China Revises Recombinant Insulin Technical Guideline for Drug Development and Quality Control

CDE Announcement No. 32 of 2026 – Effective May 8, 2026

On May 8, 2026, China’s National Medical Products Administration (NMPA) Center for Drug Evaluation (CDE) published Announcement No. 32 of 2026, releasing the revised “Technical Guideline for the Pharmaceutical Research and Evaluation of Recombinant Insulin Products.”

The updated guideline replaces the earlier framework that applied only to biosimilar insulin products and now covers pharmaceutical research at the marketing application stage for both innovative products and biosimilars.

Products explicitly within scope include:

• Human insulin
• Human insulin analogues: insulin glargine, insulin aspart, insulin lispro, and insulin glulisine
• Insulin derivatives: insulin detemir, insulin degludec, and insulin icodec
• Compound preparations containing insulin may refer to the guideline as appropriate, but are not explicitly within mandatory scope

The revision establishes a more unified regulatory framework for recombinant insulin development, manufacturing, quality research, and biosimilarity assessment in China.

Quality by Design and Lifecycle Quality Systems Receive Strong Emphasis

The CDE places significant emphasis on Quality by Design (QbD) principles throughout insulin development and manufacturing.

Applicants are expected to:

• Conduct comprehensive manufacturing and quality studies
• Identify critical quality attributes (CQAs)
• Establish lifecycle quality systems
• Apply risk-based raw material controls
• Develop scientifically justified impurity control strategies

Given the chronic and high-frequency use of insulin therapies, the guideline places particular focus on impurity management and long-term product quality control.

Cell Banks, Raw Material and Component Sourcing

The revised document introduces more detailed requirements for production strains, cell lines, seed banks, and raw material management.

Application dossiers should include detailed information on:

• Target genes
• Expression vectors
• Host strains or cell sources
• Construction methods
• Genetic stability
• Passage stability
• Adventitious agent testing

The guideline states that single-clone picking by streaking should be avoided during establishment and recovery of master and working seed banks, to maintain uniformity across production stages. For prokaryotic expression systems, the bacteriophage risk management is specifically highlighted throughout seed banks and upstream manufacturing.

On sourcing, the guideline takes a clear policy direction: use of animal- or human-derived components in production should be avoided wherever possible, and the use of recombinantly expressed proteases is specifically encouraged over animal-derived alternatives. Where animal-derived components are necessary, biosafety risks must be fully evaluated and residues monitored and controlled.

For raw materials with multiple suppliers, applicants must study and compare the potential impact of different sources on product quality and conduct sufficient comparability studies.

Modified Insulin Products: Chemistry, Impurity, and Reference Standard Expectations

One of the guideline’s more technically detailed sections concerns chemically modified insulin products, particularly those using fatty acid side chains. Chemical molecular modifiers can affect pharmacokinetics, immunogenicity, receptor affinity, and overall safety. Applicants are expected to establish controls over modifier sourcing, manufacturing, and quality evaluation early in development.

Expectations for modified insulin products include:

• Process-related impurity analysis
• Degradation product assessment
• Structural confirmation studies
• Stability testing
• Comparability evaluations after source or process changes
• Mutagenic impurity risk assessment under ICH M7

For modifiers containing stereochemical configurations, methods such as single-crystal X-ray diffraction and nuclear magnetic resonance may be used to confirm stereostructure. Unintended linkage reactions between impurities and insulin should be evaluated during modification process development.

Reference Standards and International Units

The guideline introduces a specific and compliance-critical requirement for reference standard expression: where an international standard exists, potency results must be expressed in international units (IU), and simple analogy-based conversion methods may not be used to express results in IU.

Where no international or national reference standard exists, applicants must establish an internal reference standard management system with primary and secondary standards. It is recommended that representative batches from confirmatory clinical studies be used to establish the primary reference standard, which may then be used to calibrate secondary standards.

