What Is the Biosimilar Approval Pathway in China for Foreign Manufacturers?

1. The Regulatory Framework for Biosimilars in China

China established its formal biosimilar regulatory pathway in 2015 with the release of the Technical Guidelines for the Development and Evaluation of Biosimilars (Trial) by the Center for Drug Evaluation (CDE) under the NMPA. These guidelines were updated in 2021 to incorporate international experience and address implementation challenges identified during the first wave of biosimilar approvals. The framework draws heavily from EMA biosimilar guidelines while incorporating China-specific requirements.

The Chinese biosimilar pathway is distinct from the abbreviated new drug application (ANDA) pathway used for small-molecule generics. Unlike generics, which require only bioequivalence studies, biosimilars must demonstrate similarity across multiple dimensions through a stepwise comparability exercise. The concept is based on the principle that a biosimilar is “similar but not identical” to the reference product, with the expectation that any minor differences are clinically insignificant.

Since the pathway was established, China has become one of the world’s most active biosimilar markets. By early 2026, the NMPA had approved over 50 biosimilars across multiple therapeutic areas, including monoclonal antibodies targeting TNF-alpha (infliximab, adalimumab, rituximab), VEGF (bevacizumab), HER2 (trastuzumab), and RANKL (denosumab), as well as biosimilars of recombinant proteins such as filgrastim and epoetin alfa. The market is projected to reach $15 billion by 2027, driven by an aging population, increasing chronic disease burden, and government policies promoting biologic therapy access.

2. The Stepwise Comparability Exercise

Foreign manufacturers must follow a rigorous stepwise comparability exercise to demonstrate that their biosimilar candidate is highly similar to the NMPA-approved reference product. The process consists of three sequential stages:

2.1 Analytical (Quality) Comparability

The foundation of any biosimilar development program is comprehensive analytical characterization demonstrating that the biosimilar candidate is highly similar to the reference product in terms of:

• Primary and higher-order structure: Amino acid sequence verification, disulfide bond mapping, secondary and tertiary structure analysis using circular dichroism, FTIR, and NMR spectroscopy
• Post-translational modifications (PTMs): Glycosylation patterns (including glycan profiling by LC-MS), deamidation, oxidation, and other PTMs that may affect safety or efficacy
• Biological activity: Binding affinity to target receptors and Fc receptors, effector functions (ADCC, CDC, complement binding), and enzymatic activity for enzyme-based biologics
• Purity and impurities: Aggregates, fragments, host cell proteins, DNA residuals, and process-related impurities
• Product-related substances: Charge variants, size variants, and degradation products
• Stability: Forced degradation studies, real-time and accelerated stability data across multiple lots of both biosimilar and reference product

The CDE expects state-of-the-art analytical methods, including orthogonal techniques for each critical quality attribute (CQA). For monoclonal antibody biosimilars, the analysis typically involves 50-80 separate assays covering each CQA. The acceptance criteria for analytical similarity are based on the quality range of the reference product, typically requiring the biosimilar to fall within the reference product’s confidence interval.

2.2 Non-Clinical Comparability

After demonstrating analytical similarity, foreign manufacturers conduct non-clinical studies to confirm that any minor differences detected during analytical characterization do not translate into toxicologically relevant differences:

• In vitro pharmacodynamics: Comparative studies on target binding, cell-based activity, and receptor occupancy
• In vitro toxicology: Comparative cytotoxicity, immunotoxicity, and tissue cross-reactivity studies
• In vivo pharmacokinetics (PK): Comparative PK studies in relevant animal species, typically rats or cynomolgus monkeys
• In vivo toxicology: Repeat-dose toxicity studies in a relevant species, including toxicokinetics, immunogenicity assessment, and histopathology
• Local tolerance: Studies at injection sites for parenteral formulations

The CDE has adopted a risk-based approach to non-clinical requirements. If the analytical similarity is very high and the mechanism of action is well understood, the CDE may accept reduced non-clinical packages. Conversely, for biosimilars with residual analytical uncertainties or complex mechanisms of action, more extensive non-clinical data may be required.

2.3 Clinical Comparability

The final and most resource-intensive stage involves clinical studies to confirm that the biosimilar and reference product have equivalent clinical performance:

• Clinical pharmacokinetics (PK) study: A comparative PK study in healthy volunteers or patients, typically using a crossover or parallel design. The CDE accepts both European and Chinese PK data, but increasingly expects at least a bridging PK study in Chinese subjects
• Clinical pharmacodynamics (PD) study: A comparative PD study using validated biomarkers where available. For drugs with well-established PD markers (e.g., absolute neutrophil count for filgrastim), a dedicated PD study may serve as the primary clinical evidence
• Comparative clinical efficacy and safety trial: A randomized, parallel-group trial in a sensitive and homogeneous patient population, typically using equivalence margins of 0.8-1.25 for the primary efficacy endpoint. The CDE has specific expectations for equivalence margin justification, statistical power, and sensitivity analysis
• Immunogenicity assessment: Comparative evaluation of anti-drug antibody (ADA) development, including neutralizing antibodies, throughout the clinical program. The CDE follows ICH S6 guidelines for immunogenicity testing strategy

