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Drug Manufacturing Surveillance Regulation

Source:
Derived from the network
2020/04/10 17:29
[Abstract]:

Drug Manufacturing Surveillance Regulation
 
(Promulgated under Decree No.28 of State Administration for Market Regulation on January 22, 2020)
 
Chapter I  General Provisions
 
Article 1  In order to strengthen the administration of drug manufacturing and standardize drug production activities, this Regulation has been formulated according to the laws and administrative regulations, such as Drug Administration Law of the People’s Republic of China (hereinafter referred to as the “Drug Administration Law”), Law of the People’s Republic of China on Traditional Chinese Medicine, Vaccine Administration Law of the People's Republic of China (hereinafter referred to as the “Vaccine Administration Law”), Administrative Licensing Law of the People’s Republic of China and Regulation for Implementation of Drug Administration Law of the People’s Republic of China. 
 
Article 2  Production of marketed drugs and the relevant surveillance activities within the territory of the People's Republic of China should be conducted in accordance with this Regulation.
 
Article 3 In engaging in drug production activities, laws, regulations, rules, standards and norms should be followed to ensure the authenticity, accuracy, integrity and traceability of whole-process information.
To carry out drug production activities, approval should be obtained from the drug regulatory authority of the corresponding province, autonomous region or municipality directly under the Central Government, the drug manufacturing license should be obtained, and good manufacturing practice should be strictly abided to ensure the manufacturing process persistently complies with regulatory requirements.
The drug marketing authorization holder shall establish a drug quality assurance system, fulfill marketing release responsibilities and be responsible for the quality of drugs granted with drug registration certificates. 
Manufacturers of decoction pieces of Chinese medicines shall fulfill relevant obligations of drug marketing authorization holders and ensure the production of decoction pieces of Chinese medicines continually complies with regulatory requirements.
Manufacturers of raw material should organize production according to approved manufacturing processes and strictly abide by good manufacturing practice to ensure the drug production continually complies with regulatory requirements. 
Manufacturers of excipients and primary packaging materials and containers subject to bundling review and other entities and individuals engaged in drug production related activities shall undertake corresponding responsibilities according to law. 
 
Article 4 Drug marketing authorization holders and drug manufacturers shall establish and implement drug traceability systems, endow traceability labels of sales package units at each level as specified, implement drug traceability using information-based means, timely and accurately document and retain drug traceability data and provide traceability information to the drug traceability coordination service platform. 
 
Article 5 The National Medical Products Administration, NMPA, is the competent agency to regulate nationwide drug production and shall supervise and guide drug production supervision and administration work of drug regulatory authorities of provinces, autonomous regions and municipalities directly under the Central Government. 
The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government is responsible for regulating the drug production within its administrative division and shall undertake licensing, inspection and punishment in drug production.
The Center for Food and Drug Inspection (the “CFDI”) of NMPA shall organize the formulation of drug inspection technical standards and documents, undertake overseas inspection and organize vaccine inspection, analyze and assess risks found in inspection, make inspection conclusions and propose handling suggestions, and guide and assess the quality management systems of drug inspection agencies of provinces, autonomous regions and municipalities directly under the Central Government.
The Information Center of NMPA is responsible for the construction and management of the drug traceability coordination service platform and drug safety credit archives and the unified coding of drug production sites. 
The professional technical institutions for drug review, inspection, audit, monitoring and evaluation set or designated by drug regulatory authorities undertake the technical work and draw technical conclusions according to their duties, providing technical supports for the regulation of drug production. 
 
Chapter II  Manufacturing Authorization 
 
Article 6  To engage in Drug manufacturing activities, following criteria shall be met: 
(1) staffed with pharmaceutical technicians, engineering technicians and corresponding skilled workers who are qualified in accordance with applicable laws. The legal representative, the principal of the company, the person in charge of production management (hereinafter referred to as “production responsible person”), the persons in charge of quality management (hereinafter referred to as “quality responsible person”), qualified persons and other relevant personnel shall comply with the conditions stipulated  in the Drug Administration Law or the Vaccine Administration Law;
(2) having the premises, facilities, equipment and hygienic environment required for drug production;
(3) having the institutions and personnel capable of quality control and testing for drugs to be produced; and
(4) having instruments and equipment essential for quality management and testing for drugs to be produced;
(5) having rules and regulations to ensure the quality of drugs, and in compliance with the requirements of Good Manufacturing Practice (GMP).
To engage in vaccine manufacturering activities, following criteria shall also bemet: 
(1) having a suitable scale and sufficient production capacity reserves; 
(2) having established and equipped with the biosafety assurance system and facilities and equipment; and 
(3) satisfying the needs for disease prevention and control.
 
