FOI 244 1112 Document 7 - Therapeutic Goods Administration · PDF fileCONCLUSION 21 21 21 22 22 24 25 26 ... MET 04/008-1 I Index : ... DE1.B ultimate elongation after tensile set

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POLY IMPLANTS PROTHESES

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PROTOCOLE DE VIEILLISSEMENT ACCELERE DES IMPLANTS PREREMPLIS DE GEL DE SILICONE EMBALLES SOUS BLISTERS ET

STERILISES A L'OE

PROTOCOL OF ACCELERATED AGING OF EO STERILISED, BLISTER PACKAGED SILICONE GEL PRE

FILLED BREAST IMPLANTS

Redacteur / Written by Verificateur / Reviewed by Approbateur / Approved by

Nom G. BALL/ON L. GOSSART J. BUREL

Name F. MOREAU Ingenieur METHODES

Fonction Technicien METHODES Resp. METHODES Directeur QUAL/TE Function Methodology Engineers Methodology Leader Quality Maneger

Methodology Technician

Signature


Reference: MET 04/008-1

1. PURPOSE AND SCOPE

1.1; SCOPE

1.2. PURPOSE

-I Index : NA I Application date: NA

2. REFERENCES AND DEFINITIONS

2.1. STANDARD AND DOCUMENT REFERENCES

2.2. DEFINITIONS AND ABBREVIATIONS

2.2.1. Definitions « MECHAN ICAl TESTS» 2.2.2. Abbreviations

3. REMINDER OF INPUT DATA

3.1. CRITERIA OF ACCEPTABLE STABILITY LEVEL

3.1.1. Chemical criteria 3.1.2. Physical criteria 3.1.3. Microbiological criteria 3.1.4. Toxicological criteria 3.1.5. Biocompatibility

3.2. REQUIREMENTS

\page 2/26

4

4

5

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6 6

7

7

7 7 8 8 8

9

3.2.1. Requirements on the container = envelope 9 3.2.2. Requirements on content = silicone gel 10 3.2.3. Requirements on the general aspect and characteristics of the whole 10 3.2.4. Requirements on the Blister packaging 11 3.2.5. Requirements on sterility 11

4. ACCELERATED AGING OF STERILE MEDICAL PACKAGING 12

4.1. PURPOSE OF THE ACCELERATED AGING 12

4.2. THEORETICAL ACCELERATED AGING 12

4.3. EQUIPMENT 12

4.4. DEFINITIONS OF ABBREVIATIONS 13

4.5. DETERMINATION OF THE ACCELERATED AGING· FACTOR 14

4.6. DETERMINATION OF THE ACCELERATED AGING TIME 14

4.7. STEPS OF THE ACCELERATED AGING PROTOCOL 15

4.8. ACCELERATED AGING PROTOCOL ON THE PACKAGING 16

4.9. DETERMINATION OF TESTS PERFORMED ON THE PACKAGING 18

4.9.1. Modes of operation of tests on the packaging 18 4.9.2. Acceptance criteria of tests on the packaging 19

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4.9.3. Sampling 20

4.10. DETERMINATION OF STERIL:lTYTESTS PERFORMED ON AN IMPLANT 21

4.10.1. Mode of operation of sterility tests 4.10.2. Acceptance criteria of sterility tests 4.10.3. Sampling

4.11. DETERMINATION OF TESTS PERFORMED ON IMPLANTS

4.11.1. Modes of operation of tests on 1M 4.11.2. Acceptance criteria 4.11.3. Sampling

5. CONCLUSION

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1. PURPOSE AND SCOPE

1.1. SCOPE

Poly Implants Protheses uses a « Blister» type packaging to pack the silicone gel pre-filled breast

implants that are ethylene oxide sterilised.

This new packaging replaces the ({ sachet)} type packaging whose 5-year expiration date was validated in project PR 01/03: « Validation of the 5-year expiration date of ethylene oxide sterilised sachet packaged breast implants)} and report MET 04/002 « Summary of. the validation of the 5-year expiration date of ethylene oxide sterilised, sachet packaged breast implants".

