Non-Penicillin Beta-
Lactam Drugs:  A CGMP 
Framework for Preventing 
Cross-Contamination 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Carla Lankford at 301-796-5203.  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2022 
Pharmaceutical Quality/Manufacturing Standards (CGMP) 
Revision 1 
 
15249987dft_NonPenicillinBetaLactam.docx 
06/02/22   
Non-Penicillin Beta-
Lactam Drugs:  A CGMP 
Framework for Preventing 
Cross-Contamination 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2022 
Pharmaceutical Quality/Manufacturing Standards (CGMP) 
Revision 1 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 3 
A.  Regulatory Framework ................................................................................................................. 3 
B.  Beta-Lactam Compounds .............................................................................................................. 4 
1. Beta-Lactam Antibacterial Drugs .................................................................................................... 5 
2. Non-Antibacterial Beta-Lactam Compounds ................................................................................... 6 
a.  Beta-lactamase inhibitors .......................................................................................................... 6 
b.  Beta-lactam intermediates and derivatives ............................................................................... 6 
c.  Other products containing a beta-lactam structure .................................................................... 7 
III.  RECOMMENDATIONS .................................................................................................. 7 
A.  Non-Penicillin Beta-Lactam Antibacterial Drugs ....................................................................... 7 
B.  Non-Antibacterial Beta-Lactam Compounds .............................................................................. 7 
GLOSSARY................................................................................................................................... 9 
REFERENCES ............................................................................................................................ 11 
APPENDIX A:  CHEMICAL STRUCTURES OF REPRESENTATIVE  
BETA-LACTAM COMPOUNDS ............................................................................................. 13 
APPENDIX B: DESIGN FEATURES AND CONTROLS TO PREVENT CROSS-
CONTAMINATION ................................................................................................................... 14 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Non-Penicillin Beta-Lactam Drugs:  
2  A CGMP Framework for Preventing Cross-Contamination 
3  Guidance for Industry1 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION 
18   
19  This guidance describes methods, facility design elements, and controls that are important in 
20  preventing drugs2 from being cross-contaminated with compounds containing a beta-lactam 
21  ring.3  This guidance also provides information regarding the relative health risk of, and the 
22  potential for, cross-reactivity in the classes of non-penicillin beta-lactam antibacterial drugs and 
23  non-antibacterial beta-lactam compounds.4   
24   
25  This guidance recommends complete and comprehensive separation5 of the manufacturing 
26  operations of non-penicillin beta-lactam antibacterial drugs from the manufacturing operations of 
27  other drugs.  For manufacturers of non-antibacterial beta-lactam compounds, this guidance 
28  provides recommendations on cross-contamination prevention strategies, including examples of 
29  relevant design features and control approaches for those seeking to justify a cross-contamination 
30  prevention strategy other than complete and comprehensive separation when appropriate. 
31   
 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research at the Food and Drug Administration.   
 
2 For the purpose of this guidance, the term drugs includes biological products. 
 
3 See Appendix A, Chemical Structures of Representative Beta-Lactam Compounds. 
 
4 For the purposes of this guidance, the term non-penicillin beta-lactam antibacterial drug(s) refers to any drug that 
is not a penicillin, has a chemical structure that includes one or more beta-lactam rings, and has an antibacterial 
mechanism of action.  The term non-antibacterial beta-lactam compound(s) refers to any compound, including an 
intermediate or derivative, that is not a penicillin, has a chemical structure that includes one or more beta-lactam 
rings, and has a mechanism of action other than an antibacterial mechanism of action. 
 
5 See the definition of complete and comprehensive separation in the Glossary. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
32  Penicillin can be a sensitizing agent that triggers hypersensitivity or an allergic reaction in some 
33  people.6  Drug cross-contamination is the contamination of one drug with one or more different 
34  drugs or compounds.  Accordingly, facilities and controls must be designed to prevent cross-
35  contamination of other drugs with penicillin in accordance with the current good manufacturing 
36  practice (CGMP) regulations (i.e., 21 CFR 211.42(d), 21 CFR 211.46(d), and 21 CFR 211.176).  
37  Because non-penicillin beta-lactam antibacterial drugs and non-antibacterial beta-lactam 
38  compounds can also be sensitizing agents, drug cross-contamination with such compounds could 
39  initiate the same types of drug-induced life-threatening allergic reactions that penicillins can 
40  trigger.  Therefore, manufacturers handling any non-penicillin beta-lactam antibacterial drugs or 
41  non-antibacterial beta-lactam compounds should treat such drugs or compounds similarly to 
42  penicillin to prevent cross-contamination, thereby reducing the potential for drug-induced, life-
43  threatening allergic reactions.   
44   
45  The information in this guidance is intended for human drug manufacturers (including finished 
46  pharmaceutical manufacturers, active pharmaceutical ingredient (API) manufacturers, re-
47  packagers, and outsourcing facilities7) with operations that include one or more beta-lactam 
48  compounds.   
49   
50  The contents of this document do not have the force and effect of law and are not meant to bind 
51  the public in any way, unless specifically incorporated into a contract.  This document is 
52  intended only to provide clarity to the public regarding existing requirements under the law.  
53  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
54  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
55  Agency guidance means that something is suggested or recommended, but not required. 
56   
57  This guidance revises the guidance for industry of the same title issued in April 2013.  When 
58  finalized, this guidance will replace the April 2013 guidance.  Significant changes from the 2013 
59  guidance include: 
60   
 
