627 - 19 - ASB17061 EBR Lot No EA102-U (201-300) (Japa - Eng Final) )

(税行子田) 　　　　　(茂魔樹田)
Sample information Lot No. 10111607 2010.11.16 2010.11.16
Sample name BTTN process for cleaning evaluation test of D108 Shaft side surface
BTTN process for cleaning evaluation test - analytical conditions
Equipment No. : HPLC057-HAP
Analysis conditions Column : Cadenza CD-Cl 8 (3.0f x 50 mm，3 μ m #JC16A9L)
Temperature: 40 ° C Detection: 225 nm Flow rate: Approximately 0.5 mL / min Infusion: 5 μ L
Sample cooler temperature : 10 °C
Mobile phase A : MeCN : water ＝4 : 1
Date and time of 11/16/2010, 14 : 13 : 35
measurement
Control No. ID No. HPC057-HAP (Formerly known as ID No. 30235-203)
Infusion 1/1
Method name BTTN (#EA102-U) (Process for cleaning evaluation test)
Operator’s name Etsuko Yukita
VWD : Absorbance
Retention time Peak area Height Area % Peak width 50 %

0.536 2.564 0.944 3.332 % 0.043
minutes minutes
0.654 3.321 0.488 4.315 % 0.112
minutes minutes
0.865 5.899 0.930 7.665 % 0.083
minutes minutes
1.163 49.737 9.767 64.630 % 0.076
minutes minutes
1.570 2.927 0.435 3.803 % 0.107
minutes minutes
1.784 12.509 0.679 16.255 % 0.309
minutes minutes
Total 76.957 13.243
Page 1 of 1 2010/11/16 14 : 21 : 08
BTTN (Wiping)
Qt value [related substances] calculation sheet (blank correction calculation)

Date of testing : 2010 Year 11 Month 16 Day
Tested by Confirmed by
(税行子田) 　 (茂魔樹田)
2010.11.16 　2010.11.16
Device name : D108, Plant equipment Sampling : 1st time
Sample solution chart No. : 10111607
Blank solution chart No. : 10111605
Peak No. R.T. (min) Peak area value of Peak area value of Qt value ※
sample solution blank solution

1 0.536 2.564 2.528 0.036
2 0.654 3.321 2.924 0.397
3 0.865 5.899 5.445 0.454
4 1.163 49.737 48.215 1.522
5 1.570 2.927 2.688 0.239
6 1.784 12.509 12.445 0.064
Sum of each Qt value 2.712

※ Each Qt value = Peak area value of the sample solution - Peak area value of the blank solution
• If the Qt value is (1: minus), enter “0” in the Qt value field.
Production
Manager
(茂魔樹田)　　　　　　　　　　　　　
2010.11.16
6
(税行子田) 　　　　　　(茂魔樹田)　　　　
Sample name BTTN process for cleaning evaluation test of D108 bottom of the main body
BTTN PROCESS FOR INTERVAL CLEANING EVALUATION TEST - Analysis conditions
Equipment No. : HPC057-HAP
Analysis conditions Column : Cadenza CD-C18 (3.0f x 50 mm, 3 μ m #JC16A9L)
Temperature : 40 °C Detection : 225 nm Flow rate : Approximately 0.5 mL/min Infusion : 5 μ L
Date and time of 11/16/2010, 14 : 21 : 11
measurement
Control No. ID No. HPC057-HAP(旧 ID No. 30235-203)
Infusion 1/1
Method name BTTN (#EA1 02-U) (Process for cleaning evaluation test)
VWD : Absorbance

0.399 2.631 0.637 2.711 % 0.057
minutes minutes
0.538 2.587 0.955 2.666 % 0.043
minutes minutes
0.656 3.176 0.462 3.273 % 0.115
minutes minutes
3.868 5.930 0.936 6.110 % 0.083
minutes minutes
1.167 50.580 9.982 52.115 % 0.076
minutes minutes
1.576 3.192 0.449 3.288 % 0.107
minutes minutes
1.781 13.878 0.741 14.299 % 0.318
minutes minutes
2.612 5.941 0.782 6.121 % 0.108
minutes minutes
3.474 BTTN 9.140  1.134 9.417 % 0.125
minutes
Total 97.055 16.079
Page 1 of 1 2010/11/16 14 : 29 : 00
BTTN (Wiping)

(税行子田) (茂魔樹田)
Device name : D108, Plant equipment Sampling : 1st time
2010.11.16 2010.11.16

1 0.399 2.631 0 2.631
2 0.538 2.587 2.528 0.059
3 0.656 3.176 2.924 0.252
4 0.868 5.930 5.445 0.485
5 1.167 50.580 48.215 2.365
6 1.576 3.192 2.688 0.504
7 1.781 13.878 12.445 1.433
8 2.612 5.941 0 5.941

※ Each Qt value = Peak area value of sample solution - Peak area value of blank solution
If the Qt value is (1: minus), enter “0” in the Qt value field.
Production
Manager
(茂魔樹田)
2010.11.16
5
(税行子田) 　　　　　　(茂魔樹田)　　　　
Sample name BTTN PROCESS FOR AIR CLEANING EVALUATION TEST OF D108 INSIDE THE BAG FILTER
BTTN PROCESS FOR CLEANING EVALUATION TEST - Analysis conditions
Analysis conditions Column : Cadenza CD-C18 (3.0f x 50 mm, 3 μ m #JC16A9L)
Date and time of 11/16/2010, 14 : 28 : 54
measurement
Infusion 1/1
Method name BTTN (#EA102-U) process steps during cleaning evaluation test
VWD : Absorbance

0.537 2.698 0.970 3.586 % 0.043
minutes minutes
0.659 2.611 0.360 3.469 % 0.144
minutes minutes
0.866 6.293 0.970 8.364 % 0.085
minutes minutes
1.166 48.078 9.480 63.896 % 0.076
minutes minutes
1.573 2.858 0.442 3.798 % 0.105
minutes minutes
1.790 12.707 0.713 16.887 % 0.319
minutes minutes
Total 75.245 12.936
Page 1 of 1 2010/11/16 14 : 36 : 28
BTTN (Wiping)

　(税行子田) (茂魔樹田)　
　2010.11.16 2010.11.16
Device name : D108, バゲマイルタＸＸ Sampling : 1st time

1 0.537 2.698 2.528 0.170
2 0.659 2.611 2.924 0
3 0.866 6.293 5.445 0.848
4 1.166 48.078 48.215 0
5 1.573 2.858 2.688 0.170
6 1.790 12.707 12.445 0.262
Writing
2010.11.16
E. Y.
If the Qt value is (1: minus), enter “Ui” in the Qt value field.
Production
Manager
(茂魔樹田)　　　　　　　　　
　　　　
2010.11.16
5
(税行子田) 　　　　(茂魔樹田)　　　　
Sample information Lot No. 10111604 　　2010.11.16 2010.11.16
Sample name BTTN PROCESS FOR INTERVAL CLEANING EVALUATION TEST - Standard solution－2
Analysis conditions Column : Cadenza CD-18 (3.0f x 50 mm, 3 μ m #JC16A9L)
Temperature : 40 °C Detection : 225 nm Flow rate : approx. 0.5 mL/min Infusion : 5 μ L Sample
cooler temperature : 10 °C
Date and time of 11/16/2010, 10 : 37 : 52
measurement
Control No. ID No. HPC057-HAP(Formerly known as ID No. 30235-203)
Infusion 1/1
VWD : Absorbance

0.535 0.042 1.001 14.645 % 0.045
minutes minutes
0.860 4.433 0.797 21.344 % 0.075
minutes minutes
3.446 BTTN 13.294  1.633 64.011 % 0.126
minutes minutes
Total 20.768 3.431
Page 1 of 1 2010/11/16 10 : 45 : 23
(税行子田) 　　　　　　(茂魔樹田)　　　　
Sample name BTTN PROCESS FOR INTERVAL CLEANING EVALUATION TEST - Blank solution
Analysis conditions Column: Cadenza CD-C18 (3.0f x 50 mm, 3 μ m #JC16A9L)
Mobile phase A : MeCN : water＝4 : 1
Date and time of 11/16/2010,11 : 03 : 08
measurement
Infusion 1/1
VWD : Absorbance

