Iso 10993 13 1999

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I S T D - B S I B S E N IS0 10’793-L3-ENGL 1999 I1 b 2 4 b b 9 0755737 7 b 2
I BRITISH STANDARD BS EN IS0

10993-13:1999
Biological evaluation of
medical devices -
Part 13: Identification and quantification
of degradation products from polymeric
medical devices
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The European Standard E N IS0 10993-13:1998has the status of a

British Standard
ICs 11.100
NO COPYING WíTHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAW
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S T D - B S I BS E N IS0 10773-L3-ENGL 1777 H L b 2 4 b b 7 0755740 4ôq M
BS EN IS0 10993-13:1999
National foreword
This British Standard is the English language version of EN IS0 10993-131998.It is
identical with IS0 10993-13:1W8.
The UK participation in its preparation was entrusted to Technical Committee
CW26, Biological testing of medical and dental materiais and devices, which has the
responsibility to:
- aid enquirers to understand the text;
- present to the responsible internationai/European committee any enquiries

on the interpretation, or proposals for change, and keep the UK interests
informed;
- monitor related international and European developments and promulgate
them in the UK.
A list of organizations represented on this committee can be obtained on request to

its secretary.
Cross-references
Attention is drawn to the fact that CEN and CENELEC Standards nonnally include
an annex which lists normative references to international publications with their
corresponding European publications. The British Standards which implement
international or European publications referred to in this document may be found in
the BSI Stan&& Catalogue under the section entitled ‘‘International Standards
Correspondence Index”,or by using the “F’ind facility of the BSI Standards
Electronic Catalogue.
A British Standard does not purport to include ali the necessary provisions of a
contract. Users of British Standards are responsible for their correct application.
Compliance with a British Standard does not of itself confer immunity
from legal obligations.
Summary of pages
This document comprises a front cover, an inside front cover, the EN IS0 title page,
the EN IS0 foreword page, the IS0 title page, pages ii to v, a blank page, pages 1 to
10, the annex ZA page and a back cover.
been prepared under the

direction of the Health and Amd. No. Date Text affected
Environment Sector Committee,
was published under the
authority of the Standards
Committee and comes into effect
on 15th February 1999
O BSI 02-1999
ISBN O 580 30969 X

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EUROPEANSTANDARD
NORME EUROPÉENNE
EUROPÄISCHE NORM November 1998
ICs 11.100
Descriptors:
English version
Biological evaluation of medical devices - Part 13: Identification

and quantification of degradation products from polymeric
medical devices (IS0 10993-13: 1998)
Evaluation biologique des dispo9iöfs médicaux Parüe 13: - -
Biologische Beurteilungvon Medianprodukm Teil 13:
Idenliflcation el quantificationde produits de dégradabion Qualitativerund quantitativer Nachweisvon
de dispositifs médicaux b base de polymères (IS0 10993- Abbauproduktenin Medizinproduldenaus Polymeren(IS0
13:1998) 10993-131998)
This European Standard was approvedby CEN on 15 November 1998.
CEN members are bound to comply with the CENICENELEC Intemal Regulationswhich stipulate the conditions for giving this European
Standardthe status of a nationalstandardwithout any alteration. Up-todatelists and bibliographicalreferences concerning such national
ｗｗｗ．ｂｚｆｘｗ．ｃｏｍ
standards may be obtained on application to the Central Secfetaiat or to any CEN member.
This EuropeanStandard exists in three officialversions (English, French, German). A version in any other language made by translation
under the responsibilityof a CEN member into its own language and notified to the Central Secretariathas the same status as the official
versions.
CEN members are the nationalstandards bodies of Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece,
Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and United Kingdom,
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EUROPEAN COMMITTEE FOR STANDARDIZATION

COMITE EUROPEEN DE NORMALISATION
EUROPÄISCHES KOMITEE FOR NORMUNG
Central Seweîarliit. N e de Stiissart, 36 81050 B N S ~ ~ ~ S
Q 1998 CEN All rights of exploitation in any form and by any means resewed Ref. No. EN IS0 10993-13:1998 E
worldwide for CEN national Members.