Article 7  An applicant, who is engaging in the activities for producing drug products, raw materials or decoction pieces of Chinese medicines, shall submit an application to the drug regulatory authority of each province, autonomous region or municipality directly under the Central Government where the manufacturer is located according to the requirements on application documents specified in this Regulation and by the National Medical Products Administration. 
A drug marketing authorization holder entrusting any other person for manufacturing drug products shall comply with the conditions specified in items (1), (3) and (5) in Paragraph 1 under Article 6 of this Regulation, sign a entrustment agreement and quality agreement with a pharmaceutical manufacturer complying with relevant conditions, submit related agreements and application documents of the actual manufacturing site to the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government where the drug marketing authorization holder is located and apply for the drug production license according to provisions in this document.
The applicant shall be responsible for the authenticity of all information on the materials for application. 
 
Article 8  After receiving the application, the drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall give various treatments to the different cases: 
(1) for those applications beyond its functions and authority, a prompt decision of not acceptance should be made and the applicant can be informed to resubmit the application to the applicable administrative agency;
(2) if administrative licensing is not needed for any application item by law, the non-acceptance of the application thereof shall be informed to the applicant in time;
(3) for those applied documents which have any error that can be corrected on the spot, then the corrections are allowed to be made by the applicant on the spot;
(4) for those application documents incomplete or nonconforming to the required format examination, then the Notification on Correcting and Supplementing Materials should be sent to the applicant on the spot or within the next 5 days by notifying all the materials that need to be corrected and supplemented at one time to the applicant. In the event of none notification was made within and after the time limit, it will be regarded as the application has been accepted since the date of the application is received by the authority. 
(5) the application will be accepted if the materials are complete and conforming to the required format examination, or if the applicant has submitted all the supplementary and corrected materials as required.
The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall, either acceptance or non-acceptance against the application for the drug manufacturing license, issue a Notification of Acceptance or a Notification of Non-Acceptance with the seal of the authority specially designated and the date.
 
Article 9  The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall make a decision within 30 days from the date in which the application is accepted.
The application shall be approved if it meets the requirements after review, and the drug manufacturing license shall be issued within 10 days from the date of written approval. A written decision to disapprove the application along with an explanation therefor shall be given if it does not satisfy the requirements.
The drug regulatory authority of the province, autonomous region or municipality directly under the Central Government shall organize technical review and evaluation of application documents and on-site inspection. 
 
Article 10  The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall publish the following information on the website and work place of the administrative agency, including required conditions, procedures, deadlines, a list of all submitted documents and a sample application form for the application for the drug manufacturing license.
The information in connection with granting the drug manufacturing license by the drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall be disclosed to public, and the public shall have the right to access it.
 
Article 11  The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall disclose the review result and provide convenience to the applicant to inquire about the review progress during review of the application of drug manufacturing license. 
Without the consent of the applicant, the drug regulatory authority, professional technical institutions and their staff shall not disclose the commercial secrets, undisclosed information or confidential business information submitted by the applicant, unless otherwise specified by law or where national security or major social and public interests are involved.
 
Article 12  Where an application for the drug manufacturing license directly involves the significant interests of the applicant and stakeholders, the applicant and stakeholders have the right to apply for a hearing pursuant to applicable laws and regulations. 
During the review on the application of a drug manufacturer, the drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall, with respect to public interests in the approvals, disclose such matters to the public and hold a hearing procedure therefor.
 
Article 13  The drug manufacturing license is valid for a period of 5 years and made in two versions of original and duplicate. The format of drug manufacturing license thereof shall be unified and determined by the NMPA. The electronic drug manufacturing license and the paper license have the same legal effect.
 
Article 14  The drug manufacturing license shall describe the following information including License number, classification code, company name, unified social credit code, residence (business place), name of the legal representative, name of the company principal, name of production responsible person, name of quality responsible person, name of the qualified person, address of manufacturing site and production scope, the authority which issues the License, the date of issuance, and the validity period etc.
The items of company name, unified social credit code, residence (business place) and legal representative etc. shall be consistent with that described in business license issued by the market supervision and administration authority.
 
Article 15  Items specified by the drug manufacturing license are classified into two categories: License items and filed items.
License items refer to the address of manufacturing site and the production scope.
Filed items refer to the enterprise name, residence (business place), name of the legal representative, name of the company principal, name of production responsible person, name of quality responsible person, name of the qualified person, etc.
 
Article 16  In the case of changes in drug manufacturing license items, an application therefor shall be submitted to the authority that issued the drug manufacturing license (the “Issuing Authority”). Any change in License items without prior approval is not allowed.
The Issuing Authority shall, within 15 days from the date in which it receives an application of the company for such changes, make a decision on whether to approve such changes. In the case of disapproval, the authority shall send the company a written explanation for disapproval and inform the company that it has the right to ask for an administrative reconsideration or file an administrative lawsuit pursuant to applicable laws.
To change the address of manufacturing site or the production scope, the drug manufacturer shall, in accordance with the provisions of Article 6 of this Regulation and relevant technical requirements, submit relevant materials related to the changes to the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government where the it is located for review and approval. 
To build, rebuild or expand a workshop or production line at the original site or another site, relevant regulations and technical requirements shall be satisfied, relevant materials regarding the change shall be submitted to the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government where it is located for GMP compliance inspection. The manufacturer shall be notified of the inspection results. Products can be sold to the market on the premise that the inspection results comply with relevant regulations and the product meets release requirements. Related changes shall be specified in the duplicate of the drug manufacturing license. 
Where the above changes involve information included in the drug registration certificate and its attachments, they shall be approved by the drug regulatory authority of the province, autonomous region or municipality directly under the central government and reported to the Center for Drug Evaluation of National Medical Products Administration for updating related information in the drug registration certificate and its attachments.
 
