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To do a good job of quality management system verification under the medical device registrant system，Improve the quality of medical device registration quality management system verification，According to the Regulations on the Supervision and Administration of Medical Devices (Decree No. 739 of The State Council) and the Measures for the Administration of Registration and Filing of Medical Devices (Decree No. 47 of the General Administration of Market Supervision), the Measures for the Administration of Registration and filing of in vitro diagnostic reagents (Decree No. 48 of the General Administration of Market Supervision), the Measures for the Supervision and Administration of Medical Device Production (Decree No. 53 of the General Administration of Market Supervision) and other requirements，The State Drug Administration has revised the Guidelines for the Verification of the Quality Management System for Medical Device Registration (see Annex).，Hereby published，Effective from the date of promulgation。The Notice of the State Drug Administration on Issuing the Verification Guidelines for the Quality Management System of Medical Device Registration (No. 19, 2020) shall be repealed at the same time。
Hereby inform。
Attachment: Verification Guide for medical device Registration Quality management system
附件
Medical device registration quality management system verification guide
I. Purpose and basis
To strengthen the medical device registration quality management system verification management，Ensure the quality of inspection work，According to the Regulations on the Supervision and Administration of Medical Devices, the Measures for the Registration and filing of Medical Devices, the Measures for the registration and filing of in vitro diagnostic reagents, the Measures for the supervision and Administration of Medical Device Production, the Standards for the quality Management of Medical Device Production, the Standards for the quality management of Medical device Clinical Trials, and the regulations for the management of medical device Registration and self-examination》Etc., develop this guide。
2. Scope of application
This guide applies to the on-site verification of the registered quality management system of Class II and Class III medical devices carried out by the medical device regulatory authorities。
3. Basic requirements
3.1(Quality Management System)The registration applicant (referred to as the applicant) shall comply with the requirements of the Medical Device Manufacturing Quality Management Practice and the appendix，Based on scientific knowledge, experience and risk management principles，Establish a quality management system that is compatible with the product realization process，Including commissioned production (if any), clinical evaluation (including clinical trials) and other links，To ensure its effective operation during the whole life cycle management of medical devices，Ensure design, development, production and other process data true, accurate, complete and traceable，And consistent with the registration information。
3.2(Registration verification requirements)The registration quality management system verification shall be organized in combination with the registration and application data, focusing on the design and development, procurement, production management, quality control and other contents related to product development and production。Product authenticity verification shall be comprehensive and objective。
3.3(Self-inspection and verification requirements)Submit againstThe self-inspection report shall be in accordance with the"Medical device registration self-test management provisionsIn combination with the submitted product technical requirements, the applicant's quality management system and ability are verified item by item。
3.4(Commissioned activity inspection, extended inspection requirements)For applicants who entrust other enterprises with design, development, product production and other activities, the scope of verification shall cover entrusted research and development and entrusted production activities。When necessary, extended inspection shall be carried out on other units that provide products or services for the research and development or production of medical devices。
4. Focus on the content of verification
4.1Principles of quality management system
4.1.1(Quality Management System)The applicant shall, in combination with the characteristics of the product, establish a quality management system covering design and development, production, quality control and release audit that is compatible with the product realization process, and shall include commissioned production (if any), clinical evaluation (including clinical trials), etc。
4.1.2(Risk Management)The applicant shall establish a risk management system to assess the quality risks of the product realization process based on scientific knowledge and experience to ensure product quality。
4.1.3（自检）Where the applicant carries out self-inspection, the self-inspection work 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 management organization suitable for the research and development and production of medical devices, clarify the responsibilities of each department, and ensure that the design and development and technology conversion are reasonable and traceable。
4.2.2（人员）The applicant shall be equipped with an appropriate number and corresponding R & D, production and quality control personnel, personnel should have the professional knowledge and work skills suitable for the application of registered products。
4.2.3(Key personnel)Management representative, production person in charge, quality person in charge, technical person in charge, product release audit person and other key personnel should be familiar withRegistered productThe key quality control, key production operation requirements。
4.2.4(self-testing personnel)Where the applicant submits the self-inspection report, the quality inspection department shall be equipped with a sufficient number of full-time inspection personnel。The educational background and technical ability of the inspectors shall match the product inspection work。Inspectors, examiners, approving personnel, etc. shall be authorized by the applicant in accordance with regulations。
4.3Plant, facilities and equipment
4.3.1(Plant facilities)applicantIt shall be equipped with plants and facilities suitable for the production of registered products。Product design and development should be carried out in suitable plants and facilities。The factories and facilities for the production of inspection products (referred to as registered inspection products) and clinical trial products that apply for registration shall meet the quality control requirements of the products。
4.3.2(Production equipment)applicantIt shall be equipped with production equipment and technological equipment suitable for the production of the declared and registered products。The production equipment and process equipment of registered inspection products and clinical trial products shall meet the requirements of product quality and production scale。
4.3.3(Inspection equipment)applicantEnvironmental facilities and instruments that meet the requirements of product inspection methods shall be equipped。For laboratories that carry out special professional inspections, the environmental facilities shall meet the specific professional requirements。
4.3.4(Registered laboratory and clinical trial product production)Plant facilities and equipment used for the development and production of registered inspection products and clinical trial products and related usage records shall be maintained。If force majeure cannot be retained, shall be retained to prove the product research and development, production, verification and other product realization process activities true, complete and traceable evidence。
4.4File management
4.4.1(System document)The applicant shall establish quality management system documents suitable for the application of registered products, including quality manuals, procedure documents, technical documents and data records。Technical documents shall include product technical requirements and related standards, production process rules, operation instructions, inspection and test operation rules and other relevant documents。Data recording shall ensure traceability of activities such as product design and development, material procurement, production, quality control and product release。
