FDA Identifies Common Preapproval Inspection Deficiencies

One of the common deficiencies cited during drug preapproval inspections is inadequate process design or justification for the commercial process/control strategy, CDER Office of Pharmaceutical Quality Division of Inspectional Assessment quality assessment lead Quallyna Porte told a 7/22 Pharmaceutical Quality Symposium webcast. Porte said inspection teams typically have three objectives when conducting preapproval inspections — assessing the readiness for commercial manufacturing, assessing the conformance to the application, and a data integrity audit. When assessing commercial manufacturing readiness, other common deficiencies cited include:

• Significant general good manufacturing practice issues
• Commercial scale equipment not qualified
• Analytical methods not transferred/verified/fully validated
• Failure to adequately investigate unexpected deviations, discrepancies, trends, and out-of-specification results
• Lack of GMP training or GMP understanding

Under the second objective, conformance to the application, inspectors are determining whether firms are conforming to what is indicated in the application, according to Porte. One of the common deficiencies is the commercial scale equipment listed in the application is not available. For example, a facility listed as a labeling/packaging facility for a particular application is inspected and no equipment is found, she said. Other common deficiencies under conformance to the application include: 

• Manufacturing process changes and/or in-process control revisions not reported after filing
• Method updates not reported after filing
• Implemented process control strategy does not match what is described in the application

Under the third objective, the data integrity audit, Porte said a common deficiency is unknown impurities or failing stability results not submitted in the application. For example, she said, the application shows that everything is passing and when the facility is inspected failing results are detected. “These should have been part of the application packet but they were nowhere to be seen, and so that is definitely a red flag,” she noted. Other common deficiencies include: 

• Holding studies not representative of actual conditions
• Retesting failing results until conformity achieved
•  Failing results routinely attributed to analyst error
•  Lack of audit trails in the laboratory data acquisition system
• Data reported in application was average of test results including failing results

Porte also reviewed common deficiencies found in responses to Form 483s submitted after the preapproval inspection. One common item is where the response identifies training and standard operating procedure updates under Corrective and Preventive Action. “What we need is an assessment of the impact on application, and the data supporting the conclusions,” she said. “Another deficiency is when the 483 response reveals the need to provide updates to the application. At that point in time, if amendments need to be prepared then they should be submitted in a timely fashion to allow for review and that could impact the review cycle time.”

If the 483 response indicates that data integrity findings affect the application, there needs to be a sponsor assessment on the impact of the data integrity findings on the veracity, accuracy and suitability of the application data, Porte told the webinar. Also, any remediation plan should include a detailed analysis of actions to correct the data

Additionally, Porte’s presentation touched on sponsors withdrawing facilities during an application review, which may affect its approvability. She said factors that are considered include the data/information generated at the facility to support approval, GMP status of facility being withdrawn, and the completeness of the supply chain/manufacturing operations. She offered the following as “helpful hints:”

• Identify which existing facilities or new facilities will replace the withdrawn facility
• Assess impact of data/information provided by site and ensure additional data is available as appropriate to support the new facility and the submission
• Provide comparison of manufacturing process/equipment as appropriate

To view a recording of Porte’s presentation, click here.