Contamination Control and Data Integrity Issues: Granules India Receives USFDA Warning Letter

Failure of Contamination Control Systems

The observations connect lapses in three areas, raising concerns over overall contamination control systems.

1. Facility Maintenance Issues: Bird droppings and feathers in the AHU area on air purification units, ducts, tanks, cleaning units, and floors raised concerns of contamination of air supplied to critical manufacturing equipment.
2. Failure to Maintain a Robust Program to Assure Performance of Equipment: The firm failed to inspect and maintain AHU systems. There was no Quality unit oversight and evaluation of conditions during filter replacement and routine maintenance. The lack of oversight prevented detection of potential failures and contamination risks. The Quality unit’s role in verifying the condition of critical equipment like AHU, air supply ducts, HEPA filters, and filter integrity, accumulated residues, and overall cleanliness during filter change and preventive maintenance was not defined. The USFDA 483 issued to Granules India observed that Engineering personnel did not understand the purpose of the HEPA filters and simply replaced the filters as per frequency. The filters were severely damaged and torn in several sections. Powdery residues were also observed encrusted in the HEPA filter chambers and extruding from the corners of the HEPA filters, indicating compromised filter integrity.
3. Inadequate Cleaning and Maintenance of Equipment: The investigators observed significant contamination in multiple air supply ducts of manufacturing equipment. Filters in the air purifier system ducts were rendered ineffective due to inadequate cleaning and maintenance. Swab samples collected from the areas after the HEPA in the ducts showed residues from different drug products and too numerous to count (TNTC) microbial contamination. There were no documented cleaning procedures for the section of ducts after HEPA.

In its response to the FDA, Granules India contended that it analyzed control (reserve samples) and performed an impact assessment. Based on maximum allowable carry-over (MACO) calculations, the risk to drug product safety is low; Firm also provided assurance of low microbiological contamination risk to products. Birds were entering the facility through numerous gaps in the exterior wall of the facility, and the Firm proposed to block the entry points with nets. Granules India confirmed damage to filters, increased pressure differentials, and proposed to monitor pressure differentials to determine when cleaning or replacement of filters is required.

cGMP Records and Data Integrity Issues

Large amounts of torn cGMP records, including analytical balance printouts and manufacturing/testing data, were observed in waste bags. The Form 483 observed employees recording data on uncontrolled white paper and disposing of GMP documents and records like analytical instrument printouts and other raw data documents.

Granules India provided supporting documentation to show that the deviation did not affect product quality and identified several root causes, including lack of clarity in documentation practices and data integrity protocols, inadequate SOPs, employee misinterpretation of requirements, failure to archive defective and illegible printouts, and lack of control over raw data sheets. However, the FDA contended that the firm’s quality system does not ensure accuracy and integrity of data.

The FDA found the responses of the Firm inadequate in several respects. FDA’s objections included:

• Testing of limited reserve samples cannot conclude products are contaminant-free. Cross-contamination will not be uniform.
• MACO approach for contaminant carry-over can be applicable to validated processes; it cannot be applied when the cleaning process itself is not defined and exposure is inconsistent.
• The CAPA proposed for preventing bird entry in AHU areas by netting is not good enough as it still allowed smaller animals and insects to enter the AHU area. The response lacked a thorough root cause analysis and assessment of similar vulnerabilities elsewhere.
• The firm failed to address the root cause for damage to filters, assess risks to airflow, and cross-contamination identified during inspection.
• The FDA has asked the firm for a comprehensive and independent assessment of cleaning effectiveness, identification of residues, and other manufacturing equipment which could be similarly affected. The firm must take immediate remediation measures if cross-contaminated batches are released for distribution, implement improvements in the cleaning program, cleaning verification, and cleaning validation program with emphasis on worst-case conditions like difficult-to-clean molecules, equipment, and locations. The FDA has asked the firm to establish routine and vigilant operations management oversight of facilities and equipment for prompt detection of contamination issues, implement timely technological upgrades, preventive maintenance, and effective execution of repairs.