HLB’s liver cancer drug has once again faced a delay in approval after the FDA identified remediation requirements (Form 483) during an unannounced general cGMP inspection of Hengrui Pharmaceutical’s manufacturing facility. However, the inspection was conducted separately from the liver cancer drug approval process, and no issues were reportedly identified with rivoceranib’s manufacturing process itself.
The setback has drawn attention as the camrelizumab chemistry, manufacturing and controls (CMC) issue, which had been the final hurdle from previous complete response letters (CRLs), had effectively been resolved during the FDA review process. The unexpected manufacturing facility issue has become a source of disappointment within the industry.
According to News1 reporting on July 14, Elevar Therapeutics, HLB’s U.S. subsidiary, was notified by its partner Hengrui Pharmaceutical earlier this month, shortly before the CRL was issued, that the FDA had completed its review of camrelizumab without any significant issues.
The latest review cycle suggests that the camrelizumab CMC-related issues, which had been the reason behind the first and second CRLs for the liver cancer drug, have been addressed.
HLB’s liver cancer drug received its first CRL after the FDA identified 10 remediation items during a 2024 inspection related to camrelizumab CMC. Hengrui Pharmaceutical later improved its manufacturing processes and submitted for another review, but the FDA issued another CRL after identifying three additional remediation items at the same manufacturing facility.
Hengrui Pharmaceutical subsequently resolved two of the three issues and addressed the remaining issue by modifying the manufacturing process.
The FDA requested stability data over a certain period to confirm consistency of the revised manufacturing process. Hengrui submitted the related data when resubmitting its biologics license application (BLA) and continued providing additional stability data during the review period to demonstrate that the requirements had been met.
Through manufacturing process improvements and additional stability data submissions, HLB and Hengrui Pharmaceutical are understood to have resolved the causes behind the previous two CRLs. The FDA also indicated that the camrelizumab review had been completed without outstanding issues, raising expectations that approval could proceed without another inspection. However, the approval process was halted by unexpected cGMP issues at the rivoceranib manufacturing facility.
In April, the FDA conducted a general cGMP inspection of the Hengrui facility to assess compliance at a manufacturing site producing active pharmaceutical ingredients (API) for generic drugs marketed in the U.S.
The inspection was not a pre-approval inspection (PAI) conducted as a prerequisite for rivoceranib approval, but rather a routine regulatory inspection of a facility producing ingredients for drugs already marketed in the U.S.
During the inspection, the FDA identified multiple deficiencies related to manufacturing and quality control systems and issued a Form 483.
Because the facility also produces the API for rivoceranib, the FDA determined that even if the findings were not directly related to rivoceranib’s manufacturing process, the agency could not approve a drug using materials produced at the facility until broader cGMP deficiencies at the manufacturing site were resolved.
Ultimately, the unresolved manufacturing facility findings and pending corrective actions became the direct reason for the latest CRL.
Reports that the camrelizumab BLA review had been completed first emerged through Chinese media outlets.
Chinese biotechnology publication Amino Observation reported that “Hengrui Pharmaceutical had completed improvements to all issues identified at the PD-1 (camrelizumab) manufacturing facility during the previous two inspections, and the FDA was reportedly satisfied with the corrective actions.”
The news later spread to South Korea, prompting expectations among shareholders that the camrelizumab CMC issue, previously viewed as a major obstacle to approval, had been resolved. Shareholders also sought confirmation of the report.
The key factor for future approval will be how quickly Hengrui Pharmaceutical can address the cGMP findings at the rivoceranib manufacturing facility and obtain confirmation from the FDA.
An industry official said, “Once the manufacturing facility’s cGMP compliance is confirmed, the approval review for rivoceranib can resume. Attention is now focused on Hengrui Pharmaceutical’s timeline for corrective actions and the FDA’s follow-up verification process.”