Inadequacy of Investigations, Root cause and CAPA – USFDA Untitled Letter to Laurus

The Untitled Letter issued to Laurus cite two issues.

1. Quality unit failed to perform adequate investigation of critical deviations, identify root cause or implement corrective and preventive actions (CAPA).

• An OOS in hold time study of an intermediate for assay and purity was passed off as an isolated event.
• Following an OOS incident of a water system sample for TOC, resampling was done and passing results obtained, but the original OOS was not investigated nor any sampling process improvements were implemented. 
• In a deviation for equipment damage observed during batch to batch cleaning, the investigation did not adequately evaluate product impact due to particle contamination. Only batches manufactured after product change over cleaning were evaluated by performing filtration test on samples and it was concluded that there is no contamination in the intermediate batches. All potentially impacted batches were evaluated and complete batch was not screened for particles. The CAPA stated filtration steps during subsequent processing at customer end would remove any potential contamination. However, customers were not informed about potential contamination or informed to perform filtration.

As per Untitled letter in the response to USFDA Laurus provided procedural improvements and a degradation study identifying the impurity observed during hold time studies, and reiterated it do not inform customers of potential contamination. FDA found the response inadequate as it dd not address the inadequacy in investigation, did not provide any actions to improve root cause identification and CAPA implementation and did not make any commitment to inform customers about quality issues and potential for contamination.

2. Failure to clean equipment to prevent contamination, carry over of residues

• Dirt and residues observed in an equipment during inspection. But the preventive maintenance report three days prior to the inspection showed the equipment to be in “Clean state”.

FDA found the Laurus response that it trained the engineers on preventive maintenance and inspected all equipment inadequate. The response failed to address the discrepancy between the preventive maintenance report claiming the equipment to be in “Clean state” and actual condition of equipment with dirt and residue.

As FDA itself says inspection observations are just a snapshot and may not capture all deviations at a site. When an USFDA 483 specific examples of inadequate investigations, simply reopening the investigations mentioned in the report to identify the root cause and CAPAs (for example identifying the impurity in hold time study or implementing procedural improvements for checking equipment damage or particulates) is not enough. Of course immediate actions are required. But the underlying concern is that these examples could point to a larger systemic issue. There’s a possibility that other investigations were also inadequate, leading to unidentified root causes and ineffective CAPAs. This can create a cycle of recurring deviations.

To address this comprehensively, firms should conduct a thorough evaluation of all deviations and failures across a defined period, ideally encompassing all batches within expiry. This evaluation should assess the adequacy of investigations, root cause identification, and implemented CAPAs with a defined protocol. Based on the evaluation, identify the actual root causes for incidents where initial investigations fell short. Implement CAPAs that target these root causes and use the findings to educate the Quality and Operations teams. This only can significantly improve a company’s investigation process, leading to more effective root cause identification and CAPAs.

Similarly the observation of dirt and residue in an equipment documented as clean raises several concerns. It suggests potential lapses in cleaning of equipment across other preventive maintenance activities. This also highlights a broader issue of data integrity and record reliability. Corrective actions of training engineers on proper preventive maintenance and inspecting all equipment are necessary immediate steps. However, a more extensive assessment is vital to determine the scope of the issue, its root causes, and past impacts. This assessment shall be done with comprehensive protocols covering aspects like:

• Personnel:
  • People involved in the incident, their training, understanding of the Jobs, SOPs and checklists, cGMP awareness,
  • Process of qualification of personnel for tasks
  • Probable causes for the lapses – ignorance of the procedure, attitude towards GMP and practices
• Extent of Such lapses:
  • Evaluation of other personnel for similar lapses (against the same matrix of assessment as above)
  • Review of the preventive maintenance (PM) history and records of equipment, including persons involved in the PM activity
• Products Impact and Risks:
  • Type of Equipment and their complexity, potential for residues and dirt to remain after maintenance
  • Checkpoints / alternate processes in place if any to prevent contamination of products (for e.g. cleaning / verification of equipment before taking for production)
  • Products manufactured in each equipment, Manufacturing process and risk and severity of contamination from residues.