Appendix

Guidelines for verification of medical device registration quality management system

One、Purpose and basis

To strengthen the verification management of medical device registration quality management system and ensure the quality of verification, This guide is formulated in accordance with the Regulations on the Supervision and Administration of Medical Devices, the Administrative Measures for the Registration and Filing of Medical Devices, the Administrative Measures for the Registration and Filing of In Vitro Diagnostic Reagents, the Administrative Measures for the Supervision of the Production of Medical Devices, the Administrative Standards for the Production Quality of Medical Devices, the Administrative Standards for the Quality of Clinical Trials of Medical Devices, and the Administrative Provisions for the Self inspection of Medical Devices.

Two、Scope of application

This guideline is applicable to the on-site verification of the registered quality management system of Class II and Class III medical devices by the medical device regulatory authority.

Three、 Basic requirements

3.1 (Quality Management System) The applicant for registration (hereinafter referred to as the applicant) shall establish a quality management system suitable for the product realization process, including commissioned production (if any), clinical evaluation (including clinical trial) and other links, in accordance with the requirements of the Medical Device Production Quality Management Specification and its appendix, based on scientific knowledge, experience and risk management principles, To ensure its effective operation in the whole life cycle management process of medical devices, to ensure that the design, development, production and other process data are true, accurate, complete and traceable, and consistent with the registration application materials.

3.2 (Requirements for registration verification) The registration quality management system verification shall be organized in combination with the registration application materials, focusing on the design and development, procurement, production management, quality control and other contents related to product development and production. The verification of product authenticity shall be comprehensive and objective.

3.3 (Self inspection and verification requirements) For those who submit self inspection reports, the applicant's quality management system and capabilities shall be verified item by item in accordance with the Administrative Provisions on Self inspection of Medical Device Registration and in combination with the submitted product technical requirements.

3.4 (Requirements for inspection of entrusted activities and extended inspection) For applicants who entrust other enterprises with design and development, product production and other activities, the scope of inspection shall cover entrusted R&D and entrusted production activities. When necessary, extended inspection shall be carried out for other units that provide products or services for the research, development and production of medical devices.

Four、 Key inspection contents

4.1 Principles of quality management system

4.1.1 (Quality management system) The applicant shall establish a quality management system that covers design and development, production, quality control, release audit and other aspects in line with the product realization process, and shall include commissioned production (if any), clinical evaluation (including clinical trial), etc.

4.1.2 (Risk management) The applicant shall establish a risk management system to assess the quality risk of the product realization process according to scientific knowledge and experience to ensure the product quality.

4.1.3 (Self inspection) If the applicant conducts self inspection, the self inspection work shall be incorporated into the product quality management system and meet the requirements.

4.2 Organization and personnel

4.2.1 (Organization) The applicant shall establish a management organization suitable for the research, development and production of medical devices, define the responsibilities of each department, and ensure that the design, development and technology conversion are reasonable and traceable.

4.2.2 (Personnel) The applicant shall be equipped with an appropriate number of R&D, production and quality control personnel, who shall have the professional knowledge and work skills appropriate to the products applied for registration.

4.2.3 (Key personnel) The management representative, production principal, quality principal, technical principal, product release reviewer and other key personnel shall be familiar with the key quality control and key production operation requirements of the declared registered products.

4.2.4 (Self inspection personnel) If the applicant submits the self inspection report, the quality inspection department shall provide a sufficient number of full-time inspection personnel. The educational background and technical ability of the inspectors shall match the product inspection work. The inspectors, reviewers, approvers, etc. shall be authorized by the applicant in accordance with the provisions.

4.3 Plant, facilities and equipment

4.3.1 (Factory buildings and facilities) The applicant shall be equipped with factory buildings and facilities suitable for the production of the registered products. Product design and development shall be carried out in appropriate plants and facilities. The factory buildings and facilities for the production of inspection products (hereinafter referred to as registered inspection products) and clinical trial products applied for registration shall meet the requirements of product quality control.