Manufacturing Expectations Cover the Full Production Process

Beyond reference standard requirements, the guideline establishes comprehensive manufacturing and process control expectations covering all stages of insulin production.

Fermentation and Upstream Controls 

Applicants are expected to systematically evaluate and monitor key process parameters including: 

• Temperature  
• pH  
• Dissolved oxygen  
• Feeding rate  
• Viable cell density 
• Cell viability  
• Key Metabolite concentrations (lactate, acetate, ammonium ions) 
• Aggregate proportion  
• Host cell protein residues  

Process characterization studies should be conducted in a standardized manner to establish process control strategies. 

The guideline recommends avoiding antibiotic use during fermentation wherever possible. If antibiotics are necessary, they should comply with Chinese Pharmacopoeia requirements, downstream removal capability must be fully verified, residues must be strictly controlled in quality standards, and – importantly - warning statements must be included in the package insert where applicable. This labelling obligation is explicit in the guideline and goes beyond residue control alone. 

Enzymatic Cleavage and Modification 

For enzymatic cleavage, applicants should study protease ratios, reaction conditions, cleavage efficiency, byproduct formation, and intermediate stability. For chemically modified insulin products, applicants must characterize modification reactions and evaluate whether impurities in raw materials or intermediates could generate unintended byproducts under the established reaction conditions. 

Crystallization, Drying, and Formulation 

Crystallization and drying processes are among the key steps for ensuring drug substance stability. The guideline addresses: 

• Crystallization method selection (isoelectric precipitation or zinc ion-induced crystallization) 
• Drying parameters (freeze-drying or spray drying) 
• Formulation screening 
• Sterilizing filtration 
• Filling operations 

For biphasic premixed insulin products, the CDE specifically addresses protamine sulfate source control, isophane point studies, sedimentation behavior, particle size distribution, and resuspension performance. 

On overfilling and overages: the guideline states these should be avoided as far as possible in actual production. Where necessary, the amount, rationale, and justification must be explained based on sufficient research and supported by validation studies. 

Validation Requirements  

Process validation should generally include at least three consecutive commercial-scale representative batches. 

Validation activities include: 

• Process performance validation  
• Impurity removal validation  
• Intermediate hold-time studies  
• Chromatography media and ultrafiltration membrane cassette lifetime validation  
• Sterilizing filter validation  
• Media fill validation  
• Transportation validation or qualification  

For prefilled injection pens, the guideline requires validation of assembly operations, including cartridge storage time before assembly, transfer conditions, and potential effects on product quality. 

Batch pooling is specifically restricted: it may not be used to resolve quality defects in individual batches, and drug substances manufactured using different processes may not be pooled for subsequent production. 

Impurity Control Is a Central Focus  

The guideline provides extensive detail on identification, characterization, and control of product-related impurities. 

For innovative insulin products: 

• Product-related impurities above 0.10% should be identified and quantified  
• Individual impurities above 0.50% should also undergo activity studies and assessment of potential safety and efficacy impact  

For biosimilars: 

• Impurity levels should generally not exceed those of the reference product  
• New impurities or elevated impurity levels require process optimization and safety assessment  
• New single impurities between 0.10% and 0.50% require identification, quantification, and evaluation of potential clinical impact  
• New single impurities above 0.50% may require reconsideration of biosimilar feasibility  

For compound preparations, a technically specific requirement applies: impurity limits must be calculated as a percentage of the specific active ingredient that produces the impurity not as a percentage of the total active pharmaceutical ingredients in the formulation. This differs from standard single-component practice and directly affects how companies set specifications for compound insulin submissions. 

The guideline also addresses stereoisomers, positional isomers, chiral isomers, elemental impurities, and potentially genotoxic impurities associated with modified insulin products. 