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S T D - B S I B S EN IS0 L0773-13-ENGL 1777 Lb24bbS 0 7 5 5 7 4 2 2 5 7
EN IS0 10993-13~1998
Foreword
The text of the Intemational Standard IS0 10993-13:1998 has been prepared by Technical
Committee ISOTTC 194 “Biological evaluation of medical devices” in collaboration with
Technical Committee CENTTC 206 “Biocompatibility of medical and dental materials and
devices”, the secretariat of which is held by NNI.
This European Standard shall be given the status of a national standard, either by
publication of an identical text or by endorsement, at the latest by May 1998, and conflicting
national standards shall be withdrawn at the latest by May 1998.
This European Standard has been prepared under a mandate given to CEN by the
European Commission and the European Free Trade Association, and supports essential
requirements of EU Directive@).
According to the CENICENELEC Internal Regulations, the national standards organizations

of the following countries are bound to implement this European Standard: Austria, Belgium,
Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy,
Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and the United
Kingdom.
Endorsement notice
The text of the Intemational Standard IS0 10993-13:1998 was approved by CEN as a
European Standard without any modification.
NOTE: Normative references to International Standards are listed in annex ZA (normative).
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EN IS0 10993-13:1998
INTERNATIONAL IS0
STANDARD 109934 3
First edition
1998-11-15
Biological evaluation of medical devices -

Part 13:
Identification and quantification of degradation
products from polymeric medical devices
Evaluation biologique des dispositifs médicaux -
Pattie 13: Identification et quantification de produits de dégradation de
dispositifs médicaux a base de polymères
Reference number
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EN IS0 10993-13~1998
Contents Page
1 scope ....................................................................................................... 1
2 Normative references ............................................................................. 1
3 Definitions ............................................................................................... 2
4 Degradationtest methods ..................................................................... 2
4.1 General procedures ............................................................................. 2
4.2 Accelerated degradation test ............................................................. 5
4.3 Real-time degradation test.................................................................. 5
5 Test procedures...................................................................................... 6
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5.1 Initial material characterization.......................................................... 7
5.2 Accelerated degradation test ............................................................. 7
5.3 Real-time degradation test.................................................................. 8
6 Test report ............................................................................................... 9
Annex A Analytical methods ................................................................ 10
Descriptors: medical equipment. medicaldevices. polymers. plastics products. tests. biological tests. determination. deterioration.

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STD.BSI B S EN IS0 L0993-L3-ENGL 1 9 9 9 Zb24bb9 07557Li5 Tbb
EN IS0 10993-13:1998
Foreword
IS0 (the International Organization for Standardization) is a worldwide
federation of national standards bodies (IS0 member bodies). The work of
preparing International Standards is normally carried out through IS0
technical committees. Each member body interested in a subject for which
a technical committee has been established has the right to be represented
on that committee. International organizations, governmental and non-
governmental, in liaison with ISO, also take part in the work. IS0
collaborates closely with the International Electrotechnical Commission
(IEC) on all matters of elecîrotechnical standardization.
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Draft International Standards adopted by the technical committees are

circulated to the member bodies for voting. Publication as an International
Standard requires approval by at least 75 O/O of the member bodies casting
a vote.
International Standard IS0 10993-13 was prepared by Technical
Committee ISO/TC 194, Biological evaluation of medical devices.
I S 0 10993 consists of the following parts, under the general title Biological
evaluation of medical devices:
Part 1: Evaluation and testing
Part 2: Animal welfare requirements
Part 3: Tests for genotoxicity, carcinogenicity and reproductive

toxicity
Part 4: Selection of tests for interactions with blood
Part 5: Tests for cylotoxicjty: in vitro methods
Part 6: Tests for local effects after implantation
Pari 7: Ethylene oxide sterilization residuals
Part 9: framework for the identification and quantification of potential

degradation products
Part 1O: Tests for irritation and sensitization
Part 1I : Tests for systemic toxicity
Part 12: Sample preparation and reference materials
Part 13: Identification and quantification of degradation products from

polymeric medical devices
Copyright British Standards Institution iii

EN IS0 10993-13~1998
- Part 74: Identification and quantification of degradation products from

ceramics
- Part 15: Identification and quantification of degradation products from
metals and alloys
- Part 76: Toxicokinetic study design for degradation products and
leachables
Annex A of this part of IS0 10993 is for information only.

