Warning letter Sun Pharma Dadra Unit: Ineffective Quality Systems

During the December 2023 inspection, FDA investigator discovered stagnant liquid or water in the duct of a manufacturing equipment after the air purifier and micron filter. This was traced to a faulty valve which failed to completely close and seal when it was last disassembled in June 2023. Analysis of the liquid showed numerous peaks in the chromatogram corresponding to previous manufactured drug products, actives in the drug products and their degradants. Microbial analysis of the liquid showed high total aerobic microbial counts (TAMC) and yeast and mould count (TYMC). The high-velocity air passing through this contaminated section of the duct posed a risk of contaminating drug products manufactured in the equipment. As a consequence of these observations, Sun Pharma recalled several batches of potentially impacted drug products. More than 25 lots of tablets manufactured between June 2023 and December 2023 were recalled due to microbial contamination in stagnant water in the duct of the manufacturing equipment. (Reference: USFDA Enforcement Reports)

In response to the FDA’s form 483, Firm informed the agency about the recall and rejection of potentially contaminated batches. Also the maintenance programme was assessed by a third party consultant which identified numerous gaps but there were no critical or major findings. However, FDA found the response inadequate. FDA pointed out that the investigation failed to identify all the unknown peaks in the stagnant liquid and did not address the cross contamination issue sufficiently. FDA has asked the Firm to perform a comprehensive independent assessment of its cleaning programme and effectiveness and provide remediation plans, provide CAPA plan for vigilant operations management of facility and equipment, review methodology used to identify the unknown peaks and scope of investigation and sufficiency of related CAPA.

Learnings

During the inspection FDA observed issues in Maintenance programme and monitoring of equipment, which led to other concerns over overall programme for Cleaning and cleaning effectiveness and Capabilities to identify and characterise contaminants. The assessment and remediation actions should address all the three issues

Maintenance programme & Monitoring:

Companies should have a good grasp of its manufacturing equipment and facilities and potential for contamination due to manufacturing equipment. A systematic assessment is essential to identify potential contamination risks due to equipment

• Identify non dedicated equipment: These pose a higher risk of cross-contamination
• Perform a risk assessment: To assess what can go wrong / fail and what is the Likelihood of failure, Detectability if a failure should happen and Severity. Identify measures to
  • Reduce Likelihood of failures – For e.g. Improve quality of components, materials (like lubricants), technical upgrades to equipment, Increasing frequency of maintenance
  • Improve Detectability of failures – For e.g. Alarms, Improved frequency of monitoring
  • Reduce Severity – For e.g. Improved frequency of monitoring leading to timely corrective actions,
• Identify conditions which can cause contamination, product impact – For e.g. proximity of exhaust vents from manufacturing area to air inlets of air supply units, acidic fumes / humidity causing corrosion to equipment part, components and so on.

Based on the assessment enhance the maintenance and monitoring programme comprehensively. This could include (but not limited to) -revising frequency of preventive maintenance, regular inspection of critical equipment, technical upgrades of equipment, modification / relocation / replacement of equipment, enhancement of operating and maintenance procedures, periodic review of trends. Review the performance of maintenance programme in management reviews.

Cleaning and cleaning effectiveness:
When critical deficiencies in cleaning practices and procedures are observed this need to be addressed comprehensively to allay concerns of cross contamination of products and assess status of the products released to market. FDA expects a comprehensive, retrospective and independent assessment of total scope of cross contamination due to concerns over cleaning effectiveness. This exercise shall cover all manufacturing equipment, identify all vulnerabilities in the cleaning and verification procedures and assess risk of any contaminated product being released to market.

