Provisions for the Lot Release of Biological Products

　　(CFDA Decree No.39)

　　Provisions for the Lot Release of Biological Products, deliberated and adopted at the executive meeting of China Food and Drug Administration on December 20, 2017, is hereby promulgated and shall go into effect as of February 1, 2018.

　　Minister: Bi Jingquan

　　December 29, 2017

　　Provisions for the Lot Release of Biological Products

　　Chapter I General Provisions

　　Article 1 In order to strengthen the supervision and administration of biological products, regulate the lot release of biological products, and ensure the safety and efficacy of biological products, these Provisions are hereby formulated in accordance with relevant regulations in the Drug Administration Law of the People's Republic of China (hereinafter referred to as the Drug Administration Law).

　　Article 2 For the purpose of these Provisions, lot release of biological products refers to the supervision and administration of China Food and Drug Administration (hereinafter referred to as the CFDA) for vaccines, blood products, in vitro diagnostic reagents for plasma source screening test which have obtained marketing authorization, and other biological products stipulated by the CFDA by designating drug control institutions to conduct dossier review, on-site inspection and sample testing for each batch of products before marketing or importation.

　　Products failing to pass lot release shall not be marketed or imported.

　　Article 3 Lot release applicants shall be domestic and overseas pharmaceutical enterprises holding drug approval documents. An overseas pharmaceutical enterprise shall authorize its office within the territory of China or an enterprise legal person in China as its agent to apply for the lot release.

　　The products subject to lot release shall be manufactured as per the process approved by the CFDA. Enterprises shall be responsible for the authenticity of the materials, records and data generated during the production and testing processes of the products subject to lot release. The materials for lot release shall be reviewed, signed and issued by the Qualified Person of the enterprise.

　　Before the marketing of each batch of products or when each batch of products are imported, the lot release applicant shall voluntarily submit the application for lot release, fulfill the statutory obligations in the lot release activities in accordance with law, and ensure that the quality of the products under the application for lot release is reliable and the application dossiers, process records, testing data and the samples for lot release are authentic.

　　Article 4 The CFDA shall be in charge of lot release of biological products nationwide, specifies the scope of product varieties subject to lot release, designates lot release institutions, and guides the implementation of lot release.

　　Food and drug regulatory departments of all provinces, autonomous regions and municipalities directly under the Central Government shall be responsible for routine regulation of the applicants for lot release within their respective administrative regions, assisting the lot release institutions in conducting on-site inspection, organizing on-site sampling of products subject to lot release, disposal of products failing to pass lot release as well as investigation and handling of violations in the lot release process.

　　The lot release institutions designated by the CFDA shall be responsible for the acceptance, dossier review, on-site inspection and sample testing and making the decision on lot release in accordance with the law.

　　The CFDA entrusts the National Institutes for Food and Drug Control (hereinafter referred to as the "NIFDC") to organize the development of technical requirements and detailed rules of technical assessment for lot release, conduct capability evaluation and assessment of drug control institutions which are to undertake lot release or expand the scope of product varieties subject to lot release, and offer guidance, technical training and assessment and evaluation for other lot release institutions.

　　Center for Food and Drug Inspection of CFDA (hereinafter referred to as the "CFDI") shall be responsible for on-site inspection during lot release.

　　Article 5 The CFDA shall establish a risk-based regulation system for the products subject to lot release. If necessary, on-site inspection may be carried out to validate the authenticity and reliability of the application dossiers for lot release.

　　Article 6 The review and test for the lot release of biological products shall be conducted in accordance with the drug registration requirements approved by the CFDA and also meet the requirements of the Pharmacopoeia of the People's Republic of China (hereinafter referred to as "the ChP").

　　Chapter II Determination of Lot Release Institutions

　　Article 7 The lot release institutions and the product varieties subject to lot release in their charge shall be determined by the CFDA.

　　The CFDA shall, in accordance with the needs of lot release work, in a timely manner announce the selection criteria and conditions for added lot release institutions and the product varieties added by the lot release institutions.

　　Article 8 The drug control institutions meeting the selection criteria and conditions in self-evaluation may submit an application to the food and drug regulatory departments of the provinces, autonomous regions or municipalities directly under the Central Government which shall report to the CFDA after preliminary review.

　　The NIFDC shall carry out capability evaluation and assessment on the drug control institution submitting the application. The CFDA designates the drug control institutions to undertake lot release of the corresponding product varieties according to assessment results, or expands the scope of product varieties subject to lot release in the charge of such institutions.

　　Article 9 The NIFDC shall, in accordance with the needs of lot release, make an evaluation on the lot release institutions and report the evaluation results to the CFDA in a timely manner.

　　Article 10 Under any of the following circumstances, the CFDA shall disqualify the lot release institution if it:

　　(I) makes major mistakes due to its own fault, causing serious consequences;

　　(II) issues a false testing report;

　　(III) fails to meet the criteria and conditions for the lot release institution after evaluation.

　　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.

　　Chapter V Re-review

　　Article 33 If the lot release applicant holds objection to the Notice of Lot Release of Biological Products, it may propose an application for re-review to the original lot release institution or directly to the NIFDC within 7 days after receiving the Notice.

　　Article 34 The original lot release institution or the NIFDC shall decide whether or not to re-review within 20 days since the day when it receives the lot release applicant's application for re-review, and the content of re-review is only limited to the items in the original application or the original dossiers submitted by the applicant. If re-test is required as stipulated, the sample shall be the one retained by the original lot release institution, and the time limit shall conform to Article 22 hereof.

