Technical Guideline For Animal-Derived Medical Device Registration
2021-06-22
Technical Guideline for Animal-Derived Medical Device Registration (2017 revision) The guideline is intended to guide registration applicants in preparing registration materials for animal-derived medical devices. Some medical devices may contain materials of animal origin. These materials are diverse. They can constitute the main components of the device (such as bovine / pig-derived heart valves, sheep gut sutures, hemostatic materials, etc.), coatings, or infiltration agents (such as heparin, gelatin, collagen, etc.) , and can also become auxiliary materials used in the production (such as tallow, etc.). The use of animal tissues and their derivatives may give medical devices better performance than non-biologically derived materials such as metals, plastics, and fabrics. However, on the other hand, their application to the human body will increase the safety risks of virus transmission and immunogenicity, and there are difficulties in material characterization. Therefore, the evaluation of the safety of animal medical devices needs to consider more aspects than conventional medical devices. If the registration applicant has the above considerations when preparing the medical device registration application documents, it will help to more fully and scientifically evaluate the risk-benefit ratio of medical device products. The guideline is based on the general requirements of the technical documents (study data, risk analysis documents, product technical requirement, and IFU) in the registration application documents, and the requirements for special attention and additional discussion on the characteristics of animal-derived medical device products. In addition, registration applicants should also comply with the “Administrative Measures for the Registration of Medical Devices” (China Food and Drug Administration Decree No. 4), —— 2 — “Administrative Regulations on the IFU and Labels of Medical Devices” (China Food and Drug Administration Decree No. 6), “Announcement on Publication of Medical Device Registration Information Requirements and Approval Document Format” (China Food and Drug Administration Announcement No. 43 of 2014) and other related document requirements issued by the State Administration and refer to YY/T 0771 / ISO 22442 standard series and other technical documents to submit registration application documents. Registration applicant should determine whether the specific content is applicable based on the characteristics of the specific product. If it is not applicable, the reason and corresponding scientific basis shall be elaborated. Registration applicant should also enrich and refine the contents of registration application documents based on the characteristics of specific products. The guideline is a guidance document for registration applicants and technical reviewers of medical device-related management departments. It does not limit the technical review of related products by relevant management departments and the preparation of registration application documents by registration applicants. The guideline does not include administrative matters involved in registration approval, nor is it enforced as a regulation. If there are other methods that can meet the requirements of relevant regulations, they can also be used, but detailed study data and verification data should be provided. The guideline should be used in compliance with relevant regulations. The guideline is formulated under the current system of laws and standards and the current level of cognition. With the continuous improvement of laws and standards and the continuous development of science and technology, the relevant content of this guideline will also be adjusted in a timely manner. The guideline is a revised version of the Guideline for Registration and Application Documents of Animal-Derived Medical Device Products. The main amendments include: — 3 —— Adjusting the structure of the guideline, titles at various levels and related content in accordance with the Medical Device Supervision and Administration Regulations and supporting regulations; adding principles for the study, evaluation and control of animal-derived medical devices; The principles of validation of virus inactivation / removal of animal-derived medical devices were refined and adjusted from the text to the appendix; the criteria for determining the effectiveness of virus inactivation / removal processes were adjusted. I. Scope of application The guideline applies to the registration application of medical device products (except in vitro diagnostic medical devices) made entirely of or derived from animal tissue. The guideline also applies to the registration application of medical device products that use animal tissue derivatives or materials that are naturally obtained from animals (such as milk, wool, etc.). II. Basic requirements On the basis of meeting the general requirements, following content are also required to be added in product registration application documents for animal-derived medical devices: (I) Research data For animal-derived medical devices, technical content related to controlling viral and / or infectious factor infections and immunogenicity risks are required to be added in research data. In view of the different types and different numbers of viruses and / or infectious agents that infect humans, and the types and degrees of different types of animals that are susceptible to infection by viruses and infectious agents are also very different, the determination of animal species plays an important role in the risk assessment of —— 4 — animal-derived medical devices. In addition, the geographic origin, age, position of selection, and tissue type of animals also directly affect the risk of animal-derived materials. For the risk control of infectious virus and infectious factors, it is necessary to start from at least source control and process control. Relying only on source control or process control cannot ensure that the risk is minimized. To ensure the controllability of risks, enterprises should establish a set of control and traceability systems specifically for animal-derived risk factors in the production quality system in accordance with the relevant requirements of medical device production quality management specifications. In the production process of animal-derived materials or medical devices, it is necessary to consider setting related steps for virus inactivation / removal. These steps can use