Guidelines for verification of medical device registration quality management system

Revised exposure draft

1.Purpose and basis

To strengthen the verification management of medical device registration quality management system,Ensure the quality of inspection work,according to Regulations on the supervision and administration of medical devices  Administrative measures for registration and filing of medical devices  Administrative measures for registration and filing of in vitro diagnostic reagents  Measures for the supervision and administration of medical device production  Medical device production quality management specification  Code for quality management of clinical trials of medical devices  Regulations on self inspection management of medical device registration etc.,Develop this guide.

2.Scope of application

This guideline is applicable to the second category of medical device On site verification of registration quality management system for class III medical devices.

3.Basic Requirements

3.1 quality management system  The applicant for registration shall Medical device production quality management specification And appendix requirements,Based on scientific knowledge Experience and quality risk management principles,Establish a quality management system suitable for the product realization process,Including entrusted production if there be  clinical evaluation  Including clinical trials Etc,To ensure its effective operation in the whole life cycle management process of medical devices,Guarantee design and development Production and other process data are true complete Traceability,And consistent with the registration and declaration materials.

3.2 Registration verification requirements It shall organize the verification of the registration quality management system in combination with the registration application materials,Focus on product development Design and development related to production purchase Production management Quality control, etc.The verification of product authenticity shall be comprehensive objective.

3.3 Self inspection and verification requirements To submit self inspection report,Should be in accordance with Regulations on self inspection management of medical device registration ,Combined with the submitted product technical requirements,Confirm the quality control system and capability of the registration applicant item by item.

3.4 Extended inspection requirements Development of existing design Registration applicant who entrusts other enterprises with product production and other activities,The scope of verification shall cover the entrusted R & D or entrusted production enterprises.If necessary,Extended inspection shall be conducted for other units that provide products or services for the development of medical devices.

4.Key verification contents

 4.1Quality management system principles

  4.1.1 quality management system  The applicant shall combine the characteristics of the product,Establishment covers design development production Quality management system suitable for product realization process such as quality control and release audit,And shall include entrusted production if there be  clinical evaluation  Including clinical trials etc..

  4.1.2 risk management  The applicant shall establish a quality risk management system,Evaluate the quality risk of product realization process according to scientific knowledge and experience,To ensure product quality.

  4.1.3 Self test Applicant's self inspection,The self inspection shall be incorporated into the product quality management system and meet the requirements.

 4.2Organization and personnel

  4.2.1 Organization The applicant shall establish a relationship with the design and development of medical devices Management organization suitable for production,Define the responsibilities of each department,Ensure that design and development knowledge and technology transformation are reasonable and traceable.

  4.2.2 personnel The applicant shall provide an appropriate number of R & D personnel with corresponding qualifications Production and quality control personnel,The personnel shall have the professional knowledge and work skills appropriate to the products applied for registration.

  4.2.3 Key personnel Management representative Production leader Quality Director Key personnel such as product release audit shall be familiar with the key quality control of the product Key production operation requirements.

  4.2.4 Self inspection personnel Applicant submits self inspection report,The quality inspection department shall be equipped with a sufficient number of full-time inspectors.Educational background of inspectors The technical capability shall match the product inspection work.Inspector Reviewer The approval personnel shall be authorized by the applicant in accordance with the provisions.

 4.3workshop Facilities and equipment

  4.3.1 Plant facilities The applicant shall be equipped with plants and facilities suitable for the production of the declared registered products.Product design and development shall be carried out in appropriate plants and facilities.Plant and facilities for development and production of inspection and clinical trial products,It shall meet the quality control requirements for R & D and developed products.

  4.3.2 Production equipment The applicant shall be equipped with production equipment and technological equipment suitable for the production of the declared registered products.Equipment and equipment for the development of registered inspection and clinical trial products,It shall meet the requirements of product quality and development scale.

  4.3.3 Inspection equipment The applicant shall be equipped with instruments, equipment and environmental facilities that meet the requirements of inspection methods.Laboratory for special professional inspection,Its environmental facilities shall meet its specific professional requirements.

  4.3.4 Production of registered inspection and clinical trial products The plant facilities and equipment used for registration inspection and clinical trial product development and relevant use records shall be kept.In case of force majeure,Product development Sample production and verification records shall be complete Authenticity and traceability.

