FDA finalizes guidance on food effect studies, issues draft on contamination prevention for non-penicillin beta-lactam drugs

Regulatory NewsRegulatory News | 27 June 2022 |  By 

The US Food and Drug Administration (FDA) recently issued two guidances for industry: a final guidance on how to conduct food effect studies for oral drugs being considered for investigational new drug (IND) and new drug applications (NDAs), and a draft guidance outlining a current good manufacturing practice (CGMP) framework for preventing penicillin from cross contaminating non-penicillin beta-lactam drugs and compounds.

Food effect studies
The final guidance on clinical pharmacology considerations for food effect studies in IND and DNA drugs, which replaces the 2002 final guidance Food-Effect Bioavailability and Fed Bioequivalence Studies,” outlines nonbinding recommendations on how food effect studies should be designed and conducted as well as specific considerations for different patient populations, food effect studies on oral drugs that should be taken with soft foods, oral drugs that are liquids, and oral drugs that should be swallowed whole.
Determining how oral drugs interact with food is “critical to optimize the safety and efficacy of the product” and can help stakeholders understand the pharmacokinetics of a drug under certain conditions like fasting or through systemic exposure to food with differing fat and caloric content, the agency said.
“Food-drug interactions can have a significant impact on the safety and efficacy of the drug and can be manifested in different ways,” the agency explained. “In some cases, co-administration of a drug with food can increase the systemic exposure of the drug, leading to improved efficacy or higher rates of adverse reactions. In other cases, administration of a drug with food can lower the systemic absorption of a drug, thereby reducing the efficacy.” Industry conducting food studies should have a detailed understanding of the oral drug’s exposure-response and clinical dosing scenarios to properly interpret food effect studies, FDA said.
Changes from the draft guidance, which was issued in February 2019, include removing a description of study timing as well as language about food effect studies by population pharmacokinetic analysis, and an addition by FDA of model-informed drug development approaches.
Preventing cross-contamination of non-penicillin beta-lactam drugs
FDA also issued a draft guidance outlining a framework of methods, designs and controls for preventing cross-contamination of non-penicillin beta-lactam antibacterial drugs and compounds, which serves as an update for a 2013 guidance with the same title. The new draft guidance also contains FDA recommendations for CGMP requirements on preventing cross-contamination of these products, including the separate manufacturing of non-penicillin beta-lactam antibacterial drugs from other drug manufacturing processes, as well as alternate recommendations when complete separation of manufacturing is not possible.
“[W]hen there is uncertainty regarding the risks associated with non-antibacterial beta-lactam compounds, or there is a known risk of adverse effect in patients, FDA recommends that drug manufacturers implement a complete and comprehensive separation cross-contamination prevention strategy, as is recommended for non-penicillin beta-lactam antibacterial drugs, to prevent beta-lactam cross-contamination,” they wrote.
The draft guidance goes into detail about the potential health risks of cross-reactivity of non-penicillin beta-lactam antibacterial drugs and non-antibacterial beta-lactam compounds. “Like beta-lactam antibacterial drugs, non-antibacterial compounds containing a beta-lactam ring could have similar sensitizing and allergenic properties and may pose a significant health risk to patients,” FDA explained. “For many beta-lactam compounds the immunopathological mechanisms leading to cross-reactivity and hypersensitivity reactions have not been studied extensively or are not well understood.”
“This, and the combined effect of multiple variables (e.g., dosage forms, patient history of sensitization, differences in pharmacokinetics), make it difficult to determine the sensitizing potential of many beta-lactam compounds,” they wrote. “Nevertheless, the potential life threatening hazard associated with beta-lactam compounds indicates that manufacturers should establish beta-lactam manufacturing operations that are completely and comprehensively separate from those of other drugs, to prevent cross-contamination.”
FDA made significant changes to the 2022 draft guidance from the 2013 guidance, expanding the scope to include all compounds without an antibacterial mechanism of action that have a chemical structure with at least one beta-lactam ring. The agency described the difference between non-penicillin beta-lactam antibacterial drugs and non-antibacterial beta-lactam compounds as well as how it interprets terms like allergic reaction, cross-reactivity, and complete and comprehensive separation.
The agency also made recommendations to industry for alternative cross-contamination strategies not outlined in the guidance, such as in cases where evidence points to low risk of patient hypersensitivity or allergic reactions.
“In such cases, if a manufacturer considers a prevention strategy other than complete and comprehensive separation to suffice, robust data to support no incidence or a clear threshold below which adverse reactions are exceedingly unlikely to occur should be available for FDA assessment,” they wrote.
Assessing the Effects of Food on Drugs in Investigational New Drugs and New Drug Applications-Clinical Pharmacology Considerations; Guidance for Industry; Availability
Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination; Draft Guidance for Industry; Availability


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