1、Designation: F2103 11F2103 18Standard Guide forCharacterization and Testing of Chitosan Salts as StartingMaterials Intended for Use in Biomedical and Tissue-Engineered Medical Product Applications1This standard is issued under the fixed designation F2103; the number immediately following the designa
2、tion indicates the year oforiginal adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.INTRODUCTIONBiopolymers from marine sources h
3、ave been studied and used in commercial applications andproduct development for a number of years. Chitosan, a linear polysaccharide consisting ofglucosamine and N-acetyl glucosamine derived mainly from crustacean shells, has been used in manytechnical applications such as water purification (as a f
4、locculant), in cosmetics, and recently as aproposed fat-binding weight control product. In solution, the cationic nature of chitosan gives thispolymer a mucoadhesive property. Chitosan and its salts can be used as a matrix or scaffold materialas well as in non-parenteral delivery systems for challen
5、ging drugs. Chitosan salts have been shownto increase the transport of polar drugs across the nasal epithelial surface. The purpose of this guideis to identify key parameters relevant for the functionality and characterization of chitosan andchitosan salts for the development of new commercial appli
6、cations of chitosan salts for the biomedicaland pharmaceutical industries.1. Scope1.1 This guide covers the evaluation of chitosan salts suitable for use in biomedical or pharmaceutical applications, or both,including, but not limited to, tissue-engineered medical products (TEMPS).1.2 This guide add
7、resses key parameters relevant for the functionality, characterization, and purity of chitosan salts.1.3 As with any material, some characteristics of chitosan may be altered by processing techniques (such as molding, extrusion,machining, assembly, sterilization, and so forth) required for the produ
8、ction of a specific part or device. Therefore, properties offabricated forms of this polymer should be evaluated using test methods that are appropriate to ensure safety and efficacy.1.4 WarningMercury has been designated by EPA and many state agencies as a hazardous material that can cause centraln
9、ervous system, kidney, and liver damage. Mercury, or its vapor, may be hazardous to health and corrosive to materials. Cautionshould be taken when handling mercury and mercury-containing products. See the applicable product Material Safety Data Sheet(MSDS) for details and EPAs website (http:/www.epa
10、.gov/mercury/faq.htm) for additional information. Users should be awarethat selling mercury or mercury-containing products, or both, in your state may be prohibited by state law.1.5 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this stand
11、ard.1.6 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibilityof the user of this standard to establish appropriate safety safety, health, and healthenvironmental practices and determine theapplicability of regulatory limitatio
12、ns prior to use.1.7 This international standard was developed in accordance with internationally recognized principles on standardizationestablished in the Decision on Principles for the Development of International Standards, Guides and Recommendations issuedby the World Trade Organization Technica
13、l Barriers to Trade (TBT) Committee.1 This guide is under the jurisdiction of ASTM Committee F04 on Medical and Surgical Materials and Devices and is the direct responsibility of Subcommittee F04.42on Biomaterials and Biomolecules for TEMPs.Current edition approved March 1, 2011June 1, 2018. Publish
14、ed March 2011August 2018. Originally approved in 2001. Last previous edition approved in 20072011 asF2103 01F2103 11.(2007)2. DOI: 10.1520/F2103-11.10.1520/F2103-18.This document is not an ASTM standard and is intended only to provide the user of an ASTM standard an indication of what changes have b
15、een made to the previous version. Becauseit may not be technically possible to adequately depict all changes accurately, ASTM recommends that users consult prior editions as appropriate. In all cases only the current versionof the standard as published by ASTM is to be considered the official docume
16、nt.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States12. Referenced Documents2.1 ASTM Standards:2D2196 Test Methods for Rheological Properties of Non-Newtonian Materials by Rotational ViscometerF619 Practice for Extraction of Medical Pla
17、sticsF748 Practice for Selecting Generic Biological Test Methods for Materials and DevicesF749 Practice for Evaluating Material Extracts by Intracutaneous Injection in the RabbitF756 Practice for Assessment of Hemolytic Properties of MaterialsF763 Practice for Short-Term Screening of Implant Materia
