USFDA 483 / Lupin, Pithampur, India / FEI 3007549629/ Inspection Mar 21 – Mar 29, 2023 / FDA Inspectors – Eileen A Liu, Yvins Dezan / Observation 2 & 3

The Observations 2 A & B and Observation 3 which cites several market complaints for foreign capsules in sealed bottles, short counts / under filled sealed bottles are linked

Observation 2

There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has been already distributed.

Specifically,

A. The Firm failed to document deviations/ equipment failures occurring during manufacturing and packing in the batch record, Initiate investigations, including risk assessments, and appropriate corrective and preventive actions (CAPAs) into the breakdown of critical process equipment / critical breakdown notifications. 

The firm recorded 1695 breakdown notifications from January 2019 to March 2023 for one equipment (but investigated only 41 – 2.41% ) and 64 breakdown notifications for another (and investigated only 7  – 10.9%). 

B. Deviation investigations are not thoroughly investigated and appropriate action are not taken to prevent recurrence. For example,

a. Deviation #DEV-IP-136-20-0062 revealed that a foreign filled capsule was found by Firm’s inspector during the visual inspection of a batch of Capsules. Investigations revealed the foreign empty capsule was supplied in shipment of specific empty Capsules for the product by a vendor. The Firm utilized this batch of empty capsules where the foreign empty capsule was found for other batches, which were also released to the US market. However, the Firm failed to file a Field Alert Report (FAR).

b. Deviation #DEV-IO-136-22-0003. Manufacturing data was not captured in the data acquisition software during manufacture of batch (US market). Manufacturing data was lost for 10 minutes (for a critical step, according to the Manager of production who also stated there was no product impact). However, this is a recurring deviation and you initiated an ineffective CAPA for manufacturing data previously lost and where it was proposed to capture the data manually in the batch records).

c. Deviation DEV-IO-136-19-0034. During manufacture of batch production person noticed that data recording was not started. The root cause was attributed to human error where it is stated the operator might have missed to switch ON power button, although it is stated in the investigation report there was no identification available whether the switch was on or off. However, you failed to interview the operator prior to reaching the root cause, and the batch record does not delineate any instructions for the operator regarding turn on/off of the switch. 

C. Firm failed to implement controls to support the integrity of data. 16 breakdown notifications were recorded where manufacturing data was not captured in the data acquisition software for some manufacturing and packing equipment during batch operations, for U.S. marketed products. However, only one out of 16 breakdown is investigated. All the batches were released for US. 

In addition, two repeated critical breakdown notifications were recorded where data was not captured /aborted during manufacture of batches for U.S. market. However, Firm failed to investigate the reason and take appropriate action to prevent recurrence. 

D. Assigned root causes for laboratory OOS result are not always scientifically justified. Specifically,

a. OOS/C/19/IN2/SS/014 observed in dissolution test for a batch of tablets in 3 Month long term (LT) stability study. One of the hypothesis studies demonstrated that the wrong filter usage and not discarding aliquots during filtration would cause a similar OOS result. The investigation concluded root cause for OOS is laboratory (human) error. However investigation did not contain confirming information because the conclusion of wrong filters used was not substantiated by the analyst interview and the filters had been discarded. No manufacturing investigation was conducted. Observed OOS results were invalidated, retest results which were within specifications were reported, and the batch remained in the US market with an expiration date of January 2021.

b. OOS/C/20/IN2/SS/004, OOS result in related substances test of tablets, during stability study at 24 months for an individual unspecified impurity. Hypothesis study and investigation concluded root cause for the unknown impurity peak was contamination of sample solution during sample preparation. However the contamination was not admitted by the analyst. Further, the assigned root cause referenced an unrelated OOS investigation were an experiment was conducted during sample preparation. Different probable contamination sources were not assessed. No manufacturing investigation was conducted. The root cause of contamination attributed to the observed impurity in the batch was unsupported. The OOS results were invalidated, retest results were accepted. Batch remained in U.S. market with an expiration date of January 2021.

c. OOS/C/20/IN2/SS/006 Capsule batch OOS for assay during stability study at 3 Month Long term. Hypothesis study and investigation concluded root cause for the OOS was improper shaking during sample solution preparation. Assigned root cause is unsupported because analyst stated applicable STP was followed. Further investigation study demonstrated different combinations did not product passing results on the batch. Firm lacked scientific justification that improper shaking attributed to OOS result. Observed OOS invalidated, retest results were accepted and the batch remained in U.S. market till expiration date. 