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iv
EN IS0 10993-13:1998
Introduction
This part of IS0 10993 was developed from ISOTTR 10993-9. Degradation
products covered by this standard are formed primarily by chemical bond
scission due to hydrolytic and/or oxidative processes in an aqueous
environment. It is recognized that additional biological factors, such as
enzymes, other proteins and cellular activity, can alter the rate and nature
of degradation.
It should be kept in mind that a polymeric device may contain residuals and
leachables such as monomers, oligomers, solvents, catalysts, additives,
fillers and processing aids. These components which, if present, may
interfere with the identification and quantification of the degradation
products, need to be considered and accounted for. It should be
recognized that residual monomers may generate the same degradation
products as the polymer itself.
The identified and quantified degradation products form the basis for
biological evaluation in accordance with IS0 10993-1, for risk assessment
in accordance with IS0 14538 and, if appropriate, for toxicokinetic studies
in accordance with I S 0 10993-16.
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STD.BSI BS E N IS0 L0993-13-ENGL 1999 E L b 2 4 b b 9 0 7 5 5 7 4 8 7 7 5 E
EN IS0 10993-13~1998
Biological evaluation of medical devices -

Part 13:
Identification and quantification of degradation products from polymeric
medical devices
1 scope
This part of IS0 I0993 provides guidance on general requirements for the design of tests for identifying and
quantifying degradation products from finished polymeric medical devices ready for clinical use.
This part of IS0 10993 describes two test methods to generate degradation products, an accelerated degradation
test as a screening method and a real-time degradation test. For materials which are intended to polymerize in situ,
the set or cured polymer is used for testing. The data generated are used in the biological evaluation of the polymer.
This pari of IS0 10993 considers only those degradation products generated by a chemical alteration of the finished
polymeric device. It is not applicable to degradation of the device induced during its intended use by mechanical
stress, wear or electromagnetic radiation.
The biological activity of the debris and soluble degradation products is not addressed in this part of IS0 10993, but
should be evaluated according to the principles of IS0 10993-1 and IS0 14538.
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Because of the wide range of polymeric materials used in medical devices, no specific analytical techniques are
identified or given preference. No specific requirements for acceptable levels of degradation products are provided
in this pari of IS0 10993.
2 Normative references
-:ne following standards contain provisions which, through reference in this text, constitute provisions of this pari of
IS0 10993. At the time of publication, the editions indicated were valid. All standards are subject to revision, and
parties to agreements based on this part of IS0 10993 are encouraged to investigate the possibility of applying the
most recent editions of the standards indicated below. Members of IEC and IS0 maintain registers of currently valid
international Standards.
IS0 3696:1987, Water for analytical laboratory use - Specification and test methods.
IS0 10993-1:1997, Biological evaluation of medical devices -Part 7: Evaluation and testing.
IS0 10993-9:-'), Biological evaluation of medical devices - Part 9: Framework for identification and quantification
of potential degradation products.
IS0 10993-12:1996, Biological evaluation of medical devices - Part 72: Sample preparation and reference
materials.
' To be published.

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EN IS0 10993-13:1998
IS0 10993-16:1997, Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation
products and leachables.
IS0 13781:1997, Poly(L-lactide)resins and fabricated forms for surgical implants - In vitro degradation testing.
IS0 14538:-” Biological evaluation of medical devices - Establishment of permissible limits for sterilization and
process residues using health-based risk assessment.
3 Definitions
For the purposes of this part of IS0 10993, the definitions given in IS0 10993-1, IS0 10993-9, IS0 13781 and the
following definitions apply.
3.1 residual monomer

unreacted chemical compound(s) used to build the polymeric chains and still present in the final polymeric material
3.2 degradation product

chemical compound derived from the breakdown of the polymeric material, including any compound produced by
consecutive chemical reactions
3.3 polymeric material
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materials consisting of long-chain and/or crosslinked molecules composed of units called monomers
3.4 hydrolytic degradation

scission of chemical bonds in a polymer by the attack of water
3.5 oxidative degradation ｗｗｗ．ｂｚｆｘｗ．ｃｏｍ

