eo sterilization product adoption rationale

Sterilization Technical Report: Adoption of a Vascular Grafts into an Ethylene Oxide Sterilization Cycle

AUTHORIZATION LIST

Approvers in PDM:

Department Approval Level

Microbiology SupervisorQuality Manager

Sterilization Technical Report Adoption of a Vascular Grafts into an Ethylene Oxide Sterilization Cycle

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Sterilization Technical Report: Adoption of a Vascular Graft into an Ethylene Oxide Sterilization Cycle

Overview

1. Purpose

1.1 To document a technical review for adopting two candidate products into two qualified ethylene oxide sterilization cycles. The candidate products are Vascular Grafts.

1.1 This review is conducted in order to comply with the recommendations of standard ISO 11135-1:2007, section C.7.1 for introducing new or modified products into previously qualified ethylene oxide sterilization cycles.

1.2 The technical review documented in this sterilization technical report intends to demonstrate the following:

1.2.1 That the Vascular Grafts are equivalent to a predicate product from an ethylene oxide sterilization perspective.

1.2.2 That the Process Challenge Device (PCD) represents a greater challenge to ethylene oxide sterilization than the Vascular Graft and therefore can represent these grafts during routine sterilization processes using the cycles/chamber/facilities disclosed in sections 3.2 and 3.3 of this report.

2 Scope

2.1 The technical review documented in this sterilization technical report applies to the Vascular Graft manufactured and packaged as described in section 7 of this document. The catalog numbers of the products covered by this technical review are listed in product specification ____________.

Sterilization Technical Report Adoption of a Vascular Graft into an Ethylene Oxide Sterilization Cycle

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Overview, continued

3 Background

3.1 The Vascular Grafts are new products to be manufactured at _______________. These products are modified versions of two currently existing (predicate) products. The modification of these existing products for manufacturing Vascular Grafts consist of the addition of a coating element

3.2 The predicate Vascular Graft is sterilized with an ethylene oxide cycle called __________ which is run in chamber number ___ at the _________ site of __________. The capability of this cycle to deliver a minimum SAL (sterility assurance level) of 10-6 is determined by the use of Process Challenge Device (PCD). The qualification of the Process Challenge Device (PCD) for the _______ cycle in chamber ____ was qualified as documented in sterilization qualification report _____________.

3.3 The predicate Vascular Graft has also been qualified for sterilization with an additional ethylene oxide cycle called _________ which is run in chamber number ____ at the _______________ site of _________. The capability of this cycle to deliver a minimum SAL (sterility assurance level) of 10-6 is determined by the use of Process Challenge Device (PCD). The qualification of the Process Challenge Device (PCD) for cycle _________ in chamber ____ was qualified as documented in sterilization qualification report __________.

3.4 The new Vascular Grafts will be sterilized with ethylene oxide using the same cycles/chamber/facilities disclosed in sections 3.2 and 3.3 of this report.


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Overview, continued

4 Applicable DocumentsThe documents and standards applicable to this sterilization technical report are disclosed below.

Document Name Document NumberSterilization of health care products- Ethylene oxide- Part 1: Requirements for development, validation, and routine control of a sterilization process for medical devices

ANSI/AAMI/ISO 11135-1:2007

Sterilization of health care products- Ethylene oxide- Part 2: Guidance on the application of ANSI/AAMI/ISO 11135-1


Sterilization of health care products -- Biological indicators -- Part 1: General ANSI/AAMI/ISO 11138-1:2006

Sterilization of medical devices - Microbiological methods-Part 2: Tests of sterility performed in the validation of a sterilization process


Ethylene oxide residual testing limits ANSI/AAMI/ISO 10993-7:2008

________________________________________________________________


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Overview, continued

5 DefinitionsThe following are the definitions for the terms or abbreviations included in this protocol.

Term or Abbreviation DefinitionBioburden Population of viable microorganisms on or in product

and/or sterile barrier system.Biological Indicator (BI) Test system containing viable microorganisms in a

defined amount and with a defined resistance to a specified sterilization process.

CFU Colony forming unit: a micro-organism propagule (spore or cell) from which a colony has grown.

EO Ethylene OxideECH Ethylene ChlorohydrinLethality Comparison A comparison of the lethal effects of a sterilant on the

natural or inoculated bioburden of different devices.Process Challenge Device (PCD)

Item designed to constitute a defined resistance to a sterilization process and used to assess performance of the process.

Sterilant A sterilizing agentSub-lethal (Fractional) cycle

Partial sterilization cycle in which the exposure time and/or other parameters are reduced from those commonly used in routine sterilization processes so that the relative inactivation rates for biological indicators and/or product can be compared through testing.