0.537 2.528 0.931 3.405% 0.042
minutes minutes
0.651 2.924 0.432 3.939 0.108
minutes minutes
0.864 5.445 0.892 7.334 0.081
minutes minutes
1.163 48.215 9.531 64.940 0.075
minutes minutes
1.568 2.688 0.410 3.620 0.104
minutes minutes
1.804 12.445 0.676 16.762 0.322
minutes minutes
Total 74.245 12.871
Page 1 of 1 2010/11/16 11 : 10 : 39
Crystal formation name : ASB17061 Production instructions / records, numbers : 10HA-SM010 1/1
(batch No): EA102-U Production room cleaning 5/7

Production
Manager
BTTN PROCESS (茂魔樹田)

[Production room cleaning 一 5] S202 Centrifuge Push
2010.11.16
1. Purpose : Cleaning between the steps
2. Contents of use Production room name : S202 Centrifuge Push

Before cleaning the contents of use : BTTN crystal filtration
After cleaning the contents of use : ASB16726 process at the 2010.11.12 2010.11.12
same time 4-1 Start date and time : 13 : 58 End date and time :
ASB16726 CRYSTAL FILTRATION 14 : 09
Confirmed by : Ka. N.
3. Cleaning effect Confirmation by test
Visual Confirmation by test 2010.11.12 2010.11.12
4-2 Start date and time : 14 : 09 End date and time :
4. Cleaning method 14 : 19
< Distant machine booth > Confirmed by : Ka. N.
4-1 Wipe the outer surface of the centrifuge, the operation 2010.11.12 2010.11.12
panel, and the inside of the centrifuge with a special cloth. 4-3 Start date and time : 14 : 20 End date and time :
4-2 After washing the floor with a cleaning tool, drain the 14 : 27
water accumulated in the driver. Confirmed by : Ka. N.
< Changing room > 2010.11.12 2010.11.15

4-3 Wipe the booth, locker, and the floor with a special cloth. 4-4 Start date and time : 14 : 30 End date and time :
10 : 03 XX Ka. N.
<Centrifuge Pooh, changing room> Confirmed by : Ka. N.
4-4 Dry the whole.
2010.11.15 2010.11.15
4-5 Visually check and confirm that there is no dust or dirt. 4-5 Start date and time : 10 : 09 End date and time :
(If inappropriate, follow the instructions provided for by the 10 : 06
Production Manager). Visual Confirmation by test Decision :－ Appropriate
4-6 Spray around the floor.
2010.11.15 2010.11.15
10 : 09
Remarks: ： None
Operator’s 中た AppropriateKa. N.Appropriate 天田釆 S.T

signature
with
remarks
Crystal formation name : ASB17061 Production instructions / records, numbers : 10HA-SM010 1/1
ロ外番号 : EA102-U Production room

cleaning 6/7 Production
Manager
BTTN PROCESS
(茂魔樹田)
[Production room cleaning 一 6] D108 Drying room
1. Purpose : Cleaning between the steps 2010.11.16
2. Contents of use Production room name : D108 乾燥造

Before cleaning the contents of use : BTTN crystal filtration
After cleaning the contents of use : in the ASB17061 process 2010.11.12 2010.11.12
ASB17061 Appropriate crystal 4-1 Start date and time : 9 : 40 End date and time : 10
: 00
3. Cleaning effect Confirmation by test Confirmed by : Ka. N.
Visual Confirmation by test
2010.11.12 2010.11.12
4. ‘Cleaning method 4-2 Start date and time : 10 : 30 End date and time :
< Work room > 10 : 40
4-1 D108 Wipe off the outer surface, operation panel, and Confirmed by : Ka. N.
piping with a special cloth.
2010.11.12 2010.11.12
4-2 Wipe windows, walls and doors with a special cloth. 4-3 Start date and time : 10 : 43 End date and time :
10 : 54
4-3 Daku "Rinse the hose with running water. Confirmed by : Ka. N.
4-4 After washing the floor with a cleaning tool, drain 1 of the 2010.11.12 2010.11.12
water accumulated in the driver. 4-4 Start date and time : 11 : 00 End date and time :
11 : 32
<Changing room, bathroom> Confirmed by : Ka. N.
4-5 Wipe the walls, doors and lockers with a special cloth.
2010.11.12 2010.11.12
4-6 After cleaning the floor, wipe it off with a special cloth. 4-5 Start date and time : 11 : 34 End date and time :
11 : 39
<Whole Drying room> Confirmed by : Ka. N.
4-7 Dry.
2010.11.12 2010.11.12
4-8 Visually check and confirm that there is no dust or dirt. 4-6 Start date and time : 11 : 39 End date and time :
(If inappropriate, follow the instructions provided for by the 11 : 44
Production Manager). Confirmed by : Ka. N.
4-9 Spray ethanol around the floor (including the hbaki). 2010.11.12 2010.11.16
4-7 Start date and time : 11 : 58 End date and time : 9
: 07
2010.11.16 2010.11.16
4-8 Start date and time : 9 : 08 End date and time : 9 :
09
Visual Confirmation by test Decision : Appropriate
2010.11.16 2010.11.16
4-9 Start date and time : 9 : 10 End date and time : 9
: 13
Remarks: None
Operator’s 中た AppropriateKa. N.Appropriate 天田釆 S.T

