Provisions for the Lot Release of Biological Products (CFDA Decree No.39)

 Chapter III Application for Lot Release

Article 11 Before the initial application for lot release of the new biological product approved for marketing, the lot release applicant shall register and file in the Information Management System for Lot Release. The following materials shall be submitted for registration:

(I)  Registration form for biological products subject to lot release;

(II) Drug approval documents;

(III) Supporting documents for legal production;

For relevant materials in line with the requirements, the NIFDC shall complete the registration confirmation of the product under application in the Information Management System for Lot Release within 10 days.

In case of any change in the registered information, the lot release applicant shall make a timely change in the Information Management System for Lot Release.

Article 12 For each product subject to the application for lot release, the lot release applicant shall establish an independent template for the summary of the production and control test records of lot release, which shall be submitted to the NIFDC for verification and then distributed after approval to the lot release institution and the applicant by the NIFDC. In case of a revision of the verified template for the summary of the production and testing records of lot release required, the lot release applicant shall submit an application to the NIFDC. The template shall not be changed until verified by the NIFDC.

Article 13 After completion of manufacturing and testing of biological products subject to lot release administration, the lot release applicant shall fill out the Application Form for Lot Release of Biological Products in the Information Management System for Lot Release, and apply to the lot release institution under jurisdiction for lot release in the place where the drug manufacturer applying for lot release is located or the place where the port at which the drug is to be imported is located.

Article 14 The lot release applicant shall propose a sampling application to the food and drug regulatory departments of the provinces, autonomous regions or municipalities directly under the Central Government or the sampling institutions designated thereby by virtue of the Application Form for Lot Release of Biological Products; sampling personnel shall organize on-site sampling within 5 days, and seal the samples. The lot release applicant shall be responsible for delivering the sealed samples under the stipulated conditions to the lot release institution to handle registration for lot release, and shall also submit lot release application dossiers.

Food and drug regulatory departments of all provinces, autonomous regions and municipalities directly under the Central Government shall be responsible for organizing the sampling of products subject to lot release for production or importation within their respective administrative regions, determining relatively fixed sampling institutions and personnel to file at the lot release institutions, training the sampling institutions and personnel and conducting supervision and guidance for sampling work.

Article 15 In case of applying for lot release, the lot release applicant shall provide the following supporting documents, materials and samples:

(I)  Application Form for Lot Release of Biological Products;

(II) Drug approval documents;

(III) Supporting documents for legal production;

(IV) Post-marketing change approval documents;

(V)  Summary of batch production and testing records signed by the  Qualified Person of the drug manufacturer and affixed with the seal of the enterprise;

(VI) For the products with the same batch number which meet the testing requirements for lot release of relevant product variety in terms of quantity, test-related intermediate products, standard substances, reagents and other materials shall be provided when necessary;

(VII)  Description of the changes in the key personnel including the Qualified Person;

(VIII) Other materials relating to product quality.

For an imported vaccine product or blood product, the certificate of origin of the country or region where the manufacturer is located and the lot release supporting documents issued by the local drug regulatory authority shall be provided at the same time, as well as their Chinese translations notarized. If an imported product is exempted from lot release in the country of origin, supporting documents for exemption of lot release shall be provided.

If the relevant supporting documents are photocopies, they shall be affixed with the seal of the enterprise.

Summary of batch production and testing records of biological products refers to a document summarizing the testing results on all production processes and critical quality control links of a certain batch of biological products. Such document shall be reviewed and determined by the quality management department and Qualified Person of the enterprise.

Article 16 After receiving the application dossiers and samples, the lot release institution shall immediately verify and properly preserve the same after registration and signature confirmation by the two parties. If the lot release applicant cannot sign for confirmation on the spot, it shall submit a written commitment in advance.

The lot release institution shall decide whether or not to accept within 5 days. If the lot release institution agrees to accept, it shall issue a Registration Form for Lot Release of Biological Products; if not, it shall return the application, issue the Non-acceptance Notice with the reason explained.

If the application dossiers are incomplete or nonconforming to the prescribed form, the lot release institution shall inform the lot release applicant of all contents to be supplemented and corrected and the time limit for supplementation in writing all at once within 5 days. Where the lot release institution fails to notify the applicant within the time limit, it shall be regarded as acceptance as of the date of receipt of application dossiers.

If application dossiers are found with the error that can be corrected on the spot, the lot release applicant is allowed to make rectification on the spot.

