ASTM F2347-03

Standard Guide for Characterization and Testing of Hyaluronan as Starting Materials Intended for Use in Biomedical and Tissue Engineered Medical Product Applications

SIGNIFICANCE AND USE
This guide contains a listing of those characterization parameters that are directly related to the functionality of hyaluronan. This guide can be used as an aid in the selection and characterization of the appropriate hyaluronan for a particular application. This guide is intended to give guidance in the methods and types of testing necessary to properly characterize, assess, and ensure consistency in the performance of a particular hyaluronan. It may have use in the regulation of these devices by appropriate authorities.
The hyaluronan covered by this guide may be gelled, cross-linked, extruded, or otherwise formulated into biomedical devices for use in tissue engineered medical products or drug delivery devices for implantation as determined to be appropriate, based on supporting biocompatibility and physical test data. Recommendations in this guide should not be interpreted as a guarantee of clinical success in any tissue engineered medical product or drug delivery application.
To ensure that the material supplied satisfies requirements for use in TEMPs, several general areas of characterization should be considered. These are: identity of hyaluronan, physical and chemical characterization and testing, impurities profile, and performance-related tests.
SCOPE
1.1 This guide covers the evaluation of hyaluronan suitable for use in biomedical or pharmaceutical applications, or both, including, but not limited to, Tissue Engineered Medical Products (TEMPs).
1.2 This guide addresses key parameters relevant to the characterization and purity of hyaluronan.
1.3 As with any material, some characteristics of hyaluronan may be altered by processing techniques, such as cross-linking and sterilization, required for the production of a specific formulation or device. Therefore, properties of fabricated forms of this polymer should be evaluated using test methods that are appropriate to ensure safety and efficacy and are not addressed in this guide.
1.4 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.

General Information

• Status: Historical
• Publication Date: 31-Oct-2003
• ICS: 11.120.99 - Other standards related to pharmaceutics
• Technical Committee: F04 - Medical and Surgical Materials and Devices
• Drafting Committee: F04.42 - Biomaterials and Biomolecules for TEMPs

Relations

• Replaced By: ASTM F2347-11 - Standard Guide for Characterization and Testing of Hyaluronan as Starting Materials Intended for Use in Biomedical and Tissue Engineered Medical Product Applications
• Effective Date: 01-Mar-2011
• Referred By: ASTM F2027-16 - Standard Guide for Characterization and Testing of Raw or Starting Materials for Tissue-Engineered Medical Products
• Effective Date: 01-Nov-2003

Standards Content (Sample)

