Inadequate Manufacturing Control Strategy for Adventitious Virus Testing
Severity: criticalThe manufacturing control strategy for toripalimab does not align with current industry standards and ICH Q5A guidelines. There is no adventitious virus testing performed for unprocessed bulks (UPBs) in non-US manufacturing processes that share common equipment and/or materials with toripalimab manufacturing for the US market, posing a risk of adventitious virus cross-contamination and manufacturing facility disruptions.
Recommended response: Implement comprehensive adventitious virus testing for unprocessed bulks (UPBs) for all products manufactured on shared equipment, replace high-risk multi-use materials, sterilize shared product-contact equipment, and provide a rationale for alignment with ICH Q5A. Confirm availability of compliant drug product for resubmission.
Cited: ICH guideline Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin recommends that “Appropriate testing for viruses should be performed at the unprocessed bulk level [...]”, To fulfill 21 CFR 601.20(b) requirements, confirm that toripalimab drug product produced from drug substance manufactured after implementation of the corrective measurements described in items a and b will be available within the review timeline of the re-submitted application.
Reserved Comment on Prescribing Information
Severity: infoComments on the proposed labeling are reserved until the application is otherwise adequate. The applicant is encouraged to review labeling review resources, including regulations and related guidance documents, and use the Selected Requirements for Prescribing Information (SRPI) checklist.
Recommended response: Review labeling review resources, including regulations and guidance documents, and use the SRPI checklist to ensure compliance with format items. Submit updated content of labeling in SPL format with the response.
Reserved Comment on Carton and Container Labeling
Severity: minorComments on the proposed carton and container labeling are reserved until the application is otherwise adequate. A specific statement regarding the Medication Guide is required.
Recommended response: Add the bolded statement or appropriate alternative regarding the Medication Guide to the carton and container labeling per 21 CFR 208.24(d).
Cited: Add the following bolded statement or appropriate alternative to the carton and container labeling per 21 CFR 208.24(d): 'ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide.'
Proprietary Name Resubmission Required
Severity: infoThe proposed proprietary name was found acceptable pending approval of the application in the current review cycle. It needs to be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name with the response to application deficiencies.
Comprehensive Safety Update Required
Severity: majorA comprehensive safety update is required with the response to deficiencies. This includes data from all nonclinical and clinical studies/trials, detailed changes in the safety profile, tabulations of new and combined safety data, comparison of adverse event frequencies, retabulation of premature trial discontinuations, case reports for deaths/serious adverse events, updated exposure information, and worldwide safety experience.
Recommended response: Provide a detailed safety update encompassing all nonclinical and clinical data, including new findings, combined data tabulations, comparisons, and narrative summaries for serious adverse events and deaths, as outlined in the letter.
