FDA Warning letter to Natco over Cleaning issues, destruction of cGMP records

As expected FDA has taken regulatory action and issued a Warning letter to Natco, following critical observations during inspection at Natco’s Kothur facility in India. The site was inspected in October 2023, by investigators Pratik S. Upadhyay and Saleem A. Akhtar

USFDA Warning letter to Natco

Cleaning issues: During the inspection investigators had observed residues inside and throughout two non dedicated manufacturing equipment. An analysis of the residue samples showed presence of multiple active pharmaceutical ingredients (upto 800 times acceptable levels). Swab samples from other areas of the equipment also identified residues of APIs throughout the equipment.

Deficient investigations and Questionable practices in Disposition of cGMP records: For critical discrepancies like missing batch record pages, recording critical steps 25 days after production, missing sample weight balance printouts in analytical records, changing the sample weight 22 days after analysis etc investigations were concluded without a root cause determination supported by evidence or initiating CAPA. The inspection also identified questionable practices regarding the disposition and destruction of CGMP records by employees of QC/Microbiology, Production, Engineering and Maintenance. Torn pieces of raw data sheets, balance print outs, batch record sheets, data recorded in uncontrolled white paper, tissue papers, note book pages, gloves were observed in scrap yard.

Response to observations were deficient:

FDA found Natco’s responses to the deviations deficient. FDA stated in the Warning letter that cross contamination is not uniform and testing control samples and placebo batches do not prove products are free of contamination from visibly dirty equipment. Natco also failed to acknowledge and address contamination from product contact surfaces, unknown peaks in swab samples collected. No interim controls were provided for equipment cleaning

On the issue of deficient investigations Natco had committed to conduct a review of all investigations from January 2021 to the end of 2023. However FDA stated the response is inadequate as it does not include the protocol to conduct the review and lacks a comprehensive assessment into the type and extent of records destroyed.

 FDAs directions in the Warning letter:

FDA asked Natco to conduct a comprehensive and independent review of cleaning processes, evaluate the scope of cross-contamination hazards on batches released for distribution, identity of residues, identify inadequacy of cleaning procedures and practices across each piece of manufacturing equipment and also identify source of contamination other than manufacturing equipment. Natco should determine adequacy of analytical methods to identify residue carry over, investigate unknown peaks detected in reserve samples, address issues of interference of product matrix and co-eluting peaks and enhance cleaning effectiveness, cleaning verification across all products and equipment.

FDA has asked Natco for a comprehensive and independent assessment of overall system for investigations, staff competencies, quality unit decision rights, executive management support. Natco should submit an action plan to remediate quality system, for significant improvements in investigation competencies, quality assurance unit oversight and written procedures. Natco shall also submit a holistic assessment report of the inadequacy of investigations and lack of CGMP documentation control for all batches produced from January 2021 until the end of 2023.

Natco had committed suspension of all production for US markets and the FDA has asked Natco to notify FDA before commencement of drug manufacturing operations.

Qvents Review of the Natco 483 observations:

Qvents had reviewed the critical observations in the USFDA 483 issued to Natco in a post in February 2023 – USFDA 483 / Natco Pharma India/ Oct 2023 / Cleaning deficiencies, Data Integrity. The post highlighted the need to develop equipment cleaning procedures with involvement of a CFT to have a robust and effective cleaning programme, cleaning verification checkpoints for each equipment part, comprehensive assessment of potential for similar events across all manufacturing equipment and lines, assessment of adequacy of current cleaning procedures  across all equipment and enhancement of cleaning procedures and test procedures. Qvents also advised that cross contamination hazard on all distributed batches within valid expiry should be assessed, high risk batches identified.

To improve cGMP practices Qvents pointed out that the top management shall drive the establishment of the right Quality culture with right messaging, leadership by example, proper management oversight and establishing robust procedures for control of documents and data integrity. Improve the cGMP compliance and investigation competencies of the team by sensitising personnel regularly through training programmes, seminars / case studies on data integrity issues, focusing on investigating the primary event or root cause, facilitating small group workshops to Identify issues and rectify the same, implementing appropriate reward and recognition (R&R) systems which reward Quality & Compliance and weed out the bad elements. Qvents also highlighted that the CAPA should address comprehensive assessment of potential for similar cGMP document control issues across all batches manufactured and distributed against a matrix of parameters like missing pages, additional pages, missing balance printouts and so on.