NOTICE: This standard has either been superseded and replaced by a new version or withdrawn.
Contact ASTM International (www.astm.org) for the latest information
Designation: F2347 – 03
Standard Guide for
Characterization and Testing of Hyaluronan as Starting
Materials Intended for Use in Biomedical and Tissue
Engineered Medical Product Applications
This standard is issued under the fixed designation F2347; 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 (´) indicates an editorial change since the last revision or reapproval.
INTRODUCTION
Hyaluronan, which in this guide will encompass hyaluronic acid, hyaluronate, and its salt forms, is
the simplest of the glycosaminoglycans. Hyaluronan is soluble in water and forms highly viscous
solutions.Hyaluronanisfoundinubiquitouslyinthebodyaspartoftheextracellularmatrixoftissues,
with high concentrations in the synovial fluid, vitreous humor, and skin, as well as in cartilage.
Hyaluronan has found uses in a variety of products ranging from viscosupplements (treatment of
osteoarthritis), adhesion prevention (prevention of post-surgical adhesions), viscoelastics (ocular
protection), and dermal implants (lip augmentation and wrinkle removal). New applications, such as
scaffolds for tissue engineering, are emerging. The aim of this guide is to identify key parameters
relevant to the characterization of hyaluronan for the development of new commercial applications of
hyaluronan for the biomedical and pharmaceutical industries.
1. Scope 2. Referenced Documents
1.1 This guide covers the evaluation of hyaluronan suitable 2.1 ASTM Standards:
for use in biomedical or pharmaceutical applications, or both, D2196 Test Methods for Rheological Properties of Non-
including, but not limited to, Tissue Engineered Medical Newtonian Materials by Rotational (Brookfield type) Vis-
Products (TEMPs). cometer
1.2 This guide addresses key parameters relevant to the F619 Practice for Extraction of Medical Plastics
characterization and purity of hyaluronan. F748 Practice for Selecting Generic Biological Test Meth-
1.3 As with any material, some characteristics of hyaluro- ods for Materials and Devices
nan may be altered by processing techniques, such as cross- F749 Practice for Evaluating Material Extracts by Intracu-
linking and sterilization, required for the production of a taneous Injection in the Rabbit
specific formulation or device. Therefore, properties of fabri- F756 Practice for Assessment of Hemolytic Properties of
cated forms of this polymer should be evaluated using test Materials
methods that are appropriate to ensure safety and efficacy and F763 Practice for Short-Term Screening of Implant Materi-
are not addressed in this guide. als
1.4 This standard does not purport to address all of the F813 Practice for Direct Contact Cell Culture Evaluation of
safety concerns, if any, associated with its use. It is the Materials for Medical Devices
responsibility of the user of this standard to establish appro- F895 Test Method for Agar Diffusion Cell Culture Screen-
priate safety and health practices and determine the applica- ing for Cytotoxicity
bility of regulatory requirements prior to use. F981 Practice forAssessment of Compatibility of Biomate-
rials for Surgical Implants with Respect to Effect of
This guide is under the jurisdiction of ASTM Committee F04 on Medical and
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 [e-mail]. For Annual Book of ASTM
Current edition approved Nov. 1, 2003. Published December 2003. DOI: Standards volume information, refer to the standard’s Document Summary page on
10.1520/F2347-03. the ASTM website.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.
F2347 – 03
Materials on Muscle and Bone ISO EN 12442-3 Animal Tissues and Their Derivative
F1251 Terminology Relating to Polymeric Biomaterials in Utilized in the Manufacture of Medical Devices—Part 3:
Medical and Surgical Devices Validation of the Elimination and/or inactivation of Virus
F1439 Guide for Performance of Lifetime Bioassay for the and Transmissible Agents
Tumorigenic Potential of Implant Materials International Conference on Harmonization (ICH) S2B
F1903 Practice for Testing For Biological Responses to Genotoxicity AStandardBatteryforGenotoxicityTesting
Particles in vitro of Pharmaceuticals (July 1997)
F1904 Practice for Testing the Biological Responses to International Conference on Harmonization (ICH) Q1A
Particles in vivo ICH HarmonizedTripartiteGuidanceforStabilityTesting
F1905 Practice For Selecting Tests for Determining the of New Drug Substances and Products (September 2001,
Propensity of Materials to Cause Immunotoxicity Revision 1)
F1906 Practice for Evaluation of Immune Responses In FDA Guideline on Validation of the Limulus Amebocyte
