1.1 本指南旨在提供特性、性能、测试方法和标准化方法，以评估和鉴定特定的可聚合胶原制剂和使用这些制剂生产的胶原聚合物材料。 1.2 本指南侧重于I型胶原的纯化可聚合形式的表征，I型胶原是哺乳动物结缔组织和器官（包括皮肤、骨骼、肌腱和血管）中最丰富的胶原。可聚合的I型胶原可来源于多种来源，包括但不限于动物或尸体组织、细胞培养、重组细胞培养和化学合成。 1.2.1 本指南涵盖了可聚合胶原和由可聚合胶原制备的胶原聚合材料的评估，这些材料用作伤口和止血敷料、外科植入物、组织工程医疗产品（TEMP）基质、治疗细胞或分子的输送载体和3D 体外 用于基础研究、诊断、药物开发和毒性测试的组织系统。今天市场上的大多数胶原蛋白产品都作为器械进行监管，因为它们的主要目的不是通过体内或体外的化学作用实现的。 然而，根据其预期用途和主要作用模式，包含可聚合胶原或胶原聚合物材料的医疗产品可以作为器械、生物、药物或组合产品进行调节。 1.2.2 可聚合的胶原或胶原自组装意味着胶原组合物表现出来自其组分的自发大分子组装，而无需添加外源因素，如交联剂。可聚合胶原蛋白可包括但不限于:( 1. )组织衍生的单体胶原，包括原胶原或去端胶原，以及低聚胶原； ( 2. )胶原蛋白和肽通过 体外 使用或不使用重组技术的细胞培养；以及( 3. )化学合成的胶原模拟肽。应注意的是，胶原聚合材料产品的形式也会有所不同，可能包括聚合的可注射溶液 原地 以及预制片材、颗粒、球体、纤维、海绵、基质/凝胶、涂层、薄膜和其他形式。 1.2.3 本指南可作为I型原纤维胶原或其他胶原类型的表征和标准化模板- 装配 1.3 本指南未为评估可聚合胶原和胶原聚合物材料的生物安全性（生物相容性）提供重要依据。虽然胶原聚合物材料通过提供细胞粘附和蛋白水解域以及物理约束（例如，结构、细胞基质牵引力）来引导细胞反应的能力已通过广泛的临床和基础研究得到充分证明 ( 1- 5. ) , 2. 用户可参考ISO 10993系列评估医疗器械的生物风险。特定应用的生物相容性和适用性由产品制造商负责。 1.4 以国际单位制表示的值应视为标准值。本标准不包括其他测量单位。 1.5 以下预防性警告仅适用于测试方法部分，章节 6. 和 7. ，本指南的: 本标准并不旨在解决与其使用相关的所有安全问题（如有）。本标准的使用者有责任在使用前建立适当的安全、健康和环境实践，并确定监管限制的适用性。 1.6 本国际标准是根据世界贸易组织技术性贸易壁垒（TBT）委员会发布的《国际标准、指南和建议制定原则决定》中确立的国际公认标准化原则制定的。 =====意义和用途====== 4.1 本文件旨在为以下各项的生产、表征、测试和标准化提供指导:( 1. )可聚合胶原原料；以及( 2. )用可聚合胶原配方生产的胶原聚合材料，用于外科植入物、TEMP基质、治疗细胞和分子载体以及3D 体外 用于基础研究、药物开发和毒性测试的组织系统。本指南可用于选择、表征和标准化合适的可聚合胶原起始配方以及由特定用途的可聚合胶原蛋白制备的胶原聚合材料。 并非所有测试或参数都适用于胶原蛋白的所有用途，用户应选择并证明测试的子集用于表征目的。 4.2 以下类型的用户可以使用本指南: 4.2.1 希望为其产品设定规格或为客户或用户提供表征数据的可聚合胶原蛋白和胶原聚合材料制造商。他们还可以使用术语和表征部分来指定和区分可聚合胶原和胶原聚合物材料的性质。 4.2.2 使用可聚合胶原作为起始材料的胶原聚合材料的生产商。 生产商可使用本指南评估和表征可聚合胶原蛋白的多种来源。他们还可以使用本指南帮助评估和比较可聚合胶原和胶原聚合物材料的单一或多个来源。 4.2.3 研究人员可以将本指南作为可用于可重复评估可聚合胶原和胶原聚合物材料的性能和测试方法的参考。 4.3 本指南涵盖的胶原蛋白可用于广泛的应用、形式或医疗产品，例如（但不限于）伤口和止血敷料、外科植入物或注射剂（包括 原地 成型）、混合医疗器械、TEMP、可注射（包括 原地 形成）或可植入的递送载体，用于治疗细胞、分子和药物，以及3D 体外 用于基础研究、药物开发和毒性测试的组织系统或模型。可聚合胶原和胶原聚合物材料的实际应用应基于生物相容性、特定应用性能测量以及化学、物理和生物测试数据等因素。本指南中的建议不应被解释为任何特定研究或医学应用的成功保证。 4.4 在确定所供应的胶原蛋白是否满足上述医疗和研究应用的要求时，应考虑以下一般领域:可聚合胶原蛋白的来源、杂质分布以及全面的化学、物理和生物特性和测试。 4.5 在确定所供应的胶原蛋白是否满足医疗和研究产品（包括TEMP、治疗载体和3D）的使用要求时，应考虑以下文件或来自相关监管机构的与器械、生物制剂、药物和组合产品的生产、监管和监管批准有关的其他相关指导文件 体外 组织系统: FDA CFR: 21 CFR 3:产品管辖权: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR搜索cfm？CFR部分=3 21 CFR 58:非临床实验室研究的良好实验室规范: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR搜索cfm？CFR零件=58 FDA/CDRH CFR和指南: 21 CFR第803部分:医疗器械报告: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR搜索cfm？CFR零件=803 21 CFR 812:研究器械豁免: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR搜索cfm？CFR零件=812 21立方英尺814: 医疗器械上市前批准: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR搜索cfm？CFR零件=814 21 CFR 820:质量体系法规: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR搜索cfm？CFR零件=820 医疗器械制造商设计控制指南: http://www.fda.gov/cdrh/comp/designgd.pdf 预生产质量保证计划建议 医疗器械制造商（FDA 90-4236）: http://www.fda.gov/cdrh/manual/appende.html 上市前批准申请的审查和检查 根据生物研究监测计划指南草案 行业和FDA员工: http://www.fda.gov/cdrh/comp/guidance/1602.pdf FDA/CDRH搜索引擎: CDRH指南搜索引擎: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfggp/ 搜索.cfm CDRH上市前批准（PMA）搜索引擎: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/ pma.cfm格式 CDRH 510（k）搜索引擎: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/ pmn.cfm CDRH公认标准搜索引擎: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/ 搜索.cfm FDA/CBER CFR和指南: 21 CFR 312:研究新药申请: http: //www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR搜索cfm？CFR零件=312 21 CFR 314:FDA批准上市新药的申请: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR搜索cfm？CFR零件=31 21 CFR 610:一般生物制品标准: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR搜索cfm？CFR零件=610 21 CFR 1271:人体细胞、组织及细胞和组织基产品: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR搜索cfm？CFR零件=1271 细胞和基因治疗指南和其他出版物: http://www.fda.gov/cber/genetherapy/gtpubs. htm Human Tissue Guidances and Other Publications: http://www.fda.gov/cber/tissue/docs.htm CBER Product Approval Information: http://www.fda.gov/cber/efoi/approve.htm 21 CFR 600, 601 BLA Regulations: http://www.access.gpo.gov/nara/cfr/waisidx_07/21cfrv7_07.html 21 CFR 210, 211 GMP Regulations: http://www.access.gpo.gov/nara/cfr/waisidx_07/21cfr210_07.html