signature
with
remarks
TAD (Dissolution)
TAD process for cleaning evaluation test (dissolution test))
1．Purpose :
Implementation of cleaning evaluation test between TAD processes.
2. Minute analysis, measurement conditions
2-1 minutes analysis
Use a high performance liquid chromatography (HPLC) registered with GMP equipment. Operate according to the standard
operating procedure manual.
2-2 Measurement condition
力ラム : Cadenza CD-C18 (3.0 ϕ x 50 mm, 3 μ m Intakt ( stock) 製)
力ラム温度 : 40 °C Constant temperature in the vicinity
Mobile phase : MeCN/Water mixture (2 : 3)
Flow rate : Approximately 0.5 mL / mm (TAD Retention time approximately 3.4 minutes)
Detection : 225 nm
Minute analysis time : 6 mm
Infusion quantity : 5μL
Sample dissolution solution : MeCN/Water mixture (1 : 1)
Needle cleaning solution : Sample dissolution solution
Minute analysis parameter : Prepare appropriate settings for the HPLC and measurement conditions used.
Follow the instructions provided for by the Production Manager.
Glass vial used : Silane treated brown glass vials used
2-3 How to prepare the test solution
1) Mobile phase
Mix MeCN with distilled water or ultrapure water in a volume of 2 : 3.
2) Sample dissolution solution
Mix MeCN with distilled water or ultrapure water at a volume of 1 : 1.
2-4 Chart numbering
All HPLC measurement charts include Chart numbering filled in.
The chart number indicates the 8-digit number of the Christian era (last 2 digits) + Infusion month and day (4 digits) + same day
serial number (2 digits).
Example) In the case of the third Infusion on the XX day of XX in 20 △△ year, the numbering will be [△△ 〇〇 x 03].
3. System compatibility test
3-1 Expiration date of system conformity test
The result of the System compatibility test is valid as long as the HPLC conforming to the System compatibility test is
continuously in the steady operation state. The end of the "steady operation state" here means the following state.
1) When the Mobile Phase is stopped
2) While replacing the Mobile phase
3) in caseWhile replacing the column
3-2 Retention time の確認
1) Weigh about 20 mg of standard TAD in a 100 mL volumetric flask, dissolve in Sample dissolution solution, and measure up.
2) 1) Weigh accurately with a 5 mL measuring pipette, transfer to a 20 mL volumetric flask, and measure up with sample
dissolution solution.
3) 2) Weigh accurately with a 5 mL measuring pipette, transfer to a 50 mL measuring flask, and measure up with sample
dissolution solution to prepare the measurement solution.
1
TAD (Dissolution)
4) Infuse the prepared measurement solution 5μL into HPLC and perform minute analysis under the Measurement condition of
2.2-2. Enter the obtained Retention time in the System compatibility test data sheet 1), and the Retention time is the criterion.
Confirm that it is within.
3-3 Confirmation by of the theoretical plates
1) 3-2 From the measurement results for which the retention time was confirmed in, the obtained retention time and peak height
of 50% are suitable for the system.
Fill out the compatibility test data sheet 2), find the theoretical plate number (N), and confirm that N is 1000 or more.
2) If N is less than 1000, measure again after the baseline stabilizes, or replace the force ram and mobile phase according to the
instructions of the Production Manager, and then measure again.
TR ＝ Retention time
Theoretical plate (N) = 5.54 x
W0.5 ＝ Peak width 50 %
3-4 Confirmation by of the infusion reproducibility
1) 3-3 The theoretical plate was confirmed in the measurement results, and then 10 uL of the measurement solution was
repeatedly infused into the HPLC twice in succession, and minute analysis was performed under the Measurement condition of
2.2-2 (measurement was repeated 3 times in total). ..
2) Fill in the obtained Peak area on the system suitability test data sheet 3), determine the relative standard deviation (RSD), and
confirm that the RSD is 2.0% or less.
3) If the RSD exceeds 2.0%, measure again after the baseline stabilizes, or replace the force ram and mobile phase according to
the instructions of the Production Manager, and then measure again.
n = Number of measurements
Relative standard deviation (RSD) = Xi = i-th measurement
XAVE = Average value
4. Cleaning evaluation test
4-1 Preparation of standard solution and minute analysis
1) 3. 3-4The final measurement result used to calculate the Confirmation by of the infusion reproducibility is defined as
standard solution-1.
2) 3. 3-1 Accurately measure the measurement solution prepared in step 1 with a 5 mL measuring pipette, transfer it to a
50 mL volumetric flask, and use a sample solution to make a standard solution-2.
3) Infuse the prepared standard solution-2 5 μL into HPLC and perform minutes analysis under the measurement condition
of 2.2-2.
Standard solution concentration C1, C2 and lAD Peak area value in the standard solution Qs1, QS2 asked for.
W : Standard product TAD sampling amount ( (mg) F : Content of standard BEIN product (%)
Standard solution－1 TAD concentration C1 (mg/L) = W x (F/100) x (1/4)
Standard solution－2 TADconcentration C2 (mg/L) = C1 x (1/10)
4-2 Blank solution minute analysis
1) Sampling the solvent used for cleaning.
2) Weigh this solution with a 10 mL whole pipette, transfer to a 100 mL eggplant flask, concentrate and dry.
3) Weigh the sample dissolution solution with a 10 mL whole pipette .), and irradiate with ultrasonic waves if necessary.
4) Infuse 5uL of this solution into HPLC and perform minutes analysis under the Measurement conditions of 2. 2-2.
4-3 Minute analysis of the sample solution
1) Sampling the cleaning solution for the dissolution test.
2) Weigh this solution with a 10 mL volumetric pipette, transfer to a 100 mL eggplant flask, concentrate and dry.
3) Weigh the Sample dissolution solution with a 10 mL volumetric pipette and irradiate with ultrasonic waves if necessary.
4) Infuse 5 μL of this solution into HPLC and perform minutes analysis under the Measurement conditions of 2. 2-2.
5. Calculation of test results
5-1 Calculation of Qt value
Qt value is the test chart, TAD is the Peak area value, and related substances are all peaks except TAD.
2
ＴＡＤ (Dissolution)
For the Qt value of related substances, enter the area value of the sample solution other than TAD and the area value of the
blank solution in the Qt value [related substances] calculation sheet (blank correction calculation), obtain the Qt value, and obtain
the Qt value and transfer to Qt
Each Qt value = Peak area value of the sample solution - Peak area value of the blank solution
5-2 Calculation of results
Enter each value in the measurement result data sheet and perform the calculation of results according to the following Formula .
Calculation Formula 1 Residual concentration C (mg/L) = [ (C1-C2) x (Qt-Qs1/ (Qs1—Qs2) + C1]
C1 (ｍｇ/Ｌ) : Residual concentration of (TAD, related substances) in the sample solution
C1 (ｍｇ/Ｌ) : Standard solution－1 ＴＡＤ concentration
C2 (ｍｇ/Ｌ) : Standard solution－2 ＴＡＤ concentration
Qs1 : Standard solution－1 ＴＡＤ Peak area
Qs， : Standard solution－2 ＴＡＤ Peak area
Qt : Calculated Peak area of TAD Peak area and related substances in sample solution
Residual value C, of related substances is calculated as a reference value.
Calculation Formula 2 of the residual value C' (ｍｇ/１００ｃｍ 2) = [ＴＡＤ C (ｍｇ/Ｌ) ] x Solvent quantity () / (internal area
of the equipment (m2) x 100)
Solvent amount (L) = Solvent amount used for cleaning
Residual concentration C (mg / L) of TAD is below the limit of quantification, or N.D. In the case of, the quantification limit
concentration is used as the residual concentration , and the Formula 1: C (mg / L)  Enter a check in the column. Check the
 column in the Formula below to calculate the residual amount of TAD (mg / 100 cm ). 2
Residual value C' (mg / 100 cm 2) = Quantification limit concentration C (mg / L) x Solvent quantity (L) / {(internal area of the
equipment) (m2) ) x100 }
Solvent quantity (L) ＝ Solvent quantity used for cleaning
6．Decision
Confirm that the residual value of TAD is 0.05 mg / 100 cm 2 or less, and it is less than the allowable limit value in the
measurement result data sheet.  Check the box to complete the cleaning.
When the residual value of TAD is 0.05 mg / 100 cm 2 or more, it is equal to or more than the allowable limit value in the
measurement result data sheet.  Check the box and perform re-cleaning according to the operation procedure.
3
BTTN (Wiping)
BTTN process of cleaning evaluation test (Wiping test)

1. Purpose :
Implementation of BTTN cleaning evaluation test.
GMP Equipment Registered High Performance Liquid Chromatography (hereinafter HPLC) is used. The operation is performed
according to the standard operating procedure.
力ラム : Cadenza CD-C18 (3.0 ϕ x 50 mm, 3 μ m Intakt ( stock) made by)
力ラム温度 : 40 °C Constant temperature in the vicinity
Mobile phase : MeCN/Water mixture (4 : 1)
Flow rate : Approximately 0.5 mL / min (BTTN Retention time approximately 3.6 minutes)
Detection : 225 nm
Minute analysis time : 6 min
Sample dissolution solution : MeCN
swab fluid : Sample dissolution solution
Abstraction fluid : Sample dissolution solution
Minute analysis parameter : Prepare appropriate settings for the HPLC and measurement conditions used.
Wiper used : Alpha Sampling Swab (TX715) (Made by the ITW texwipe Company)

1) Mobile phase
Mix MeCN with distilled water or ultrapure water at a volume of 4: 1.
2-4 Chart numbering

All HPLC measurement charts include Chart No. Fill in.
Chart No. Indicates the 8-digit number of the Christian era (last 2 digits) + Infusion month and day (4 digits) + same day serial
number (2 digits).
Example) In the case of the third Infusion on the XX day of the 20th △△ year, the numbering will be [△△ OO x x 03].

3-1 Expiration date of system conformity test
The results of the System compatibility test are valid as long as the HPLC conforming to the System compatibility test is
continuously in the steady operation state. The end of the "steady state" here means the following state.
3) While replacing the force ram
3-2 Confirmation by of Retention time

1) Weigh about 20 mg of the standard BTTN in a 100 mL volumetric flask, dissolve in a sample dissolution solution, and
measure.
2) Weigh the solution of 1) accurately with a 5 mL volumetric flask, transfer it to a 20 mL volumetric flask, and measure it with a
sample dissolution solution.
3) Weigh the solution of 2) accurately with a 5 mL measuring pipette, transfer it to a 50 mL volumetric flask, and measure it with
sample dissolution solution to make a measurement solution.
1
BTTN (Wiping)
4) Infuse 5UL of the prepared measurement solution into HPLC and perform minute analysis under the Measurement condition
of 2.2-2. Enter the obtained Retention time in the System compatibility test data sheet 1), and the Retention time is the criterion.
Confirm within the criteria.