If the application is not accepted by the lot release institution, the applicant shall not re-apply for lot release to some other lot release institution.

Article 17 For biological products in urgent national disease prevention and control needs, upon approval by the CFDA, the enterprise may apply to the lot release institution for lot release immediately after completion of manufacturing.

Before the lot release institution makes any conclusion of "pass" in lot release, the lot release applicant shall supplement the lot release application dossiers and submit them to the lot release institution.

Chapter IV Review, Test, Inspection and Release

Article 18 Lot release may be conducted by means of independent dossier review or by combining dossier review with sample test, and on-site inspection may be conducted as required. For the lot release mode as well as the testing items and testing proportion for different products, the NIFDC shall organize the demonstration and each lot release institution shall conduct test in accordance with the determined mode for lot release and specifications.

In the process of the lot release of a specific product, the lot release institution may make a comprehensive evaluation according to the process and quality control maturity of the product variety and previous lot release and dynamically adjust the testing items and testing frequency in the registration specification of the product variety. Where there is any nonconforming item of the products subject to lot release, the lot release institution shall add the testing frequency on the corresponding item of the products of subsequent batches.

Article 19 Dossier review including:

(I)  Whether the content of the application dossiers meet the requirements;

(II)  Whether the raw materials and subsidiary, bacterial strains/seeds, viral strains/seeds and cells used for production are consistent with those approved by the CFDA;

(III) Whether the production process and process control are consistent with those approved by the CFDA and meet the requirements in the ChP;

(IV) Whether the testing items, testing methods and results of bulk, final bulk and finished products meet the requirements stipulated by the ChP and the drug registration specifications;

(V)  Where there is abnormality in the analysis on the trend of key quality indicators of the product;

Whether the product package, label and package inserts are consistent with those approved by the CFDA;

(VI) Other items to be reviewed.

Article 20 The lot release institution shall, in accordance with the previous quality management over the lot release applicant and the technical maturity and quality stability of corresponding product variety, carry out on-site inspection of different proportions for the product under application for lot release and may take sample for test as needed.

Article 21 Under any of the following circumstances, the product shall be subject to whole-item test in accordance with the registration specification and may be subject to the test on partial items until at least three consecutive batches of products manufactured pass the lot release:

(I) The product of the lot release applicant newly approved for marketing by the CFDA ;

(II) Change of production site which is approved;

(III) Change of production process which is approved;

(IV) For the products have not been applied for lot release for two consecutive years;

(V)  Production is approved to resume after ordered production suspension for violation of relevant laws and regulations;

(VI) There is information suggesting that the quality of the corresponding product or quality control has potential risks;

(VII) Other circumstances where whole-item test is required for three consecutive batches.

Article 22 The lot release institution shall complete lot release within the work time limit stipulated herein. The time for the lot release applicant to supplement and correct the materials and the time for on-site verification, on-site inspection and technical evaluation shall not be included in the time limit for lot release.

Lot release shall be completed within 60 days for vaccine products and within 35 days for blood products and the in vitro diagnostic reagents for plasma source screening test. Where a re-test is required, the time limit for lot release may be extended by two test cycles of the item, and the lot release applicant shall be informed.

If the time limit for lot release indeed needs to be extended due to product characteristics or testing item, the NIFDC shall determine and publicize the time limit after review.

Article 23 If the lot release institution is unable to complete lot release within the stipulated time limit due to force majeure, handling of public health emergencies or other reasons, it shall inform the lot release applicant in writing of the extended time limit for lot release, reasons and expected time of recovery. If the lot release institution indeed can hardly complete lot release, the NIFDC may coordinate with other lot release institutions for undertaking the work.

Article 24 If the lot release institution believes that relevant data in the application dossiers needs to be verified or supplemented, it shall notify the lot release applicant of supplementing data in writing and specify the time limit for reply.

The lot release institution, under the premise of guaranteeing independence of dossier review, sample test and other technical review work, may communicate with the lot release applicant about specific problems requiring explanation in the lot release process.

Where the authenticity of the application dossiers for lot release and the samples is in double or needs further verification, the lot release institution shall promptly send personnel to the manufacturer for on-site verification, and may notify the food and drug regulatory departments of the provinces, autonomous regions or municipalities directly under the Central Government to send law enforcement personnel to cooperate in the verification depending on the circumstances. Where the enterprise is confirmed to have authenticity problems, lot release shall be disapproved.

