Major Release | CDE Notice No. 36 Draws the "Red Line" for Generic Drugs
On May 20, 2026, the National Medical Products Administration Center for Drug Evaluation (CDE) officially issued Notice No. 36, simultaneously releasing two important documents: "Major Deficiency Situations in Pharmaceutical Research of Chemical Generic Drugs" and "Major Deficiency Situations in Bioequivalence Studies of Chemical Generic Drugs."
Source:https://www.cde.org.cn/main/news/viewInfoCommon/4b9bc30439f2c64fa87ec503210d3c75
This means that China's chemical generic drug review system has formally established a rigid red-line mechanism covering the full chain of pharmaceutical research + BE .
The past lenient model of "find a problem, issue a deficiency letter, go back, revise, and resubmit" has completely ended.It has been replaced by a "one-vote veto" system: once a major deficiency is touched, the CDE will no longer provide an opportunity to supplement materials and will directly refuse approval.From "efficiency first" to "quality first," regulators have sent a clear signal to the industry: enterprises are the primary parties responsible for quality and must get it right from the very beginning.
Comparison of Old and New Review Logic
Under the strictest "review rejection storm" in history, what untouchable high-voltage lines do R&D project initiation and pharmaceutical research face?
Interpretation of the Core Red Lines
🔴 Red Line 1: Failure of on-site inspection or sample testing
Data falsification, untruthful original records, and non-standard processes are zero-tolerance once discovered; samples whose own quality fails to meet standards are treated the same way.
🔴 Red Line 2: Different applicants sharing study data ("one product, multiple sales")
The industry's chronic problem of one CRO study dossier being used multiple times is explicitly prohibited by the new rules. Once it is found during review that the application materials of different applicants share study data (including starting material studies, intermediate studies, quality studies, stability studies, etc.), it will be determined as a major deficiency. This means the "one dossier, multiple uses" practice for CRO materials has become history, and each application project must establish an independent experimental design logic and a complete data chain.
🔴 Red Line 3: Changing the API supplier during review
After submission for review, any change involving the need to re-produce samples and re-examine stability, including changes to the API supplier, production site, manufacturing process, production batch size, or formulation excipients, will trigger direct rejection.
🔴 Red Line 4: Wrong selection of reference listed drug
Failing to select the drug according to the national catalog, selecting a formulation invalidated due to safety risks, or failing to conduct comparative studies all constitute major deficiencies. Moreover, because the domestic catalog update has a delay, enterprises must regularly check the latest status to ensure compliance; otherwise the entire project will fail.
🔴 Red Line 5: Failure of API, excipients, and packaging materials to pass review
If the technical review conclusion for a key API, pharmaceutical excipient, or packaging material is "not approved," or if chemical reagents are used in place of pharmaceutical excipients in the application, it will be directly determined as a major deficiency.
🔴 Red Line 6: Fundamental deficiencies in formulation and process research
Starting material selection that does not comply with ICH Q11; filing by directly refining an already approved API; filing multiple processes for the same product; using Class 1 organic solvents without sufficient irreplaceability justification; or registration batches produced only at laboratory small-scale, etc.
🔴 Red Line 7: Major deficiencies in quality studies and stability studies
Key quality control items (such as related substances) not adequately studied; separation between the main peak and adjacent impurities in the related substances method <1.5; the quality of the applied drug significantly lower than marketed products of the same variety; impurity LOQ exceeding 30% of the impurity limit; or out-of-specification new impurities appearing in long-term stability without identification, etc.
⚠️Genotoxic Impurities — Specifically Called Out in the Documents
The documents specifically emphasize: ifgenotoxic impurities such as mesylate esters, nitrosamines, and aromatic aminesare not proactively screened and controlled, with the threshold of toxicological concern (TTC) set at 1.5 μg/day, once identified as an unrecognized/uncontrolled potential genotoxic impurity, it will be directly judged as a major deficiency. This is the clause with the highest technical threshold and the most explicit special requirement in these documents.
The signal conveyed by the new rules is very clear:
Shift the quality management gate forward from the review stage to the R&D stage; enterprises must establish "zero-defect" awareness at the very start of project initiation, rather than hoping for correction opportunities during the review process.