1) From the measurement results for which the retention time was confirmed in 3-2, enter the obtained retention time and peak
height of 50% in the system suitability test data sheet 2), obtain the theoretical plate (N), and N is 1000 or more. Make sure that.
2) If N is less than 1000, measure again after the baseline stabilizes, or replace Column and Mobile phase according to the
instructions provided for by the Production Manager, and then measure again.
Theoretical plate (Ｎ) = 5.54 x TR = Retention time

W0.5 = Peak width 50 %

1) The measurement result in which the theoretical plate was confirmed in 3-3 and then 10 μL of the measurement solution were
repeatedly infused into HPLC twice in succession.
2. Perform minutes analysis under the Measurement condition of 2-2 (Measurement repeated 3 times in a row with Total).
2) Fill in the obtained Peak area in the system suitability test data sheet 3), determine the Relative standard deviation (RSD), and
confirm that the RSD is 2.0% or less.
3) If the RSD exceeds 2.0%, measure again after the baseline stabilizes, or replace the force ram and mobile phase according to
the instructions of the Production Manager, and then measure again.
Relative standard deviation (ＲＳＤ) = n = Number of measurements

Xi = i-th measurement
XAVE = Average value
4 Cleaning evaluation test

1) 3. 3-4 The final measurement result used to calculate the Confirmation by of the infusion reproducibility is defined as standard
solution-1.
2) 3. 3-1Accurately weigh the measurement solution prepared in step 1 with a 5 mL volumetric pipette, transfer it to a 50 mL
volumetric flask, and use a sample solution to make a standard solution-2.
3) Infuse the prepared Standard solution-2 5pL into HPLC and perform minute analysis under the measurement condition of 2.2-
2.
Find the BETN Peak area values Qs, Os1, Qs in the Standard solution concentration C1, C2 and standard solution.
W: Standard product BTTN sampling amount (mg) F: Standard product BTTN content (%)
Standard solution－1 BTTN concentration C1 (ｍｇ/Ｌ) = W x (F/100) x (1/4)
Standard solution－2 BTTN concentration C2 (ｍｇ/Ｌ) = C1 x (1 / 10)
4-2 Blank solution Preparation and minute analysis

1) Prepare 4 Wai / Bae, 2 soak in swab solution to moisten, and leave 2 dry.
2) Cut off the head part of the wiper (4 in total) of 1), put it in a container (centrifugal settling tube, etc.), and add Abstract 40 mL.
3) Add vibration for 2 minutes while occasionally mixing with an ultrasonic generator (medium: water at room temperature).
4) Infuse 5 μL of this solution into HPLC and perform minute analysis under the Measurement conditions of 2.2-2.
4-3 Preparation of sample solution and analysis of minutes
1) Prepare two wipers, one is soaked in swab liquid to moisten it, and the other is used while it is dry.
There is no distinction between the back and front of the wiper, but here each side is referred to as side A and side B.
2) Wiping the sample collection site vertically with the A side of the wet wiper, and immediately wipe it in the same direction with
the A side of the dry wiper.
3) Wiping laterally with the B side of the wet wiper at the same sample collection site, and immediately wipe in the same direction
with the B side of the dry wiper.
4) 呂にワイ, くーを 2 本用意して, 1) ~ 3) repeat.
5) 拭き取った全てのワイ，×一 (計 4 本) のヘッド部を切り離し, 容器 (還心沈殿管等) に入れ, Abstract40 mL を加える.
6) Occasionally drops with an ultrasonic generator (medium: water at room temperature) L) Add vibration for 2 minutes while
mixing.
7) 本浴液 5 μ L を HI-'L じに Infusion し 2. 2-2 の則定条件にて minutes 析を実行する.
2
BTTN (Wiping)
4 Confirmation by of calculation results

Qt value is the test chart, BTTN is the heak area value, and related substances are BTTN .
For all peaks except BTTN , enter the area value of the sample solution other than BTTN and the area value of the blank
solution in the Qt value [related substances] calculation sheet (blank correction calculation), and enter the Qt value. Obtained,
transferred the measurement result data sheet to the related substance Qt.
Each Qt value = Peak area value of sample solution - Peak area value of blank solution
According to the following Formula , enter each numerical value in the measurement result data sheet and perform the
Calculation of results.
Mark "○" in the maximum value column of calculated C, and calculate the residual value C, using that value.
Calculation Formula 1 Residual concentration C (ｍｇ/Ｌ) = [ (C1-C2) x (Qt-Os1) / (Qs1-Qs2) + C1 ]
C (ｍｇ/Ｌ) : Residual concentration of (BTTN , related substances) in the sample solution
C1 (ｍｇ/Ｌ) : Standard solution－1 BTTN concentration
C2 (ｍｇ/Ｌ) : Standard solution－2 BTTN concentration
Qs1 : Standard solution－1 BTTN Peak area
Qs2 : Standard solution－2 BTTN Peak area
Qt : Calculated Peak area of BTTN Peak area and related substances in sample solution
Residual value C, of related substances is calculated as a reference value.

Calculation Formula 2 of the residual value C’ (mg / 100 cm2 ) ＝ [Maximum value BTTN C (ｍｇ/Ｌ) ] x 0.04
0.04 ＝Solvent quantity used for wiper immersion (L)
If the residual concentration C (mg / L) of BTTN is below the limit of quantification or N.D., the concentration of quantification
limit concentration  Check the box to calculate the maximum BTTN C (mg / L) and U BTTN residual amount (mg / 100
cm2)..
Residual value C’ (mg/100 cm2) ＝[Limit of Quantitation concentration C (ｍｇ/Ｌ) ] x 0.04
0.04 ＝Solvent quantity used for wiper immersion (L)
5. Decision
Confirm that the residual value of BTTN is 0.05 mg / 100 cm2 or less, and put a check in the column below the allowable limit
value of the measurement result data sheet to complete the cleaning.
When the residual value of BTTN is 0.05 mg / 100 cm 2 or more, it is equal to or more than the allowable limit value in the
measurement result data sheet. Put a check in the pottery and follow the operating procedure (rewashing).
3
Crystal formation name : ASB17061 Production instructions / records, numbers・10HA-SM010 Preparation 10/16
Lot No. : EA102-U Preparation amount calculation list

 Calculation Formula checked
BETN process Preparation calculation standard is BTTN Gross weight standard
Operation < *9 > BTTN

BTTN weight Preparation (kg) = 91.60 kg 
Operation < *2 > THF ( x 4.0 voI)
BTTN weight Preparation (kg) x 4.0 = 91.60 x 4.0 = 366.4  366 L 

(Rounded off to the first decimal place)
Operation < *3 > EtOAc ( x 5.0 vol)

(Rounded off to the second decimal place)
Operation < *4 > ZnO ( x 3.00 eq)
BTTN weight Preparation (kg) x ZnO molecular weight x 3.00

_____________________________________
BTTN molecular weight
= 91.60 x 81.37 / 799.33 = 27.994  27.974 kg 

(Rounded off to the third place of the decimal point)
Operation < *5 > NaOAc ( x 5.00 eq)
BTTN weight Preparation (kg) x NaOAc molecular weight x 5.00

________________________________________
= 91.60 x 82.03 x 5.0 47.001  47.00 kg 

___________________
799.33 (Rounded off to the third place of the decimal point)
Operation < *6 > EtONH2-HCl ( x 3.60 eq)
BTTN weight Preparation (kg) X EtONH2-HCl molecular weight

_______________________________________________ X 3.60
BTTN minutes 子量
= 91.60 x 97.54 x 3.60 = ４０．２３９ 40.24 kg 

_______________
799.33
Drafted by Confirmed by Productio

n
Manager
2010.11.12 2010.11.12 2010.11.1
2
(明兵野) (茂魔樹田) (茂魔樹

田)
ＸＸ
2010.11.ＸＸ
S. H.
Crystal formation name : ASB17061 Production instructions / records, numbers・10HA-SM010
Preparation 11/16
Lot No. : EA102-U Preparation amount calculation list

Preparation calculation standard is BTTN Gross weight standard

BETN process
Operation < *10 > THF ( x 1.0 voI)

Operation < *13 > Na2CO3 ( x 4.00 eq)
BTTN weight Preparation (kg) X Na2CO3 molecular weight

____________________________________________ x 4.00
BTTN minutes 子量
= 91.60 x 105.99
__________________________ x 4.00 = 48.584  48.58 kg 
799.33 (Rounded off to the third place of the decimal point)
Operation < *16 > EtOAc ( x 5.0 voI)

Operation < *23 > EtOAc ( x 5.0 vol)

Drafted by Confirmed by Productio

n
Manager
2010.11.12 2010.11.12 2010.11.1
2
(明兵野) (茂魔樹田) (茂魔樹

田)
ＸＸ
2010.11.ＸＸ
S. H.
Product name : ASB17061 Clinical trial drug substance manufacturing instructions / records
Lot No. EA102-U Document No. : 10HA-SM010 フ口 — 26/52
Date of working : 2010.11.15 ~ 2010.11.15

