Cipla Warning letter cites gaps in Complaint handling, failure to submit FARs, Media fill failures, GMP records in scrap Read More..

The Warning letter (dated November 17, 2023) follows the FDA inspection at Cipla’s Pithampur, Indore facility (FEI 3008581988) in February 2023. The site was inspected by USFDA investigators Saleem A Akhtar, Jose E Melendez.

The Warning letter cites:

1. Investigation into Complaint, impact assessment and corrective and preventive actions (CAPA) taken are inadequate. More than 3000 complaints received from time of commercial manufacturing (April 2020) till December 2022 for Albuterol Sulfate metered dose inhaler (MDI) aerosol. Complaints raised concerns of “No spray”, “Empty or Less weight” inhalers. Investigations into the high number of complaints concluded no risk to product quality and many complaints remained unresolved for extended period of time (upto 314 days). Problem was concluded as due to particles from the MDI valve got lodged in the actuator blocking drug delivery and four defective lots of MDI valves were identified as affected by the issue. Though a critical issue was identified with the container closure system, investigation classified final severity of the complaints as non critical, no FAR (Field Alert Report) required and no market actions are required. Firms’ response to FDA justified product quality complaints represent only 0.011% of total units distributed; the Ratio of number of complaints to total number of units distributed is not acceptable indicator of product quality. Passing results of retain sample testing cannot be used as a reason to disregard the validity of complaints that are of high severity and occur at a low frequency. Also the Issue with defective valve remain unresolved, as shown by more than 2000 complaints between Jan and August 2023 with similar issues and batches involved in these complaints used MDI valves beyond the four defective lots earlier identified. Production process and input material controls are inadequate to produce product with reliable functionality. Six lots of Aluterol sulfate was recalled in July 2023 for defective MDI valve, but there was no comprehensive assessment to determine other batches potentially impacted and scope of recall. FDA asked the Firm for a comprehensive independent assessment of systems and procedures for all failure investigations (complaints, deviations, OOS and so on), CAPA programme, all container closure defects and management strategy and actions.
2. Multiple aborted and contaminated Media Fill incidents between February 2021 and March 2022 are not adequately evaluated. There is no overall assessment of atypical invalidation of media fills, the reasons were variously identified as damaged filter housing, choked filter, filter dislocation, damaged valve gasket etc. Different microorganisms were isolated from Media fills – gram-negative microbe Ralstonia picketii, Pseudomonas stutzeri, Stenotrophomonas maltophilia. But investigations failed to substantively evaluate personnel and environmental monitoring (EM) data during production of the Media fill batches. Also, environmental monitoring (EM) – filling surface monitoring- was suspended without adequate justification between January 2020 and August 2022. The EM plan is not scientifically sound. Presence of highly pathogenic microorganisms in aseptic processing environment present heightened risk to patients and require effective remediation. Equipment failures may go undetected during commercial manufacture and finished goods testing alone cannot establish sterility of all units. Firm is asked to perform a comprehensive independent third party assessment of media fill programme, source of gram negative microorganisms isolated in aspect area/equipment, retrospective evaluation of failure investigations, assessment of all failure modes of aseptic processing operations, risk assessment of all contamination hazards, assessment of EM programme, establish remediation and CAPA plans including plans to ensure appropriate aseptic operations,  plans for improved production oversight.
3. Inadequate Quality Unit (QU) oversight over control of GMP records. During audit observed numerous torn pieces of printer weigh slips from drug product packaging, sample label in scrap. QU is responsible for monitoring of Production areas, control of GMP records and ensure employees demonstrate understanding and adherence to Firm’s procedures and systems. Firms Quality system does not adequately ensure adequacy and integrity of data. Firm’s response that it has enhanced the systems and procedures is inadequate; It do not assess impact of poor documentation practices on other distributed batches. FDA recommend engaging a cGMP consultant for remediation plan and asks for comprehensive assessment of extent of data integrity (DI) deficiencies including risk to patients caused by release of drugs affected by lapses of DI.

In the Warning letter FDA also highlight incidents of  similar cGMP observations at other facilities of the Firm and state the Management oversight and control over manufacture of drugs is inadequate. FDA asks for immediate and comprehensive assessment of global manufacturing operations by Executive Management and ensure compliance with FDA requirements.

USFDA 483

Warning letter