ASTM F2579-06

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Designation: F 2579 – 06
Standard Specification for
Amorphous Poly(lactide) and Poly(lactide-co-glycolide)
Resins for Surgical Implants
This standard is issued under the fixed designation F 2579; 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 synthesized from combinations of d-lactide and l-lactide that
differ by more than 1.5 total mole percent (1.5 % of total
1.1 This specification covers virgin poly(lactide) and
moles).
poly(lactide-co-glycolide) resins able to be fully solvated at
1.4 This specification addresses material characteristics of
30°C by either methylene chloride (dichloromethane) or chlo-
both poly(lactide) and poly(lactide-co-glycolide) resins in-
roform (trichloromethane).The poly(d,l-lactide) homopoly-
tended for use in surgical implants and does not apply to
mers covered by this specification are considered to be
packaged and sterilized finished implants fabricated from these
amorphous (that is, void of crystallinity) and are polymerized
materials.
either from meso-lactide or from equimolar (racemic) combi-
1.5 As with any material, some characteristics may be
nations of d-lactide and l-lactide. The poly(d,l-lactide-co-
altered by processing techniques (such as molding, extrusion,
glycolide) copolymers covered by this specification are also
machining, assembly, sterilization, etc.) required for the pro-
considered to be amorphous and are co-polymerized from a
duction of a specific part or device. Therefore, properties of
combination of glycolide and either meso-lactide or racemic
fabricated forms of this resin should be evaluated indepen-
quantities of d-lactide and l-lactide, and typically possess
dently using appropriate test methods to assure safety and
nominal mole fractions that equal or exceed 50 % lactide.
efficacy.
1.2 Since poly(glycolide) is commonly abbreviated as PGA
1.6 This standard does not purport to address all of the
for poly(glycolic acid) and poly(lactide) is commonly abbre-
safety concerns, if any, associated with its use. It is the
viated as PLA for poly(lactic acid), these polymers are com-
responsibility of the user of this standard to establish appro-
monly referred to as PGA, PLA, and PLA:PGA resins for the
priate safety and health practices and determine the applica-
hydrolyticbyproductstowhichtheyrespectivelydegrade.PLA
bility of regulatory limitations prior to use.
is a term that carries no enantiomeric specificity and therefore
alsoencompassestheisotactic d-PLAand l-PLAmoieties,each
2. Referenced Documents
of which carries potential for crystallization. Therefore, spe-
2.1 ASTM Standards:
cific reference to d,l-PLA is essential to appropriately differ-
D 1505 Test Method for Density of Plastics by the Density-
entiate the amorphous atactic/syndiotactic d,l-lactide based
Gradient Technique
polymers and copolymers covered by this specification.
D 1898 Practice for Sampling of Plastics
1.3 This specification is not applicable to lactide based
D 2857 Practice for Dilute Solution Viscosity of Polymers
polymers or copolymers that possess isotactic polymeric seg-
D 3536 Test Method for Molecular Weight Averages and
ments sufficient in size to deliver potential for lactide based
Molecular Weight Distribution of Polystyrene by Liquir
crystallization. This specification is not applicable to lactide-
Exclusion Chromatography (Gel Permeation
co-glycolide copolymers that possess glycolide segments suf-
Chromatography-GPC)
ficient in size to deliver potential for glycolide based crystal-
D 3593 Test Method for Molecular Weight Averages and
lization, thereby requiring fluorinated solvents for complete
Molecular Weight Distribution of Certain Polymers by
dissolution under room temperature conditions. This specifica-
Liquid Size-Exclusion Chromatography (Gel Permeation
tion is specifically not applicable to lactide-co-glycolide co-
Chromatography GPC) Using Universal Calibration
polymers with glycolide mole fractions greater than or equal to
D 4603 Test Method for Determining Inherent Viscosity of
70 % (65.3 % in mass fraction). This specification is not
applicable to block copolymers or to polymers or copolymers
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
This specification is under the jurisdiction of ASTM Committee F04 on contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Medical and Surgical Materials and Devices and is the direct responsibility of Standards volume information, refer to the standard’s Document Summary page on
Subcommittee F04.11 on Polymeric Materials. the ASTM website.
Current edition approved Oct. 1, 2006. Published November 2006. Withdrawn.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.
F2579–06
Poly(Ethylene Terephthalate) (PET) by Glass Capillary racemic combination of d-lactide and l-lactide.The amorphous
Viscometer poly(d,l-lactide-co-glycolide) copolymers covered by this
E 386 Practice for Data Presentation Relating to High- specification can be of variable copolymer ratios and shall be
Resolution Nuclear Magnetic Resonance (NMR) Spectros- composed of a combination of glycolide and either meso-
copy lactide or a racemic combination of d-lactide and l-lactide
E 1252 Practice for General Techniques for Obtaining In- where the glycolide mole fraction is less than 70 % (65.3 % in
frared Spectra for Qualitative Analysis mass fraction). To assure such composition and the attainment
F 748 Practice for Selecting Generic Biological Test Meth- of the desired properties, the following tests are to be con-
ods for Materials and Devices ducted.