NOTE The water may have a neutral, acidic or alkaline pH value and may contain additional chemical compounds or ions.
scission of chemical bonds in a polymer by the attack of oxidizing agent@)
3.6 debris
particulate material produced by the degradation of a polymeric material
4 Degradation test methods
4.1 General procedures
4.1.1 Test design
In accordance with IS0 10993-9, degradation tests shall be used to generate, identify and/or quantify degradation
products. If degradation is observed in an accelerated test, identification and quantification of the degradation
products may provide sufficient information for risk analysis. Where this information is insufficient or absent, real
time testing shall be performed. The sequence of steps which shall be followed is described in detail in this part of
IS0 10993.
NOTE The accelerated degradation test may be used as a screening test. If no degradation is observed in the accelerated
test, no real-time degradation test should be necessary.
4.1.2 Sample preparation
When not specifically addressed by the selected method@),the general aspects of sample preparation shall be in
accordance with IS0 10993-12.

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STD.BSI BS E N IS0 L0773-23-ENGL L777 Lb24bb7 0755750 323
EN IS0 10993-13:1998
4.1.3 Initial material characterization
The analytical methods used for the initial material characterization shall be appropriate for the polymeric material
under investigation. The analytical techniques used shall be reported and justified.
Annex A of this part of IS0 10993 presents a list of analytical methods and their application range for the
Characterization of polymeric materials.
4.1.4 Reagents and apparatus
4.1.4.1 l e s t solutions
All test solution(s) used shall be described and justified in the test report.
4.1.4.1.1 Reagents for hydrolytic degradation
For hydrolytic degradation the following solutions are suggested:
a) water for analytical laboratory use, grade 2, in accordance with IS0 3696;
b) buffer, e.g. in accordance with IS0 13781.
4.1.4.1 9 Reagents for oxidative degradation
For oxidative degradation the following solutions are suggested:
a) water and hydrogen peroxide, e.g. 3 % hydrogen peroxide solution, Pharmacopoeia grade;
b)
H,O,I.
Fenton's reagent [mixture of dilute hydrogen peroxide solution and iron(1l) salts, e.g. 100 pmol Fe" and 1 rnrnol
These oxidative solutions may not be stable at elevated temperatures or for a prolonged time. Therefore the
oxidative capacity shall be maintained in an appropriate range.
This stability range shall be specified, justified and reported.
4.1.4.1.3 Other test solutions
Other test solutions for a specific polymer or a specific application site may be chosen.
NOTE If a biological assay of the debris or the degradation solution is to be made, then the use of antibacterial or antifungal
additives will interfere with these assays and it may be necessary to maintain a sterile environment for the duration of the real-
time degradation test.
4.1.4.2 Container
Depending on the test solution, chemical grade glassware, polytetrafluoroethylene or polypropylenecontainers in an

