Thursday, 20 June 2024 / Published in News, NMPA Registration in China, Pharmaceuticals & DMF

China Contract Drug Manufacturing Provisions

China Contract Drug Manufacturing Provisions were issued back in October 2023 to strengthen the supervision and management of the entrusted production of drugs to ensure the quality and safety of drugs throughout their lifecycle.

The announcement emphasizes the holder’s primary responsibility for drug quality and safety, requiring robust quality management systems, stringent audits, and strict compliance with regulatory standards.

Here is a reminder of the key impacts on Drug Marketing Authorization Holders (MAHs), Contract Drug Manufacturers (CMOs) as well as Chinese provincial Medical Products Administrations (MPAs):

1. Stricter Licensing and Inspections:

Drug production licenses (Class B) for contract drug manufacturing require stringent application reviews and compliance with drug Good Manufacturing Practice (GMP) standards.
Provincial drug regulatory authorities will conduct thorough on-site inspections focusing on staffing, quality management systems, and management of entrusted production.
For sterile drugs, key personnel must have at least five years of practical experience in production and quality management, including three years in sterile drugs.

2. Quality Management:

MAHs must establish a dedicated management department and a comprehensive quality management system for the entire production process.
On-site audits of the MAH’s and the CMO’s quality management systems must be conducted at least once a year.
Material suppliers must be evaluated and audited at least once a year to ensure compliance with statutory standards.

3. CMO (Entrusted Production) Conditions:

Production of traditional Chinese medicine injections and multi-component biochemical drugs requires specific experience and a history of continuous production and sales without serious adverse reactions.
Comprehensive annual audits and assessments of GMP compliance and production processes are mandated.
Marketing Authorization Holders must submit detailed research data and audit reports to the provincial drug regulatory department for approval.

4. Post-Marketing and Risk Management:

A post-marketing change control system must be established, including internal change classification, procedures, and risk management.
Reviews and risk assessments must be conducted at least once every quarter, with corrective and preventive measures to improve the quality management system.

5. Laboratories and Testing:

MAHs may build their own quality control laboratories to carry out inspections or entrust the CMO to conduct inspections.
If holders use third-party inspection agencies, they must review the qualifications and capabilities of these agencies, sign a contract inspection agreement, and report to the provincial drug regulatory department.
The MAH must supervise the whole process of the contracted/entrusted inspection.
For sampling inspections, every 10 batches of finished products must include at least 1 batch of main raw materials, intermediate products (stock solution), and finished products. If fewer than 10 batches are produced in a year, at least one batch must be sampled and inspected.

6. Quality Agreements and Commissioned Production Agreements:

Quality Agreements: MAHs must sign quality agreements with the CMO detailing responsibilities and ensuring compliance with quality standards. These agreements must cover the entire production process and ensure both parties’ quality management systems are effectively integrated.
Commissioned Production Agreements: These agreements should specify the operational aspects of the production process, including roles, responsibilities, and obligations of both the MAH and the CMO (entrusted manufacturer). This includes regular audits and compliance with GMP.

7. Specific Product Regulations:

Strict guidelines apply for the production of biological products, traditional Chinese medicine injections, and multi-component biochemical drugs.
Annual on-site audits of the suppliers of main raw materials used in production are required.

8. Additional Supervision:

Annual comprehensive inspections by provincial MPAs are required, focusing on key positions, quality management audits, change management, and risk control.
Annual Inspection Plans: Provincial MPAs must develop and implement annual plans for supervision and inspection.
Random or Spot Inspections: Both the MAH and the provincial MPA are required to conduct random or spot inspections:
- Random Inspections by the MAH: The holder must conduct random on-site audits of the quality management systems and production processes of the entrusted production enterprises to ensure compliance with quality standards and statutory requirements.
- Random inspections by the authorities: Provincial MPAs must regularly organize random or spot inspections of the MAH’s and CMO’s operations. These inspections will focus on compliance with GMP, the effectiveness of quality management systems, and the implementation of risk management measures.
Extended Inspections: Extended inspections are required for specific scenarios:
- If there is a serious adverse reaction associated with the entrusted production varieties.
- If sampling inspections reveal non-compliance or quality issues.
- To investigate and verify the implementation of corrective measures after any identified quality issues or regulatory violations.

9. Regulatory Compliance and Penalties:

Non-compliance with the announced requirements may result in suspension of production activities, revocation of drug production licenses, or other legal actions.
MAHs and China Contract Drug Manufacturers must rectify inconsistencies within a set timeframe (specific timeframes to be determined by provincial drug regulatory departments) or face penalties.

10. Drugs That Cannot Be Commissioned:

The following drugs cannot be commissioned for production:
- Blood products
- Narcotic drugs
- Psychotropic substances
- Toxic drugs for medical use
- Pharmaceutical precursor chemicals
Additionally, compound preparations containing narcotic drugs, psychotropic drugs, and precursor chemicals cannot be commissioned for production according to relevant regulations.
Special provisions apply to vaccines and other specified products, which must be followed accordingly.