A comprehensive assessment of cleaning and cleaning effectiveness should be a systematic protocol driven activity:

• Review all manufacturing equipment and separate dedicated and non dedicated equipment
• For each non dedicated equipment perform and document a detailed assessment against a checklist, for e.g.:
  • Review of current cleaning procedure for each equipment
  • Does cleaning procedure cover cleaning of all product contact areas
  • Are all product contact areas verified for cleanliness after cleaning activity
  • Does the manufacturing equipment have accessories or components like air supply ducts, ducts for other utilities like nitrogen, inert gases, utility lines like water, steam
  • Whether the accessories and components have potential for accumulation of contaminants. Are such accessories and components routinely cleaned and verified after each cleaning.
  • Are there rough surfaces, holes, other hidden pockets where product dust can accumulate. Are all such pockets specifically cleaned and verified
  • Whether the cleaning and verification procedure cover all hard to clean and difficult to access areas in the equipment
  • Whether all possible contaminants, degradants that can potentially contaminate the equipment surfaces and product identified, considering all products manufactured with the equipment
  • Has the cleaning verification evaluated all such possible contaminants. Are appropriate limits applied for all possible contaminant residues.
  • Are the methods and procedures used for testing of the residues adequately validated
  • Whether possibility of microbial contamination considered. Are there procedures and steps to prevent microbial contamination of equipment and product from equipment
  • Whether the equipment cleaning and verification include verification of microbial contamination (like swab tests)
  • Are all sampling methods for cleaning samples (like rinse sampling or swab sampling) validated
  • Is there potential for contamination due to any gaps identified in the assessment.

Answer each checkpoint with Yes or No along with rationale. Based on this identify the list of actions for enhancing cleaning, cleaning effectiveness and cleaning verification with timelines. If there are any products which are at risk of cross contamination, initiate actions for product recall. Such a comprehensive assessment and action should give confidence to the FDA that all cleaning procedures are comprehensively reviewed, gaps and corrective measures identified and implemented / under implementation.

Identification and characterisation of contaminants

In incidents of unknown peaks in chromatograms raising concerns of potential contamination, adequate efforts shall be made for identification of all unknown peaks. This is key for establishing possible sources of contamination and take appropriate corrective measures. Such efforts shall include an assessment of the unknown peaks against all potential contaminants. For example, define and execute a protocol for assessment of cross contamination covering all products handled in the area, actives (APIs) involved in the products, degradants from the products and the API. A systematic assessment can provide much more information on the unknown peaks rather than a simple LCMS or GCMS runs.

In the OOS investigation for a stability OOS at 12month station for unknown impunity, the root cause kept changing. Initially it was dirty glassware, though similar peak was observed in other batches and previous stability station sample. During inspection when the assigned root cause of dirty glassware was challenged, the investigation was reopened and root cause was concluded as contamination from another product analysed at the same time. But the retention times were not matching with unknown peak. And in the response to the FDA 483, root cause assigned was laboratory contamination. The Warning letter cited the response was inadequate, investigations lack root cause determination and scientific rationale and evidence. FDA has asked the Firm for an independent and comprehensive review of:

• All invalidated OOS results of last 3 years and determine whether causative laboratory error is conclusively identified with scientific justification and evidence
• Where causative laboratory error is inconclusive perform thorough Production review/ investigation
• Systems for investigation of OOS as well as deviations, discrepancies, complaints, failures
• CAPA program and effectiveness
• Laboratory systems, practices, procedures, competencies.

The Warning letter also highlights that inadequate investigation of extraneous peaks is a repeat observation at the site. The Firm was issued a Response letter in September 2017 where in it was stated that glassware contamination should not be a frequent justification for rejecting or invalidating OOS results.

Learnings
Invalidation of OOS results without adequate scientific rationale and evidence flags 3 concerns – 1) Robustness of Laboratory processes 2) Robustness of Product and manufacturing process 3) Robustness of Quality systems, Quality Unit and its functions. As FDA pointed out in the Warning letter, remediation actions should cover assessment of all three areas.