enclosed system shall be used. Controls shall be used in order to assess contaminants from the container.
Evidence shall be provided that containers do not interfere with the analysis.
4.1.4.3 Balance
The balance used to determine mass loss shall be capable of weighing the initial sample mass with the precision
required. For materials designed to be resorbed, a precision of 1 Yo is appropriate, for materials designed to resist
degradation, a precision of at least 0,lo/o shall be used. The accuracy of the balance for resorbable polymers shall
be 0,l %, and for stable polymers 0,Ol %,of the total sample mass.
The precision and standard deviation of the method of the determination of mass loss shall be stated in the test
report.
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EN IS0 10993-13~1998
4.1.4.4 Drying apparatus
Any apparatus capable of drying the test samples to constant mass without contamination or loss of volatile
degradation products shall be used.
The apparatus shall be described and defined in the test report.
4.1.4.5 Vacuum source
Any apparatus capable of producing a sufficient vacuum (< 500 Pa) in the drying apparatus is appropriate.
4.1.4.6 Separation apparatus
Any apparatus capable of separating the debris produced during the degradation study shall be used. This may
involve an inert filter, a temperature-controlledcentrifuge or a combination thereof.
4.1.5 Number of test samples
At least three test samples shall be used for each test period. These should be the finished product itself or
representative samples thereof. A separate container shall be used for each sample. One blank shall be used for
each test period.
NOTE If a valid statistical analysis is required, more samples at each test period should be used.
4.1.6 Shepe and size of test samples
It must be appreciated that the size and the shape of the specimen are critical for the generation of relevant
amounts of degradation products. If a part of the finished device is used as the test sample, then surfaces which are
normally not in contact with the biological environment should be avoided or minimized.
The size, shape and surface area of the sample should be chosen in such a way that equilibrium with the
degradation solution and a constant mass for the determination of the mass balance can be reached in an
acceptable time.
NOTE 1 Under certain circumstances it may be necessary to fabricate a test sample using the same processing, cleaning and
sterilization methods as are used in the fabrication of the device.
NOTE 2 With resorbable polymers, equilibrium with the degradation solution may not be reached.
4.1.7 Masshrolume ratio
The ratio of the mass of the test sample to the volume of the test solution should be at least 1:lO. The samples shall
be fully immersed in the test solution.
The choice of the ratio used shall be reported and justified in the test report.
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NOTE The ratio 1:lO was chosen for practical reasons. When using this ratio, however, it should be considered that the
release of degradation products may interfere with the progress of degradation itself and may influence the rate of the
degradation and the equilibrium of the degradation reaction(s).
4.1.8 Sample pretreatment
To set up the mass balance, the sample shall be dried to a constant mass. If the device contains volatile
components, an appropriate drying method shall be selected.
In this case, the drying method and the conditions shall be stated and justified in the test report.
4
I 4.1.9 pH
If the pH of the test solution is relevant, the pH shall be maintained in an appropriate range. The pH chosen shall be
appropriate to the site of intended use (e.9. the acidic stomach). Changes in the pH induced by physiological
phenomena, e.g. during an inflammatory response, shall be considered.
The pH shall be reported and justified in the test report.
NOTE 1 Elevated temperatures can change the pH value.
NOTE 2 It should be recognized that if the pH value is not maintained in the appropriate range, the degradation products
generated may or may not be the same as those that occur under biological conditions.
4.1.1 O Determinationof the mass balance
When the sample is removed from the test solution, the sample shall be rinsed with adequate quantities of analytical
grade water. The rinse water and any debris loosened by the rinse water shall be added to the test solution. The
sample and the debris eventually obtained from the separation apparatus shall be dried to a constant mass. Then
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the mass balance shall be determined.
4.1.1 1 Final material characterization
The material shall be characterized using the same methods as used in the initial material characterization.
4.2 Accelerated degradation test
4.2.1 Temperature
appropriate, 70 "C +l O C shall be used.

Choose a temperature greater than 37 "C and below the melting or softening range of the polymer. When
The temperature chosen shall be reported and justified in the test report.
NOTE Higher temperatures may lead to side reactions which may not occur at lower temperatures.
4.2.2 Test periods
For devices whose intended use is longer than 30 days, test periods of 2 and 60 days shall be used. For devices
whose intended use is less than 30 days, test periods of 2 and 7 days shall be used. Additional test periods may be
chosen depending on the polymer under investigation or the intended use of the device.
The test periods shall be reported and justified.
NOTE For devices made from resorbable polymers, this test period may last until the device has lost its integrity (as defined
for the individual material).
4.3 Real-time degradation test
4.3.1 Temperature
Carry out the test at 37 OC f 1 "C.
4.3.2 Test period
For devices whose intended use is longer than 30 days, test periods of 1 month, 3 months, 6 months and
12 months shall be used. For devices whose intended use is less than 30 days, four alternative test periods shall be
used, including 30 days. Additional test periods may be chosen depending on the polymer under investigation or the
intended use of the device.
The test periods shall be reported and justified.

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S T D - B S I BS EN IS0 L O 7 7 3 - L 3 - E N G L 1 9 9 9 m l b 2 q b b 7 O755753 O32
EN IS0 10993-13:1998
NOTE For devices made from resorbable polymers, this test period may last until the device has lost its integrity (as defined
for the individualmaterial).
5 Test procedures
The steps to be followed are described in the flowchart in table1 .
NOTE For evaluation of crosslinked polymer systems, the decision for further action will be based on the mass balance
calculation and a measurement of the density of crosslinking instead of molecular masdmolecular mass distribution
determination.
Table 1
Initlal material characterization

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,
M ACCELERATED DEGRADATION TEST
Sample
Separate solids and fluid phase

