1、Designation: F 2579 08Standard Specification forAmorphous Poly(lactide) and Poly(lactide-co-glycolide)Resins for Surgical Implants1This standard is issued under the fixed designation F 2579; the number immediately following the designation indicates the year oforiginal adoption or, in the case of re
2、vision, 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.1. Scope1.1 This specification covers virgin poly(lactide) andpoly(lactide-co-glycolide) resins able to be ful
3、ly solvated at30C by either methylene chloride (dichloromethane) or chlo-roform (trichloromethane). The poly(d,l-lactide) homopoly-mers covered by this specification are considered to beamorphous (that is, void of crystallinity) and are polymerizedeither from meso-lactide or from equimolar (racemic)
4、 combi-nations of d-lactide and l-lactide. The poly(d,l-lactide-co-glycolide) copolymers covered by this specification are alsoconsidered to be amorphous and are co-polymerized from acombination of glycolide and either meso-lactide or racemicquantities of d-lactide and l-lactide, and typically posse
5、ssnominal mole fractions that equal or exceed 50 % lactide.1.2 Since poly(glycolide) is commonly abbreviated as PGAfor 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, PLA, and PLA:PGA resins for thehydrolyt
6、ic byproducts to which they respectively degrade. PLAis a term that carries no enantiomeric specificity and thereforealso encompasses the isotactic d-PLAand l-PLAmoieties, eachof which carries potential for crystallization. Therefore, spe-cific reference to d,l-PLA is essential to appropriately diff
7、er-entiate the amorphous atactic/syndiotactic d,l-lactide basedpolymers and copolymers covered by this specification.1.3 This specification is not applicable to lactide basedpolymers or copolymers that possess isotactic polymeric seg-ments sufficient in size to deliver potential for lactide basedcry
8、stallization. This specification is not applicable to lactide-co-glycolide copolymers that possess glycolide segments suf-ficient in size to deliver potential for glycolide based crystal-lization, thereby requiring fluorinated solvents for completedissolution under room temperature conditions. This
9、specifica-tion is specifically not applicable to lactide-co-glycolide co-polymers with glycolide mole fractions greater than or equal to70 % (65.3 % in mass fraction). This specification is notapplicable to block copolymers or to polymers or copolymerssynthesized from combinations of d-lactide and l
10、-lactide thatdiffer by more than 1.5 total mole percent (1.5 % of totalmoles).1.4 This specification addresses material characteristics ofboth poly(lactide) and poly(lactide-co-glycolide) resins in-tended for use in surgical implants and does not apply topackaged and sterilized finished implants fab
11、ricated from thesematerials.1.5 As with any material, some characteristics may bealtered by processing techniques (such as molding, extrusion,machining, assembly, sterilization, etc.) required for the pro-duction of a specific part or device. Therefore, properties offabricated forms of this resin sh
12、ould be evaluated indepen-dently using appropriate test methods to assure safety andefficacy.1.6 The values stated in SI units are to be regarded asstandard. No other units of measurement are included in thisstandard.1.7 This standard does not purport to address all of thesafety concerns, if any, as
13、sociated with its use. It is theresponsibility of the user of this standard to establish appro-priate safety and health practices and determine the applica-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2D 1505 Test Method for Density of Plastics by the Densi
14、ty-Gradient TechniqueD 2857 Practice for Dilute Solution Viscosity of PolymersD 3536 Test Method for Molecular Weight Averages andMolecular Weight Distribution of Polystyrene by LiquirExclusion Chromatography (Gel PermeationChromatography-GPC)3D 3593 Test Method for Molecular Weight Averages andMole
15、cular Weight Distribution of Certain Polymers byLiquid Size-Exclusion Chromatography (Gel PermeationChromatography GPC) Using Universal Calibration31This specification is under the jurisdiction of ASTM Committee F04 onMedical and Surgical Materials and Devices and is the direct responsibility ofSubc
16、ommittee F04.11 on Polymeric Materials.Current edition approved Dec. 1, 2008. Published January 2009. Originallyapproved in 2006. Last previous edition approved in 2006 as F 2579 061.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.