 1. Laboratory processes:

In invalidated OOS investigations with laboratory error as root cause, concern is whether the root cause is conclusive or inconclusive and identified CAPAs are adequate to prevent recurrence. If a root cause is conclusive, it would be supported with evidence and sound rationale or else it is inconclusive. An OOS caused by laboratory error, for e.g poor column performance with distorted peaks, instrument malfunction like a sudden drop in pressure in HPLC, abnormal results caused by usage of wrong glassware (like assay less by 50% due to dilution error) etc. are examples of conclusive laboratory error. Mostly they have evidence in the form of electronic records or the errors are very obvious. However, projected causative laboratory errors like glassware contamination, sample contamination, sample exposure, lack of awareness of analyst and so on and so forth cannot be considered conclusive root causes. They are mostly hypothesis. For both conclusive and nonconclusive laboratory errors, corrective actions (CAPAs) should be established. And if OOS are getting repeated, obviously there is an issue with the root cause(s) and CAPA.

Develop an assessment matrix for invalidated OOS, define scope & period of assessment with rationale. :

• evaluate whether root causes identified are conclusive or inconclusive,
• If conclusive what is justification and evidence
• if inconclusive what is scientific rationale
• is CAPA established, is CAPA extended to other methods and products
• Are there recurrence of issue post implementation of CAPA, Is CAPA effective,
• What additional actions are required
• Timelines for additional actions
• And In case of Inconclusive OOS is Manufacturing investigation performed.

The assessment shall come up with a list of actions with timelines for enhancing the robustness of Laboratory processes. Also identify the list OOS incidents which will require Manufacturing investigation.

2. Product and Manufacturing processes:

Perform a comprehensive Manufacturing investigation for invalidated OOS without a conclusive laboratory error. Evaluate

• Product history (e.g – last 3 years) – Number of batches manufactured, number of valid OOS, number of invalid OOS, number of deviations, number of complaints
• Deviation history of the product; Whether such deviations can cause the OOS; If not Why
• Complaint history of the product; Any similar issues in complaint, whether the root cause for complaints can cause such OOS; If not Why
• Failure history (OOS, OOT etc) of the product; Any similar issues in failure, whether the root cause of past failures can cause such OOS; If not Why
• Are all CAPAs related to past deviations, complaints, failures closed; If not what is targeted timeline
• Are manufacturing steps adequate, What is rationale
• Are Equipment suitable and adequate, What is rationale
• Concerns on Raw Material variability; Rationale
• Process Capability Measures (for e.g CpK of different parameters like Assay, Related Substances, Content Uniformity etc)

Based on this assessment identify further actions required for improving Product / Process robustness, closure of open CAPAs, Timelines

3. Quality Systems, Quality Unit and functions:

Accepting root causes for OOS (and other failures) without scientific rationale and willingness to change the root cause each time, again without justification all raises concerns of Quality Unit oversight, investigation competencies and adequacy of procedures. This call for a comprehensive assessment of Quality unit functions, competencies, knowledge and bandwidth to investigate deviations and failures and adequacy of procedures.

a. Brain storm reasons for lapses in investigations by Quality unit with involvement of executive management and identify actions; For e.g.

• Quality Unit competency and bandwidth for Investigation of OOS, Laboratory Incidents:
• Adequacy of personnel / Workload
• Attitude issues for GMP & Compliance:

Perform similar assessment for competence and skills for Quality oversight over Manufacturing, Engineering, Computerised systems, Materials. Actions could include developing specific teams for review of QC /Laboratory practices and incidents; hiring specific leadership skills; reskilling programme, increasing team strength, behavioural assessment, programmes for improving approach to GMP implementation, redeployment staff

b. Procedural improvements

• Detailed checklists for OOS investigation and review, to be completed before OOS disposition with check points like:
  • Is root cause established
  • Is it conclusive / inconclusive laboratory error
  • Is evidence/ rationale available and justified
  • Is Manufacturing investigation performed
  • Is Impact assessment performed; Is scope of impact assessment justified
  • Are CAPAs established
• Establish similar checklists for review of deviation investigations, complaint investigations
• Establish process and frequency for review of laboratory adverse trends – for e.g. (but not limited to) Invalid OOS, Laboratory errors / incidents, CAPA status, Complaints due to laboratory error, Stability delays, Deviations (planned & unplanned)

Such an exercise will go a long way forward in revealing underlying issues of Quality incidents and failures and establishing corrective actions to prevent recurrence of failures.