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Technical Review

6 Synopsis of Technical Review

6.1 This technical review follows the recommendations of standard ISO 11135-1:2007, section C.7.1 for introducing new or modified products into previously qualified ethylene oxide sterilization cycles. Based on those recommendations this technical review will consist of the following activities:

6.1.1 Comparison of the new Vascular Graft with the predicate Vascular Graft used for the qualification of the _________ sterilization cycle and with the predicate Vascular Graft used for the qualification of the ________ sterilization cycle. The comparison will assess similarities in the following factors which are the most relevant for sterilization processes:

Product Bioburden Product Materials Product Basic Geometry Manufacturing Environment Packaging Components Packaging Configuration Packaging Bulk Density Levels of EO Residues

6.1.2 Comparison of fully packaged new Vascular Grafts with the Process Challenge Device from a sterilization perspective. The comparison will assess the following factors which are the most relevant for sterilization processes:

Resistance to ethylene oxide/heat/humidity penetration Magnitude of microbiological challenge to sterilization

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7 Analysis for Technical Review

7.1 Comparison of the predicate Vascular Graft with the new Vascular Grafts.

7.1.1 Product Bioburden

7.1.1.1 Table 1 discloses the bioburden content of the predicate and the new Vascular Grafts. Scanned copies of the bioburden reports are included as attachments to this Sterilization Technical Report in the PDM system.

7.1.1.2 The data shows that the bioburden content of the new Vascular Grafts is four levels of magnitude lower than the population of endospores in the biological indicators used to manufacture the process challenge devices for the validation and routine monitoring of their EO sterilization cycles.

7.1.1.3 The data also shows that the bioburden species present in the new Vascular Grafts are not endospores formers. Thus their resistance to adverse environmental conditions (such as exposure to ethylene oxide gas) can be expected to be significantly lower than that exhibited by the species present in the BIs (Bacillus atrophaeus) which is considered to be one of the two most suitable species to provide appropriate resistance to any ethylene oxide sterilization process.1

7.1.1.4 Therefore the bioburden of these new Vascular Grafts does not represent a challenge to the _______ or _______ sterilization cycles.

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Table 1. Product Bioburden Data

Product / Batch #

Testing Facility / Report Number /

Year-Quarter Tested

*Bioburden Data

SampleMicrobial

CountPredominant

Species

Average Bioburden

BI Spore Population

Predicate Vascular Grafts / 11111111

1 64Gram + Rods:

0%Gram – Rods:

2%Gram + Cocci:

90%Gram – Cocci:

0%Endospore Formers:

0%Mold/Yeasts:

8%

153

106

2 182

3 105

4 351

5 62

New Vascular Graft I / 22222222

1 20Gram + Rods:

0%Gram – Rods:

0%Gram + Cocci:

95%Gram – Cocci:


0%Mold/Yeasts:

5%

45.9

2 62

3 26

4 74

5 48

New Vascular Graft II/ 33333333

1 3Gram + Rods:

0%Gram – Rods:

0%Gram + Cocci:

92%Gram – Cocci:


0%Mold/Yeasts:

8%

7.7

2 6

3 3

4 12

5 15

*Bioburden values are adjusted to reflect correction factors determined at the vendors for microbiological testing.

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7.1.2 Products Materials

7.1.2.1 Table 1 lists the materials present in the predicate Vascular Graft and the new Vascular Grafts. The information shows the following:

7.1.2.1.1 All materials are synthetic, dry and chemically inert. These types of materials do not support microbial growth. Therefore the materials do not appear to be a factor that can adversely impact the bioburden content of these products.

Table 2. Materials Present in Products

New CoatedVascular Graft I

Predicate Vascular Graft New PV Vascular GraftPredicate Unsupported

Vascular Graft coating material:

Phenoxypolyethoxyethanol Monofilament Bead and

Quantum Yarn: Expanded Polytetrafluoroethylene and Polytetrafluoroethylene

Guideline Printing Blue Ink: Ammonium Perfluorooctanoate; CI Pigment Blue 28; Cobalt Aluminate Spinel; Octyl or Nonyl Phenoxypolyethoxyethanol; Polytetrafluoroethylene; Surfactant

Monofilament Bead and Quantum Yarn: Expanded Polytetrafluoroethylene and Polytetrafluoroethylene

Guideline Printing Blue Ink: Ammonium Perfluorooctanoate; CI Pigment Blue 28; Cobalt Aluminate Spinel; Octyl or Nonyl Phenoxypolyethoxyethanol; Polytetrafluoroethylene; Surfactant

coating material: Phenoxypolyethoxyethanol

Graft Outer Substrate: Warp Knit Polyester

Graft Inner Substrate: PTFE and Isoparaffinic Hydrocarbon

Bonding Agent: Corethane 7.5% with DMA (N, N-Dimethylacetamide)

Guideline: Ammonium Perfluorooctanoate; CI Pigment Blue 28; Octyl or Nonyl Phenoxypolyethoxyethanol; Diethylene Glycol.