1.1 This guide is intended to provide characteristics, properties, test methods, and standardization approaches for evaluation and identification of specific polymerizable collagen formulations and collagen polymeric materials produced with these formulations. 1.2 This guide focuses on characterization of purified polymerizable forms of type I collagen, which is the most abundant collagen in mammalian connective tissues and organs, including skin, bone, tendon, and blood vessels. Polymerizable type I collagen may be derived from a variety of sources including, but not limited to, animal or cadaveric tissues, cell culture, recombinant cell culture, and chemical synthesis. 1.2.1 This guide covers evaluation of polymerizable collagens and collagen polymeric materials prepared from polymerizable collagens for use as a starting material for wound and hemostatic dressings, surgical implants, substrates for tissue-engineered medical products (TEMPs), delivery vehicles for therapeutic cells or molecules, and 3D in-vitro tissue systems for basic research, diagnostics, drug development, and toxicity testing. Most collagen products on the market today are regulated as devices since their primary intended purpose is not achieved through chemical action within or on the body. However, a medical product comprising polymerizable collagens or collagen polymeric materials may be regulated as a device, biologic, drug, or combination product depending on its intended use and primary mode of action. 1.2.2 Polymerizable collagen or collagen self-assembly implies that the collagen composition exhibits spontaneous macromolecular assembly from its components without the addition of exogenous factors such as cross-linking agents. Polymerizable collagens may include but are not limited to: ( 1 ) tissue-derived monomeric collagens, including tropocollagen or atelocollagen, and oligomeric collagens; ( 2 ) collagen proteins and peptides produced through in vitro cell culture, with or without using recombinant technology; and ( 3 ) chemically synthesized collagen mimetic peptides. It should be noted that the format of collagen polymeric material products also will vary and may include injectable solutions that polymerize in situ as well as preformed sheets, particles, spheres, fibers, sponges, matrices/gels, coatings, films, and other forms. 1.2.3 This guide may serve as a template for characterization and standardization of type I fibrillar collagen or other collagen types that demonstrate polymerization or self-assembly. 1.3 This guide does not provide a significant basis for assessing the biological safety (biocompatibility) of polymerizable collagens and collagen polymeric materials. While the ability of collagen polymeric materials to guide cellular responses through provision of cellular adhesion and proteolytic domains as well as physical constraints (for example, structural, cell-matrix traction force) has been well documented through extensive clinical and basic research studies ( 1- 5 ) , 2 users are directed to the ISO 10993 series for evaluating biological risks of medical devices. The biocompatibility and appropriateness of use for a specific application is the responsibility of the product manufacturer. 1.4 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard. 1.5 The following precautionary caveat pertains only to the test method portion, Sections 6 and 7 , of this guide: This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use. 1.6 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee. ====== Significance And Use ====== 4.1 The objective of this document is to provide guidance in the production, characterization, testing, and standardization of: ( 1 ) polymerizable collagen starting materials; and ( 2 ) collagen polymeric materials produced with polymerizable collagen formulations, used for surgical implants, substrates for TEMPs, vehicles for therapeutic cells and molecules, and 3D in-vitro tissue systems for basic research, drug development, and toxicity testing. This guide can be used as an aid in the selection, characterization, and standardization of the appropriate polymerizable collagen starting formulations as well as collagen polymeric materials prepared from polymerizable collagens for a specific use. Not all tests or parameters are applicable to all uses of collagen and users are expected to select and justify a subset of the tests for characterization purposes. 4.2 This guide can be used by the following types of users: 4.2.1 Manufacturers of polymerizable collagens and collagen polymeric materials who wish to set specifications for their products or provide characterization data for customers or users. They may also use the terminology and characterization sections to specify and differentiate the properties of polymerizable collagens and collagen polymeric materials. 