4.4.2(R&D original record)The original materials of design and development shall be included in the file management。In addition to the direct output test data, auxiliary records in the design and development process should be kept, such as records of main materials, instrument and equipment use records, weighing records, preparation records, etc。To carry out clinical trials, records of test instruments (reagents) in the process of clinical trials shall be kept, records of storage and transportation, records of recovery and disposal, etc。
4.4.3(Verification data)The applicant shall retain the research data and records verified after product design and development or technology transfer, and shall ensure that the data is true, accurate, complete and traceable。
4.4.4(Clinical trial document Management)The applicant shall establish a clinical trial basic document management system according to the "Medical devices./The In Vitro Diagnostic Reagents Clinical Trial Basic Documentation Catalogue requires the management of clinical trial documentation and ensuring its authenticity, completeness and traceability。
4.5Design and development
4.5.1(Design and development document)Medical device design and development documents should be derived from design and development planning, input, output, review, verification, confirmation, conversion, change related documents, including records established in the design and development process, should ensure that the final output process of previous design and development and related activities can be traced。
4.5.2(Design and development input)Design and development input should generally include laws and regulations, national standards, industry standards, domestic and foreign guide documents, standard products or reference material information (in vitro diagnostic reagent products), user needs, product scope of application, technical indicators of previous 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 meet the needs of users and product design requirements, and shall pay attention to the scope of product application, functionality, safety, effectiveness, and quality control。
4.5.3.1(Passive medical devices)无The raw material components of the source medical device shall meet the relevant standards and requirements, and the biocompatibility evaluation shall be completed for the part of the product that comes into contact with the human body。When reusable sterile products are repeatedly sterilized, the performance of the finished product should be evaluated and the study of tolerance to repeated sterilization should be completed。
4.5.3.2(Active medical devices)Active medical devices shall complete relevant studies according to the requirements of the standard, such as electric shock hazard protection, mechanical hazard protection, radiation hazard protection, overtemperature hazard protection, electromagnetic compatibility, biocompatibility, etc。
4.5.3.3(Animal origin includes allogeneic medical devices)动Source medical devices shall完成Animal species (strains must be identified if the risk is related to the strain), geographical origin (for species whose geographical origin cannot be determined)，Provide identification and traceability requirements during the life of the source animal), age (where applicable in relation to risk，For example, the susceptibility of animals to naturally occurring transmissible spongiform encephalopathy), the types of sample sites and tissues, the health status of animals and tissues, and the applicability of virus inactivation methods。
4.5.3.4(in vitro diagnostic reagents)The main raw materials, intermediates and important excipients involved in the research process of in vitro diagnostic reagents should be clearly source and meet the requirements, and the equipment, instruments and reagents used in the research process should meet the research requirements。
4.5.4(Verification confirmation)Based on the results of the risk assessment, the applicant shall determine the scope and extent of the work to be verified or validated and ensure that key elements of the operation are effectively controlled。
4.5.5(Design conversion)The applicant shall maintain all records of product design conversion activities，To demonstrate that the design and development outputs have been adequately validated and applicable to routine production before becoming final product specifications，And ensure that the production process in the use of determined raw materials and equipment conditions，Continuously and steadily produce products that meet the intended use and product technical requirements。Such as: sterilization process of aseptic products and related equipment and facilities verification and confirmation, the realization of basic safety and basic performance of active medical devices confirmation evaluation, in vitro diagnostic reagents production process, process parameters and batch scale-up verification。
4.5.6(Packaging, expiration date, reuse)The applicant shall conduct research on product packaging, expiration date or number of re-uses and keep relevant records, such as: product packaging design and verification, stability study data, product specifications and minimum sales unit label design records。
4.5.7(Verification record)Detailed original data records of design and development verification activities should be kept, including verification schemes, verification reports, verification records (such as test data, sample handling records, etc.), and auxiliary records。
4.5.8(Clinical Confirmation Management)In the process of design and development confirmation, if it is necessary to confirm the registered product by clinical trial, the applicant shall perform the corresponding duties in accordance with the clinical trial plan and contract, and keep the relevant documents and records。
4.5.9(Requirements for clinical trial products)For products to be tested in clinical trials, before the start of clinical trials, 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 clinical trials。Records of relevant evaluation and validation processes should be maintained。
4.5.10(Clinical Trial Product Management)The applicant shall maintain the distribution, storage and recovery of clinical trial products/Return record。
4.5.11(Design and development changes) Design and development changes include product changes, citation document updates (such as regulations, mandatory standards), design conversion changes (such as equipment, raw material suppliers, processes, environment, etc.), external change requirements (inspection, animal experiments, clinical trials, technical review changes), changes caused by mandatory medical device standards，It shall be subject to risk assessment, verification or confirmation，Ensure changes are controlled。
4.5.12(Commissioned R & D management)Where there is commissioned research and development, the applicant shall have quality management measures for relevant activities。
4.5.12.1(Agent capability Assessment)The applicant shall specify the scope and extent of product research and development activities entrusted。The R&D capability and continuous technical support capability of the entrusted R&D institution shall be required and evaluated accordingly。
4.5.12.2The applicant shall sign a commissioned research and development agreement with the commissioned research and development institution, which clearly stipulates the responsibilities of each party, research and development content and related technical matters。The applicant shall be responsible for the process and results of the commissioned research and development, and shall have measures to ensure the reliability of the commissioned research and development 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(Commissioned research and development technical documents)The applicant shall ensure that the entrusted R&D institution transfers the design and development output documents in accordance with the agreement requirements and meets the design and development input requirements。
4.6采购
4.6.1(Procurement system)The applicant shall establish procurement control procedures to ensure that the procured goods comply with the specified requirements。
4.6.2(Source of raw materials)The raw materials required for registered inspection products and clinical trial products, including packaging materials and software in direct contact with the products, should have legal source proof, such as supply agreement, order, invoice, warehouse receipt, delivery note, copy of approval documents, etc。
4.6.3(Major Material purchase)The purchase time or supply time of the main raw materials shall correspond to the production time of the product, and the quantity purchased shall meet the production demand of the product, and there shall be an inspection report or qualification certificate。