Radio opaque removable bead: Radio opaque polypropylene / polyethylene monofilament; Barium Sulfate.

Graft Outer Substrate: Warp Knit Polyester

Graft Inner Substrate: PTFE and Isoparaffinic Hydrocarbon

Bonding Agent: Corethane 7.5% with DMA (N, N-Dimethylacetamide)

Guideline: Ammonium Perfluorooctanoate; CI Pigment Blue 28; Octyl or Nonyl Phenoxypolyethoxyethanol; Diethylene Glycol.

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7.1.3 Products Basic Geometry

7.1.3.1 All of these vascular grafts have the same basic geometry which is that of an elongated, hollow tubular body (cylindrical shape) of uniform radius throughout its length.

7.1.3.1.1 The open ends of the grafts are considered to be the main route of entry for the sterilant into their lumen.

7.1.3.1.2 These products are manufactured in sizes that are identical in their length to diameter ratio. Therefore all represent the same degree of challenge for the penetration of the sterilant through their open ends and into their lumen.

Note: There is variation in the thickness of the walls of the grafts. However at present there is no information on the degree of permeability of the walls of these vascular grafts to ethylene oxide. Therefore the effect of this variation, if any, on ethylene oxide sterilization is not known.

7.1.3.2 With the exception of the Unsupported Vascular Graft, these products include a monofilament bead that is wrapped around their external surface.

7.1.3.2.1 The presence of this monofilament bead does not appear to be a factor of significance for the sterilization process. This is substantiated by the evidence disclosed in sterilization validation report _______, which documents the results of a lethality comparison of supported grafts and unsupported grafts. The results showed that exactly the same lethality (the same amount of BI inoculated samples showing microbial growth) is achieved with both types of products when sterilized with ethylene oxide.

7.1.3.3 The equivalence of these products in their basic geometry and their dimensions renders them equivalent in the degree of challenge that they may present for sterilant penetration.

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7.1.4 Manufacturing Environment

7.1.4.1 All of these products are manufactured in production cells located in exactly the same type of environment: an ISO Class 8 Clean Room.

7.1.4.2 The criteria for determining the acceptability of the environmental manufacturing conditions is the same for all of these products. This includes the following factors:

Physical Factors: temperature, relative humidity, air differential pressure, concentration and size of air particulate matter

Biocontamination: amount of microbial contaminants in air and product contacting surfaces

7.1.4.3 The use of the same type of manufacturing environment and the same criteria for determining acceptability of environmental conditions ensures the same degree of control for reducing the introduction of contaminants into these products. This renders them equivalent in the degree of microbiological challenge that they may present to the sterilization process. This is substantiated by the product bioburden data disclosed in section 7.1.1 of this technical report.

7.1.5 Packaging Components

7.1.5.1 The packaging components are exactly the same for all these vascular grafts. A list of these components is provided in Table 3.

7.1.5.2 The use of the same packaging components provides equivalence in all factors related to sterilization:

7.1.5.2.1 Equivalent effect in product bioburden content from direct contact with inner packaging components.

7.1.5.2.2 Equivalent resistance to ethylene oxide/heat/humidity penetration during the sterilization process.

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Table 3. Packaging Components for all Vascular Grafts Sterilized with Ethylene Oxide

Component Part NumberShelf cartonInner TrayOuter Tray

Inner Tyvek LidOuter Tyvek Lid

DFULabel

7.1.6 Packaging Configuration

7.1.6.1 The packaging configuration is exactly the same for all these vascular grafts. This includes the following:

7.1.6.1.1 The arrangement of shelf cartons inside the sterilization shipper.

7.1.6.1.2 The arrangement of the sterilization shipper in the pallet that is introduced into the sterilization chamber.

7.1.6.2 Figures A provides an illustration of the packaging configuration of shipper cartons inside the sterilization shipper of these vascular grafts.

7.1.6.3 The use of the same packaging configuration provides equivalence in the level of resistance of the product loads to the penetration of ethylene oxide, heat and humidity during the sterilization process.

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Figure A. Configuration of Shelf Cartons Inside Sterilization Shipper

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7.1.7 Packaging Bulk Density

7.1.7.1 Table 4 discloses the data for the packaging bulk density of the products under consideration. The table also discloses the maximum densities validated for each of the two ethylene oxide sterilization cycles under consideration.

7.1.7.2 The data shows that the bulk density of sterilization shippers fully packaged with the new Vascular Grafts is below the maximum density qualified for the two ethylene oxide sterilization cycles under consideration. Therefore the bulk density of a shipper fully packaged with the new Vascular Grafts is not a factor that can adversely impact the effectiveness of the two ethylene oxide sterilization cycles under consideration.

