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Warning letters, 483s, Recalls, Import Alerts, Audit observations

Updated on May 15, 2024

USFDA 483 / Sun Pharma, Mohali, India / FEI 3002807979 / USFDA Investigators: Justin A Boyd, Teresa I Navas, Jonah S Ufferfilge  / Aug 3-12, 2022 / Observation 1, 2 / Backdating, Non contemporaneous documentation

USFDA 483 to Sunpharma, Mohali unit in Aug 2022 cites Data integrity issues and Backdating, records of activities performed by personnel and personal entry /exits record do not match, deficient investigations. Further the site was put under OAI category and in April 2023 USFDA issued a Consent Decree /Non compliance letter restricting release of batches to U.S  from the Mohali site 

USFDA 483

Observation 1.

Failure to thoroughly review any unexplained discrepancy, whether or not the batch has been already distributed.

  1. Investigations into alleged backdating in QA, QC confirmed backdating; but investigations were not thorough, did not interview / evaluate all QA reviewers, QC employees, did not include thorough review of all other work by employees where backdating was confirmed, did not include specific actions to identify whether backdating is still occurring and extent of previous backdating. 
  2. Disclosure about backdating by a current employee was closed without further investigations for lack of additional information, without justifying why information was not available to initiate investigation.  
  3. OOS investigation 571594 confirmed cross contamination of drug product tablet batches. The investigation led to recall of some batches. However, other batches were released to the market because detected cross contamination was below specification for unknown impurities. Investigation could not determine if cross contamination was uniformly distributed throughout the batches. Investigation did not identify any specific source of contamination, except that use of shared equipment is the likely root cause.

Observation 2.

Established sampling plans, test procedures and laboratory control mechanisms are not documented at the time of performance.

1. Building access records showed an employee responsible for collecting samples did not enter the building where the samples were documented to have been collected, or that employee was in a different building at the time the samples was documented to have been collected. 

a. Samples were documented as having been collected by an employee from production block; but the building access records show the employee accessed the Documentation cell in a different building (using badge access cards); the badge access cards show no entrance or exit from Production block. In another instance badge access records show employee in production service floor while sampling records show samples collection from another block & building at the same time.

b. Badge access records show an employee leaving microbiology laboratory at 11.03, while sampling documentation show sampling performed at 11.03 in service floor of production block. The badge access records show no entry, exit of employee from service floor. (Other similar incidents are observed)

c. In another instance, sample records show sampling performed in manufacturing area in the production block at 12:37 by an employee, but badge access records show the employee was entering the Quality Dining Room at 12:35, in a different building. (Other similar instances are observed – Observations d,e,f)

2. Entries were not made into GMP records contemporaneously. 

a. On August 3, 2022 Logbook for incubator did not have an end of incubation date, time and signature for samples collected on July 27th, 2022 and withdrawn and read on August 1, 2022. (Other similar observations) 

  • Data Integrity issues, backdating of records are an Absolute and Fundamental No-No for Pharma industry (and for that matter for all businesses). Companies should establish strong culture and values – Integrity, Honesty, Compliance to GMP – across the organisation. This should be led by the topmost management of the company. This has to sustained in the organisation through continuous efforts:
    • In depth review & audit of the systems, processes and practices in each site, periodically. Keep tab of the actual baseline and level of the company and different sites in Integrity, Honesty and Compliance. During such audits, monitor activities in depth, how it is performed, documented, when issues (quality events) occur how that is being handled.
    • Conduct small forum workshops, open discussions in each function / department regularly. In departments with more number of people conduct multiple sessions, limit the personnel in each session to 15-20 so that each person gets time to express issues, concerns, suggestions. In such sessions discuss areas where integrity issues happen/can happen (e.g. backdating, release of batches without review and later documentation, data manipulation, records are non-contemporaneous and so on), reasons for such actions (For e.g. Management / Organisational pressures for results / releases which causes personnel into actions and decisions without adequate assessment, Facility /Infrastructure Equipment /Instrument issues, gaps
    • Address the issues. Inculcate a culture where if deviations / failures happen, they are investigated in sufficient detail with adequate time before the issue is concluded and closed; and people are not forced to take decisions under pressure. Empower the team members and the Quality unit to take appropriate decisions.
    • With empowerment of teams and personnel and providing necessary time and management support for the right behaviour, systemic problems of data integrity and non compliance are sure to get addressed. (W. Edwards Deming, father of the continuous quality improvement philosophy, wrote that 94% of issues in the workplace are systemic. Only 6% are attributable to individual-level, idiosyncratic factors). And the exceptions (habitual offenders, persons with wrong attitude) should be weeded out of the system firmly. Have an appropriate Reward and Recognition (R&R) system which supports Compliance and Integrity and zero tolerance for the wrong behaviour and attitude.
  • And when deviation, non-compliance, integrity events and incidents happen, investigate the event as well as impact in depth. The actions should speak for the Company’s intention and approach – No compromise on Integrity, Compliances. No short cuts – when specific events related to specific personnel are identified, all actions / activities performed by the individual to be assessed. And if such events have caused failing /potentially failing batches to be released into the market, root cause investigation and impact analysis should be thorough – i.e.
    • what caused the primary failure, root cause for failure (data integrity, or a deviation like OOS result is an outcome of a fault in a process, system. The investigation should focus on establishing the root cause for the primary failure).
    • Impact analysis and remediation actions. How many batches released into the market could have potential impact, and what is the impact on patient safety. Accordingly take remediation actions. Cover all batches under valid expiry in the scope of assessment.