6 The term sensitizing (allergenic) is commonly used in guidances for industry in discussions related to immunology. 
 
7 Section 503B of the Federal Food, Drug, and Cosmetic Act describes the conditions that must be satisfied for drug 
products compounded by a registered outsourcing facility to be exempt from certain statutory requirements.  For the 
purposes of this guidance and for outsourcing facilities only, processing of beta-lactam compounds does not refer to 
mixing, reconstituting, or other such acts performed in accordance with directions contained in the manufacturers 
approved labeling and other manufacturer directions consistent with that labeling at the immediate point of 
dispensing for administration to the intended patient if these limited activities are performed via closed fluid-
pathway, single-use sterile transfer devices under appropriate local containment controls to prevent facility exposure 
to beta-lactam compounds.  Although use of these sterile transfer devices (accomplishing transfers through the use 
of needles and needleless connectors) greatly mitigates risk of lost containment while preparing a drug in 
accordance with labeled directions, it is possible that breakage or spillage of the content of a pharmacy bulk package 
occurs.  To prevent the risk of facility (e.g., surfaces, air) and product contamination with beta-lactam compounds, 
the outsourcing facility should have in place additional containment strategies, including restricting all preparation 
activities to only dedicated isolators, barrier units, or containment hoods to strictly localize any potential exposure.  
Use of appropriate procedures is also essential, including employing detailed steps for managing any localized 
aerosolization from a breakage/spillage incident by immediate and thorough decontamination with beta-lactam 
inactivating cleaning agent(s).  The containment and decontamination procedures should be validated for their 
intended purposes of strictly preventing cross-contamination with beta-lactam compounds.    
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
61    Clarifying that the scope of the guidance also includes all compounds, including 
62  intermediates or derivatives, that are not a penicillin, have a chemical structure that 
63  includes one or more beta-lactam rings, and have a mechanism of action other than an 
64  antibacterial mechanism of action 
65   
66    Providing FDAs interpretation of terms, such as allergic reaction, cross-reactivity, and 
67  complete and comprehensive separation, used in this guidance 
68   
69    Clarifying the distinction between non-penicillin beta-lactam antibacterial drug(s) and 
70  non-antibacterial beta-lactam compound(s)  in terms of the cross-contamination and 
71  patient exposure risks and the strategies appropriate for manufacturing operations 
72  involving each category 
73   
74    Providing recommendations for drug manufacturers that seek to justify alternative cross-
75  contamination prevention strategies for non-antibacterial beta-lactam compounds   
76   
77   
78  II.  BACKGROUND 
79   
80  A.  Regulatory Framework 
81   
82  Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)) 
83  requires that drugs (including APIs) be manufactured in compliance with CGMP.  Drugs that are 
84  not manufactured in compliance with CGMP are considered adulterated.  Furthermore, 
85  manufacturers of finished pharmaceuticals are required to comply with the CGMP regulations at 
86  21 CFR parts 210 and 211.  
87    
88  Several CGMP requirements for finished pharmaceuticals address facility and equipment design, 
89  controls, and cleaning.  For example, regarding design and construction features,  211.42(c) 
90  requires building and facility provisions in general to prevent cross-contamination of drug 
91  products.  Specifically, the regulation states that [t]here shall be separate or defined areas or 
92  such other control systems for the firms operations as are necessary to prevent contamination or 
93  mixups . . . .  
94   
95  With respect to penicillin,  211.42(d) requires that [o]perations relating to the manufacture, 
96  processing, and packing of penicillin shall be performed in facilities separate from those used for 
97  other drug products for human use. 8   
98   
99  Similarly,  211.46(d) requires air-handling systems for the manufacture, processing, and 
100  packing of penicillin to be completely separated from those for other drugs for human use.  
101  Additionally,  211.176 requires manufacturers to test non-penicillin drug products for penicillin 
 