Article 17 In the case of changes in the filing items for the drug manufacturing license, an application for filing such changes shall be submitted to the Issuing Authority within 30 days after the approval of the market supervision and administration authority for such changes or the completion of such changes by the company. The Issuing Authority shall deal with such changes within 10 days after receiving such an application from the company.
 
Article 18  After any change made to the drug manufacturing license, the Issuing Authority shall: (i) specify the changed information and the time in which such changes are made on the duplicate of the drug manufacturing license; (ii) issue a new drug manufacturing license as the new original version which describes the changed information; and (iii) withdraw the old original version of the drug manufacturing license. The expiration date of the drug manufacturing license remains the same after such changes.
 
Article 19  In the case of continuing the production of drugs following the expiration of the drug manufacturing license, the company shall apply to the Issuing Authority for re-issuance of the drug manufacturing license 6 months ahead of the expiration.
The Issuing Authority shall review such an application in accordance with risk management principles taking into account the facts about the company’s compliance with drug administration laws and regulations, the performance of GMP and quality systems. A decision on whether to re-issue the drug manufacturing license shall be made by the Issuing Authority prior to the expiration. The Issuing Authority shall: (i) re-issue a new License if the company is eligible for the re-issuance, and withdraw the old original version of the License; and (ii) notify the company in writing of the decision to reject the re-issuance along with an explanation therefor, simultaneously inform the company that it has the right to ask for an administrative reconsideration or file an administrative lawsuit pursuant to applicable laws. In the event of none decision made within and after the time limit, it will be deemed approval for the re-issuance, and the Issuing Authority shall go through the formalities accordingly thereafter.
 
Article 20  In any of the following circumstances, the Issuing Authority shall revoke the drug manufacturing license and make an announcement:
(1)An application for the revocation of the drug manufacturing license is voluntarily submitted;
(2)The drug manufacturing license has expired but not been re-issued;
(3)The business license has been withdrawn or cancelled according to law;
(4)The drug manufacturing license has been withdrawn or cancelled according to law
(5)Other circumstances the administrative license shall be revoked specified by laws and regulations.
 
Article 21  In the event that a drug MAH or manufacturer has lost the drug manufacturing license, they may apply to the Issuing Authority for a replacement of the License. The Issuing Authority shall issue the replaced drug manufacturing license consistent with the previously authorized contents within 10 days. The information such as License number and validity period specified on the replaced License shall be the same as that specified on the original License.
 
Article 22  No entity or individual shall forge, alter, rent, lend, or buy and sell the drug manufacturing license.
 
Article 23  The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall update the information on the activities, including issuance, re-issuance, changes, replacement, revocation, rescission and cancellation, done to the drug manufacturing license in the drug safety credit archive of the NMPA within 10 days from the date in which such activities conducted. 
Chapter III  Production Management
 
Article 24  Engaging in drug production activities shall comply with the GMP and the manufacturing process shall be in accordance with the national drug specifications, drug registration specifications and the process approved by drug regulatory authorities. The site management file shall be submitted and continuously updated, the risk assessments of the quality system operation and continuous improvements thereto shall be made to ensure a continuous compliance with statutory requirements throughout the whole process. Production and inspection records shall be complete and accurate. No fabrication or falsification is allowed.
 
Article 25 The vaccine MAH shall have the premises, facilities and equipment necessary for vaccine production and inspection, be staffed with qualified management personnel, establish sound quality management systems and have the capability to produce vaccines complying with registered requirements. If the vaccine production requirements are beyond its capability, then the entrustment to other companies has to be approved by NMPA. 
 
Article 26 In drug production activities, good manufacturing practice shall be followed, and drug production quality management systems covering all factors influencing drug quality shall be established to ensure the whole process of drug production persistently complies with regulatory requirements.
 
Article 27 A drug MAH shall establish drug quality assurance system, have dedicated personnel to independently undertake responsibilities for drug quality management, regularly review the quality management systems of contracted drug manufacturers and contracted drug distributors and supervise their capability for persistent quality assurance and control. 
 