4.6.4(Purchase record)The procurement records of major raw materials shall conform to the requirements of product design 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 procurement of raw materials for in vitro diagnostic reagents shall have procurement contracts or procurement records。The procurement of quality control products, calibration products and enterprise reference products should meet the traceability requirements, such as samples from human sources, there should be the inspection method, inspection process, inspection data, inspection records of the corresponding raw materials, as well as proof materials indicating biosafety。
4.6.6(In vitro diagnostic reagents key material requirements)After in vitro diagnostic reagents are designed and finalized, the key raw materials themselves, such as antigen (source, amino acid sequence, conformation, etc.), antibody (source, cell line, etc.), primer probe sequence, etc., should not change。
4.7生产
4.7.1(Development and production requirements)The applicant shall organize the production activities of registered inspection products and clinical trial products in accordance with the requirements of the Medical Device Production Quality Management Practice。
4.7.2(Production process documents)The applicant shall prepare production process regulations, operation instructions and other documents, and specify key processes and special processes。On animal-derived medical devices, inactivate and remove viruses and/Or infectious agent processes and methods for reducing the immunogenicity of animal-derived materials/Or process shall be confirmed。
4.7.3(Production and recording requirements)It shall organize the production of registered inspection products and clinical trial products in accordance with the production process regulations, and truthfully fill in the production records。Production records shall be true, accurate, complete and traceable。
4.7.4(In vitro diagnostic reagent production requirements)The production of in vitro diagnostic reagents should ensure that the preparation concentration, production process and quality control process of different working fluids meet the requirements of the design output, especially the concentration and activity of bioactive materials should ensure stability and meet the relevant standards。The material balance of raw materials shall meet the requirements。
4.8Quality control
4.8.1（Basic requirement）The applicant shall establish quality control procedures, specify product inspection departments, personnel, operation and other requirements, and specify the use of inspection instruments and equipment, calibration and other requirements, as well as product release procedures。
4.8.2（自检）Where the applicant carries out self-inspection, it shall incorporate the quality management requirements related to self-inspection into the enterprise quality management system documents (including quality manuals, procedures, operation instructions, etc.) in accordance with the requirements of relevant inspection work and self-inspection of declared products, and ensure its effective implementation and control。
4.8.3(Inspection equipment)applicantFiles, operating procedures and measurements of inspection equipment and environmental facilities shall be established and kept/Calibration certification, service and maintenance records。
4.8.4(inspection procedure)Based on the principles of science and risk management, the incoming inspection procedures for raw materials, semi-finished products and finished products shall be formulated and the basis shall be clearly formulated。
4.8.5(Inspection record)Inspection reports and records of registered inspection, clinical trials and other related products shall be kept, including original records such as incoming inspection, process inspection and finished product inspection, inspection reports or certificates, and inspection method confirmation or verification records。Where there is commissioned inspection of some projects, there should be relevant project inspection reports and commissioned inspection agreements。
4.8.6(Release procedure)Product release procedures shall be established and implemented to clarify product release conditions and requirements for review and approval。
4.8.7(Tracing of in vitro diagnostic reagents)The traceability process of in vitro diagnostic reagents should be reasonable, and the process and method of assigning each batch of products should be consistent。
4.8.8（留样）The applicant shall retain a certain number of registered inspection products and clinical trial products in combination with the characteristics of the products。The quantity and specifications of products produced or samples retained shall meet the needs of product inspection and clinical evaluation (including clinical trials)。The destination of the samples shall be traceable。
4.9Commissioned production
4.9.1(General requirements)Where there is entrustment in the process of producing products, the applicant shall specify the departments and personnel responsible for guiding and supervising the quality management system of the entrusted production enterprise。In principleA management representative shall be appointed to be responsible for the quality control of commissioned production。
4.9.2（人员）The applicant shall be equipped with full-time quality management personnel, who shall be familiar with the key quality control of the product and the key production operation requirements, and be able to evaluate, review and supervise the quality management system of the applicant and the entrusted production enterprise。Entrusted to a production enterpriseKey personnel such as the production person in charge, the quality person in charge, and the production release auditor shall be familiar with the key quality control and key production operation requirements of the entrusted products。
4.9.3(Trust agreement)applicantAn entrustment agreement shall be signed with the agent，Clarify the rights, obligations and responsibilities of both parties，The agreement shall at least include the production conditions of the entrusted manufacturer, the transfer of technical documents, material purchase control, production process and process control, finished product inspection, product release control, document and record control, change control, quality management system audit, etc，Ensure that the entrusted production enterprises organize production in accordance with laws and regulations, medical device production quality management norms, mandatory standards, and product technical requirements。
4.9.4(on-site audit)Before commissioning production, the applicant shall carry out on-site evaluation and audit of the quality management system of the entrusted production enterprise, and 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 suitable for 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 ensureProduct technical requirements, production processes, raw material requirements, instructions and labels and other product technical documents can be effectively transferred to the entrusted production enterprises。
4.9.6(Technical document conversion and process verification)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 technical documents to ensure that the key technical parameters and operation methods of the product technical requirements are consistent with those handed over by the applicant。Trial production and process validation should be carried out, and trial production should include all transferred production processes and quality control processes。
4.9.7(Technology transformation risk control)The applicant shall, in combination with the original production process documents, compare and evaluate the production process documents executed by the entrusted production enterprise to ensure that the risks caused by 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 products carried out by the entrusted production enterprise, and review the relevant process documents and reports。
4.9.8（Registered inspection products and clinical trial product production）Where the applicant carries out the production of registered inspection products and clinical trial products in the commissioned production enterprise, it shall ensure that the commissioned production enterprise has plants, facilities and equipment suitable for the production of the products。The applicant shall ensure the completion of process verification or validation and other related work。
