Notes: For frequently asked questions concerning technical issues, China Center for Drug Evaluation (CDE) releases answers on its website. According to the updated regulations, BaiPharm makes slight modifications to some answers. In case of any discrepancies, CDE's official announcements shall prevail. If you have enquiries about drug marketing authorization in China, please contact BaiPharm for professional help.
The Submission and Acceptance of Drug Registration Applications
Bioequivalence (BE) Study
Selection of Reference Listed Drugs
Quality and Therapeutic Equivalence Evaluation of Generic Drugs
Biological Product R&D
Associated Review and Approval of APIs, Excipients, and Packaging Materials
Administration and Requirements for Changes
This article covers topic 6, 7, 8, and 9. For Q&As on the first five topics, please refer to BaiPharm's previous articles:
You can also download the whole Q&A report at the end of this article.
Topic 6: Biological Product R&D
Q1: What are the requirements for the manufacturing site to be used in clinical trials for cell therapy products? What about process control?
A1: Viruses and cells used in human clinical trials should be produced in compliant with pharmaceutical GMP. As for plasmids used in production, the requirements depend on specific use conditions. If the plasmids are directly used as vectors for in vitro genome editing, they are recommended to be produced in GMP-compliant conditions.
Applicants are required to control the manufacturing process in accordance with China's current GMP and can refer to other countries' and regions' GMP for cell therapy products. Cell therapy products can neither tolerate the virus inactivation processes, nor go through terminal sterilization or sterilization filtration. Therefore, it is particularly important to control their manufacturing process.
In appropriate stages of the manufacturing process, applicants should establish testing items and acceptance criteria for process control, to ensure that the product's manufacturing process is comprehensively monitored and the quality control is consistent between different production batches.
In addition, considering the manufacturing techniques, equipment, operations, and administrative standards, applicants should formulate measures to prevent the confusion, contamination and cross-contamination of different batches of products, and ensure the traceability of the whole manufacturing process (from tissue/cell collection, production, transportation, to clinical use).
Q2: Can animal/human serum be used in the culture of cell therapy product?
A2: Animal/human serum should be avoided as much as possible in the manufacturing of cell therapy products. If the animal/human serum is necessary, the applicant should provide sufficient research materials specifying the necessity of using the serum in cell culture. After validating the necessity, the applicant should provide the reasons for choosing a certain type of serum and using a specific amount, and clarify the serum's source and quality standards. The applicant should establish a quality control system, test the residues, and evaluate safety risks. In the technical review, CDE will evaluate the risks and benefits comprehensively considering the product's value in clinical use.
CDE advises the applicant to learn about serum safety validation requirements referring to Technical Guidelines on Cell Therapy Product Research and Evaluation. In addition, CDE encourages the applicant to actively explore for safer serum substitutes with clearer compositions to be used in future production.
A3: The applicant should use the strain or cell which has clear culture, legal source, as well as quality good enough for the R&D phase, and the safety of the final product. CDE advises the applicant to provide the traceability information according to the specific purchase channel. The information includes but is not limited to certificate documents, culture process, passaging, and assay.
CDE also suggests that under the precondition of fulfilling the Chinese Pharmacopoeia standards and ICH guidelines, the applicant should establish a strain/cell bank according to the product's actual conditions and test the strains/cells comprehensively.
Q4: Currently, the lentiviral packaging system is usually the third-generation four-plasmid virus packaging system. Is it permitted to use the second-generation three-plasmid lentiviral packaging system?
A4: In chimeric antigen receptor (CAR) T cell products, lentiviral vectors are often used to introduce target genes. The reverse mutation of lentiviral vectors and the insertion of viral genes into the human genome, which are intrinsic risks in the use of CAR T products, should be considered in product design and quality control, and kept under long-term monitoring in subsequent researches.
The four-plasmid lentiviral packaging system further deletes unnecessary elements for viral packaging, restructures related gene sequences, and separates multiple genes for expression on different plasmids. As a consequence, the possibility is reduced for lentiviral reverse mutation and homologous recombination. Therefore, if the applicant intends to use the lentiviral system, CDE recommends safer plasmid system for packaging lentiviruses, and viral vectors with self-inactivating (SIN) structures.If using a higher-risk plasmid system, the applicant should evaluate the potential risks and explain the rationality of using this system. If sufficient evidence cannot be provided, CDE advises the applicant to conduct safety studies.