4.3.2 (Production equipment) The applicant shall be equipped with production equipment and process equipment that are suitable for the production of the registered product. The production equipment and process equipment for registered inspection products and clinical trial products shall meet the requirements of product quality and production scale.

4.3.3 (Inspection equipment) The applicant shall be equipped with environmental facilities and instruments that meet the requirements of product inspection methods. The environmental facilities and conditions of laboratories for special professional inspection shall meet the specific professional requirements.

4.3.4 (Production of registered inspection and clinical trial products) The factory facilities and equipment used for R&D and production of registered inspection products and clinical trial products as well as relevant use records shall be kept. In case of force majeure that can not be retained, evidence materials that can prove the authenticity, integrity and traceability of product development, production, verification and other product realization process activities shall be retained.

4.4 Document management

4.4.1 (System documents) The applicant shall establish quality management system documents suitable for the products applied for registration, including quality manuals, procedure documents, technical documents and data records. Technical documents shall include product technical requirements and relevant standards, production process procedures, operation instructions, inspection and test operation procedures and other relevant documents. Data records shall ensure traceability of product design and development, material procurement, production, quality control, product release and other activities.

4.4.2 (R&D original record) The original data of design and development shall be included in the document management. In addition to the directly output test data, the auxiliary records in the design and development process, such as the main material receiving records, instrument and equipment use records, weighing records, and preparation records, shall also be kept. For clinical trials, the warehouse out records, storage and transportation records, recovery and disposal records of test instruments (reagents) related to the clinical trials shall be kept.

4.4.3 (Verification data) The applicant shall keep the research data and records of verification after product design and development or technology transfer, and shall ensure the authenticity, accuracy, integrity and traceability of the data.

4.4.4 (Management of clinical trial documents) The applicant shall establish a management system for basic clinical trial documents, manage relevant clinical trial documents according to the requirements of the Directory of Basic Clinical Trial Documents of Medical Devices/In Vitro Diagnostic Reagents, and ensure their authenticity, integrity and traceability.

4.5 Design and development

4.5.1 (Design and development documents) The medical device design and development documents shall be derived from the relevant documents of design and development planning, input, output, review, verification, confirmation, conversion and change, including the records established in the design and development process, and shall ensure that the final output process of previous design and development and related activities are traceable.

4.5.2 (Design and development input) Design and development input shall generally include laws and regulations, national standards, industrial standards, domestic and foreign guidance documents, standard or reference material information (applicable to IVD reagent products), user needs, product application scope, technical indicators of previous generation or similar products, product risks, etc.

4.5.3 (Design and development output) The design and development output shall meet the input requirements, as well as the user's needs and product design needs. Attention shall be paid to the product's scope of application, functionality, safety, effectiveness and quality controllability.

4.5.3.1 (Passive medical devices) The components of raw materials of passive medical devices should meet the requirements of relevant standards, and the biocompatibility evaluation should be completed for the part of the product in contact with the human body. During the re sterilization of reusable sterile products, the performance of the finished product should be evaluated and the study on tolerance to re sterilization should be completed.

4.5.3.2 (Active medical devices) Active medical devices shall complete relevant research according to standard requirements, such as electric shock hazard protection, mechanical hazard protection, radiation hazard protection, over temperature hazard protection, electromagnetic compatibility, biological compatibility, etc.

4.5.3.3 (Animal origin includes allogeneic medical devices) Animal origin medical devices should complete animal species (if the risk is related to the strain, the strain should also be specified), geographical origin (for species whose geographical origin cannot be determined, the identification and traceability requirements for the survival period of the source animal should be provided), age (applicable when the risk is related, such as the susceptibility of animals to naturally occurring transmissible spongiform encephalopathy) Research on the type of the sampling site and tissue, the health status of the animal and the sampling tissue, and the applicability validation of the virus inactivation method.

4.5.3.4 (In vitro diagnostic reagents) The main raw materials, intermediates, important auxiliary materials, etc. involved in the research process of in vitro diagnostic reagents shall be clearly sourced and meet the requirements, and the equipment, instruments and reagents used in the research process shall meet the research requirements.