Debris Fluid phase
ｗｗｗ．ｂｚｆｘｗ．ｃｏｍ Sample Debris Fluid phase
Dry sample and debris
Set up mass balance
I Evaluatlon:
I
Change in mass balance: (Y)es or (N)o
Change in molecular masdmolecularmass

distribution: (Y)es or (N)o
No degradation Check the bulk

has been
time
degradation
test is I
samplddebris degraded;
observed. end for degradation
of test, no real- products andior quantify
quantify
polymr
go to real-time leachables fron degradation
degradation the fluid phase products from
test. andfor go to the fluid phase
-t
No degradation Check the bulk
has been
of test
sampleidebris
observed, end for degradation
products
Polymer not
degraded;
quantify
Identify and
quantify
identify and leachables anc
polymer
leachables from degradation
the fluid phase. products from
necessary.
I 1
real-time andfor go to ~
degradation real-time
test. degradation
(see note in test. (see note in
5.2.4.1) (see 4.1) 5.3.4.1)
(see 4.1) (see4.1)
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EN IS0 10993-13:1998
5.1 Initial material characterization
The initial material characterization shall address the bulk polymer and the residuals and additives present in the
final device. Because of the difficulties of retrospective analysis, this information is best obtained from the supplier
or manufacturerof the material. It is important to fully characterize the purity of the polymer and the additives used
in its formulation.
5.2 Accelerated degradation test
5.2.1 Measurementof initial mass
Dry the test sample to constant mass. Determine the mass of the test sample.
5.2.2 Separation of sample, debris and solution
5.2.2.1 Separation by filtering
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Dry a filter under vacuum at room temperature to constant mass. Determine the mass of the filter. Separate sample
with possible debris from the degradation solution by means of the weighed filter. If necessary, vacuum or pressure
filtering can be used. Wash the contents of the filter three times with analytical grade water.
5.2.2.2 Separation by centrifuging
Determine the mass of a dry and clean centrifuge tube. Transfer the degradation test sample solution into the
centrifuge tube and close the tube prior to separation. Spin the tube in the centrifuge to obtain a firm debris pellet.
Carefully decant the supernatant solution into a container. Resuspend the pellet in analytical grade water and spin
again. Decant the supernatant solution again and add this solution to the container. Repeat this procedure two more
times.
5.2.3 Analysis
5.2.3.1 Determination of mass balance
Dry the filter and its contents or the centrifuge tube and its contents under vacuum at room temperature to a
constant mass. Determine the mass of the filter and its contents or the centrifuge tube and its contents. Determine
the mass loss of the sample.
5.2.3.2 Sample and debris characterization
The molecular mass and the molecular mass distribution are determined by appropriate methods (see also
annex A).
5.2.4 Evaluation (see table 1)
5.2.4.1 Case 1 (NoMo)
No change in mass balance and molecular mass/distribution:
No degradation has been observed. The test is terminated; no real-time degradation test is necessary.
NOTE Under some circumstances, it may be necessary to confirm this result by further investigations in line with IS0 10993-9.
5.2.4.2 Case 2 (Nones)
No change in mass balance, but molecular mass/distribution has changed:
Check the bulk sample/debris for degradation products. Proceed with real-time degradation test, if necessary
(see 4.1).

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EN IS0 10993-13:1998
5.2.4.3 Case 3 (Yerno)

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Change in mass balance, but no change in molecular mass/distribution:
Polymer is not degraded, fluid phase contains leachables which shall be assessed according to IS0 10993-1.
Proceed with real-time degradation test, if necessary (see 4.1).
5.2.4.4 Case 4 (Yedïes)
Change in mass balance and change in molecular masddistribution:
Identify and quantify leachables and polymer degradation products from the fluid phase and check the bulk sample
and debris for degradation products. Proceed with real-time degradation test, if necessary (see 4.1).
5.3 Real-time degradation test
5.3.1 Measurement of initial mass
Dry the test sample to constant mass. Determine the mass of the test sample.
5.3.2 Separation of sample, debris and solution
5.3.2.1 Separation by filtering
Dry a filter under vacuum at room temperature to constant mass. Determine the mass of the filter. Separate sample
with possible debris from the degradation solution by means of the weighed filter. If necessary, vacuum or pressure
filtering can be used. Wash the contents of the filter three times with analytical grade water.
5.3.2.2 Separation by centrifuging