BETN process
Preparation amount calculation standard : BTTN reaction kettle : K201

gross weight < *9 > Time : 9 : 05
Oxygen concentration : 3.3 % ( ≤ 5%)
3000L GL reaction kettle (K201) ……… — ………………………………………….…………….
[Nitrogen substitution] < * 1 > Confirmation by : A. Y. Y. S.
Oxygen concentration 5% or less < *2 > Time : 9 : 09 ~ 9 : 26
Note quantity : 336.4 L
……… — ………………………………………….…………….
THF 366 L  [Note] < *2 > Confirmation by : Ka. N. Y. S.
(standard 377 L) < x 4.0 voI > < *3 > Time : 9 : 30 ~ 9 : 36
……… — ………………………………………….…………….
EtOAc 458 L  [Note] < *3 > Confirmation by : Ka. N. Y. S.
(standard 472 L) < x 5.0 voI) < *4 > Under nitrogen air flow
Time : 9 : 38 ~ 9 : 40
Note quantity : 27.97 kg
ZnO 27.97 kg  [Addition] < *4 > ……… — ………………………………………….…………….
(standard 28.80 kg) < x 3.00 eq> Confirmation by : Y. S. A. Y.
< *5 > Time : 9 : 42 ~ 9 : 43
ＮａＯＡｃ 47.00 kg  [Addition] < *5 > ……… — ………………………………………….…………….
(standard 48.39 kg) < x 5.00 eq > Confirmation by : Y. S. A. Y.
< *6 > Time : 9 : 45 ~ 9 : 49
EtONH2-HCl 40.24 kg  [Addition] < *6 > Note quantity : 40.24 kg
(standard 41.43 kg) < x 3.60 eq > ……… — ………………………………………….…………….
Confirmation by : A. Y. S. H.
[Heating] < *7 > < *7 > Target tempereture : 45 °C
41 ~ 49 °C Ti Internal Internal Internal Rotati Remar
[Stirring] < *8 > me temperat temperat temperat on ks
41 ~ 49 °C ure ure ure SV speed
more than 60 minutes [ °C ] [ °C ] [ °C ] [ rpm ]
9: 18.2 28.8 40.0 55.1
*1 (K201) 50
10 : 36.4 49.0 49.0 54.8
20
Instructions 10 : 41.0 49.0 49.0 75.2 Bapple
Production 37 Appropri
Manager ate
Liquid
Meter
(茂魔樹田) :
:
2010.11.12
……… — ………………………………………….…………….
Confirmation by : A. Y. Y. S.
< *8 > Target tempereture : 45 °C

Ti Internal Internal Internal Rotati Remar
me temperat temperat temperat on ks
ure ure ure SV speed
[ °C ] [ °C ] [ °C ] [ rpm ]
10 : 41.0 49.0 49.0 75.2 Bapple
37 Appropri
ate
Liquid
Meter
10 : 450. 48.0 49.0 75.2
57
12 : 45.6 45.0 45.0 94.9
00
……… — ………………………………………….…………….
Confirmation by : Ka. N. Y. S.
Operator’s Akira YanoA.Y 太田蔵樹 SH　中たゆ xxxKa. N.田合 xx 手ｘｘｘｘ

signature
with
remarks
Date of working : 2010.11.15 ~ 2010.11.15

BETN PROCESS
reaction kettle : K201

*1 (K201) < *9 >
Time : Internal Internal Internal Remarks
BTTN 91.60 kg  [Note] < *9 > temperature temperature temperature
(standard 94.30 kg ) [ °C ] [ °C ] SV
[ °C ]
12 : 05 45.5 45.0 45.0
12 : 11 43.2 45.0 45.0
THF 92 L  [Note] < *10 > Additional quantity : 91.60 kg
(standard 94 L) ……… — ………………………………………….…………….
[Stirring ] < *11 > Confirmation by : Y. S. A. Y.
41 ~ 49 °C < *10 > BTTN FOR WASHING
[sampling] < *12 > temperature temperature temperature
Process control test-4 [ °C ] [ °C ] SV
Confirmation of reaction completion [ °C ]
Condition : BTTN /BTTN <+ 0.010 19 : 13 43.3 45.0 45.0
12 : 16 43.0 45.0 45.0
Note quantity: 92.3 L
Na2CO3 48.58 kg  [Addition] < *13 > Note quantity : 336.4 L
(standard 50.52 kg) < x 4.00 eq > ……… — ………………………………………….…………….
< *11 >
[Holding pressure cooling] < *14 > Target tempereture : 45 °C
20 ~ 30 °C Ti Internal Internal Internal Rotati Remar
: ure ure ure SV speed
*2 (K201) [ °C ] [ °C ] [ °C ] [ rpm ]
12 : 43.0 44.8 45.0 94.4
16
13 : 46.1 44.8 45.0 97.3
Instructions 16
Production 14 : 45.4 45.0 45.0 97.4
Manager 16
15 : 45.8 45.0 45.0 97.4
16
(茂魔樹田) 16 : 45.4 45.0 45.0 96.9
16
17 : 45.4 45.0 45.0 96.5
2010.11.12 17
……… — ………………………………………….…………….
Confirmation by : Y. S. A. Y.
<12>Operation <* 11)>Sampling 1h after the start. After that, sampling is
performed every 1h. Confirmation of the end point of the amidine reaction
Tim Process control test ー 4 Remark
e
BTTN remaining 0.219 Appropriate  Not appropriate 14 : 00
BTTN remaining Appropriate  Not appropriate ：
BTTN remaining Appropriate  Not appropriate ：
……… — ………………………………………….…………….
< *13 >
[ °C ] [ °C ] [ °C ] [ rpm ]
17 : 45.4 45.0 45.0
08
17 : 44.9 45.0 45.0
11
……… — ………………………………………….…………….
< *14 > Internal temperature SV = 20 ~ 25 °C
[ °C ] [ °C ] [ °C ] [ rpm ]
17 : 44.8 44.9 22.0 96.4
11
18 : 30.0 22.0 22.0 55.3
47
:
:
:
……… — ………………………………………….…………….
signature
with
remarks
Date of working : 2010.11.15 ~ 2010.11.19

BTTN process
*2 (K201) reaction kettle : K213
[Stirring ] < *15 > < *20 > Perform nitrogen substitution before appropriate inorganic salt crawling
20 ~ 30 °C Time : 16 : 15
more than 8 times Oxygen concentration : 1.0 % ( ≤ 5%)
……… — ………………………………………….…………….
(transfer) Confirmation by : A. Y. Y. S.
*3 (K201)
< *21 > Internal temperature 設定目安 : 60 °C Degree of vacuumsv 設定目安 5.0 kPa
Internal Internal Internal Degree Gauge Distillation

EtOAc 458 L  [Note] < Tim temperature temperature temperature of pressure quantity
*16 > e SV vacuum
(standard 472 L) < x 5.0 voI) [ °C ] [ °C ] [L] [KPa] [MPaG] [L]
9 : 34 22.0 21.8 21.8 15.0 0. —
(　transfer) : 45 15.3 21.8 40.0 10.0 -0.95 —
*4 (K201) 10 : 15.8 40.1 40.0 10.3 -0.95 14040L
10
: 37 15.9 40.1 40.0 10.3 -0.95 14040L
Filtration (FD201  PF-3) 11 : 16.3 40.0 40.0 10.3 -0.95 14060L
11
: 33 16.3 40.3 40.0 10.3 -0.95 14040L
12 : 16.7 4.01 40.0 10.3 -0.95 14040L
[Nitrogen substitution ] < *17 > 05
　　　Oxygen concentration 5% or less : 38 17.1 4.03 40.0 10.3 -0.95 14040L
　　　　　　　　　*3 (K201) 13 : 18.3 4.01 40.0 10.3 -0.95 14040L
21
[Inorganic appropriate salt ]* 　< *18 > Distillatyion quantity: 820 L
XX...
Confirmation by : S. H. Y. S.
*4 (K201)  [Washing] < *19
> < *22 >
Time : : 13 : 35 ~ 13 : 36
Note quantity : 437 L 2010.11.19 (signed Ｙ.Ｓ.) A. Y.
(Waste inorganic salt) Lotion Confirmation by : A. Y. S. H.
solution)
3000 L GL reaction kettle (K213)
[Nitrogen substitution] < *20 >

Oxygen concentration 5% or less
[Concentration under reduced pressure]

