4.1 The objective of this document is to provide guidance in the production, characterization, testing, and standardization of: (a) collagen polymers as a starting material for surgical implants, substrates for tissue-engineered medical products (TEMPs), vehicles for therapeutic cells and molecules, and 3D in-vitro tissue systems for basic research, drug development, and toxicity testing; and (b) self-assembled collagen-based materials produced with collagen polymer formulations. This guide can be used as an aid in the selection, characterization, and standardization of the appropriate collagen polymer starting material as well as associated self-assembled collagen-based products for a specific use. Not all tests or parameters are applicable to all uses of collagen.

4.2 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, hybrid medical devices, tissue-engineered medical products (TEMPs), injectable 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 the collagen polymers and associated self-assembled collagen-based 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 research or medical application.

4.3 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 collagen polymer, impurities profile, and comprehensive chemical, physical, and biological characterization and testing.

4.4 The following documents or other relevant guidances 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 for characterizing polymerizable collagens is intended to provide characteristics, properties, test methods, and standardization approaches for use by producers, manufacturers, and researchers to identify specific collagen polymer formulations and associated self-assembled collagen-based products produced with these formulations. This guide will focus on the characterization of polymer forms of Type I collagen, which is the most abundant collagen in mammalian connective tissues and organs, including skin, bone, tendon, and blood vessels. Type I collagen may be derived from a variety of sources including, but not limited to, animal or cadaveric tissues, cell culture, recombinant, and chemical synthesis. This guide is intended to focus on purified Type I collagen polymers 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, drug development, and toxicity testing. Polymerizable or self-assembly implies that the collagen composition exhibits spontaneous macromolecular assembly from its components in the absence of the addition of exogenous factors including cross-linking agents. Self-assembling collagen polymers may include, but are not limited to: (1) tissue-derived atelocollagens, monomers, and oligomers; (2) collagen proteins and peptides produced using recombinant technology; and (3) chemically synthesized collagen mimetic peptides. It should be noted that the format of associated self-assembled collagen-based 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. This guide may serve as a template for characterization and standardization of other fibrillar collagen types that demonstrate polymerization or self-assembly.

1.2 The ability of self-assembled collagen 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 (1, 2)² and basic research studies (3, 4). The biocompatibility and appropriateness of use for a specific application(s) is the responsibility of the product manufacturer.

1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.

1.4 Warning—Mercury has been designated by the Environmental Protection Agency (EPA) and many state agencies as a hazardous material that can cause central nervous system, kidney, and liver damage. Mercury, or its vapor, may be hazardous to health and corrosive to materials. Caution should be taken when handling mercury and mercury-containing products. See the applicable product Material Safety Data Sheet (MSDS) for details and the EPA website (http://www.epa.gov/mercury/faq.htm) for additional information. Users should be aware that selling mercury or mercury-containing products, or both, in your state may be prohibited by state law.

1.5 The following precautionary caveat pertains only to the test method portion, Section 5, 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 and health practices and determine the applicability of regulatory limitations prior to use.