Article 28  The legal representative and the principal of a drug MAH shall be fully responsible for drug quality and fulfill the following responsibilities:
(1)appoint a dedicated quality responsible person to independently undertake responsibilities for drug quality management;
(2)appoint a dedicated qualified person to independently fulfill responsibilities for drug marketing release;
(3)supervise normal operation of the quality management system;
(4)regularly carry out quality system audits of drug production related activities of related parties including drug manufacturers and suppliers to ensure persistent regulatory compliance;
(5)fulfill change management responsibilities according to technical requirements for changes; 
(6)carry out quality assessment of contracted distributors and communicate with users; 
(7)cooperate with drug regulatory authorities in extension inspection of the drug MAH and related parties;
(8)in case of major safety events related to drug quality, timely report and carry out risk management according to the holder’s risk management plan to ensure risks are timely controlled;
(9)other responsibilities specified by laws and regulations. 
 
Article 29 The legal representative and principal of a drug manufacturer shall be responsible for drug production of the company in all aspects and perform the following duties:
(1)appoint a qualified dedicated person who is independently in charge of drug quality management, supervising the implementation of GMP, ensuring suitable in-process control and quality control to guarantee the compliance of drugs with national drug standards and drug registration specifications;
(2)appoint a qualified dedicated person to be responsible for the drug release by manufacturing site;
(3)supervise the daily operation of the quality management system and guarantee the in-process control and quality control, and authenticity of records and data;
(4)in case of major safety events related to drug quality, report them in time and take risk management according to the risk management plan formulated by the company to ensure that the risks are timely controlled.
(5)other responsibilities specified by laws and regulations.
 
Article 30 Drug MAHs and manufacturers shall conduct health examination each year for those personnel in directly contact with drugs and file their health information. The persons suffering infectious diseases or other diseases that may contaminate drugs shall not engage in any production activity in direct contact with drugs.
 
Article 31 Drug MAHs and manufacturers shall conduct risk assessment, control, validation, communication, review and other quality management activities, and timely take effective risk control measures for identified risks to ensure product quality. 
 
Article 32 The drug manufacturers shall conduct assessment on the suppliers or producers which supply the materials including raw material, excipients, packaging materials and container in direct contact with drug products involved in manufacturing, to ensure that the sourcing and use of such materials satisfy regulatory requirements. 
The raw material and excipients for the manufacture of drug products shall meet the requirements for pharmaceutical use and relevant requirements in the corresponding GMP. The packaging materials and container in direct contact with drug products shall meet the requirements for pharmaceutical use and the standards for ensuring human health and safety.  
 
Article 33 Manufacturers of raw material, excipients, packaging materials and container in direct contact with drug products that have been approved or passed bundling evaluation, review and approval shall abide by the GMP formulated by the NMPA and the relevant requirements on bundling evaluation, review and approval, ensure the continuous compliance of the quality assurance system, accept quality auditing of drug MAH and supervisory inspection or extension inspection by drug regulatory authorities.
 
Article 34 The drug manufacturers should define the qualification and validation items, and implement as scheduled. Drug manufacturers shall evaluate the facilities, equipment, manufacturing process and cleaning methods on a regular basis, ensuring its continually maintained validation status.
 
Article 35 Drug manufacturers shall have control measures to prevent any contamination, cross-contamination, mix-up and error, and regularly review and evaluate the suitability and effectiveness of these control measures to ensure that the drugs are qualified for the defined national drug specifications and drug registration specifications and in compliance with the GMP.
Drug MAHs and manufacturers shall not manufacture other products having negative influence on drugs in drug manufacturing workshops.
 
Article 36 There shall be control measure available for drug packaging to reduce the risks of mix-ups and errors. Drug packages shall be protected against any contamination during storage and transportation of drugs within shelf life.
The descriptions in drug package inserts and labels shall be scientific, standardized and accurate; texts shall be clear and intelligible. Any modification or supplement by means of pasting, cutting, or erasing made to the package inserts and labels is not allowed.
 
Article 37 Drug manufacturers shall establish standard procedures for drug release by clarifying the release specification and conditions, and review the quality testing results, key production records and deviation control and conduct quality testing for the drugs. Only the drugs with qualified specification and conditions as well as the signature of the qualified person can be released. 
The MAH shall establish a marketing release procedure to review the testing results and release documents of the product released by the drug manufacturers, and the drug products can be released only after signed off by qualified person. 
Decoction pieces of Chinese medicines may be released from the factory and sold only if they conform to the national drug standards or the processing standards formulated by the drug regulatory authorities of the province, autonomous region or municipality directly under the Central Government.
 
Article 38 Drug MAHs and manufacturers shall perform self-inspection each year, monitoring the implementation of good manufacturing practice, assess whether the company comply with requirements of relevant regulations and put forward necessary corrective and preventive actions.
 
Article 39 A drug MAH shall establish an annual report system in which production and sales, post-marketing studies and risk management are reported annually to the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government in according with the provisions of NMPA. 
The vaccine MAHs shall, in accordance with the provisions, submit an annual report to the NMPA.
 