Q5: In terms of testing sterility, mycoplasma, replication-competent lentivirus (RCL), and other safety indicators, can the applicant use new self-established method to replace the conventional methods in the Chinese Pharmacopoeia or general guidelines for the testing before product release?
A5: Based on the characteristics of cell therapy drugs, the applicant can develop new sterility and mycoplasma testing methods for the testing before product release, but the new methods should be fully validated.
It should be noted that when the new method is not fully validated that it can replace the traditional methods in the Chinese Pharmacopoeia, it is recommended to use the traditional method for parallel testing while using the new testing method before product release. CDE also suggests the applicant collecting data of different testing methods during clinical trials, conduct complete methodological research and validation, and submit research data in subsequent applications.
In addition, while using the new and conventional methods in parallel, if the cellular drug must be used on humans as soon as possible while there is inconsistency between the testing results of the two methods, the applicant should formulate emergency remedial measures in advance.
As RCL is an important safety risk concern, when applying for clinical trials, it is recommended that the applicant should use the validated cell culture method in the general guidelines to complete the RCL testing for virus (supernatant and end-of-production cells).
For final cell products, the applicant can use a methodologically validated rapid method for RCL testing before product release, and the samples should be kept. When necessary, the applicant should use the indicator cell culture method for retrospective testing and analysis. In addition, the applicant should monitor the RCL during the production process. For products with higher risks (such as products based on the selection of plasmid systems), the RCL testing requirements should be appropriately higher.
The applicant should set reasonable positive and negative controls for each batch of cell culture testing. The testing method's sensitivity and sample numbers should meet the safety requirements based on the dose used in clinical research. Also, the applicant should consider the virus particles' inhibitory effects on RCL testing.
Q6: How to conduct the stability study for cell therapy product in the clinical trial application stage?
A6: CDE recommends the applicant to design stability study plan according to ICH Guideline Q5C, Technical Guidelines on Biological Product Stability Studies, Technical Guidelines on Cell Therapy Product Researches and Evaluations, and Key Points for Cell Therapy Products’ Pharmacological Studies and Documentation for Clinical Trial Applications. The plan should cover the research's product batches, research conditions, testing items, and testing frequency.
In clinical trial application, the cell product's stability study document should cover all the stages of storage, transportation, and use of the samples. After meeting the basic requirements for clinical use, the applicant can enrich and improve the stability study during the clinical trial.
CDE advises the applicant to conduct researches on representative samples according to the specific cell therapy products' availability. The samples include the collected tissue/cell samples, intermediate samples during the production, final cell products, samples in clinical use, etc. The samples' cell densities and volumes should be able to represent those in actual production and use.
The applicant should also design the stability study plan based on the cell therapy product's characteristics. For example, if the product is a liquid dosage form, the applicant should pay attention to vibration's impact on cells. If the product is a frozen dosage form, the applicant should study how cryopreservation and restoration affect the cells.
Q7: What information should be included in the safety evaluation and compatibility research on the containers and packaging materials with direct / short-term contact with the cell therapy product?
A7: For the clinical trial application, CDE advises the applicant to provide basic information, including the container's and packaging material's sources, quality standards, biological safety research data, etc.
CDE also advises the applicant to complete the preliminary evaluation of compatibility between the product and the packaging container (small-sized container of the same material with the bigger ones is also acceptable) before applying for clinical trials. The applicant should ensure the safety of clinical use, with particular attention to the compatibility between cells/excipients (such as dimethyl sulfoxide, also known as DMSO) and containers, and the corresponding safety risks.
On the premise of ensuring the safety of the samples for clinical trials, the basic performance testing and the packaging material's biological evaluation conducted by the supplier, as well as the preliminary stability study results that meet the clinical trial needs, can be used as the references for evaluating the compatibility of packaging materials.
