Chapter III Manufacture Management

Article 24 Engaging in drug manufacture activities shall comply with the GMP and the manufacturing process shall be in accordance with the national drug standards, drug registration specifications and the manufacturing process approved by drug regulatory departments. The site management file shall be submitted and continuously updated, the risk assessments and continuous improvements of the quality system operation shall be made to ensure a continuous compliance with statutory requirements throughout the whole process. Manufacturing and test records shall be complete and accurate. No fabrication or falsification is allowed.

Article 25 The vaccine MAH shall have the premises, facilities and equipments necessary for vaccine manufacturing and test, 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 manufacturing requirements are beyond its capability and the manufacturing needs to be entrusted, the entrustment to other companies shall be approved by NMPA.

Article 26 Undertaking of drug manufacturing shall comply with the GMP. A quality management system shall be established and improved for drug manufacturing, which gives into consideration all factors influencing drug quality, to ensure that the whole process of drug manufacturing continuously complies with statutory requirements.

Article 27 A drug MAH shall establish drug quality assurance system, have dedicated personnel to independently undertake responsibilities for drug quality management, regularly conduct audits on the quality management systems of the drug contract manufacturers and drug distributors, to supervise and ensure their continuous capability of 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 manufacturing related activities of related parties including drug manufacturers and suppliers to ensure continuous regulatory compliance;

(5) fulfill change management responsibilities according to technical requirements for changes;

(6) carry out quality evaluation of contracted distributors and communicate with users;

(7) cooperate with the drug regulatory departments in extended inspection of the drug MAH and related parties;

(8) in case of major safety events related to drug quality, promptly report and carry out risk management according to the holder's risk management plan to ensure risks are controlled in a timely manner;

(9) other responsibilities specified by laws and regulations.

Article 29 The legal representative and principal of a drug manufacturer shall be responsible for drug manufacturing 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, to supervise the implementation of the GMP, ensure suitable in-process control and quality control and 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 on 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 controlled in a timely manner;

(5) other responsibilities specified by laws and regulations.

Article 30 Drug MAHs and manufacturers shall conduct health examination each year for those personnel in direct 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 manufacturing 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 promptly take effective risk control measures for identified risks to ensure product quality.

Article 32 The drug manufacturers shall conduct assessment on the suppliers or manufacturers which supply the materials including active drug ingredients, excipients, primary 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 active drug ingredients and excipients for the manufacture of drug products shall meet the requirements for pharmaceutical use and relevant requirements in the corresponding GMP. The primary 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 active drug ingredients, excipients, primary 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, and accept quality auditing of drug MAH and supervision and inspection or extended inspection by drug regulatory departments.

Article 34 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, to ensure it is continuously 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 standards and drug registration specifications and in compliance with the GMP.

Drug MAHs and manufacturers shall not manufacture other products having negative influence on drug quality in drug manufacturing workshops.

Article 36 There shall be control measures 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 legible. 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 manufacturing 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.

Prepared Slices 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 department of the province, autonomous region or municipality directly under the Central Government.

Article 38 Drug MAHs and manufacturers shall perform self-inspection each year, monitor 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 Drug MAHs shall establish an annual report system in which manufacturing and sales, post-marketing studies and risk management are reported annually to the drug regulatory department of the province, autonomous region or municipality directly under the Central Government in accordance 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 conduct continuous risk-benefit assessment and risk control for drugs, formulate a risk management plan for post-marketing drugs, voluntarily conduct post-marketing studies and further verify the safety, effectiveness and quality controllability of drugs and strengthen ongoing management of post-marketing 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. Once suspected adverse reactions are discovered, they shall be reported in a timely manner as required.

Article 42 Where a drug MAH entrusts the drug manufacturing, it shall comply with relevant regulations on drug administration.

The drug MAH shall, if it entrusts a qualified drug manufacturer to manufacture drugs, assess the quality assurance capability and risk management capability of contracted accepting company, in accordance with the requirements in the guidelines for the quality agreement of contracted drug manufacturing 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 manufacture the entrusted drugs.

Active drug ingredients that are approved or have passed bundling review shall generally be manufactured independently and not allowed to be entrusted for manufacturing.

Article 43 Drug MAHs shall, in accordance with the GMP, manage and control any change in manufacturing process, and establish process standard procedures according to the approved manufacturing process. To make changes in manufacturing process, a drug MAH shall conduct studies and obtain the approval according to law, file or report such changes to applicable authorities and accept the supervision and inspection by drug regulatory departments.