4.5.4 (Verification and confirmation) The applicant shall determine the scope and extent of work to be verified or confirmed based on the risk assessment results, and ensure that the key elements of relevant operations can be effectively controlled.

4.5.5 (Design conversion) The applicant shall keep all records of product design conversion activities to show that the design and development output has been fully verified and applicable to conventional production before becoming the final product specification, and ensure that the production process can continuously and stably produce products that meet the intended use and product technical requirements under the conditions of using the determined raw materials and equipment. For example, validation and confirmation of sterilization process and related equipment and facilities of sterile products, confirmation and evaluation of realization of basic safety and basic performance of active medical devices, production process of in vitro diagnostic reagents, process parameters and batch scale-up validation.

4.5.6 (Packaging, expiry date and reuse) The applicant shall conduct research on product packaging, expiry date or reuse times and keep relevant records, such as packaging design and verification of products, stability research data, product instructions and design records of minimum sales unit labels.

4.5.7 (Validation records) Detailed original data records of design and development validation activities shall be kept, including validation schemes, validation reports, validation records (such as test data, sample processing records, etc.), auxiliary records, etc.

4.5.8 (Clinical confirmation management) In the process of design and development confirmation, if the application for registration of products needs to be confirmed by clinical trials, the applicant shall perform the corresponding duties according to the clinical trial scheme and contract, and keep the relevant documents and records.

4.5.9 (Requirements for clinical trial products) Before the clinical trial starts, the applicant shall ensure that the product design has been finalized and the product inspection has been completed, and its safety and functionality are suitable for the clinical trial. Records of the relevant assessment and validation processes should be maintained.

4.5.10 (Management of clinical trial products) The applicant shall keep records of distribution, storage, transportation, recovery/return of clinical trial products.

4.5.11 (Design and development changes) Design and development changes, including product changes, updates of reference documents (such as laws and regulations, mandatory standards), changes in design conversion (such as equipment, raw material suppliers, processes, environment, etc.), external change requirements (inspection, animal testing, clinical trials, technical review change opinions), changes caused by changes in mandatory medical device standards, shall be subject to risk assessment Verify or confirm to ensure that changes are controlled.

4.5.12 (Entrusted R&D management) For entrusted R&D, the applicant shall have quality management measures for related activities.

4.5.12.1 (Evaluation of the Consignee's Capability) The applicant shall specify the scope and extent of product R&D activities entrusted. The R&D capability and continuous technical support capability of the entrusted R&D institution shall be required and evaluated accordingly.

4.5.12.2 (Entrusted R&D Agreement) The applicant shall sign an entrusted R&D agreement with the entrusted R&D institution, which clearly stipulates the responsibilities of each party, R&D content and related technical matters. The applicant shall be responsible for the process and results of the commissioned R&D, and shall have measures to ensure the reliability of the commissioned R&D process data. The entrusted R&D institution shall comply with the requirements of the agreement and ensure that the R&D process is standardized and the data is true, accurate, complete and traceable.

4.5.12.3 (Entrusted R&D technical documents) The applicant shall ensure that the entrusted R&D institution hand over the design and development output documents in accordance with the requirements of the agreement and meet the design and development input requirements.

4.6 Procurement

4.6.1 (Procurement system) The applicant shall establish procurement control procedures to ensure that the purchased items meet the specified requirements.

4.6.2 (Source of raw materials) Raw materials required for registered inspection products and clinical trial products, including packaging materials, software, etc. in direct contact with the products, shall have legal source certificates, such as supply agreement, order, invoice, warehousing note, delivery note, copies of approval supporting documents, etc.

4.6.3 (Procurement of main materials) The purchase time or supply time of main raw materials should correspond to the production time of the product, the purchase quantity should meet the production demand of the product, and there should be an inspection report or certificate of conformity.

4.6.4 (Procurement records) The procurement records of main raw materials shall comply with the product design requirements and the provisions of the procurement agreement, and the records shall be true, accurate, complete and traceable.

