Chinese authority expands inspection of medical device, IVD and drug overseas

Regulations for the Administration of Overseas Inspection of Pharmaceuticals & Medical Devices (No. 101 of 2018)

Chapter I General

Article 1 This Regulations has been developed in accordance with the requirements of Drug Administration Law of the People’s Republic of China, Medical Device Regulations and applicable statutes to regulate the overseas inspection of pharmaceuticals & medical devices.

Article 2 This Regulations applies to the inspections of overseas processes in relation to the development and manufacturing of pharmaceuticals and medical devices that have been or are intended to be marketed within the territory of the People's Republic of China.

Article 3 For the purpose of these Regulations, overseas inspections of pharmaceuticals and medical devices refer to the inspections conducted by the National Medical Products Administration (“NMPA”) to confirm the authenticity, reliability and compliance of the processes related to the overseas development and manufacturing of pharmaceuticals and medical devices.

Article 4 The NMPA is responsible for the overseas inspection and management of pharmaceuticals and medical devices. Center for Food and Drug Inspection of NMPA (”CFDI”) is responsible for the specific organization and implementation of overseas inspections of pharmaceuticals and medical devices. Relevant departments handling inspection, review and evaluation of pharmaceuticals and medical devices assist in the conduct of overseas inspections.

Article 5 The NMPA discloses the basic situation and outcomes of inspection in accordance with the requirements of government information disclosure.

Article 6 Inspectors and the inspected organizations shall strictly abide by the anti-corruption requirements.

Article 7 Inspectors shall strictly abide by laws, regulations and inspection disciplines, and keep state secrets and the secrets of the organizations inspected.

Chapter II Inspection Tasks

Article 8 The NMPA determines the inspection tasks through risk assessment and random sampling taking into account recommendations of relevant departments on to-be-inspected products and their respective development and manufacturing sites. In the event a change in the inspection task(s) is indeed required due to regulatory purpose, adjustment(s) can be made to the inspection task(s) per provisions of the NMPA on management of foreign affairs involved in overseas inspection.

Where necessary as indicated, extended inspections can be conducted on the manufacturing sites, suppliers and/or other contract organizations of raw materials, excipients and/or packaging materials.

Article 9 The determination of inspection tasks shall consider risk factors in relation to medical products/medical devices such as registration review and approval, supervision and inspection, testing, complaint reports, and monitoring of adverse reactions and adverse events. Focus shall be placed on the following situations:

(I) Potential risks discovered during review and approval;

(II) Non-compliance of inspection or batch release, indicating that there are risks with the quality management system;

(III) Possible product safety risks as indicated by adverse reaction or adverse event monitoring;

(IV) Other violations of laws and/or regulations as indicated by complaint reports or other information;

(V) There are adverse records on the marketing approval holder, the medical device registrant or the filer (hereinafter referred to as “the holder”);

(VI) Presence of major problems with the holder's quality management system, as evidenced by the findings of on-site inspection(s) conducted by foreign regulatory authorities;

(VII) There is a need of inspection again after rectification;

(VIII) Other situations for which overseas inspections are required.

Article 10 The CFDI shall send Overseas Inspection Notice (Annex 1) to the holder or their agent based on the overseas inspection tasks of the NMPA. The holder shall submit to the CFDI Letter of Authorization (see Annex 2 for corresponding requirements) and Basic Information Form of Product under Overseas Inspection (Annex 3) within twenty (20) working days, and site master files and other materials required for the inspection based on the Listing of Site Master Files (Annex 4) within forty (40) working days, as of the date of receipt of Overseas Inspection Notice.

The CFDI may retrieve technical materials relating to the inspection of the varieties depending on the need of inspection, and the technical information obtained shall be maintained confidential through necessary measures, and shall be included in the inspection files after the inspection.

The holder must appoint a domestic agent (where the agent of medical device shall be the agent of the medical device registrant or the filer) and issue an authorization in accordance with the relevant requirements. The agent is responsible for the liaison between the medicine regulatory authority and the holder, undertakes adverse medicine reactions or medical device adverse event monitoring, and is responsible for product traceability and recall. The agent shall perform the relevant responsibilities and obligations of the medical devices for domestic marketed medicines as prescribed by laws and regulations, and assist the medicine regulatory authorities to carry out investigations on the overseas development of products, the inspection of production sites and violations of laws and regulations.

In the event of a change in the agent, the holder shall, after completing the change procedures stipulated by laws and regulations, delegate the new agent to submit a new Letter of Authorization to the CFDI in a timely fashion. Said Letter of Authorization shall clarify that the termination date of authorization for the outgoing agent shall be start date of authorization for the new agent.

Article 11 Upon receipt of Basic Information Form of Product under Overseas Inspection, The CFDI preliminarily determines an inspection schedule based on the overall arrangement of the inspection work and serves an Overseas Inspection Pre-notice (Annex 5) to the holder.