8 See the definition of complete and comprehensive separation in the Glossary. 
 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
102  where the possibility of cross-contamination exists and prohibits manufacturers from marketing 
103  such drugs if detectable levels of penicillin are found.9  
104   
105  Although FDA has not issued CGMP regulations specific to APIs, section 501(a)(2)(B) of the 
106  Federal Food, Drug, and Cosmetic Act requires all drugs (including APIs) to be manufactured in 
107  compliance with CGMP.  FDA recommends that drug manufacturers follow the International 
108  Council for Harmonisation (ICH) guidance for industry Q7 Good Manufacturing Practice 
109  Guidance for Active Pharmaceutical Ingredients (September 2016).10  Because some APIs are 
110  sensitizing compounds that may cause anaphylactic reactions, preventing cross-contamination in 
111  APIs is as important as preventing cross-contamination in finished drug products.  Accordingly, 
112  ICH Q7 recommends using dedicated production areas, which can include facilities, air handling 
113  equipment, and processing equipment, in the production of highly sensitizing materials, such as 
114  penicillins and non-penicillin beta-lactam antibacterial drugs like cephalosporins.11 
115   
116  B.  Beta-Lactam Compounds 
117   
118  Beta-lactam antibacterial drugs, including penicillin and the non-penicillin classes, share a basic 
119  chemical structure that includes a three-carbon, one-nitrogen cyclic amide structure known as the 
120  beta-lactam ring.  The side chain associated with the beta-lactam ring is a variable group that 
121  contributes to antibacterial activity.  (Appendix A shows the chemical structures of some beta-
122  lactam compounds.)    
123   
124  The beta-lactam ring and side chains are also responsible for the allergenic properties of beta-
125  lactam antibacterial drugs.  These structures can induce the formation of antigenic determinants 
126  that lead to the production of specific immunoglobulin E (IgE) antibodies that can induce Type 1 
127  hypersensitivity (allergic) reactions in susceptible individuals.   
128   
129  There are compounds other than beta-lactam antibacterial drugs that contain the beta-lactam ring.  
130  Some of these compounds are derivatives and intermediates used or produced in the manufacture 
131  of beta-lactam drugs.  Some beta-lactamase inhibitors contain a beta-lactam ring, as do some 
132  drugs that have no antibacterial activity, such as certain lipid-lowering and antiviral drugs.   
133   
134  Like beta-lactam antibacterial drugs, non-antibacterial compounds containing a beta-lactam ring 
135  could have similar sensitizing and allergenic properties and may pose a significant health risk to 
136  patients.  For many beta-lactam compounds the immunopathological mechanisms leading to 
137  cross-reactivity and hypersensitivity reactions have not been studied extensively or are not well 
138  understood.  This, and the combined effect of multiple variables (e.g., dosage forms, patient 
 
9 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)).  Alternative 
validated test methods to detect penicillin residues may be used if demonstrated to be equivalent to or better than the 
referenced method.  For example, the LC-MS/MS method has been validated for detecting several beta-lactam 
compounds, and could be validated for detecting others as well (Qiu et al. 2018). 
  