During the clinical trial, the applicant should conduct a complete compatibility study according to the composition and storage conditions of the cell preparation following the relevant guidelines.
Q8: For biological products that obtained marketing authorization outside China, are they permitted to be imported for one time to be used as the reference drugs in clinical trials
A8: According to NMPA's Announcement on the Items Relevant to One-time Import of Biological Reference Products Used in Clinical Trials (No. 94 Announcement in 2018), products of the two categories below can be imported for one time:
Originator biological products that have obtained marketing authorization in China, but the drug R&D institutes or manufacturing companies are not able to obtain them immediately on the Chinese domestic market;
Originator biological products that have obtained marketing authorization outside China, and obtained the clinical trial authorization in China.
A9: For biological product changes, the applicant should conduct sufficient technical evaluation and verification. Comparability research is the basis and key to a successful evaluation of biological product changes. The research aims to confirm whether the changes have adverse effects on quality, safety, and efficacy of biological products by collecting relevant technical data and analyzing them in comparison.
The applicant does not need to conduct post-change nonclinical/clinical studies if the before-after comparability is proved by sufficient analyses on the manufacturing process, quality attributes, and stability studies.
The applicant needs to conduct bridging or confirmatory clinical trials if the non-clinical trial research cannot prove the changes' effects on product safety and efficacy because of the following three circumstances:
① Quality analysis and comparison results are not accepted;
② There are major differences between the pre- and post-change products; or
③ There are deficiencies in the comparability research projects.Proving comparability does not mean the quality attributes are exactly the same in pre- and post-change products, but they should be highly similar. Also, based on the existing knowledge and research results, the evidence is sufficient for predicting that the quality attribute change won't have any adverse effects on product safety or efficacy.
Q1: If the applicant has filed the drug master file of the active pharmaceutical ingredient (API) according to former CFDA's Announcement on Adjusting the Review and Approval of APIs, Pharmaceutical Excipients, and Packaging Materials (No. 146 Announcement in 2017), how should the applicant apply for independent review of the API according to Article 43* of the Administrative Measures for Drug Registration?
*Article 43 stipulates that APIs that are generic versions of APIs in the marketed drugs in China can apply for independent review and approval.
A1: For API that has obtained a filing number according to the No. 146 Announcement, the applicant can apply for changing the review procedure by using the "Already Filed. Apply for Review" function under the item with the corresponding filing number, if the API meets either condition below:
1. The API's filing number has not been associated with the finished dosage form's review.
2. The API has completed the associated review together with the finished dosage form, but the API's filing status is marked as "I (inactive)" in the associated review conclusion.
If meeting either condition above, the applicant should choose whether the application materials have any change from the filed materials when applying for post-filing review. For materials without changes, the applicant should submit the "re-filing commitment letter" to CDE; for materials with changes, the applicant should re-submit a complete set of application materials according to current requirements.
In addition, the applicant should make sure that the filed chemical API has been accepted by CDE before choosing it for the associated review for the marketing authorization application of the finished drug product. For chemical APIs that have been filed according to No. 146 Announcement, the applicant can change the review procedure via "Already Filed. Apply for Review" function.
Q2: How to file for the same API with different manufacturing processes?
A2: In principle, the filer should file for the API under different filing numbers and submit filing documents separately.
Q3: If the finished dosage form applicant chooses to use the API manufactured outside China and without being filed in China, can the API supplier submit the confidential data by itself without disclosing them to the applicant who submits the registration application of the finished dosage form
A3: According to NMPA's Announcement on the Items Relevant to the Associated Review, Approval, and Supervision of Drugs (No. 56 Announcement in 2019), for APIs, excipients, and packaging materials (the three altogether referred to as AEPs) that cannot be filed at CDE's platform due to special reasons, the finished dosage form applicant can submit the AEP research data together with the finished drug application to CDE.
For convenience, the API data (including confidential information) can be directly sent by the overseas API supplier to CDE. But the API documents should be associated with the finished dosage form's application documents. The finished dosage form's name, the application item, the applicant's name, and contact person, and contact details, etc. should be specified in the documents. The application which passed the format review will be accepted by CDE.