Observation 3

Written records of investigation of a drug complaint do not include the findings of the investigation and follow up.

Specifically, complaint investigations are deficient. Firm has received several repeated market complaints for Tablets and Capsules (observation of foreign capsules) marketed in the U.S. In the resulting investigations, it is concluded the complaints are unconfirmed. However, our (FDA inspectors)
inspectional walkthroughs and some of the investigations revealed some of the foreign tablets are actually manufactured at the facility and are being filled into the capsule products. Our Firm have not taken any effective measures to prevent recurrence.

A. Firm received several complaints for foreign tablets/capsules, including two complaints for Capsules (#DPC-1O-134-21-0041 on July 19, 2021 and DPC-1O¬134-22-0069 on July 1, 2022) where the complainant reported that a foreign tablet with no marking were found in a sealed bottle. Firm concluded in the investigation, this did not occur at the facility which were unconfirmed. However (inspectors) observed the Firm processed a Deviation #DEV/IO-136-200062 where a foreign filled capsule with different marking was found by the Firms visual inspector in a batch of Capsules in the inspection area on October 20, 2020. 

In addition, (the Inspectors) observed during inspectional walkthroughs that the packaging lines are not equipped with Vision system for detecting foreign capsules and tablets. (Inspectors) also observed that in-process samples (tablets) collected from equipment (ID #TCM303) are returned to the equipment/batch during inspectional walkthrough on 21st March 2023. 

B. Firm recorded at least 40 complaints for short count / underfilled and for different products from 2019 to date. Firm has not taken any appropriate actions to prevent recurrence, and concluded they did not happen at the facility through deficient investigations. (Inspectors)  observed during inspectional walk throughs that Firm only challenge Check Weighers at the ___of the manufacturing and packing operations. In addition, (inspectors) observed that Firm recorded 18 notifications from the equipment breakdown for Check Weighers during operation where the Check Weighers were not working or the ….. was not working. (As reported in Observation 2)

To prevent (repeat) issues like foreign capsules in sealed bottles, short count / underfill in sealed bottles several measures to be in place.

• If there is an issue at Vendor end, where different colour /spec empty capsules are getting mixed up, this need to be addressed. Companies should have good control on the vendors – Meaningful vendor audits (looking at depth extent of controls and GMP practices), corrective actions for deficiencies. If issues are recurring actions including delisting vendors who do not comply to be considered.
• Procedural controls should be established to ensure no contamination / mix up / defectives adding back due to return of inprocess / other samples to the batch. No return of samples which has gone out of the line (like Inprocess testing lab) to batch, inspection before returning any samples picked from the line.
• Visual systems should be implemented and validated. Manual Visual inspection may pick some of the abnormalities / failures, but this will not be foolproof. A Visual Inspection / Camera system in the packaging line followed by manual visual inspection lends strength to be process. And the manual Visual inspectors should be periodically rotated (e.g every two hours) to avoid errors due to fatigue. This should be part of procedure.
• Check Weigher systems should be reliable. They do not have a direct impact on quality. But still considering the scope for complaints due to short counts, underfilled bottles, empty blisters etc the Check Weighers should be robust for the purpose.
• Complaint investigations (and all failure investigations) should have depth. The Investigation process should be able to pull out data from different Quality events recorded within the company (like Deviations) which could have a bearing on the complaint. Repeat complaints should be addressed with seriousness (Remove an attitude of – This cannot happen at our facility, preconceived conclusions where investigation gets reduced to documentation of justifications). In the complaint investigation procedure / investigation checklist there should be check points to look at whether any related internal deviations / incidents / OOS have occurred / recorded.
  • The complaint investigations should be handled by a cross functional team (CFT) using appropriate tools. In larger organizations it could be possible that different Quality events are handled by different teams. But there should be adequate interfaces between different teams / members to ensure all possible angles and factors are covered and an appropriately constituted CFT will add strength to failure investigation.
  • Management reviews (Quality leadership, Leadership Management) with defined agenda to review Quality events, trends can also add strength to the company’s Quality systems, investigation process. Repeat complaints and trends, repeat deviation events should raise eye brows in an effective Management review; and lead to additional evaluations and investigations and effective CAPAs. 
• The failure investigations including Deviations investigations should look at the impact on other batches and products and take appropriate actions. And if there is an impact / potential impact on distributed batches, appropriate actions should be taken. When it is a U.S batch, companies should file Field Alert Report (FAR) within 3 days of the deviation /failure unless the investigation is completed concluding no potential impact; and documented with rationale. While the investigation /impact assessment can continue and actions taken commensurate with risk to patient. [A recall may not be warranted on observation of a foreign filled capsule in a batch, if it is concluded this will not have a patient impact and scientifically justified (e.g. only a wrong capsule shell, but same active in the capsule); but this will still call for a FAR]. 

