Apatinib Mesylate

Even though Hengrui Pharma has resolved the manufacturing problems cited in a recent FDA complete response letter, a second citation stands in the way of the company and its partner Elevar Therapeutics’ fourth attempt at an approval for their liver cancer combination. The two companies’ combination of camrelizumab and rivoceranib was recently snubbed by the FDA for a third time for the treatment of first-line liver cancer. In the complete response letter (CRL) dated July 9, the FDA cited open deficiencies at a manufacturing facility, as laid out in a Form 483, as the sole reason for the rejection. However, on July 15, Elevar’s parent company HLB announced that the Hengrui facility cited in the CRL had earned an official Voluntary Action Indicated (VAI) classification from the FDA. A VAI tag means the FDA found only minor issues that are not bad enough to force any punishment. The facility, located on the Jinqiao Road of the Chinese city of Lianyungang, is responsible for making rivoceranib active pharmaceutical ingredient. By that time, the FDA’s original target decision date of July 23 was still a week away. In its July 15 announcement, HLB said Elevar would request a Type A meeting and “intends to pursue a more expedited formal regulatory inquiry with the agency.” Investors were puzzled by the timing of events. With the Form 483 hiccup resolved less than a week after the CRL—well ahead of the initial PDUFA target date—investors questioned why the FDA issued a swift rejection rather than waiting for the decision deadline. As it turns out, a second Form 483 was slapped on another Hengrui facility related to the filing late in the review cycle. Even though the FDA didn’t cite that site in the CRL, Elevar and Hengrui still need to solve that problem to have any chance of securing an approval for camrelizumab and rivoceranib unless they switch to another qualified plant. Following an inspection between June 23 and July 3, 2026, the FDA issued a Form 483 to Hengrui’s facility located on Dongjin Road in Lianyungang. According to HLB, the Dongjin plant is responsible for finished drug product production. The facility was also the subject of another Form 483 issued in 2023. In the new Form 483 (PDF), obtained by Fierce Pharma, the FDA cited nine observations regarding aseptic processing, quality control and facility maintenance. For a workshop producing aseptic injectables, the FDA noticed a lack of formal risk assessments or scientific justification for placing biological or chemical indicators during cleaning validation. FDA inspectors also flagged certain quality unit oversight shortfalls, including changes to batch records that were not approved by quality assurance personnel. In some cases, these modifications were meant to address incorrect information such as expiration dates, filling yield and illuminance specification. The agency also took issue with how the facility investigated unexplained batch discrepancies. In one case, retained samples were not tested for foreign particles in a timely manner following a customer complaint. In another case, a batch of an unnamed product that exceeded compounding hold-time limits was released to the U.S. in June without supporting stability analysis. In its July 15 release, HLB said Hengrui planned to submit its written response and correction plan related to the second Form 483 to the FDA by July 24. Even though the agency didn’t cite the Dongjin facility in its CRL, Hengrui and Elevar need it to be in compliance with good manufacturing practice to win FDA approval. As this second Form 483 was issued on July 3, it was not mentioned in the CRL, likely because it came too late in the FDA’s review cycle. The agency is not obligated to review information that comes so close to the wire at the risk of disrupting its goal date. It can wrap up the current review cycle and issue a CRL by citing existing outstanding facility issues, while effectively pushing reviews of any outstanding responses or new data to the next review cycle in a resubmission. The recent citation for the Dongjin facility aside, investors were baffled by the timing of the FDA’s CRL shortly before the VAI determination for the Jinqiao API plant. Under federal regulations, the PDUFA date represents a deadline. Just as the FDA has approved drugs ahead of time, the agency is required to issue its decision immediately once the review team finishes assessing all components of an application, rather than holding onto the decision for a future event that may or may not come. In this case, the agency is not obligated to hold an open application just to wait for real-time facility remediation to conclude. For the Jinqiao facility, the FDA issued an 11-observation Form 483 (PDF) following an inspection between April 7 to 15. It was a routine surveillance check-up not specifically tied to the rivoceranib application. Following Hengrui’s response, the FDA’s Office of Manufacturing Quality (OMQ) on May 29 received a report from the inspections office recommending a potential official action indicated classification, according to records obtained by Fierce Pharma. An intra-agency meeting happened on July 9, and the OMQ also considered potential shortage concerns related to a drug product. “Based on our review of the findings from the inspection, including the firm’s responses, and a written commitment of proposed corrective actions, OMQ determined that the inspection classification is voluntary action indicated (VAI),” an FDA decision letter (PDF) dated July 22 shows. Hengrui and Elevar now have two options. One is to formally challenge the FDA’s decision, which will involve a time-consuming appeal process. The other is to resubmit their applications after resolving the Dongjin Form 483, with the hopes of getting a minor Class 1 classification that comes with a fast, three-month review period. The two companies’ approval bid for the PD-1/VEGFR combo has been thwarted by the FDA three times now, each time by manufacturing shortfalls, with the previous two centered o n Hengrui’s camrelizumab facility. Now, the two companies are considering utilizing a contractor. “Following this CRL, we have resumed discussions on production strategy,” HLB said in a recent investor Q&A. “We plan to resolve the current issues together with Hengrui Pharma, while considering a two-track strategy in the mid-to-long-term that includes securing a separate production base utilizing a U.S. CMO. Given that this is a product we intend to sell for over 10 years, we believe we cannot continue to bear the same manufacturing facility risks repeatedly.”