A validation of the expiration date of blister packaged IMGHC is ongoing (project PR 01/06' "Validation of the 5-year expiration date of ethylene oxide sterilised blister packaged breast implants"). This validation is based on the FDA guidance "Shelf life of medical devices" (April 1991). This guide is used as basis to define the inpufdata allowing us to validate our products at5 years. Breast implants used for this validation were sterilised in August - September 2000 (age of implants: 3 years %).

Further to the design examination of the TOV during the first quarter 2004, the expiration date of ethylene oxide sterilised silicone gel pre-filled breast implants, packaged in,double blisters cannot be fixed at 5 years but at 3 years (age of implants at the time of validation).

Tests on the packaging and on implants are performed in real time until 5 years. However, we think of setting forth accelerated aging tests so as to validate quicker expiration date.

1.2. PURPOSE

The purpose of this report is to describe the protocol detailing the accelerate,d aging performed on the IMGHC packaging, in accordance with the ASTM F191:\O-02 « Standard Guide Accelerated Aging of Sterile Medical Device Packages », so as to validate quicker the 5-year expiration date of IMGHC.

This Standard applies only to the packaging. However, in addition to the tests on the packaging, we would like to perform tests on implants that underwent this accelerated aging.


Reference: MET 04/008-1 !Index: NA !·APPlication date: NA ! Page 5/26

2. REFERENCES AND DEFINITIONS

2.1. STANDARD AND DOCUMENT REFERENCES

Names Titles

~STM F1980 - 02 ~tandard guide of accelerated aging of sterile medical device packages

NF T 46-002 (1988) ~ulcanised or thermoplastic rubber, tensile tests

NF EN 12180 (2000) Non active surgical implants. Body contouring implants. Specific requirements related o breast implants.

ISO 5893 (1993) :rest equipment for rubbers and plastics - Types for tensile strength, flexion and pompression (constant translation speed) - Description

ASTM D 412 (1997) Standard test methods for vulcanized rubber and thermoplastic rubbers ar)d hermoplastic elastomers - Tension

~STM F 703 (1996) Standard specification for implantable brel:ist prostheses

~STM F 1929 (1998) Standard method f9r detecting leaks in porous medical packaging by dye penetration

j ~STM 0 3078 (1994) Determination of leaks in flexible packaging by bubble emission

NF EN 868;.1 Materials and packaging systems for medical devices to sterilize. Part 1 : General requirements and testing methods Materials and packaging systems for medical devices to sterilize. Part 10 : Adhesive

NF EN 868-10 coated non woven materials of polyefine for use in the manufacture of heat sealable pouches, reels and lids - Requirements and test methods

Guide FDA (1991) Shelf life of medical device

METD3/009 Validation protocol of the 5-year expiration date of ethylene oxide sterilised and blister packaged breast implants

PR 00/09 Project« validation of production (new parameters) )}

MEA 03/001 !Test methods oftensiJe machines MTS 200/M - Tests on 1M, GAB and EXP (H2 type specimens)

MEA 03/004 Testing methods on tensile machine MTS 200/M - Peel tests on blister-lid seal

SQ1/02 DOT 202 Technical file of IMGHC

PR 01/03 !Validation of the 5-year expiration date of ethylene oxide sterilised sachet packaged breast implants

MET 04/002 ~alidation of the 5-year expiration date of ethylene oxide steri~jsed sachet packaged breast implants

PR 01/06 Validation of the 5-year expiration date of ethylene oxide sterilised blister packaged breast implants


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2.2. DEFINITIONS AND ABBREVIATIONS

2.2.1. Definitions {( MECHANICAL TESTS"»

Names Definitions

It is the maximal elongation at the time of rupture of a specimen submitted to a constant Ultimate elongation stress. Elongation is calculated as compared to the initial length Lo located between the

extenso meter pinches. Breaking strength It is the maximal force at the time of rupture of the specimen expressed in N. Tensile set - loss of It is the remaining elongation of a specimen after being elongated at 300% for 3 minutes and elasticity left at rest for 3 minutes. Elongation calculated as compared to the initial length.

