On May 24, China National Medical Products Administration (NMPA) issued the draft Notice of Enhancing the Supervision of Drug Marketing Authorization Holders (MAHs) That Outsource Manufacture (hereafter referred to as the Notice). The Notice came with an appendix: Guidance for On-site Inspection of Drug MAHs That Outsource Manufacture. The draft is open to public advice until June 23 this year.
The Notice stipulates that provincial medical products administration should conduct strict inspections of MAHs, with requirements specified in four aspects:
1. Manufacturing outsourcing authorization;
2. Quality management for outsourced manufacture;
3. Supervision and inspection of MAHs that outsource manufacture;
4. Others.
The Notice also elaborates MAHs’ obligations and responsibilities, which are summarized as follows.
1. Obligation to Get Manufacture Outsourcing Authorization
If the MAH outsources manufacture, applies for category B drug manufacturing license*, or apply for a change to authorized items indicated in the B license. The provincial medical products administration of the province where the MAH is located will scrutinize:
1) the application documents;
2) the GMP compliance notice;
3) the consent to the outsourcing.
Documents 2) and 3) are given by the provincial administration of the province where the outsourced party is situated. This means that, to acquire manufacturing authorization, the outsourced party should get the documents 2) and 3) from its local provincial regulator.
*Drug manufacturing license categories:
A is for MAHs that manufacture drugs by themselves;
B is for MAHs that outsource drug manufacture to other parties;
C is for drug manufacturing companies that accept the manufacture outsourced from MAHs .
D is for companies that manufacture active pharmaceutical ingredients (APIs).
Notes: APIs are assigned with filing numbers (not drug registration certificates) if their drug master files (DMF) have been filed to the Center for Drug Evaluation (CDE).
2. Obligation to Ensure Quality Management
The MAH shall establish a management department with clear responsibilities, equipped with enough personnel suitable for the scale of drug production and supply, and establish a quality management system (QMS) covering the entire process of drug production in accordance with regulations. If outsourcing the manufacture of sterile drugs, the MAH's Responsible Person for Quality and Qualified Person (QP) shall have at least five years of experience in drug production and quality management, of which at least three years should be for sterile drugs.
MAHs of traditional Chinese medicine (TCM) injections and multi-component biochemical drugs shall have the capability to manufacture the products independently. (Please note that this requirement is stricter than the Drug Administration Law which allows all MAHs to choose outsource manufacture or not). Biological product (excluding vaccines and blood products) MAHs are encouraged to have the capability to manufacture the products independently. If the MAH has insufficient production capacity and needs to outsource manufacture to another company’s site, the holder should manage the outsourcing activity according to the regulations on post-marketing changes of drugs.
Related Regulations:
- Provisions for Post-approval Changes of Drugs (Interim)
- Classification of Changes Items of Marketed Chemical Drugs and Dossier Requirements
- Technical Guidelines on Studies of Post-marketing CMC Changes to Chemical Drugs (Trial)
- Technical Guidelines on Clinical Changes for Marketed Chemical Drugs and Biological Products
For outsourcing the manufacture of biological products (excluding vaccines and blood products), TCM injections, and multi-component biochemical drugs, the holder shall establish a QMS covering the entire manufacturing process, which includes the raw materials (biological materials, TCM raw material, TCM decoction pieces, TCM extracts, raw materials of animal origin, etc.).
The MAH shall conduct on-site audits of raw material suppliers every year. If multiple manufacturing sites are involved, the place of origin, source, supplier, and quality standards of raw materials used in each site shall be consistent.
In principle, the MAH shall conduct regular sampling inspections of at least one batch among 10 batches of critical materials, intermediates (crude liquids), and finished products. If less than 10 batches are produced every six months, at least one batch of the abovementioned products should be subject to sampling inspection.
Relevant requirements shall be clearly stated in the quality agreement between the MAH and the company that undertakes the outsourced manufacture. MAHs should also assign experienced persons to work at the entrusted manufacturer company.
The MAH shall strictly manage the incoming inspections of active pharmaceutical ingredients (APIs), excipients, packaging materials and containers that directly contact the drug, and strengthen the inspections before market release.
3. Obligation to Self-inspect
The MAH that outsources manufacture shall conduct a comprehensive self-inspection in accordance with the Administrative Rules on Supervising Drug Marketing Authorization Holder as the Main Entity to Fulfill Responsibilities for Drug Quality and the Notice. The self-inspection’s key points include:
- the establishment of a QMS covering the whole process of drug development, manufacture, supply, and use;
- the establishment and improvement of the organizational body;
- the key personnel;
- regular audits of the QMS of the outsourced manufacturer;
- the establishment and implementation of the training management system, annual report system, pharmacovigilance system, and drug traceability system;
- periodic reviews and analyses in consideration of product risks, as well as regular self-inspections or internal audits.
BaiPharm’s Comment
China’s MAH regulations are rather generally outlined in the Drug Administration Law. The Law grants MAHs the freedom to outsource manufacture to a third party, to some degree boosting the R&D institutes and non-manufacturer companies to develop new drugs. Yet the outsourcing activities could be complex to regulate. The draft Notice manifests China NMPA’s efforts to make more detailed regulations to improve the whole MAH system. Ask BaiPharm if you’d like to know more about MAH-related regulations.
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