Advanced Analytical Characterization  

The guideline identifies several advanced analytical approaches for structural confirmation, impurity analysis, formulation characterization, and biosimilarity assessment, including: 

• Mass spectrometry  
• Nuclear magnetic resonance  
• Single-crystal X-ray diffraction  
• Analytical ultracentrifugation  
• Dynamic and static light scattering  

Structural confirmation should extend from primary structure through higher-order structure characterization. 

For modified long-acting insulin products such as insulin degludec and insulin detemir, the guideline recommends studying tertiary and quaternary structures related to mechanism of action, including insulin hexamers and multi-hexamers where feasible. 

Where an in vitro activity assay is proposed to replace an in vivo biological activity assay, comprehensive method bridging studies must be conducted to systematically verify the correlation and comparability between the two methods before the substitution is accepted. 

Biosimilar Similarity Studies  

For biosimilar insulin products, the guideline requires both quality similarity and stability similarity studies. Drug products should generally be selected for similarity studies because quality attributes may differ between the drug substance and final product. 

The guideline also discusses: 

• Batch selection and representativeness  
• Reference product preprocessing  
• Higher-order structure comparisons  
• Formulation-related effects  
• Expression-system-related impurity differences  

A significant development timeline point: for biosimilar insulin products, the commercial manufacturing process and scale should be determined before the start of pivotal clinical trials. This is necessary to ensure material consistency between clinical trial samples, commercial products, and the reference drug, and has direct implications for development planning and manufacturing readiness. 

Stability and Delivery Device Expectations 

The guideline requires stress, accelerated, and long-term stability studies before marketing application submission, each using at least three representative batches. Simulated-use stability studies must also be conducted, covering worst-case usage conditions including end-of-shelf-life product, high-frequency use, and exposure to high temperature, high humidity, low temperature, and light. 

A specific and additional stability requirement applies to drug substance shelf life: applicants must provide either stability data or a protocol for post-marketing concurrent verification demonstrating that drug substance stored to the end of its shelf life can still be used to produce drug product meeting the proposed shelf life. This is a separate obligation from standard stability studies and should be planned early. 

For multi-dose products containing preservatives, antimicrobial effectiveness testing should be conducted during both long-term stability studies and simulated-use studies to demonstrate microbial safety at the end of shelf life. 

For delivery device compatibility, the guideline addresses silicone oil quality and siliconization controls, container-closure compatibility, needle compatibility, injection performance, and use-related risk assessment for prefilled syringes and pen injectors. Where users install needles separately, compatible needle specifications must be stated in the package insert. 

Practical Implications for Insulin Manufacturers 

For companies pursuing recombinant insulin registrations in China, the revised guideline signals a clear shift toward more stringent and technically sophisticated expectations across product quality, manufacturing control, and lifecycle management.  

Key implications include: 

• Earlier determination of commercial manufacturing process and scale, particular for biosimilar develops who must lock process before pivotal trials 
• Expanded impurity characterization programs, including compound-preparation-specific limit calculation methods  
• Broader reference standard management obligations, including IU expression requirements where international standards exist  
• Explicit antibiotic labelling obligations where fermentation antibiotic use is necessary 
• End-of-shelf-life drug substance stability protocols as a separate submission requirement 
• Recombinant protease sourcing preference over animal-derived alternatives 
• More comprehensive supplier qualification, raw material controls, and transportation qualification  
• Greater reliance on advanced analytical characterization and in vitro/in vivo bioassay bridging where substitution is proposed  

Manufacturers preparing future China submissions should evaluate whether existing analytical packages, process controls, stability strategies, and comparability approaches remain aligned with the revised framework. 

For companies navigating China biologics registration requirements, contact Cisema for expert pharmaceutical regulatory consulting support. 

Further Information 

• Explore Cisema’s Pharmaceutical Consulting services 

References

• Announcement No. 32 of 2026 “Technical Guideline for the Pharmaceutical Research and Evaluation of Recombinant Insulin Products.” ‍
• Technical Guideline for the Pharmaceutical Research and Evaluation of Recombinant Insulin Products (Revised Edition).pdf