4.9.9(Material Purchase)The applicant shall clarify the procurement method, procurement approach, quality standards and inspection requirements of the commissioned product materials, and implement procurement in accordance with the requirements of the medical device commissioned production quality agreement。When necessary, the applicant and the entrusted production enterprise together to screen, audit, sign quality agreements, regular review of material suppliers。
4.9.10(Production process Management)The applicant shall, together with the entrusted production enterprise, clarify the monitoring methods and standards for product process flow, process parameters, outsourced processing (such as irradiation sterilization, ethylene oxide sterilization, anodizing, spraying process, etc.), material flow, batch number and marking management, production record traceability and other production processes，Specify who authorizes monitoring，And keep monitoring records。
4.9.11(Document Management)The documents jointly held by the applicant and the entrusted manufacturer shall at least include the entrustment agreement, product technical requirements, raw material requirements, production processes and inspection procedures, product specifications and labels, and product release procedures implemented by the entrusted manufacturer。
4.9.12(Product release)applicantProduct release review and approval procedures should be established and ensure that both partiesRelease registered inspection products, clinical trial products and marketed products in accordance with their respective responsibilities。The commissioned production enterprise shall formulate production release audit procedures, shall ensure that the commissioned production products meet the applicant's acceptance standards and keep release records。All records relating to the production of products shall be true, accurate, complete and traceable。
4.9.13(Regular audit)applicantThe entrusted production management situation and related records of the entrusted production enterprise shall be reviewed regularly, and the audit records shall be kept。The entrusted production enterprise shall keep all production records related to entrusted production, and may provide them to the applicant for reference at any time。If the entrusted production enterprise has the same product in production, it should have a significantly different number, batch number and process identification management method 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, and shall promptly notify the entrusted production enterprise of any design changes and procurement changes and supervise the implementation。For changes to the quality management system of the entrusted production enterprise that may affect the quality of the product, the applicant shall have measures to ensure that the entrusted production enterprise can inform the applicant in a timely manner and carry out a joint assessment。
4.9.15(Applicant's responsibility)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。
4.10Product authenticity
4.10.1(Registered inspection products)Registration of inspection products, including inspection product batch number (No/Serial number, etc.) and specifications, inspection time, inspection quantity, inspection basis, inspection conclusion, key raw materials and/Or components and other information, calibration substances and/Or quality control substances, inspection product photos (including photos of independent software release version information), labels and other information, should be consistent with the production record and traceable。
4.10.2(Clinical trial products)Clinical trial products, including clinical trial product lot numbers (No/Serial number, etc.) and specifications shall be consistent with production records and traceable。
4.10.3(Development and production traceability requirements)The production batch and production batch number or product number, specifications and models/Package specifications, quantity of each batch, batch number and quantity of registered inspection products and clinical trial products, batch number and quantity of retained sample products, batch number or product number and quantity of existing product production, batch number and quantity of main raw materials, etc., shall be traceable。
4.10.5(Production and inspection records)Production records, process inspection original records, finished product inspection original records, etc. shall meet the requirements of design output files。
4.10.6（留样）If it is necessary to retain samples, the samples shall be retained, and the product ledger and the observation record of the samples shall be kept。
5. Judgment principle of on-site verification results
5.1There are a number of verification items in this guide73Item, where annotated“*”Key item32Item, general item41Item (see attached table)。The on-site inspection team shall make the items one by one against all the verification items“符合”、“inconformity”或者“inapplicability”Decision result of。Judge as“inconformity”In the verification of items, inspectors shall record in detail the specific problems existing。
5.2Principles for judging the results of on-site verification
The conclusion of on-site verification is divided into“Pass the check”、“Failed verification”、“Pass the verification after rectification”、“Failed to pass the verification after rectification”4case。
5.2.1If on-site verification does not find that the applicant does not meet the project, the recommended conclusion is“Pass the check”。
5.2.2If on-site verification finds one of the following circumstances, the recommended conclusion is“Failed verification”。（1On-site verification finds that the applicant has authenticity problems;(2The on-site verification did not find the authenticity problem, but found that the applicant had key items3Items (including) above or general items10The above items (including) do not meet the requirements。
5.2.3On-site verification did not find any authenticity problems, and it was found that the applicant had key items3Items (not included) below and general items10If the following items (not included) do not meet the requirements, the recommended conclusion is“Review after rectification”。The verification conclusion is“Review after rectification”The applicant shall be registered after the completion of the verification6Complete the rectification within a month and submit a one-time rectification report to the original verification department. If necessary, the verification department can carry out on-site review。If all the project rectification meets the requirements, the recommended conclusion is“Pass the verification after rectification”。
5.2.4For the failure to submit the rectification report within the prescribed time limit or the review still does not meet the project, the recommended conclusion is“Failed to pass the verification after rectification”。
附表
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Chapter name
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章节
序号
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内容
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Decision result
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符合
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不
符合
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不
适用
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Principles of quality management system
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*4.1.1
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(Quality Management system) The applicant shall, in combination with the characteristics of the product, establish a quality management system covering design and development, production, quality control and release audit that is compatible with the product realization process, and shall include commissioned production (if any), clinical evaluation (including clinical trials), etc。
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4.1.2
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(Risk management) The applicant shall establish a risk management system to assess the quality risks of the product realization process based on scientific knowledge and experience to ensure product quality。
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*4.1.3
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(Self-inspection) Where the applicant carries out self-inspection, the self-inspection work shall be incorporated into the product quality management system and meet the requirements。
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Organization and personnel
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4.2.1
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(Organization) The applicant shall establish a management organization suitable for the research and development and production of medical devices, clarify the responsibilities of each department, and ensure that the design and development and technology conversion are reasonable and traceable。