< *21 > >
　　　　　　　　　35 ° C or less
Concentrate to a liquid volume of 458 L
or less in the kettle
（standard 472L）
,< x 5.0 vol >
[Check the liquid quantity] < *22 >
When the amount of liquid in the

kettle exceeds 458 L、
< + 21> <* 22 of the operation repeat.
（standard 472L）
< x 5.0 vol >
*4 (K213)
Instructions
Production
Manager
（茂魔樹田）
2010.11.12

signature
with
remarks
D3HA-D01S05_Form 1_Production instructions・Procedure for record creation
2010.5.1 Implementation
70 - 28/52 - 2
[ Production record (1) ]
Lot No. : EA102 – U Process name : BETN Date of working : Year 2010 Month 10 Day 16 ~ Year 2010 Month 11 Day
PROCESS 18
番号 Time : 作業内容及びデータの記録 Confirmed Confirmed Remarks
by－1 by－2
18 9 : 38 K201  FD201 ＸＸ Diagnosis fluid Y. S. S. H.
ろ Appropriate 南な
ＸＸＸＸ PF-3 XX Y. S. S. H.
: 50 More Y. S. S. H.
PF-320 It's unreasonable
11 : 30 PF-ろのう紙、 Y. S. S. H.
Reinforce the cloth
: 45 ろ Appropriate 南な Y. S. S. H.
14 : 30 PF-ろのう紙、 Y. S. S. H.
う布を変援
: 45 3Appropriate を中約 Y. S. S. H.
20 : 50 3Appropriate を中約 Y. S. S. H.
18 9 : 10 3 Appropriate を教面 Y. S. S. H.
2010.11.17
10 : 00 FD201 液を面ｘｘＸＸ Y. S. S. H.
: 10 XX FD201 ＸＸＸＸ Y. S. S. H.
: 20 XX Y. S. S. H.
20 : 50 ＸＸＸＸ 304.0 L Y. S. S. H.
2010.11.18 9 : 01 FD201 液を面ｘｘ Y. S. S. H. ケーキ XX 9.5 cm
　　排あえ育液
10 : 30 ＸＸＸＸ Y. S. S. H. 排あえ育液ＸＸ
18 14 : 10 ＸＸＸＸ Y. S. S. H. 教面をする
15 : 09 ケーキ教面を切れ Y. S. S. H.
19 : 15 ＸＸＸＸ Y. S. S. H.
ＸＸＸＸ
: 30 ＸＸＸＸ Y. S. S. H.
16 : 35 ＸＸＸＸ Y. S. S. H.
: 40 ＸＸＸＸ Y. S. S. H.
作業者署名大タ田壁え YS 広田蔵料 SH

Date of working : 2010.11.19 ~ 2010.11.24

BETN PROCESS
*4 (K213) Reaction kettle : K213
EtOAc 458 L  [Note ] < *23 > < *23 >

(standard 472 L ) < x 5.0 vol >
Time Internal Outside temperature Outside temperature SV remarks
[Concentration under reduced pressure] temperature
< *２ 4 > 13:4 21.6 20.1 22.3
9
　　　　　　35 ° C or less 13:5 19.4 20.1 22.3
Liquid volume in the kettle 6
Concentrate to 458 L or less Note: 458.6L
　　　　　（standard 472L） ……… — ………………………………………….…………….
[Check the liquid quantity] < *２ 5 > < *24 > Target internal temperature setting: 60 °C Target degree of vacuum SV setting:
When the amount of liquid in the kettle 5.0 kPa
exceeds 458 L、 Intern Intern Intern Degre Gauge Distilla
< *21 > < *22 > Operation repeat. Time al al al e of pressur tion
（standard 472 L）*3 (K201) : temp temp temp vacuu e quantit
eratu eratu eratur m y
EtOAc 458 L  [Note] < *２ 6 > re re e
(standard 472 L) 　　　　 SV
Adjust the liquid volume in the kettle to [ °C ] [ °C ] [L] [KPa] [MPaG [L]
458 L ]
(standard 472L） < x 5.0 voI) 9 : 34 22.0 21.8 21.8 15.0 0. —
: 45 15.3 21.8 40.0 10.0 -0.95 —
10 : 10 15.8 40.1 40.0 10.3 -0.95 14040L
Instructions : 37 15.9 40.1 40.0 10.3 -0.95 14040L
11 : 11 16.3 40.0 40.0 10.3 -0.95 14060L
Production
: 33 16.3 40.3 40.0 10.3 -0.95 14040L
Manager 12 : 05 16.7 4.01 40.0 10.3 -0.95 14040L
（茂魔樹田） : 38 17.1 4.03 40.0 10.3 -0.95 14040L
2010.11.12 13 : 21 18.3 4.01 40.0 10.3 -0.95 14040L
Distillation quantity : 420 L
Confirmation by : S.H.Y.S.
[holding pressure colling]<27> < *25 >
20 ~ 5 °C Check the liquid volume with LM-1
Time : : 16 : 24 ~ 16 : 26
*5(K213) Liquid volume in the kettle (signed) A. Y.
Confirmation by : A. Y.S. H.
Cleaning of equipment between processes
[Equipment cleaning-14) <*26> <*25> Calculate the amount of EtOAc added from the amount of liquid
Reaction kettle (cleaning of K201) confirmed in
Time Internal Outside Outside Remark

temperature temperature temperature
SV
16 :27 19 .1 -1.2 -1.8
Instructions :28 19 .4 -2.4 -1.8
Production
<27>After cooling, let stand overnight
Manager
（茂魔樹田） Time Internal Outside Outside Rotation remark

temper temperatur temperatur speed
2010.11.12 ature e SV
16 :29 19.3 -2.7 -10.2 50
16 :57 3.5 -8.2 0.0 50
9 :03 1.3 -0.2 -0.2 -
0 :01 1.1 -0.2 -o.2 -

signature
with
remarks
D3HA-D01S05_Form 1_Production instructions・Procedure for record creation
2010.5.1 Implementation
2010.10.26
7D 29/52 - 2 XX
Y. S.
Lot No. : EA102 – U Process name :BETN Work day : Year 2010 Month 11 Day 19 ~ Year 2010 Month 11 Day 16
process
番号 Time : 作業内容及びデータの記録 Confirmed Confirmed Remarks
by－1 by－2
*26 16 : 26 EtOAc Preparation quantity Y. S. S. H.
- K213 Strict internal liquid volume 448 L
- BTTN Preparation quantity output 91.60 kg
91.60 kg x 5.0 = 458.0  458 L
*42 14 = 30 458 L adjustment Y. S. S. H.
458 - 448 = 10  10 L
作業者署名大タ田壁え YS 広田蔵料 SH

K213 2010.9.30
Flow rate LM-1 Average K213 K202 2010.10.21
meter value Competitive Flow rate LM-1 Average Liquid of
part minute meter value K202x
liquid competition
volume club minute
approx. 448 approx.
L 233 L
ASB17061 (EA102-U)
BETN PROCESS process
< * 22 > Check the liquid quantity
LM-1 order type(目型) 2656 y = 1.9171 x 2656 + 5526.6　　　　　　　　(茂魔樹田)
434.7  435 L Yoshiyuki Sugita
2010.11.19 2010.11.19 S. H.
< *25 > Check the liquid quantity
LM-1 order type(目型) 2649 y = 1.9171 x 2649 + 5526.6
= 448.2  448 L
 Series
— Linear (series)
ASB17061 (EA102-U) 　BETN PROCESS　< *14 > Taro Hosei
Nuclear salt weekly starry night K201 house lend (保在大郎)
貯蒸時トレント（全ラペーン） (2010.11.1 ５ ~ 2010.11.16) 　　Yoshiyuki Sugita
2010.11.18 2010.11.16 S. T.
(Japanese text (Menaing in English

used in the image) language)
外温制御 External temperature

control
control
境件電流 Boundary current
境井回転数
バッフル Sakai rotation speed
液位 baffle
到素 Liquid level
レンジ Towards
Range
ASB17061（ＥＡ１０２Ｕ） BETN PROCESS　
K201 内造レンド (保在大郎)
(2010.11.16 ~ 2010.11.17) Yoshiyuki Sugita 2010.11.17
2010.11.16 S. T.


control
control
境井回転数
液位 Baffle
到素 Liquid level
レンジ Towards
Range
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　ASB17061（ＥＡ１０２Ｕ） BETN PROCESS　　
K201 内造レンド (茂魔樹田)

　　　　　　　　　　　　　　　　　　　　　　　　　　 (2010.11.17 ~ 2010.11.18) Yoshiyuki Sugita 2010.11.18
2010.11.18 S. T.


control
control
境井回転数
パッフル Sakai rotation speed
液位 Baffle
到素 Liquid level
レンジ Towards
Range
ASB17061（ＥＡ１０２Ｕ） BETN PROCESS
核塩う週利スタリー夜のろ流液貯属時　　　　　　　　　　K213 内造レンド < *27 > (茂魔樹田)
貯蒸時トレント（ろページ）　　　　　　　　　　(2010.11.16 ~ 2010.11.17) 　 Yoshiyuki Sugita 2010.11.17
2010.11.19 Y. S. 2010.11.17 S. T.


