After consulting on the draft in Nov. 2022, China implements Administrative Rules on Supervising Drug Marketing Authorization Holder as the Main Entity to Fulfill Responsibilities for Drug Quality (hereafter referred to as the Rules) from Mar. 1, 2023.
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The Rules applies to MAHs in China, requiring them to
- obey the Drug Administration Law and relevant laws & regulations;
- comply with Good Manufacturing Practices (GMP), Good Supply Practices (GSP), Good Pharmacovigilance Practices (GVP);
- establish and improve the drug quality management system;
- be responsible for the safety, effectiveness, and quality controllability during drug development, manufacture, supply, and use.1
The Rules details the drug quality responsibilities in the following aspects:
Main Aspects of Drug Quality Responsibilities in China
MAH Organization and Departments
- Legal representative, responsible person of the corporate
- Responsible person for manufacture
- Responsible person for quality
- Qualified person (QP)
- Responsible person for pharmacovigilance
MAH Quality Management Requirements
Managing active pharmaceutical ingredients (APIs), excipients, and packaging materials
Managing post-marketing changes
Managing market release
Managing entrusted manufacture
Managing storage and transportation
Managing drug traceability
Managing drug recall
Establishing pharmacovigilance system
Conducting post-marketing study
Handling drug safety events
Reporting halted production
Fulfilling legal liability
MAH Quality Management Mechanism
Reviewing batch records
Management analysis and review of drug manufacture and quality at least once every quarter
Writing annual report
Conducting internal review/audit
The detailed responsibilities are as follows:
1. Organization and Department
MAH shall establish departments with clear responsibilities for
- non-clinical study;
- clinical trial;
- manufacture & supply;
- post-marketing study;
- monitoring and handling adverse reactions, etc.
The quality management department should be independent from other departments. It is responsible for fulfilling the whole-process quality management responsibilities, engaging in all quality-related activities, and reviewing all the documents related to quality management.
2. Responsibilities of Key Persons
All the key persons shall be full-time employees of the MAH.
Legal Representative, Responsible Person of the Corporate
Taking full responsibilities for drug quality:
1) Taking full charge of the routine management of the corporate, and fulfilling the entity responsibility for the whole-process quality;
2) Designating the responsible person for drug quality, and providing necessary conditions and resources to ensure the quality management department function independently;
3) Designating the qualified person for independently fulfilling the responsibility of releasing products to the market;
4) Handling major safety events related to drug quality, to ensure immediate control of the risks;
5) Establishing the training & examination system for manufacture management and quality management;
6) Appointing the person responsible for pharmacovigilance.
Responsible Person for Manufacture
Managing drug manufacture:
1) Ensuring drugs are manufactured and stored according to the approved process;
2) Ensuring the factory and facility function well, and completing necessary validation to ensure drug quality;
3) Ensuring the manufacture management training system function effectively; conducting trainings and exams for all the persons involved in drug manufacture management.;
Responsible Person for Quality
Managing drug quality:
1) Establishing quality control and quality assurance systems, supervising the implementation of GMP, GSP, and GVP, as well as ensuring the quality management system function effectively;
2) Ensuring the manufacturing process control and drug quality control comply with relevant regulations and standards;
3) Ensuring the data and records of drug manufacturing and testing are authentic, accurate, complete, and traceable;
4) Ensuring the quality management training system function effectively; conducting trainings and exams for all staff members engaged in drug quality management.
Qualified Person (QP)
1) Independently responsible for releasing products to the market;
2) Ensuring the manufacture and testing of each released batch of products comply with drug registration requirements, quality standards, and relevant regulation.
*Products shall never be released to the market without the QP’s signature.
Responsible Person for Pharmacovigilance
Establishing, operating, and continuously improving the pharmacovigilance system, to ensure the system complies with relevant laws, regulations, and GVP.
3. Auditing AEP Suppliers
MAHs shall audit the suppliers of APIs, excipients, and packaging materials & containers (altogether abbreviated as AEPs). To be more specific, MAH shall ensure the purchased AEPs comply with the requirements for medicinal use, quality management rules of NMPA, and requirements for associated review of AEPs and finished dosage forms.
4. Managing Post-marketing Changes
MAHs shall establish the system for controlling post-marketing changes, including
- formulating the classification principles for internal changes, change lists, change procedures, and risk management requirements;
- determining the change classification only after sufficient research, evaluation, and necessary validation. If entrusting manufacture to another company, the MAH shall conduct the research, evaluation, and validation together with the entrustee.
- carrying out the change after approval/filing, or recording the change in the annual report.
5. Managing Market Release
MAHs as manufacturers shall
- establish procedures for releasing products to the market;
- clarify standards and conditions for market release;
- review the quality testing result, critical manufacturing record, and deviation control situation;
- conduct quality testing.
If the MAH entrusts manufacture to another company, the MAH shall still make market release procedures, review the entrustee’s market release procedures, clarify release standards, and review the drug testing result and market release documents. When necessary, the MAH can review the entrustee’s manufacturing record, testing record, and deviation investigation.
If the products are qualified, they can be released with the QP’s signature.
6. Managing Entrusted Manufacture
In case of manufacture entrusted to another company, the MAH shall first evaluate the entrustee’s quality assurance and risk management capabilities, and then sign quality agreement and entrustment agreement with the entrustee. View the detailed requirements at BaiPharm’s report “Key Points for Manufacturing Entrustment Under China's MAH System”
The MAH shall never transfer the obligations and responsibilities that shall be taken by itself to the entrustee.
