1、Designation: F 2579 06e1Standard 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
2、revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon (e) indicates an editorial change since the last revision or reapproval.e1NOTESection 5.9 was added and figures were corrected editorially in January 2007.1. Scope1.1 This specifi
3、cation covers virgin poly(lactide) andpoly(lactide-co-glycolide) resins able to be fully 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
4、crystallinity) and are polymerizedeither from meso-lactide or from equimolar (racemic) 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 ei
5、ther meso-lactide or racemicquantities of d-lactide and l-lactide, and typically possessnominal 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), th
6、ese polymers are com-monly referred to as PGA, PLA, and PLA:PGA resins for thehydrolytic 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 crystal
7、lization. Therefore, spe-cific reference to d,l-PLA is essential to appropriately differ-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 isot
8、actic polymeric seg-ments sufficient in size to deliver potential for lactide basedcrystallization. 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
9、 fluorinated solvents for completedissolution under room temperature conditions. This 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 c
10、opolymers or to polymers or copolymerssynthesized from combinations of d-lactide and l-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 i
11、n surgical implants and does not apply topackaged and sterilized finished implants fabricated 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 o
12、f a specific part or device. Therefore, properties offabricated forms of this resin should be evaluated indepen-dently using appropriate test methods to assure safety andefficacy.1.6 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is therespon
13、sibility 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 Density-Gradient TechniqueD 1898 Practice f
14、or Sampling of Plastics3D 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 andM
15、olecular 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 ofS
16、ubcommittee F04.11 on Polymeric Materials.Current edition approved Oct. 1, 2006. Published November 2006.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standar
17、ds 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 Viscosity ofPoly(Ethylene Terephthalate) (PET) by Glass CapillaryViscometerE 386 Pract
18、ice 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 AnalysisF 748 Practice for Selecting Generic Biological Test Meth-ods for Materials and Devices2.2 Other Document
19、s:United States Pharmacopeia (USP), Edition 264ISO 10993-9, Biological Evaluation of Medical Devices,Part 9: Degradation of Materials Related to BiologicalTesting, Annex A5ICH Q3C(R3) International Conference on Harmonisationof Technical Requirements for Registration of Pharmaceu-ticals for Human Us
20、e, Quality Guideline: Impurities:Residual Solvents621 CFR 820 Code of Federal Regulations, Title 21, Part820, Quality System Regulation7ANSI/ISO/ASQ Q9000 Quality Management Systems,Fundamentals and Vocabulary8ANSI/ISO/ASQ Q9001 Requirements83. Terminology3.1 Definition:3.1.1 virgin polymerthe initi
21、ally delivered form of apolymer as synthesized from its monomers and prior to anyprocessing or fabrication 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
22、for use of such resin in themanufacture of an implantable medical product. Such qualityincludes adequate control 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 (inclu
23、ding monomer han-dling, synthesis, pelletization/grinding and all subsequent)shall be undertaken under conditions 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 specificatio
24、n shall be composed either of meso-lactide or aracemic combination of d-lactide and l-lactide. The amorphouspoly(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 racem
25、ic combination of d-lactide and l-lactidewhere the glycolide mole fraction is less than 70 % (65.3 % inmass 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
26、 shall be confirmedeither by infrared,1H-NMR, or13C-NMR spectroscopy.5.2.2 Infrared Identification:5.2.2.1 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 ap
27、pear in a suitablereference spectrum. Analysis shall be conducted using infra-red spectroscopy practices similar 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. Whi
28、le poly(lactide-co-glycolide) copolymers will each have their own respectivespectrum that will vary in response 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 indicat
29、ive ofsample crystallinity or either known or unknown impurities,including residual monomer, solvents, and 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
30、) copolymer may be confirmedthrough sample dissolution,1H-NMR spectroscopy, and theuse of a suitable reference spectrum. Sample dissolution is ineither deuterated chloroform, deuterated dichoromethane (me-thylenechloride) or other substantially proton-free solvent ableto fully solvate the specimen w
31、ithout inducing competingspectral bands. Analysis shall be conducted using practicessimilar to those described 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
32、).5.2.4 Carbon-13 Nuclear Magnetic Resonance (13C-NMR)Identification:5.2.4.1 Identity of either poly(lactide) 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 using
33、practices similar to those described in Practice E 386.5.2.4.2 Additional spectral bands may be indicative ofknown or unknown impurities, 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.
34、5 to +2.5 degrees when measured in either chloroform,4Available from U.S. Pharmacopeia (USP), 12601 Twinbrook 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 fr
35、om ICH Secretariat, c/o IFPMA, 30 rue de St-Jean, P.O. Box 758,1211 Geneva 13, Switzerland. Available online 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.
36、access.gpo.gov.8Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor, New York, NY 10036, http:/www.ansi.org.F257906e12methylenechloride, or tetrahydrofuran at 20C using a pola-rimetry method equal to or equivalent to the Optical Rotationprocedure described within US
37、P .5.4 Molar Mass:5.4.1 The molar mass of the virgin polymer shall beindicated by inherent viscosity in dilute solution (IV). Inaddition to inherent viscosity (but not in place of), massaverage molar mass and molar mass distributions maybedetermined by gel permeation chromatography (GPC) accord-ing
38、to Test Method D 3536 or D 3593, but using eitherchloroform or dichloromethane and polystyrene calibrationstandards.5.4.2 Determine the inherent viscosity of the polymer pref-erentially in chloroform at 30C using procedures similar tothose described in Practice D 2857 and Test Method D 4603.Determin
39、ation at a lower temperature of 25C is allowable,Example 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 10
40、0 % d,l-PLA homopolymer 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 (p
41、ass or fail, with 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 individua
42、lly supplied product 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
43、Net mass of contents,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 g
44、uidelines for 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 defin
45、itions (normative).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 b
46、y internal andexternal 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
47、 Requirements 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
48、(in ppm)CopolymerRatioSpecificRotationRequirement 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 info
49、rmation 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-red or aNMR analysis, both of which provide broad chemical charac-terization of the analytes organic composition. Utilization ofsuch broad characterization methods provide analytic ability toreadily identify either a differing polymer (including incorrectcopolymer ratios) or the correct pol