10 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
11 See section IV.D Containment (4.4) of ICH Q7. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
139  history of sensitization, differences in pharmacokinetics), make it difficult to determine the 
140  sensitizing potential of many beta-lactam compounds.  Nevertheless, the potential life-
141  threatening hazard associated with beta-lactam compounds indicates that manufacturers should 
142  establish beta-lactam manufacturing operations that are completely and comprehensively 
143  separate from those of other drugs, to prevent cross-contamination. 
144   
145  1.  Beta-Lactam Antibacterial Drugs 
146   
147  Currently, beta-lactam antibacterial drugs include:  
148   
149    Penicillins (e.g., ampicillin, oxacillin)  
150    Cephalosporins (e.g., cephalexin, cefaclor)  
151    Penems (e.g., imipenem, meropenem)  
152    Monobactams (e.g., aztreonam) 
153   
154  Beta-lactam antibacterial drugs display properties of cross-reactivity, in which the secondary 
155  exposure need not be to the same compound.  For example, patients with a history of 
156  hypersensitivity to a drug in one of the above classes, for example penicillin, may also 
157  experience an IgE-mediated reaction to a drug in another class, such as cephalosporins and 
158  penems (Saxon et al. 1988; Saxon et al. 1987; Prescott et al. 2004).  
159   
160  Although the frequency of allergic reactions due to cross-reactivity between beta-lactam classes 
161  can be lower than the risk within a class (Salkind et al. 2001), the hazard posed still may be life-
162  threatening (Khan and Solensky 2010).  Further similarities between non-penicillin beta-lactam 
163  antibacterial drugs and penicillins are as follows: 
164   
165    It is difficult to define the minimal dose below which allergic responses are unlikely to 
166  occur in humans (Dayan 1993; Blanca et al. 1996)  
167   
168    There is a lack of suitable animal or receptor testing models that are predictive of human 
169  sensitivity (Olson et al. 2000)  
170   
171    The threshold dose at which allergenic response could occur is extremely low and 
172  difficult to detect with commonly used analytical methods (Perez Pimiento et al. 1998; 
173  Shepard 1991) 
174   
175  Although beta-lactam antibacterial drugs may be chemically similar, they can differ in 
176  pharmacokinetics, antibacterial activity, and the potential to cause serious allergic reactions 
177  (Bernstein et al. 2008).  It is clinically difficult to determine the occurrence and rate of allergic 
178  cross-reactivity among beta-lactam antibacterial drugs in humans.  Therefore, undiagnosed or 
179  underreported cases of cross-reactivity may exist.  Some beta-lactam antibacterial drugs may 
180  have negligible potential for cross-reactivity with beta-lactam antibacterial drugs of other classes, 
181  whereas beta-lactam derivatives may potentially exhibit sensitizing activity before the 
182  incorporation of side chains that confer antibacterial activity.  Regardless of the rate of cross-
183  reactivity among beta-lactam antibacterial drugs or the mechanism of action by which such 
184  cross-reactivity may occur, a potential health risk to patients  life-threatening anaphylaxis  
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185  can result from cross-contamination among all classes of drugs and compounds containing a 
186  beta-lactam ring.12 
187   
188  2.  Non-Antibacterial Beta-Lactam Compounds 
189   
190  a.  Beta-lactamase inhibitors 
191   
192  Beta-lactam compounds such as clavulanic acid, tazobactam, and sulbactam are irreversible 
193  inhibitors of many beta-lactamases.  These compounds, which are potential sensitizing agents, 
194  are typically used in combination with specific beta-lactam compounds to reduce degradation 
195  and preserve antibacterial activity (e.g., amoxicillin-clavulanate, piperacillin-tazobactam).  
196  Because beta-lactamase inhibitors typically are used in combination with specific beta-lactam 
197  antibacterial drugs, clinical observations of hypersensitivity reactions may be attributed to the 
198  beta-lactam antibacterial component rather than to the beta-lactamase inhibitor.  Yet 
199  hypersensitivity reactions to clavulanic acid are reported in the literature, sometimes in the 
200  absence of a hypersensitivity reaction to the co-administered beta-lactam antibacterial drug, 
201  amoxicillin (Salas et al. 2017). 
202   
203  b.  Beta-lactam intermediates and derivatives 
204   
205  Some beta-lactam intermediate compounds and derivatives possess similar sensitization and 
206  cross-reactivity properties to those of beta-lactam compounds.  Beta-lactam intermediate 
207  compounds usually are precursor materials that undergo molecular change or purification before 
208  they are used in the manufacture of beta-lactam APIs.  As a result of these molecular changes, 
209  intermediate compounds containing a beta-lactam ring in their structures may be recognized by 
210  the immune system as an antigen that triggers an allergic response.  For example, 6-
211  aminopenicillanic acid (6-APA) serves as the intermediate for the formation of all synthetic 
212  penicillins that are formed by attaching various side chains.  The structure of 6-APA includes 
213  beta-lactam and thiazolidine rings.  The beta-lactam ring is relatively unstable and can open.  In 
214  the case of 6-APA, the opening of the beta-lactam ring leads to the formation of a penicilloyl 
215  moiety, which is the major antigenic determinant of penicillin.  This moiety is thought to be a 
216  common cause of penicillin urticarial reaction (Celik et al. 2008).   
217   
218  Beta-lactam derivatives are by-products that may arise during manufacturing (i.e., an impurity or 
219  degradant) that include a beta-lactam ring structure.  Like intermediates, beta-lactam derivatives 
220  could have sensitizing properties and may develop antigenic properties that can produce allergic 
221  reactions.  Beta-lactam manufacturing processes (e.g., fermentation and synthesis) may create 
222  beta-lactam intermediates or derivatives with unknown health consequences.   
 
