FDA Releases Draft Guidance and Urges Industry to Address Concerns Regarding Non-Penicillin Beta-Lactam Drugs Cross-Contamination

Background

This original guidance released by FDA in April 2013 describes the importance of implementing manufacturing controls for manufacturers and repackagers to prevent cross-contamination of finished pharmaceuticals and active pharmaceutical ingredients (APIs) with nonpenicillin beta-lactam drugs.

The 2013 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 penicillin and nonpenicillin beta-lactams).

Finally, the 2013 guidance clarifies that manufacturers generally should use separate facilities for the manufacture of nonpenicillin 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. It is important to note that penicillin can be a sensitizing agent that triggers a hypersensitive allergic immune response in some people. Therefore, the agency has recommended, in line with current regulations, the implementation of methods for preventing cross-contamination of other drugs with penicillin. See, for example, 21 CFR §§ 211.42(d), 211.46(d), and 211.176 and ICH Q7 “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients.”

Significant Changes

FDA announced the availability of a draft guidance titled “Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination” dated June 23, 2022.² This guidance revises the final guidance of the same title issued on April 17, 2013, and expands the scope of the guidance to include all compounds containing a beta-lactam ring in their structure. All beta-lactam compounds, nonpenicillin beta-lactam antibacterial drugs, and nonantibacterial beta-lactam compounds (including intermediates and derivatives) are included in the new guidance scope.

Consistent with the original April 2013 guidance, the agency recommends that manufacturers have complete and comprehensive separation between nonpenicillin beta-lactam antibacterial drugs and manufacturing operations of other drugs. For manufacturers of nonantibacterial beta-lactam compounds, this guidance provides recommendations on cross-contamination prevention strategies, including examples of relevant design features and control approaches for those seeking to justify a cross-contamination prevention strategy other than complete and comprehensive separation, when appropriate.

Significant changes from the 2013 guidance include the following:

• Clarifying that the scope of the guidance also includes all compounds, including intermediates or derivatives, that are not a penicillin, have a chemical structure that includes one or more beta-lactam rings, and have a mechanism of action other than an antibacterial mechanism of action. The previous guidance included only containment controls for APIs and finished drugs and was not clear on the chemical structure that the agency uses to define a beta-lactam subject to this guidance.

• Providing FDA’s interpretation of terms, such as allergic reaction, cross-reactivity, and complete and comprehensive separation, used in this guidance. The original guidance discussed that there should be separation, but this newly issued draft guidance further defines this separation as “complete and comprehensive.”

• Clarifying the distinction between nonpenicillin beta-lactam antibacterial drug(s) and nonantibacterial beta-lactam compound(s) in terms of the cross-contamination and patient exposure risks and the control strategies appropriate for manufacturing operations involving each category. In contrast to the original guidance released in April 2013, the new 2022 guidance cites literature sources that report hypersensitivity reactions from beta-lactamase inhibitors and beta-lactam intermediates and derivatives.

• Providing recommendations for drug manufacturers that seek to justify alternative cross-contamination prevention strategies for nonantibacterial beta-lactam compounds. This justification for alternative cross-contamination strategies should align closely with the quality risk management principles described in ICH Q9 Quality Risk Management.³

Next Steps for Industry

Industry should evaluate whether these new items within the scope of the newly released draft guidance apply to the manufacturing operations being performed at their sites. For example, this new draft guidance broadened the scope of the guidance to include “intermediates and derivatives” as well as compounds that “have a chemical structure that includes one or more beta-lactam rings and have a mechanism of action other than an antibacterial mechanism of action.” The new guidance includes Appendix A: Chemical Structures of Representative Beta-Lactam Compounds.² Companies manufacturing starting materials or intermediates should take close note of the recommendations described in this newly issued draft guidance and ensure that proper cross-contamination strategies have been implemented and scientifically justified through proper risk management at their facilities.

Note that FDA will heavily prioritize controls in place to prevent cross-contamination at facilities during on-site inspections. The new guidance includes Appendix B: Design Features and Controls to Prevent Cross-Contamination², which lists examples of strategies that can be used, including and not limited to use of closed systems such as an isolator, separation and containment of different manufacturing processes, use of dedicated equipment and air systems, and strict controls over cross-over points for personnel, products, waste, materials, and equipment.

The concept of establishment of cross-contamination controls continues to be a major focus during regulatory inspections and also applies more broadly to risk-based controls established for high-potency active pharmaceutical ingredients, steroids, cytotoxic compounds, and other compounds that may pose a higher patient risk due to cross-contamination.

¹ Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination Guidance, released on April 17, 2013.

² Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination Draft Guidance, released on June 23, 2022.

³ Guidance for Industry ICH Q9 Quality Risk Management.