ASTM F2212-02(2007)e1
(Guide)Standard Guide for Characterization of Type I Collagen as Starting Material for Surgical Implants and Substrates for Tissue Engineered Medical Products (TEMPs)
Standard Guide for Characterization of Type I Collagen as Starting Material for Surgical Implants and Substrates for Tissue Engineered Medical Products (TEMPs)
SCOPE
1.1 This guide for characterizing collagen-containing biomaterials is intended to provide characteristics, properties, and test methods for use by producers, manufacturers, and researchers to more clearly identify the specific collagen materials used. With greater than 20 types of collagen and the different properties of each, a single document would be cumbersome. This guide will focus on the characterization of Type I collagen, which is the most abundant collagen in mammals, especially in skin and bone. Collagen isolated from these sources may contain other types of collagen, for example, Type III and Type V. This guide does not provide specific parameters for any collagen product or mix of products or the acceptability of those products for the intended use. The collagen may be from any source, including, but not limited to, animal or cadaveric sources, human cell culture, or recombinant sources. The biological, immunological, or toxicological properties of the collagen may vary, depending on the source material. The properties of the collagen prepared from each of the above sources must be thoroughly investigated, as the changes in the collagen properties as a function of source materials is not thoroughly understood. This guide is intended to focus on purified Type I collagen as a starting material for surgical implants and substrates for Tissue-Engineered Medical Products (TEMPs); some methods may not be applicable for gelatin nor for tissue implants. This guide may serve as a template for characterization of other types of collagen.
1.2 The biological response to collagen in soft tissue has been well documented by a history of clinical use (1,2) and laboratory studies (3,4 5,21). Biocompatibility and appropriateness of use for a specific application(s) is the responsibility of the device manufacturer.
1.3 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 requirements prior to use.
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e1
Designation:F2212–02 (Reapproved 2007)
Standard Guide for
Characterization of Type I Collagen as Starting Material for
Surgical Implants and Substrates for Tissue-Engineered
Medical Products (TEMPs)
This standard is issued under the fixed designation F 2212; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (e) indicates an editorial change since the last revision or reapproval.
e NOTE—Formatting and grammar were corrected editorially throughout in April 2007.
INTRODUCTION
Collagen-based medical devices are becoming more prevalent, especially in the area of soft tissue
augmentation. The use of collagen in surgery dates back to the late 1800s, with the use of catgut
sutures, human cadaveric skin, and fascia. More recently, collagen has been used in hemostatic
sponges, dermal equivalents, injectables for soft tissue augmentation, as a matrix for cell-based
products and as a vehicle for drug delivery. It is because of the versatility of collagen in medical
applications that specific characterizations should be performed as a way to compare materials.
1. Scope Products (TEMPs); some methods may not be applicable for
gelatin nor for tissue implants. This guide may serve as a
1.1 This guide for characterizing collagen-containing bio-
template for characterization of other types of collagen.
materials is intended to provide characteristics, properties, and
1.2 The biological response to collagen in soft tissue has
test methods for use by producers, manufacturers, and re-
been well documented by a history of clinical use (1, 2) and
searchers to more clearly identify the specific collagen mate-
laboratory studies (3, 4, 5, 21). Biocompatibility and appropri-
rials used. With greater than 20 types of collagen and the
ateness of use for a specific application(s) is the responsibility
different properties of each, a single document would be
of the device manufacturer.
cumbersome. This guide will focus on the characterization of
1.3 The following precautionary caveat pertains only to the
Type I collagen, which is the most abundant collagen in
test method portion, Section 5, of this guide. This standard
mammals, especially in skin and bone. Collagen isolated from
does not purport to address all of the safety concerns, if any,
thesesourcesmaycontainothertypesofcollagen,forexample,
associated with its use. It is the responsibility of the user of this
Type III and Type V. This guide does not provide specific
standard to establish appropriate safety and health practices
parameters for any collagen product or mix of products or the
and determine the applicability of regulatory requirements
acceptability of those products for the intended use. The
prior to use.