Article 40 Drug MAHs shall: (i) conduct continuous risk-benefit assessment and risk control for drugs; (ii) formulate a risk management plan for post-marketing drugs; and (iii) voluntarily conduct post-marketing studies; (iv) further verify the safety, effectiveness and quality controllability of drugs and strengthen ongoing management of post-approval drugs.
 
Article 41 Drug MAHs shall establish pharmacovigilance systems and carry out pharmacovigilance work according to good pharmacovigilance practice developed by the NMPA.
Drug MAHs and drug manufacturers shall make constant investigations into quality, efficacy and adverse reactions of their drugs. Suspected adverse reactions, if discovered, shall be reported timely as required. 
 
Article 42 Where a drug MAH entrusts the drug production, it shall comply with relevant regulations on drug administration.
The drug MAH shall, if it entrusts a qualified drug manufacturer to produce drugs, assess the quality assurance capability and risk management capability of contracted receiving company, in accordance with the requirements in the guidelines for the quality agreement of contracted drug production formulated by the NMPA, sign a quality agreement and an entrustment agreement, and supervise its performance of obligations agreed in the agreements. 
The entrusted company shall not entrust another third party to produce the entrusted drugs.
Raw material that are approved or have passed bundling review shall generally be manufactured independently and not allowed to be entrusted for production.
 
Article 43 Drug MAHs shall, in accordance with the GMP, manage and control any change in manufacturing process, and establish process standard procedures therefor according to the approved manufacturing process. A drug MAH shall, in the case of any change in manufacturing process, conduct studies therefor, legally obtain the approval, file or report such changes to applicable authorities, and accept the supervision and inspection by drug regulatory authorities.
 
Article 44 Drug MAHs and manufacturers shall annually conduct the product quality review and documentation of the quality of all the produced drugs by type to ensure stable and reliable manufacturing process and suitability of current specifications for raw materials, excipients and finished products.
 
Article 45 A drug MAH and manufacturer shall, in the case of any change in the organization, the company principal, production responsible person, quality responsible person and qualified person related to its quality management system, complete the registration formality within 30 days as of occurrence of the change.
Vaccine MAHs shall, within 15 days as of occurrence of changes, report changes in personnel at key position including production responsible person, quality responsible person and qualified person to drug regulatory authorities of provinces, autonomous regions or municipalities directly under the Central Government where they are located.
 
Article 46 With respect to the drugs included in the list of drugs in shortage which are subject to report the shutdown thereof to applicable authorities, any drug MAH which intends to shut down the production of such drugs shall report the shutdown to the drug regulatory authority of each province, autonomous region or municipality directly under the Central Government where the drug MAH is located 6 months ahead of the shutdown. In the event of unexpected shutdown, the drug MAH shall report it to the drug regulatory authority of each province, autonomous region or municipality directly under the Central Government where it is located within 3 days. Where necessary, a report shall be made to the NMPA.
The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall, after receiving such reports, promptly notify the Leading Units of Joint Consultation Mechanism for Guaranteed Supply of Drugs in Shortage at the same tier.
 
Article 47 If the drug MAH is a oversea enterprise, it shall authorize a legal person within the territory of China to perform the obligations set forth in the Drug Administration Law and this Regulation, and to provide cooperation for overseas inspections.
 
Article 48 Where the manufacturing site of a drug MAH is outside the territory of China, it shall organize production according to the Drug Administration Law and this Regulation and provide cooperation for overseas inspections.
 
Chapter IV  Regulation and Inspection
 
Article 49 The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall, within its administrative region, be responsible for the supervision and administration of the drug MAHs, and manufacturers of drug products, chemical raw materials and decoction pieces of Chinese medicines. 
The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall carry out routine supervision and inspection of suppliers and manufacturers of raw materials, pharmaceutical excipients and packaging materials and container in direct contact with drug products and, when necessary, carry out extension inspection. 
 
Article 50 Where the drug MAH and the consigned manufacture are located in different provinces, autonomous regions or municipalities directly under the Central Government, the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government where the drug MAH is located shall be responsible for the supervision and administration of the drug MAH, and the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government where the consigned manufacture is located shall be responsible for the supervision and administration of the consigned manufacturer. Drug regulatory authorities of provinces, autonomous regions or municipalities directly under the Central Government shall strengthen intercommunication of supervisory inspection information and timely update supervisory inspection information in drug safety credit archives, carry out investigations and impose administrative handling on the drug MAHs or consigned manufacturers based on the disclosed information and updated supervision information in drug safety credit archives and, when necessary, may carry out joint inspection.
 