This is tough, laborious, time consuming; but there is no easier way. Which is why prevention is better than cure.

 

  • When failures / OOS due to cross contamination happen, there is no justification for batch release considering impurities are within specification limits. Impurity specification limits -known or unknown- are for related impurities of a product. Cross contamination is a foreign entity in a product; no specification limits are applicable here. And a contamination cannot be considered to be uniformly distributed in a batch (and hence cannot be reliably estimated). Such impacted batches should not be released for market. And investigations into failures due to cross contamination should be focused to identify potential specific sources of contamination and taking corrective and preventive actions (CAPAs) for each potential cause / source. Assigning broad / general reasons / causes (like use of non dedicated equipment as reason for cross contamination), do not lead to specific actions to prevent future recurrence.
  • Access cards for personnel is good system to prevent unauthorised accesses, demonstrate compliance. But this has to be practiced with discipline. Organisations should establish procedures and processes to ensure that personnel follow the discipline of swiping their access cards when entering different areas (or where electronic access cards are not implemented, recording entry / exits in appropriate log books. Have systems / checks to ensure personnel do not exchange / share access  cards..
  • Engage third party Compliance and Data Integrity expert(s) to investigate and assess the extent depth of data integrity issues. Cover all actions of personnel with whom data integrity issues are identified. Cover all batches within expiry. Cover all such QMS processes / activities (like process validation, equipment and system qualifications) which could have potentially been impacted and hence cannot be considered valid. Perform the assessment with a well-defined protocol. Based on the assessment:
    • Take remediation measures, such as Recall / Stop distribution of batches released and can be impacted.
    • Perform revalidation / requalification of all QMS processes which could have been impacted.
  • Initiate small forum discussions, regular Integrity / Compliance audits for monitoring and tracking whether backdating, non-contemporaneous recordings and other data integrity issues are still occurring. Take actions as described under What companies should do..
  • Evaluate all previous OOS incidents due to cross contamination and assess whether there are other instances where batches which are impacted due to cross contamination but released with a justification of complying to specifications. Based on the evaluation such potentially impacted batches should be recalled / stopped from further distribution. Extend investigation to identify specific causes /reasons that can cause cross contamination during manufacture/ packing /handling. Implement CAPAs for each potential cause.
  • Investigate the depth of issue of conflicting records of activities performed vs employee entry / exit records:
    • covering all personnel for instances of such conflicts.
    • Investigate all observed cases of conflicting records of activities performed vs employee entry / exit records.
    • Expand the scope of such investigation to cover all activities performed by personnel where such issues are discovered.
  • Evaluate the impact of the such actions on the products in market. Alternate controls, checks and balances (eg. Inprocess results, trends, reanalysis of representative batches) may be drawn upon to rationalise the impact / non impact on products and batches. Further take remediation actions (eg. Recall) on potentially impacted batches.
  • A comprehensive training and coaching programme for employees on cGMPs, Compliance, Data Interity, Investigations, Impact analysis and actions (with multiple sessions, regular evaluations through questionnaire as well as assessment on the job).
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  • Qvents Team

    May 18, 2023

    FDA has published the Consent Decree letter issued to Sunpharma. Access the same @ https://www.fda.gov/media/167956/download. In the letter FDA has mentioned that “On March 13, 2017, FDA authorized Sun to resume drug manufacturing operations at the Mohali facility; however, the Mohali facility remains a Covered Facility under the Decree”. However, based on the August 2022 inspection FDA has determined that, the facility is not compliant with applicable regulations and the Decree. FDA has ORDERED Sun Pharma to take corrective actions before any batches are released for distribution in U.S. Sun Pharma should appoint an independent cGMP expert who should submit to FDA a written batch certification protocol which should be approved by FDA. The cGMP expert shall witness manufacture and testing of all drugs, provide a written certification for each batch signed by cGMP expert as well as responsible Sun Pharma employee. This should be submitted to FDA prior to releasing each batch.