Biocompatibility Testing Using ELISATests, Lymphocyte Test as an End-Product Endotoxin Test for Human and
Proliferation, and Cell Migration AnimalParenteralDrugs,BiologicalProductsandHealth-
3 7
2.2 USP Documents: care Products, DHHS, December 1987
USP <61> Microbial Limit Tests FDA Interim Guidance for Human and Veterinary Drug
USP <71> Sterility Tests Products and Biologicals, Kinetic LAL Techniques,
USP <85> Bacterial Endotoxins Tests DHHS, July 15, 1991
USP <231> Heavy Metals AAMITIRNo.7:1999 ChemicalSterilantsandHighLevel
USP <731> Loss on Drying Disinfectants: A Guide to Selection and Use
USP <1211> Sterilization and Sterility Assurance of Com- AAMI ST67/CDV-2: 1999 Sterilization of Medical
pendial Articles Devices—Requirements for Products Labeled “Sterile”
2.3 EP Documents: 21 CFR 312 FDATitle 21, Food and Drugs, Investigational
EP Monograph 1472 Sodium Hyaluronate New Drug Applications
EP 2.6.1 Sterility
2.4 Other Referenced Documents: 3. Terminology
ISO 10993 Biological Evaluation of Medical Devices
3.1 Definitions:
ISO 10993-1 Biological Evaluation of Medical Devices—
3.1.1 hyaluronan, n—a polysaccharide with a disaccharide
Part 1: Evaluation and Testing
repeating unit composed of D-glucuronic acid and N-acetyl-
ISO 10993-7 Biological Evaluation of Medical Devices—
D-glucosamine in b-(1→3) linkage. Each disaccharide unit is
Part 7: Ethylene Oxide Sterilization Residuals
attached to the next by b-(1→4) bonds. Hyaluronan is a linear
ISO 10993-9 Biological Evaluation of Medical Devices—
polymer.Othercommonnamesarehyaluronicacidandsodium
Part 9: Framework for Identification and Quantification of
hyaluronate.
Potential Degradation Products
3.1.2 hydrocolloid, n—a water-soluble polymer of colloidal
ISO 10993-17 Biological Evaluation of Medical
nature when hydrated.
Devices—Part 17: Establishment of Allowable Limits for
3.1.3 molecular mass average (molecular weight average),
Leachable Substances
n—the given molecular weight (Mw) of hyaluronan will
ISO 14160-1998 Sterilization of Single-Use Medical De-
always represent an average of all of the molecules in the
vices Incorporating Materials of Animal Origin—
population. The most common ways to express the Mw are as
Validation and Routine Control of Sterilization by Liquid
— —
the number average (M ) and the weight average (M ). The
n w
Chemical Sterilants
two averages are defined by the following equations:
ISO 11737-1: 1995 Sterilization of Medical Devices—
Microbiological Methods—Part 1: Estimation of Popula-
NM wM NM
— ( — ( (
i i i i i i i i i
M 5 and M 5 5
n w
tion of Microorganisms on Products
N w NM
( ( (
i i i i i i i
ISO 11737-2: 1998 Sterilization of Medical Devices—
where:
Microbiological Methods—Part 2: Tests of Sterility Per-
5 N = number of molecules having a specific molecular
i
formed in the Validation of a Sterilization Process
weight M, and
i
ISO 13408-1: 1998 Aseptic Processing of Health Care
5 w = weight of molecules having a specific molecular
i
Products—Part 1: General Requirements
weight M.
i
ISO EN 12442-1 Animal Tissues and Their Derivative
Utilized in the Manufacture of Medical Devices—Part 1:
Analysis and Management of Risk
Available from ICH Secretariat, c/o IFPMA, 30 rue de St-Jean, P.O. Box 758,
1211 Geneva 13, Switzerland.
3 7
Available from U.S. Pharmacopeia (USP), 12601Twinbrook Pkwy., Rockville, Available from U.S. Food and Drug Administration, 5600 Fishers Lane,
MD 20852. Rockville, MD 20857-0001.
4 8
Available from European Directorate for the Quality of Medicines (EDQM), Available from Association for the Advancement of Medical Instrumentation,
Council of Europe, BP 907, 67029 Strasbourg, France. 1110 North Glebe Rd., Suite 220, Arlington, VA 22201-4795.
5 9
Available fromAmerican National Standards Institute (ANSI), 25 W. 43rd St., Available from Standardization Documents Order Desk, DODSSP, Bldg. 4,
4th Floor, New York, NY 10036. Section D, 700 Robbins Ave., Philadelphia, PA 19111-5098
F2347 – 03
— —
5. Chemical and Physical Test Methods
Inapolydispersemolecularpopulationtherelation M > M
w n
— — 5.1 Identity of Hyaluronan—The identity of hyaluronan can
is always valid. The coefficient M / M is referred to as the
w n
be established by several methods including, but not limited to
polydispersity index, and will typically be in the range 1.2 to
the following:
3.0 for commercial hyaluronan.
5.1.1 Sodium Hyaluronate Monograph EP 1472.
3.1.4 depolymerization, n—reductioninlengthofapolymer
5.1.2 Fourier Transform Infrared Spectroscopy (FT-IR)—
chain to form shorter polymeric units. Depolymerization may
Almost all organic chemical compounds absorb infrared radia-
reduce the polymer chain to smaller molecular weight poly-
tion at frequencies characteristic for the functional groups in
mers, oligomeric, or monomeric units, or combination thereof.
the compound. A FT-IR spectrum will show absorption bands