2.2.2. Abbreviations

Abbreviation Full name

1M Breast Implant IMGHC-LS Smooth surface high cohesivity gel pre-filled breast implant IMGHC-TX Textured surface high cohesivity gel pre-filled breast implants LC Limit conditions ILC Inferior Limit Conditions SLC Superior Limit Conditions NA Non Applicable A% Ultimate elongation F Breaking strength


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3.- REMINDER OF INPUT DATA

3.1. CRITERIA OF ACCEPTABLE STABILITY lEVEL

Input data are both made of stability acceptable levels and requirements we determine so as to meet the criteria of stability acceptable level. Criteria of stability acceptable level are issued from the FDA guidance «Shelf life of medical devices.». This document, specific to expiration date, is the only document we found allowing to define objectives to reach so as to validate an expiration date.

3.1.1. Chemical criteria

• Degradation: do any active ingredients or components of the device degrade over time in a manner which adversely affects device safety or performance?

• Interaction: do ingredients or components interact to alter the device? Does the device have interactions among the various components that cause degradation of the ability to perform the intended function?

• Device and packaging interaction: Is there interaction between the device and package that has undesirable effects?

• Manufacturing process: do any of the manufaoturing processes. alter the chemistry of the raw materials, components. or finished device in a manner which adversely affects the device safety or performance?

3.1.2. Physical criteria

• Physical criteria: does the device have physical characteristics that vary with time (appearance. elasticity. tensile strength •... ) that may cause concern to the user?

• Manufacturing process: do the different steps in the manufacture of the device affect the physical characteristics of the individual components or the finished device in a manner which adversely affects the device safety or performance?

• Storage conditions: do the storage conditions (temperature, humidity •... )have an effect on the device in a manner which adversely affects device safety or performa!1ces ?


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3.1.3. Microbiological criteria

• Sterility: do sterile devices remain sterile? Maintenance of sterility is primarily determined by the maintenance of package and seal integrity.

• Environment control: is an environmental control program needed during' manufacturing or storage to monitor and adjust the microbial load in or on the device and packaging below an established tolerance level to prevent adverse degradation of the product?

• Integrity: do the device's barrier characteristics change?

3.1.4. Toxicological criteria

• Toxicology: do device degradation by-products form duri.ng storage or use that produce a adverse toxic effect?

3.1.5. Biocompatibility

• Biocompatibility: does the biocompatibility of the product change adversely during storage or use?

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3.2. REQUIREMENTS

In order to meet the criteria of acceptable stability level, we set forth several requirements.

ReCjuirements below only bring together those allowing to assure the product quality after 5-year

expiration.

3.2.1. Requirements on the container = envelope

• DE1: Mechanical characteristics on implants all along the shelf life DE1.1 thickness comprised between 0.37 mm and 0.63 mm for smooth surface implants DE1.2 difference of thickness between the minimal point and the maximal point lower than

0.13 mm for smooth surface implants DE1.3 thickness comprised between 0.57 mm and 0.95 mm for textured surface implants DE1.4 difference of thickness. between the minimal point and the maximal point lower than

0.22 mm for textured surface implants DE1.5 ultimate elongation greater than or equal to 450 % DE1.6 breaking strength greater than or equal to 8.0 N . DE1.7 tensile set at 300 % for 3 minutes lower than or equal to 10 % DE1.B ultimate elongation after tensile set test at 300% for 3 minutes greater than or equal to

400% DE1.9 breaking strength after tensile set test at 300% for 3 minutes greater than or equal to

7,5N DE1.10 elongation at 300% for 10 seconds of the specimen containing the mould code without

rupture DE1.11 elongation at 300% for 10 seconds of specimens containing the glued part {( envelope

+ closure patch » without rupture DE1.12 ultimate elongation of specimens containing the glued part ({ envelope + closure

patCh » after resistance test at 300% greater than or equal to 400 % DE1.13 breaking strength of specimens containing the glued part {( envelope + closure patch»

after resistance test at 300% greater than or equal to 7.5 N.