12 After reviewing relevant scientific and medical literature, FDA determined that the relative risk of cross-reactivity 
associated with aztreonam, when compared to other beta-lactams, is a matter of scientific uncertainty.  Recently 
there is an increased body of evidence in published scientific literature describing that patients with ceftazadine 
hypersensitivity can experience cross-reactivity to aztreonam.  Accordingly, this guidance does not recommend 
manufacturing controls that treat aztreonam differently from other beta-lactam drugs.  As with any nonbinding 
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 should discuss with 
FDA as early as possible about alternative separation designs and control strategies for a non-penicillin beta-lactam 
monobactam, such as aztreonam. 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
223   
224  c.  Other products containing a beta-lactam structure  
225   
226  As discussed above, compounds containing a beta-lactam ring have a sensitizing potential, and 
227  subsequent exposure to those compounds or related compounds due to cross-contamination may 
228  result in severe allergic reactions in some patients.  Therefore, manufacturers should manage the 
229  risk of cross-contamination throughout the products life cycles, not only non-penicillin beta-
230  lactam antibacterial drugs, but also products with no antibacterial activity that may be potential 
231  sources of a beta-lactam ring (e.g., degradants that contain a beta-lactam ring even though the 
232  parent compound may not).   
233   
234   
235  III.  RECOMMENDATIONS  
236   
237  Because of the potential health risks of cross-reactivity and hypersensitivity reactions associated 
238  with beta-lactam compounds, manufacturers risk management strategies should include 
239  stringent controls to prevent cross-contamination.   
240   
241  The risks associated with the cross-reactivity of beta-lactam antibacterial drugs have been 
242  described (Terico and Gallagher 2014; Joint Task Force on Practice Parameters 2010; Celik et al. 
243  2008); however, the risks associated with the cross-reactivity of non-antibacterial beta-lactam 
244  compounds are less well understood.  Accordingly, FDA addresses beta-lactam antibacterial 
245  drugs and non-penicillin beta-lactam compounds separately in this guidance.  Specific 
246  recommendations for beta-lactam antibacterial drugs and non-antibacterial beta-lactam 
247  compounds are further detailed below. 
248   
249  A.  Non-Penicillin Beta-Lactam Antibacterial Drugs 
250   
251  The manufacturing operations of any class of non-penicillin beta-lactam antibacterial drugs 
252  should be completely and comprehensively separated from areas in which any other drugs for 
253  human use are manufactured, including any other class of beta-lactam antibiotics.  This 
254  separation includes independent air handling systems.  Manufacturing operations that are 
255  restricted solely to products within a specific class of non-penicillin beta-lactam antibacterial 
256  drugs (e.g., cephalosporins) generally would not mandate separate facilities and air handling 
257  systems for each of those products; production campaigning in the same facility and appropriate 
258  cleaning (including qualification to demonstrate removal of beta-lactams) after each campaign 
259  may be sufficient to prevent cross-contamination. 
260   
261  B.  Non-Antibacterial Beta-Lactam Compounds 
262   
263  As with non-penicillin beta-lactam antibacterial drugs, non-antibacterial beta-lactam compounds 
264  have the potential to induce allergic reactions.  Similar difficulties exist in characterizing and 
265  quantifying the potential health risks posed by non-antibacterial beta-lactam compounds (i.e., 
266  defining the minimal dose below which allergic responses are unlikely to occur in humans, lack 
267  of suitable animal or receptor testing models predictive of human sensitivity, and the likelihood 
268  that the threshold dose for human allergenic response could be extremely low and difficult to 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
269  detect with current analytical methods).  Nevertheless, consideration should be given to the 
270  potential health risks that may be life-threatening.  Thus, when there is uncertainty regarding the 
271  risks associated with non-antibacterial beta-lactam compounds, or there is a known risk of 
272  adverse effect in patients, FDA recommends that drug manufacturers implement a complete and 
273  comprehensive separation cross-contamination prevention strategy, as is recommended for non-
274  penicillin beta-lactam antibacterial drugs, to prevent beta-lactam cross-contamination.   
275   
276  However, there may be conditions under which manufacturers may justify the use of alternative 
277  cross-contamination prevention strategies for certain non-antibacterial beta-lactam compounds.13  
278  For example, non-antibacterial beta-lactam compounds can have widely varying molecular 
279  structures, and there may be cases where direct studies have shown no incidence of, or 
280  exceedingly low potential for, adverse events involving hypersensitivity or allergic reactions in 
281  patients.  In such cases, if a manufacturer considers a prevention strategy other than complete 
282  and comprehensive separation to suffice, robust data to support no incidence or a clear threshold 
283  below which adverse reactions are exceedingly unlikely to occur should be available for FDA 
284  assessment.  An extensive body of data to evaluate this potential approach can include in vitro 
285  data, animal studies, clinical studies,14 experience with related products, and published scientific 
286  literature.  Manufacturers should use appropriate risk management tools to assess the risks and to 
287  design and implement prevention strategies that prevent cross-contamination and mix-ups.  This 
288  would include consideration of a combination of rigorous facility design, segregation, process, 
289  and procedural controls, and ongoing life cycle risk review.15  Examples of such design and 
290  controls provisions are provided in Appendix B.  
291   
 
13 See the definition of control strategy in the Glossary. 
 
14 If a clinical investigation is necessary to demonstrate the safety or effectiveness of a proposed drug product, 
generally this type of study goes beyond the scope of information that may be relied upon as necessary for approval 
of an abbreviated new drug application. 
 
