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)
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`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)
`
`
`
`
`
`
`
`
`
` P. 2
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`UT Ex. 2047
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`TABLE OF CONTENTS
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`
`
`INTRODUCTION....................................................................................................................1
`I.
`II. BACKGROUND ......................................................................................................................2
`III. RECOMMENDATIONS.........................................................................................................7
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`Guidance for Industry1
`
`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.
`
`
`
`INTRODUCTION
`
`I.
`
`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.
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`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.
`
`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 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
`
`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).
`
` 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.
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`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
`
` 9
`
` 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.
`
`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.
`
` 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
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`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
`
`
`
`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:
`
`
`
`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.
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`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
`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.
`
`
`
`
`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 Middleton’s Allergy: Principles and Practice,7th ed. (electronic) (2009). Chapter 68: Drug Allergy.
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`Contains Nonbinding Recommendations
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`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.
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`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.
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