• DE2 : Chemical degradation of breast implant envelopes all along the shelf life

• DE3 : Maintenance of non cytotoxicity on bre.ast implant envelopes all along the shelf life

I DE3.1 I envelopes of 5-year-old or more implants should not be cytotoxic

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3.2.2. Requirements on content = silicone gel

• DE4: Physico-chemical characterization of th.e· silicone gel contained in implants all along the shelf life

DE4.1 the silicone fLel penetrability should be by 17.0 +/- 3.0 mm DE4.2 silicone gel cohesivity conforming to RD 00/013 « Cohesivity test of the silicone gel» DE4.3 absence of apparition of new chemical functions in the silicone gel DE4A no disappearance of existing chemical functions in the silicone gel

• DE5: Maintenance of non cytotoxicity of the implantsilicone gel all along the shelf life

I DE5.1 I the silicone gel contained in 5-year-old or more implants should not be cytotoxic

3.2.3. Requirements on the general aspect and characteristics of the whole

• DE6 : General aspect of implants all along the shelf life

DE6.1 silicone gel pre-filled implants should be transparent (container + content) and exempt from any asperity

DE6.2 silicone gel pre-filled implants should be malleable and elastic when touching them

DE6.3 traceability written on closure patches of silicone gel pre-filled implants should be easy to read and correspond to the information of the corresponding product label.

• DE7 : Weight of implants all along the shelf life·

the weight of silicone gel pre-filled implants should conform to PIP criteria written in the DE7.1 technical file SQ1/02 DOT 202 (+1- 2.5% of the volume written in accordance with the'

NF EN 12180) ·


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3.2.4. Requirements on the Blister packaging

• DE8: Maintenance of properties of the Blister packaging during the whole shelf life

DEB.1 Blister-lid seals have to be continuous and uniform in accordance with the test in UV light

DEB.2 Blister-lid seals have to be waterproof in accordance with the tests with colouring solutions (methylene blue, toluidine blue) and the bubble emission test.

DEB.3 Blister-lid seals have to be resistant enough to assure the packaging closure while being easily opened, the whole being uniform (peel test on tensile machine)

DEB.4 Blister:lid seals have to be easily opened and show a uniform sealing zone (manual peel test).

DEB.S The packaging should constitute a microbial barrier DEB.6 The packaQing should constitute a physical protection of the medical device

3.2.5. Requirements on sterility

•. DE9: Sterility and apyrogenicity of implants during the whole shelf life


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4. ACCELERATED AGING OF STERILE MEDICAL PACKAGING

4.1. PURPOSE OF THE ACCELERATED AGING

Developing a protocol of accelerated aging allows determining quickly effects, if there are any, caused by time and environment on integrity of a sterile packaging and on physical properties of materials composing it.

The information obtained will be used to validate expiration date.

The method of accelerated aging applies to the primary packaging on the whole and does not deal with interactions or compatibility between package and product.

This protocol will follow the F1980-02 {( Standard Guide Accelerated Aging of Sterile Medical Device Packages ».

4.2. THEORETICAL ACCELERATED AGING

The accelerated aging of materials refers to accelerated variations of their properties with time, i.e. properties related to safety represented by the material or packaging and its function.

In a study of accelerated aging, the packaging undergoes a more or less severe stress, or more frequent stress than in normal conditions for a rather short time length.

Techniques of accelerated aging are based on the hypothesis that chemical reactions involved in· the deterioration of materials follow the Arrhenius Law. This Law says that an increase or decrease of temperature by 10·C in a homogenous process provokes a variation of the chemical reaction speed which is doubled or divided by 2.

4.3. EQUIPMENT

• One room allowing exposure to circulating air of samples (individually or several in a container) at chosen temperature and relative humidity.

• A control equipment allowing to maintain the room in chosen atmospheriC conditions by respecting limit tolerances.

• A hygrometer that should have a relative humidity of +/- 2% accuracy. • A thermometer that should be 0.1 or 0.2°F accurate.



4.4. DEFINITIONS OF ABBREVIATIONS

AA = Accelerated Aging: Storage of samples at a high temperature (T AA) so as to stimulate aging in real time in a reduced length of time.

AAF = Accelerated Aging Factor: Proportional factor to the estimated or calculated time so as to reach the same level of change of physical property as on a packaging stored in some conditions in real time RT (Real Time).

T AA = Accelerated Aging Temperature: Temperature at which the study of accelerated aging is conducted and which can be based on an estimation of the storage temperature or an estimation of the temperature of use or both.

AAT = Accelerated Aging Time: Time during which the accelerated aging is performed.

T RT = Ambient temperature = Real Time Temperature: Storage temperature of samples used for aging in real time

Package shelf life: Time during which a packaging can be stored at ambient temperature or in lower storage conditions and keep all its properties.