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4.2.2
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(Personnel) The applicant shall be equipped with an appropriate number and corresponding R & D, production and quality control personnel, personnel should have the professional knowledge and work skills suitable for the application of registered products。
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Organization and personnel
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*4.2.3
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(Key personnel) Key personnel such as the management representative, the production person in charge, the quality person in charge, the technical person in charge, and the product release auditor shall be familiar with the key quality control and key production operation requirements of the registered product。
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*4.2.4
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(self-inspection personnel) Where the applicant submits the self-inspection report, the quality inspection department shall be equipped with a sufficient number of full-time inspection personnel。The educational background and technical ability of the inspectors shall match the product inspection work。Inspectors, examiners, approving personnel, etc. shall be authorized by the applicant in accordance with regulations。
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Plant, facilities and equipment
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*4.3.1
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(Plant facilities) The applicant shall be equipped with plants and facilities suitable for the production of the registered products。Product design and development should be carried out in suitable plants and facilities。The factories and facilities for the production of inspection products (referred to as registered inspection products) and clinical trial products that apply for registration shall meet the quality control requirements of the products。
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*4.3.2
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(Production equipment) The applicant shall be equipped with production equipment and technological equipment suitable for the production of the registered products。The production equipment and process equipment of registered inspection products and clinical trial products shall meet the requirements of product quality and production scale。
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*4.3.3
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(Inspection equipment) The applicant shall be equipped with environmental facilities and instruments that meet the requirements of product inspection methods。For laboratories that carry out special professional inspections, the environmental facilities shall meet the specific professional requirements。
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*4.3.4
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(Production of registered inspection and clinical trial products) The plant facilities and equipment used for research and development and production of registered inspection products and clinical trial products and related use records shall be kept。If force majeure cannot be retained, shall be retained to prove the product research and development, production, verification and other product realization process activities true, complete and traceable evidence。
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File management
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*4.4.1
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(System documents) The applicant shall establish quality management system documents suitable for the application of registered products, including quality manuals, procedure documents, technical documents and data records。Technical documents shall include product technical requirements and related standards, production process rules, operation instructions, inspection and test operation rules and other relevant documents。Data recording shall ensure traceability of activities such as product design and development, material procurement, production, quality control and product release。
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4.4.2
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(R & D original records) The original design and development data shall be included in the file management。In addition to the direct output test data, auxiliary records in the design and development process should be kept, such as records of main materials, instrument and equipment use records, weighing records, preparation records, etc。To carry out clinical trials, records of test instruments (reagents) in the process of clinical trials shall be kept, records of storage and transportation, records of recovery and disposal, etc。
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File management
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4.4.3
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(Verification data) The applicant shall retain the research data and records of product design and development or technology transfer verification, and shall ensure that the data is true, accurate, complete and traceable。
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4.4.4
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(Clinical trial document management) The applicant shall establish a clinical trial basic document management system according to the "Medical Devices./The In Vitro Diagnostic Reagents Clinical Trial Basic Documentation Catalogue requires the management of clinical trial documentation and ensuring its authenticity, completeness and traceability。
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Design and development
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*4.5.1
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(Design and development documents) Medical device design and development documents should be derived from design and development planning, input, output, review, verification, confirmation, conversion, change related documents, including records established in the design and development process, should ensure that the final output process of previous design and development and related activities can be traced。
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4.5.2
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(Design and development input) Design and development input should generally include laws and regulations, national standards, industry standards, domestic and foreign guide documents, standard products or reference material information (in vitro diagnostic reagent products), user needs, product scope of application, technical indicators of previous or similar products, product risks, etc。
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*4.5.3
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(Design and development output) The design and development output shall meet the input requirements, as well as meet the needs of users and product design requirements, and shall pay attention to the scope of product application, functionality, safety, effectiveness, and quality control。
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4.5.3.1
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(Passive medical devices) The raw material components of passive medical devices shall meet the relevant standards and requirements, and the biocompatibility evaluation of the product and the human body contact part shall be completed。When reusable sterile products are repeatedly sterilized, the performance of the finished product should be evaluated and the study of tolerance to repeated sterilization should be completed。
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4.5.3.2
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(Active medical devices) Active medical devices shall complete relevant studies according to the requirements of the standard, such as electric shock hazard protection, mechanical hazard protection, radiation hazard protection, overtemperature hazard protection, electromagnetic compatibility, biocompatibility, etc。
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Design and development
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4.5.3.3