7. Managing Storage and Transportation
MAHs shall ensure the storage and transportation of drugs comply with GSP. If the MAH entrusts storage and transportation to another company, the MAH shall
- evaluate the entrustee’s quality assurance and risk management capabilities;
- sign an entrustment agreement and quality agreement with the entrustee;
- periodically review the entrustee’s storage and transportation management.
8. Establishing Drug Traceability System
- establish and implement drug traceability system;
- establish the informational traceability system by itself or an entrusted third party;
- mark the traceable sign on each layer of drug packages for sale;
- provide traced information to the downstream suppliers and institutions that use the drug;
- accurately record the drug’s whole-process information in time during the whole process to realize drug traceability;
- submitting the traced data to medical products administrations.
9. Establishing Drug Recall System
MAHs shall establish and improve the drug recall system. The whole recall process includes recalling the drugs that have quality issues or other safety risks, notifying the relevant companies or institutions that use the drug, and submitting the investigation report, recall plan, and recall notification to the local provincial-level medical products administration. Check more details at BaiPharm’s report “Drug Recall in China: MAHs Shall Shoulder the Main Responsibility”.
10. Establishing Pharmacovigilance System
MAHs shall establish the pharmacovigilance system and a department specially for pharmacovigilance. To reduce drug safety risks to the minimum, MAHs shall follow GVP and conducting pharmacovigilance work, including monitoring, identifying, evaluating, and controlling drug adverse reactions and other adverse reactions related to drug use. Read detailed requirements at BaiPharm’s report “Decoding China's Good Pharmacovigilance Practices (GVP)”.
11. Conducting Post-marketing Study
MAHs shall make post-marketing risk management plan, conduct corresponding studies, and evaluate the drug’s benefits and risks based on the drug safety, efficacy, and quality controllability studies.
Predicated on the evaluation result, MAHs shall take measures to improve drug’s quality and mange risks, including revising the medication package inserts, improving the quality standards and manufacturing process, suspending manufacture and sale, recalling the drugs, applying for annulling the drug registration certificate, etc.
For drugs with conditional approval, MAHs shall also manage risks and complete corresponding studies before the deadline set by China NMPA.
12. Handling Drug Safety Event
MAHs shall make plans for handling drug safety events and periodically conduct trainings and emergency rehearsals. When a severe safety event happens related to drug quality, the MAH shall immediately take effective measures on the drug, its APIs, excipients, packaging materials & containers with direct contact to the drug, as well as the production line to prevent further hazards.
13. Reporting Halted Production
MAHs shall establish a system to report the halted production of drugs in shortage. For drugs in the shortage list, MAHs shall report to the local provincial-level medical products administration six months before stopping the production. For unexpected stop, MAHs shall report to the same administration within 3 days after the stop. When necessary, MAHs shall also report to NMPA.
14. Fulfilling Legal Liability
MAHs shall be capable of fulfilling legal liability. The compensation shall suit the product’s risk level, market size, and the personal injury compensation standards. MAHs shall have liability capability certification or commercial insurance contracts.
MAHs shall establish administrative procedures and systems for liable compensation. If a consumer suffers damage from drug quality issues and first claims compensation from the MAH, the MAH should pay the consumer first, and then ask the insurance company to reimburse its financial loss.
15. Conducting Batch Record Review
Quality management persons shall ensure each batch of drugs comply with GMP in manufacture and testing, investigate the deviations, and control potential quality risks.
The responsible person for quality shall ensure that
- the manufacturing records and testing records are reviewed before market release,
- quality-related changes are reviewed and approved;
- major deviations and out-of-specification (OOS) test results are investigated and handled.
16. Quarterly Management Analysis
With product risks in consideration, the responsible person for quality shall conduct periodic review and analysis of manufacture management and quality management. In principle, the person shall study and analyze repetitive and new risks at least once every quarter, make corrective and preventive measures, and continuously improve the quality management system.
The person responsible for the corporate shall listen to person responsible for quality’s report and advice on drug quality risk prevention and control, and offer necessary conditions and recourses.
17. Submitting Annual Report
MAHs shall establish an annual report system. The person responsible for the corporate shall designate an agency or person specially for the annual report. The report’s information shall be authentic, accurate, complete, traceable, and compliant with laws and regulations.
Based on NMPA’s template, the report’s writer shall compose the report with the manufacture, sales, post-marketing study, risk management, and other situations in the last calendar year.
After the approval by the corporate’s legal representative or responsible person, the MAH shall submit the report to the local provincial-level medical products administration. Learn more at BaiPharm’s report “China Implements New Rules on Drug MAH's Annual Reports”.
18. Conducting Internal Audit/Review
MAHs shall periodically carry out internal audit/review to monitor the compliance to GMP, GSP, and GVP. MAHs shall make plans and records for the audit/review, and compose reports which at least include the basic information of the audit/review, the evaluation conclusion, and advice for corrective and preventive measures.
19. Managing Training
MAHs shall establish a system to manage trainings. Plans shall be made afterwards for the trainings for employees to prepare for the management of R&D, manufacture, quality, sales, pharmacovigilance, post-marketing study, and continuous trainings.
The trainings shall at least include relevant regulations, as well as responsibilities and necessary techniques for the positions. For the trainings, MAHs shall keep records and evaluate effectiveness.
20. Special Regulations for Certain Drugs
For anesthetics, psychoactive drugs, toxic drugs for medical use, chemical precursors that belong to the drug category, radioactive drugs, vaccines and other biologics, traditional Chinese medicine (TCM) decoction slides, and TCM granules, MAHs shall follow the corresponding regulations if there is any.
Contact BaiPharm if you would like to consult about China’s MAH-related regulations.