Article 51 Drug regulatory authorities shall establish and improve the system of auditor professionalism and specialization by clarifying qualification criteria, inspection duties, hierarchical management, skill training, code of conduct, performance evaluation and withdrawal procedures for the inspectors, to improve their professionalism and skill level. Inspectors shall have a good knowledge of pharmaceutical laws and regulations and also professional pharmaceutical knowledge.
Drug regulatory authorities shall be staffed with sufficient inspectors according to their regulatory power, the scale of the pharmaceutical industry and inspection tasks to satisfy the reasonable need of inspection security. In areas where manufacturers produce high-risk drugs such as vaccines, suitable number of drug inspectors who have inspection skills and experience on high-risk products such as vaccines should also be staffed. 
 
Article 52 Drug regulatory authorities of provinces, autonomous regions and municipalities directly under the Central Government may, as needed for supervision and administration, carry out pre-marketing GMP compliance inspection as required below on drug marketing authorization applicants holding drug manufacturing license and consigned manufacturers:
(1)For varieties having failed GMP compliance inspection for manufacturing conditions of the products, pre-marketing GMP compliance inspection shall be carried out. Where drug registration site inspection is needed for the drug to be produced, the NMPA Center for Drug Evaluation shall notify the CFDI and inform the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government where the manufacturing site is located and the applicant; and the CFDI shall coordinate the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government to carry out concurrently drug registration site inspection and pre-marketing GMP compliance inspection. 
(2)Where drug registration site inspection is not needed for the drug to be produced, the NMPA Center for Drug Evaluation shall inform the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government where the manufacturing site is located and the applicant; and the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government shall carry out pre-marketing GMP compliance inspection of its own accord.
(3)For varieties having passed GMP compliance inspection for manufacturing conditions of the products, the drug regulatory authorities of related provinces, autonomous regions and municipalities directly under the Central Government shall decide whether or not to carry out pre-marketing GMP inspection according to risk management principles.  
Where pre-marketing GMP compliance inspection is carried out, after completion of the inspection, the inspection conduct and inspection results shall be included into a written report as an important basis for marketing supervision of the drug. Where the pre-marketing GMP compliance inspection involves changes to items in the drug manufacturing license, the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government issuing the license shall make decisions according to the procedure for making changes.
Commercial-scale batches having passed pre-marketing GMP compliance inspection may be placed on the market after the drug registration certificate has been obtained if product release requirements are met. Drug MAHs shall intensively strengthen production and marketing, risk management measures for the above batches. 
 
Article 53 The main content of drug production regulation and inspection includes: 
(i) their implementation of applicable laws and regulations, the GMP, GVP and related technical guidelines; 
(ii) whether pharmaceutical production activities are consistent with related contents in the drug variety archives;
(iii) their compliance with the standards for vaccine storage and transportation management; 
(iv) their quality agreements and entrustment agreements for entrusted drug production; 
(v) the implementation of risk management plans; and 
(vi) the management of changes.
Drug production inspections include: licensing inspection; routine inspection; causal inspection; and other inspections.  
 
Article 54 The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall stick to the principles of risk management and whole-process management and control, and in accordance with the risk analysis and assessment, establish annual inspection plan and carry out the inspection. The annual inspection plan shall at least include: the inspection scope, items, methods, priorities, requirements, time limits, and inspection agency. 
 
Article 55 The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall determine inspection frequency based on the drug varieties, dosage form, regulation category, taking into account overall national situation of drug safety, drug safety risk warning information, major drug safety events and related investigation and handling information as well as the previous inspections, monitoring of adverse reactions, complaints and whistle-blowing. 
(1) the manufacturers which produce anesthetics, psychotropic drugs under Classification 1 and drug precursor chemicals shall be inspected at least once each quarter.
(2) the GMP compliance inspection of high-risk drug manufacturers including vaccines, blood products, radioactive drugs, toxic drugs for medical use and sterile drugs shall be conducted at least once a year.
(3) with respect to the manufacturers which produce the products not mentioned above, a proportional number of such manufacturers shall be selected for supervisory inspection every year, meanwhile each drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall complete the inspections of all such manufacturers located in its administrative region within 3 years.
(4) supervisory inspection of a specified proportion of suppliers and manufactures of raw materials, excipients and packaging materials and container in direct contact with drug products shall be carried out each year to cover all companies within respective administrative regions in 5 years; 
Drug regulatory authorities of provinces, autonomous regions and municipalities directly under the Central Government may adjust the inspection frequency depending on the practical situation of drug production supervision within respective administrative regions. 
 
Article 56 When organizing supervisory inspections, the NMPA and the drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall: (i) make inspection plans to clarify the inspection standards; (ii) record the on-site inspections truthfully; (iii) conduct the inspections in accordance with relevant rules when sample testing or study is required; (iv) draw clear conclusions of inspections, and notify the inspected companies in writing of any issue discovered in the inspection; and (v) notify the inspected company of corrective actions (if any) it needs to take and the deadline therefor, and inspect the situations after corrections if necessary.
During the supervisory inspection, two or more inspectors shall be assigned by the drug regulatory authority to the inspected company, and the inspectors shall present the proof of law enforcement to the inspected company. The personnel of the drug regulatory authority shall not disclose any trade secrets which he/she is aware of. 
 
