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

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.