3. China-Specific Reference Product Requirements

A critical distinction between China’s biosimilar pathway and that of the EMA or FDA is the reference product requirement. The CDE requires the reference product to be the version approved and marketed in China, not the US- or EU-approved originator. This has significant implications:

• Separate sourcing: Foreign manufacturers must source the China-approved reference product, which may have different manufacturing processes, formulations, or presentations than the global reference product
• Analytical bridge study: If a foreign manufacturer has established similarity to the EU or US reference product, an analytical bridge study comparing the China-approved reference product to the EU/US reference product may be necessary to leverage existing data
• Reference product variability: The China-approved reference product may exhibit different batch-to-batch variability due to manufacturing differences, requiring a broader analytical characterization to establish the acceptance range
• Clinical data bridging: Clinical data generated against an EU or US reference product may not be directly acceptable for China registration unless a bridging strategy is developed

The CDE has shown some flexibility in recent years. For biosimilars that have already been approved in the EU, US, or Japan, the CDE may accept a reduced clinical package if a comprehensive analytical bridge demonstrates high similarity between the China reference product and the reference product used in the foreign clinical program. This “global development” approach is increasingly common among foreign manufacturers.

4. Approval Timelines for Foreign Manufacturers

The biosimilar approval timeline in China depends on the extent of clinical data required and the CDE’s current workload. Typical timelines are:

Foreign manufacturers that have already obtained approval in a mature regulatory jurisdiction (EMA, FDA, PMDA) and submit comprehensive bridging data can potentially reduce the China-specific timeline to 2-3 years. The CDE has implemented a priority review pathway for biosimilars that address significant unmet medical needs, which can reduce the review period to 6-9 months.

5. Interchangeability and Substitution

China does not currently have a formal interchangeability designation equivalent to the US FDA’s interchangeable biosimilar status. However, several practical considerations affect market access:

• Automatic substitution: Chinese regulations do not permit automatic substitution at the pharmacy level. Prescriptions must specify the product by brand or manufacturer name
• Hospital formulary decisions: Individual hospital pharmacy and therapeutics committees decide whether to include specific biosimilars on the hospital formulary. Some hospitals have established their own interchangeability policies that may favor one biosimilar over others
• Provincial tender policies: Provincial procurement processes may treat biosimilars as interchangeable for tender purposes, awarding contracts to the lowest-priced option within a therapeutic category
• NRDL pricing: Biosimilars that enter the NRDL (National Reimbursement Drug List) are generally positioned at a discount of 20-40% to the reference product price, creating market-driven substitution

6. Manufacturing and Quality Considerations for Foreign Manufacturers

Foreign manufacturers establishing biosimilar production in China face specific manufacturing challenges:

6.1 Technology Transfer to Chinese Facilities

Many foreign manufacturers choose to manufacture biosimilars at their existing global facilities and import the finished product, rather than establishing local Chinese manufacturing. This approach preserves manufacturing consistency but exposes the product to import tariffs and supply chain risks. Alternatively, technology transfer to a Chinese contract manufacturer (CDMO) can reduce costs but requires careful management to ensure comparability between global and Chinese-produced batches.

6.2 GMP Inspection Requirements

All biosimilar manufacturing facilities must pass NMPA GMP inspections, which follow the Good Manufacturing Practice for Pharmaceutical Products standards (the Chinese equivalent of EU GMP Part I/II for biological products). Foreign manufacturing facilities are subject to pre-approval inspections (PAIs) by NMPA inspectors, either on-site or through remote inspection procedures that became established during the COVID-19 pandemic and continue in use.

6.3 Comparability After Process Changes

Any manufacturing process changes during development or after approval require re-demonstration of comparability through additional analytical and potentially clinical studies. This is particularly relevant for foreign manufacturers that transfer processes between global and Chinese facilities.

7. Market and Competitive Landscape

China’s biosimilar market is becoming increasingly competitive, with several dynamics that foreign manufacturers must navigate:

• Domestic competition: Chinese companies such as Shanghai Henlius Biotech, Innovent Biologics, RemeGen, and Zhaoke Ophthalmology have established strong biosimilar pipelines with faster development timelines and lower cost structures
• Price competition: NRDL negotiation has driven biosimilar prices 60-80% below the originator product price, compressing margins and favoring manufacturers with efficient production processes
• Second-wave biosimilars: Competition is expanding from simple monoclonal antibodies to more complex biologics including fusion proteins, antibody-drug conjugates (ADCs), and bispecific antibodies
• Regulatory convergence: China’s biosimilar standards are converging with international guidelines, creating opportunities for global biosimilar manufacturers to seek simultaneous EMA/NMPA or FDA/NMPA approval

8. Conclusion

China’s biosimilar approval pathway offers a clear regulatory framework for foreign manufacturers but demands substantial investment in analytical characterization, clinical development, and regulatory affairs. The pathway is materially more complex than small-molecule generic approval and requires a dedicated China regulatory strategy from the outset of product development. The key success factors for foreign manufacturers include investing in comprehensive analytical similarity assessment against the China-approved reference product, developing a robust clinical bridging strategy, building relationships with CDE reviewers, and establishing a competitive cost structure for pricing in China’s price-sensitive market.