4.6.5 (In vitro diagnostic reagent purchase record) The purchase of raw materials for in vitro diagnostic reagents shall have a purchase contract or purchase record. The procurement of quality control products, calibrators and enterprise reference materials shall meet the traceability requirements. For samples involving human sources, there shall be inspection methods, inspection processes, inspection data, inspection records of corresponding raw materials, as well as evidentiary materials indicating biological safety.

4.6.6 (Requirements for key materials of in vitro diagnostic reagents) After the design of in vitro diagnostic reagents is finalized, the key raw materials such as antigen (source, amino acid sequence, conformation, etc.), antibody (source, cell line, etc.), primer probe sequence, etc. shall not change.

4.7 Production

4.7.1 (Requirements for development and production) The applicant shall organize the production of registered inspection products and clinical trial products in accordance with the requirements of the Medical Device Production Quality Management Specification.

4.7.2 (Production process documents) The applicant shall prepare production process procedures, operation instructions and other documents, and define key processes and special processes. For medical devices of animal origin, the process of inactivating and removing viruses and/or infectious factors and the method and/or process of reducing the immunogenicity of animal derived materials shall be confirmed.

4.7.3 (Production and record requirements) The production of registered inspection products and clinical trial products shall be organized according to the production process procedures, and the production records shall be filled in truthfully. Production records shall be true, accurate, complete and traceable.

4.7.4 (Production requirements for in vitro diagnostic reagents) The production of in vitro diagnostic reagents shall ensure that the preparation concentration, production process and quality control process of different working solutions meet the requirements of design output, especially the concentration and activity of bioactive materials shall be stable and conform to relevant standards. The material balance of raw materials shall meet the requirements.

4.8 Quality control

4.8.1 (Basic requirements) The applicant shall establish quality control procedures, specify requirements for product inspection departments, personnel, operations, etc., and specify requirements for the use and calibration of inspection instruments and equipment, as well as procedures for product release.

4.8.2 (Self inspection) If the applicant carries out self inspection, he/she shall incorporate the quality management requirements related to self inspection into the enterprise's quality management system documents (including quality manual, procedures, operation instructions, etc.) in accordance with the requirements of relevant inspection work and self inspection of declared products, and ensure their effective implementation and control.

4.8.3 (Inspection equipment) The applicant shall establish and keep the archives, operating procedures, measurement/calibration certificates, use and maintenance records of inspection equipment and environmental facilities.

4.8.4 (Inspection procedures) Based on scientific and risk management principles, the incoming inspection procedures for raw materials, inspection procedures for semi-finished products and finished products, etc. shall be formulated and the basis for formulation shall be clarified.

4.8.5 (Inspection records) Inspection reports and records of registered inspection, clinical trials and other related products shall be kept, including: original records of incoming inspection, process inspection and finished product inspection, inspection reports or certificates, and inspection method confirmation or verification records. If some items are entrusted for inspection, relevant item inspection reports and entrusted inspection agreements shall be provided.

4.8.6 (Release procedure) The product release procedure shall be established and implemented, and the product release conditions, review and approval requirements shall be specified.

4.8.7 (Traceability of in vitro diagnostic reagents) The traceability process of in vitro diagnostic reagents should be reasonable, and the assignment process and method of each batch of products should be consistent.

4.8.8 (Sample Retention) The applicant shall retain a certain number of registered inspection products and clinical trial products in combination with product characteristics. The quantity, specification and model of products produced or retained shall meet the needs of product inspection and clinical evaluation (including clinical trials). The whereabouts of the reserved samples shall be traceable.

4.9 Entrusted production

4.9.1 (General requirements) In case of entrustment in the production process, the applicant shall specify the departments and personnel responsible for guiding and supervising the quality management system of the entrusted production enterprise. In principle, the management representative shall be designated to be responsible for the quality management of entrusted production.

4.9.2 (Personnel) The applicant shall be equipped with full-time quality management personnel, who shall be familiar with the key quality control and key production operation requirements of the product, and be able to evaluate, review and supervise the quality management system of the applicant and the entrusted production enterprise. The production principal, quality principal, production release reviewer and other key personnel of the entrusted production enterprise shall be familiar with the key quality control and key production operation requirements of the entrusted production products.