2.2 Other Documents:
5.2 Chemical Identification:
United States Pharmacopeia (USP), Edition 26
5.2.1 The identity of the virgin polymer shall be confirmed
1 13
ISO 10993-9, Biological Evaluation of Medical Devices,
either by infrared, H-NMR, or C-NMR spectroscopy.
Part 9: Degradation of Materials Related to Biological
5.2.2 Infrared Identification:
Testing, Annex A
5.2.2.1 Identity of either poly(lactide) homopolymer or
ICH Q3C(R3) International Conference on Harmonisation
poly(lactide-co-glycolide) copolymer may be confirmed
ofTechnicalRequirementsforRegistrationofPharmaceu-
through an infrared spectrum exhibiting major absorption
ticals for Human Use, Quality Guideline: Impurities:
bands only at the wavelengths that appear in a suitable
Residual Solvents
reference spectrum. Analysis shall be conducted using infra-
21 CFR 820 Code of Federal Regulations, Title 21, Part
red spectroscopy practices similar to those described in Prac-
820, Quality System Regulation
tice E 1252.Atypical infrared transmission reference spectrum
ANSI/ISO/ASQ Q9000 Quality Management Systems,
and a typical infrared absorption reference spectrum for
Fundamentals and Vocabulary
d,l-PLAhomopolymerareshowninFig.1.Whilepoly(lactide-
ANSI/ISO/ASQ Q9001 Requirements
co-glycolide) copolymers will each have their own respective
spectrum that will vary in response to copolymer ratio, this
3. Terminology
analytic method typically lacks sensitivity sufficient for quan-
3.1 Definition:
tification of copolymer ratio as specified in 7.1.2.
3.1.1 virgin polymer—the initially delivered form of a
5.2.2.2 Additional spectral bands may be indicative of
polymer as synthesized from its monomers and prior to any
sample crystallinity or either known or unknown impurities,
processing or fabrication into a medical device.
including residual monomer, solvents, and catalysts (refer to
limits specified in Table 1).
4. Materials and Manufacture
5.2.3 Proton Nuclear Magnetic Resonance ( H-NMR) Iden-
4.1 All raw monomer components and other materials
tification:
contacting either the raw monomer(s) or resin product shall be
5.2.3.1 Identity of either poly(lactide) homopolymer or
of a quality suitable to allow for use of such resin in the
poly(lactide-co-glycolide) copolymer may be confirmed
manufacture of an implantable medical product. Such quality
through sample dissolution, H-NMR spectroscopy, and the
includes adequate control of particles and other potential
use of a suitable reference spectrum. Sample dissolution is in
contaminants that may affect either the toxicity of or the cell
either deuterated chloroform, deuterated dichoromethane (me-
response to the as-implanted or degrading final product.
thylenechloride) or other substantially proton-free solvent able
4.2 All polymer manufacturing (including monomer han-
to fully solvate the specimen without inducing competing
dling, synthesis, pelletization/grinding and all subsequent)
spectral bands. Analysis shall be conducted using practices
shall be undertaken under conditions suitable to allow for use
similar to those described in Practice E 386.
of such resin in the manufacture of an implantable medical
5.2.3.2 Additional spectral bands may be indicative of
product.
known or unknown impurities, including residual monomer,
5. Chemical Composition
solvents, and catalysts (refer to limits specified in Table 1).
5.1 The amorphous poly(d,l-lactide) polymers covered by
5.2.4 Carbon-13 Nuclear Magnetic Resonance ( C-NMR)
this specification shall be composed either of meso-lactide or a
Identification:
5.2.4.1 Identity of either poly(lactide) homopolymer or
poly(lactide-co-glycolide) copolymer may be confirmed in a
Available from U.S. Pharmacopeia (USP), 12601Twinbrook Pkwy., Rockville,
solid state through C-NMR spectroscopy and the use of a
MD 20852-1790, http://www.usp.org.
suitable reference spectrum.Analysis shall be conducted using
Available fromAmerican National Standards Institute (ANSI), 25 W. 43rd St.,
practices similar to those described in Practice E 386.
4th Floor, New York, NY 10036, http://www.ansi.org.
Available from ICH Secretariat, c/o IFPMA, 30 rue de St-Jean, P.O. Box 758,
5.2.4.2 Additional spectral bands may be indicative of
1211 Geneva 13, Switzerland. Available online at http://www.ich.org/LOB/media/
known or unknown impurities, including residual solvents and
MEDIA423.pdf
catalysts (refer to limits specified in Table 1).
