[E-Daily Reporter NA EUN-KYUNG ] It has been confirmed that the reason behind HLB INC.(028300)’s new liver cancer drug, Riboceranib, receiving its third Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) was an unannounced inspection of Hanting Pharmaceutical’s manufacturing facility—an event that even HLB PHARMACEUTICAL had not anticipated. The FDA discovered issues at the manufacturing facility during a routine current Good Manufacturing Practice (cGMP) inspection of other generic drugs sold in the U.S., and since the active pharmaceutical ingredient (API) for Riboceranib is also produced at the same plant, this affected the approval review process. It is reported that HLB INC. was not even informed of the inspection in advance.

Generic Drug Inspection Impacts New Drug Approval… HLB INC.: “We Were Not Aware in Advance”

The most significant feature of this CRL is that its cause differs from the previous two instances. While the previous two CRLs were related to the manufacturing facility for the biologic drug camrelizumab, this time the issue stemmed from a general cGMP inspection of the manufacturing facility for the active pharmaceutical ingredient (API) of riboceranib. With no way to confirm whether the issues raised in the previous two CRLs had been resolved, additional concerns were raised in this third CRL.

According to HLB INC., the FDA issued a Form 483 to the facility in question while inspecting the active pharmaceutical ingredient (API) manufacturing process for other generic drugs currently sold in the United States. Subsequently, considering that the same facility also produces the API for riboceranib, the FDA has put the approval of the New Drug Application (NDA) for riboceranib on hold. A Form 483 is a document in which an FDA inspector notifies a company of manufacturing and quality control deficiencies identified during an on-site inspection.

HLB INC. officials stated, “The manufacturing facilities that were the cause of the previous two CRLs and this CRL are different,” adding, “This general cGMP inspection was not a Pre-Approval Inspection (PAI) for the approval of riboceranib, but rather a routine inspection of the manufacturing processes for other generic drugs currently sold in the U.S.” When asked whether the issues cited in the previous CRLs had been resolved, the official explained, “We cannot definitively state that the existing issues related to the camrelizumab manufacturing facility have been resolved,” adding, “This is because the FDA has not yet issued a final determination regarding that facility.”

Interestingly, neither HLB INC. nor its U.S. subsidiary, Eleva, was aware in advance that this inspection was taking place. An HLB INC. official said, “From Hangzhou Pharmaceutical’s perspective, since the inspection concerned other generic drugs rather than Riboceranib, it appears they did not share this information,” adding, “After receiving this CRL, we have requested Form 483 and Hangzhou Pharmaceutical’s response materials.”

Consequently, the company has not yet been able to confirm the exact findings or Hangseo Pharmaceutical’s corrective action plan. HLB PHARMACEUTICAL plans to determine its resubmission strategy after reviewing Form 483, Hangseo Pharmaceutical’s Corrective and Preventive Actions (CAPA), and the final classification results of the general cGMP inspection, which is expected by the end of this month.

An HLB INC. official said, “In principle, if a resubmission is not made within one year of receiving the CRL, the application is automatically withdrawn,” adding, “However, if more time is needed for corrective actions, we may discuss an extension of the deadline with the FDA through a Type A meeting or similar channels.” The official continued, “At this point, we must first review Form 483 and Hangseo Pharmaceutical’s response before we can determine a specific timeline for resubmission.”

“Restoring Trust in the Manufacturing Facility Is Key”… Former FDA Expert: “Re-inspection Inevitable”

HLB INC. is emphasizing that since this CRL stemmed from a general cGMP inspection, it is not directly related to the production of riboceranib. However, Professor Lee Jang-ik of Seoul National University’s College of Pharmacy—who served as a clinical pharmacology reviewer and team leader at the FDA for over 10 years—explained that if issues were found at the same manufacturing facility, it would be difficult to view them as matters unrelated to the approval review.

Professor Lee explained, “If a product is manufactured at the same facility, it cannot be viewed as completely separate from the specific drug manufacturing process; if there are factors that could indirectly affect it, the FDA can naturally reflect this in the approval review.”

In this CRL, the FDA stated that it may conduct a Pre-Approval Inspection (PAI) if necessary after the manufacturing facility issues are resolved. While HLB INC. has previously raised the possibility of substituting an on-site inspection with a Report-Based Inspection (RLI), experts believe that, given the current situation—having received a third CRL—the FDA is highly likely to require a re-inspection rather than granting approval based solely on a review of documents. In particular, they emphasized that even a re-inspection would not be easy if the documents do not demonstrate sufficient improvements.

Professor Lee stated, “It will be difficult to grant approval until it is confirmed that the issues have been clearly resolved,” adding, “There is a high probability that a re-inspection will take place.” He continued, “If the FDA cannot be convinced that the manufacturing facilities have been sufficiently improved based solely on the data submitted by Hangseo Pharmaceutical, it may be difficult to even schedule a re-inspection,” adding, “Since on-site inspections are time- and cost-intensive—the FDA typically dispatches at least two inspectors—they do not readily conduct them when it is unclear whether improvements have been made.”

To strengthen its response to the FDA, Hangseo Pharmaceutical recruited Ji Feng, a former AstraZeneca executive, as President and Chief Operating Officer (COO), and replaced the plant manager with a former FDA official. The company has also conducted five mock inspections, and HLB PHARMACEUTICAL is reported to have supported Hangseo Pharmaceutical during this process. Nevertheless, with the receipt of a third CRL, whether the company will ultimately receive approval now depends on the specific findings listed in Form 483 and how proactively Hangseo Pharmaceutical addresses them.

Professor Lee stated, “The number of CRLs received is not the decisive factor [in whether approval will be granted]. As long as the requirements set by the FDA are met, approval can be obtained even if there have been multiple CRLs.” However, he added, “Receiving three CRLs suggests that Hangzhou Pharmaceutical either does not fully understand the FDA’s requirements or has failed to implement them.” He went on to point out, “This is not a problem that can be solved simply by replacing executives or managers. The manufacturing facilities and the entire quality control system must be improved to a level that satisfies the FDA.”