Standard Specification for

Virgin Poly(glycolide)and Poly(glycolide-co-lactide)Resins for Surgical Implants with Mole Fractions Greater Than or Equal to70%Glycolide1

This standard is issued under thefixed designation F2313;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.

1.Scope

1.1This specification covers both virgin poly(glycolide) resin and poly(glycolide-co-lactide)resin with mole fractions greater than or equal to70%glycolide.This specification is not applicable to glycolide:lactide copolymers with mole fractions exceeding30%lactide.

1.2Since poly(glycolide)is commonly abbreviated as PGA for poly(glycolic acid)and poly(lactide)is commonly abbre-viated as PLA for poly(lactic acid),these polymers are com-monly referred to as PGA and PGA:PLA resins for the hydrolytic byproducts to which they respectively degrade. 1.3This specification addresses material characteristics of both virgin poly(glycolide)and poly($70%glycolide-co-lactide)resins intended for use in surgical implants and does not apply to packaged and sterilizedfinished implants fabri-cated from this material.

1.4As with any material,some characteristics may be altered by processing techniques(such as molding,extrusion, machining,assembly,sterilization,and so forth)required for the production of a specific part or device.Therefore,proper-ties of fabricated forms of this resin should be evaluated independently using appropriate test methods to ensure safety and efficacy.

1.5This standard may suggest use of hazardous materials, operations,and equipment.This standard does not purport to address safety concerns associated with its use.It is the responsibility of the user of this standard to establish appro-priate safety and health practices and to determine the applicability of regulatory limitations prior to use.

2.Referenced Documents

2.1ASTM Standards:2

D1505Test Method for Density of Plastics by the Density-Gradient Technique

D18Practice for Sampling of Plastics

D2857Practice for Dilute Solution Viscosity of Polymers D3536Test Method for Molecular Weight Averages and Molecular Weight Distribution by Liquid Exclusion Chro-matography(Gel Permeation Chromatography—GPC)3 D3593Test Method for Molecular Weight Averages and Molecular Weight Distribution of Certain Polymers by Liquid Size-Exclusion Chromatography(Gel Permeation Chromatography—GPC)Using Universal Calibration3

D4603Test Method for Determining Inherent Viscosity of Poly(Ethylene Terephthalate)(PET)by Glass Capillary Viscometer

E386Practice for Data Presentation Relating to High-Resolution Nuclear Magnetic Resonance(NMR)Spectros-copy

E1252Practice for General Techniques for Obtaining In-frared Spectra for Qualitative Analysis

F748Practice for Selecting Generic Biological Test Meth-ods for Materials and Devices

2.2Other Standards:

United States Pharmacopeia(USP)Edition2

ISO10993-9Biological Evaluation of Medical Devices, Part9:Framework for Identification and Quantification of Potential Degradation Products,Annex A5

21CFR820,United States Code of Federal Regulations, Title21—Food and Drugs Services,Part820—Quality System Regulation6

ANSI/ISO/ASQ Q9000-2000,Quality Management Sys-tems;Fundamentals and V ocabulary5

ANSI/ISO/ASQ Q9001-2000,Quality Management Sys-tems;Requirements5

3.Terminology

3.1Definitions:

1This specification is under the jurisdiction of ASTM Committee F04on

Medical Surgical Materials and Devices and is the direct responsibility of Subcom-mittee F04.11on Polymeric Materials.

Current edition approved Nov.1,2003.Published November2003.

2For referenced ASTM standards,visit the ASTM website,www.astm.org,or contact ASTM Customer Service at service@astm.org.For Annual Book of ASTM Standards volume information,refer to the standard’s Document Summary page on the ASTM website.

3Withdrawn.

4Available from U.S.Pharmacopeia(USP),12601Twinbrook Pkwy.,Rockville, MD20852.

5Available from American National Standards Institute(ANSI),25W.43rd St., 4th Floor,New York,NY10036.

6Available from U.S.Government Printing Office Superintendent of Documents, 732N.Capitol St.,NW,Mail Stop:SDE,Washington,DC20401.

Copyright©ASTM International,100Barr Harbor Drive,PO Box C700,West Conshohocken,PA19428-2959,United States.3.1.1virgin polymer,n—the form of poly(glycolide)or poly(glycolide-co-lactide)as synthesized from its monomers and prior to fabrication into a medical device.

4.Materials and Manufacture

4.1All raw monomer components and other materials contacting either the raw monomer(s)or resin product shall be of a quality suitable to allow for use of such resin in the manufacture of an implantable medical product.

4.2All polymer manufacturing(including monomer han-dling,synthesis,pelletization/grinding and all subsequent) shall be undertaken under conditions suitable to allow for use of such resin in the manufacture of an implantable medical product.