RT = Real Time aging: Storage time of samples at- ambient temperature

RTE = Real Time Equivalent: Real time equivalent to accelerated aging conditions

to = beginning of the aging study

Q1D = aging factor corresponding to an increase or decrease of temperature by 10°C

T m = Temperature at which the material melts

Tg = Vitreous transition temperature

Ta = Alpha temperature = Heat distortion temperature

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4.5. DETERMINATION OF THE ACCELERATED AGING FACTOR

An estimation of the accelerated aging factor (AAF) is given by the following equation:

IAAF = 0 10 [(TAA -\T)/10JI

with

• 010 = constant reaction coefficient for a temperature variation by 10°C

• TRT = Ambient temperature (to store samples) • T AA = Superior limit temperature of use for the packaging

Remarks:

• Generally, T AA has to be lower than at least 10°C of the material vitreous transition temperature

• T AA has to be greater than 20 -25°C as compared to T RT.

4.6. DETERMINATION OF THE ACCELERATED AGING TIME

The accelerated aging time necessary to be e,quivalent to the real time is determined by dividing . the real time by AAF :

IAAT = RT/AAFl

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4.7. STEPS OF THE ACCELERATED AGING PROTOCOL

• Choose the value for Q10 = 1,8 or 2 (it is generally chosen Q10 = 2 : standard factor).

• Define the expected shelf life of the packaging

• Define time intervals between aging tests by including tests at to.

• Define test conditions, ambient temperature (T RT).and . accelerated aging temperature (T AA)'

• Calculate the testing time using Q1Q, T RT and T AA.

• Define properties of the packaging materials, sealing forces and integrity tests, size of samples and acceptance criteria.

•

•

•

Note down the age of samples exposed at T AA. In parallel, note down the age of samples being in real aging conditions at T RT.

Evaluate performances of the packaging after accelerated aging depending on its initial properties (e.g. sealing force, integrity)

Evaluate the packaging or its properties or both, after aging in real conditions depending on the initial properties.



4.8. ACCELERATED AGING PROTOCOL ON THE PACKAGING

• Choose the value for Q10

We choose Q10= 2 (generally used value).

• Define the expected shelf life of the packaging

Expiration date of EO sterilised IMGHC packaged in double blisters is determined at 5 years.

• Define time intervals between aging tests, including tests at to.

Sterile IMGHC implants are 3 years and 7 month-old. To reach 5 years, an accelerated aging of 1 year and 5 months has to be performed (Le. 17 months = 518 days).

• Define the testing conditions, ambient temperature (T RT) and accelerated aging temperature (T.u>.

The storage temperature of implants is by : T RT= 20°C. The chosen accelerated aging temperature is: T AA= 50°C :- temperature lower than Tg of PETG (Tg=81°C) and temperature greater than 30°C from temperature T RT .•

• Calculate the testing time by using Q1D, T RT and T AA.

Arrhenius Law gives:

with

Ql0 = 2°C TRT= 200e TAA = sooe

The accelerated aging time is defined by the following relation :

!AAT = RT/AAF = 65 daysl with: - RT = 518 days

AAF=8

IMGHC implants will thus be stored for 65 days in a heated room at SO°C.


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• Define properties of the packaging materials, sealing forces and integrity tests, size of samples and acceptance criteria.

See section 4.9.

• Note down the age of samples exposed at T AA' In parallel, note down the age of samples located in real aging conditions at T RT'

At T AA. at the end of the protocol, IMGHC will be 5-year-old while the age of IMGHC being in real aging concjitions at T RT will be 3 years and 8 months.

.• Evaluate the packaging performances after accelerated aging depending on the initial properties (e.g. sealing force, integrity).

The packaging performances after accelerated aging will be dealt with in another report.

• Evaluate the packaging or its properties, or both, after aging in real conditions depending on initial properties.

Validation is ongoing. Refer to project PR 01/06 "Validation of expiration' date of EO sterilised, silicone gel pre-filled breast implants, packaged in double blisters".