AvailablefromU.S.GovernmentPrintingOfficeSuperintendentofDocuments,
732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401, http://
5.3 Specific Rotation:
www.access.gpo.gov.
5.3.1 The virgin polymer shall have a specific rotation of
Available fromAmerican National Standards Institute (ANSI), 25 W. 43rd St.,
4th Floor, New York, NY 10036, http://www.ansi.org. –2.5 to +2.5 degrees when measured in either chloroform,
F2579–06
(Example infrared spectra are alternative presentations of an amorphous 100% d,l-PLA homopolymer.)
FIG. 1 Poly(d,l-lactide) Resin Infrared Spectra
methylenechloride, or tetrahydrofuran at 20°C using a pola- ing to Test Method D 3536 or D 3593, but using either
rimetry method equal to or equivalent to the Optical Rotation chloroform or dichloromethane and polystyrene calibration
procedure described within USP <781>. standards.
5.4 Molar Mass: 5.4.2 Determine the inherent viscosity of the polymer pref-
5.4.1 The molar mass of the virgin polymer shall be erentially in chloroform at 30°C using procedures similar to
indicated by inherent viscosity in dilute solution (IV). In those described in Practice D 2857 and Test Method D 4603.
addition to inherent viscosity (but not in place of), mass Determination at a lower temperature of 25°C is allowable,
average molar mass and molar mass distributions maybe provided the utilized equipment delivers the required thermal
determined by gel permeation chromatography (GPC) accord- control and an experimentally supported 30°C equivalent
F2579–06
(Example infrared spectra are alternative presentations of an amorphous 85% d,l-PLA:15% PGA (mole ratio) copolymer.)
FIG. 2 Poly(lactide-co-glycolide) Resin Infrared Spectra
concentration-appropriate extrapolated result is also reported tion or precipitation from solution can result in formation of
within the supplied certification. If the required sample of the
gels and will produce inconsistency and variation in observed
subject copolymer ratio does not fully dissolve in chloroform,
drop times. Inherent viscosity is determined utilizing the
alternatively utilize dichloromethane (methylene chloride) as
following:
the dissolution solvent. Note that incomplete sample dissolu-
F2579–06
(Example infra-red spectrum of an amorphous 50% d,l-PLA:50% PGA (mole ratio) copolymer.)
FIG. 2 Poly(lactide-co-glycolide) Resin Infrared Spectra (continued)
(Example NMR spectrum of an amorphous 100% d,l-PLA homopolymer.)
FIG. 3 Poly(d,l-lactide) Nuclear Magnetic Resonance Spectrum
F2579–06
(Example NMR spectrum of an amorphous 85% d,l-PLA:15% PGA (mole ratio) copolymer.)
FIG. 4 Poly(d,l-lactide-co-glycolide) Nuclear Magnetic Resonance Spectra
TABLE 1 Physical/Chemical Property Requirements for Virgin Amorphous Poly(lactide) and Poly(lactide-co-glycolide) Resins
Total Total Solvent Individual Solvent (Optional) (Optional)
Residual Combination Residual(s) and Residual Heavy Metals, Residual Copolymer Specific
Analyte
Monomer, Residual(s) Applicable ICH Water (ppm as Pb) Catalyst Ratio Rotation
(%) (in ppm) Limit(s) (in ppm) (%) (in ppm)
A
Requirement <2.0 % <1000 ppm Report both for all #0.5 % #10 ppm #150 ppm 63 % of target -2.5°
B
(by mass) solvent(s) utilized (by mass) (minus Sn) Sn (by mole) to +2.5°
A
Up to 3 % if deemed acceptable by purchaser (see 5.5.1).
B
Utilizing moisture determination method agreed upon by supplier and purchaser.
F2579–06
2+
ln~t/t !v ln~t/t ! tions. Since stannous tin (Sn ) can also form tin (II) sulfide
o o
IV 5 or (1)
w C
andtherebycarriespotentialtoinfluencetestresults,theexcess
amount ascertained by alternative analytic means (see below)
where:
to be directly attributable to both stannic and stannous tin may
IV = inherent viscosity (at 30°C in dL/g),
be ignored, provided that the cumulative lead (Pb) equivalent
t = efflux time in seconds for diluted solution,
total of the remaining listed heavy metals elements determined
t = efflux time in seconds for source solvent,
o
through the same alternative analytic means (see discussion
w = mass of polymer being diluted (in grams),
andcalculationscontainedinX2.5)remainsbelowa10ppmas
v = dilution volume in deciliters (Note: 1 dL = 100 mL),
...