• Equipment generating electronic data should be in compliance to 21 CFR Part 11 requirements and loss manufacturing data is a GMP violation. It is not sufficient justification that the Firm has manual documentation procedure and Quality Management systems (QMS). It is possible that companies have old legacy systems with hardware / software limitations causing loss of data, missing data and other deviations from GMP requirements for control of electronic data. Companies should have a comprehensive documented assessment of the equipment and systems  – whether it is a GxP system, risk from the system (such as loss of data, gaps in compliance to 21 CFR Part 11 requirements) and a plan in place to replace /upgrade systems. Meanwhile there should be alternate controls established, like manual recording. It cannot be like when deviation happens, system fails to record data, perform manual recording – otherwise depend on a unreliable electronic recording of data. This is not a consistent approach with GxP rationale. The more critical the equipment / system, the more risk, more priority for such upgradations / replacements of equipment and systems. 

• Companies should have procedures / systems in place to record, review and conclude on deviations like breakdowns / breakdown notifications. It can be either through raising deviation notes as required by procedures for handling deviations; or part of other documentation like Batch documentation. Reviewing the machine data, electronic data, breakdown notifications etc.should be prompt during / immediately after a batch operation. Have a system for recording breakdowns / breakdown notifications / alarms etc. which occur during batch operations, reconcile the same at the end of the batch – whether it is critical, impact, resolution. Based on criticality and impact specific deviation can be logged as per Deviation procedure and investigated and concluded before batch release. CAPAs identified shall be logged and tracked through procedures for handling CAPAs. This can be a Batch record review and release check point – are breakdowns / notifications reviewed / reconciled / concluded.

• OOS Investigations and handling should be consistent, rationale for invalidation sound. The OOS investigation procedure should be detailed and in compliance to the USFDA (Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production) & MHRA ( Out-of-specification investigations) guidelines. The procedure should address in a systematic manner:

  • Phase 1A investigation – obvious Laboratory errors
  • Phase 1B investigation – extended investigation into potential laboratory errors
  • Phase 2 – full scale investigation covering production process, sampling methods, additional laboratory investigation
  • When laboratory investigation is not conclusive, and projected root causes are based on hypothesis of potential errors, there should always be a production process investigation to determine whether the OOS is due to lapses/concerns in production process.
  • Phase 1B investigation should be done meticulously, as this becomes the basis of many hypothesis testing – such as impact of inadequate shaking of solutions, using wrong filters, not filtering solutions properly, sample contamination and so on. It should not be hurried (typically, checking all the points with a Yes). Even when an Analyst is broadly aware of the methods / procedures, potential areas where human errors can occur should be identified during the Phase 1B investigation. This is what is further evaluated through hypothesis testing.
  • Clearly defined responsibilities of laboratory analyst (following the test methods and procedures fully, reporting the OOS promptly, documenting obvious errors), laboratory supervisor (review of the OOS results, test solutions, instruments, data and documents, analyst interview to check knowledge and procedures followed), Quality unit (review of laboratory investigation, extend OOS investigation to production process and controls, evaluation of root cause and CAPA identified and their adequacy, impact assessment and remediation action, conclusion of investigation, batch release decision) in OOS investigation. There should be appropriate checklists to document all aspects of investigation to ensure no areas are missed.
  • All test solutions, test accessories of sample analysis should be retained till results are calculated; This is important for Phase 1A & 1B investigation, in case the results are reported OOS.
  • Criteria for retesting and resampling should be well defined.
  • Extension of investigation to other potential areas which could be similarly impacted (e.g if the root cause was in inadequate calibration or maintenance of specific laboratory instrument, whether similar situation can occur in other instruments ad methods)
  • Impact assessment (whether other batches, products could be similarly impacted) and remediation actions
  • Review of implementation of all remediation measures and CAPAs
  • Tracking of OOS trends, periodic review of trends to see recurrence of OOS incidents
  • Effectiveness evaluation of CAPA. (If CAPAs are effective, the incidence should not recur).

