Hengrui's FDA Rejection: Form 483 Lists PD-1 Drug Plant Shortfalls

Hengrui Pharma, a leading pharmaceutical company in China, has encountered significant regulatory challenges from the U.S. Food and Drug Administration (FDA). Within a year, three of its facilities have received Form 483s and one has been issued a warning letter, highlighting various deficiencies and non-compliance issues.

In December 2023, the FDA conducted a two-week inspection of Suzhou Suncadia Biopharmaceuticals, a subsidiary of Hengrui, and issued a 10-page Form 483 outlining ten observations. The FDA's inspection revealed several problems, including inadequate control over equipment systems crucial for data integrity, lack of established procedures to prevent microbiological contamination of sterile drug products, insufficient visual inspections before product releases, and potential raw material mix-ups intended for different markets. These issues led to the FDA's rejection of camrelizumab, a PD-1 inhibitor, and rivoceranib, a VEGFR inhibitor, for treating newly diagnosed liver cancer.

Hengrui Pharma responded with a comprehensive report addressing the FDA's concerns. Elevar Therapeutics' CEO, Saeho Chong, Ph.D., mentioned that the FDA's drug review team was satisfied with their response and encouraged resubmission of their application by the end of September or October. However, the facility must pass another FDA inspection to gain approval.

The extent of the issues at the Suncadia plant is surprising, considering it has been manufacturing camrelizumab for the Chinese market since 2019. The drug is approved in China for nine indications, including first-line liver cancer treatment. Despite producing nearly 2 million bottles of camrelizumab in 2021, Hengrui stopped detailing the drug's performance in financial reports due to increasing competition in China’s PD-1/L1 market.

In May 2023, Chinese authorities successfully inspected the Suncadia site. However, the FDA's findings raised serious concerns, such as improper use of an "admin" account for critical manufacturing systems, manual data integration without adequate instructions, replaceable production forms, and inadequate decontamination procedures after high-risk interventions. Additionally, the FDA noted the absence of proper procedures to prevent contamination and insufficient controls to ensure product standards.

Beyond the Suncadia situation, Hengrui's manufacturing capabilities have been under scrutiny. The FDA escalated an eight-observation Form 483 into a warning letter for Hengrui’s small-molecule finished drugs facility in Lianyungang. The main issue was inadequate data oversight, with discarded records and unrestricted access to production batch records. Hengrui's response, which included new document management procedures and employee training, was deemed inadequate by the FDA. The agency suggested a comprehensive investigation into data inaccuracies and a risk assessment to address the issue.

Furthermore, the Lianyungang facility faced criticism for improper physical separation of working areas, which may compromise drug sterility. Despite Hengrui’s commitment to improve, the FDA recommended a detailed risk assessment and remediation plan. Hengrui has pledged to respond to the FDA and resolve the highlighted issues, asserting that product quality and safety remain unaffected. The Lianyungang facility produces 12 generics for the U.S. market, contributing $12.4 million in revenue in 2023, which is about 0.39% of Hengrui’s total revenue.

In August, another Hengrui facility on Dongjin Road in Lianyungang received a Form 483 with nine observations. Issues included non-representative sample testing, inadequate lab controls, deficient maintenance procedures to control aseptic conditions, and lack of proper environmental monitoring. Both the Dongjin Road and Huanghe Road facilities produce apatinib for the Chinese market.

Hengrui Pharma has stated that patient safety and regulatory compliance are their top priorities across their global manufacturing network.

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