Reference: MET 04/008-1 /Index: NA I Application date: NA Ipage 16/26

4.9. DETERMINATION OF TESTS PERFORMED ON THE PACKAGING

Several tests are performed so as to control the status of packaging and seals:

• Control of seal uniformity

• Control of seal waterproofness

• Control of seal resistance

These tests are performed at PIP, either at the Studies, R&D department, or at the Quality Control department, depending on the necessary equipment.

4.9.1. Modes of operation oftests on the packaging

Type of Type of test Standard Necessary equipment Mode of operation

control Put external blisters equipped with external

Seal uniformity In UV light none UV light at 365 nm lids one after another by the sealing zone, blister side, under UV light Control the 4 sides Emerge the external blister, lid side, in the methylene blue· solution for 15 minutes (the seal must be completely emerged and the lid

Colouring A big enough basin

should not press the bottom of the bag) solution Remove the blister from the solution, rinse it penetration none

A methylene blue with water and dry it

toward inside ·solution at 2%

Control if the solution penetrates or not in the blisters seals

After 24 hours, control the seals again Remove the external lid and perform another test on the internal lid

A big enough syringe Using a syringe, introduce the toluidine blue solution and bring it back by seals of external

Seal Colouring

blister. imperviousness

solution ASTM F

A toluidine blue Walt for 20 seconds at each seal border.

penetration solution at 0.05% toward outside

1929 (penetration indicator)

Control if the solution penetrates or not in seals.

blisters and TRITON X-100 at Remove the external lid and perform the test

0,5% (wetting agent) again on the internal lid. Fill in the basin with water and position the

A big enough basin internal blister into water. Add a weight to ballast the blister

Emission of A vacuum box with

Position the whole in a vacuum box ASTM 0 calibrated manometer

bubbles under 3078 A calibrated timer

Putit under vacuum at -0,7 bar vacuum

A weight (if necessary) Wait for 30 seconds at this pressure. Note down observations Start atmospheric pressure again. Note down observations


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Type of Type ottest Standard Necessary equipment Mode of operation

control Manually remove the external lid, observe the

Manual peel none none sealing zone on the external blister .

Seal Manually remove the internal lid, observe the

resistance sealing zone.on the internal blister

NFEN Tensile machine MTS The size of specimens, cutting sizer of (internal

Tensile peel 868-10

200/M with calibrated and external) blisters as well as mode of force sensor 100N operation are described in MEA 031004

These tests allow demonstrating that all materials composing the packaging as well as seals which assemble it are all microbial barriers. In accordance with the flow chart of NF EN 868-1 Standard (flow chart of the microbial barrier evaluation), the packaging system will thus be qualified as microbial barrier.

Sterility and apyrogenicity tests performed on implants (see §4.1 0) will confirm this result: implant sterility is kept by the packaging system.

4.9.2. Acceptance criteria of tests on the packaging

Conformity criteria Under UV, the sealing zone has a regular and intense blue colour.

Seal uniformity In UV light The coating and sealing uniformity Is verified by the absence of chimneys, clouds and white bubbles.

Colouring solution penetration Imperviousness is verified by the absence of toluidine blue infiltration toward inside blisters in all sealing points after test implementation, and after 24 hours.

Seal Colouring solution penetration Imperviousness is verified by the absence of toluidine blue infiltration

imperviousness toward outside blisters in all sealing points after test implementation.

Emission of bubbles under Imperviousness is verified by the absence of bubble emission in all

vacuum the sealing points during the test and by the absence of water infiltration inside the packaging. Two observations were' made:

Manual peel Easy to open (no opening resistance and no lid tear) Uniformity of the sealing zone by the presence of a white uniform zone at the seal location Three observations are made:

Seal resIstance - Easy to open (maximal tolerance of lear resistance was determined at 1.00 kN/m)

Tensile peel - Seal resistance (minimal tolerance of tear resistance was determined at: 0,08 kN/m) . Uniformity of the sealing zone (maximal tolerance on the

standard deviation of the whole results obtained of tear resistance on a blister was determined at : 0,15 kN/m)

r -,


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4.9.3. Sampling

So as to be representative, 3 packaging per type of tests will be used.