4.4file management

4.4.1 System documents The applicant shall establish the quality management system documents corresponding to the products applied for registration,Including quality manual Procedure documents Technical documents and data records, etc.Technical documents shall include product technical requirements and relevant standards Production process specification Operation instruction Inspection and test procedures and other relevant documents.data Records shall ensure product design and development Material purchase production Quality Control Traceability of product release and other activities.

4.4.2 Original R & D records The original data of design and development shall be included in document management.Except for test data directly output,Auxiliary records during design and development shall also be kept,For example, major material collection records Instrument and equipment use record Weighing record Preparation records, etc,Ensure traceability of design and development process.To conduct clinical trials,The test instruments related to the clinical trial process shall be retained reagent Delivery record Storage and transportation records Recycling and disposal records, etc.

4.4.3 Validation data The applicant shall retain the research materials and data verified after product design and development or technology transfer,Including but not limited to relevant reviews of non clinical studies and clinical studies Scheme and report, etc,And shall ensure the authenticity of the data accuracy Complete and traceable.

4.4.4 Clinical trial document management The applicant shall establish a basic document management system for clinical trials,Press medical apparatus and instruments/Contents of basic documents to be kept for clinical trials of in vitro diagnostic reagents It is required to keep relevant clinical trial documents and ensure their authenticity accuracy Complete and traceable.

4.5Design development

4.5.1 Design and development documents The design and development documents of medical devices shall be derived from the design and development planning input output Design conversion activities verification Relevant documents confirmed,Including records established during design and development,The traceability of the final output process of previous design and development and its related activities shall be ensured.

4.5.2 Design and development input Design and development input shall generally include laws and regulations national standard Industry standard Domestic and foreign guide documents Standard or reference material information Application of in vitro diagnostic reagents  Technical indicators of previous generation or similar products Product risks, etc,At the same time, the input should include a clear scope of application.

4.5.3 Design and development output The design and development output shall meet the input requirements,And meet the needs of users and product design,Attention should be paid to the scope of application of the product Functionality Security Effectiveness Quality controllability.

4.5.3.1 Passive medical devices The components of raw materials of passive medical devices shall meet the requirements of relevant standards,And complete the biocompatibility study.Reusable sterile products during repeated sterilization,The raw material performance shall be evaluated and the study on tolerable repeated sterilization shall be completed.

4.5.3.2 Active medical devices Active medical devices shall be identified Implement mandatory national standards for medical electrical equipment Industry standards and other requirements,And complete the protection against electric shock hazard Mechanical hazard protection Radiation hazard protection Overtemperature hazard protection electromagnetic compatibility  Biocompatibility, etc.

4.5.3.3 Animal origin Allogeneic medical devices Medical devices of animal origin shall complete the species of animals If the risk is related to the strain, the strain shall be defined  Geographical origin For species whose geographical origin cannot be determined,Provide identification and traceability requirements during the survival of source animals  Age Applicable when related to risk,For example, animals' susceptibility to naturally occurring transmissible spongiform encephalopathy  Sampling site and type of tissue Health status of animals and tissues Risk assessment and related research on the applicability of virus inactivation methods.

4.5.3.4 In vitro diagnostic reagent Main raw materials involved in the study of in vitro diagnostic reagents intermediate The source of important auxiliary materials shall be clear and meet the requirements,Equipment used during the study Instruments and reagents shall meet the research requirements,Ensure reliable and traceable data.

4.5.4 Validation The applicant shall determine the confirmation or verification work to be carried out,To prove that the key elements of relevant operations can be effectively controlled.The scope and extent of confirmation or verification shall be determined through risk assessment.

4.5.5 Design transformation verification The applicant shall keep all records of product design conversion activities,To show that the design and development output has been fully verified and suitable for routine production before becoming the final product specification,And ensure that the production process uses the determined raw materials and equipment,Continuously and stably produce products that meet the expected use and product technical requirements.as Validation and validation of sterilization process and related equipment and facilities for sterile products Realization confirmation evaluation of basic safety and basic performance of active medical devices In vitro diagnostic reagent production process Process parameters and batch amplification verification.

4.5.6 packing term of validity Reuse The applicant shall inspect the product packaging Carry out research and keep relevant records on validity period or repeated use times, etc,as Product packaging design and packaging integrity verification Stability study data Design records of product specifications and minimum sales unit labels, etc.