Determine the mass of a clean dry centrifuge tube. Transfer the degradation test sample solution into the centrifuge
tube and close the tube prior to separation. Spin the tube in the centrifuge to obtain a firm debris pellet. Carefully
decant the supernatant solution into a container. Resuspend the pellet in analytical grade water and spin again.
Decant the supernatant solution again and add this solution to the container. Repeat this procedure two more times.
5.3.3 Analysis
5.3.3.1 Determinationof mass balance
Dry the filter and its contents or the centrifuge tube and its contents under vacuum at room temperature to a
constant mass. Determine the mass of the filter and its contents or the centrifuge tube and its contents. Determine
the mass loss of the sample.
5.3.3.2 Sample and debris characterization
The molecular mass and the molecular mass distribution are determined by appropriate methods (see also
annex A).
5.3.4 Evaluation (see table 1)
5.3.4.1 Case 1 (Nomo)
No change in mass balance and molecular masddistribution:
No degradation has been observed. The test is terminated.

NOTE Under some circumstances, it may be necessary to confirm this result by further investigations in line with IS0 10993-9.
5.3.4.2 Case 2 (NoRes)
No change in mass balance, but molecular masddistribution has changed:

EN IS0 10993-13:1998
Check the bulk sample/debris for degradation products.
5.3.4.3 Case 3 (Yes/No)
Change in mass balance, but no change in molecular mass/distribution:
Polymer is not degraded, fluid phase contains leachables which shall be assessed according to I S 0 10993-1
5.3.4.4 Case 4 (YesJïes)
Change in mass balance and change in molecular mass/distribution:
Identify and quantify leachables and polymer degradation products from the fluid phase and check the bulk sample
and debris for degradation products.
--`,``,`,,``,,`,`,,````,`,``,-`-`,,`,,`,`,,`---
6 Testreport
The test report shall include the following information:
description of the test material, batch or lot number, dimensions and number of samples tested;
test solution and conditions;
detailed description and justification of the test methods used, including (where appropriate) specificity,
sensitivity, detection and quantification limits;
method used to determine mass loss, including precision and standard deviation;
mass/volume ratio of sample, shape of sample;
sample pretreatment and drying method;
selected pH;
test temperature;
test periods;
test results:
1) mass balance,
2) molecular masddistribution (crosslink density),
3) results of tests run on the solution, debris and/or bulk polymer,

4) identified degradation products,
5) rationale for final decision;
k) conclusions.

Reproduced by IHS under license with BSI - Uncontrolled Copy Licensee=University of Hong Kong/5910986001 9
~~ ~ ~
STD.BSI B S E N IS0 L0773-L3-ENGL 1777 IL b 2 q b b î 0 7 5 5 7 5 7 788
EN IS0 10993-13:1998
Annex A
(informative)
Analytical methods
The following analytical methods are suggested for the characterization of the polymeric material, if appropriate:
solution viscometry (molecular mass average, branching);
swellability (crosslink density);
rheology (melting range, melt viscosity, thermal stability, molecular mass distribution);
chromatographic methods (e.g. gas and/or high performance liquid chromatography for residual monomers,
additives and leachables; size exclusion/gel permeation chromatography for molecular mass averages and
changes in molecular mass distribution);
spectroscopic methods (e.g. ultraviolet spectroscopy, infrared spectroscopy, nuclear magnetic resonance,
mass spectroscopy for identity, composition, distributions; atomic absorption spectroscopy for catalyst content,
heavy metals);
thermal analysis (e.g. differential scanning calorimetry for glass transition, melting range or softening point,
blends).
Because a finished medical device may contain several materials from several sources, an intensive literature study
and the request of reliable analytical data from the suppliers is strongly recommended to minimize the analytical
work.
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10
EN IS0 10993-13:1998
Annex ZA (normative)
Normative references to international publications
with their relevant European publications
This European Standard incorporates by dated or undated reference, provisions from other
publications. These normative references are cited at the appropriate places in the text and the
publications are listed hereafter. For dated references, subsequent amendments to or revisions
of any of these publications apply to this European Standard only when incorporated in it by
amendment or revision. For undated references the latest edition of the publication referred to
applies.
EN mx
IS0 3696 1987 Water for analytical laboratory use - EN IS0 3696 1995
Specificationand test methods
IS0 10993-1 1997 Biological evaluation of medical devices - EN IS0 10993-1 1997
Part 1: Evaluation and testing
--`,``,`,,``,,`,`,,````,`,``,-`-`,,`,,`,`,,`---
IS0 10993-12 1996
-
Biological evaluation of medical devices
Part 12: Sample preparation and reference
materials
EN IS0 10993-12 1996
IS0 10993-16 1997 Biological evaluation of medical devices - EN IS0 10993-16 1997
Part 16: Toxicokinetic study design for
degradation products and leachables