collagen may be from any source, including, but not limited to,
animal or cadaveric sources, human cell culture, or recombi-
2. Referenced Documents
nant sources. The biological, immunological, or toxicological
2.1 ASTM Standards:
properties of the collagen may vary, depending on the source
E 1298 Guide for Determination of Purity, Impurities, and
material. The properties of the collagen prepared from each of
Contaminants in Biological Drug Products
the above sources must be thoroughly investigated, as the
F 619 Practice for Extraction of Medical Plastics
changes in the collagen properties as a function of source
F 720 Practice for Testing Guinea Pigs for Contact Aller-
materials is not thoroughly understood. This guide is intended
gens: Guinea Pig Maximization Test
to focus on purified Type I collagen as a starting material for
surgicalimplantsandsubstratesforTissue-EngineeredMedical
The boldface numbers in parentheses refer to the list of references at the end of
This guide is under the jurisdiction of ASTM Committee F04 on Medical and this standard.
Surgical Materials and Devices and is the direct responsibility of Subcommittee For referenced ASTM standards, visit the ASTM website, www.astm.org, or
F04.42 on Biomaterials and Biomolecules for TEMPs. contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Current edition approved Feb. 1, 2007. Published February 2007. Originally Standards volume information, refer to the standard’s Document Summary page on
approved in 2002. Last previous edition approved in 2002 as F 2212 – 02. the ASTM website.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.
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F2212–02 (2007)
F 748 Practice for Selecting Generic Biological Test Meth- EN 12442-2—Part 2 Controls on Sourcing, Collection and
ods for Materials and Devices Handling
F 749 Practice for Evaluating Material Extracts by Intracu- EN 12442-3—Part 3 Validation of the Elimination and/or
taneous Injection in the Rabbit Inactivation of Virus and Transmissible Agents
F 756 Practice for Assessment of Hemolytic Properties of 2.4 U. S. Pharmacopeia Documents:
Materials United States Pharmacopeia (USP), Edition XXIV (24)
F 763 Practice for Short-Term Screening of Implant Mate- USP 24/NF 19 Viral Safety Evaluation of Biotechnology
rials Products Derived from Cell Lines of Human or Animal
F 813 PracticeforDirectContactCellCultureEvaluationof Origin
Materials for Medical Devices 2.5 Code of Federal Regulations:
F 895 Test Method forAgar Diffusion Cell Culture Screen- Code of Federal Regulations, Title 21, Part 820
ing for Cytotoxicity Federal Register Vol. 43, No. 141, Friday, July 21, 1978
F 981 Practice for Assessment of Compatibility of Bioma- Human Cells, Tissues and Cellular and Tissue-Based Prod-
terials for Surgical Implants with Respect to Effect of ucts, Establishment Registration and Listing. 21 CFR
Materials on Muscle and Bone Parts 207, 807, and 1271
F 1251 Terminology Relating to Polymeric Biomaterials in Federal Register/Vol. 66, No. 13, Jan 19, 2001/Rules and
Medical and Surgical Devices Regulations, page 5447
F 1439 Guide for Performance of Lifetime Bioassay for the Suitability Determination for Donors of Human Cell and
Tumorigenic Potential of Implant Materials Tissue-based Products, 21 CFR 1271 Part C, Proposed
F 1903 Practice for Testing For Biological Responses to Rule
Particles in vitro Current Good Tissue Practice for Manufacturers of Human
F 1904 Practice for Testing the Biological Responses to Cellular and Tissue-Based Products, Inspection and En-
Particles in vivo forcement. Proposed Rule. Federal Register/Vol. 66, No.