4.2.2 Producers of collagen polymeric materials that use polymerizable collagen as starting materials. Producers may use this guide to evaluate and characterize multiple sources of polymerizable collagen. They may also use this guide to assist with evaluation and comparison of single or multiple sources of polymerizable collagen and collagen polymeric materials. 4.2.3 Researchers may use this guide as a reference for properties and test methods that can be used to reproducibly evaluate polymerizable collagens and collagen polymeric materials. 4.3 The collagen covered by this guide may be used in a broad range of applications, forms, or medical products, for example (but not limited to) wound and hemostatic dressings, surgical implants or injectables (including in-situ forming), hybrid medical devices, TEMPs, injectable (including in-situ forming) or implantable delivery vehicles for therapeutic cells, molecules, and drugs, and 3D in-vitro tissue systems or models for basic research, drug development, and toxicity testing. The practical application of polymerizable collagens and collagen polymeric materials should be based, among other factors, on biocompatibility, application-specific performance measures, as well as chemical, physical, and biological test data. Recommendations in this guide should not be interpreted as a guarantee of success for any specific research or medical application. 4.4 The following general areas should be considered when determining if the collagen supplied satisfies requirements for use in the above mentioned medical and research applications: source of polymerizable collagen, impurities profile, and comprehensive chemical, physical, and biological characterization and testing. 4.5 The following documents or other relevant guidance documents from appropriate regulatory bodies relating to the production, regulation, and regulatory approval of devices, biologics, drugs, and combination products should be considered when determining if the collagen supplied satisfies requirements for use in medical and research products, including TEMPs, therapeutic delivery vehicles, and 3D in-vitro tissue systems: FDA CFR: 21 CFR 3: Product Jurisdiction: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=3 21 CFR 58: Good Laboratory Practice for Nonclinical Laboratory Studies: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=58 FDA/CDRH CFR and Guidances: 21 CFR Part 803: Medical Device Reporting: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=803 21 CFR 812: Investigational Device Exemptions: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=812 21 CFR 814: Premarket Approval of Medical Devices: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=814 21 CFR 820: Quality System Regulation: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=820 Design Control Guidance for Medical Device Manufacturers: http://www.fda.gov/cdrh/comp/designgd.pdf Preproduction Quality Assurance Planning Recommendations for Medical Device Manufacturers (FDA 90-4236): http://www.fda.gov/cdrh/manual/appende.html The Review and Inspection of Premarket Approval Applications under the Bioresearch Monitoring Program—Draft Guidance for Industry and FDA Staff: http://www.fda.gov/cdrh/comp/guidance/1602.pdf FDA/CDRH Search Engines: CDRH Guidance Search Engine: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfggp/ search.cfm CDRH Premarket Approval (PMA) Search Engine: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/ pma.cfm CDRH 510(k) Search Engine: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/ pmn.cfm CDRH Recognized STANDARDS Search Engine: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/ search.cfm FDA/CBER CFR and Guidances: 21 CFR 312: Investigational New Drug Application: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=312 21 CFR 314: Applications for FDA Approval to Market a New Drug: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=31 21 CFR 610: General Biological Products Standards: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=610 21 CFR 1271: Human Cells, Tissues and Cellular and Tissue-Based Products: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=1271 Cellular & Gene Therapy Guidances and Other Publications: http://www.fda.gov/cber/genetherapy/gtpubs.htm Human Tissue Guidances and Other Publications: http://www.fda.gov/cber/tissue/docs.htm CBER Product Approval Information: http://www.fda.gov/cber/efoi/approve.htm 21 CFR 600, 601 BLA Regulations: http://www.access.gpo.gov/nara/cfr/waisidx_07/21cfrv7_07.html 21 CFR 210, 211 GMP Regulations: http://www.access.gpo.gov/nara/cfr/waisidx_07/21cfr210_07.html