Article 25 For any of the following circumstances, the lot release institution shall notify food and drug regulatory departments of the provinces, autonomous regions or municipalities directly under the Central Government in the place where the enterprise is located, order the enterprise to analyze and identify the reasons, propose the recommendations for on-site inspection to the CFDI and simultaneously report to the CFDA :

(I) Sterility and other important safety indicators are nonconforming in the test;

(II) Efficacy and other efficacy indicators are nonconforming in the test of two consecutive batches;

(III) Dossier review prompts that serious problems may exist in the product production quality control;

(IV) Where there is a problem in the authenticity of the application materials for lot release or the samples;

(V) Other circumstances prompting major quality risks of the product.

During the investigation and handling of the above problems, the application for lot release of corresponding product variety of the enterprise shall be suspended.

Article 26 After receiving the recommendations for on-site inspection, the CFDI shall conduct on-site inspection within 20 days.

The CFDI shall, within 10 days upon completion of the inspection, organize the technical evaluation on the quality risks of relevant batches of products proposed by the lot release institution, make a clear conclusion, form an on-site inspection report and send it to the lot release institution and the CFDA. The CFDA will determine the time limit for on-site inspection overseas depending on specific conditions.

After identifying the reasons for the problems and complete the rectification, the enterprise shall report to the food and drug regulatory departments of the provinces, autonomous regions or municipalities directly under the Central Government and the lot release institution. The application for lot release may be resumed after it passes the on-site inspection by the CFDI.

Article 27 If the lot release applicant applies for withdrawal of its lot release application due to non-quality problem, it shall provide the explanation, and may withdraw the application only upon approval by the lot release institution and shall report such withdrawal to the food and drug regulatory departments of the provinces, autonomous regions or municipalities directly under the Central Government.

If the lot release institution has confirmed through review that the dossier has defects or the testing results do not comply with the requirements, the application shall not be withdrawn by the lot release applicant.

Article 28 The lot release institution shall make decision on lot release based on dossier review, sample test or on-site inspection and other results. If the requirements are met, the institution shall issue a Certificate for Lot Release of Biological Products which is affixed with the special seal for lot release, and send it to the lot release applicant.

For the sales of biological products subject to lot release administration, a copy of the Certificate for Lot Release of Biological Products for this batch shall be presented and affixed with the seal of the enterprise.

Article 29 For those in any of the following circumstances, the lot release shall be disapproved, and a Notice of Disapproval of Lot Release of Biological Products shall be issued to the lot release applicant and copy to the food and drug regulatory departments of the provinces, autonomous regions or municipalities directly under the Central Government in the place where the lot release applicant is located:

(I)  Any dossier does not meet the requirements as found in the review;

(II)  Any nonconforming sample is found in the test;

(III) It is identified in the on-site inspection to violate the Good Manufacturing Practice for Drugs and have serious defects;

(IV) It is identified in the on-site inspection that the product has systematic quality risks;

(V)  The lot release applicant fails to supplement and correct the materials within the prescribed time limit without valid reason;

(VI) Other circumstances in noncompliance with the laws and regulations.

Article 30 Biological products disapproved for lot release shall be destroyed by the lot release applicant in accordance with relevant regulations under the supervision of the food and drug regulatory departments of the provinces, autonomous regions or municipalities directly under the Central Government. The imported biological product shall be destroyed under the supervision of the food and drug regulatory departments in the place where the port is located or returned to overseas manufacturer.

The lot release applicant shall also report the destruction records to the food and drug regulatory departments and the corresponding lot release institution simultaneously.

Article 31 Where the product of the enterprise is identified to have serious defects in the lot release, involving the batches that have already been marketed and distributed, the CFDA shall immediately notify the lot release applicant. The lot release applicant shall immediately take such measures as stopping the sales and use and recalling the defective products and destruct them in accordance with relevant regulations and under the supervision of the food and drug regulatory departments of the provinces, autonomous regions and municipalities directly under the Central Government. The lot release applicant shall also report the destruction records to the food and drug regulatory departments and the corresponding lot release institution simultaneously.

For the recall of product, a lot release applicant shall not be exempted from other legal liabilities to be borne according to law.

Article 32 Lot release institutions shall summarize their annual lot release work. The NIFDC, after summarization and analysis, shall report to the CFDA before the end of March each year.