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(Animal origin includes allogeneic medical devices) Animal origin medical devices should be completed animal species (if the risk is related to the strain, the strain needs to be defined), geographical origin (for species whose geographical origin cannot be determined)，Provide identification and traceability requirements during the life of the source animal), age (where applicable in relation to risk，For example, the susceptibility of animals to naturally occurring transmissible spongiform encephalopathy), the types of sample sites and tissues, the health status of animals and tissues, and the applicability of virus inactivation methods。
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4.5.3.4
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(In vitro diagnostic reagents) The main raw materials, intermediates, and important excipients involved in the research process of in vitro diagnostic reagents should be clearly derived and meet the requirements, and the equipment, instruments and reagents used in the research process should meet the research requirements。
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4.5.4
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(Validation) The applicant shall, based on the results of the risk assessment, determine the scope and extent of the work to be validated or validated and ensure that key elements of the operation can be effectively controlled。
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4.5.5
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(Design Conversion) The Applicant shall maintain all records of product design conversion activities，To demonstrate that the design and development outputs have been adequately validated and applicable to routine production before becoming final product specifications，And ensure that the production process in the use of determined raw materials and equipment conditions，Continuously and steadily produce products that meet the intended use and product technical requirements。Such as: sterilization process of aseptic products and related equipment and facilities verification and confirmation, the realization of basic safety and basic performance of active medical devices confirmation evaluation, in vitro diagnostic reagents production process, process parameters and batch scale-up verification。
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4.5.6
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(Packaging, expiration date, reuse) The applicant shall conduct research on product packaging, expiration date or reuse times and keep relevant records, such as: product packaging design and verification, stability study data, product specifications and minimum sales unit label design records。
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4.5.7
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(Verification records) Detailed original data records of design and development verification activities shall be kept, including verification schemes, verification reports, verification records (such as test data, sample handling records, etc.), and auxiliary records。
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Design and development
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4.5.8
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(Clinical confirmation Management) In the process of design and development confirmation, if the declared registered product needs to be confirmed by clinical trial, the applicant shall perform the corresponding duties in accordance with the clinical trial plan and contract, and keep the relevant documents and records。
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4.5.9
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(Requirements for clinical trial products) Before the clinical trial begins, 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 clinical trials。Records of relevant evaluation and validation processes should be maintained。
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4.5.10
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(Clinical Trial Product Management) The applicant shall maintain the distribution, storage, transportation, and recovery of clinical trial products/Return record。
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4.5.11
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(Design and development changes) Design and development changes include product changes, citation document updates (such as regulations, mandatory standards), design conversion changes (such as equipment, raw material suppliers, processes, environment, etc.), external change requirements (inspection, animal experiments, clinical trials, technical review changes), changes caused by mandatory medical device standards，It shall be subject to risk assessment, verification or confirmation，Ensure changes are controlled。
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4.5.12
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(Commissioned research and development management) Where there is commissioned research and development, the applicant shall have quality management measures for related activities。
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4.5.12.1
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The applicant shall clarify the scope and extent of product research and development activities entrusted。The R&D capability and continuous technical support capability of the entrusted R&D institution shall be required and evaluated accordingly。
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Design and development
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4.5.12.2
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The applicant shall sign a commissioned research and development agreement with the commissioned research and development institution, which clearly stipulates the responsibilities of each party, research and development content and related technical matters。The applicant shall be responsible for the process and results of the commissioned research and development, and shall have measures to ensure the reliability of the commissioned research and development 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。
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4.5.12.3
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(Commissioned R & D Technical Documents) The applicant shall ensure that the entrusted R & D institution transfers the design and development output documents in accordance with the agreement requirements and meets the design and development input requirements。
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采购
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*4.6.1
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(Procurement system) The applicant shall establish procurement control procedures to ensure that the purchased goods comply with the specified requirements。
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4.6.2
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(Source of raw materials) The raw materials required for registered inspection products and clinical trial products, including packaging materials and software in direct contact with the products, should have legal source proof, such as supply agreement, order, invoice, warehouse receipt, delivery note, copy of approval documents, etc。
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*4.6.3
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The purchase time or supply time of the main raw materials shall correspond to the production time of the product, and the purchased quantity shall meet the production demand of the product, and there shall be an inspection report or qualification certificate。
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*4.6.4
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(Procurement records) The procurement records of major raw materials shall comply with the requirements of product design and the provisions of the procurement agreement, and the records shall be true, accurate, complete and traceable。
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采购
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4.6.5
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(In vitro diagnostic reagent procurement records) The procurement of raw materials for in vitro diagnostic reagents shall have procurement contracts or procurement records。The procurement of quality control products, calibration products and enterprise reference products should meet the traceability requirements, such as samples from human sources, there should be the inspection method, inspection process, inspection data, inspection records of the corresponding raw materials, as well as proof materials indicating biosafety。