• Comprehensive assessment of all manufacturing equipment against a well defined protocol identifying aspects such as (but not limited to): Type of Deviations with respect to breakdowns and breakdown notifications (missing data and other failures), Frequency of Deviations, Probable root causes (including reasons such as legacy equipment/system, software issues, hardware issues), Impact/Risk of such deviations, Proposed CAPAs and timelines, Alternate controls. Based on this assessment work out a plan for upgradation / replacement (long term) and alternate systems (such as manual documentation) for immediate controls. The scope of review shall be at least covering the expiry date of all distributed batches.
• Establish system / procedure / checklists for recording and review of all breakdowns / breakdown notifications during batch operation / immediately after the batch. Make it part of Batch record review / Release checklists.
• Re-Open the investigation into Deviation(s) for foreign filled capsules / unmarked capsules.
  • Align with vendors of empty capsules for investigating the discrepancies and establish root cause and corrective actions at vendor end.
  • Vendor audit of the suppliers with an objective of identifying sources of errors / scope for corrective actions. Ensure the identified CAPAs are implemented through follow up.
  • Establish corrective actions to improve detection of such failures at the Firm – Vision systems in packaging lines, Improved procedure for manual Visual inspection with periodic rotation of inspectors
• An assessment of all the complaints received covering a reasonable timeframe to get a good overall overview of different type of complaints. The assessment should also cover all batches within expiry. Review all the complaints received against a well defined protocol covering  – Whether Complaint was substantiated / Unsubstantiated, Whether there are internal quality events recorded for similar issues (deviations, OOS), Root cause identification status. Whether sufficient CAPAs are identified / implemented, Effectiveness of CAPAs (by reviewing recurrence of similar events after CAPA implementation), Additional measures required if any, GxP risk assessment of the complaint / root causes, Rationale if no GxP risk / risk to patient safety, Impact on other batches / products where there is a GxP Risk / risk to patient safety, Mitigation actions to be taken (like recall where a risk exist) and rationale if no mitigation actions are necessary. Based on this draw up an action plan for additional CAPA / mitigation actions such as recall and implement.
• Review and revamp the OOS handling procedure ( as detailed under What companies should do..). Training and coaching to personnel on revised OOS procedure.
• Review all invalidated OOS of (covering all batches within expiry) against a defined protocol with check points such as but not limited to- Is probable root cause(s) identified, are the root causes established with sound rationale, whether a manufacturing investigation is performed (to be performed if not done) and any manufacturing related root causes for the observed OOS, Is an impact assessment performed considering the root cause (impact on other batches, products), Identification of Impacted batches, Remediation actions taken/ to be taken on impacted batches, status of CAPAs, whether any additional actions are necessary. Based on the assessment draw up an action plan.
• Review and upgrade the Check Weigher systems; Increase frequency of challenge tests during batch operation.
• Review and revamp the Failure investigation procedure /Complaint investigation procedure – Cross functional Teams (CFT), Check points for reviewing similar quality events, their investigations and CAPAs and CAPA effectiveness and other enhancements.
• Review the Management Review procedure / practices. Quality events / Failure investigations /Trends should be part of Management review meeting (Quality leadership, Senior Executive leadership) with assessment of sufficiency of actions, need for additional actions and follow up.