5.Chemical Composition

5.1Polymers covered by this specification shall be com-posed either of glycolide,or of a combination of glycolide and lactide where the lactide content does not exceed30%(34.7% by weight).To ensure such composition and the attainment of the desired properties,the following tests are to be conducted.

5.2Chemical Identification:

5.2.1The identity of the virgin polymer shall be confirmed either by infrared,1H-NMR,or13C-NMR spectroscopy.

5.2.2Infrared Identification:

5.2.2.1Identity of either poly(glycolide)homopolymer or poly(glycolide-co-lactide)copolymer may be confirmed through an infrared spectrum exhibiting major absorption bands only at the wavelengths that appear in a suitable reference spectrum.Analysis shall be conducted using prac-tices similar to those described in Practice E1252.A typical infrared transmission reference spectrum for PGA homopoly-mer is shown in Fig. 1.A typical infrared transmission reference spectrum for a90%PGA:10%l-PLA copolymer is shown in Fig.2.

5.2.2.2Additional spectral bands may be indicative of known or unknown impurities,including residual solvents and catalysts(refer to limits specified in Table1).

5.2.3Proton Nuclear Magnetic Resonance(1H-NMR)Iden-tification:

5.2.3.1Identity of either poly(glycolide)homopolymer or poly(glycolide-co-lactide)copolymer may be confirmed through sample dissolution,1H-NMR spectroscopy,and the use of a suitable reference spectrum.Sample dissolution is in deuterated hexafluoroisopropanol(D-HFIP)or other proton-free solvent able to fully solvate the specimen.Analysis shall be conducted using practices similar to those described in Practice E38

6.

5.2.3.2Additional spectral bands may be indicative of known or unknown impurities,including residual solvents and catalysts(refer to limits specified in Table1).

5.2.4Carbon-13Nuclear Magnetic Resonance(13C-NMR) Identification:

5.2.4.1Identity of either poly(glycolide)homopolymer or poly(glycolide-co-lactide)copolymer may be confirmed in a solid state through13C-NMR spectroscopy and the use of a suitable reference spectrum.Analysis shall be conducted using practices similar to those described in Practice E38

6.

5.2.4.2Additional spectral bands may be indicative of known or unknown impurities,including residual solvents and catalysts(refer to limits specified in Table1).

5.3Molecular Weight:

5.3.1The molecular mass of the virgin polymer shall be indicated by inherent viscosity in dilute solution(IV).In addition to inherent viscosity(but not in place of),weight average molecular mass and molecular mass distributions may be determined by gel permeation chromatography(GPC) according to Test Methods D3536or D3593,but using hexafluoroisopropanol(HFIP)solvent and poly methyl-methacrylate(PMMA)calibration standards.

5.3.1.1Determine the inherent viscosity of the polymer either in hexafluoroisopropanol(HFIP)or hexafluoroacetone sesquihydrate(HFAS)at30°C using procedures similar to those described in Practice D2857and Test Method D4603. Inherent viscosity is determined utilizing the following equa-tion:

IV5

ln

t

t o~v!

w(1) where:

IV=inherent viscosity(at30°C in dl/gram),

t=efflux time in seconds for diluted solution,

t o=efflux time in seconds for source solvent,

w=weight of polymer being diluted(in grams),and

v=dilution volume in deciliters(Note:1dl=100mL). Resin concentration for IV analysis must be0.5%w/v or less,with resin analyte concentrations of0.1%w/v(that is, 0.001g/ml or1mg/ml)recommended.When reporting results, identify the solvent utilized,analyte concentration,and analy-sis temperature.

5.4Residual Monomer:

5.4.1The virgin polymer shall have a combined total residual monomer content less than or equal to2%by weight.

5.4.1.1Determine weight percent residual monomer by gas chromatography,1H-NMR spectroscopy(using D-HFIP or other proton-free solvent able to fully solvate the specimen),or other suitably sensitive analytic method as agreed upon by supplier and purchaser.

5.5Residual Solvents:

5.5.1If any solvent is utilized in any resin manufacturing or purification step,determine residual levels of any utilized solvent(s)by gas chromatography or other suitable method as agreed upon by supplier and purchaser.Acceptable residual levels of a solvent shall be reflective of toxicity,with a maximum acceptable level(regardless of toxicity)presented in Table1.

5.6Heavy Metals:

5.6.1Determine residual Heavy Metals per Method II, Chapter231of U.S.Pharmacopeia.

