Deficient Method Validations, Aseptic area controls – Concerns in USFDA 483 to Cipla

Cipla facility at Verna, Goa was audited by USFDA during June 2024 ending with issuance of USFDA form 483 with six observations. The site was inspected from 10 June to 21 June 2024 by three investigators Tamil Arasu, Eileen A.Liu and Joseph A Piechocki. The audit revealed lapses and weaknesses in Method Validations, Aseptic area controls, Cleaning and disinfecting procedures of aseptic areas, Investigation of failures and deviations, Control of Computer systems and SOP Compliance. Deficiencies in aseptic area controls were observed by Eileen Liu while computer system control issues were observed by Joseph Piechocki.

Methods not validated:

The 483 listed several test methods as not validated, verified or transferred appropriately. Methods listed include inhouse methods and compendial methods of drug products, APIs, in process samples. Inadequate validation /verification of compendial test methods seems to be a new thread getting picked up in FDA audits. 

Aseptic Area controls are deficient:

Environmental monitoring in aseptic areas : Audit raised concern that viable surface monitoring conducted in Grade A areas may not be ensuring all microbial contamination are recognised. Sampling was observed to be performed at random with no systematic sampling plan to ensure uniform coverage of all areas. The SOPs for Environmental monitoring and Microbial monitoring lacked sufficient details of how to swab covering maximum surface area or how to sample flexible pipes. It was left to discretion of operators. An interesting issue was raised on the validation of test methods for surface monitoring. The results of surface monitoring were reported as less than specified cfu values, the Grade A action limits, but the limit of detection was not established. The validation of test methods performed by inoculating surfaces and observing no growth, do not assure that the microbial counts are less than the specified cfu.

Cleaning and disinfecting procedures of room and equipment were deficient to produce aseptic conditions in aseptic processing areas Deficiencies were also observed in Cleaning and Disinfecting procedures followed in aseptic areas. While the intend of disinfectant spray is decontamination of areas which operators cannot reach, the process is not qualified to demonstrate the effectiveness of the same. Operators were also observed to be walking and climbing over to clean machines in Grade A areas, but were not thoroughly sanitising the disinfecting the machine bed while backing out from the area after cleaning. Also, the cleaning technique were not appropriate as operators were seen to be using the same side of cleaning wipe for multiple cleaning strokes.

Failures, Deviations and OOS were not thoroughly reviewed

A media fill (MF) failure with observation of two turbid units was attributed to pinholes, presence of moisture and leakage, and damage caused during transport of the units to incubator. The investigation failed to provide conclusive evidence that the Media Fill failure was due to damaged and leaking containers and not result of failures in aseptic filling process. A stability OOS for assay at 36month time point  was attributed to usage of a specific sonicator compartment for sample preparation, though this compartment was used routinely for sample preparation. It is worth pointing out here that FDA expects thorough manufacturing investigations when root causes are inconclusive as highlighted in several FDA Warning letters.

Control of Computer systems

During the review of software applications such as PC Visual and FactoryTalk View, several deficiencies were identified in user access controls. Notably, user privileges assigned to different roles were inappropriate. For instance, QA personnel were granted “Admin” privileges, which included the ability to modify date and time, create or delete users, and delete batches along with all privileges of the other two user groups – “Operator” and “Supervisor”. Additionally, the review process for user access and assigned privileges was inadequate. Discrepancies were found between the documented user groups in the User Privilege Document and the actual user groups available in the system. System was observed to have additional user groups like Default,” “Administrators,” and “Engineers”. Furthermore, some personnel had multiple user accounts, which were used interchangeably.” These are issues the Operations and Quality units should be wary of. Often, during machine installation and commissioning, various user groups are created for trial runs. Unfortunately, these groups are sometimes forgotten and left behind. Personnel may inadvertently end up using these forgotten user accounts for routine operations.

All procedures applicable to Quality unit were not fully followed

The form 483 also observed instances where the Quality system procedures were not fully followed. Change controls or action items were not initiated as provided for in the procedurefor Formats for lab operation and Guidance for awareness documents issued during analytical testing of drug substance. Form for Stock Transfer (Plant to Plant) were not completed during material transfers,missing entries observed in equipment log book for equipment verification.

The observations outlined in the USFDA Form 483 provide valuable insights into current trends and focus areas for FDA inspectors during audits. Pharma Operations and Quality teams may do well to reflect on the current trends and proactively enhance the robustness of their systems, ensuring they are always audit-read

USFDA 483