18、lsF813 Practice for Direct Contact Cell Culture Evaluation of Materials for Medical DevicesF895 Test Method for Agar Diffusion Cell Culture Screening for CytotoxicityF981 Practice for Assessment of Compatibility of Biomaterials for Surgical Implants with Respect to Effect of Materials onMuscle and I
19、nsertion into BoneF1251 Terminology Relating to Polymeric Biomaterials in Medical and Surgical Devices (Withdrawn 2012)3F1439 Guide for Performance of Lifetime Bioassay for the Tumorigenic Potential of Implant MaterialsF1903 Practice for Testing For Biological Responses to Particles In VitroF1904 Pr
20、actice for Testing the Biological Responses to Particles in vivoF1905 Practice For Selecting Tests for Determining the Propensity of Materials to Cause Immunotoxicity (Withdrawn 2011)3F1906 Practice for Evaluation of Immune Responses In Biocompatibility Testing Using ELISATests, Lymphocyte Prolifera
21、tion,and Cell Migration (Withdrawn 2011)3F2260 Test Method for Determining Degree of Deacetylation in Chitosan Salts by Proton Nuclear Magnetic Resonance (1HNMR) SpectroscopyF2602 Test Method for Determining the Molar Mass of Chitosan and Chitosan Salts by Size Exclusion Chromatography withMulti-ang
22、le Light Scattering Detection (SEC-MALS)2.2 Ph. Eur. Document:Ph. Eur.4 Monograph Chitosan Chloride, Nov. 20002.3 ISO Documents:5ISO 1099331-8 Biological Evaluation of Medical DevicesQuantities and Units Part 8: Physical Chemistry and MolecularPhysicsISO 13408-1: 1998 Aseptic Processing of Health Ca
23、re Products Part 1: General RequirementsISO 10993-122442-1 Biological Evaluation of Medical DevicesPart 1: Evaluation and TestingMedical Devices UtilizingAnimal Tissues and Their Derivatives Part 1: Application of Risk ManagementISO 10993-3Part 3:22442-2 Tests for Genotoxicity, Carcinogenicity and R
24、eproductive ToxicityMedical Devices UtilizingAnimal Tissues and Their Derivatives Part 2: Controls On Sourcing, Collection, and HandlingISO 10993-9Part 9:22442-3 Framework for Identification and Quantification of Potential Degradation ProductsMedicalDevices UtilizingAnimal Tissues and Their Derivati
25、ves Part 3: Validation of the Elimination and/or Inactivation of Virusesand Transmissible Spongiform Encephalopathy (TSE) AgentsISO 10993-17Part 17: Methods for Establishment of Allowable Limits for Leachable Substances Using Health-Based RiskAssessment5ISO 13408-1: 1998:80000-9:2009 Aseptic Process
26、ing of Health Care ProductsPart 1: General Requirements Quantities andunits Part 9: Physical Chemistry and Molecular Physics2.4 ICH Documents:6International Conference on Harmonization (1997) Guidance for Industry M3 Nonclinical Safety Studies for the Conduct ofHuman Clinical Trials for Pharmaceutic
27、als 62 FR 62922International Conference on Harmonization (1996) Guideline for Industry S2A Specific Aspects of Regulatory GenotoxicityTests for Pharmaceuticals 61 FR 18199International Conference on Harmonization (1997) Guidance for Industry S2B Genotoxicity: A Standard Battery forGenotoxicity Testi
28、ng of Pharmaceuticals 62 FR 62472International Conference on Harmonization (1994) Guideline for Industry S5A Detection of Toxicity to Reproduction forMedicinal Products 59 FR 48746International Conference on Harmonization (1996) Guidance for Industry S5B Detection of Toxicity to Reproduction forMedi
29、cinal Products: Addendum on Toxicity to Male Fertility 61 FR 153602 For referencedASTM standards, visit theASTM website, www.astm.org, or contactASTM Customer Service at serviceastm.org. For Annual Book of ASTM Standardsvolume information, refer to the standards Document Summary page on the ASTM web
30、site.3 The last approved version of this historical standard is referenced on www.astm.org.4 Available from EDQM, Publications and Services European Pharmacopoeia, BP 907 226, avenue de Colmar, F-67029 Strasbourg Cedex 1, France.5 Available from American National Standards Institute (ANSI), 25 W. 43
31、rd St., 4th Floor, New York, NY 10036, http:/www.ansi.org.International Organization forStandardization (ISO), ISO Central Secretariat, BIBC II, Chemin de Blandonnet 8, CP 401, 1214 Vernier, Geneva, Switzerland, http:/www.iso.org.6 Available from ICH Secretariat, c/o IFPMA, 30 rue de St-Jean, PO Box
32、 758, 1211 Geneva 13, Switzerland.F2103 182International Conference on Harmonization (1996) Guideline for Industry S1AThe Need for Long-term Rodent CarcinogenicityStudies of Pharmaceuticals 61 FR 8153International Conference on Harmonization (1998) Guidance for Industry S1B Testing for Carcinogenici
33、ty of Pharmaceuti-cals 63 FR 8983International Conference on Harmonization (1995) Guideline for Industry S1C Dose Selection for Carcinogenicity Studies ofPharmaceuticals 60 FR 11278International Conference on Harmonization (1997) S1CR Guidance for Industry Addendum to Dose Selection forCarcinogenici
34、ty Studies of Pharmaceuticals: Addition of a Limit Dose and Related Notes 62 FR 64259International Conference on Harmonization (ICH) Q1AICH Harmonized Tripartite Guidance for Stability Testing of New DrugSubstances and Products (September 23, 1994)2.5 FDA Documents:7FDA Guideline DHHSFDA Guideline o