15 Consideration of alternative cross-contamination prevention strategies will be subject to assessment by FDA, on a 
case-by-case basis, at the time of application review. 
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292  GLOSSARY 
293   
294  Allergic reaction:  An immunologic reaction experienced by an individual to a drug or 
295  compound mediated by a number of mechanisms, including, for example, IgE-mediated 
296  activation of mast cells and basophils; direct activation of mast cells and basophils; sensitized T-
297  cell-induced inflammation; complement activation; contact system activation; or coagulation 
298  system activation.  In any given patient, exposure to a drug or compound may trigger an allergic 
299  reaction caused by more than one mechanism.  Allergic reactions may be life-threatening events, 
300  such as anaphylaxis and other syndromes associated with cardiovascular collapse and death. 
301   
302  Complete and comprehensive separation:  A cross-contamination prevention strategy that 
303  consists of:  (1) the complete physical separation of beta-lactam production area(s) (including 
304  separate air handling system(s)) from production areas for other drugs; and (2) additional design 
305  and procedural controls for facilities, equipment, material, and personnel that are necessary to 
306  support and maintain the integrity of the physical separation (e.g., dedicated equipment; utilities 
307  management (waste flow, including the potential for beta-lactam production exhaust to 
308  contaminate an adjacent building air intake, vacuum systems); people/material/equipment flow; 
309  personnel gowning, decontamination; monitoring containment; testing; compliance with 
310  procedures; investigations).  It is required by regulation for penicillin manufacturing, including 
311   211.42(d):  separation of facility and equipment, and  211.46(d):  separate air handling 
312  systems, and it is recommended to prevent cross-contamination with other non-penicillin and 
313  non-antibacterial beta-lactam drugs and compounds.  The essential element and foundation of 
314  this strategy is complete physical separation (i.e., isolation and sealing off) as described in 
315  paragraph 142 of the preamble to the final rule, Current Good Manufacturing Practice in 
316  Manufacture, Processing, Packing, or Holding (43 FR 45014 at 45038, September 29, 1978):  
317   
318  Separation can be achieved . . . by effectively isolating and sealing off from one another 
319  these two types of operations.  This does not necessarily mean separation by geographical 
320  distance or the placement of these operations in separate buildings.  Effective means can 
321  almost certainly be developed to separate such activities from one another to prevent 
322  cross-contamination problems within a single building. 
323   
324  In other words, although separate buildings would ensure separation of beta-lactam operations 
325  from non-beta-lactam operations, it is feasible for one building to contain a dedicated area for 
326  beta-lactam manufacturing that is completely isolated and sealed off from the rest of the 
327  building.  For example, separate entries and exits to the beta-lactam segment of the building 
328  would be necessary to ensure comprehensive separation.  In the limited cases in which this 
329  design concept could be considered, a risk assessment should demonstrate that the design 
330  provides as much protection against cross-contamination as is achieved by manufacturing in a 
331  separate building. 
332   
333  Control strategy:  As defined in the ICH guidances for industry Q8(R2) Pharmaceutical 
334  Development (November 2009), Q10 Pharmaceutical Quality System (April 2009), and Q11 
335  Development and Manufacture of Drug Substances (November 2012), a control strategy is 
336  established through use of quality risk management and consists of a planned set of controls that 
337  ensure process performance and product quality.  These controls can be related to facility and 
  9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
338  equipment operating conditions, monitoring and testing of incoming materials, process 
339  performance and product quality, and personnel following procedures.   
340   
341  As stated above, complete and comprehensive separation is itself both a facility design strategy 
342  and a control strategy for preventing beta-lactam cross-contamination.  In the sense that the 
343  strategy consists of complete segregation of manufacturing operations, it is unique among cross-
344  contamination prevention strategies, distinguished from those alternative strategies that would 
345  be employed in shared or multiuse facilities.  Alternative strategies rely primarily on design and 
346  procedural controls involving facilities, equipment, material, and personnel, and do not 
347  necessarily include the physical separation of manufacturing areas.   
348   
349  Cross-reactivity:  The process by which a compound induces a hypersensitivity immune 
350  response, such as an allergic reaction, due to the sensitizing effects of a prior exposure to a 
351  different, but chemically related, antigen.  Also referred to as cross-sensitivity or cross-
352  sensitization. 
353   
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Draft  Not for Implementation 
354  REFERENCES 
355   
356  Bernstein, IL, J Li, DI Bernstein, R Hamilton, SL Spector, R Tan, S Sicherer, DBK Golden, DA 
357  Khan, RA Nicklas, JM Portnoy, J Blessing-Moore, L Cox, DM Lang, J Oppenheimer, CC 
358  Randolph, DE Schuller, SA Tilles, DV Wallace, E Levetin, and R Weber, 2008, Allergy 
359  Diagnostic Testing:  An Updated Practice Parameter, Annals of Allergy, Asthma & 
