The focus on beta‑lactam antibiotics has primarily concentrated on penicillin and its derivatives because of the issue of severe allergy or anaphylaxis that can occur in individuals with sensitivities to these products. Over the years, as more and more non‑beta‑lactam antibiotics were introduced to the market, there has also been growing concern that these new products could elicit the same adverse reactions as penicillin. The FDA guidance was never really crystal clear on how to treat these products in the context of their manufacturing environments to prevent cross‑contamination and reduce the risk associated with their manufacture and potential cross‑contamination. The newly released guidance addresses these issues.
The major changes from the 2013 guidance are listed as:
- 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 that of an antibacterial
- Providing the FDA’s interpretation of terms, such as allergic reaction, cross‑reactivity, and complete and comprehensive separation, used in this guidance
- Clarifying the distinction between non‑penicillin beta‑lactam antibacterial drug(s) and non‑antibacterial beta‑lactam compound(s) in terms of cross‑contamination and patient exposure risks, as well as control strategies appropriate for manufacturing operations involving each category
- Providing recommendations for drug manufacturers that seek to justify alternative cross‑contamination prevention strategies for non‑antibacterial beta‑lactam compounds
The bottom line is that the “guidance recommends manufacturers have complete and comprehensive separation between non‑penicillin beta‑lactam antibacterial drugs and manufacturing operations of other drugs. For manufacturers of non‑antibacterial 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.”
For as long as I have been in the industry (and that is just about forty‑two years), the FDA’s stance has always been that facilities for penicillin and non‑beta‑lactam antibiotics should be fully separated, but the Agency also stressed that it was possible to have them in the same building. The Agency’s compliance folks also stressed they have not seen great examples of successful, long-term commingling production of these products in the same building. Hopefully, this guidance provides the best and most current thinking regarding the issue, but the bottom line, as outlined above, seems to be the preferred position. At one time, the FDA’s feelings (only somewhat jokingly) were that if you have a penicillin facility and want to change it to something else there, the only thing you could do fully to satisfy the Agency’s concerns was to make it a parking lot.
The Agency does note that “[T]he risks associated with the cross‑reactivity of beta‑lactam antibacterial drugs have been described (Terico and Gallagher 2014; Joint Task Force on Practice Parameters 2010; Çelik et al. 2008); however, the risks associated with the cross‑reactivity of non‑antibacterial beta‑lactam compounds are less well understood. Accordingly, FDA addresses beta‑lactam antibacterial drugs and non‑penicillin beta‑lactam compounds separately in this guidance. Specific recommendations for beta‑lactam antibacterial drugs and non‑antibacterial beta‑lactam compounds are further detailed” in the guidance, which can be found here.
There are also two helpful appendices in the draft guidance, one that addresses chemical structures of representative beta‑lactam products, and a second that provides recommendations on design features and controls for preventing cross‑contamination. The guidance is a welcome addition towards clarifying the Agency’s position.