5.6.2Heavy Metals generally refers to divalent cations of the elements antimony(Sb),arsenic(As),cadmium(Cd), copper(Cu),mercury(Hg),and lead(Pb).Since stannous tin (Sn2+)carries potential to influence test results,the amount ascertained by alternative analytic means(see below)to be directly attributable to tin in may be ignored,provided that

the

N OTE—Supplied example infra-red spectrum is of“Dexon Medical Suture(beige)”as acquired from the Hummel Polymer Library,available from: Thermo Nicolet Corporation,5225Verona Road,Madison,WI53711-4495,USA.

FIG.1Poly(glycolide)Resin Infrared Spectrum

N OTE—Supplied example infra-red spectrum is of“Vicryl Medical Suture(violet)”as acquired from the Hummel Polymer Library,available from: Thermo Nicolet Corporation,5225Verona Road,Madison,WI53711-4495,USA.

FIG.2Poly(90%glycolide-co-10%lactide)Resin Infrared Spectrum

cumulative total amount of the listed Heavy Metals elements remains below the USP 10ppm as lead limit.5.7Residual Catalyst (Optional):

5.7.1Determine the amount of residual tin (Sn)by atomic absorption/emission (AA)spectroscopy or inductively coupled plasma (ICP)spectroscopy.If a catalyst other than tin is utilized,suitable methods to both determine and report residue shall be utilized.

6.Physical Properties

6.1Determine the density in accordance with Test Method D 1505.

7.Performance Requirements 7.1Identification Requirements :

7.1.1Identity of poly(glycolide)homopolymer or poly(glycolide-co-lactide)copolymer must be confirmed through either an infrared,a 1H-NMR spectrum (using D-HFIP or other proton-free solvent able to fully solvate the specimen),or a 13C-NMR spectrum which exhibits major absorption bands only at the wavelengths/chemical shifts that appear in a suitable reference spectrum.

7.1.2Copolymer ratio of poly(glycolide-co-lactide)poly-mer must be determined through a 1H-NMR spectrum (using D-HFIP or other proton-free solvent able to fully solvate the specimen).Ratio of glycolide to lactide should be 63%mole percentage of target.This same 1H-NMR spectrum may also be utilized to provide the identification requirements of 7.1.1.7.2Molecular Weight Requirements :

7.2.1The finished resin product must meet the specified molecular weight requirements agreed upon between the sup-plier and purchaser as measured by inherent viscosity.Optional molecular weight distribution criteria may also be specified and agreed upon as measured by the GPC methods described above.

7.3Physical/Chemical Property Requirements :

7.3.1The virgin polymer shall have the chemical and physical properties as listed in Table 1as determined by the methods described above.

8.Dimensions,Mass,and Permissible Variations

8.1Finished product resin may be supplied in either pellet-ized or granular form,with requirements as agreed upon between the supplier and purchaser.

9.Sampling

9.1Where applicable,the requirements of this specification shall be determined for each lot of the virgin polymer by sampling sizes and procedures according to Practice D 18.10.Certification

10.1A certificate of compliance that contains,at minimum,the following information shall be supplied for each shipment:

10.1.1Supplier identification (including address and phone contact numbers),

10.1.2Resin lot number,10.1.3Date of certification,

10.1.4Chemical description of polymer (including,if ap-propriate,the targeted copolymer ratio designated specifically by weight or by mole),

10.1.5Applicable CAS registry number,

10.1.6Experimentally determined copolymer ratio (if a copolymer,with results designated by weight or by mole),10.1.7Inherent viscosity (in dl/g;with solvent,temperature,and analyte concentration in solution),

10.1.8Residual monomer content (combined total in weight %),and

10.1.9Heavy metals (pass or fail,with applicable limit specified).

11.Packaging and Package Marking

11.1Packaging material shall be of such composition that it provides an effective barrier to the entry of moisture.

11.2Each of the individually supplied product packaging shall possess a label that contains,at minimum,the following information:

11.2.1Supplier identification,

11.2.2A chemical description of the polymer (including,if appropriate,the targeted copolymer ratio designated specifi-cally by weight or by mole),11.2.3Resin lot number,

11.2.4Net weight of contents,

11.2.5Inherent viscosity (in dl/g),and 11.2.6Final packaging date.

12.Supplementary Requirements 12.1Biocompatibility :

12.1.1Due to potential for an increase in local acidity as a result of the normal hydrolytic degradation process,suitability of these materials for human implantation will be dependent on the specific application.The biological tests appropriate for the specific site,such as those recommended in Practice F 748may be used as a guideline.

12.1.2No known surgical implant material has ever been shown to be completely free of adverse reactions in the human body.However,long term clinical experience with specific compositions and formulations of the material class referred to in this specification has shown that an acceptable level of biological response can be expected,if the material is used in appropriate applications.