4.5.7 Verification record Detailed original data records of design and development verification activities shall be maintained,Include validation protocol Validation report Verification record Such as test data Sample handling records, etc  Auxiliary records, etc.

4.5.8 Clinical confirmation During design and development validation,If the registered product needs to be confirmed by clinical trial,The applicant shall perform corresponding duties in accordance with the clinical trial plan and the contract,And keep relevant documents and records.

4.5.9 Requirements for clinical trial products Products for clinical trials,Before clinical trial start,The applicant shall ensure that the product design is finalized and the product inspection has been completed,Its security Functional for clinical trials,Keep records of relevant assessment and validation processes.

4.5.10 Clinical trial product management The applicant shall track and manage the prototype for the test in the whole process/Distribution of products storage and transportation recovery/Return, etc,And keep relevant records.

4.5.11 Design and development changes Design and development changes including product changes Reference file update Changes to design transformations Such as equipment Raw material supplier workmanship Environment, etc  Change request from outside test Animal experiment Clinical trials Technical review change comments  Changes caused by changes in mandatory medical device standards, etc,Should be subject to risk assessment Verification or confirmation,Ensure changes are controlled.

4.5.12 Entrusted R & D management On the existence of entrusted R & D Development case,The applicant shall have quality management measures for relevant activities.

4.5.12.1 (Assessment of the Capabilities of the Agent) The applicant shall clarify the scope and extent of the r&d activities entrusted by the product R&D activities, as well as the requirements on the R&D capability and continuous technical support capability of the entrusted R&D institution, and evaluate the R&D capability and continuous technical support capability of the entrusted R&D institution to ensure that it meets the requirements.

4.5.12.2 (Research and development of entrust agreement) research and development institutions entrusted development agreement with the applicant shall, specify the responsibility, the research content and the related technical matters, the applicant shall be responsible for the process and result of commissioned research and development, and to ensure that entrusts the data reliability in the process of research and development, research and development institutions shall abide by the agreement calls for a trustee, Ensure that the r&d process is standardized and the data is true, accurate and traceable.

4.5.12.3 (Entrusted R&D Technical Documents) The applicant shall ensure that the entrusted R&D institution shall hand over the design and development output documents in accordance with the requirements of the agreement, and shall be able to judge whether the entrusted R&D output meets the requirements of the design and development input.

4.6 Purchasing

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

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

4.6.3 (Procurement of Key Materials) The purchase time or delivery time of the main raw materials shall correspond to the trial production time of the products, the purchased quantity shall meet the requirements of the trial production of the products, and there shall be inspection report or qualification certificate.

4.6.4 (Purchase Records) The purchase control records of key parts and components and raw materials expected to contact with human body shall meet the product design requirements and be traceable.

4.6.5 (Procurement Records of in Vitro Diagnostic Reagents) In the procurement of raw materials for quality control products, calibration products and enterprise reference products involving human samples, emphasis should be placed on the inspection methods, inspection processes, inspection data and inspection records of the corresponding raw materials, as well as the inspection records of biological safety. Purchase contracts or purchase records shall be kept for other raw materials.

4.6.6 (Requirements for Key Materials of In Vitro Diagnostic Reagents) During the design and development of in vitro diagnostic reagents, the key raw materials themselves such as antigen (source, amino acid sequence, conformation, etc.), antibody (source, cell line, etc.) and primer probe sequence should not change.

4.7 The production

4.7.1 (Requirements for Development and Production) The applicant shall organize the development and production of registered test products and clinical trial products in accordance with the requirements of the Quality Management Standard for The Production of Medical Devices.

4.7.2 (Production process documents) Production process rules and operation instructions shall be prepared, including production process rules for registered inspection, clinical trials and other products, and key processes and special processes shall be defined. For medical devices of animal origin, methods and/or processes for inactivation and removal of viruses and/or infectious agents and for reducing the immunogenicity of animal derived materials should be identified.

4.7.3 (Production and Record Requirements) Production of registered inspection products and clinical test products shall be organized in accordance with the production process rules, and batch production records shall be truthfully filled in. Batch production records shall be accurate, complete and traceable.

Registration with the batch number (number/serial number, etc.) and specifications, inspection time, basis, test conclusion, the key raw material, and/or parts information such as the standard to control the quality and/or samples, (in vitro diagnostic reagents for), and other information, and attach product pictures, information such as label, should be consistent with the production batch records are traceable.

