Market Supervision Bureau of each district, market supervision bureau of Lingang xinpian District, Inspection Bureau, food and Drug Inspection Institute, drug examination center and monitoring center:
The Interim Provisions of Shanghai Municipality on the supervision and administration of drugs for the treatment of auto chimeric antigen receptor T cells (car-t) has been reviewed and approved at the 13th director’s office meeting of the Municipal Drug Administration on June 29, 2022, and is hereby printed and distributed to you. Please comply with them.
It is hereby notified.
Annex:Interim Provisions of Shanghai Municipality on the supervision and administration of drugs for auto chimeric antigen receptor T cell (car-t) therapy
Shanghai Municipal Drug Administration
July 11, 2022
Interim provisions of Shanghai Municipality on the supervision and administration of autologous chimeric antigen receptor T cells (car-t) therapeutic drugs
Article 1 (purpose and basis)In order to strengthen the post marketing supervision and administration of autologous chimeric antigen receptor T cell (car-t) therapeutic drugs (hereinafter referred to as cell therapeutic drugs) in this city and ensure the quality and safety of cell therapeutic drugs, these Provisions are formulated in accordance with the drug administration law of the people’s Republic of China (hereinafter referred to as the drug administration law), the measures for the supervision and administration of drug production and other relevant laws, regulations and rules.
Article 2 (scope of application)The holder of the marketing license of cell therapy drugs in this city (hereinafter referred to as the holder) shall comply with the relevant national regulations and the requirements of these regulations, ensure the quality of cell therapy drugs, implement drug traceability through information means, and ensure the safety, effectiveness, quality controllability and accessibility of cell therapy drugs.
The production enterprises of cell therapy drugs (hereinafter referred to as production enterprises), the units of distribution, transportation and use of cell therapy drugs, the production enterprises of raw and auxiliary materials and packaging materials used in cell therapy drugs, and other units and individuals engaged in production activities related to cell therapy drugs shall meet the relevant requirements of these provisions.
Article 3 (division of labor and jurisdiction)Shanghai Municipal Drug Administration（以下简称市药品监管局）负责本市细胞治疗药品生产、批发和零售连锁经营环节的质量监督管理工作，并指导区市场监督管理局（以下简称区市场监管局）开展细胞治疗药品零售、使用环节的质量监督管理工作。
Each district market supervision bureau is responsible for the quality supervision and management of the retail and use of cell therapy drugs within its jurisdiction.
Article 4 (requirements for agency personnel)The holder and manufacturer shall obtain the drug production license, set up production management, quality management, supply chain management, information management and other departments corresponding to the business scale, and have a quality management system that meets the production requirements of cell therapy drugs. The holder shall set up a pharmacovigilance department as required.
The person in charge of production management, the person in charge of quality management, the quality authorized person and the person in charge of pharmacovigilance shall have relevant professional knowledge and work experience and be able to perform their duties in the management of production, quality and pharmacovigilance. The person in charge of production management, the person in charge of quality management and the quality authorized person shall have professional knowledge in pharmacy, microbiology, biology, cell biology, immunology or biochemistry. The person in charge of pharmacovigilance shall have medical, pharmaceutical, epidemiological or related professional background.
Article 5 (quality management system)The holder and the manufacturer shall establish a quality management system that meets the requirements of the”good manufacturing practice for drugs” and its relevant appendices and is compatible with the characteristics and production form of cell therapy drugs. The quality management system should cover the management of suppliers of raw materials, auxiliary materials and packaging materials, the acceptance of supplier materials, and the production, storage, distribution and handover of drugs. When adopting the commissioned production mode, the quality management system of the holder and the commissioned production enterprise shall be effectively connected.
Article 6 (production process)The holder and the manufacturer shall carry out production in strict accordance with the”good manufacturing practice for drugs” and its relevant appendices, as well as the drug registration standards and production processes approved by the drug regulatory department.
If the production process needs to be changed, the holder and the production enterprise shall carry out sufficient verification and Research on the content of the production process change in accordance with the requirements of the measures for the administration of drug registration, the measures for the administration of post marketing changes of drugs (for Trial Implementation), and the guiding principles for pharmaceutical change research of listed biological products (for Trial Implementation), and obtain approval, filing or reporting in accordance with the law.
Article 7 (facilities and equipment)The production enterprise shall comply with the requirements of the”good manufacturing practice for drugs” and its relevant appendices, and have plants and equipment suitable for the production mode and scale. The production of cell therapy drugs should be carried out in the area of an independent plant. Closed systems and disposable consumables should be used in the production process as far as possible to reduce the risk of pollution and cross contamination.
Article 8 (Digital traceability requirements)The holder and the production enterprise shall ensure that the information in the whole process of production activities is true, accurate, complete and traceable, implement the production process traceability through information means in accordance with the requirements of relevant laws, regulations, rules and standards, and establish a digital traceability system covering the whole process of supplier material acceptance, production, inspection, release, transportation, handover and so on.
Each supplier’s material and corresponding products shall be provided with a unique number code for identification and traceability. The minimum package products on the market shall upload drug traceability information in accordance with the requirements of the State Drug Administration on the construction of information traceability system for key varieties.
Article 9 (biosafety requirements)The production and inspection of cell therapy drugs should meet the requirements of the biosafety law of the people’s Republic of China and relevant regulations, and do a good job in biosafety protection.