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*4.6.6
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(Requirements for key materials of in vitro diagnostic reagents) After in vitro diagnostic reagents are designed and finalized, the key raw materials themselves, such as antigens (source, amino acid sequence, conformation, etc.), antibodies (source, cell line, etc.), primer probe sequence, etc., should not change。
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生产
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*4.7.1
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(Development and production requirements) The applicant shall organize the production activities of registered inspection products and clinical trial products in accordance with the requirements of the Medical Device Production Quality Management Practice。
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*4.7.2
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(Production process documents) The applicant shall prepare production process regulations, operation instructions and other documents, and specify key processes and special processes。On animal-derived medical devices, inactivate and remove viruses and/Or infectious agent processes and methods for reducing the immunogenicity of animal-derived materials/Or process shall be confirmed。
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*4.7.3
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(Production and record requirements) shall organize the production of registered inspection products and clinical trial products in accordance with the production process regulations, and truthfully fill in the production records。Production records shall be true, accurate, complete and traceable。
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4.7.4
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(In vitro diagnostic reagent production requirements) The production of in vitro diagnostic reagents should ensure that the preparation concentration of different working fluids, production process, quality control process, etc. meet the requirements of the design output, especially the concentration and activity of bioactive materials should ensure stability, and meet the relevant standards。The material balance of raw materials shall meet the requirements。
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Quality control
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4.8.1
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(Basic requirements) The applicant shall establish quality control procedures, specify product inspection departments, personnel, operation and other requirements, and specify the use of inspection instruments and equipment, calibration and other requirements, as well as product release procedures。
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*4.8.2
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(Self-inspection) Where the applicant carries out self-inspection, it shall incorporate the quality management requirements related to self-inspection into the enterprise quality management system documents (including quality manuals, procedures, work instructions, etc.) in accordance with the requirements of relevant inspection work and self-inspection of declared products, and ensure its effective implementation and control。
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4.8.3
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(Inspection equipment) The applicant shall establish and keep the files, operating procedures and measurement of inspection equipment and environmental facilities/Calibration certification, service and maintenance records。
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4.8.4
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(Inspection procedures) shall be based on the principles of science and risk management, formulate raw material incoming inspection procedures, semi-finished products and finished products inspection procedures, and clearly formulate the basis。
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*4.8.5
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(Inspection records) Inspection reports and records of registered inspection, clinical trials and other related products shall be kept, including original records such as incoming inspection, process inspection and finished product inspection, inspection reports or certificates, and inspection method confirmation or verification records。Where there is commissioned inspection of some projects, there should be relevant project inspection reports and commissioned inspection agreements。
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*4.8.6
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(Release procedures) Product release procedures shall be established and implemented to clarify product release conditions and requirements for review and approval。
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Quality control
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4.8.7
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(In vitro diagnostic reagent traceability) In vitro diagnostic reagent traceability process should be reasonable, each batch of product assignment process and assignment method should be consistent。
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4.8.8
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(Sample retention) The applicant shall retain a certain number of registered inspection products and clinical trial products in combination with product characteristics。The quantity and specifications of products produced or samples retained shall meet the needs of product inspection and clinical evaluation (including clinical trials)。The destination of the samples shall be traceable。
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Commissioned production
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4.9.1
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(General requirements) In the production of products in the process of entrustment, the applicant shall be responsible for the guidance and supervision of the entrusted production enterprise quality management system of the department and personnel。In principle, a management representative should be appointed to be responsible for the quality control of commissioned production。
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*4.9.2
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(Personnel) The applicant shall be equipped with full-time quality management personnel, who shall be familiar with the key quality control of the product and the key production operation requirements, and be able to evaluate, review and supervise the quality management system of the applicant and the entrusted production enterprise。The key personnel of the entrusted production enterprise, such as the production person in charge, the quality person in charge, and the production release auditor, shall be familiar with the key quality control and key production operation requirements of the entrusted product。
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*4.9.3
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The applicant shall sign an entrustment agreement with the agent，Clarify the rights, obligations and responsibilities of both parties，The agreement shall at least include the production conditions of the entrusted manufacturer, the transfer of technical documents, material purchase control, production process and process control, finished product inspection, product release control, document and record control, change control, quality management system audit, etc，Ensure that the entrusted production enterprises organize production in accordance with laws and regulations, medical device production quality management norms, mandatory standards, and product technical requirements。
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Commissioned production
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4.9.4
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(on-site audit)Before commissioning production, the applicant shall carry out on-site evaluation and audit of the quality management system of the entrusted production enterprise, and 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 suitable for the entrusted production products。
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*4.9.5
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(Design conversion) The applicant shall jointly plan and complete the design conversion activities with the commissioned production enterprise to ensure that product technical requirements, production processes, raw material requirements and product technical documents such as instructions and labels can be effectively transferred to the commissioned production enterprise。
