with FDA are invited to do so through the application submission and review process.