USFDA 483 / Jubilant Roorkee / 3006895982 /1 Aug 2022 / Yvins Dezan & Rajiv R Srivastava / Observation 2

Written records are not always made of investigations into unexplained discrepancies:  

A.     Firm failed to investigate twenty-five (25) equipment failures/errors “Cannot Operate because of failure” observed on 07/21/2022 in the Lab Solutions Ver. 1.108 ( data acquisition software) for UV-Visible Spectrometer equipment (ID #QC/UVS/003 and QC/UVS/004) ranging from February 02, 2019 to June 10, 2022 period. The UV-Visible Spectrophotometer is utilized for qualitative and quantitative analysis of drug product and drug substances. The equipment has been used to analyse products and release for distribution to US market.

B.   Firm has not initiated an investigation for following equipment failures observed during inspectional walkthroughs to determine when the malfunction occurred, if the equipment was in use, and perform any impact assessment of the current and previous samples or load ran on the equipment. The equipment below was labelled “Out of Service / Do not Use”:. 

1.     Equipment ID #QC/XXX/002 placed “Out of Service/ Do not Use” on July 06, 2022 due to “display not working”

2.     Equipment (ID #QC!XXX. 009) was placed “Out of Service/ Do not Use” on July 2022 due to “Key panel not working”. In addition, you do not maintain an equipment usage logbook for the equipment.

C.     We observed the system (ID #QC /XXX/003) displayed an error message during our inspectional walkthrough on July 20, 2022. However, you have not taken any actions to address this and your current equipment SOP OC188 Rev-2~ (Operation, maintenance and cleaning procedure of the equipment) does not delineate any provisions for addressing this type of error message. In addition, you do not maintain an equipment usage logbook for the equipment. 

D.    You failed to investigate alarms observed in the data acquisition system (SCADA) and you do not perform a documented review of the alarm logs and audit trail for the software:

1.     Microbiology lab: Fail, Fail, …………PLC to SCADA communication failure………fail……..fail. PLC to SCADA communication fail.

Firms should perform an assessment of all equipment, instruments (QC labs, Manufacturing, Engineering) for GxP criticality, document the same and have comprehensive procedures for review of audit trails of all equipment, instruments (type of audit trails to be reviewed, handling of audit trail events etc), log books for logging operations and breakdowns, handling break downs, error messages, critical alarms

For all systems that generate electronic data there should be adequate procedures for reviewing the audit trails. The procedures should detail the different audit trails recorded in the system and periodic review of the audit trials (eg: every batch or sample load or as per defined frequency). Review of the audit trail should be documented with assessment and conclusion of events recorded in the audit trail (e.g.: A print of the audit trail can be taken and reviewed by the quality unit with appropriate comments and conclusions or audit trail review could be documented against a review checklist). The audit trail review procedure should give guidance on what events / messages are critical and need investigation and which of them are normal/ /transactional. If events are repeated often, they should be escalated to equipment service provider for permanent solution.

All laboratory equipment should have usage logbooks. All equipment breakdowns (out of service) should be logged with date and time. (For e.g.: log the breakdown in the equipment logbook along with primary evaluation comments. Also identify whether it require logging of a quality event (e.g. logging a deviation) and investigation and if investigation is not required document the justification. The equipment operation procedure (SOP) should give guidance on what type of breakdowns, error message etc require an investigation, impact assessment. 

When observations are made during regulatory inspections, it would be appropriate to document a quality event (e.g.: a deviation) and initiate an investigation. Necessary immediate remediation actions should be taken where feasible. If the event is not having a quality impact document the same as part of the investigation. 

Procedure for alarms handling should be part of the operational SOP for all GMP critical equipment and instruments which generate alarms. Alarms may be categorised as Critical / Major / Only for alert (information) & actions required to be taken against different alarms should be listed. Equipment and systems should ideally have an alarm log with traceability to the activity performed (such as a sample set analysis). Review of the test and results should include a review of the alarm log of equipment’s involved. A print of the alarm log can be taken and reviewed and the same can be filed along with test results; alternatively use an alarm review checklist. Typical alarm review documentation will show there was no abnormal events / alarms or in case of any abnormal critical alarms, the actions that were taken, impact assessment and conclusion. (Similar procedure for alarm handling should be implemented for other GxP equipment & systems as well – e.g. manufacturing equipment, HVAC systems etc).  