4.9.3 (Entrustment Agreement) The applicant shall sign an entrustment agreement with the entrusted party to clarify the rights, obligations and responsibilities of both parties. The agreement shall at least include the production conditions of the entrusted production enterprise, the transfer of technical documents, the control of material procurement, the control of production process and process, the inspection of finished products, the control of product release, the control of documents and records, the control of changes, and the audit of the quality management system, so as to ensure that the entrusted production enterprise complies with laws and regulations Medical device production quality management specifications, mandatory standards, and product technical requirements organize production.

4.9.4 (On site audit) Before entrusted production, the applicant shall carry out on-site evaluation and audit on the quality management system of the entrusted production enterprise. The audit content shall at least include the organization and personnel, plant and facilities, equipment, production management, quality control capabilities, etc., to ensure that the entrusted production enterprise has a quality management system compatible with the entrusted production products.

4.9.5 (Design conversion) The applicant shall jointly plan and complete the design conversion activities with the entrusted production enterprise to ensure that the product technical requirements, production process, raw material requirements, instructions, labels and other product technical documents can be effectively transferred to the entrusted production enterprise.

4.9.6 (Transformation of technical documents and process validation) The entrusted production enterprise shall, in combination with its own production conditions and quality management system, convert the applicant's product technical documents into its own technical documents to ensure that the key technical parameters and operation methods required by the product technology are consistent with those handed over by the applicant. Trial production and process validation shall be carried out. Trial production shall include all transferred production processes and quality control processes.

4.9.7 (Risk control of technology transformation) The applicant shall, in combination with the original production process documents, compare and evaluate the production process documents implemented by the entrusted production enterprises to ensure that the risks arising from changes in the quality management system such as production conditions have been fully identified and controlled. The applicant shall participate in the verification and confirmation work related to the entrusted production products carried out by the entrusted production enterprise, and review the relevant process documents and reports.

4.9.8 (Production of registered inspection products and clinical trial products) Where the applicant carries out the production of registered inspection products and clinical trial products in the entrusted production enterprise, it shall ensure that the entrusted production enterprise has plants, facilities and equipment suitable for product production. The applicant shall ensure the completion of process validation or confirmation and other related work.

4.9.9 (Material procurement) The applicant shall specify the procurement method, procurement approach, quality standards and inspection requirements of the entrusted production products and materials, and implement the procurement in accordance with the requirements of the medical device entrusted production quality agreement. When necessary, the applicant and the entrusted production enterprise jointly screen, review, sign quality agreements, and periodically re evaluate the material suppliers.

4.9.10 (Production process management) The applicant shall, together with the entrusted production enterprise, specify the monitoring methods and standards for the product process flow, process parameters, outsourcing processing (such as irradiation sterilization, ethylene oxide sterilization, anodizing, spraying process, etc.), material flow, batch number and identification management, traceability of production records and other production processes, designate authorized monitoring personnel, and keep monitoring records.

4.9.11 (Document management) The documents jointly held by the applicant and the entrusted production enterprise shall at least include: the entrustment agreement, product technical requirements, raw material requirements, production process and inspection procedures, product instructions and labels, and product release procedures implemented by the entrusted production enterprise.

4.9.12 (Product release) The applicant shall establish product release review and approval procedures, and ensure that both parties release registered inspection products, clinical trial products and marketed products according to their respective responsibilities. The entrusted production enterprise shall formulate production release review procedures, ensure that the entrusted products meet the acceptance standards of the applicant, and keep release records. All records related to product production shall be true, accurate, complete and traceable.

4.9.13 (Regular review) The applicant shall regularly review the entrusted production management and relevant records of the entrusted production enterprise, and keep the review records. The entrusted production enterprise shall keep all the production records related to the entrusted production, and may provide them to the applicant at any time for future reference. If the entrusted production enterprise has the same product in production, it shall adopt the management method of serial number, batch number and process identification that are significantly different from the entrusted production product to avoid confusion.