control
control
境井回転数
液位 Baffle
到素 Liquid level
レンジ Towards
Range
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　ASB17061（ＥＡ１０２Ｕ）　BETN PROCESS 　　　　　
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　K213 内造レンド < *27 > 　　　　　　　　　　　(茂魔樹田)

　
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　(2010.11.19 ~ 2010.11.18) Yoshiyuki Sugita 2010.11.18
2010.11.18 S. T.


control
control
境井回転数
液位 Paffle
到素 Liquid level
レンジ Towards
Range
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　ASB17061（ＥＡ１０２Ｕ）　BETN PROCESS 　　　　　
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　K213 内造レンド < *27 > 　　　　　　　　　　　(茂魔樹田)

　　　　　　　　　　　　(2010.11.18 ~ 2010.11.19) 　　　　　Yoshiyuki Sugita 2010.11.19
2010.11.19 S. T.


control
control
境井回転数
液位 Baffle
到素 Liquid level
レンジ Towards
Range
　　　　　　　　　　　　　　　　　　　　　　　　ASB17061（ＥＡ１０２Ｕ）　BETN PROCESS < *27 > 　　　　　　　　　　　　　　　　　　　　1/4
K213 内造レンド　　　(茂魔樹田)
2010.11.22 S. T.


control
control
境井回転数
液位 Baffle
到素 Liquid level
レンジ Towards
Range
ASB17061（ＥＡ１０２Ｕ）　BETN PROCESS < *27 > 　保在大郎 2/4

　　　　　　　　　　　　　　　　　　　　　　　　　　 (2010.11.20 ~ 2010.11.22) 　　Yoshiyuki Sugita 2010.11.22　　
2010.11.22 S. T.


control
control
境井回転数
液位 Baffle
到素 Liquid level
レンジ Towards
Range
ASB17061（ＥＡ１０２Ｕ）　BETN PROCESS < *27 > 保在大郎 3/4
K213 内造レンド　(茂魔樹田)
2010.11.22 S. T.


control
control
境井回転数
液位 Baffle
到素 Liquid level
レンジ Towards
Range
ASB17061（ＥＡ１０２Ｕ）　BETN PROCESS < *27 > 保在大郎 4/4

2010.11.22 S. T.


control
control
境井回転数
液位 Baffle
到素 Liquid level
レンジ Towards
Range
2010.11.24
ASB17061 (EA102-U)  (signed) S. T. BETN PROCESS < *27 > 保在大郎 1/4

2010.11.24 S. T.


control
control
境井回転数
液位 Baffle
到素 Liquid level
レンジ Towards
Range
ASB17061（ＥＡ１０２Ｕ） BETN PROCESS　　< *27 > 保在大郎 2/4
2010.11.24 S. T.


control
control
境井回転数
液位 Paffle
到素 Liquid level
レンジ Towards
Range
2010.11.24 S. T.


control
control
境井回転数
液位 baffle
到素 Liquid level
レンジ Towards
Range
K213 内造レンド　　(茂魔樹田)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　(2010.11.22 ~ 2010.11.24) Yoshiyuki Sugita 2010.11.24
2010.11.24 S. T.


control
control
境井回転数
液位 Baffle
到素 Liquid level
レンジ Towards
Range
D3HA-D01S06_Form 2_Production Instructions・Procedure for creation for record purpose 2010.5.1 Execution
Production record (3) Weighing record :
Nomenclature ASB17061
of clinical trial
drug substance
Process name BETN PROCESS
1/7 2010.11.19 Lot No. EA102-U
signed Ｙ.Ｓ.　
Product name Axis responsibility Lot No. Weighing G 67742.2 L ✓

source equipment T 67375.8 L ✓
*2 Mitsubishi 25TOH 25 Ka. N. N 366.4 L ✓
THF Chemical
(charge)
Weighing Date of weighing Confirmation by
equipment item done
No.
OF-14 2010.10.15 Y. S.
*10 source equipment T 67745.3 L ✓
Mitsubishi 25TOH 25 Ka. N. N 92.3 L ✓
THF Chemical
(charge)
equipment item done
No.
OF-14 2010.10.15 Y. S.
Product name Axis responsibility Lot No. Weighing G __________________
source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.
Operator’s remarks with signature : None

of clinical trial
drug substance
Process name BETN
2/7 2010.11.19 Lot No. EA102-U
Signed Ｙ.Ｓ.　
Product name Axis responsibility Lot No. Weighing G 28.25 kg ✓

source equipment T 0.28 kg ✓
*4 Kunisaki 208V1665 Y. S. N 27.97 kg ✓
ZnO Chemical Co.,
Ltd.
equipment item done
No.
WE-14 2010.10.12 S. H.
source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

of clinical trial
drug substance
Process name BETN process
3/7 2010.11.19 Lot No. EA102-U
signed Ｙ.Ｓ.

*5 Daito Chemical 00710M Ka. N. N 24.9 kg ✓
MaOAc (1) Co., Ltd.
equipment item done
No.
WE-14 2010.11.15 S. H.
*5 source equipment T 0.73 kg ✓
Daito Chemical 00710M Ka. N. N 22.10 kg ✓
MaOAc (2) Co., Ltd.
equipment item done
No.
WE-14 2010.11.15 Y. S.
*5 source equipment T
N 47.00 kg ✓
NaOAc Weighing Date of weighing Confirmation by
equipment item done
(1) ~ (2) Total　 No.
Ka. N. Y. S.
source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

of clinical trial
drug substance
4/7 2010.11.19 Lot No. EA102-U
signed Ｙ. S.

*6 JINAN YOUNG YD20100520 Y. S. N 24.87 kg ✓
EtNH2 – HCl (1) TECHNICAL
DEVELOPMENT
equipment item done
No.
WE-14 2010.11.12 S. H.
JINAN YOUNG YD20100520 Y. S. N 15.37 kg ✓
EtNH2 – HCl (2) TECHNICAL
DEVELOPMENT
equipment item done
No.
WE-14 2010.11.12 S. H.
*5 source equipment T _______________
2010.11.12 (signed) S. H. N 40.24 kg ✓
EtNH2 – HCl equipment item done
No.
(1) ~ (2) XX S. H. Y. S.
source equipment T _______________
N
equipment item done
No.

N
equipment item done
No.

N
equipment item done
No.

N
equipment item done
No.

N
equipment item done
No.

of clinical trial
drug substance
5/7 2010.11.19 Lot No. EA102-U
signed Ｙ. S.

*13 Tokukas Co., Ltd. 00615 Ka. N. N 25.62 kg ✓
Na2CO3 (1) Weighing Date of weighing Confirmation by
equipment item done
No.
WE-14 2010.11.15 Y. S.
Tokukas Co., Ltd. 00615 Ka. N. N 22.96 kg ✓
Na2CO3 (2) Weighing Date of weighing Confirmation by
equipment item done
No.
WE-14 2010.11.15 Y. S.
N 48.58 kg ✓
Na2CO3 Weighing Date of weighing Confirmation by
equipment item done
(1) ~ (2) Total No.
Ka. N. Y. S.
source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

of clinical trial
drug substance
6/7 2010.11.19 Lot No. EA102-U
signed Ｙ.Ｓ.

source equipment T 4324.6 L ✓
*3 Kunisaki Chemical 00710M Ka. N. N 458.6 L ✓
EtOAc (1) Co., Ltd.
Weighing equipment Date of weighing Confirmation by
item No. done
WE-14 2010.11.15 S. H.
Kunisaki Chemical 210061 Ka. N. N 304.0 L ✓
EtOAc (2) Co., Ltd.
（1st loading day) Weighing equipment Date of weighing Confirmation by
item No. done
QT203B 2010.11.15 S. H.
EtOAc (3) Co., Ltd.
（2nd loading dau) item No. done
QT203B 2010.11.17 S. H.
EtOAc Co., Ltd.
(1) ~ (2) Weighing equipment Date of weighing Confirmation by
（2 load days) item No. done
QT203B 2010.11.17 S. H.
*16 source equipment T __________________
Ka. N. S. H. N 458.8 L ✓
EtOAc Weighing equipment Date of weighing Confirmation by
(1) ~ (3) Total item No. done
(signed) Ka. N.
(signed)
2010.11.18
EtOAc Co., Ltd.
item No. done
QT203B 2010.11.19 S. H.
EtOAc Co., Ltd.
item No. done
QT203B 2010.11.19 S. H.
source equipment T
N
item No. done

of clinical trial
drug substance
7/7 2010.11.19 Lot No. EA102-U
signed Ｙ.Ｓ.