13.Guidance for Manufacturing Control and Quality

Assurance

13.1Acceptable levels of manufacturing control are highly desirable and may apply to manufacture of the resin.Good

TABLE 1Physical/Chemical Property Requirements for Virgin Poly(glycolide)and and Poly(glycolide-co-lactide)Resins

Analyte Residual Monomer,

(Total,%)Residual Solvent(s),

(Total,%)Residual Water,

(%)Residual Tin (Sn),

(ppm)

Heavy Metal,(ppm as Pb)Copolymer Ratio Requirement

<2.0%(by weight)

#0.01%(by weight)

#0.5%(by weight)A

#100ppm

#10ppm (minus Sn)

63%of target (by mole)

A

Utilizing moisture determination method agreed upon by supplier and

purchaser.

13.1.2ANSI/ISO/ASQ Q9000-2000;Quality Management Systems;Fundamentals and V ocabulary:Provides fundamen-tals for quality management systems as described in the ISO 9000family(informative);and specifies quality management terms and their definitions(normative),and

13.1.3ANSI/ISO/ASQ Q9001-2000;Quality Management Systems;Requirements:Presents requirements for a quality management system.The application of this standard can be used by an organization to demonstrate its capability to meet customer requirements for products and/or services,and for assessment of that capability by internal and external parties.

14.Keywords

14.1poly(glycolic acid);poly(glycolide);PGA;poly(gly-colide:lactide);poly(glycolide-co-lactide);PLA;PGA:PLA; polyglycolic:lactic acid

APPENDIXES (Nonmandatory Information) X1.NOMENCLATURE

X1.1Poly(glycolide)is commonly abbreviated as PGA for poly(glycolic acid),the chemical byproduct to which it de-grades after hydrolysis.PGA contains no chiral carbon and therefore has no stereoisomeric forms(enantiomers)that re-quire identification.Poly(lactide)is commonly abbreviated as PLA for poly(lactic acid),the chemical byproduct to which it degrades after hydrolysis.PLA does contain a chiral carbon and therefore has two stereoisomeric forms(enantiomers)that require appropriate identification within the specification.The levorotatory enantiomeric form,which rotates plane polarized light to the left,is most commonly abbreviated with an l and alternatively with a(-)or S designation.The dextrorotatory enantiomeric form,which rotates plane polarized light to the right,is most commonly abbreviated with a d,and alternatively with a(+)or R designation.A racemic mixtures of these two lactide enantiomers is commonly abbreviated with a d,l desig-nation,and alternatively with a(+,-)or a R,S designation. Within the medical products industry and its literature,abbre-viations for the lactide copolymeric segment are typically in the form l-PLA,d-PLA,or d,l-PLA for polymer fabricated from the racemic combination of the two isomers.

X2.RATIONALE

X2.1This specification is written for virgin PGA or PGA:PLA resin and is not intended to be applied to objects(for example,test samples or devices)fabricated from PGA or PGA:PLA.The properties of objects fabricated from PGA or PGA:PLA resins,such as mechanical properties,are dependent upon the processing conditions used during fabrication and thus fall outside of the scope of this PGA/PGA:PLA resin standard.Properties in this specification are therefore specified only for PGA resin and PGA:PLA copolymer resin(with a glycolide mole fraction$70%)and not for its fabricated form. Several potentially applicable ASTM standards are listed in Section2(Referenced Standards),which may be followed to determine fabricated-form properties for devices and test samples fabricated from these resins.

X2.2PGA or PGA:PLA resin may be synthesized with many different molecular weight ranges and distributions.Each such system will possess unique molecular weight dependent properties.Therefore certain physical,mechanical,and thermal properties(for example,glass transition,melt temperatures, and tensile properties)are not specified in this specification.

X2.3Most PGA or PGA:PLA resin suppliers will provide analyses upon request relating to bioburden or pyrogens,or both.Bioburden is a measure of the number of viable cell colonies(aerobic,anaerobic,and spore cells)per gram of resin material.Pyrogen content is a measure of the presence of bacterial endotoxins which is commonly measured by the Limulus Amebocyte Lysate test.Because these properties may be significantly influenced by the exposure of the resin to any nonsterile environment,such properties are not required in this specification.

X2.4While it is obviously ideal to have zero foreign particles within any bioabsorbable implant material,under practical processing conditions it must be expected that pro-cessing related particles of foreign matter may be present to some degree.Unfortunately,at this time,there are no known published studies dealing with typical foreign particles in this resin material or their effect upon resin properties.Such a specification may be established in the future as information regarding this parameter is developed by methods such as round-robin use of this specification for selected samples of PGA or PGA:PLA resin from various commercial

sources.

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