BS EN IS0
10993-13~1999
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presents the UK view on standads in Europe and at the international level. It is
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It is the constant aim of BSI to improve the quality of our products and services. We
would be gratefuì if anyone finding an inaccuracy or ambiguity while using this
British Standard would inform the Secretary of the technical committee responsible,
the identity of which can be found on the inside front cover. Tel 0181 996 9000.
--`,``,`,,``,,`,`,,````,`,``,-`-`,,`,,`,`,,`---
Fax: O181 996 7400.

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I S T D - B S I B S E N IS0 10’793-L3-ENGL 1999 I1 b 2 4 b b 9 0755737 7 b 2

I BRITISH STANDARD BS EN IS0

The European Standard E N IS0 10993-13:1998has the status of a

NO COPYING WíTHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAW

Copyright British Standards Institution

- aid enquirers to understand the text;

- present to the responsible internationai/European committee any enquiries

A list of organizations represented on this committee can be obtained on request to

been prepared under the

ISBN O 580 30969 X

Copyright British Standards Institution

Biological evaluation of medical devices - Part 13: Identification

This European Standard was approvedby CEN on 15 November 1998.

EUROPEAN COMMITTEE FOR STANDARDIZATION

Central Seweîarliit. N e de Stiissart, 36 81050 B N S ~ ~ ~ S

Copyright British Standards Institution

S T D - B S I B S EN IS0 L0773-13-ENGL 1777 Lb24bbS 0 7 5 5 7 4 2 2 5 7

According to the CENICENELEC Internal Regulations, the national standards organizations

NOTE: Normative references to International Standards are listed in annex ZA (normative).

Copyright British Standards Institution

S T D - B S I BS EN IS0 10993-13-ENGL 1979 W 1 b 2 4 b b 7 0 7 5 5 7 4 3 193

Biological evaluation of medical devices -

2 Normative references ............................................................................. 1

4 Degradationtest methods ..................................................................... 2

4.1 General procedures ............................................................................. 2

4.2 Accelerated degradation test ............................................................. 5

4.3 Real-time degradation test.................................................................. 5

5.1 Initial material characterization.......................................................... 7

5.2 Accelerated degradation test ............................................................. 7

5.3 Real-time degradation test.................................................................. 8

6 Test report ............................................................................................... 9

Annex A Analytical methods ................................................................ 10

Copyright British Standards Institution

STD.BSI B S EN IS0 L0993-L3-ENGL 1 9 9 9 Zb24bb9 07557Li5 Tbb

Draft International Standards adopted by the technical committees are

Part 1: Evaluation and testing

Part 2: Animal welfare requirements

Part 3: Tests for genotoxicity, carcinogenicity and reproductive

Part 4: Selection of tests for interactions with blood

Part 5: Tests for cylotoxicjty: in vitro methods

Part 6: Tests for local effects after implantation

Pari 7: Ethylene oxide sterilization residuals

Part 9: framework for the identification and quantification of potential

Part 1O: Tests for irritation and sensitization

Part 1I : Tests for systemic toxicity

Part 12: Sample preparation and reference materials

Part 13: Identification and quantification of degradation products from

Copyright British Standards Institution iii

- Part 74: Identification and quantification of degradation products from

Annex A of this part of IS0 10993 is for information only.

Copyright British Standards Institution

STD.BSI BS E N IS0 L0993-13-ENGL 1999 E L b 2 4 b b 9 0 7 5 5 7 4 8 7 7 5 E

Biological evaluation of medical devices -

Copyright British Standards Institution

S T D - B S I B S EN IS0 L0993-13-ENGL 1797 M Lb2LibbS 0755749 b o l W

3.1 residual monomer

3.2 degradation product

3.3 polymeric material