Batch numbers (serial numbers, etc.) and specifications of clinical trial products shall be consistent with and traceable to manufacturing batch records.

4.7.4 (Production requirements for In vitro Diagnostic Reagents) For in vitro diagnostic reagents, it shall ensure that the preparation concentration, production process and process quality control of different working fluids meet the design output requirements, especially the concentration and activity of bioactive materials shall be stable and meet 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, stipulate the requirements of product inspection department, personnel and operation, as well as the use and calibration of inspection instruments and equipment.

4.8.2 (Self-inspection) When conducting self-inspection, the applicant shall, in accordance with the requirements of relevant inspection work and self-inspection of declared products, incorporate the quality management requirements related to the self-inspection work into the documents of the quality management system of the enterprise (including quality manual, procedure, operation instruction, etc.), and ensure the 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) The inspection procedures for incoming raw materials, semi-finished products and finished products shall be formulated based on the principles of science and risk control and shall provide the basis.

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 confirmation or verification records of test methods. If some items are entrusted with inspection, relevant project inspection report and inspection agreement shall be provided.

4.8.6 (Release Procedure) Product release procedures shall be established and implemented, and product release conditions, review and approval requirements shall be clarified.

4.8.7 (Traceability of in vitro diagnostic Reagents) The traceability process of in vitro diagnostic reagents shall be reasonable, and the value assignment process and experimental data of each batch of products shall be consistent.

4.8.8 (Retention Samples) The applicant shall retain a certain number of registered inspection products and clinical trial products based on the characteristics of the products. The quantity, specifications and models of the products to be developed or retained shall meet the needs of product inspection, product inspection and clinical evaluation (including clinical trials) for commissioned production, and the whereabouts of the products shall be traceable.

4.9 Commissioned Production

4.9.1 (General Requirements) In the case of entrustment in the process of product development and production, the applicant shall specify the departments and personnel responsible for guiding and supervising the quality management system of the entrusted manufacturer. In principle, the management representative shall be appointed to take charge of the quality control of commissioned 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 products and be able to evaluate, review and supervise the quality management system of the registrant and the entrusted manufacturer. The management representative, the responsible person of production, the responsible person of quality, the audit person of production release 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 products.

4.9.3 (Agency Agreement) The applicant shall sign an agreement with the entrusted party, clear, rights, obligations and responsibilities between the trustees shall at least include production enterprise production conditions, the transfer of technical documents, material procurement control, production process and process control, finished product inspection, product release control, file and record control, change control, quality management system audit, etc., Ensure that the entrusted manufacturer organizes production in accordance with laws and regulations, medical device production quality management standards, mandatory standards and product technical requirements.

4.9.4 (On-site audit) Before commissioned production, the applicant shall carry out on-site assessment and examination of the quality management system of the commissioned production enterprise, which shall at least include the organization and personnel, plant and facilities, equipment, production management and quality control ability, etc., to ensure that the commissioned production enterprise has a quality management system suitable for the commissioned products.

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

4.9.6 (Transformation of Technical Documents and Process Verification) The entrusted manufacturer shall, in combination with its own production conditions and quality management system, convert the product technical documents of the applicant into its own technical documents and ensure that the key technical parameters and operation methods of product technical requirements are consistent with those handed over by the applicant. Pilot production and process validation shall be carried out and pilot production shall include all transferred production processes and quality control processes.

4.9.7 (Risk Control of Technology Transformation) The applicant shall compare and evaluate the production process documents executed by the entrusted manufacturer in combination with the original production process documents to ensure that the risks caused by changes in the quality management system such as production conditions have been identified and controlled. The applicant shall participate in the confirmation and verification work related to the entrusted products carried out by the entrusted manufacturer, and examine the verification and confirmation process documents and verification reports.

4.9.8 (Production of Registered Test Products and Clinical test Products) Where the applicant conducts the production of registered test products and clinical test products in the entrusted manufacturer, it shall have sites, facilities and equipment suitable for the production of the products. The applicant shall ensure that the process verification or confirmation and other relevant work have been completed before production.