Article 44 Drug MAHs and manufacturers shall annually conduct the product quality review and documentation of the quality of all the drugs manufactured by variety to ensure stable and reliable manufacturing process and suitability of current specifications for active drug ingredients, 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 departments 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, the shutdown of which shall be reported to applicable authorities. If any drug MAH intends to shut down the manufacturing of such drugs, it shall report the shutdown to the drug regulatory department of the 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 department of the 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 department shall, after receiving such reports, promptly notify the leading units of joint consultation mechanism for guaranteed supply of drugs in shortage of the same level.

Article 47 If the drug MAH is an 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 these Regulations, 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 manufacturing according to the Drug Administration Law and these Regulations and provide cooperation for overseas inspections.

Chapter IV Supervision and Inspection

Article 49 The drug regulatory department of the 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 active drug ingredients and Prepared Slices.

The drug regulatory department of the province, autonomous region or municipality directly under the Central Government shall carry out routine supervision and inspection of suppliers and manufacturers of active drug ingredients, pharmaceutical excipients and primary packaging materials and container in direct contact with drug products and, when necessary, carry out extended inspection.

Article 50 Where the drug MAH and the entrusted manufacturer are located in different provinces, autonomous regions or municipalities directly under the Central Government, the drug regulatory department 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 department of the province, autonomous region or municipality directly under the Central Government where the entrusted manufacturer is located shall be responsible for the supervision and administration of the contract manufacturer. Drug regulatory departments of provinces, autonomous regions or municipalities directly under the Central Government shall strengthen intercommunication of supervision and inspection information and promptly update the information in drug safety credit archives, and may carry out investigations and impose administrative handling on the drug MAHs or contract 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 The drug regulatory department shall establish and improve the system of professional and specialized inspectors by clarifying qualification criteria, inspection duties, hierarchical management, skill training, code of conduct, performance evaluation and withdrawal procedures, to enhance their professionalism and skill level. The inspectors shall be familiar with drug laws and regulations, and have professional knowledge in drugs.

The drug regulatory department 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 tasks. 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 The drug regulatory departments 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 on drug marketing authorization applicants holding Drug Manufacturing Certificate and its contract manufacturer as required below:

(1) For varieties having not passing GMP compliance inspection for manufacturing conditions of the products, pre-marketing GMP compliance inspection shall be carried out. Where drug registration on-site inspection is needed for the drug to be manufactured, the NMPA Center for Drug Evaluation shall notify the CFDI and inform the drug regulatory department 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 department of the province, autonomous region or municipality directly under the Central Government to concurrently carry out drug registration on-site inspection and pre-marketing GMP compliance inspection.

(2) Where drug registration on-site inspection is not needed for the drug to be manufactured, the NMPA Center for Drug Evaluation shall inform the drug regulatory department 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 department 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 departments 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 Certificate, the drug regulatory department 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 approval license has been obtained if product release requirements are met. Drug MAHs shall intensively strengthen manufacturing and marketing, risk management measures for the above batches.

Article 53 The main content of drug manufacturing supervision and inspection includes:

(1) Drug MAHs and drug manufacturers’ implementation of applicable laws and regulations, the GMP, GVP and related technical guidelines;

(2) whether pharmaceutical manufacturing activities are consistent with related contents in the drug variety archives;

(3) their compliance with the standards for vaccine storage and transportation management;

(4) their quality agreements and entrustment agreements for entrusted drug manufacturing;

(5)  the implementation of risk management plans; and

(6)  the implementation of change management.

Supervision and inspections include: licensing inspection; routine inspection; causal inspection; and other inspections.

Article 54 The drug regulatory department of the 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, content, methods, priorities, requirements, timelines, and inspection agency.

Article 55 The drug regulatory department of the province, autonomous region or municipality directly under the Central Government shall determine inspection frequency based on the drug varieties, dosage form, regulation categories, taking into account overall national situation of drug safety, drug safety risk warning information, major drug safety events and related investigations and handling information as well as the previous inspections, monitoring of adverse reactions, complaints and whistle-blowing.

(1) the manufacturers which manufacture narcotic drugs, psychotropic drugs under Classification I 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 manufacture the products not mentioned above, a proportional number of such manufacturers shall be selected for supervision and inspection every year, meanwhile each drug regulatory department of the 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)  supervision and inspection of a specified proportion of suppliers and manufactures of active drug ingredients, excipients and primary packaging materials and container in direct contact with drug products shall be carried out each year and cover all companies within respective administrative regions in 5 years.

