Guidance for Industry 
 
 
Non-Penicillin Beta-Lactam 
Drugs: 
A CGMP Framework for 
Preventing Cross-
Contamination
 
   
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
April 2013 
Current Good Manufacturing Practices (CGMPs)   
Guidance for Industry 
 
 
Non-Penicillin Beta-Lactam 
Drugs:  
A CGMP Framework for 
Preventing Cross-
Contamination 
 
 
 
 
 
Additional copies are available from: 
Office of Communications  
Division of Drug Information, WO51, Room 2201 
 Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave.  
Silver Spring, MD 20993-0002  
Phone: 301-796-3400; Fax: 301-847-8714  
druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
April 2013 
Current Good Manufacturing Practices (CGMP) 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION....................................................................................................................1 
II.   BACKGROUND......................................................................................................................2 
III.  RECOMMENDATIONS.........................................................................................................7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  i Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
 
Non-Penicillin Beta-Lactam Drugs:  
A CGMP Framework for Preventing Cross-Contamination 
 
 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance. 
 
 
 
I.  INTRODUCTION 
 
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.   
 
The information in this guidance is intended for manufacturers of finished pharmaceuticals and 
APIs, including repackagers.  Other establishments that handle drugs, such as pharmacy 
compounders, may find this information useful.  
                                                 
1 This guidance was developed by the Office of Compliance, Office of Manufacturing and Product Quality, in the 
Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.   
    1 Contains Nonbinding Recommendations 
 
  
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidance documents describe the Agencys 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. 
 
II.   BACKGROUND 
 
A.  Regulatory Framework 
 
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.  
  
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 firms 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  
 
Although FDA has not issued CGMP regulations specific to APIs, the Agency has provided 
guidance to API manufacturers in the guidance for industry, ICH4 Q7, Good Manufacturing 
                                                 
2 Preamble to the final rule, Current Good Manufacturing Practice, Processing, Packing, or Holding. 43 FR 45014 
at 45038 (September 29, 1978). 
 
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 at 
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM095812.pdf.  NB: This link works as of 
5/18/2012. 
  
4 International Conference on Harmonization. 
 
    2 Contains Nonbinding Recommendations 
 
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 
 
 
B.  Beta-Lactam Antibiotics 
 
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 
classes8:  
 
  penicillins (e.g., ampicillin, oxacillin)  
  cephalosporins (e.g., cephalexin, cefaclor)  
  penems (e.g., imipenem, meropenem)  
  carbacephems (e.g., loracarbef)  
  monobactams (e.g., aztreonam) 
   
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   
                                                 
5 We update guidance documents periodically.  To make sure you have the most recent version of a guidance, check 
the Guidance Page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  
6 See section IV.D Containment (4.4) of the ICH Q7 guidance. 
 
7 Approved beta-lactam antibiotics are listed in FDAs 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. 
   
8 Yao, JDC, and RC Moellering, Jr., Antibacterial agents, in Manual of Clinical Microbiology, 9th edition, edited by 
PR Murray et al., Washington D.C., ASM Press, 2007. 
 
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 
    3 Contains Nonbinding Recommendations 
 
 
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 present11 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: 
 
  It is difficult to define the minimal dose below which allergic responses are unlikely to 
occur in humans. 12  
  There is a lack of suitable animal or receptor testing models that are predictive of human 
sensitivity. 13  
  The threshold dose at which allergenic response could occur is extremely low and 
difficult to detect with current analytical methods.14 
 
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.   
 
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 
_______________________ 
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.  
 
10 Salkind, AR, PG Cuddy, and JW Foxworth, 2001, Is this patient allergic to penicillin? An evidence-based analysis 
of the likelihood of penicillin allergy, JAMA, 285:2498-2505. 
 
11 Khan, D. and R Solensky , 2010, Drug Allergy, J Allergy Clin Immunol. 125(2): S131. 
 
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. 
 
13 Olson, H, G Betton, D Robinson, K Thomas, A Monro et al., 2000, Concordance of the toxicity of 
pharmaceuticals in humans and in animals, Regul Toxicol Pharmacol, 32:56-67. 
 
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. 
 
15 Bernstein, IL, JT Li, DI Bernstein, et al., 2008, Allergy diagnostic testing: an updated practice parameter, Ann 
Allergy Asthma Immunol, 100:S1-S148. 
 
    4 Contains Nonbinding Recommendations 
 
manufacturers should take steps to control for the risk of cross-contamination for all beta-lactam 
products.16 
 
C.  Beta-Lactamase Inhibitors 
 
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. 
 
D.  Beta-Lactam Intermediates and Derivatives 
 
Some beta-lactam intermediate compounds and derivatives also possess similar sensitization and 
crossreactivity 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.   
 
                                                 
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. 
 
17 Middletons Allergy: Principles and Practice,7th ed. (electronic) (2009). Chapter 68: Drug Allergy.  
    5 Contains Nonbinding Recommendations 
 
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.
    6 Contains Nonbinding Recommendations 
 
III.  RECOMMENDATIONS  
 
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.    
 
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. 
 
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. 
    
    7