In hyaluronan, acid hydrolysis of the glycosidic bonds is the
relating to bond stretching and bending and can therefore serve
primary mechanism.
as a unique fingerprint of a specific compound. Direct FT-IR
3.1.5 degradation, n—change in the chemical structure,
analysis of hyaluronan powder is perhaps the easiest technique
physical properties or appearance of a material. Degradation of
to perform. One method utilizes a horizontal attenuated total
polysaccharides occurs via cleavage of the glycosidic bonds,
reflectance (HATR) accessory with a zinc-selenium (ZnSe)
usually by acid catalyzed hydrolysis. Degradation can also
crystal (or equivalent) having a sample trough and a pressure
occur thermally and by alkali. It is important to note that
plate. Record background and sample spectra between 4000
degradation is not synonymous with decomposition. Degrada-
-1
and 600 cm at an appropriate resolution. Label the peaks.
tion is often used as a synonym for depolymerization when
-1
Typical frequencies (cm ) for hyaluronan (sodium salt) are
referring to polymers. Degradation (depolymerization) of hy-
3275-3390(b),1615(s),1405(m),1377(m),1150,1077,1045
aluronan may also occur enzymatically by the action of
(s), 946 (m), 893 (w). The peak designators are: sh: sharp; s:
hyaluronidases.
strong; m: medium; w: weak; b: broad.Atypical FT-IR HATR
3.1.6 decomposition, n—structural changes of hyaluronan
spectrum is shown in Fig. 1. A reference spectrum can be
duetoexposuretoenvironmental,chemical,orthermalfactors.
obtained form the European Pharmacopoeia.
Decomposition may occur at temperatures as low as 121°C
5.2 Physical and Chemical Characterization of Hyaluro-
during autoclaving. Decomposition can result in deleterious
nan:
changes to the hyaluronan.
5.2.1 The composition and sequential structure of hyaluro-
3.1.7 pyrogen, n—any substance that produces fever when
nan can be determined by the following method: High-
administered parenterally.
1 13
resolution H- and C-nuclear magnetic resonance spectros-
3.1.8 endotoxin, n—a high molecular weight lipopolysac-
copy (NMR). Hyaluronan should be dissolved in D O. If the
charide (LPS) complex associated with the cell wall of
resulting solution is viscous, viscosity may be reduced by
gram-negative bacteria that is pyrogenic in humans. Though
chemical or enzymatic depolymerization. A typical H-NMR
endotoxins are pyrogens, not all pyrogens are endotoxins.
spectrum of hyaluronan is shown below. Hyaluronan is char-
3.1.9 non-animal derived, n—a term describing the absence
acterized by calculating parameters such as glucuronic acid:
of any animal-derived tissue, proteins, or products in the
N-acetylglucosamine ratio. Some literature references to the
manufacturing process.
determination of composition and structure of hyaluronan are
given in the References section (1-4).
4. Significance and Use
5.2.2 Molecularmass(molecularweight)ofhyaluronanwill
4.1 This guide contains a listing of those characterization
define certain performance characteristics such as viscosity or
parameters that are directly related to the functionality of
gel strength, or both.As such and depending on the sensitivity
hyaluronan. This guide can be used as an aid in the selection
of a particular end use to these variations, determination of
and characterization of the appropriate hyaluronan for a
molecular mass directly or indirectly may be necessary. Com-
particular application. This guide is intended to give guidance
mercial hyaluronan is polydisperse with respect to molecular
in the methods and types of testing necessary to properly
weight (M ). M may be expressed as the number average
w w
characterize,assess,andensureconsistencyintheperformance
(M ) or the weight average (M ). Molecular weights may be
N W
of a particular hyaluronan. It may have use in the regulation of
determined by methods such as, but not limited to the follow-
these devices by appropriate authorities.
ing:
4.2 The hyaluronan covered by this guide may be gelled,
5.2.2.1 Molecular Weight Determination Based on Intrinsic
cross-linked, extruded, or otherwise formulated into biomedi-
Viscosity—The intrinsic viscosity describes a polymer’s ability
cal devices for use in tissue engineered medical products or
to form viscous solutions in water and is directly proportional
drug delivery devices for implantation as determined to be
to the average molecular weight of the polymer. The intrinsic
appropriate,basedonsupportingbiocompatibilityandphysical
viscosity is a characteristic of the polymer under specified
test data. Recommendations in this guide should not be
solvent and temperature conditions; it is independent of con-
interpreted as a guarantee of clinical success in any tissue
centration. The intrinsic viscosity (h) is directly rela
...