A.   Initiate an investigation on the  observation equipment failures / errors “Cannot Operate because of failure” in the Lab Solutions Ver. 1.108 ( data acquisition software”; a quality event (deviation) may be logged on the observation.

·      Evaluate the error message displayed with respect to why, when, where and what impact the error message would have on the activity performed on the equipment. Evaluate the specific cited error message as well as other messages the equipment / system can generate. Based on this identify critical error messages, which could have an impact on quality of the batches analysed on the machine. If the cited error message is a critical message, evaluate the impact on the batches analysed om the equipment – adequate consideration may be given to subsequent controls, test results for the specific parameter, test results of other parameters while performing the impact assessment. Also review the list of products & batches (with a valid expiry date) in which the equipment is used for any critical error messages in the instrument/software; perform an impact assessment on any batches with critical error message in the instrument. Accordingly identify actions to be taken on distributed batches. If no actions are necessary the same should be supported with sound scientific rationale. The investigation, evaluation performed should be adequately documented and and included in the response to FDA on 483. Escalate the frequent occurrence of the error message with equipment service provider (Vendor) to work out permanent solution.

        Further corrective and preventive measures to be implemented to prevent such observations in future. For all systems generating electronic data, establish and implement procedures for review of audit trail addressing all the points identified above  – Refer – What companies should have in place (to avoid such observations -A.

B.     Investigate the observations:

·        Equipment ID #QC/XXX/002  – due to “display not working”

·        Equipment (ID #QC!XXX. 009)  -due to “Key panel not working”.

It will be appropriate to log a deviation and do the investigations. Evaluate the error message displayed with respect to why, when, where and what impact the error message would have on the activity performed on the equipment. Evaluate the error message displayed as well as what other messages can be generated by the equipment, what impact the error messages would have on the activity performed on the equipment. Based on this identify critical error messages. Evaluate whether such critical messages could have an impact on quality of the batches analysed on the machine – adequate consideration may be given to subsequent control. Review the list of products for which the equipment is used in analysis and evaluate whether any of the batches /products tested on the equipment and are with valid expiry will have an impact.  Accordingly identify actions to be taken on distributed batches. If no actions are necessary the same should be supported with sound scientific rationale. The investigation, evaluation performed should be adequately documented. (And included in the response to FDA on 483).

Further corrective and preventive measures to be implemented to prevent such observations in future. Implement log books for all analytical equipment, log breakdowns. Establish procedure for actions in case of breakdown of equipment addressing the action points elaborated above (What companies should have in place (to avoid such observations – B) covering logging of breakdowns, evaluation and investigation where necessary and documentation. This may be captured in the respective equipment operation procedures.

C.    The actions for the observation C will be similar to that explained above under B. Log a deviation on the observation and evaluate. Also document immediate actions taken on the observation; include any evidence of actions taken – such as equipment screen shot, log book entry. Perform and document the investigation as elaborated under B and establish corrective and preventive actions (CAPA).

D.   Investigate the alarm on the specific system. Evaluate the equipment / SCADA system and identify all alarms that can be generated by the system. Evaluate what impact the alarm would have on the activity performed on the equipment. Based on this identify critical alarms. Review the alarm logs and audit trail for the software and identify where critical alarms are recorded and perform an impact assessment.  Accordingly identify actions to be taken on distributed batches if any. If no actions are necessary the same should be supported with sound scientific rationale. The investigations, evaluation performed should be adequately documented. (And included in the response to FDA on 483). 

Establish corrective and preventive actions covering points elaborated above (What companies should have in place (to avoid such observations – D) – Alarm handling procedure, classification of alarms, review & reconciliation of the alarms. 

General

The observations A, B, C, D are related. The one common theme is about the procedures practices in place for Handling of equipment breakdowns / error messages and review of audit trial. It will be appropriate to establish a comprehensive guideline procedure for Maintenance of analytical equipment covering (but not limited to) below points: 

• Logging of equipment breakdowns and evaluation.
• The procedure should clarify for what type of error messages investigations will be necessary and procedure for documentation of investigation, root cause(s) and CAPAs. 
• Handling of Error messages. All equipment operational procedure would document handling of error messages as applicable. Classification of error messages and actions required.
• Handling of alarms. All equipment operational procedure would document handling of alarms as applicable. Classification of alarms and actions required. Alarm reconciliation.
• Review of audit trail for errors, alarms, periodicity