USFDA 483 for Glenmark Facility Highlights Cleaning Failures and Beta-Lactam Contamination Risks

USFDA 483 issued to Glenmark Pharma’s Pithampur facility (FEI: 3008565058) in India flagged critical deviations in cleaning and beta-lactam contamination control issues. Other deviations cited include lapses in handling Out-of-Specification (OOS) and Out-of-Trend (OOT) results, analytical method validations and delays in stability testing. The facility was inspected in February 2025 by USFDA investigators Tamil Arasu and Saleem A Akhtar. Following the inspection, Glenmark initiated recall of several lots of non-beta-lactam drugs due to beta-lactam contamination concerns in March 2025.

1. Deficient Cleaning Procedures & Contamination and Cross-contamination Concerns:

Equipment and utensils are not cleaned effectively to prevent cross-contamination. Incidents of carryover residue levels in cleaned equipment exceeding specification limits was observed indicating that the cleaning methods in use are not effective in removing residues consistently.

• Deficiencies in Containment, Contamination Control of Beta-lactam drugs:

The investigators observed several critical deficiencies in the handling of non-penicillin beta-lactam drugs at the facility along with other non-beta-lactam drugs in shared spaces and equipment.

• shared sampling, dispensing areas, equipment, air handling systems, and primary packing areas
• dust collectors for areas and equipment were not product specific
• the acceptable carryover residue limits for shared equipment failed to account for “unique nature” of the product (beta-lactam-specific concerns).
• residues were not routinely monitored during product change overs and later while monitoring started, the limits applied were in ppm levels.
• no decontamination procedures were in place for shared equipment
• procedures permitted operators from beta-lactam areas to work in non-beta-lactam areas on the same day after simple gowning, degowning.
• no periodic monitoring for beta-lactam residues in products manufactured using shared equipment

As per FDA, contamination of non-beta-lactam drugs with beta-lactam drugs presents great risk to patient safety, and no safe level of penicillin contamination has been determined to be a tolerable risk. (Centrient Warning letter – December 2022).

FDA cGMP requirements (FDA guidance: Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination) recommend that the section of facility manufacturing beta-lactam products be dedicated, isolated and completely and comprehensive separated from other non-beta-lactam manufacturing areas.  Analytical method for the analysis of beta-lactam contamination in environment and in non-beta-lactam drug products should achieve limit of detection (LOD) of 0.2 ppb In line with the FDA’s published analytical method.

• Handling of Out-of-Specification (OOS) and Out-of-Trend (OOT) incidents

Investigation of Out-of-Specification (OOS) and Out-of-Trend (OOT) results in dissolution tests were not thorough, batches were released despite unresolved discrepancies and root causes are not sufficiently supported.

• when annual stability batches failed, reserve samples from all batches were not tested, despite the manufacturing processes being the same.
• several OOS results were attributed to analyst error or issues with specific accessories, despite other capsules passing in the same sample set.
• In another set, OOS results in dissolution was attributed to API particle size though there was no change in source of API or specification and no issues in dissolution in the prior 3 years.

Also in several instances of extraneous peaks recorded during dissolution, assay, content uniformity and impurity tests, root cause are either not identified or adequately supported.

• Failures in Analytical Test Methods:

All test methods used for drug products and APIs are not adequately validated or verified. For analytical test methods for specific optical rotation, and identification tests by IR (Infrared), UV (Ultraviolet), and TLC (Thin Layer Chromatography) appropriate parameters like specificity or precision are not verified.

• Stability Testing Delays:
• For several commercial samples stability studies are not completed in a timely manner with delays varying from 1-12 months at different stability stations

The Glenmark 483 observations underscore the importance of adhering to fundamental cGMP practices in Pharma manufacturing: adequate cleaning and cleaning verification of equipment, a comprehensive contamination control strategy with dedicated facilities for beta-lactam drugs, thorough investigation and impact assessment of OOS/OOT incidents to establish root causes and prompt mitigation actions, timely testing of stability samples, and proper validation or verification of all test methods.

References

1. USFDA 483 (Glenmark, February 2025)
2. FDA guidance: Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination
3. Qvents post: Concerns of Beta-lactam Contamination Triggers Massive Recall by Glenmark