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4.9.6
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(Technical document conversion and process verification) The entrusted production enterprise shall, in combination with its production conditions and quality management system, convert the applicant's product technical documents into its technical documents to ensure that the key technical parameters and operating methods of the product technical requirements are consistent with those handed over by the applicant。Trial production and process validation should be carried out, and trial production should include all transferred production processes and quality control processes。
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4.9.7
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(Technology transformation risk control) The applicant shall, in combination with the original production process documents, compare and evaluate the production process documents executed by the entrusted production enterprise to ensure that the risks caused by 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 products carried out by the entrusted production enterprise, and review the relevant process documents and reports。
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*4.9.8
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(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 commissioned production enterprise, it shall ensure that the commissioned production enterprise has factories, facilities and facilities suitable for product production备。The applicant shall ensure the completion of process verification or validation and other related work。
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4.9.9
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(Material procurement) The applicant shall clarify the procurement method, procurement approach, quality standards, inspection requirements of the commissioned product materials, and implement procurement in accordance with the requirements of the medical device commissioned production quality agreement。When necessary, the applicant and the entrusted production enterprise together to screen, audit, sign quality agreements, regular review of material suppliers。
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Commissioned production
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4.9.10
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(Production process management) The applicant shall, together with the entrusted production enterprise, clarify the monitoring methods and standards for product process flow, process parameters, external processing processes (such as irradiation sterilization, ethylene oxide sterilization, anodizing, spraying process, etc.), material flow, batch number and marking management, production record traceability and other production processes，Specify who authorizes monitoring，And keep monitoring records。
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4.9.11
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(Document management) The documents jointly held by the applicant and the entrusted production enterprise shall at least include: the entrustment agreement, the product technical requirements, raw material requirements, production processes and inspection procedures, product specifications and labels, and product release procedures。
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*4.9.12
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(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 in accordance with their respective responsibilities。The commissioned production enterprise shall formulate production release audit procedures, shall ensure that the commissioned production products meet the applicant's acceptance standards and keep release records。All records relating to the production of products shall be true, accurate, complete and traceable。
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4.9.13
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(Regular review) The applicant shall regularly review the entrusted production management of the entrusted production enterprise and relevant records, and keep audit records。The entrusted production enterprise shall keep all production records related to entrusted production, and may provide them to the applicant for reference at any time。If the entrusted production enterprise has the same product in production, it should have a significantly different number, batch number and process identification management method from the entrusted production product to avoid confusion。
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4.9.14
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(Communication mechanism) The applicant shall establish an effective communication mechanism with the entrusted production enterprise, and shall promptly notify the entrusted production enterprise of any design changes and procurement changes and supervise the implementation。For changes to the quality management system of the entrusted production enterprise that may affect the quality of the product, the applicant shall have measures to ensure that the entrusted production enterprise can inform the applicant in a timely manner and carry out a joint assessment。
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4.9.15
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(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 continuous improvement of the quality management system, and implement the supervision of the entrusted production enterprise。
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Product authenticity
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*4.10.1
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(Registered inspection products) Registered inspection products, including the inspection product batch number (No/Serial number, etc.) and specifications, inspection time, inspection quantity, inspection basis, inspection conclusion, key raw materials and/Or components and other information, calibration substances and/Or quality control substances, inspection product photos (including photos of independent software release version information), labels and other information, should be consistent with the production record and traceable。
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*4.10.2
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(Clinical Trial products) Clinical trial products, including clinical trial product lot numbers (No/Serial number, etc.) and specifications shall be consistent with production records and traceable。
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*4.10.3
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(Development and production traceability requirements) Production of product batches and production batch numbers or product numbers, specifications and models/Package specifications, quantity of each batch, batch number and quantity of registered inspection products and clinical trial products, batch number and quantity of retained sample products, batch number or product number and quantity of existing product production, batch number and quantity of main raw materials, etc., shall be traceable。
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*4.10.4
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(Procurement records) The procurement records of raw materials used for product production shall be kept, including at least: raw material name, model specification, batch number, material (brand number), supplier (manufacturer), quality standard and purchase acceptance, purchase voucher, import and export records and ledger, etc。The relevant information of the procurement record shall be consistent with the corresponding contents of the production record and the registered inspection report。
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*4.10.5
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(Production and inspection records) Production records, process inspection original records, finished product inspection original records, etc. shall meet the requirements of the design output file。
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*4.10.6
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(Sample retention) If it is necessary to retain samples, the product shall be retained, and the product ledger and the observation record of the sample shall be kept。
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