Warning Letter Breakdown: Poor Complaint Handling, Contamination Controls, and Minimizing Problems Tied to Defective Inhalers
Cipla received a warning letter listing ongoing issues with its Indian manufacturing facility. Earlier this year, the facility was the subject of a Form 483.
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The FDA recently issued a warning letter to Cipla for multiple violations of CGMP.
As was outlined in an earlier Form 483, the warning letter said the facility failed to properly follow up on thousands of customer complaints regarding its albuterol sulfate inhalation aerosol used to treat bronchospasm in patients with asthma, bronchitis, emphysema, and other lung diseases. More than 3,000 complaints were filed with the company between 2020 and 2022, with more than 90% of the customer complaints centered on product performance issues.
The company also lacked adequate controls to prevent microbiological contamination and showed poor oversight of CGMP records.
The warning letter was issued after a 12-day inspection of Cipla's facility in Pithampur, India, in February 2023 and was made public on the FDA's website on November 21, 2023.
Here’s a breakdown, some lessons, and recommendations for avoiding these issues.
Inadequate investigation of quality defect complaints
Cipla received about 3,000 complaints regarding their Albuterol Sulfate Inhalation Aerosol, mainly categorized as "no spray" or "empty/less weight." The company's investigation was found inadequate due to a lack of timely corrective actions and failure to extend investigations to other potentially affected batches.
"Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications whether or not the batch has already been distributed. Your investigations into quality defect complaints of Albuterol Sulfate Inhalation Aerosol were inadequate because they lacked appropriate and timely corrective actions and preventive actions (CAPAs). You also failed to extend your investigations to other potentially affected batches".
Teams must conduct thorough and timely investigations of all quality complaints and extend these investigations to other batches that might be affected.
Develop a standardized electronic tracking system for logging complaints. The best systems we see categorize complaints by type, severity, and product batch.
Train staff on detailed complaint analysis techniques. Conduct workshops on root cause analysis techniques such as the '5 Whys' or Fishbone Diagrams.
Establish a clear chain of command for escalating serious complaints, ensuring they are reviewed by senior quality management.
Ensure every complaint is investigated for potential impact on other batches. Develop a checklist for assessing the potential impact of a defect on other product batches.
Document all findings and actions taken in response to each complaint. Be sure to use a standardized form for documenting investigations, actions taken, and resolution outcomes.
Relevant FDA Regulation: 21 CFR 211.192 (Unexplained Discrepancies; Failures Investigation)
Supplementary Guidelines/Frameworks: FDA Guidance on Investigating Out-of-Specification (OOS) Test Results, ICH Q9 (Quality Risk Management)
Download our white paper on clearing complaint backlogs for a more specific discussion on handling inefficient complaint handling.
Inadequate container-closure system
Cipla’s investigation identified critical issues with the container-closure system of their inhalers, but the problem was minimized and classified as non-critical. This led to defective batches remaining on the market.
"Drug delivery you classified the “Final Severity of Complaint” as “Non-Critical” determined that no FAR was required and concluded that no market action was warranted. The impacted Albuterol Sulfate Inhalation Aerosol batches remained on the market through expiry. Inadequate container-closure parts or assembly processes can directly lead to production of poor-quality inhaler medicines with severe functionality or integrity defects". Adequate attention must be paid to the integrity and functionality of container-closure systems. Any deficiencies identified should be addressed promptly and thoroughly, and if necessary, market actions should be considered to prevent patient exposure to defective products.