Topic 8: Requirements for Changes
Q1: When applying for renewing the license of an imported drug, can the applicant apply for the change of the drug's strength at the same time?
A1: No, the applicant is not allowed to do so. According to the former CFDA's Announcement on Items Relevant to License Renewal of Imported Drugs (No. 18 Announcement in 2009), it is not allowed to apply for renewing an imported drug's license and changing the manufacturing site / strength at the same time. To change the manufacturing site / strength, the applicant should submit an independent supplemental application.
A2: Please refer to the table below:
Applicant name change
Applicant entity change
Technical change (e.g., manufacturing site change)
According to the former CFDA's Announcement on Further Regulating the Acceptance of Drug Registration Applications (No. 122 Announcement in 2015), the applicant can submit the change application to the regulator which previously accepted the corresponding drug registration application.
- If the drug registration application was accepted by the provincial medical products administration, then the change application should be submitted to the corresponding medical products administration, which will report to CDE about the change.
- If the drug registration application was accepted by CDE, then the change application should be submitted to CDE, which will directly change the information.
Same as above.
The new applicant should submit a supplemental application. After being accepted, the supplemental application should be reviewed in association with the drug registration application.
Q3: What category does the change of drying method from tray drying to fluid bed drying in the chemical drug manufacturing process belong to?
A3: As the change from tray drying to fluid bed drying may have significant impacts on the product quality, such a change belongs to Category III (major) changes as per the Technical Guidelines on Researches on Changes to Chemical Drug With Marketing Authorization. Also, the change of drying method may impact the drug's bioavailability. Therefore, for oral solid drugs difficult to dissolve, the applicant needs to conduct the bioequivalence study before changing the drying method.
Q4: What kind of application should the applicant submit for changing the manufacturing site of the API used in the imported finished dosage form?
A4: Changing the API's manufacturing site may have influences on the finished dosage form's quality. CDE advises the applicant to submit a supplemental application that needs technical review.
Q5: Should the applicant submit an application for adding a strength if it adds a strength for the tablet core of a sugar-coated chemical drug?
A5: CDE advises the applicant to submit an application for changing the manufacturing process.
Q6: Can the application for changing the marketing authorization holder and the manufacturing site be combined with the application for imported drug license renewal?A6: According to the Announcement on Items Relevant to License Renewal of Imported Drugs, the license renewal applications for an imported drug should not be combined with supplemental applications. To change the manufacturing site or add a strength, the applicant should submit independent supplemental applications.
Topic 9: Other Q&As
Q1: Can a foreign company's resident representative office perform as an agency for the foreign marketing authorization holder (MAH) in China?
A1: No, they cannot. According to Administrative Measures for Drug Registration, a foreign applicant should appoint a legal corporate entity to carry out affairs related to drug registration. The Administrative Provisions on Filing for Permanent Agencies of Foreign Companies stipulates that foreign companies' resident representative offices are not legal corporate entities and can only engage in non-profit activities related to the foreign company's businesses in China.
Q2: Can manufacturing process exploration and manufacturing condition establishment be placed during the clinical trial?
A2: When applying for clinical trial, the applicant should determine the steps, parameters, and production process control measures of the cellular drug's manufacturing process that is compatible with the clinical trial. The manufacturing process should be evaluated in terms of its transfer from being used in the laboratory to being used in the human clinical trial. The applicant should support the reasonable and steady manufacturing process to meet the supply of cellular drugs during the clinical trial, and ensure the product safety and the process & quality controllability.
It is also necessary to compare and analyze the differences and commonalities between ①the non-clinical animal research and the non-registered clinical trial (if applicable) and ② the clinical trial in terms of manufacturing process (in a broad sense, including manufacturing process, site, raw materials, and scale) and product quality. If there are quality differences, the applicant should further analyze and evaluate whether it is necessary to conduct relevant bridging studies or restart researches on manufacturing processes for clinical trials. If there is a need for changing the manufacturing process during clinical trials, it is recommended for the applicant to refer to ICH Q5E Guidelines and other relevant Chinese/international technical guidelines to conduct sufficient researches on the changes. The applicant should analyze the comparability of product safety, efficacy (based on specific situations), and quality controllability before and after the changes.
