Hengrui Pharma facilities in China have received three Form 483s and a warning letter from the FDA in less than a year.
A lengthy Form 483 from the FDA listed a range of concerns that led to the agency’s surprise rejection of Jiangsu Hengrui Pharma and Elevar Therapeutics’ PD-1 inhibitor camrelizumab in May.
The 10-page, 10-observation document was issued to Suzhou Suncadia Biopharmaceuticals, a wholly owned subsidiary of Hengrui, in December 2023 following a two-week inspection of the company’s facility in Suzhou, China, according to a copy of the document (PDF) recently obtained by Fierce Pharma.
Problems uncovered by FDA inspectors included a lack of control over equipment systems meant to protect data integrity, an absence of established procedures to prevent microbiological contamination of sterile drug products, insufficient visual inspections before product releases, failures to implement appropriate controls to ensure product standards, plus potential mix-ups between raw materials meant for the Chinese and U.S. markets.
Deficiencies at the Suncadia plant were the main reason behind the FDA’s rejection of the monoclonal antibody camrelizumab and the small-molecule VEGFR inhibitor rivoceranib as a combination regimen for newly diagnosed liver cancer.
Following the citation, Hengrui provided a “very long, comprehensive” response to the FDA, Elevar CEO Saeho Chong, Ph.D., told Fierce Pharma during an interview last week. According to Chong, the FDA’s drug review team told the two companies that it was satisfied with Hengrui’s response during a meeting earlier this month. The FDA also encouraged Hengrui to refile its application, and the two companies are now targeting resubmissions around the end of September or October. But to enable an approval, a separate FDA inspection team will still need to clear the plant, and that may involve reinspecting the facility, Chong said.
The breadth of the manufacturing problems uncovered by the FDA is surprising considering Suncadia has been producing camrelizumab for the Chinese market since 2019. The drug has been approved in China in nine indications, including as a first-line liver cancer treatment with rivoceranib, also known as apatinib, since January 2023.
In 2021 alone, Hengrui said it produced nearly 2 million bottles of camrelizumab. The company stopped separating the drug’s performance in its financial reporting from 2022 onward as competition in China’s PD-1/L1 market heated up.
In a securities filing published last week, Hengrui said the Suncadia site passed a manufacturing inspection conducted by Chinese authorities between May 29 and June 1.
FDA observations
FDA inspectors, for their part, flagged multiple specific examples of production shortfalls. In one case related to potential threats to data integrity, the FDA noted that manufacturing operations staffers used an “admin” account, which should be controlled by IT for critical manufacturing computer systems, to make certain product batches following a computer incident.
In another case, a purity analysis data integration was conducted manually without adequate instructions to ensure accuracy, even though an automatic reporting system existed. At a different point, FDA noted that certain forms for production and control records could be replaced without being easily detected.
As for potential contamination threats, the FDA zeroed in on human activities, or “high-risk interventions,” in close proximity to the aseptic area, which need to be performed with care because they can introduce contamination. The FDA was worried that some parts of the working area were not decontaminated properly after such operations.
Further, the FDA said the Hengrui site didn’t have proper procedures in place to prevent microbiological contamination of sterile drug products. Again, the FDA meticulously pointed out details such as whether a new side of a sanitizing wipe was used during a cleaning.
What’s more, the FDA dinged the Hengrui facility for not implementing sufficient controls “to ensure that drug products conform to appropriate standards of identity, strength, quality and purity.” The agency raised three past batch deviations to make its point. In one case, Hengrui didn’t perform a retrospective analysis of a leak during the production of a batch to understand the potential impacts on the sterility of previously made batches.
Although camrelizumab would mark the first opportunity for the Suncadia biologics unit to supply medicines for the U.S. market, Hengrui already has U.S. market experience on the small-molecule side of its production business. However, the Chinese pharma giant’s manufacturing capabilities have been called into question lately—beyond simply the camrelizumab situation.
Warning letter in Lianyungang
The FDA just escalated a prior eight-observation Form 483 into a warning letter for Hengrui’s small-molecule finished drugs facility in the Chinese city of Lianyungang. The agency issued the warning letter last week after deeming Hengrui’s March response to the site's Form 483 inadequate.
At the top of the FDA’s list of concerns was an observation that the Lianyungang facility lacked adequate data oversight. As the FDA sees it, the plant’s quality assurance (QA) department simply was not functional.
During an inspection in January, FDA staffers spotted discarded records, as well as a “production manager’s unrestricted access to blank production batch records” and other documents, according to the warning letter. Further, employees were able to fill out new records and discard old ones with no assurance that the data were original or accurate, the FDA noted.
In its response, Hengrui said it would reassess its document management software to require better controls. The firm created new procedures for document destruction and trained its employees with it. But the FDA said Hengrui’s remedies didn’t include a comprehensive assessment into employees creating new records, nor did the company identify the root cause or scope of the data shortfalls.
The data integrity problem appeared to be so serious that the FDA offered a long list of suggestions. The agency urged Hengrui to investigate the extent of these inaccuracies, to conduct a risk assessment of the potential effect, and to implement corrective and preventative plans.
The FDA also criticized the Lianyungang facility over inadequate physical separation of working areas, which may compromise the sterility of drugs. Despite Hengrui’s commitment to provide better protections, the FDA suggested that the company work on a comprehensive risk assessment of all contamination hazards and a detailed remediation plan.
In a statement to Fierce Pharma, Hengrui said it will respond to the FDA’s letter as requested and is fully committed to addressing the agency’s concerns.
“[A]fter a comprehensive investigation and evaluation, we have determined the issues raised in the warning letter have not affected the quality or safety of the products manufactured at this site,” Hengrui said.
The Lianyungang facility, located on Huanghe Road, is responsible for making 12 generics for the U.S. market, according to local media outlet Yicai (Chinese). In 2023, those U.S. exports contributed about $12.4 million in revenue, or about 0.39% of Hengrui’s total haul, according to Yicai. The warning letter does not affect the export of those drugs, Hengrui said.
“As always, patient safety is our top priority, and we work to ensure the highest levels of regulatory compliance across our global network of manufacturing sites,” the company added.
Dongjin Road plant shortfalls
To add to the company’s list of headaches, the FDA in August issued a separate Form 483 to another Hengrui facility located on Dongjin Road in Lianyungang. Hengrui has altogether four manufacturing facilities in its hometown of Lianyungang.
That letter flagged nine observations, according to a copy (PDF) obtained by Fierce Pharma. Among the deficiencies, the FDA found that some samples taken for specification measurements were not properly representative of their batches and that lab controls lacked good testing procedures. The agency also flagged deficient systems or procedures for maintaining equipment to control aseptic conditions, for monitoring environmental conditions, and for preventing microbiological contamination, among other problems
Both the Huanghe Road and Dongjin Road facilities produce apatinib for the Chinese market.
Editor's Note: The story has been updated with additional comments from Hengrui.