current steps already in the production process. If the existing production process cannot meet the requirements for virus inactivation / removal, additional appropriate virus inactivation / removal steps need to be added. Applicants need to fully consider the impact of this step on the performance of medical devices. In order to reduce the immunogenicity risk of animal-derived materials, it is generally necessary to take corresponding measures in the production process to reduce its immunogenicity, such as decellularization treatment, purification, and other physical or chemical methods for substances with potential immunogenicity (such as nucleic acids, proteins, polysaccharides, lipids, and other small molecule substances) are removed or their epitopes are eliminated / hidden. Manufacturers need to verify their effectiveness in reducing the immunogenicity of materials. However, these processing measures and processing steps for inactivation and removal of viruses and / or infectious agents may be at the expense of the performance of the material itself or the addition of new risks, and manufacturers need to fully evaluate their adverse effects on the product, in order to — 5 —— ensure that the product can ultimately be used safely and effectively. Therefore, at least the following contents are required to be added in the research data:
A detailed description of the species of animal (if the risk is related to the strain, the strain needs to be identified), the geographical origin (for species whose geographic origin cannot be determined, the identification and traceability information of the source animal during its survival should be provided), and the age (applicable when it is related to the risk, such as the animal’s susceptibility to spontaneous spongiform encephalopathy that occurs naturally), position of selection and type of tissue, and health of the animal and the tissue;
Description and validation data or related information regarding the process of inactivating and removing viruses and / or infectious agents during production (see Appendix 1 for principles of inactivating and removing viruses);
Description of methods and / or processes, quality control indicators and confirmatory experimental data or related data for reducing the immunogenicity of animal-derived materials (see Appendix 2 for principles of immunogenicity study, evaluation and control). (II) Risk analysis document For animal-derived medical devices, analysis, control and residual risk analysis of virus and / or infectious factor infection and immunogenicity risk are required to be added to this part of data. In view of the potential risks associated with the use of animal-derived materials, registration applicants need to specify the advantages of using animal-derived materials in their medical devices under registration compared with non-animal-derived materials in order to fully evaluate the risk / benefit ratio of using animal derived materials. —— 6 — For different animal-derived medical devices, the immunogenicity risk will also vary according to the type and position of selection of the animal. Therefore, it is necessary to effectively control the immunogenicity risk based on a full analysis of the risk of immunogenicity. The risk analysis of infection with viruses and / or infectious agents shall include the raising, transportation, slaughtering of animals, the collection and processing of animal-derived materials, and the use of animal-derived medical devices in human body. Therefore, at least the following contents are required to be added in the product risk analysis report:
The basis for using animal-derived materials and the comparative analysis of animal-derived materials with other materials, and the risk / benefit analysis of animal-derived materials that are not replaced with other materials;
Risk analysis (including breeding methods, breeding conditions, use of animal-derived protein feed, epidemic prevention, transportation, etc.) and corresponding control measures for animals that may be infected with viruses and / or infectious agents during the breeding process;
Risk analysis and corresponding control measures for products that may be infected with viruses and / or infectious factors during material taking and processing;
Risk analysis and corresponding control measures for humans that may be infected with viruses and / or infectious agents by animal-derived medical devices during the use of the product;
Risk analysis and corresponding control measures on the immunogenicity of the human body due to contact with animal-derived materials during the use of the product. Note: Item 5 can be provided in accordance with YY/T 0771 / ISO 22442. (III) Product technical requirement — 7 —— Registration applicants shall formulate control indicators of the final product immunogenicity in the product technical requirement. These control indicators are generally performance indicators of the final product that can indirectly reflect the effective control of the immunogenicity of the product through in vitro assays. For example, residual DNA content, residual antigen content, residual miscellaneous protein content, etc. (based on risk analysis, select appropriate indicators according to different situations). If the immunogenicity risk of the product mainly depends on the control of the production process, and the in vitro assays involved in the performance indicators used to control the immunogenicity cannot be performed on the final product, the relevant control information of the intermediate product should be provided in the research data. Product performance research data need to provide the scientific basis for formulating the specific limits and test methods of the above control indicators to prove that the immunogenicity of the product can be controlled to an acceptable range (based on relevant standards, literature data, comparison with marketed products, and / or the results of an immunotoxicology test). (IV) Instructions for use For the consideration of the patients’ right of informed consent, it is necessary to clearly indicate in the product description which animal and which tissue the product was taken from. III. Other issues that need attention
For medical devices made from derivatives of animal tissues or naturally derived substances (such as chitosan, silk, beeswax, etc.), this guideline should also be followed. For some provisions that may not be directly applicable, the registration applicant shall make corresponding explanations and explain the reasons for not applicable.