35、n Validation of the Limulus Amebocyte Test as an End-Product Endotoxin Test for Human and AnimalParenteral Drugs, Biological Products and Healthcare Products DHHS, December 1987FDA Interim Guidance for Human and Veterinary Drug Products and Biologicals. Kinetic LAL Techniques DHHS, July 15,19912.6 A
36、NSI Documents:5ANSI/AAMI/ISO 11737-1: 1995 Sterilization of Medical DevicesMicrobiological MethodsPart 1: Estimation of Bioburdenon ProductANSI/AAMI/ISO 11737-2: 1998 Sterilization of Medical DevicesMicrobiological MethodsPart 2: Tests of SterilityPerformed in the Validation of a Sterilization Proce
37、ss2.7 AAMI Documents:8AAMI TIR No. 191998:191998 Guidance for ANSI/AAMI/ISO 109937: 1995, Biological Evaluation of MedicalDevicesPart 7: Ethylene Oxide Sterilization ResidualsAAMI/ISO 141601998:14160:1998 Sterilization of Single-Use Medical Devices Incorporating Materials ofAnimal OriginValidation a
38、nd Routine Control of Sterilization by Liquid Chemical SterilantsAAMI ST67/CDV-2: 1999:ST67/CDV-2:1999 Sterilization of Medical DevicesRequirements for Products Labeled “Sterile”2.8 EN United States Pharmacopeia Documents:9EN 12442-1USP Chapter Animal Tissues and Their Derivative Utilized in the Man
39、ufacture of Medical DevicesPart 1:Analysis and Management of RiskBiological Tests and Assays: Bacterial Endotoxins TestsEN 12442-Part 3:USP Chapter Validation of the Elimination and/or Inactivation of Virus and TransmissibleAgentsMicrobial Limit TestsUSP36-NF31 Elemental ImpuritiesUSP Chapter USP Ch
40、apter Sterility TestsUSP Chapter Sterilization and Sterility Assurance of Compendial ArticlesUSP 24/NF192.9 NIST Document:10NIST Special Publication 811 Guide for the Use of the International System of Units (SI)2.10 U.S. Code of Federal Regulations:1121CFR312: Title 21 Code of Federal Regulations,
41、Part 312 Investigational New Drug Application3. Terminology3.1 Definitions:3.1.1 chitosan, na linear polysaccharide consisting of (14) linked 2-acetamido-2-deoxy-D-glucopyranose (GlcNAc) and2-amino-2-deoxy-D-glucopyranose (GlcN).3.1.1.1 DiscussionChitosan is a polysaccharide derived by N-deacetylati
42、on of chitin.3.1.2 decomposition, nstructural changes of chitosans as a result of exposure to environmental, chemical, or thermal factors,such as temperatures greater than 200C.7 Available from Food and Drug Administration (FDA), 5600 Fishers Ln., Rockville, MD 20857, http:/www.fda.gov.8 Association
43、 for the Advancement of Medical Instrumentation, 111 N. Glebe Rd., Suite 220, Arlington, VA 222014795.9 Available from European Committee for Standardization, CEN Management Centre, 36 rue de Stassart, B-1050 Brussels, Belgium.U.S. Pharmacopeial Convention(USP), 12601 Twinbrook Pkwy., Rockville, MD
44、20852-1790, http:/www.usp.org.10 Available from National Institute of Standards and Technology (NIST), 100 Bureau Dr., Stop 1070, Gaithersburg, MD 20899-1070, http:/www.nist.gov.11 Available from U.S. Government Printing Office, Superintendent of Documents, 732 N. Capitol St., NW, Washington, DC 204
45、01-0001, http:/www.access.gpo.gov.F2103 1833.1.2.1 DiscussionDecomposition can result in deleterious changes to the chitosan.3.1.3 degradation, nchange in the chemical structure, physical properties, or appearance of a material.3.1.3.1 DiscussionDegradation of polysaccharides occurs by means of clea
46、vage of the glycosidic bonds, usually by acid catalyzed hydrolysis.Degradation can also occur thermally. Note that degradation is not synonymous with decomposition. Degradation is often used asa synonym for depolymerization when referring to polymers.3.1.4 degree of deacetylation, nthe fraction or p
47、ercentage of glucosamine units (deacetylated monomers) in a chitosanpolymer molecule.3.1.5 depolymerization, nreduction in length of a polymer chain to form shorter polymeric units.3.1.5.1 DiscussionDepolymerization may reduce the polymer chain to oligomeric or monomeric units, or both. In chitosan,
48、 hydrolysis of theglycosidic bonds is the primary mechanism.3.1.6 dispersity, nmeasure of the heterogeneity of sizes of molecules or particles in a mixture, calculated by the ratio ofMw/Mn.3.1.7 endotoxin, npyrogenic high molar mass lipopolysaccharide (LPS) complex associated with the cell wall ofgr
49、am-negative bacteria.3.1.7.1 DiscussionThough endotoxins are pyrogens, not all pyrogens are endotoxins. Endotoxins are specifically detected through a LimulusAmebocyte Lysate (LAL) test.3.1.8 molecular mass average (molecular weight average), nthe given molecular weight (Mw)(M) of a chitosan will alwaysrepresent an average of all of the molecules in the population. The most common ways to express the MwM are as the numberaverage (Mn) and the weight average (Mw). The two averages are defined by the following equati
