USFDA 483 to Laurus: Lapses in investigation of equipment damage, OOS

• Investigations into damage to manufacturing equipment did not adequately address potential particulate contamination. All potentially impacted batches were not assessed for particles. Only samples from batches after product change over cleaning were evaluated for particles by filtration test; but entire batch was not screened for particles, which lack scientific rationale. Investigations stated the batches met the specifications, there is no impact and the batches were consumed in further stages. Customers were not informed about the deviation. The investigations claimed that the particles would be removed by the downstream filtration steps and do not affect product quality, but did not provide any scientific evidence or documentation for the same.
• OOS Investigations were inadequate, multiple examples are cited.
  • A failure of Key starting material for assay and impurities concluded it was an isolated case and no further actions were documented.
  • Key stating material passed for assay during inprocess test, but failed in impurities in finished testing. The investigation identified improper inprocess sampling as probable cause, while procedure for inprocess sampling do not specify the correct sampling procedure
  • OOS investigation into a TOC (Total Organic Carbon) failure did not correlate the TOC results with other test like TAMC (total aerobic microbial count) and conductivity.

• Investigations into damage to manufacturing equipment did not adequately address potential particulate contamination. All potentially impacted batches were not assessed for particles. Only samples from batches after product change over cleaning were evaluated for particles by filtration test; but entire batch was not screened for particles, which lack scientific rationale. Investigations stated the batches met the specifications, there is no impact and the batches were consumed in further stages. Customers were not informed about the deviation. The investigations claimed that the particles would be removed by the downstream filtration steps and do not affect product quality, but did not provide any scientific evidence or documentation for the same.
• OOS Investigations were inadequate, multiple examples are cited.
  • A failure of Key starting material for assay and impurities concluded it was an isolated case and no further actions were documented.
  • Key stating material passed for assay during inprocess test, but failed in impurities in finished testing. The investigation identified improper inprocess sampling as probable cause, while procedure for inprocess sampling do not specify the correct sampling procedure
  • OOS investigation into a TOC (Total Organic Carbon) failure did not correlate the TOC results with other test like TAMC (total aerobic microbial count) and conductivity.

Equipment Damage & Investigations

• During preventive maintenance activity (PM) and product change over cleaning, verify equipment for damages and document. This can help in identifying issues proactively, narrow down the window for number of batches to be evaluated when an equipment damage is observed.
• Whenever a maintenance or repair on an equipment is performed to address equipment damage (e.g., patches or plugs in a reactor, gasket damages and so on), ensure to document a traceable incident investigation report.
• After observing an equipment damage, all batches manufactured in the equipment from a scientifically sound cut off date (like a previous preventive maintenance check or cleaning check with no damage recorded) shall be assessed for potential particulate contamination
• In the Equipment damage investigation reports identify the location and size of the damage, include pictures, discuss the potential for particles shredding due to the damage. Not all damages may shred particles and contaminate the product. Pictures help bring this clarity.
• Assess the type of damage and potential to shred particles, will it continue to shred particles over time or could it be one time issue. For example, a disintegrating gasket or seal, rusting surface etc., may continue to shred particles during use; a metal chipping or glass chipping may cause a shredding only at the time of incident. This can help narrow down the number of batches to be evaluated and taken for further actions (screening, recall etc).
• Perform an objective risk assessment of the impact of the particulate shredding on the batch(es). Many APIs, Intermediate, Key starting material will have downstream processes like filtration, layer separation which can remove particulate matter. For e.g. during layer separations particulates could settle on the bottom and if the product is in top layer, contamination risk will be minimal. Make a documented assessment of the filtration process, filters used, filter pore size. (Typical filter pore size could be 3-5 micron or smaller with filter clothes, filter cloth+Hyflo bed or cartridge filters. In such cases possibility of particulates passing through during filtration and risk to product will be minimal. For example, as per USP <789> Limit of number of particles >10u size is 50 particles per ml for Ophthalmic solutions).
• For visual evaluation of particulates verify the entire batch (for e.g. visually check for particles by passing the material over a sifter screen slowly). Particulate contamination cannot be expected to be spread uniformly across the batch. A filtration test can only be an additional support for visual screening of the entire batch, but cannot be a substitute.
• In incidents with risk of particulate contamination in APIs and Intermediates, the ideal corrective action is removal of contaminants by dissolving the material in a suitable solvent (typically process solvent from product is precipitated or crystallised) and filtration. Also verify the filter for any particles and document. This gives confidence that the batch is free of particulates.

Inadequate assessment of potential particulate contaminations poses risk to product quality and safety and also has regulatory consequences. When such issues are reported a comprehensive assessment shall be performed and remediation actions taken.

• Review and identify inadequate equipment damage investigations spanning a period from date of manufacture of the earliest batch still within expiry to current date. On current date, evaluate all the equipment for any damage and potential impact. If there is potential for unacceptable levels of contamination in batches, initiate market actions like recall.
• Enhance SOPs and procedures with checks and checklists to verify equipment damage during preventive maintenance and change over cleaning. Include checkpoints for equipment damage, size and location of damage, picture / drawing of damage, evaluation of particle shredding potential, assessment of batches that could be affected.

Review and enhance procedures for Hold time studies and OOS investigations addressing aspects to be investigated in case of failures – assessment of packing, shelf life, storage conditions for Hold time study failures; review of TAMC trends in case of TOC failures.