F 1905 Practice For Selecting Tests for Determining the 5/January 8, 2001/Proposed Rules, pages 1552-1559
Propensity of Materials to Cause Immunotoxicity Guidance for Screening and Testing of Donors of Human
F 1906 Practice for Evaluation of Immune Responses In Tissue Intended for Transplantation, Availability. Federal
Biocompatibility Testing Using ELISATests, Lymphocyte Register/Vol. 62, No. 145/July 29, 1997/NoticesDraft
Proliferation, and Cell Migration Guidance for Preclinical and Clinical Investigations of
F 1983 Practice for Assessment of Compatibility of Urethral BulkingAgents used in the Treatment of Urinary
Absorbable/Resorbable Biomaterials for Implant Applica- Incontinence. November 29, 1995. (ODE/DRARD/
tions ULDB), Document No. 850
F 2148 Practice for Evaluation of Delayed Contact Hyper- Guidance for Industry and for FDA Reviewers, Medical
sensitivity Using the Murine Local Lymph Node Assay Devices Containing Materials Derived from Animal
(LLNA) Sources(Exceptfor In VitroDiagnosticDevices),Novem-
2.2 ISO Standards: ber 6, 1998, U.S. Department of Health and Human
ISO 10993-1 Biological Evaluation of Medical Devices— Services, Food and Drug Administration, Center for De-
Part 1: Evaluation and Testing vices and Radiological Health
ISO 10993-3—Part 3 Tests for Genotoxicity, Carcinogenic- CFR 610.13(b), Rabbit Pyrogen Assay
ity and Reproductive Toxicity 2.6 ICH Documents:
ISO 10993-9—Part 9 Framework for Identification and International Conference on Harmonization (1997) Guid-
Quantification of Potential Degradation Products ance for Industry M3 Nonclinical Safety Studies for the
ISO 10993-10 Biological Evaluation of Medical Devices— Conduct of Human Clinical Trials for Pharmaceuticals 62
Part 10: Tests for Irritation and Delayed-Type Hypersen- FR 62922
sitivity International Conference on Harmonization (1996) Guide-
ISO 10993-17—Part 17 Methods for Establishment of Al- line for Industry S2A Specific Aspects of Regulatory
lowable Limits for Leachable Substances Using Health- Genotoxicity Tests for Pharmaceuticals. 61 FR 18199
Based Risk Assessment International Conference on Harmonization (1997) Guid-
ISO 13408-1: 1998 Aseptic Processing of Health Care ance for Industry S2B Genotoxicity: A Standard Battery
Products—Part 1: General Requirements for Genotoxicity Testing of Pharmaceuticals 62 FR 62472
2.3 EN (European Norm) Documents: International Conference on Harmonization (1994) Guide-
EN 12442-1 Animal Tissues and their Derivatives Utilized line for Industry S5A Detection of Toxicity to Reproduc-
in the Manufacture of Medical Devices—Part 1:Analysis tion for Medicinal Products. 59 FR 48746
and Management of Risk
Available from U.S. Pharmacopeia (USP), 12601Twinbrook Pkwy., Rockville,
MD 20852.
4 7
Available from International Organization for Standardization (ISO), 1 rue de AvailablefromU.S.GovernmentPrintingOfficeSuperintendentofDocuments,
Varembé, Case postale 56, CH-1211, Geneva 20, Switzerland. 732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401.
5 8
Available from European Committee for Standardization, CEN Management ICH Secretariat, c/o IFPMA, 30 rue de St-Jean, P.O. Box 758, 1211 Geneva 13,
Centre 36, rue de Stassart B-1050 Brussels, Belgium. Switzerland.
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F2212–02 (2007)
International Conference on Harmonization (1996) Guid- Devices—Part 7: Ethylene Oxide Sterilization Residuals
ance for Industry S5B Detection of Toxicity to Reproduc- AAMI/ISO14160-1998 SterilizationofSingle-UseMedical
tion for Medicinal Products: Addendum on Toxicity to Devices Incorporating Materials of Animal Origin—
Male Fertility. 61 FR 15360 Validation and Routine Control of Sterilization by Liquid
International Conference on Harmonization (1996) Guide- Chemical Sterilants
line for Industry S1A The Need for Long-term Rodent AAMI ST67/CDV-2: 1999 Sterilization of Medical
Carcinogenicity Studies of Pharmaceuticals. 61 FR 8153 Devices—Requirements for Products Labeled “Sterile”
International Conference on Harmonization (1998) Guid- 2.9 Other References:
ance for Industry S1B Testing for Carcinogenicity of Draft Guidance for Preclinical and Clinical Investigations of
Pharmaceuticals. 63 FR 8983 UrethralBulkingAgentsUsedintheTreatmentofUrinary
International Conference on Harmonization (1995) Guide- Incontinence, November 29, 1995. (ODE/DRARD/
line for Industry S1C Dose Selection for Carcinogenicity ULDB), Document No. 850.