For medical devices that do not contain animal tissue or its derivatives in some —— 8 — components, but use or come into contact with animal-derived materials included in this guideline during the production process (e.g.in the process of preparing sodium hyaluronate by microbial fermentation, the culture medium containing animal-derived ingredients is used). In principle, corresponding risk analysis and control measures, as well as relevant verification data or documents, need to be submitted.
For animal species that are not normally used for medical devices, relevant research data on the species suitability for human use shall be provided.
For the animal fat derivatives, animal charcoal and amino acids mentioned in the Appendix of YY/T 0771.1 / ISO 22442-1 “Animal-derived medical devices Part 1: Risk management applications”, if it is proved that the treatment process complies with related requirements in YY/T 0771.1 / ISO 22442-1, it is no longer necessary to submit the virus removal / inactivation validation research data for its processing. IV. Terminology Animals: vertebrates or invertebrates other than humans [including amphibians, arthropods (such as crustaceans), birds, corals, fish, reptiles, molluscs, mammals, etc.] Derivative: Substance obtained from animal materials by a manufacturing process, such as hyaluronic acid, collagen, gelatin, monoclonal antibodies, chitosan and albumin. Infectious agents: bacteria, molds, yeasts, parasites, viruses, TSE factors, and unclassified pathogens. Removal: The process of reducing the number of viruses and infectious agents. Inactivation: The process of reducing the ability of a virus and / or infectious agent to cause an infection or a pathogenic response. V. References 1.”Administrative Measures for the Registration of Medical Devices” (China Food and Drug Administration Decree No. 4) — 9 —— 2.”Administrative Regulations on Medical Device IFU and Labels” (China Food and Drug Administration Decree No. 6) 3.”Announcement on the Requirements for the Publication of Medical Device Registration Application Materials and the Approval Document Format” (China Food and Drug Administration Announcement No. 43 of 2014)
YY/T 0771.1-2009/ISO 22442-1:2015 “Medical devices utilizing animal tissues and their derivatives – Part 1: Application of risk management”
YY/T 0771.2-2009/ISO 22442-2:2007 “Medical devices utilizing animal tissues and their derivatives – Part 2: Controls on sourcing, collection and handling”
YY/T 0771.3-2009/ISO 22442-3:2007 “Medical devices utilizing animal tissues and their derivatives – Part 3: Validation of the elimination and/or inactivation of viruses and transmissible spongiform encephalopathy (TSE) agents”
YY/T 0771.4-2015/ ISO 22442-4:2010 “Medical devices utilizing animal tissues and their derivatives – Part 4: Principles for elimination and/or inactivation of transmissible spongiform encephalopathy agents and validation assays for those processes” 8.”Guideline of Technical methods and validation for blood product removal / inactivation virus” (Guo Yao Jian Zhu [2002] No. 160)
YY/T 0606.25-2014.”Tissue engineered medical product – Part 25: Quantification of remnant DNA in biological materials utilizing animal tissues and their derivatives: Fluorescence method”