17、org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.3Withdrawn.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.D 4603 Test Method for Determining Inherent Viscosit
18、y ofPoly(Ethylene Terephthalate) (PET) by Glass CapillaryViscometerE 386 Practice for Data Presentation Relating to High-Resolution Nuclear Magnetic Resonance (NMR) Spectros-copyE 1252 Practice for General Techniques for Obtaining In-frared Spectra for Qualitative AnalysisE 1994 Practice for Use of
19、Process Oriented AOQL andLTPD Sampling PlansF 748 Practice for Selecting Generic Biological Test Meth-ods for Materials and Devices2.2 Other Documents:United States Pharmacopeia (USP), Edition 264ISO 31-8 Physical Chemistry and Molecular Physics, Part8: Quantities and Units5ICH Q3C(R3) International
20、 Conference on Harmonisationof Technical Requirements for Registration of Pharmaceu-ticals for Human Use, Quality Guideline: Impurities:Residual Solvents621 CFR 820 Code of Federal Regulations, Title 21, Part820, Quality System Regulation7ANSI/ISO/ASQ Q9000 Quality Management Systems,Fundamentals an
21、d Vocabulary8ANSI/ISO/ASQ Q9001 Requirements8NIST Special Publication SP811 Guide for the Use of theInternational System of Units (SI)93. Terminology3.1 Definition:3.1.1 virgin polymerthe initially delivered form of apolymer as synthesized from its monomers and prior to anyprocessing or fabrication
22、into a medical device.4. Materials and Manufacture4.1 All raw monomer components and other materialscontacting either the raw monomer(s) or resin product shall beof a quality suitable to allow for use of such resin in themanufacture of an implantable medical product. Such qualityincludes adequate co
23、ntrol of particles and other potentialcontaminants that may affect either the toxicity of or the cellresponse to the as-implanted or degrading final product.4.2 All polymer manufacturing (including monomer han-dling, synthesis, pelletization/grinding and all subsequent)shall be undertaken under cond
24、itions suitable to allow for useof such resin in the manufacture of an implantable medicalproduct.5. Chemical Composition5.1 The amorphous poly(d,l-lactide) polymers covered bythis specification shall be composed either of meso-lactide or aracemic combination of d-lactide and l-lactide. The amorphou
25、spoly(d,l-lactide-co-glycolide) copolymers covered by thisspecification can be of variable copolymer ratios and shall becomposed of a combination of glycolide and either meso-lactide or a racemic combination of d-lactide and l-lactidewhere the glycolide mole fraction is less than 70 % (65.3 % inmass
26、 fraction). To assure such composition and the attainmentof the desired properties, the following tests are to be con-ducted.5.2 Chemical Identification:5.2.1 The identity of the virgin polymer shall be confirmedeither by infrared,1H-NMR, or13C-NMR spectroscopy.5.2.2 Infrared Identification:5.2.2.1
27、Identity of either poly(lactide) homopolymer orpoly(lactide-co-glycolide) copolymer may be confirmedthrough an infrared spectrum exhibiting major absorptionbands only at the wavelengths that appear in a suitablereference spectrum. Analysis shall be conducted using infra-red spectroscopy practices si
28、milar to those described in Prac-tice E 1252.Atypical infrared transmission reference spectrumand a typical infrared absorption reference spectrum ford,l-PLAhomopolymer are shown in Fig. 1. While poly(lactide-co-glycolide) copolymers will each have their own respectivespectrum that will vary in resp
29、onse to copolymer ratio, thisanalytic method typically lacks sensitivity sufficient for quan-tification of copolymer ratio as specified in 7.1.2.5.2.2.2 Additional spectral bands may be indicative ofsample crystallinity or either known or unknown impurities,including residual monomer, solvents, and
30、catalysts (refer tolimits specified in Table 1).5.2.3 Proton Nuclear Magnetic Resonance (1H-NMR) Iden-tification:5.2.3.1 Identity of either poly(lactide) homopolymer orpoly(lactide-co-glycolide) copolymer may be confirmedthrough sample dissolution,1H-NMR spectroscopy, and theuse of a suitable refere
31、nce spectrum. Sample dissolution is ineither deuterated chloroform, deuterated dichoromethane (me-thylene chloride) or other substantially proton-free solvent ableto fully solvate the specimen without inducing competingspectral bands. Analysis shall be conducted using practicessimilar to those descr
32、ibed in Practice E 386.5.2.3.2 Additional spectral bands may be indicative ofknown or unknown impurities, including residual monomer,solvents, and catalysts (refer to limits specified in Table 1).5.2.4 Carbon-13 Nuclear Magnetic Resonance (13C-NMR)Identification:5.2.4.1 Identity of either poly(lacti
33、de) homopolymer orpoly(lactide-co-glycolide) copolymer may be confirmed in asolid state through13C-NMR spectroscopy and the use of asuitable reference spectrum. Analysis shall be conducted usingpractices similar to those described in Practice E 386.4Available from U.S. Pharmacopeia (USP), 12601 Twin