Donor materials and cell products containing infectious disease pathogens should be produced and stored in separate isolation areas with corresponding biosafety protection levels, and special production and storage equipment should be used.
Article 10 (sample retention management)The manufacturer shall keep the donor materials and the retention samples of cell therapy drugs in accordance with the regulations, and the retention samples shall be retained for at least one year after the expiration of the cell therapy drugs. When the collection amount of donor materials or the batch production of cell therapy drugs is small, in order to ensure the drug demand of patients, the sample retention strategy can be adjusted according to the”good manufacturing practice of drugs” and its relevant appendices.
For cell therapy drugs that may have foreign gene expression and the risk of gene integration or recombination of expression vectors, the manufacturer shall conduct a long-term sample retention evaluation, and the retention period of the samples included in the evaluation shall be extended accordingly.
Article 11 (release requirements)When the holder and the manufacturer release the cell therapy drugs for production and marketing, they should check the consistency between the donor materials and the cell therapy drugs, and review all relevant original data, process records, environmental monitoring and inspection process records, as well as the donor material collection, transportation process, acceptance and storage records. When it is confirmed that the drug production conforms to the process procedures and quality standards, the decision of drug release for marketing can be made.
Article 12 (Supply Chain Management)The holder can establish the supply chain of cell therapy drugs, prevent and control the possible risks in the storage and transportation process, and formulate emergency response plans to ensure the safety, effectiveness, quality controllability and accessibility of cell therapy drugs through self built logistics or entrusted drug handling enterprises, drug logistics enterprises, etc. The holder can establish a supply chain by referring to relevant specifications or standards.
Units participating in all links of the supply chain of cell therapy drugs should have cold chain storage facilities and equipment, information equipment, monitoring equipment, quality management system and professionals that meet the needs of the distribution and storage of cell therapy drugs, and be able to realize the traceability of the whole process of quality supervision.
Article 13 (record keeping)The holder and the manufacturer shall properly keep the records of the whole process of the collection, production, inspection, release, sales, transportation, re melting and use of the supplier’s materials, as well as the records of supplier audit, confirmation and verification, change management, deviation management, self inspection and other quality management work and pharmacovigilance work. The batch production records shall be kept for at least one year after the expiration of the drug, the pharmacovigilance records and data shall be kept for at least 10 years after the cancellation of the drug registration certificate, and other important documents shall be kept for a long time. The records and vouchers related to the purchase, storage, sale and transportation of pharmaceutical trading enterprises shall be kept for at least 5 years.
Article 14 (examination and approval of medical institutions)The holder shall examine and verify the medical institution (hereinafter referred to as the medical institution) that collects the donor materials and uses the products. Medical institutions should meet the relevant technical requirements of the health department on blood cell apheresis, have the treatment ability appropriate to the risk of clinical application, and accept the training and evaluation of the holder.
The holder shall sign a quality agreement with the approved medical institution. When it is found that the medical institution does not comply with the operating procedures and may have an adverse impact on the health of patients, the holder shall timely require the medical institution to take effective corrective and preventive measures. For medical institutions that cannot rectify as required, the holder shall remove them from the list of qualified medical institutions and timely report to the Municipal Drug Administration.
Article 15 (publication of the list of medical institutions)The holder shall publish the list of approved medical institutions on its website for the convenience of patients’ inquiry. The list and changes of medical institutions shall be reported to the provincial drug regulatory department where the relevant medical institutions are located through the Municipal Drug Administration for provincial supervision and use.
Article 16 (pharmacovigilance)The holder shall establish and improve the pharmacovigilance system, set up special institutions, allocate full-time personnel, carry out pharmacovigilance work, timely report adverse drug reaction reports and regular safety update reports of drugs, actively carry out post marketing research, and carry out long-term safety follow-up as required in accordance with the requirements of the measures for the Administration of adverse drug reaction monitoring and reporting and the pharmacovigilance quality management specifications, Continuously evaluate the risks and benefits of drugs, and take effective risk control measures for the identified risks.
The Municipal Drug Administration shall inspect the pharmacovigilance work of the holder according to the regulatory requirements.
Article 17 (annual report)The holder shall, in accordance with the provisions on the administration of annual reports of drugs, collect the production and sales, post marketing research, risk management and other information of the cell therapy drugs held by him according to the natural year, write the annual report of drugs and submit it online in a timely manner. Entrusted production enterprises, sales enterprises and other relevant units and individuals shall cooperate with the holders in the annual report.
Article 18 (supervision and inspection)The Municipal Drug Administration shall supervise and inspect the holders, production enterprises, wholesale enterprises and retail chain headquarters of cell therapy drugs in this city according to law, carry out at least one compliance inspection and one daily supervision and inspection of drug production quality management norms for production enterprises every year, and carry out at least one daily supervision and inspection for holders, wholesale enterprises and retail chain headquarters every year. Each district market supervision bureau shall carry out daily supervision and inspection on retail enterprises and medical institutions within its jurisdiction at least once a year according to law.
The Municipal Drug Administration may, as needed, carry out extended inspections on the entrusted production enterprises and entrusted distribution enterprises of the holders in this city, pharmaceutical excipients and packaging materials and container manufacturers that have direct contact with drugs.
If there is evidence to prove that there may be potential safety hazards, the Municipal Drug Administration and the district market supervision bureau shall, according to the supervision and inspection, take warnings, interviews, rectification within a time limit, and suspend production, sales, and use according to law等措施，对违法违规行为依法进行处置。