360  Immunology, 100:S1S148. 
361   
362  Blanca, M, J Garcia, JM Vega, A Miranda, MJ Carmona, C Mayorga, F Moreno, and C Juarez, 
363  1996, Anaphylaxis to Penicillins After Non-Therapeutic Exposure:  An Immunological 
364  Investigation, Clin Exp Allergy, 26:335340. 
365   
366  Celik, G, WJ Pichler, and NF Adkinson Jr, 2008, Chapter 68:  Drug Allergy.  In:  NF Adkinson 
367  Jr, B Bochner, W Busse, S Holgat, R Lemanske, FE Simons, editors, Middletons Allergy:  
368  Principles and Practice, 7th edition, Philadelphia:  Mosby Elsevier, 12051226. 
369   
370  Dayan, AD, 1993, Allergy to Antimicrobial Residues in Food:  Assessment of the Risk to Man, 
371  Vet Microbiol, 35:213226.  
372   
373  Joint Task Force on Practice Parameters, 2010, Drug Allergy:  An Updated Practice Parameter, 
374  Annals of Allergy, Asthma & Immunology, R Solensky, DA Khan, editors, Vol. 105(4):259
375  273. 
376   
377  Khan, D and R Solensky, 2010, Drug Allergy, J Allergy Clin Immunol, 125(2):S131. 
378   
379  Olson, H, G Betton, D Robinson, K Thomas, A Monro, G Kolaja, P Lilly, J Sanders, G Sipes, 
380  W Bracken, M Dorato, K Van Deun, P Smith, B Berger, and A Heller, 2000, Concordance of the 
381  Toxicity of Pharmaceuticals in Humans and in Animals, Regul Toxicol Pharmacol, 32:5667. 
382   
383  Perez Pimiento, A, M Gomez Martinez, A Minguez Mena, A Trampal Gonzalez, S de Paz 
384  Arranz, and M Rodriguez Mosquera, 1998, Aztreonam and Ceftazidime:  Evidence of In Vivo 
385  Cross-Allergenicity, Allergy, 53:624625.  
386   
387  Prescott, WA, DD DePestel, JJ Ellis, and RE Regal, 2004, Incidence of Carbapenem-Associated 
388  Allergic-Type Reactions Among Patients With Versus Patients Without a Reported Penicillin 
389  Allergy, Clin Infect Dis, 38:11021107. 
390   
391  Qiu, C, H Zhu, C Ruzicka, D Keire, and H Ye, 2018, A General LC-MS/MS Method for 
392  Monitoring Potential -Lactam Contamination in Drugs and Drug-Manufacturing Surfaces, 
393  AAPS J, 20:70, doi.org/10.1208/s12248-018-0224-7. 
394   
395  Salas, M, JJ Laguna, I Dona, E Barrionuevo, R Fernandez-Santamaria, A Ariza, E Perez-
396  Inestrosa, C Mayorga, TD Fernandez, and MJ Torres, 2017, Patients Taking Amoxicillin-
397  Clavulanic Can Become Simultaneously Sensitized to Both Drugs, J Allergy Clin Immunol 
398  Pract, 5(3):694702. 
399   
  11  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
400  Salkind, AR, PG Cuddy, and JW Foxworth, 2001, Is This Patient Allergic to Penicillin?  An 
401  Evidence-Based Analysis of the Likelihood of Penicillin Allergy, JAMA, 285:24982505. 
402   
403  Saxon, A, DC Adelman, A Patel, R Hajdu, and GB Calandra, 1988, Imipenem Cross-Reactivity 
404  With Penicillin in Humans, J Allergy Clin Immunol, 82:213217.  
405   
406  Saxon, A, GN Beall, AS Rohr, and DC Adelman, 1987, Immediate Hypersensitivity Reactions to 
407  Beta-Lactam Antibiotics, Ann Intern Med, 107(2):204215.  
408   
409  Shepard, GM, 1991, Allergy to B-Lactam Antibiotics, Immunol Allergy Clin North Am, 
410  11(3):611633. 
411   
412  Terico, AT and JC Gallagher, 2014, Beta-Lactam Hypersensitivity and Cross-Reactivity, Journal 
413  of Pharmacy Practice, Vol. 27(6) 530544.  
414   
415   
  12  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
416  APPENDIX A:  CHEMICAL STRUCTURES OF 
417  REPRESENTATIVE BETA-LACTAM COMPOUNDS 
418   
419  The beta-lactam ring (shown in red on the figures below) can result in widely varying molecular 
420  structures having a sensitizing potential.  Cross-contamination occurring during the manufacture 
421  of any of these compounds could pose a potentially life-threatening health risk to patients. 
422   
423   
424 
  13  Contains Nonbinding Recommendations 
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425  APPENDIX B:   
426  DESIGN FEATURES AND CONTROLS TO  
427  PREVENT CROSS-CONTAMINATION1 
428   
429  When considering alternative strategies to prevent cross-contamination with non-antibacterial 
430  beta-lactam compounds, the appropriate combination of controls depends on various factors such 
431  as the state of material (e.g., liquid, powder), stage of manufacturing (e.g., incoming sampling, 
432  blending, filling and sealing), and the dosage form.2  Design features and control approaches that 
433  manufacturers should consider implementing to prevent cross-contamination include, but are not 
434  limited, to:  
435   
436    Integration of a series of design provisions and controls to form a robust holistic 
437  contamination prevention system, rather than implementing controls in a piecemeal 
438  fashion, or relying on one single design or control element. 
439   
440    Use of closed systems, such as an isolator with its own air handling system, and the use 
441  of adequate dust control removal systems from exhaust air from rooms and use of air 
442  purification systems such as the use of high-efficiency particulate air filters (or better) on 
443  exhaust ducts. 
444   
445    Separation and containment of different manufacturing processes or process steps; use of 
446  barrier technology, including glove boxes. 
447   
448    Maintaining adequate pressure differentials, in tandem with use of airlocks, between 
449  areas manufacturing non-antibacterial beta-lactam compounds and those manufacturing 
450  non-beta-lactam drugs. 
451   
452    Segregated suite of rooms and other facility design features to create redundancy of 
453  separation.  
454   
455    Use of dedicated equipment and air systems.  
456   
457    Establishing rigorous and validated monitoring, cleaning, and decontamination 
458  procedures including routine verification surface testing using appropriate acceptance 
 