4.9.14 (Communication mechanism) The applicant shall establish an effective communication mechanism with the entrusted production enterprise. Any design change, procurement change, etc. shall be timely notified to the entrusted production enterprise and supervised for implementation. The applicant shall have measures to ensure that the entrusted production enterprise can timely inform the applicant and conduct joint evaluation of any change in the quality management system of the entrusted production enterprise that may affect the product quality.

4.9.15 (Responsibility of the applicant) The applicant shall trace and monitor the whole process of design and development, production, storage and transportation, and adverse event monitoring, maintain the continuous improvement of the quality management system, and implement the supervision of the entrusted production enterprise.

4.10 Product authenticity

4.10.1 (Registered inspection products) Registered inspection products, including inspection product batch number (number/serial number, etc.), specification and model, inspection time, inspection quantity, inspection basis, inspection conclusion, key raw materials and/or components and other information, calibration substances and/or quality control substances, photos of inspection products (including photos of independent software release version information), labels and other information, shall be consistent with production records and traceable.

4.10.2 (Clinical trial products) Clinical trial products, including the batch number (number/serial number, etc.) and specifications and models of clinical trial products, shall be consistent with the production records and traceable.

4.10.3 (Requirements for traceability of development and production) The product batch and production batch number or product number, specification and model/packaging specification, quantity of each batch, batch number and quantity of registered inspection products and clinical trial products, batch number and quantity of reserved samples, production batch number or product number and quantity of existing products, batch number and quantity of main raw materials, etc. shall be traceable.

4.10.4 (Purchasing records) The purchasing records of raw materials used for product production shall be kept, which shall at least include the name, model and specification, batch number, material (brand), supplier (manufacturer), quality standards and incoming acceptance, purchasing vouchers, warehousing and outgoing records and accounts of raw materials. The relevant information of the purchase record shall be consistent with the corresponding content of the production record and the registered inspection report.

4.10.5 (Production and inspection records) Production records, original records of process inspection, original records of finished product inspection, etc. shall meet the requirements of design output documents.

4.10.6 (Reserved samples) If it is necessary to retain samples, the products with reserved samples shall be retained, and the product account and observation records of reserved samples shall be retained.

Five、Judgment principle of on-site inspection results

5.1 There are 73 verification items in this Guide, including 32 key items marked with "*" and 41 general items (see the attached table). The on-site inspection team shall make the judgment results of "conforming", "nonconforming" or "inapplicable" one by one against all inspection items. For the inspection items judged as "non conformance", the inspector shall record the specific problems in detail.

5.2 Judgment principle of on-site inspection results

The on-site inspection conclusion can be divided into four situations: "passed the inspection", "failed to pass the inspection", "passed the inspection after rectification", and "failed to pass the inspection after rectification".

5.2.1 If the applicant is not found to have any nonconforming items in the on-site inspection, it is recommended that the conclusion be "passed the inspection".

5.2.2 If one of the following situations is found in the on-site inspection, it is recommended that the conclusion be "failed to pass the inspection". (1) On site inspection found that the applicant had authenticity problems; (2) No authenticity problem is found in the on-site inspection, but it is found that the applicant has more than 3 (including) key items or more than 10 (including) general items that do not meet the requirements.

5.2.3 If no authenticity problem is found in the on-site inspection, and the applicant is found to have less than 3 key items (excluding) and less than 10 general items (excluding) that do not meet the requirements, it is recommended that the conclusion be "review after rectification". The applicant whose verification conclusion is "review after rectification" shall complete the rectification within 6 months after the completion of registration verification and submit the rectification report to the original verification department at one time, and the verification department may conduct on-site review if necessary. If the rectification of all projects meets the requirements, it is recommended that the conclusion be "verified after rectification".

5.2.4 If the rectification report is not submitted within the specified time limit or there are still nonconformities in the recheck, it is recommended that the conclusion be "failed to pass the inspection after rectification".