Article 57 During supervisory inspections, drug MAHs and manufacturers shall provide relevant explanations and the following materials according to the inspection need:
(1) site management files and the materials in connection with any change;
(2) information on the inspections that have been made to the drug manufacturer and the conduction of corrective actions;
(3) the handling of unqualified drugs;
(4) information on pharmacovigilance department, personnel and system establishment, as well as information on the monitoring, identification, assessment and control of suspected adverse drug reactions;
(5) the drug types subject to conditional approval and the materials with respect to post-marketing studies;
(6) other necessary materials for review.
 
Article 58 After the on-site inspection, on-site inspection results shall be analyzed and summarized; risks of deficiencies found in the inspection shall be assessed objectively, fairly and impartially, and the on-site inspection conclusion shall be made.
The dispatching unit is responsible for the comprehensive analysis and assessment of the on-site inspection conclusion.
 
Article 59 The NMPA and the drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall, if any flaw in drug production management or vaccine storage and transportation management is found in the supervisory inspection or if evidence is available indicating the presence of potential safety risks, take corresponding actions according to law:
(1)Where GMP requirements are basically satisfied and corrections are needed, a warning letter shall be issued and, based on the risks, such actions as warning, interview and requiring correction within a specified time limit shall be taken;
(2)Where the drug has quality problems or other potential safety risks, the drug regulatory authority shall, according to the supervisory inspection results, issue a warning letter and, based on the risks, take such control actions as suspending production, sales, use, import, etc.
Where the drug has quality issue or other potential safety risks and the drug MAH shall have recalled a drug according to law but has failed to do so, the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government shall order it to recall the drug.
After the risks are eliminated, the drug regulatory authority which took the control actions shall terminate such actions.
 
Article 60 Where, during supervisory inspection of drug production, a drug is found to have quality and safety risks, a report shall be timely made to the dispatching unit. The drug regulatory authority shall report to the higher-level drug regulatory authority and the local people's government at the same level timely if such risk is a major risk of drug quality and safety by analysis and assessment.
 
Article 61 On-site control actions shall be timely taken, and evidence collection shall be performed as specified in case of any suspected violation of drug laws, regulations and rules found during drug production supervision and inspection. The drug regulatory authority shall, in accordance with its duties and authorities, investigate and handle the case according to law, and transfer the suspects to the public security organ for handling.
 
Article 62 Drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall, pursuant to applicable laws, file the information obtained while regulating and inspecting the drug MAHs and manufacturers within its administrative region in drug safety credit files and keep relevant data updated dynamically. Regulatory information includes the information on drug manufacturing authorization, routine regulation and inspection results, investigation and handling of illegal acts, spot checks for product quality, misconduct records, complaints and whistle-blowing.
 
Article 63 When conducting regulation and administration, the drug regulatory authority of each province, autonomous region or municipality directly under the Central Government and the NMPA shall not: (i) impede the normal production activities of MAHs and drug manufacturers; (ii) request or accept any money or gift; and (iii) seek any other benefits.
 
Article 64 Any individual and organization that discovers any illegal activity done by any drug MAH or manufacturer to drug production shall have the right to tip off drug regulatory authorities about such illegal activities. The authorities shall promptly verify the illegal activities and take actions against them pursuant to applicable rules and regulations.
 
Article 65 In the event of any major safety event related to drug quality, the drug MAH shall immediately take such control actions as sealing the drug product and related raw materials, excipients and packaging materials and container in direct contact with the drug product and relevant production line and immediately report such events to the drug regulatory authority of each province, autonomous region or municipality directly under the Central Government where the MAH is located and other relevant agencies. The drug regulatory authority of each province, autonomous region or municipality directly under the Central Government shall report the events to the provincial people's government as well as NMPA within 24 hours.
 
Article 66 For drug MAHs and manufacturers with bad credit records, drug regulatory authorities of provinces, autonomous regions or municipalities directly under the Central Government shall increase the supervisory inspection frequency and may impose joint punishment according to national regulations.
 
Article 67 Where the drug regulatory authority of a province, autonomous region or municipality directly under the Central Government has failed to timely discover systematic drug safety risks in manufacturing and timely eliminate drug safety risks within the supervision and administration region or the provincial people’s government has failed to fulfill drug safety responsibilities and timely eliminate major regional potential drug safety risks, the NMPA shall interview the principal persons responsible. 
The interviewed drug regulatory authority of the province, autonomous region or municipality directly under the Central Government and the local people's government shall immediately take actions to correct the drug supervision and administration work.
The interview and correction shall be included into the drug supervision and administration performance review and appraisal records of the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government and the local people’s government.
Chapter V  Legal Liability
 
Article 68 In any of the following circumstances, penalties shall be imposed in accordance with Article 115 under the Drug Administration Law:
(1) A drug MAH or a manufacturer changes the manufacturing sites or scope of production without approval; 
(2) Production is performed while the drug production license has expired. 
 