Table 4. Bulk Densities of Fully Packaged Sterilization Shippers

ProductBulk Density of Fully Packaged Sterilization

Shipper

Maximum Density for EO Cycle ______

Maximum Density for EO Cycle ______

Predicate Vascular Grafts

*75.33 kg/m3

262.4 kg / m3 150.83kg/m3

New Vascular Graft I 73.53 kg/m3

New Vascular Graft II 150.83kg / m3

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7.1.8 Levels of EO Residues

7.1.8.1 The new Vascular Grafts were tested for the presence of ethylene oxide residues after processed with two consecutive ______ sterilization cycles using chamber _____ at the ______ facility of ______, which is the main site for the sterilization of these products. A second set of samples of the new Vascular Grafts were tested for the presence of ethylene oxide residues after processed with two consecutive ______ sterilization cycles using chamber _____ at the ______ facility of ______, which is the alternate site for the sterilization of these products. Table 5 shows the results of the determination of EO residues Sterilization on these samples. These results are documented in Sterilization Residual Report __________.

7.1.8.2 The data disclosed in Table 5 demonstrates that the levels of EO

residues in Vascular Grafts sterilized using cycles _________ or _________ meet the applicable requirements of ISO 10993-7 and of the Japan Ministry of Health and Welfare Notification No. 353 (JMHW 353).

Table 5. Ethylene Oxide Residues in Vascular Grafts

Device Category

*ISO Allowable Limits(mg)

Allowable Limit per JMHW 353

(ppm)Average

Daily Dose (ADD)

24 hour period

30 day period

Lifetime Lifetime

EO ECH EO ECH EO ECH EO ECH EORequirements for Permanent Contact Devices

0.1 2 20 12 60 60 2500 50000 25

Results for New Vascular Graft I

< 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 1.0

Results for New Vascular Graft II

< 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 1.0

*Meaning of abbreviations: EO = ethylene oxide; ECH = ethylene chlorohydrin

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7.2 Comparison of the packaged Vascular Grafts with the Process Challenge Device from a sterilization perspective.

7.2.1 Resistance to ethylene oxide/heat/humidity penetration

7.2.1.1 The inner and outer Tyvek lids that are part of the sterile barrier for the new Vascular Grafts are designed to be gas and vapor permeable. Therefore they facilitate the penetration of the ethylene oxide/heat/humidity into the interior of packages containing grafts.

7.2.1.2 The Process Challenge Device (PCD) consists of a self contained biological indicator contained inside a 5 cc syringe and then placed inside a heat sealed plastic pouch. The syringe and the sealed plastic pouch are intended to lessen the rate of ethylene oxide/heat/humidity penetration to the interior of the PCD.

7.2.1.3 Therefore the design of the PCD makes it more resistant to penetration by the sterilant, heat and humidity. This contributes to make the PCD a much greater challenge to the sterilization process than the fully packaged products.

7.2.2 Magnitude of microbiological challenge to sterilization

7.2.2.1 The Process Challenge Device (PCD) includes a biological indicator (BI) contained within the PCD. This biological indicator contains high numbers of spores (106 spores per BI) of a microorganism known as Bacillus atropheaus, which is known to be one of the most resistant species to the adverse effects of ethylene oxide.1

7.2.2.2 Per the data presented in section 7.1.1 of this report, the bioburden content of the new Vascular Grafts is four levels of magnitude lower than the spores populations present in the PCD. Therefore the PCD poses a much greater microbiological challenge to sterilization than that posed by the new Vascular Grafts.

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8 Results of Technical Review

8.1 The technical review documented in this sterilization technical report supports the following assertions:

8.1.1 The new Vascular Grafts are equivalent to the predicate Vascular Graft from an ethylene oxide sterilization perspective.

8.1.2 The Process Challenge Device (PCD) represents a greater challenge to ethylene oxide sterilization than the new Vascular Grafts and therefore can represent these grafts during routine sterilization processes using the cycles/chamber/facilities disclosed in sections 3.2 and 3.3 of this report.

8.1.3 New Vascular Grafts sterilized with either cycle ________ at chamber number ____ of the _________ site of _________ or cycle ________ at chamber number ____ of the _________ site of _________ meet with all requirements from ISO and Japan Ministry of Health and Welfare for residues of ethylene oxide in implantable devices.

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9 Conclusion

9.1 The Sterilization Assurance Level of 10-6 required for the new Vascular Grafts can be achieved when these products are manufactured and packaged as described in section 7 of this technical report and sterilized using either one of the following qualified sterilization cycles:

9.1.1 Ethylene oxide cycle called _______ which is run in chamber number ____ at the __________ site of _____________.

9.1.2 Ethylene oxide cycle called __________ which is run in chamber number ____ of the _________ site of _________.

9.2 Therefore the sterilization of the new Vascular Grafts for commercial distribution can be performed using either of the cycles described in section 9.1 of this technical report.


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