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Warning letters, 483s, Recalls, Import Alerts, Audit observations

Updated on April 28, 2025

In March 2025, Glenmark initiated recall of 23 products (148 lots) in US for cGMP deviations. The recall cover a range of medicines for high blood pressure, heart diseases, epilepsy, diabetes, multiple sclerosis and others.

The recall notification issued by Glenmark suggested that the recall is initiated following cross contamination concerns of the drug products with a beta-lactam drug Ezetimibe. Glenmark facility at Pithampur, India (FEI 3008565058) was inspected by USFDA in February 2025 by FDA investigators Tamil Arasu, Saleem A Akhtar and raised significant concerns about the site sharing facilities, equipment and air supply to manufacture beta-lactam products with other non-beta-lactam products.

Ezetimibe is a non-antibacterial beta-lactam drug indicated for lowering blood cholesterol.

The USFDA 483 issued to Glenmark raises concerns about:

  • Minimum acceptable carry over limit of equipment cleaning do not consider the unique nature of the beta-lactam drugs and the limits of detection and quantification (LOD, LOQ) are inadequate.
  • No routine monitoring of residues during product change over
  • No decontamination agents are used in the facilities used to product beta-lactam products
  • Procedures allow operators from the beta-lactam product area to work in non-beta-lactam areas on the same day by following a gowning-degowning procedure
  • There is no periodic testing of non-beta-lactam products manufactured using shared equipment to ensure these do not contain traces of beta-lactam residues
  • Dust collectors used in the processing areas and equipment, for recirculated are are not product specific and the filters are not tested for traces of beta-lactam residues
  • Complaints reporting reaction and adverse drug even were not adequately investigated to assess potential contamination when the products are manufactured using shared facilities and equipment.

Beta-lactam contamination concern in non-beta-lactam drugs:

The Glenmark recall note elaborates that though the moiety ezetimibe has a beta lactam structure, the beta-lactam ring in ezetimibe is stable and does not open under physiological conditions and thus avoid formation of allergenic determinants through haptenation. It also clarifies that the ezetimibe structure lacks the R1 side chain typically present in penicillin and cephalosporins. All metabolites of ezetimibe retains the closed beta-lactam ring. For these reasons ezetimibe is unlikely to cause beta-lactam related hypersensitivity, still out of abundant caution Glenmark is initiating the recall.

However the FDA stand on beta-lactam manufacture has been that manufacturers of sensitizing non-penicillin beta-lactam based products shall treat them as similar to penicillin and have separate production facilities. Contamination of non-beta-lactam drugs with beta-lactam drugs presents great risk to patient safety, including potential anaphylaxis and death. No safe level of penicillin contamination has been determined to be a tolerable risk. As per 21 CFR § 211.42 operations relating to penicillin shall be performed in separate facilities from those used for other drug products for human use. FDA has published guidance Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination detailing importance of manufacturing controls to prevent cross contamination of drug products and active pharmaceutical ingredients (APIs) with beta-lactam drugs. There should be a comprehensive cross contamination prevention strategy comprising containment control systems and procedures, facility & engineering controls and procedural controls, risk assessment for potential contamination, environmental monitoring for beta lactam contamination of air and shared common areas, and other drug products with sufficiently sensitive methods. FDA recommends dedicated and isolated i.e., completely and comprehensively separated facility for manufacturing sensitizing nonpenicillin beta-lactam drugs in sites where other products are also manufactured.

Learnings from the incident

There have been multiple regulatory actions, recalls related to beta-lactam contamination controls in pharmaceuticals:

  • Centrinent Warning letter (December 2022) – Methods for detecting beta-lactam residue in the non-beta-lactam buildings were not sensitive; sampling methods inadequate.
  • Scynexis Recall of Brexafemme Tablets (September 2023) – due to cross contamination risk with a non-antibacterial beta-lactam at supplier manufacturing the drug substance
  • Eugia USFDA 483 and OAI classification (May 2024) – personnel interacted in shared spaces and common areas, microbiology and QC labs, non-dedicated maintenance tools, movement of documents

They highlight the FDA concerns due to the highly sensitizing nature of beta-lactams, the difficulty in determining sensitization potential, and the absence of reliable animal testing models to predict human sensitivity of penicillin and beta-lactams.

Facilities handling penicillin, non-penicillin beta-lactam drugs and beta-lactam intermediates and also other non-beta-lactam drugs should have a complete cross contamination prevention strategy. This should include:

  • Facility design provisions to prevent cross-contamination
    • Physical separation of beta-lactam production areas
    • Dedication of facilities, equipment; use of closed systems, Separate entry and exit points
    • Separate air handling units (AHUs) with proper pressure cascading
    • Dedicated equipment and accessories like AHU filter bags, maintenance tools
    • Controlled waste flow, exhaust systems
    • Separation of utilities and vacuum systems
  • Procedural controls and control of practices
    • Defined flows for personnel, materials, gowning and degowning, decontamination of gowning, laundry handling and controls
    • control on use of common facilities and areas (Cafeteria, Health centre, lockers), laboratories
    • control on movement of material (for e.g return of materials and accessories), documents (batch records, log books, other documents) from beta-lactam to non-beta-lactam areas
  • Effective decontamination procedures
  • Destruction (deactivation) of beta-lactam structural element in wastes
  • Monitoring – Environment (non-beta-lactam production areas), other common areas, personnel, products (testing and evaluation). The methods should have high sensitivity (typically Limit of detection should be less than 0.2ppb and results expected as “not detected”).
  • Validated methods for monitoring, validated sampling methods with established recovery of contaminants

If any alternative strategies are considered in any of these areas, it should be demonstrated that contamination risks are maintained well below defined acceptable levels. This will not be an easy task.

References:

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