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Sterilization Technical Report: Adoption of a Vascular Grafts into

an Ethylene Oxide Sterilization Cycle

AUTHORIZATION LIST

Approvers in PDM:

Department Approval Level

Microbiology Supervisor
Quality Manager

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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 ____________.

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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 Documents
The documents and standards applicable to this sterilization technical report are disclosed
below.

Document Name Document Number


Sterilization of health care products- Ethylene oxide- Part 1: Requirements for
ANSI/AAMI/ISO 11135-
development, validation, and routine control of a sterilization process for
1:2007
medical devices
Sterilization of health care products- Ethylene oxide- Part 2: Guidance on the ANSI/AAMI/ISO 11135-
application of ANSI/AAMI/ISO 11135-1 2:2008
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 ANSI/AAMI/ISO 11737-
sterility performed in the validation of a sterilization process 2:2006
Ethylene oxide residual testing limits ANSI/AAMI/ISO 10993-
7:2008

________________________________________________________________

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Overview, continued

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

Term or Abbreviation Definition


Bioburden 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 Oxide
ECH Ethylene Chlorohydrin
Lethality Comparison A comparison of the lethal effects of a sterilant on the
natural or inoculated bioburden of different devices.
Process Challenge Device Item designed to constitute a defined resistance to a
(PCD) sterilization process and used to assess performance of
the process.
Sterilant A sterilizing agent
Sub-lethal (Fractional) Partial sterilization cycle in which the exposure time
cycle 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.

Technical Review
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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

Technical Review

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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.

Technical Review

Table 1. Product Bioburden Data

Product / Batch Testing Facility / *Bioburden Data


# Report Number / Sample Microbial Predominant Average BI Spore
Year-Quarter Count Species Bioburden Population

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Tested
Gram + Rods:
1 64 0%
Gram – Rods: 106
2 182 2%
Gram + Cocci:
90%
Predicate Vascular 3 105
Grafts / 11111111
Gram – Cocci: 153
0%
4 351 Endospore
Formers:
0%
5 62 Mold/Yeasts:
8%
Gram + Rods:
1 20 0%
Gram – Rods:
2 62 0%
Gram + Cocci:
95%
New Vascular Graft 3 26 45.9
I / 22222222
Gram – Cocci:
0%
4 74 Endospore
Formers:
0%
5 48 Mold/Yeasts:
5%
Gram + Rods:
1 3 0%
Gram – Rods:
2 6 0%
Gram + Cocci:
92%
New Vascular Graft 3 3
II/ 33333333
Gram – Cocci: 7.7
0%
4 12 Endospore
Formers:
0%
5 15 Mold/Yeasts:
8%
*Bioburden values are adjusted to reflect correction factors determined at the vendors for microbiological testing.
Technical Review

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:

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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 Coated Predicate Unsupported


Predicate Vascular Graft New PV Vascular Graft
Vascular Graft I Vascular Graft
• coating material: • Monofilament Bead and • coating material: • Graft Outer Substrate: Warp
Phenoxypolyethoxyethanol Quantum Yarn: Expanded Phenoxypolyethoxyethanol Knit Polyester
• Monofilament Bead and Polytetrafluoroethylene and • Graft Outer Substrate: Warp • Graft Inner Substrate:
Quantum Yarn: Expanded Polytetrafluoroethylene Knit Polyester PTFE and Isoparaffinic
Polytetrafluoroethylene and • Guideline Printing Blue • Graft Inner Substrate: PTFE Hydrocarbon
Polytetrafluoroethylene Ink: and Isoparaffinic • Bonding Agent: Corethane
• Guideline Printing Blue Ammonium Hydrocarbon 7.5% with DMA (N, N-
Ink: Perfluorooctanoate; CI • Bonding Agent: Corethane Dimethylacetamide)
Ammonium Pigment Blue 28; Cobalt 7.5% with DMA (N, N- • Guideline: Ammonium
Perfluorooctanoate; CI Aluminate Spinel; Octyl or Dimethylacetamide) Perfluorooctanoate; CI
Pigment Blue 28; Cobalt Nonyl • Guideline: Ammonium Pigment Blue 28; Octyl or
Aluminate Spinel; Octyl or Phenoxypolyethoxyethanol; Perfluorooctanoate; CI Nonyl
Nonyl Polytetrafluoroethylene; Pigment Blue 28; Phenoxypolyethoxyethanol;
Phenoxypolyethoxyethanol; Surfactant Octyl or Nonyl Diethylene Glycol.
Polytetrafluoroethylene; Phenoxypolyethoxyethanol;
Surfactant Diethylene Glycol.
• Radio opaque removable
bead: Radio opaque
polypropylene /
polyethylene monofilament;
Barium Sulfate.

Technical Review

7.1.3 Products Basic Geometry

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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.

Technical Review

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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.

Technical Review

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

Component Part Number


Shelf carton
Inner Tray
Outer Tray
Inner Tyvek Lid
Outer Tyvek Lid
DFU
Label

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.

Technical Review

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Figure A. Configuration of Shelf Cartons Inside Sterilization Shipper

Technical Review

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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

Bulk Density of Fully Maximum Maximum


Product Packaged Sterilization Density for EO Density for EO
Shipper Cycle ______ Cycle ______
Predicate Vascular
*75.33 kg/m3
Grafts
262.4 kg / m3 150.83kg/m3
New Vascular Graft I 73.53 kg/m3
New Vascular Graft II 150.83kg / m3

Technical Review

7.1.8 Levels of EO Residues

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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

Allowable Limit
*ISO Allowable Limits
per JMHW 353
(mg)
(ppm)
Device
Average
Category 24 hour 30 day
Daily Dose Lifetime Lifetime
period period
(ADD)
EO ECH EO ECH EO ECH EO ECH EO
Requirements for
Permanent 0.1 2 20 12 60 60 2500 50000 25
Contact Devices
Results for New
< 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 1.0
Vascular Graft I
Results for New
< 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 1.0
Vascular Graft II
*Meaning of abbreviations: EO = ethylene oxide; ECH = ethylene chlorohydrin

Technical Review

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

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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.

Technical Review

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

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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.

Technical Review

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 _________.

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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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