The drug regulatory departments of provinces, autonomous regions and municipalities directly under the Central Government may adjust the inspection frequency depending on the practical situation of drug manufacturing supervision within respective administrative regions.

Article 56 When organizing supervision and inspections, the NMPA and the drug regulatory authority of the province, autonomous region or municipality directly under the Central Government shall make inspection plans to clarify the inspection standards, record the on-site inspections truthfully, conduct the inspections in accordance with relevant rules when sample testing or study is required. The conclusion of the inspection shall be clear and unambiguous, and the problems found during the inspection shall be notified to the inspected company in written format. If corrective actions are required, the content and the deadline of corrective actions shall be proposed, and the situation after the remediation shall be inspected if necessary.

During the supervision and inspection, the drug regulatory department shall assign two or more inspectors to the inspected company, and the inspectors shall present the proof of law enforcement to the inspected company. The personnel of the drug regulatory department shall keep confidential of the known commercial secrets.

Article 57 During the supervision and inspection, drug MAHs and manufacturers shall provide relevant explanations and the following materials according to the inspection need:

(1) site master 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, the 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 department of the province, autonomous region or municipality directly under the Central Government shall, if any deficiency in drug manufacturing or vaccine storage and transportation is found in the supervision and 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, actions such as warning, warning meeting, and requiring remediation within a specified timeline shall be taken;

(2) Where the drug has quality problems or other potential safety risks, the drug regulatory department shall, according to the supervision and inspection results, issue a warning letter and, based on the risks, take such control actions as suspending manufacturing, 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 department that took the control actions shall terminate such actions.

Article 60 Where, during supervision and inspection of drug manufacturing, a drug is found to have quality and safety risks, a report shall be promptly made to the dispatching unit. The drug regulatory department shall report to the higher-level drug regulatory department and the local people's government at the same level promptly if such risk is a major risk of drug quality and safety through analysis and assessment.

Article 61 On-site control actions shall be promptly 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 department shall, in accordance with its duties and authorities, investigate and handle the case according to laws, and transfer the suspects to the public security authorities for handling.

Article 62 The drug regulatory department of the province, autonomous region or municipality directly under the Central Government shall, pursuant to applicable laws, file the information obtained while supervising and inspecting the drug MAHs and manufacturers within its administrative region in drug safety credit archives and keep relevant data updated dynamically. Regulatory information includes the information on drug manufacturing authorization, routine supervision and inspection results, investigation and handling of illegal acts, spot checks for product quality, misconduct records, complaints and whistle-blowing.

Article 63 When conducting supervision and administration, the drug regulatory department of the province, autonomous region or municipality directly under the Central Government and the NMPA shall not impede the normal manufacturing activities of MAHs and drug manufacturers, request or accept any money or gift or seek any other benefits.

Article 64 Any individual and organization that discovers any illegal activities done by any drug MAH or manufacturer to drug manufacturing shall have the right to report to drug regulatory department about such illegal activities. The department shall promptly verify the illegal activities and take actions against them pursuant to applicable rules and regulations.

Article 65 In case 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 active drug ingredients, excipients and primary packaging materials and container in direct contact with the drug product and relevant manufacturing line and immediately report such events to the drug regulatory department of the province, autonomous region or municipality directly under the Central Government where the MAH is located and other relevant agencies. The drug regulatory department of the 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 departments of provinces, autonomous regions or municipalities directly under the Central Government shall increase the supervision and inspection frequency and may impose joint punishment according to national regulations.

Article 67 Where the drug regulatory department of the province, autonomous region or municipality directly under the Central Government has failed to promptly discover systematic drug safety risks in manufacturing and promptly eliminate drug safety risks within the supervision and administration region or the provincial people's government has failed to fulfill drug safety responsibilities and promptly eliminate major regional potential drug safety risks, the NMPA shall schedule a warning meeting with the principal persons responsible.

The drug regulatory department of the province, autonomous region or municipality directly under the Central Government and the local people's government that attends the warning meeting shall immediately take actions to remediate the drug supervision and administration work.

The warning meeting and remediation actions shall be included into the drug supervision and administration performance review and appraisal records of the drug regulatory department of the province, autonomous region or municipality directly under the Central Government and the local people's government.