FDA warns Cipla over poor contamination controls and minimizing problems tied to defective inhalers

The US Food and Drug Administration (FDA) lambasted Cipla in a recent warning letter for a number of current good manufacturing practice (CGMP) violations including failure to promptly follow up on 3,000 customer complaints about its albuterol sulfate inhalation aerosol product. Other violations included inadequate controls for preventing microbiological contamination and lax oversight of CGMP records.

The warning letter was issued following an inspection of the company’s facility in Pithampur, India after a 12-day inspection in February 2023, and was posted on the FDA’s website 21 November 2023. The warning letter follows a Form 483 report issued in March 2023.

The agency said most of the 3,000 customer complaints, or 91%, were made from April 2020 to December 2022 and involved either products containing “no spray” or “empty/less weight.” Many of these complaints remained open for up to 314 days. Cipla concluded that “there was no risk to product quality and patient safety based on a risk assessment.”

The company’s subsequent investigation found that particles from the valves in the metered dose inhalers (MDIs) became lodged in the actuators, blocking delivery of the drug. The manufacturer of the MDI valves identified four valve lots that were affected by this issue, and in two instances, the firm’s investigation found that inhalers were not able to deliver medication due to these defective valve lots.

However, the company minimized the problem by characterizing the defect as a non-critical issue and determined that no field alert report was required. The impacted albuterol sulfate inhalation aerosol batches remained on the market.

Cipla told FDA that it received 2,000 additional complaints between January 2023 and August 2023, with similar issues, such as “no spray,” “empty/less weight” and leaky containers. FDA states that “the batches associated with these complaints used valve lots beyond the four vendor lots previously identified as potentially affected.” Many of these complaints are still under investigation.

“The number of complaints you received showed a marked and adverse trend of critical drug delivery failures which fundamentally impacted the ability of patients to use your Albuterol Sulfate Inhalation Aerosol,” FDA wrote.

Cipla initiated a Class I recall of six batches of these products in June 2023 to the defective valve, yet the firm failed to extend the investigation to other batches of potentially impacted products.

Another problem found by investigators was the company’s failure to promptly evaluate a pattern of media fill failures after experiencing “multiple aborted and contaminated media fills” on filling lines between February 2021 and March 2022.

In September 2021, the firm isolated a gram negative microbe Ralstonia picketii, from multiple media fills. This media failure was tied to multiple deviations, including damaged filter housing, and dislocation of the filter. In November 2021, the firm isolated Pseudomonas stutzeri from one media. The company attributed this contamination to a puncture in the device during handling or movement of the filled samples. Additionally, in March 2022, Cipla isolated the drug-resistant gram-negative pathogen Stenotrophomonas maltophilia in multiple media fill and determined the root cause to be leakage from a damaged valve gasket and deformed filter.

“The presence of any highly pathogenic microorganism in your aseptic processing environment presents a heightened risk to patients who are, for example, immunocompromised, have cystic fibrosis, or have chronic obstructive airway disease,” FDA wrote. The agency also noted that the “presence of such microbes should receive urgent investigation and effective remediation.”

Another violation noted by investigators was Cipla’s poor oversight of original CGMP records. An investigator observed a truck loaded with bags of scrap, as well as bags stored at a scrapyard intended for shredding. The bags of scrap included numerous torn pieces of printer weigh slips for drug product packaging, as well as a microbiology laboratory sample label with quality assurance wet signatures.

“The uncontrolled destruction of CGMP records, and your lack of adequate documentation practices, raise questions about the effectiveness of your operations management and QU in assuring the integrity and accuracy of your CGMP records,” FDA wrote.

FDA made similar CGMP observations in a February 2020 warning letter about Cipla’s plant in Goa, India (RELATED: FDA Warns Cipla Over Cross-Contamination Concerns, Regulatory Focus 17 March 2020).

“These repeated failures at multiple sites demonstrate that your management’s oversight and control over the manufacture of drugs is inadequate,” FDA wrote.

FDA advised Cipla to hire a CGMP consultant and gave the company 15 days to respond to the latest warning letter.

Warning letter