Article 69 Where a drug MAH or drug manufacturer has failed to carry out production activities as per GMP requirements in any of the following circumstances and the circumstance belongs to the serious circumstances as specified in Article 126 under the Drug Administration Law, penalties shall be imposed according to law:
(1)failing to appoint a dedicated person in charge of quality to independently undertake drug quality management and supervise GMP implementation;
(2)the drug MAH has failed to appoint a dedicated qualified person to fulfill drug marketing release responsibilities; 
(3)the drug manufacturer has failed to appoint a dedicated qualified person to fulfill drug release responsibilities;  
(4)the quality management system cannot operate normally; records and data of drug production process control and quality control are not authentic; 
(5)effective risk control measures have not been timely taken for identified risks so that the product quality cannot be ensured; 
(6)other circumstances where good manufacturing practice has been seriously violated.
 
Article 70 Where manufacturers and suppliers of excipients or packaging materials and container in direct contact with drug products do not comply with the quality management standards or relevant requirements established by the NMPA and cannot ensure the quality management system persistently complies with regulatory requirements, the drug regulatory authorities of the provinces, autonomous regions or municipalities directly under the Central Government shall impose punishments in accordance with Article 126 under the Drug Administration Law.
 
Article 71 In any of the following circumstances, the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government shall impose a fine of RMB 10,000 - 30,000 yuan:
(1)failing to go through the formality for changes to recorded items for the enterprise name, residence (business place) or legal representative;; 
(2)failing to carry out health examination of personnel in direct contact with drugs each year and establish health achieves;
(3)failing to report production shutdown of drugs included into the list of drugs in shortage subject to report the shutdown thereof by the state as specified. 
 
Article 72 Where a drug regulatory authority has committed any of the following behaviors, the executives directly responsible and other persons directly responsible shall be punished according to provisions in Article 149 of the Drug Administration Law: 
(1) making concealment, giving false information or delaying the reporting of or underreporting drug safety events;
(2) failing to timely investigate and handle discovered illegal behaviors related to drug safety;
(3) failing to timely discover systematic drug safety risks or timely eliminate potential drug safety risks in the supervision and administration region, resulting in serious impacts;
(4) other behaviors of failing to fulfill drug supervision and administration responsibilities, resulting in serious adverse effects or heavy losses.
 
Chapter VI  Supplementary Provisions
 
Article 73 Time limits specified in this Regulation are calculated based on working days. Time needed for technical review and evaluation, on-site inspection and enterprise rectification in drug production licensing is not included into the time limits.
 
Article 74 Site management file refers to a summary document of drug production activities prepared by a drug manufacturer, which is a part of the files in the manufacturer’s quality management system. The requirements for site management files will be defined separately.
The manufacturing sites and overseas manufacturing sites of raw materials, excipients, packaging materials and container in direct contact with drug products having been approved or passed bundling review shall be given unified code.
 
Article 75 Warning letter refers to the letter issued by the drug regulatory authority according to law where evidence suggesting the potential presence of safety risks is found in drug regulatory activities. The warning letter shall list deficiencies, problems and correction requirements.
 
Article 76 The rule to number the drug manufacturing license shall be: abbreviation of the province + the year (four digits) + the sequence numbers (four digits). When a change is made to the company name or other items or the license is re-issued, the original drug manufacturing license number remains unchanged.
In the case of company separate, new numbers shall be coded when the original drug manufacturing license number is remained; in the case of company merger, one of the original drug manufacturing license numbers shall be remained.
 
Article 77 The classification code is an English alphabetic string that categorizes the production scope specified in the drug manufacturing license. Capital letters categorize drug MAHs and product types. A represents the drug MAH producing drugs by itself. B represents the drug MAH contract giver. C represents the drug manufacturer contract receiver. D represents the raw materials manufacturer. Lowercase letters are used for differentiating drug preparation attributes, where h represents chemical drugs, z represents Chinese patent medicines; s represents biological products; d represents IVD Reagents regulated as drugs; y represents decoction pieces of Chinese medicines; q represents medical gases; t represents special drugs and x represents others. 
 
Article 78 The production scope specified in the drug manufacturing license shall be defined pursuant to the requirements of the General Chapter of drug product under the Pharmacopoeia of People's Republic of China and other national drug standards.
 
Article 79 The provisions otherwise defined in applicable national laws and regulations for the production of vaccines, blood products, narcotics and psychotropic drugs, toxic drugs for medical use, radioactive drugs, drug precursor chemicals, shall be followed. 
 
Article 80 Vaccines for importation shall comply with standards or contract requirements in the importing countries (regions).
 
Article 81 The Regulation shall come into force on July 1, 2020. The Drug Production Regulation promulgated under Decree No.14 by the former State Food and Drug Administration on August 5, 2004 shall be abolished simultaneously.