Warning letter : Glenmark Pithampur plant

The FDA issued a warning letter to Glenmark Pharmaceuticals Limited on July 11, 2025, following an inspection of their drug manufacturing facility in Pithampur, India, from February 3 to 14, 2025. The letter outlines significant violations of Current Good Manufacturing Practice (cGMP) regulations for finished pharmaceuticals. As per the website information, the site capacity is as follows:

1. Oral solid dosages: 1490 Mn tablets
2. Immuno Suppressant Block: Capsules – 42 Mn
3. Ointment & Creams – 80 MT

Key Violations

Failure to Thoroughly Investigate Discrepancies and Failures:

1. The firm failed to adequately investigate several dissolution failures for potassium chloride extended-release (ER) capsules during stability testing.
   
2. The investigation into the root causes of these failures was insufficient, particularly regarding the impact of changes in API particle size and solution content.
3. Process changes, such as the introduction of a new component and alterations to process parameters, were not adequately investigated for their potential impact on drug performance.
4. Investigations into dissolution failures of another drug product, capsule products, were also inadequate, with insufficient validation studies to confirm root cause determination before distributing more batches.

Inadequate Written Testing Program for Stability Characteristics:

1. The firm failed to follow its written stability procedure for finished drug products, resulting in delayed stability testing for a significant proportion of samples.
2. The response to the FDA did not include test results from the delayed stability analyses or a copy of the investigation report.
3. The impact assessment for the delayed stability analyses did not adequately address the risk to patient safety.
4. The firm's failure to perform stability dissolution testing led to delays in detecting product quality failures and issuing timely recalls

Failure to Establish Adequate Laboratory Controls:

1. The firm failed to perform method validation (or verification, as appropriate) of test methods, including those for API and drug product testing of quality attributes.
2. The gap assessment did not adequately address the lack of reference to method validation or verification studies for all appropriate methods.
3. The interim impact assessment did not scientifically justify the reliability of test results in the absence of appropriate method validation/verification studies.

Specific Concerns and Required Actions from the company The FDA detailed specific concerns and required actions related to each violation: Dissolution Failures:

1. Provide a copy of the potassium chloride ER capsules investigation, including related studies.
   
2. Provide a copy of the protocol and report for the DoE study investigating particle size and solution content.
3. Provide a list of all process changes for the potassium chloride ER capsule product since product launch.

Stability Testing:

1. Provide completed stability data from the backlogged stability testing, including a plan of action for any OOS results.
2. Provide the stability load assessment protocol and report.
3. Provide a comprehensive assessment and CAPA plan to ensure the adequacy of the stability program.

Laboratory Controls: Provide a detailed assessment of all test methods to evaluate if they include sufficiently specific instructions and are supported by adequate validation studies. Production Issues The FDA noted that the firm was manufacturing drug products containing using shared equipment and air handling units. While complete separation is not required, robust cross-contamination prevention strategies are essential. The FDA acknowledged the firm's decision to discontinue the manufacture of drug products and requested notification and a detailed cross-contamination prevention plan if they decide to resume production. Repeat Violations and Management Oversight The FDA cited similar cGMP violations at other Glenmark facilities, indicating inadequate management oversight and control over drug manufacturing. Executive management is responsible for resolving all deficiencies and ensuring ongoing cGMP compliance. Drug Production Ceased and Suspended The FDA acknowledged the firm's commitment to cease production of potassium chloride ER capsules and suspend production of capsules of some drug substances for the U.S. market. The agency requested clarification on whether the firm intends to resume manufacturing these products in the future. If so, the firm must notify the FDA and demonstrate that all deficiencies have been resolved. CGMP Consultant Recommendation Based on the violations identified, the FDA recommended that Glenmark engage a qualified consultant to assist in meeting CGMP requirements. Conclusion and Required Response The FDA emphasized that the violations cited were not an all-inclusive list and that the firm is responsible for investigating and preventing recurrence. The agency requested a written response within 15 working days, detailing the actions taken to address the violations and prevent their recurrence. Failure to address the violations may result in the FDA withholding approval of new applications or supplements, refusing admission of articles manufactured at the facility into the United States, or taking other regulatory actions. Some of the potentially affected products may include Clotrimazole and Betamethasone Dipropionate cream, Potassium Chloride Extended-Release (ER) Capsules, and several other capsule products. The US supply of Glenmark's few immunosuppressant products, like tacrolimus and sirolimus, could also be affected.