Number of 1M

Seal uniformity In UVlight All external and internal

blisters

Colouring solution penetration toward 3 (external then internal)

inside blisters Seal waterproofness Colouring solution penetration toward

3 (external then internal) outside blisters

Emission of bubbles under vacuum 3 (internal)

Seal resistance Manual peel 3 (external then internal) Tensile peel 3 (external then internal)

Total number of 1M 15


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4.10. DETERMINATION OF STERILITY TESTS PERFORMED ON AN IMPLANT

4.10.1. Mode of operation of sterility tests

Implants are sent to KEYBIO laboratory, COFRAC accredited (NF EN 45001 and ISOIIEC 25)

Laboratoire KEYBIO Z.1. Les Paluds 2

Pole performance Bt C2 - BP 247 13785 AUBAGNE Cedex - France

Phone: +33 (0)4.42.84.29.00 Fax: +33 (0)4.42.84.28.84

Contact person: Mr. LISBONNE

The same implants will both undergo the sterility test and endotoxin assay (allows deciding on the implant apyrogenicity).

4.10.2. Acceptance criteria of sterility tests

Sterility test: results must certify any absence of germ growth Apyrogenicity test: results must indicate concentrations in endotoxins lower than 0,5 UllmL.

4.10.3. Sampling

So as to be representative, 3 packaging per type of surface will be used.

Number of 1M

Sterility and apyrogenicity tests 6 (3 Ls and 3 Tx)

Total number of 1M 6


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4.11. DETERMINATION OF TESTS PERFORMED ON IMPLANTS

Several tests will be performed so as to control implants (general aspect, envelope and filler material) :

• Control of the implant's general aspect

• Control of filler material • Control of envelope and gluing joint

The whole tests are performed at PIP, either at the Studies, R&D department, or at the Quality Control department, depending on the necessary equipment.

, 4.11.1. Modes of operation of tests on 1M

Type of Type of test Standard

Necessary Mode of operation

control equipment Visually control the surface aspect

Surface status (control of defects: smooth texture, - - foam texture, black points, miscellaneous defects)

Transparency - - Visually control the implant transparency Take each implant in one's hand and mix them. Control if there are any

Manual elasticity - - leakages, if it is easy to mix and if the General implant takes its initial shape after aspect mixing it.

Control the quality of the laser marking of finishing patches

Traceability - - Control if the Information written on the finishing patch correspond to those written on the product label

NF EN 12180 Calibrated Put the implant on the balance

Weight ASTM F703

balance at 0.01g Report, after . stabilisation , the weight accuracy value

Open the implant

Silicone gel cohesivity - Cohesivity cone Take out the silicone gel; it has to be by or under the superior surface at time 0 Wait for 30 minutes Open the implant

Filler material Lay down the fist on the penetrometer Penetrometer

PNR 10 n° 048 (MOE 030101). Silicone gel penetrability - (PIP

Control penetrability of the gel conta"ined matriculation nD = 048)

in the 1M For each 1M, 3 penetrability tests must be performed.

Reference: MET 04/008-1

Type of

control

Envelope and gluing joint control

Type of test

Control of thickness

Control of the material elasticity

Control of the material memory

Control of the critical joint

(gluing joint)

Control of the non critical gluing joint

(envelope . resistance by the

over-thickness created by the dipping mould

code)


I Index : NA I Application date :NA I Page 23126

Standard

NF EN 12180 ASTM F703

Necessary

equipment

A calibrated cutting press equipped with a punch for H2 type specimen

A calibrated thickness comparator

Tensile equipment MTS 200/M with calibrated force sensor 100N

Mode of operation

The size of specimens and cutting sizers of implants are described in MEA 03/001

The test performed is a measure in 3 points of each cut specimen per implant.

The size of specimens, cutting sizer of implants as well as the. mode of operation are described in MEA 03/001

One test is performed : - Ultimate elongation test with measurement of elongation and breaking strength. This test is performed on 3 speCimens.

The size of speCimens, cutting sizer of implants as well as the mode of operation are described in MEA 03/001

Two tests are performed one after another: - Tensile set test (elongation at 300% for 3

minutes) with measurement of the loss of elasticity value

• Ultimate . elongation test with measurement of elongation and breaking strength (allows verifying that even if after undergoing a previous deformation, the material keeps its elasticity properties)

These tests are performed on 1 specimen The size of speCimens, cutting sizers of implants as well as the mode of operation are described in MEA 03/001

Two tests are performed one after another: - Resistance test at 300% for 10 seconds

with control of the resistance or not of the gluing joint

- if the specimen successfully passed the previous test, an elongation test and a breaking strength test with measurement of elongation and breaking strength

These tests are performed on 2 specimens.

