Glenmark Warning Letter Cites 21 CFR 211.192 Violations at Multiple Sites

The Warning letter highlights the following:

1. Inadequate Investigation of Product Failures

< Cause of Dissolution Failure – API particle size or Process Changes? >

• Dissolution failures during stability testing were attributed to API particle size, despite inconsistent results across batches using the same API lots. A 2021 process change was later identified as a possible root cause, but FDA noted that Glenmark failed to evaluate all relevant changes. FDA also flagged gaps in the DOE studies performed to evaluate combined impact of combination of variables – API particle size and process variable – on dissolution. The DoE study did not include other process parameters previously considered critical to dissolution control.

• For another product, investigation for dissolution failure concluded variations in process parameters as contributing to dissolution failure. Process parameter changes were implemented and batches were distributed before sufficient validation studies. FDA pointed out Glenmark had determined the original parameters to be insufficient to enable a state of control and did not accept the justification that “fine-tuning” of critical process parameters within filed ranges did not require revalidation.

• FDA has requested a comprehensive review of all drug products for dissolution failures and other adverse quality signals.

2. Stability Testing Delays:

• Second issue highlighted in the Warning letter was the failure to completed stability studies in a timely manner for several commercial samples. There were delays varying from 1-12 months at different stability stations. FDA contended that Glenmark response that all delayed stability samples testing was completed by December 2024, prior to inspection and plans to enhance QC resources including manpower and equipment is inadequate. The stability load assessment was considered to have inadequate information to evaluate adequacy of resources and evaluation of risk to patient safety due to delayed stability analysis and delay in detection of failures.

3. Failures in Laboratory Controls, Analytical Test Methods:

• FDA observed Glenmark failed to perform method validation or verification of multiple test methods for APIs and drug product. These include analytical test methods for specific optical rotation, and identification tests by IR (Infrared), UV (Ultraviolet), and TLC (Thin Layer Chromatography) for which parameters like specificity or precision are not verified. Glenmark response included a gap assessment, interim impact assessment and plans to complete remaining validation, verification studies by May 31, 2025. FDA deemed the response as inadequate, emphasized that system suitability controls and calibration controls for test methods are not an adequate substitute for method validation / verification studies. FDA has asked Glenmark to perform a complete assessment of all test methods for specific instructions to ensure repeatability, whether they are supported by adequate validation or verification and submit a detailed remediation plan.

4. Deficiencies in Containment, Contamination Control:

< Non-Penicillin BetaLactam drugs in common facility >

• In the Form 483 issued to Glenmark, FDA investigators had highlighted several deficiencies in handling of non-pencillin beta-lactam drugs in shared facility. On the issue of potential cross contamination due to shared equipment and air handling units in the manufacture of certain specific class of products (warning letter cited the guidance for Non-Penicillin BetaLactam Drugs: A CGMP Framework for Preventing Cross-Contamination), FDA acknowledged that complete and comprehensive separation of facilities for manufacturing may not be required. However, the Warning letter highlighted the need to implement robust cross-contamination prevention strategies and dedicated production suites. Glenmark has since discontinued manufacturing of these products in the facility for all markets.

The Warning letter cited similar violations of the provisions of 21 CFR 211.192, inadequately investigate Out of specifications (OOS) at other Glenmark facilities – Himachal Pradesh (October 2019), Goa (November 2022), and several cGMP violations at North Carolina, U.S.A (June 2023). These facilities had also received FDA warning letters. FDA contended that the repeated failures at multiple sites demonstrate lapses in management oversight and asked Glenmark to comprehensively assess its global manufacturing operations, fully resolve all deficiencies and ensure ongoing CGMP compliance.

• Root Cause Investigations: Repeated OOS incidents demand comprehensive investigations that revisit earlier failures and explore all contributing factors. When single, isolated incidents occur, most obvious reasons may be attributed to the failure. But if these are not the real root causes, incidents recur. And then investigations must acknowledge the gaps in earlier investigations, connect the issues and pick up the underlying threads for arriving at the possible root causes. Appropriate remediation actions including timely recalls must be taken to mitigate risk to patient safety.
• Stability Program Prioritization: Timely stability testing is critical—often more so than batch release. Overloading stability programs with samples from minor deviations without evaluating necessity can strain resources and delay detection of quality issues. Stability monitoring is not a substitute for thorough investigation and risk assessment.
• Analytical Method Verification: All analytical methods need verification. The suitability of the method and at a minimum specificity, precision and recovery / limit of detection (where applicable) must be established.
• Beta-Lactam Containment: FDA has a zero-tolerance stance on beta-lactam cross-contamination – contamination of non-beta-lactam drugs with beta-lactam drugs presents great risk to patient safety, and no safe level tolerable risk has been established. Sections of facility manufacturing beta-lactam products must be dedicated, isolated and ideally completely and comprehensive separated from other non-beta-lactam manufacturing areas.