If it is truly necessary to change the critical manufacturing processes and parameters during the clinical trial, the applicant should fully analyze and evaluate the comparability before and after the changes. When necessary, the applicant should conduct bridging clinical trials on animals or humans. It is encouraged that the drug R&D institutes communicate with CDE about the research plan on changes.
Q3: How to verify the non-proprietary name of the proposed drug during the review of the drug registration application?
A3: For registration application under review and considered that it needs drug nonproprietary name verification after the technical review, CDE will notify the applicant to submit documents for verifying the drug's non-proprietary name. The applicant can also send an application to CDE for verifying the name.
A4: According to the Announcement on Items Relevant to Imported Drug Registration, the applicant should report to NMPA about the supplemental information of changing the imported drug's registration agency.
Q5: Should all the application dossiers for imported drugs be translated into Chinese?
A5: According to Administrative Measures for Drug Registration, all the application dossiers should be in Chinese, with the attached version in the original language. Chinese translation should be consistent with the original texts. Documents in neither Chinese nor the original language can be an appendix for reference.
A4: According to the Announcement on Items Relevant to Imported Drug Registration, the applicant should report to NMPA about the supplemental information of changing the imported drug’s registration agency.
Q6: The marketed innovative monoclonal antibody (mAb) products for which crab-eating macaques are used in the long-term toxicity experiments as part of the pre-clinical safety evaluation. Is it permitted to use only one species related to crab-eating macaques in the pre-clinical safety evaluation of the proposed product which is the same type of the marketed mAb products?
A6: In the preclinical safety evaluation of new mAbs, the applicant needs to consider the selection of animal species, and choose relevant animal species for preclinical research. If there is only one animal species, it is permitted to choose them for the subsequent long-term repeated-dose toxicity experiment. However, it is recommended to include toxicity studies on the second animal species in the early-stage dose-finding toxicity studies to determine the toxicity. The inclusion is meaningful for evaluating off-target toxicity.
Q7: When the impurity limit changes in new drug development, should the applicant conduct the non-clinical pharmacology and toxicology bridging studies?
A7: The total amount of impurities in the human test is supported by the corresponding data in the animal test result. If the animal test is necessary, the applicant should refer to ICH Q3 Guidelines to carry out a repeated-dose toxicity test which usually lasts 14-90 days.
Q8: Should every single unit of suppository in the package be printed with the approval number?
A8: Though there are no definite regulatory requirements in this regard, it is advised to print the approval number on each level of packaging, including the minimum packaging unit, for the sake of managing drug usage and controlling risks.
Q9: For the application of a drug imported to China, what are the requirements for drug manufacturers to use the US FDA's GMP inspection report as the GMP compliance evidence?
A9: Overseas regulator's GMP inspection report is accepted for imported drug registration. The drug manufacturer should ensure that the information on the report is consistent with the application. In addition, the report should be notarized by both a notary institution in the country from which the drug is imported and the country's embassy in China.
Q10: Does CDE accept the electronic GMP certificate from the website of France's National Agency for the Safety of Medicines and Health Products (L'Agence nationale de sécurité du médicament et des produits de santé or ANSM)?
A10: Yes, the certificate is accepted by CDE.
Q11: How to submit applications for drug-device products without marketing authorization in China?
A11: According to the Announcement on Items Relevant to Drug-device Combination Product Registration (No. 52 Announcement in 2021), the applicant should send an application to the Center for Medical Device Standardization Administration of NMPA for determining the drug/device category of the product. After the category is determined, the applicant can apply for product registration and specify that it is a "drug-device combination product" in the application form.
Q12: How to apply for registration of drug-device combination product mainly functioning as a drug?
A12: According to the Announcement on Items Relevant to Drug-device Combination Product Registration (No. 52 Announcement in 2021), the applicant should apply for registering the product as a drug and identify it as "drug-device combination product" in the application form. For application documentation requirements, the applicant should refer to Chemical Drug Registration Classification and Application Dossier Requirements or Biological Product Registration Classification and Application Dossier Requirements.