Potential cross contamination with ßlactam (beta lactam) drug substance – SCYNEXIS recall BREXAFEMME (ibrexafungerp tablets) in U.S

The disclosures and public statements from Scynexis show that there is potential for cross contamination of the antifungal drug Brexafemme with non antibacterial betalactam drug substance (API). Beta lactam drugs have potential to act as sensitising agents and can lead to hypersensitivity or allergic reactions such as swelling, rash, urticaria and anaphylaxis in some patients. As noted in the Form 8-K report by Scynexis to U.S.SEC, Scynexis became aware that non antibacterial beta lactam drug substance is manufactured using equipment common to manufacturing process of ibrexafungerp drug substance at the vendor end during review of manufacturing process and equipment by GSK (who is in a license deal with Scynexis). In the absence of the recommended segregation, there is a risk of cross contamination, and it is not known whether any ibrexafungerp has been contaminated with a beta-lactam compound. Hence the recall.

Current regulatory and FDA requirements recommend segregation of the beta lactam compounds from other compounds due to their potential to act as sensitising agents.

As per FDAs draft guidance, Non-Penicillin BetaLactam Drugs: A CGMP Framework for Preventing Cross-Contamination, non-antibacterial beta-lactam compounds can also be sensitizing agents and drug cross contamination could initiate life-threatening allergic reactions as penicillin. The guidance strongly recommends complete and comprehensive separation of the manufacturing operations of beta lactam compounds. If at all strategies other than complete segregation are adopted, this shall be supported with data from direct studies, scientific literature which show no incidence, or clear threshold of the beta lactam compound below which potential for allergic reactions is extremely low, rigorous facility design, segregation, process and procedural controls. Such controls include closed systems, dedicated equipment and air systems, dedicated personnel. The guidance notes that for many beta-lactam compounds the immunopathological mechanisms leading to cross-reactivity and hypersensitivity reactions are not extensively studied or well understood making it difficult to determine the sensitizing potential of many beta-lactam compounds.

The incident shows the criticality of cGMP compliance at vendor end, supplier (vendor, CMO) evaluation, qualification and control in Pharma manufacturing. When companies qualify vendors or CMOs (Contract Manufacturing Organisations) for manufacture and /or supply of drug products, drug substances (active ingredients – APIs), there should be rigorous evaluation to ensure there is no potential for cross contamination with sensitising materials like beta lactam compounds, other cytotoxic materials. Even after qualifying a vendor / CMO after conforming there are no highly sensitising materials or cytotoxic materials being handled in same facility, there should be an effective processes and mechanisms for getting updated promptly of any changes in suppliers (and CMOs) facility, its product mix. There should be clear and robust Quality agreement in place with vendors and CMOs which binds them to intimate the Contract giver when new products, molecules are taken up in the facility. There should be periodic audits, but in addition to periodic audits Contract givers can perform a questionnaire based review of the vendor / CMO, where in specific queries shall be asked about introduction of sensitising agents, allergens, cytotoxic drugs etc in the facility. Such reviews may be taken up at least annually to avoid surprises. The ICHQ10 Pharmaceutical Quality system guidance is categorical that a (product) owner is ultimately responsible for control of outsourced activities and quality of purchased materials. ICHQ7A guidance require (product) owners to evaluate the contract facilities and ensure compliance with cGMPs and written agreements defining the responsibilities in detail. The USFDA guidance Contract Manufacturing Arrangements for Drugs: Quality Agreements details the regulatory expectations and requirements for contract manufacturing operations and Quality agreements.