The holder shall not postpone the inspection without justification. In the event there is indeed a need to postpone the inspection due to special circumstances, a written application accompanied by justifications shall be submitted to the CFDI within ten (10) working days as of the date of service of Overseas Inspection Pre-notice. In such case, the CFDI determines the final inspection date by comprehensive evaluation of the actual inspection work to judge whether there is any situation that rejects or obstructs inspection.

Article 12 The inspection team shall in principle consist of more than three inspectors, and the inspection team shall implement responsibility system of team leader responsibility. The inspectors shall be persons who have obtained the inspector qualification in accordance with law. Experts in relevant fields can be invited to participate in the inspection work depending on the needs of inspection work.

Article 13 The holder shall coordinate and cooperate with the overseas inspection work in an all-round manner to ensure the smooth progress of the inspection, without delay, obstruction, evasion or refusal of inspection.

Article 14 The holder shall be responsible for communicating with the relevant inspected organizations (including overseas production plants, research and development institutions, manufacturing sites of raw materials, excipients and packaging materials, suppliers or other contract organizations, etc.) to coordinate and check related matters.

Article 15 The working language for overseas inspection is Chinese that materials such as application dossiers and rectification report submitted by the holder shall be in Chinese language. During the inspection period, translators who can meet the inspection requirements shall be provided.

Chapter III Inspection

Article 16 The CFDI is responsible for formulating the overseas inspection plan, and the inspection team shall conduct on-site inspections in accordance with the inspection plan. When a change to the inspection plan is required, the inspection team shall report to the CFDI for approval before implementation.

The CFDI shall provide the inspection team with centralized pre-departure education to emphasize the anti-corruption discipline and foreign affairs discipline.

Article 17 At the beginning of the on-site inspection, the inspection team shall convene an initial meeting to notify the inspected organization of the composition of the inspectors, the purpose and scope of the inspection, the inspection schedule, and state the inspection precautions and the discipline for inspection.

The inspected organization shall introduce to the inspection team the registration, production, and quality management of the product(s) to be inspected, and clarify the responsible person for the site inspection.

Article 18 During the inspection, the inspected organization shall maintain the normal production status, open relevant places and areas to the inspection team, and cooperate with the inspection of relevant facilities and equipment; according to the inspection schedule, the inspected organization shall arrange the dynamic production of the key production processes of the inspected varieties, timely provide the documents, records, electronic data, etc. required for the inspection, and truthfully answer the inquiries of the inspection team.

Article 19 The inspection team may collect relevant evidence materials by means of copying, photographing and video depending on the needs of inspection.

Article 20 If samples need to be taken during the inspection, the inspection team shall sample and seal the samples with reference to the sampling procedures and attach samples.

The sealed sample shall be returned to the territory by the holder with the sample file or brought back to the territory for inspection. The holder shall ensure that the packaging and shipping conditions of the sample are such that the quality of the sample is not affected.

Article 21 If the inspection team finds that there is a serious quality risk, it shall immediately report to the CFDI and propose preliminary disposal. After receiving the report, the CFDI shall conduct a risk assessment in a timely manner and report relevant results to the NMPA.

Article 22 Before the inspection comes to an end, the inspection team shall convene the final meeting to communicate the inspection outcomes and problems identified through inspection to the holder. The holder may state the defense and the inspection team shall keep documentation thereof.

Article 23 The inspection report shall be signed by the entire inspection team for confirmation and shall be submitted to the CFDI within ten (10) working days from the date of the inspection team returning to China.

Chapter IV Review and Handling

Article 24 After on-site inspection is completed, the CFDI shall feed Notice of Overseas Inspection Findings (Annex 6) back to the holder or their agent in writing within twenty (20) working days as of receipt of the inspection report submitted by the inspection team.

Where testing is required, the testing agency shall complete the testing or study within the statutory time limit from the date of receipt of the sample, and the time of testing or study shall not be counted in the time limit for feeding back Notice of Overseas Inspection Findings.

If any objections to the inspection outcomes, the holder may present a written statement or justification to the CFDI within ten (10) working days as of the date of service of Notice of Overseas Inspection Findings to the holder or their agent. Failure of the holder to provide such statement or justification within the specified time limit of ten (10) working days shall be deemed as no objections. The holder's statement and justification shall be included in the inspection file.

Article 25 The holder shall submit to the CFDI a report of rectifications for defects identified during overseas inspection within fifty (50) working days from the date of service of Notice of Overseas Inspection Findings. Where rectifications for the defects cannot be completed within the prescribed time limit, the holder shall submit a detailed improvement and follow-up plan followed by corresponding updates until all the rectifications have been completed.

Article 26 The CFDI shall conduct a comprehensive assessment of the on-site inspection report in conjunction with the rectifications made by the holder. The comprehensive assessment shall be completed within twenty (20) working days after receipt of the rectification report. The holder’s statement or justification, if any, may be considered together in the comprehensive assessment. If necessary as indicated, inspection may be re-initiated for the rectifications. In the event risk consulting or supplementation of materials by the hold is required during the process of comprehensive assessment, relevant time taken will not be counted in the aforesaid time limit.

Article 27 The comprehensive assessment shall adopt the principles of risk assessment taking into account the nature and severity of the defects and the product category to assess the inspection outcomes. The principle of judgment is as follows:

(I) Conforming: no defects were found during on-site inspection.