Studies of Pharmaceuticals. 60 FR 11278
3. Terminology
International Conference on Harmonization (1997)
S1C(R) Guidance for IndustryAddendum to Dose Selec-
3.1 Definitions:
tion for Carcinogenicity Studies of Pharmaceuticals: Ad-
3.1.1 adventitious agents, n—an unintentionally introduced
dition of a Limit Dose and Related Notes. 62 FR 64259
microbiologicalorotherinfectiouscontaminant.Intheproduc-
International Conference on Harmonization (ICH) Q1A
tionofTEMPs,theseagentsmaybeunintentionallyintroduced
ICH HarmonizedTripartiteGuidanceforStabilityTesting into the process stream or the final product, or both.
of New Drug Substances and Products (September 23,
3.1.2 biocompatibility, n—a material may be considered
1994) biocompatibleifthematerialsperformwithanappropriatehost
U.S. Food and Drug Administration (FDA and Committee
response in a specific application (22).
for Proprietary Medicinal Products (CPMP), 1998 Inter- 3.1.3 collagen, n—Type I collagen is a member of a family
national Conference on Harmonization (ICH), Quality of
of structural proteins found in animals. Type I collagen is part
Biotechnological Products: Viral Safety Evaluation of of the fibrillar group of collagens. It derives from the COL1A1
Biotechnology Products Derived from Cell Lines of Hu-
and COL1A2 genes, which express the alpha chains of the
man or Animal Origin, Consensus Guideline ICH Viral collagen. All collagens have a unique triple helical structure
Safety Document: Step 5
configuration of three polypeptide units known as alpha-
2.7 FDA Documents: chains. Proper alignment of the alpha chains of the collagen
FDA Guideline on Validation of the Limulus Amebocyte
molecule requires a highly complex enzymatic and chemical
Test as an End-Product Endotoxin Test for Human and interaction in vivo. As such, preparation of the collagen by
AnimalParenteralDrugs,BiologicalProductsandHealth-
alternate methods may result in improperly aligned alpha
care Products, DHHS, December 1987 chains and, putatively, increase the immunogenicity of the
U.S. Food and Drug Administration (FDA) Center for
collagen. Collagen is high in glycine, L-alanine, L-proline, and
Biologics Evaluation and Research (CBER), 1993 Points
4-hydroxyproline, low in sulfur, and contains no L-tryptophan.
to Consider in the Characterization of Cell Lines Used to
Natural, fibrillar Type I collagen is normally soluble in dilute
produce Biologicals
acids and alkalis. When heated (for example, above approxi-
U.S. Food and Drug Administration (FDA) Center for mately 40°C), collagen is denatured to single alpha chains
Biologics Evaluation and Research (CBER), 1997 Points
(gelatin). At each end of the chains are short non-helical
toConsiderintheManufactureandTestingofMonoclonal domains called telopeptides, which are removed in some
Antibody Products for Human Use, 94D-0259
collagen preparations. Through non-covalent interactions with
FDA Interim Guidance for Human and Veterinary Drug sites on adjacent helixes, fibrillogenesis is achieved. Subse-
Products and Biologicals, Kinetic LAL techniques,
quently, non-reducible cross links are formed. Type I collagen
DHHS, July 15, 1991 can be associated with Type III and Type V collagen and also
2.8 AAMI Documents:
with the other non-collagenous proteins like elastin and other
ANSI/AAMI/ISO 11737-1: 1995 Sterilization of Medical structural molecules like glycosaminoglycans and complex
Devices—Microbiological Methods—Part 1: Estimation
lipoproteins and glycoproteins.
of Bioburden on Product 3.1.4 degradation, n—change in chemical, physical, or
ANSI/AAMI/ISO 11737-2: 1998 Sterilization of Medical
molecular structure or appearance (that is, gross morphology)
Devices—Microbiological Methods—Part 2:Tests of Ste- of materia
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