
Warning letters, 483s, Recalls, Import Alerts, Audit observations
USFDA 483 to Intas cites lapses in investigation and review of failures and discrepancies in manufacture /testing & control of batches. Several examples of inadequate investigation of particulate contaminants in injectable products, Non viable particle excursion and spore forming organisms in aseptic areas, rough tablets, market complaints of odour in tablets, liquified ointment, suitability failure in endotoxin testing are cited. Intas site in Ahmedabad, India (FEI 3003157498) was issued USFDA 483 with 16 observations following inspection by USFDA investigators Rita Kabaso, Justin Boyd, Arsen Karapetyan in May 2023
Failure to thoroughly review any unexplained discrepancy, whether the batch is distributed or not:
A. Visible particles in injectables are not characterised when rejects exceed the defined limits for individual particles (Black particles, White particles, Glass particles) and /or Total particles during visual inspection. Deviations were closed with no identification of root cause, potential sources, particles were not isolated and evaluated, no CAPAs are implemented. (six instances are cited)
B. CpK, PpK values for trend analysis of Visual inspection reject rates showed process is not capable. No investigation performed for batch to batch variation. Limits for individual defect categories were not revised based on historical data.
C. Non-viable particle count (NVPC) excursions in the Grade A filling areas are not investigated to identify the root cause, impact on products being filled; No procedure to remove open vials and stoppers present at the time of machine stoppage due to excursion.
D. No effective measures taken to investigate sources and reduce the occurrence of spore forming organisms in the aseptic processing areas.
E. During manufacture of a tablet drug product batch, operator failed to identify a deviation and proceeded with the batch. The batch was released based in in process results and final batch results. Batch release COA dated 6 Oct 2022, Additional lot samples test were approved on 19 Oct 2022. Investigation did not evaluate the actual parameters set by the Production operator, adequacy of sampling process, sample size selection for additional lot samples and result variation between initial COA and additional lot sample.
F. In a deviation for rough surface observed on tablets, evaluation did not include some of the process parameters; these parameters can be altered as per Operator discretion. It is unknown when the batch samples began trending out of specification for roughness as the operators document “ok” for physical appearance. No assessment of impact on dissolution, homogeneity, efficacy performed. The lots were released for distribution. Batch was not charged for stability. It is not known how many tablets were rejected for rough surface from the total number of reject tablets (7967 as only major defect categories are documented in Batch record.
G. Approximately 206 complaints for odour or smell in tablets between January 2020 and May 2023. Investigations identified (an entity / chemical) in API and its degradation in final product as the cause for odour. But no evaluation of the API or the drug product for amount of the (an entity / chemical). A process change for API was approved by FDA, both API lots (old and new) are available at site. No statistical evaluation of the variation between the API processes.
H. A complaint investigation for an Ointment as “liquified” did not evaluate viscosity of the retainer samples
I. When endotoxin tests are invalidated due to suitability failure, test are repeated without documenting a laboratory Incident report.
Comprehensive procedures for investigation of failures and deviation and robust implementation of the procedures should be in place and implemented, personnel trained in failure investigation tools. Scientific tools for investigation like Brainstorming, Fish bone (Ishikawa) analysis involving cross functional team (CFT) to list out all potential factors and categorising them into different branches (like Men/People, Machine, Method, Measurement, Environment) shall be applied; Further a Fault tree approach to analyze and organize the potential causes can help in systematically eliminating causes that do not align and trace the most probable cause(s). Brainstorming with a experienced CFT helps in identifying and listing all potential causes. Fault tree analysis is a good tool which helps to break down the event /deviation into its various contributing causes and sub-causes in a logical and structured manner. By connecting causes using logical gates (AND, OR, NOT), systematically eliminate potential causes that do not align with the observed Top Event (discrepancy or failure) to arrive at the most probable cause(s); Trace through the AND/ OR logical gates till the most basic events are reached, which represent the root causes for the failure. A Pareto analysis can help in picking out the top 20% of the potential causes, which can be further evaluated by Fault tree analysis to get to the root cause(s) to make the investigation efficient. Once the root cause(s) is identified establish appropriate CAPAs for addressing the causes. With the root causes identified, also perform an impact analysis on other products / batches which could be similarly impacted and take up appropriate remediation actions. Document the entire investigation elaborately which gives the auditors and regulators confidence that the Quality system of the company is robust and if any events happen, the Company will go the depth of the issue and take remedial actions.
Useful links for Fault tree analysis:
Each of the failure / discrepancy as cited in the 483 could have several potential causes, which need to be evaluated and investigated by the CFT. For example:
It is very well understood in cGMP that failures/ deviations should be investigated comprehensively, root causes established, impact evaluated and corrective actions (CAPA) and remediation measures implemented. But still there could be areas/ events where the failure investigations are inadequate – like visible particles excursions, thoroughness of batch records in recording all batch operational data, excursions in aseptic areas, missing to investigate CpK/ PpK indications of process capability issues. Thoroughly evaluate the quality events / failure investigations for lapses, take up further the investigation where gaps are observed and take appropriate actions based on investigation outcome. Document the investigation in detail. Take up programmes for enhancing the competency of the team in investigations of failures; involve CFT in investigation, train the team in scientific investigation tools like Brain Storming, Bish-Bone or Ishikawa analysis, Fault Tree Analysis, FEMA.
The investigation documentation and investigation process should give confidence to the auditors that the Firm and its Quality unit can be relied on for comprehensive investigation and remedial actions when failures and discrepancies occur.
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