The size of specImens, cutting sizers of implants as well as the mode of operation are described in MEA 03/001

One test is performed :

• resistance test at 300% for 10 seconds with control of the resistance or not of the

specimen. The test is performed on 1 specimen.


Reference: MET 04/008·1 I Index : NA I Application date: NA I Page 24/26

4.11.2. Acceptan ce criteria

Conformity criteria

Surface status No defect must appear: no black point, foam texture, smooth texture or any other defect

- In case of a smooth implant, transparency should be total Transparency - .In case of a textured implant, transparency is made slightly

op~que because of texture Three observations are made:

General Manual elasticity - No leakage nor hemia

aspect - Easy mixing - Return to initial status after mixing

Two observations are made :

Traceability - Laser marking easy to read - Conformity between the. information written on the finishing

patch and those written on the product label

Weight The measured out weight must be comprised in a tolerance interval equal to +/-2.5% of the volume written on the finishing patch

Cohesivity The silicone gel cohesivity has to be lower than 30 mmafter 30. min

Rller wait material The silicone gel penetrability has to be by 17,0 +/- 3.0 mm at each

Penetrab!"ty intake. Acceptance values are different depending on the type of surface of the implant:

SMOOTH surface implant: On the whole values collected on the implant

- Minimal thickness-'· : 0,37 mm

Control of thickness - Maximal thickness: 0,63 mm - Maximal difference allowed .2.: 0,13 mm

TEXTURED surface implant: On the whole values collected on the implant

- Minimal thickness: 0,57 mm - Maximal thickness: 0,95 mm - Maximal difference allowed: 0,22 mm

Envelope Two observations are made: and glUing Control of the material elasticity - Ultimate elongation : ~ 450% joint - Breaking strength : ~ 8 N

Three observations are made: - Loss of elasticity: $ 10%

Control of the material memory - Ultimate elongation : ~ 400% - Breaking strength : ~ 7.5 N

(see photos 8 - Annex 8) Three observations are made:

Control of the critical joint (gluing - Resistance at 300% for 10 seconds: gluing joint resistance joint) - Ultimate elongation : ~ 400%

- Breaking strength: > 7,5 N Control of the non critical joint

(envelope resistance by the over- One observation is made : thickness created by the dipping mold • Resistance at 300% for 10 seconds: resistance of specimen

code)



4.11.3. Sampling

All· implants extracted that were not sent to sterility and apyrogenicity test will be tested.

Type of control Type of test Number of implants Surface status 15 Transparency 15

General aspect Manual elastiCity 15 Traceability 15 Weight 15

Filler material Cohesivity control 15 Penetrability control 15 Control of thickness 15 Control of material elasticity 15

Envelope and gluing joint Control of critical joint (gluing joint) 15 Control of non-critical jOint (envelope resistance by over- 15 thickness created by dipping mould code)

, .3


Reference: MET 04/008-1 _I Index : NA I Application date: NA 1 Page 26/26

5. CONCLUSION

This protocol describes the study of accelerated aging that we want to perform on 3-year and 7-month-old blister packaged silicone gel pre-filled breast implants. Following the ASTM F1980-02 ({ Standard Guide of Medical Accelerated Aging of Sterile Medical Device Packages », it will allow us validating quicker the 5-year expiration date of IMGHC.

Tests on the packaging will allow concluding on the qualification of microbial barrier of the blister packaging and therefore that "the implant sterility preservation. Tests on the implant sterility will confirm it.

We will also widen our tests to implants so as to verify that their properties are maintained after the accelerated aging.

The study of aging jn real conditions continues: tests on the packaging and implants are performed in real time until 5 years. They will allow confirming results obtained during the study of accelerated aging.

In a next report, a study will compare the results obtained in accelerated aging. as compared to the results obtained in natural aging.

Documents

FOI 244 1112 Document 7 - Therapeutic Goods Administration · PDF fileCONCLUSION 21 21 21 22 22 24 25 26 ... MET 04/008-1 I Index : ... DE1.B ultimate elongation after tensile set