34、brook Pkwy., Rockville,MD 20852-1790, http:/www.usp.org.5Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor, New York, NY 10036, http:/www.ansi.org.6Available from ICH Secretariat, c/o IFPMA, 30 rue de St-Jean, P.O. Box 758,1211 Geneva 13, Switzerland. Available on
35、line at http:/www.ich.org/LOB/media/MEDIA423.pdf7Available from U.S. Government Printing Office Superintendent of Documents,732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401, http:/www.access.gpo.gov.8Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor, N
36、ew York, NY 10036, http:/www.ansi.org.9Available from National Institute of Standards and Technology (NIST), 100Bureau Dr., Stop 1070, Gaithersburg, MD 20899-1070, at http:/physics.nist.gov/cuu/Units/bibliography.html.F25790825.2.4.2 Additional spectral bands may be indicative ofknown or unknown imp
37、urities, including residual solvents andcatalysts (refer to limits specified in Table 1).5.3 Specific Rotation:5.3.1 The virgin polymer shall have a specific rotation of2.5 to +2.5 degrees when measured in either chloroform,methylene chloride, or tetrahydrofuran at 20C using a pola-rimetry method eq
38、ual to or equivalent to the Optical Rotationprocedure described within USP .5.4 Molar Mass:NOTE 1The term molecular weight (abbreviated MW) is obsolete andshould be replaced by the SI (Systme Internationale) equivalent of eitherrelative molecular mass (Mr), which reflects the dimensionless ratio of
39、themass of a single molecule to an atomic mass unit see ISO 31-8, or molarmass (M), which refers to the mass of a mole of a substance and istypically expressed as grams/mole. For polymers and other macromol-ecules, use of the symbols Mw, Mn, and Mzcontinue, referring tomass-average molar mass, numbe
40、r-average molar mass, and z-averageExample infrared spectra are alternative presentations of an amorphous 100 % d,l-PLA homopolymer. (Spectra are courtesy of W. L. Gore available online at http:/pubs.acs.org/reagents/comminfo/minutes.htmlSupplied example NMR spectrum of an amorphous 100 % d,l-PLA ho
41、mopolymer is courtesy of W. L. Gore with solvent, temperature,and analyte concentration in solution); inherent viscosity (30Cextrapolated) is also reported if actual experimental value wasdetermined at 25C,10.1.8 Residual monomer content (combined total inmass %),10.1.9 Heavy metals (pass or fail, w
42、ith applicable limitspecified), and10.1.10 Residual solvent(s), if any, and applied ICH con-centration limit(s).11. Packaging and Package Marking11.1 Packaging material shall be of such composition that itprovides an effective barrier to the entry of moisture.11.2 Each of the individually supplied p
43、roduct packagingshall possess a label that contains the following information:11.2.1 Supplier identification,11.2.2 A chemical description of the polymer (including, ifappropriate, the targeted copolymer ratio designated specifi-cally by mass or by mole),11.2.3 Resin lot number,11.2.4 Net mass of co
44、ntents,11.2.5 Inherent viscosity (as analyzed, in dL/g), and11.2.6 Final packaging date.12. Guidance for Manufacturing Control and QualityAssurance12.1 Acceptable levels of manufacturing control are highlydesirable and may apply to manufacture of the resin. GoodManufacturing Practice guidelines for
45、achieving acceptablelevels of manufacturing quality control may be found in:12.1.1 21 CFR Part 820.12.1.2 ANSI/ISO/ASQ Q9000-2000Provides fundamen-tals for quality management systems as described in the ISO9000 family (informative); and specifies quality managementterms and their definitions (normat
46、ive).12.1.3 ANSI/ISO/ASQ Q9001-2000Presents require-ments for a quality management system. The application of thisspecification can be used by an organization to demonstrate itscapability to meet customer requirements for products and/orservices, and for assessment of that capability by internal and
47、external parties.13. Keywords13.1 PGA:PLA; PLA; PLA:PGA; PLGA; polyglycolic:lac-tic acid; poly(glycolide-co-lactide); poly(glycolide:lactide);poly(lactic acid); polylactic:glycolic acid; poly(lactide);poly(lactide-co-glycolide); poly(lactide:glycolide)TABLE 1 Physical/Chemical Property Requirements
48、for Virgin Amorphous Poly(lactide) and Poly(lactide-co-glycolide) ResinsAnalyteTotalResidualMonomer,(%)Total SolventCombinationResidual(s)(in ppm)Individual SolventResidual(s) andApplicable ICHLimit(s) (in ppm)(Optional)ResidualWater(%)Heavy Metals,(ppm as Pb)(Optional)ResidualCatalyst(in ppm)Copoly
49、merRatioSpecificRotationRequirement ParticulateMatter in Injections. Unfortunately, at this time, there are nostudies dealing with typical foreign particle levels in this resinmaterial or their effect upon resin properties. Such a specifi-cation may be established in the future as information regard-ing this parameter is developed by methods such as round-robin use of this standard for selected samples of PLA orPLA:PGA resin from various commercial sources.X2.4 Chemical identification with comparison to a knownstandard (per 5.2 and 7.1.2) requires either an infra-
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