(II) Conforming after rectification: on-site inspection has found that there are corrective measures for all major defects and general defects, indicating that the holder is able to take effective corrective measures and organize production per laws, regulations and technical specifications.

(III) Non-conforming: on-site inspection of the pharmaceutical product has found problems of non-compliance with regulatory requirements and technical specifications, such as data authenticity, inconsistency of product quality-affecting critical elements with the registration materials, presence of serious defects, inadequate corrective measures for major defects, infeasibility of the rectification plan, etc.; ; on-site inspection of medical device has found problems of non-compliance with regulatory requirements and technical specifications, such as data authenticity, inconsistency of product quality-affecting critical elements with the registration materials, presence of serious defects, inadequate corrective measures for major defects, infeasibility of the rectification plan, etc.

Article 28 In any of the following circumstances, the holder shall be deemed to have delayed, obstructed, restricted or rejected inspection and be directly judged as “non-conforming”:

(I) Failure to provide the required authorization document(s) within the specified time limit after the date of service of Overseas Inspection Notice; failure to provide relevant documents and/materials required within the prescribed time limit;

(II) The holder obstructed or postponed the scheduled inspection twice;

(III) Refusal of the inspected holder to arrange for dynamic production;

(IV) Failure to cooperate with the procedures for overseas inspection;

(V) Failure to cooperate with an extended inspection;

(VI) The holder is found to delay, obstruct, restrict or reject the entry of the inspection personnel into the inspected place or area, or restrict the inspection time, or set unreasonable inspection conditions or disturb the inspection;

(VII) the holder is found to delay in providing or refuse to provide or deliberately cover critical information to be inspected;

(VIII) The holder is found to reject or restrict on-site collection of evidence-related materials, or refuse to perform notarization certification procedures or submit notarized certification documents for evidence-related materials;

(IX) Other circumstances that do not cooperate with the inspection.

Article 29 After comprehensive assessment, the CFDI shall form a report of overseas inspection review, which shall be submitted to the NMPA together with relevant inspection records and documents.

When discovering any potential major quality hazards requiring emergency measures in the on-site inspection report of the inspection team or during comprehensive assessment, the CFDI shall immediately send a report to the NMPA.

Article 30 For the varieties that are in the stage of registration review and approval or belong to the category of registration review and approval, the NMPA will, taking into the conclusion(s) from comprehensive assessment, adopt corresponding measures in accordance with Drug Administration Law of the People’s Republic of China, Medical Device Regulations, Drug Registration Regulations, Regulations on Medical Device Registration and Regulations on Registration of In vitro Diagnostic Reagents.

For the varieties that have been marketed in China, the NMPA will, with consideration given to the conclusion(s) from comprehensive assessment, order corresponding risk control measures against the holder, including interviews, making rectifications within a specified time limit, issuing a warning letter, suspending the filing of drug import customs clearance, suspending the import of the medical device involved, suspending the sale and use of the medical device involved, overseeing the product recall and even revoking import approval certificates.

If the comprehensive judgment is that the requirements are not met, and the inspection reveals that the enterprise has illegal activities or the product has potential safety hazards, the NMPA shall promptly adopt risk control measures and make information disclosure per law. For those who have major quality hazards and need to take urgent measures, the NMPA shall immediately take risk control measures and handle the case in accordance with law.

Article 31 In the case of discovering suspected violations of law, the inspectors shall fix the evidence in time, and the NMPA shall organize investigation and handling in accordance with law.

Article 32 The holder shall establish a product traceability system to ensure efficient recall of products being distributed and used in the country when product recall is required as evidenced by problems identified during inspection.

Article 33 After the risk factors are eliminated or rectifications have been made, the holder may submit an application to the NMPA for on-site inspection, which can be initiated again as appropriate after review. If the requirements of laws, regulations and technical specifications are met, the relevant risk control measures shall be lifted.

Chapter V Supplementary Provisions

Article 34 The on-site inspection of processes in relation to product development and manufacturing for holders located in the Hong Kong Special Administrative Region, the Macao Special Administrative Region and the Taiwan region shall be carried out in reference to this Regulations.

Article 35 On-site inspections for the raw material, excipient and/or packaging material manufacturing sites or suppliers of home-made products located outside China shall be conducted in reference to these Regulations.

Article 36 Site master files defined in this Regulations are part of the quality management system documents, describing the enterprise’s quality management policies and activities, the implementation of manufacturing and/or quality control of medical products/medical devices at designated sites, the performance of relevant operations in adjacent or nearby buildings etc.

Article 37 This Regulations shall be interpreted by the NMPA.

Annexes:

1. Overseas Inspection Notice

2. Relevant Requirements for Holder’s Authorization of Agency for Overseas Inspection Affairs

3. Basic Information Form of Product under Overseas Inspection

4. Listing of Site Master Files (for Pharmaceuticals / Medical Devices)

5. Overseas Inspection Pre-notice

6. Notification of Overseas Inspection Outcomes