1 This appendix is intended as a resource for developing alternative facility design and control strategies for 
preventing cross-contamination involving non-antibacterial beta-lactam manufacturing operations.  Some of the 
measures discussed could also be part of a strategy involving complete and comprehensive separation that should be 
used to prevent cross-contamination involving non-penicillin beta-lactam antibacterial manufacturing operations.  
 
2 As an example, see ISPE (International Society for Pharmaceutical Engineering) Baseline Guide Volume 7, Risk-
Based Manufacture of Pharmaceutical Products (2010) for additional discussions about sources of cross-
contamination, procedures for assessing risks associated with cross-contamination, and strategies  including 
analyses of options for manufacturing controls  for mitigating this risk. 
  14  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
459  criteria for residual levels of the specific non-antibacterial beta-lactam compound.  
460  Modern methods with appropriate levels of sensitivity should be used.3  
461   
462    Use of measures to deactivate the beta-lactam ring structure (i.e., breaking the ring) to 
463  further reduce the risk of cross-contamination from residual beta-lactam levels that could 
464  be present below the limit of detection of analytical methods.  
465   
466    Dedicated personnel and control of material and personnel movement (e.g., staff entries 
467  and exits). 
468   
469    Procedures for maintenance personnel and contractors regarding garment and 
470  decontamination controls if they are working in, and moving between, multiple areas 
471  where beta-lactams may be present. 
472   
473    Strict controls over cross-over points for personnel, products, waste, materials, and 
474  equipment. 
475   
476    Examination and testing of environment for potential cross-contamination routes. 
477   
478    Quality control testing of non-beta-lactam drugs for potential beta-lactam contamination 
479  at adequate detection levels at stages of manufacturing determined by a risk assessment 
480  to be susceptible to cross-contamination; however, testing for the presence of beta-
481  lactams in drugs or the manufacturing environment is not a substitute for adequate 
482  control systems. 
483   
484    Procedural controls to prevent mix-ups of materials and products. 
485   
486    Risk assessment of changes in manufacturing products/processes, introduction of new 
487  products, and procedures in the event of a breach of controls. 
488   
489  If a reasonable possibility exists that a non-beta-lactam drug has been cross-contaminated with a 
490  non-antibacterial beta-lactam compound, the non-beta-lactam drug(s) should be tested for the 
491  presence of beta-lactam and should not be marketed if detectable levels are found. 
492   
 
3 C Qiu, H Zhu, C Ruzicka, D Keire, and H Ye, 2018, A General LC-MS/MS Method for Monitoring Potential -
Lactam Contamination in Drugs and Drug-Manufacturing Surfaces, AAPS J, 20(4):70, published May 15, 2018, 
doi:10.1208/s12248-018-0224-7. 
  15