What Can We Do in the Face of the New Rules?
After the new rules take effect, the core challenge for generic drug R&D enterprises has shifted from "how quickly can we file" to "can we get it right the first time." And to "get it right the first time," the reliability of every data node in pharmaceutical research — the completeness of the impurity profile, the robustness of analytical methods, the continuity of the supply chain, and the compliance of the traceability system — leaves no room for error.
These depend not only on the enterprise's own R&D capability but also on the credibility of every upstream reference standard and every COA. As a reference material supplier that has long served quality control in pharmaceutical research, CATO supports you in the following core dimensions:
Genotoxic impurity reference standards
For the genotoxic impurities called out in the documents — mesylate esters, nitrosamines, and aromatic amines — CATO has corresponding reference materials, supporting method development, limit verification, and the establishment of related substances analytical methods, helping you solidify the screening and control strategy for genotoxic impurities from the project initiation stage.
✦ Compliant with ICH M7 & TTC 1.5μg/day requirements
Traceable, evidence-based quality documentation
The core bottom line of the new rules is data authenticity and traceability. Through dual CNAS and ANAB accreditation, CATO provides a complete COA and traceability system for every batch, directly corresponding to the basic requirement that "inspection results be consistent with application materials."
✦ ISO 17034 · Dual CNAS · ANAB accreditation
Stability and homogeneity verified to ensure reliable reference material values
As an ISO 17034-accredited reference material producer, CATO conducts stability and homogeneity studies on every batch of reference standards/impurity reference standards to ensure stable values within the validity period and consistency between vials. This means the reference standards you use at different stages — method development, impurity quantification, and stability investigation — have a comparable quality benchmark before and after. In the context of the new rules' strict review of "data logic" and "result consistency," the reliability of the reference standard itself is the starting point for the credibility of all analytical data.
ISO 17034 · Stability studies · Homogeneity studies
Custom synthesis capability for impurity reference standards
The new rules require that "impurities exceeding the identification threshold must be identified," but many unknown impurities simply cannot be purchased as ready-made reference standards on the market. CATO has custom synthesis capabilities and can rapidly synthesize and provide structurally confirmed reference standards for unknown impurities discovered during related substances studies and stability investigations, helping you close the loop on impurity identification before filing.
✦ Unknown impurity identification · Custom synthesis · Structural confirmation
Beyond the product itself —
Full-chain quality control from production to delivery
The new rules require enterprises to extend quality control to every link. For reference standard suppliers, "qualified product" is only the starting point; every step from testing methods to warehousing and logistics must withstand traceability. CATO has established control standards above the industry norm in the following operational links:
① Dual-method cross-verification of assay (dual-method API)
CATO uses two independent analytical methods (such as qNMR and HPLC area normalization) for the assay and cross-verification of API reference standards/impurity reference standards, ensuring the accuracy and reliability of assigned values. When reviewers focus on "whether the analytical method is reasonable and the data credible," dual-method cross-verification is the most direct means to eliminate systematic errors at the source.
② Barcode-based dispensing and fully traceable shipment
Every product, from dispensing, warehousing, to outbound shipment, is traceable at the individual unit level through a barcode system. Batch number, expiry date, and dispensing records correspond one-to-one, enabling rapid provision of a complete material traceability chain in on-site inspection scenarios, forming a closed loop with the new rules' requirement of "consistency between application materials and on-site inspection."
③ Intelligent temperature control, from warehousing to receipt
At the warehousing end, CATO uses a multi-temperature-zone precise temperature-controlled warehousing system, linked in real time via a mobile APP, with immediate alarms for temperature and humidity anomalies and 24-hour online data retention. At the logistics end, cold-chain transport is used for temperature-sensitive reference standards, with GPS positioning combined with synchronized temperature data collection, ensuring the product's temperature control is traceable from warehouse to customer laboratory. The quality of reference standards depends not only on production; any loss of control during storage and transport can affect the reliability of subsequent experimental data — from warehousing to receipt, we guard every link for you.
The new rules are here, and the quality threshold will only rise. From reference standard/impurity reference standard selection to supply chain stability, CATO is willing to work with you from project initiation onward.