4.9.9 (Material Procurement) The applicant shall specify the procurement method, procurement channels, quality standards and inspection requirements of the materials for the commissioned production, and carry out the procurement in accordance with the requirements of the quality agreement for the commissioned production of medical devices. If necessary, the applicant and the entrusted manufacturer will screen and review the material suppliers, sign quality agreement and regularly review.

4.9.10 (Production Process Management) The applicant shall, together with the entrusted manufacturer, provide detailed information on the product technological process, technological parameters and outsourced processing process (such as: (radiation sterilization, ethylene oxide sterilization, anodic oxidation, spraying process, etc.), material flow, batch number and label management, production record traceability and other production processes to clarify monitoring methods and standards, designate authorized monitoring personnel, and keep monitoring records.

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

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

4.9.13 (Regular Audit) The applicant shall regularly review the management of the entrusted production and relevant records of the entrusted production enterprise, and keep audit records. The entrusted production enterprise shall keep all production records related to the entrusted production and provide them to the registrant at any time for future reference. If the entrusted manufacturer has the same product in production, the serial number, batch number and label management system shall be significantly different from the entrusted product to avoid confusion.

4.9.14 (Communication Mechanism) The applicant shall establish an effective communication mechanism with the entrusted manufacturer, and timely notify the entrusted manufacturer of any design change or purchase change and supervise its implementation. The applicant shall take measures to ensure that the entrusted manufacturer timely informs the applicant and carries out joint evaluation of any change in the quality management system of the entrusted manufacturer that may affect product quality.

4.9.15 (Applicant's Responsibility) The applicant shall trace and monitor the whole process of R&D, production, storage, transportation and adverse event monitoring, maintain the continuous improvement of the quality management system, and implement the supervision of the entrusted manufacturer.

4.10 Authenticity of products

4.10.1 (Registered test with the product) registered products for testing, including inspection batch number (number/serial number, etc.) and specifications, inspection time, inspection basis, conclusion, key information such as raw material and/or components, calibration substance and/or quality control and inspection product photos, including pictures of independent software release information, label and other information, Should be consistent with and traceable to production batch records.

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

4.10.3 (The development and production traceability requirements) and the development and production of the product batch production batch number or product number, specifications/packaging specification, each batch number, product batch number and registered products for testing and clinical trial quantity, sample product batch number and quantity, the existing production batch number or product number and quantity, main raw material batch number and quantity, etc. Shall be traceable.

4.10.4 (Purchasing Records) The purchasing records of raw materials used in the production of products shall be kept, including at least the name of raw materials, model specifications, batch number, material (brand number), supplier (manufacturer), quality standards and purchase acceptance, purchasing vouchers, in-out and in-out records and standing accounts, etc. The relevant information of the purchase record shall be consistent with the contents contained in the registered inspection report.4.10.5 (Production and Inspection Records) Production records, original process inspection records and original factory inspection records shall meet the requirements of design output files.

4.10.6 (Sample Retention) If sample retention is required, sample retention products shall be kept, and product ledger and sample retention observation records shall be kept.

5. Determination principle of on-site verification results

5.1 There are 73 items to be checked in this Guide, including 32 key items marked with "*" and 41 general items (see attached table). The on-site inspection team shall, in comparison with all the verification items, draw verification conclusions of "conformity", "non-conformity" or "inapplicability" of the items one by one. For the inspection items judged as "non-conformance", inspectors shall record the specific problems in detail.

5.2 Principles for determination of on-site verification results

The on-site verification conclusion can be divided into four scenarios: "passed verification", "failed verification", "passed verification after rectification" and "failed verification after rectification".

5.2.1 If the applicant is not found to be inconsistent with the project in the on-site inspection, the suggested conclusion is "passed the inspection".

5.2.2 If one of the following circumstances is found in on-site inspection, the recommended conclusion is "failed inspection". (1) The applicant is found to have authenticity problems through on-site inspection; (2) No authenticity problem is found in the on-site inspection, but the applicant is found to have more than 3 key items (10% of the total number of items marked "*") or more than 10 general items (10%) 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, the suggested conclusion is "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 examination department in a one-time manner. The examination department may arrange on-site review when necessary. If all items meet the requirements, the suggested conclusion is "verification after rectification".

5.2.4 If the rectification report fails to be submitted within the specified time limit or there are still unqualified items in the review, the suggested conclusion shall be "the rectification has not passed the verification".

The contents of the Schedule are as follows: