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Terumo Confidential Page 1 of 9
6180 Jackson Road, Ann Arbor, MI 48103, U.S.A.
Report of the verification of the effect of temperature

and humidity to the heparin coating
Study Number
2005-061
REPORT APPROVAL
Prepared by Date
Jun Yamashita
R&D Engineering Date
N/A N/A
Manufacturing Date
Subhan Khan
Quality and Regulatory Affairs Date
John Toigo
Form: 811653 Rev B

To verify the effect of temperature and humidity to the heparin
Document#2005-061
coating
1. Purpose:
The purpose of this study was to verify the effect of temperature and humidity to the heparin
coating under the cyclic testing. The cyclic testing condition s followed the format
established by IEC, and the temperature rate of change followed the EN45502.
These worst case conditions will provide the minimal amount of heparin activity while still
within this range.
2. Reference/Attachments:
2.1 The following documentation is used in conjunction with this study:

　　　2.1.1 Preparation of Heparin Solution #809653 rev. E
2.1.2 Preparation of 0.1% PEI Solution #809650 rev. E
2.1.3 Preparation of 0.03% Dextran Sulfate Solution #809651 rev. E
2.1.4 Inflow conduits/ outlet pipes heparin coating process #809657 rev. D
2.1.5 Stainless Steel Disc Drawing #809684 rev. B
2.1.6 Titanium Disc Drawing #809685 rev. B
2.1.7 Thrombin Inhibition Assay (TIA) #812079 rev. A
2.1.8 THI Sterilization Criteria Procedure #811891 rev. A
2.1.9 Parts cleaning procedure# 809401 rev. D
2.1.10 LAL test products and process monitoring Procedure #811177 rev. A
2.1.11 Heparin Aging study #2004-022
2.1.12 IEC 62-2-38 Basic environmental testing procedures
2.1.13 EN45502-1: 1997 AIMD General Requirements for Safety, Marking, and
Information to be provided by the manufacturer
2.2 The following equipment and tooling is used for this study:
2.2.1 Spatula, Spoon, Hemostats
2.2.2 Disposable plastic weighing trays
2.2.3 Teflon coated stirring bar p/n 811285
2.2.4 250 ml Beakers, Cole-Parmer p/n A-06010-55
2.2.5 800 ml Beakers, Cole-Parmer p/n A-06010-75
2.2.6 Personal protective equipment (Face shields, safety glasses, nitrile gloves,
cleanroom gowns, hairnets)
2.2.7 Scale, Calibration ID – 27-0026-01
2.2.8 Magnetic stirrer model# PC-510 27-0032-01
2.2.9 Magnetic stirrer model# S46415 27-0032-02
2.2.10 Heparin temperature controller, Calibration ID – 27-0001
2.2.11 Thermometer, Calibration ID – 27-0193-01
2.2.12 pH meter, p/n 27-0212-01
2.2.13 Coating process holding oven and thermometer 27-0031-01
2.2.14 Chemical fume hood 29-0203-02
2.2.15 Mixing station 27-0034-00
2.2.16 Heparin hood 27-0034-01
2.2.17 Ultrasonic cleaner model# 08892-01
2.2.18 LAL station model# SHKE3000
2.2.19 Temperature and humidity chamber PJ-349
Document#2005-061
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3. Deviations to Protocol:
The evaluation method to determine heparin activity, thrombin inhibition assay, was changed
from the previous method of #78-8067-8152-8 to #812079 rev A. Therefore the acceptance
criteria have changed from greater than 0.008 units/cm2 of heparin activity to the following
specification.
Titanium and Stainless Steel > 0.010 U/mL
THI procedures 811891A Sterilization Release Criteria and 812079A Thrombin Inhibition
Assay are in a pre- released state. Protocol indicates they have already been released. This
will not effect the testing performed in this protocol.
Graph 1, 2 and 3 (General cyclic test condition cycle A, B and C) is not detailed condition.
The cyclic test was conducted as following condition.
temperature
(degree C) humidity (%) time (hours)
Pre condition 50 18 24
50 93 5.5
25 80 1.5
st 50 93 6.5
1 day
25 93 2
0 100 3
25 93 2.5
50 93 5.5
nd 25 80 1.5
2 day
50 93 6.5
25 93 8.5
50 93 5.5
25 80 1.5
rd 50 93 6.5
3 day
25 93 2
0 100 3
25 93 2.5
50 93 5.5
th 25 80 1.5
4 day
50 93 6.5
25 93 8.5
50 93 5.5
25 80 1.5
th 50 93 6.5
5 day
25 93 2
0 100 3
25 93 2.5
50 93 5.5
th 25 80 1.5
6 day
50 93 6.5
25 93 8.5
50 93 5.5
25 80 1.5
th 50 93 6.5
7 day
25 93 2
0 100 3
25 93 2.5
50 93 5.5
th 25 80 1.5
8 day
50 93 6.5
25 93 8.5
50 93 5.5
25 80 1.5
th 50 93 6.5
9 day
25 93 2
0 100 3
25 93 2.5
50 93 5.5
th 25 80 1.5
10 day
50 93 6.5
25 93 8.5
Document#2005-061
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4. Traceability:
4.1. All the materials used during the process performance qualification are listed below.
Material Part number Lot number
Polyethyleneimine 801208 08503CC
Dextran Sulfate 801209 2324B55-100G
Sodium Chloride 801211 043832
Citric Acid Monohydrate 801210 040033
Sodium Hydroxide 801212 031355
Sodium Cyanoborohydride 801214 12807
Periodate Oxidized Heparin 809962 6351007252
Stainless Steel Disc 809684 66159
Titanium Disc 809685 80544
Sterile 70% Isopropanol 810182 3302044
Sterile water for Irrigation, USP AB-7139-09-19 16-136-JT
4.2. All equipment used during the making of the samples are listed Section 2.2.
4.3. Manufacturing records and data sheets for this study are attached.
4.4. All equipment used during the making of these samples are listed Section 2.2.
4.4.1. Sample preparation

Sample discs were cleaned according to parts cleaning procedure.
Sample discs were strung on a wire, where each disc was separated by spacers
so that the surfaces of the discs did not interfere with one another.
4.4.2. Heparin coating

Sample discs were coated according to the designated procedure under the
nominal process parameter.
4.1.3 LAL Extraction

Sample discs were submerged in USP sterile water for irrigation for one hour and
thoroughly dried to simulate the LAL test.
4.1.4 Sterilization
Samples were packed in Tyvek pouches and sent for sterilization.
　　　 4.1.5 Cyclic testing

Samples were sent to Shonan R&D center in Japan, and were processed
temperature and humidity cyclic test. Samples operating record is attached.
Document#2005-061
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5. Results:
Table 1: Summary of results, values for heparin activity are in U/mL unless otherwise noted.
Titanium disc Stainless Steel disc
Non- Cyclic Cyclic tested Non- Cyclic Cyclic tested
tested (n=10) (n=10) tested (n=10) (n=10)
Average (U/mL) 0.031485 0.019255 0.029004 0.014490
Standard Deviation 0.001790 0.002988 0.002079 0.001670
Maximum 0.033463 0.022690 0.030666 0.016935
Minimum 0.027280 0.013450 0.023496 0.011829
Acceptance criteria Greater than 0.01 U/mL Greater than 0.01 U/mL
Figure 1: Effect of cyclic testing (temperature and humidity changes) on heparin activity for
Titanium substrate
Figure 2: Effect of cyclic testing (temperature and humidity changes) on heparin activity for
Stainless Steel substrate
Document#2005-061
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Figure 3: Heparin activity summary and data distribution for titanium Non- Cyclic tested
Summary for result (U/mL)
sample = Titanium Non- Cyclic tested
Anderson-Darling Normality Test
A-Squared 0.54
P-Value 0.126
Mean 0.031485
StDev 0.001790
Variance 0.000003
Skewness -1.49790
Kurtosis 3.01141
N 10
Minimum 0.027280
1st Quartile 0.030910
Median 0.031837
0.010 0.015 0.020 0.025 0.030 0.035 3rd Quartile 0.032612
Maximum 0.033463
95% Confidence Interval for Mean
0.030205 0.032765
95% Confidence Interval for Median
0.030805 0.032704
95% Confidence Intervals 95% Confidence Interval for StDev
Mean 0.001231 0.003267
Median
0.0300 0.0305 0.0310 0.0315 0.0320 0.0325 0.0330
Figure 4: Heparin activity summary and data distribution for titanium Cyclic tested
sample = Titanium Cyclic tested
A-Squared 0.33
P-Value 0.444
Mean 0.019255
StDev 0.002988
Variance 0.000009
Skewness -0.815474
Kurtosis -0.044525
N 10
Minimum 0.013450
Median 0.020092
0.010 0.015 0.020 0.025 0.030 0.035 3rd Quartile 0.022022
Maximum 0.022690
0.017118 0.021392
0.017152 0.022035
Mean 0.002055 0.005454
Median
0.017 0.018 0.019 0.020 0.021 0.022

Document#2005-061
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Figure 5: Heparin activity summary and data distribution for Stainless Steel Non-Cyclic tested
sample = SUS Non- Cyclic tested
A-Squared 1.15
P-Value < 0.005
Mean 0.029004
StDev 0.002079
Variance 0.000004
Skewness -2.41082
Kurtosis 6.59188
N 10
Minimum 0.023496
Median 0.029539
0.010 0.015 0.020 0.025 0.030 0.035 3rd Quartile 0.030289
Maximum 0.030666
0.027516 0.030491
0.028641 0.030302
Mean 0.001430 0.003796
Median
0.0275 0.0280 0.0285 0.0290 0.0295 0.0300 0.0305
Figure 6: Heparin activity summary and data distribution for Stainless Steel Cyclic tested
sample = SUS Cyclic tested
A-Squared 0.29
P-Value 0.527
Mean 0.014490
StDev 0.001670
Variance 0.000003
Skewness -0.333207
Kurtosis -0.428854
N 10
Minimum 0.011829
Median 0.014681
0.010 0.015 0.020 0.025 0.030 0.035 3rd Quartile 0.015551
Maximum 0.016935
0.013295 0.015685
0.013243 0.015663
Mean 0.001149 0.003049
Median
0.0130 0.0135 0.0140 0.0145 0.0150 0.0155 0.0160

Document#2005-061
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6. Conclusions:
Based on the results detailed in section 5 it can be seen from figures1 and figure 2 that
temperature and humidity changes have effect on heparin activity degradation.
It can also be seen for each substrate, that heparin activity exhibits a normal distribution (α=.05)
except for Stainless Steel Non- Cyclic tested. One Stainless Steel sample of Non- Cyclic tested
is lower than the others (nine data), however the heparin activity was still 130% higher than the
acceptance criteria.
Review of the results detailed in section 5 indicate that for both Non - Cyclic tested and Cyclic
tested samples the acceptance criteria of 0.01 U/mL for heparin activity is exceeded in all cases
for both substrates.
Therefore it can be concluded that under the cyclic test, the existing heparin coating process is
able to deliver heparin activity levels that can be sustained for Pump Product Requirement
Specification already defined. ( Temperature 0-50 degree C, Humidity 10-95%RH)
Document#2005-061
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Appendix
Raw Data
Description Heparin activity (U/mL)

Ti Cyclic tested 0.01570157
Ti Non- cyclic tested 0.03119723 0.035
Ti Non- cyclic tested 0.032153489
0.03
0.035
0.005
SS Cyclic tested 0.016458968 0
SS Cyclic tested 0.016934723 0.02 Ti Non- cyclic Ti Cyclic tested SS Non- cyclic SS C
SS Cyclic tested 0.011829397 0.015 tested tested test
SS Cyclic tested 0.014267233
SS Cyclic tested 0.012012158 0.01
0.005
SS Cyclic tested 0.013884363 0
SS Cyclic tested 0.015248436 Ti Non- cyclic tested Ti Cycli
SS Non- cyclic tested 0.028532044
SS Non- cyclic tested 0.030050063 0.035
0.025
0.015
0.01
0.005
0
SS Non- cyclic tested SS Cycli

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Terumo Confidential Page 1 of 9

6180 Jackson Road, Ann Arbor, MI 48103, U.S.A.

Report of the verification of the effect of temperature

Form: 811653 Rev B

2.1 The following documentation is used in conjunction with this study:

4.4.1. Sample preparation

4.4.2. Heparin coating

4.1.3 LAL Extraction

4.1.5 Cyclic testing

Mean 0.001231 0.003267

0.0300 0.0305 0.0310 0.0315 0.0320 0.0325 0.0330

Mean 0.002055 0.005454

0.017 0.018 0.019 0.020 0.021 0.022

Mean 0.001430 0.003796

0.0275 0.0280 0.0285 0.0290 0.0295 0.0300 0.0305

Mean 0.001149 0.003049

0.0130 0.0135 0.0140 0.0145 0.0150 0.0155 0.0160

Description Heparin activity (U/mL)

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