　　In case of any of the following circumstances, re-review shall not be approved:

　　(I) The nonconforming items are those that shall not be re-tested as specified by the food and drug regulatory departments such as sterility and pyrogen (bacterial endotoxin);

　　(II) The samples are obviously uneven;

　　(III) The shelf life of the samples cannot meet the need for test;

　　(IV) The lot release applicant makes a written commitment to give up the re-test.

　　Article 35 If the re-review sustains the original decision, a Notice of Re-review Result for Lot Release of Biological Products will be issued to the applicant, and the lot release applicant's further applications for re-review will no longer be accepted; if the re-review changes the original conclusions, the original Notice of Disapproval of Lot Release of Biological Products will be withdrawn, and a Certificate for Lot Release of Biological Products will be issued.

　　Chapter VI Information Publication

　　Article 36 The CFDA shall establish a unified Information Management System for Lot Release, release the determination and adjustment by the lot release institutions and provide the lot release applicants with the searchable progress and conclusions of lot release, and summarize and disclose the lot release conclusion of the products with the lot release completed and handling decision of major issues and other information.

　　The NIFDC is responsible for daily operation and maintenance of the Information Management System for Lot Release.

　　Article 37 The lot release institution shall publicize lot release application procedures, list of materials for lot release to be submitted, sample text of application form, charging standards and basis, requirements for time limit and other information on its website or in the place where the application is accepted.

　　Article 38 The lot release institution shall disclose the lot release conclusion and other information within 7 days after the decision on lot release for each batch of products made by the institution.

　　Chapter VII Legal Liabilities

　　Article 39 Any food and drug regulatory department, or lot release institution or its staff members that violate the provisions herein and in case of any of the circumstances below shall be ordered by its superior administrative authority or supervisory authority to make rectification. If the circumstances are serious, administrative sanctions shall be given to persons directly in charge and other directly responsible persons in accordance with law:

　　(I) Not accepting the lot release application that is in conformity with statutory requirements;

　　(II) Not publicizing on the institution's website or at the acceptance place the information that should be publicized according to law;

　　(III) Failing to fulfill the obligation to inform the administrative counterparts according to the provisions during the process of lot release;

　　(IV) Not informing the lot release applicant at once of all the content needed to be supplemented or corrected, where the application dossiers and samples submitted are incomplete or not conforming with the prescribed format;

　　(V) Not stating the reasons for non-acceptance or disapproval of a lot release by law.

　　Article 40 Any food and drug regulatory department, or lot release institution or its staff members that constitutes any of the following circumstances in the lot release work shall be ordered by its superior administrative authority or supervisory authority to make rectification, and administrative sanctions shall be given to persons directly in charge and other directly responsible persons in accordance with law; if a crime is committed, criminal liabilities shall be investigated by law:

　　(I) Making the conclusions of approval for lot release for the application that does not meet the statutory requirements or acting beyond statutory authority to do so;

　　(II) Making the decision of disapproval of lot release for the application meeting the statutory requirements;

　　(III) Violating the procedure requirements to disclose relevant work information to the lot release applicant or the third party without permission during the process of lot release, causing serious consequences;

　　(IV) Accepting or asking for the property or other interests of the lot release applicant during the process of lot release.

　　Article 41 If the lot release institution issues a false testing report when undertaking the lot release work, a penalty shall be imposed in accordance with Article 86 of the Drug Administration Law.

　　Article 42 If the lot release applicant provides false data or samples, or conceal major changes that will affect product quality and obtain the Certificate for Lot Release of Biological Products by fraud, a penalty shall be imposed in accordance with Article 82 of the Drug Administration Law.

　　If the Certificate for Lot Release of Biological Products is forged, a penalty shall be imposed in accordance with Article 81 of the Drug Administration Law.

　　Article 43 If it is found in on-site inspection that drug production fails to comply with the Good Manufacturing Practice for Drugs, a penalty shall be imposed in accordance with Article 78 of the Drug Administration Law.

　　Article 44 For the sales and use of the biological products that have not obtained the Certificate for Lot Release of Biological Products, a penalty shall be imposed in accordance with Article 73 of the Drug Administration Law.

　　Chapter VIII Supplementary Provisions

　　Article 45 The time limit for lot release as prescribed in these Provisions shall be calculated by working days, excluding statutory holidays.

　　Article 46 The import of biological products which are subject to lot release administration shall also abide by laws and regulations on drug import.

　　Article 47 Formats of the Application Form for Lot Release of Biological Products, the Registration Form for Lot Release of Biological Products, the Certificate for Lot Release of Biological Products, the Notice of Disapproval of Lot Release of Biological Products, the Notice of Re-review of Lot Release of Biological Products and the Notice of Re-review Result of Lot Release of Biological Products shall be developed in a unified manner and publicized by the NIFDC.

　　Article 48 The Certificate for Lot Release of Biological Products, the Notice of Disapproval of Lot Release of Biological Products and the Notice of Re-review Result of Lot Release of Biological Products shall be numbered by the lot release institution in sequence with a format of “Lot Release X (Import) Test XXXXXXXX”, wherein the first X symbol represents the abbreviation of the administrative region of the province, autonomous region or municipality directly under the Central Government in the place where the lot release institution is located or abbreviation of the institution; for imported biological products, “Import” shall be used; and in the last 8 X symbols, the former 4 X symbols represent the AD year, and the latter 4 X symbols represent the sequence number within the year.

　　Article 49 These Provisions shall go into effect as of February 1, 2018. Provisions for the Lot Release of Biological Products (CFDA Decree No. 11) promulgated on July 13, 2004 shall be superseded simultaneously.