Manufacturing in China for China: Navigating the regulatory landscape

The rapidly growing Chinese biologics market has long attracted the attention of international pharmaceutical companies. The country’s large patient population and the significant burden of chronic and complex diseases translates into significant domestic demand for innovative biological therapies.

But for many, lack of understanding of the regulatory approval process for biologics in China has loomed as a formidable roadblock. While the National Medical Products Administration (NMPA), the agency in charge of drug registration in China, has implemented policy reforms over the past decade designed to streamline regulatory procedures for market access, the process can still be complex and time consuming, involving stringent requirements and extensive documentation.

To provide insight into the registration and approval pathway for developing and marketing biologic therapies in China for the domestic market, we recently convened a panel of Thermo Fisher experts to participate in a roundtable discussion focusing on the China regulatory landscape. Participating in the discussion were Qijun Zhang, Director of Quality for Thermo Fisher’s recently opened biologics development and manufacturing facility in Hangzhou, China; Gianluca Ronzoni, Director of Regulatory Affairs for Europe and APAC regions; and Paul Zhou, Senior Compliance Manager from the Hangzhou site.

Q: How does the regulatory journey in China compare to that of other regions, including North America and Europe?

A: Similar to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Medical Products Administration (NMPA) in China has stringent requirements for preclinical studies, clinical trials, and a comprehensive regulatory dossier, but the specifics related to study conduct, timelines, and data requirements can vary. For example, China often requires local clinical trial data for drug approval, even if the drug has already been approved in other countries. There are also specific requirements for data localization, storage, and protection. In particular, data privacy laws regulate the transfer of patient data outside of China for analysis or processing.

Q: What is the pathway to regulatory approval of a new biologic in China?

A: The process and specific requirements can vary based on the type of biologic and its classification, but broadly the journey from molecule to market follows the same path^.1

• Preclinical studies conducted in accordance with Good Laboratory Practice (GLP) guidelines to assess the safety, pharmacology, and toxicology of the new biologic.
• Clinical trial communication meeting with the NMPA’s Center for Drug Evaluation (CDE) and submission of clinical trial application, including the clinical trial protocol; an investigator’s brochure (IB) detailing the investigational product’s composition, formulation, pharmacology, toxicology, and relevant safety and efficacy data; IND application; documentation of ethics committee approval; informed consent forms; investigator qualifications; safety reporting plan; data management plan; study site information; and documentation of quality control and quality assurance measures.
• Phase I-III clinical trials to evaluate the safety and efficacy of the new biologic in human subjects, following Good Clinical Practice (GCP) guidelines.
• Submission of a comprehensive regulatory dossier to the NMPA through the CDE, including data on the drug's quality, safety, and efficacy, along with manufacturing and clinical trial data.
• Technical review of the submitted dossier involving multiple NMPA departments, including the CDE, the Center for Drug Evaluation and Research (CDER), and the National Institutes for Food and Drug Control (NIFDC).
• On-site inspections (sometimes) by the NMPA of the manufacturing facilities to assess compliance with GMP guidelines and verify the accuracy of the provided information.
• Review by panel comprising experts from relevant therapeutic areas to assess the scientific and clinical aspects of the new biologic and make recommendations.
• Approval decision by the NMPA based on the technical review, on-site inspections, and expert panel recommendations.
• Post-market surveillance, including adverse event reporting, risk management, and periodic safety updates.

Q: In the past, China’s drug registration timeline was criticized for being lengthy and unpredictable, with tens of thousands of drug registrations pending review and approval. In recent years, the Chinese government has implemented various policies and reforms² to streamline regulatory processes and facilitate market access for foreign companies. Can you describe some of those efforts?

A: Among the key reforms, there has been a focus on regulatory harmonization and alignment with international standards, including a staged implementation of ICH guidelines, which facilitates the acceptance of global clinical trial data and supports international collaboration. Additional changes include clinical trial reforms aimed at reducing the administrative burden and expediting the initiation of clinical trials in China; new intellectual property protections; accelerated and priority review pathways for certain medications; and the implementation of a Marketing Authorization Holder (MAH) system allowing pharmaceutical companies to hold the marketing authorization for drugs.

Q: One of the clinical trial reforms is the 60-day deadline for the NMPA to approve a clinical trial application. What is the impact of this policy?

A: Standardizing the CTA technical review timeline to 60 working days significantly shortens the CTA timeline. It means the sponsor can initiate the study if there is no objection from NMPA within that timeframe. In this regard, the CTA can also be tacitly approved by default if the sponsor fails to hear from the agency. The CTA amendment approval timeline is also standardized to 60 working days (NMPA approval is not needed for protocol, CMC, and nonclinical changes that don’t impact patient safety; these should be included in the annual safety update report).

Q: What is the significance of the revised MAH system implementation?

A: Previously only manufacturers could receive regulatory approvals for their products, so innovators had to invest in manufacturing facilities in order to commercialize their assets. In contrast, the MAH-based approval allows companies to outsource their manufacturing to contract manufacturing organizations. Shifting the registration process from product-based approvals to a process focused on the qualification of the MAH reduces administrative burdens and shortens registration timelines. It also puts the burden of responsibility for safety, effectiveness, and quality of a drug across its lifecycle on the MAH.

Q: Above and beyond the well-established benefits of outsourcing biologics development and manufacturing activities, including access to specialized expertise and technology, time and cost efficiencies, and risk mitigation, are there specific advantages from a regulatory perspective to partnering with a global CDMO that has manufacturing facilities in China for global companies seeking to enter the Chinese market?

A: One of the most important advantages is that global CDMOs with facilities in China will have a deep understanding of the local market dynamics, cultural nuances, and regulatory complexities. Biologic drugs in particular have unique regulatory requirements compared to small molecule drugs. Working with a global CDMO that has experience and expertise in biologics manufacturing and compliance with China's regulatory framework is crucial for ensuring the product meets the specific quality, safety, and efficacy standards set by Chinese regulatory authorities.

Realizing this benefit requires partnership due diligence. In-country manufacturing capabilities on their own are not sufficient to inform a partnership decision. Collaborating with a global CDMO that has robust quality systems, compliance with global and China-specific regulatory guidelines (such as cGMP), and a strong track record in manufacturing biologic drugs can help ensure the production of high-quality and safe products for the Chinese market.

Additionally, the CDMO can help prepare and compile the required regulatory documentation, including technical dossiers, drug master files (DMFs), and other supporting documents and provide guidance on the specific format, content, and language requirements for regulatory submissions. This support extends to crucial post-market surveillance activities, including adverse event reporting, pharmacovigilance, and compliance with product labeling and packaging regulations.

Finally, a global CDMO can collaborate on strategies for protecting partners’ intellectual property (IP) rights, including filing patents and trademarks, and implementing contractual agreements to keep proprietary information safe.

Learn more about how to bring your molecule to the China market with Thermo Fisher's biologics site in Hangzhou, China.