*9 Process product EA102-U Y. S. N 17.40 kg ✓
BTTN (1) Weighing Date of weighing Confirmation by
equipment item done
No.
WE-24 2010.11.11 S. H.
Process product EA102-U Y. S. N 15.93 kg ✓
equipment item done
No.
WE-24 2010.11.11 S. H.
equipment item done
No.
WE-24 2010.11.11 S. H.
equipment item done
No.
WE-24 2010.11.11 S. H.
equipment item done
No.
WE-24 2010.11.11 S. H.
N 91.60 kg ✓
BTTN Weighing Date of weighing Confirmation by
(1) ~ (5) Total equipment item done
No.
Y. S. S. H.
source equipment T
N
equipment item done
No.

source equipment T
N
equipment item done
No.

Product name : ASB17061 batch No: EA102-U
Production instructions  Record No. 10HA-SM010 Test No. : 13/43
ASB17061BETN PROCESS
Process control test – 4 Confirmation of reaction completion
Test data sheet ①, ②
1. Purpose :
Confirm the completion of the reaction .
2 Minute analysis, measurement conditions
GMP Equipment Registered High Performance Liquid Chromatographer (Hereafter, HPLC) is used. The operation is
standard Operation) - Perform according to the top note.
Column : Shiseido CAPCELL PAK CS DD 3 μ m (4.6 ϕx 100 mm)
Column temprature : 40 °CConstant temperature in the vicinity
Mobile phase : 0.01 mol / L Ammonium acetate aqueous solution / MeCN = 65/35
(Gradient initial condition)
Flow rate : approx. 1.0 mL/min
Detection : 230nm
Minute analysis time : 6 min (Confirmation by of the infusion reproducibility : Gradient initial condition)
40 min
(Retention time and minutes Confirmation of separation of this test
Plot Time : 1.5 min ~31 min)
Infusion quantity : 10 μ L
Minute analysis parameter : Make appropriate settings for the HPLC and measurement conditions used.
2-3 Preparation method of 0.01 mol / L ammonium acetate aqueous solution
Ammonium acetate (AcONH4 MW: 77.08) 0.77 g prepared in 1000 mL with distilled water or ultrapure water.
The scale of the preparer may be changed as appropriate.
2-4 Radiant condition
Mix Mobile phase A and Mobile phase B at the ratios shown below and send the liquid.
0 min A : B = 65 : 35 (Gradient initial condition)
0  30 min A : B = 65 : 35  5 : 95
30.1 min A : B = 65 : 35
40 min A : B = 65 : 35
40.1 min STOP
2-5 Chart numbering
Enter the chart number for all HP LG measurement charts.
The chart number indicates the 8-digit number of the Christian era (last 2 digits) + Infusion month and day (4 digits) + same day
serial number (2 digits).
Example) In the case of the third Infusion on the OO month XX day of the 20 △△ year, the numbering will be [△△ OO x x 03].
3-1 Confirmation of retention time
1) Precisely weigh about 5 mg of BTTN and BETN in 100 mL Mesuafsco, dissolve the sample; dissolve at night, and
mess up to make the measurement solution.
Product name : ASB17061 batch No: EA102-U
Production instructions / Record No. 10HA-SM010
Test No. : 14/43
2) Infuse the prepared measurement solution 10 (b) into HPLC and perform minutes analysis under the above conditions. Enter
the obtained retention time in Test data sheet (1) and confirm the retention time.
3-2 minutes checking the degree of separation
1) 3From the measurement result for which the retention time was confirmed in obtained retention time, Peak width 50%
was entered in the test data sheet ①, and the minute separation (R S) was calculated, and R S was 7 or more. Make sure
that is.
2) 2) If RS is less than 7, measure again after the baseline stabilizes, or replace Column and Mobile phase according to the
instructions provided for by the Production Manager and then measure again.
Separation time (RS) = 1.18 x TR1, TR2 = Retention time (TR2> = TR1)
W0.51, W0.52= Peak width 50 %
1) Weigh accurately about 10 mg of methyl p-hydroxybenzoate in a 100 mL volumetric flask, dissolve in the Sample
dissolution solution, and measure up to make a measurement solution. Repeat 10 μL of the measurement solution 3
times in a row () and measure.
2) Enter the obtained Peak area in the test data sheet ①, obtain the relative standard deviation (RSD) and confirm that
the RSD is 3.0% or less.
3) If the RSD exceeds 3.0%, measure again after the baseline stabilizes, or replace the force ram and mobile phase
according to the instructions of the Production Manager, and then measure again.
n = Number of measurements
Relative standard deviation (ＲＳＤ) = Xi = i-th measurement
XAVE =Average value
4 Sample collection and sample solution Preparation
Sample the reaction solution every 1 time from the start of the reaction . Appropriate the collected reaction solution with a
0.45 μm syringe filter, take about 10 μL of the obtained filtrate in a 10 mL volumetric flask, and sample dissolution. Dissolve with
solution, measure up to make sample solution.
5. Minute analysis of the sample solution and confirmation of reaction completion
Infuse 10 μL of the prepared sample solution into HPLC and perform minute analysis under the above conditions. BTTN,
BTTN Peak area values are shown in [BTTN area] and [BETN area] of the test data sheet ②. Fill in every. Calculate BTTN /
BETN by using the Formula below from the obtained area value. Trial 5 low data sheet ② [Record in BTIN / BETN / BETN.
BTTN area
BTTN / BETN = BETN area (Rounded to the fourth decimal
place)
As a result of the calculation, the reaction is terminated when BTTN / BETN becomes 0.010 or less. If it exceeds 0.010, follow
the instructions of the Production Manager. Enter the above minutes analysis result in the test data sheet ②.
Product name : ASB17061 Lot No. : EA102-U
Production instructions・Record No. : 10HA-SM010

Test No. : 15/43
Test data sheet ① ASB17061　BETN PROCESS Production

Manager
Process control test 一 4 Confirmation of reaction completion (茂魔樹田)

2010.10.25
Lot No. EA 102 – U
Date of testing : : Year 2010 Month 11 Day 15
Tested by : Shigeko Surata Confirmed by : Akira Yano
HPLC XX NO. : HPLC059 – HAP Residual control No. : EB062 - HAP
GTH Lot No. : EA 101 TAD Lot No. : TC-204
System compatibility test
Retention time and confirmation of the theoretical plates Chart No. : 10111501
Retention time Peak area Peak width 50 %

BTTN 22.965 (20.730 ~ 25.337 min) 1281.989 0.107
BETN 25.430 (22.960 ~ 28.063 min) 1196.374 0.106
< BTTN , BETN minutes separation >
1.18 x ( 25.430 - 22.965 / 0.107 + 0.106 ) = 13.6   14 
(Rounded to the 4th significant digit)
2010.10.25 F. Y. Decision criteria : 7 or more Decision :  Appropriate  Not appropriate
Confirmation by of the infusion reproducibility
Peak area value Chart No. Average value : 991.336

n = 1 : 1261.728  10111502 RSD : 0.2 %
n = 2 : 1266.262  10111503 Decision :  Appropriate (3.0 % or less)  Not appropriate
n = 3 : 1265.570  10111504
Formula :
く Average value>
( 1261.728) + 1266.262 + 1265.570 ) / 3 = 1264.5200  1264.520
(Rounded to the fourth decimal place)
<RSD>
= 0.19  0.2 
(Rounded off to the second decimal place)
Decision
 Appropriate : Since this minutes analysis system is in a state of being prepared as a system, Preparation of sample solution
and minutes analysis are started.
 Not appropriate : Since this minutes analysis system is in an undeveloped state as a system, the following Operation is
performed.
Not appropriate content  Remeasured after seeing the stability of the baseline.
 Replace Columns, or re-arrange the Mobile phase, etc..
 Miscellaneous ( _________________________________________ )
(税行子田) 　　　(茂魔樹田)
2020.10.25 2010.10.25
Sample information Lot No. 10111501
Sample name BETN PROCESS for process control test－4 Retention time and minutes and checking the
degree of separation
Analysis conditions ASB17061 (9-10 steps ) Measurement condition
Column: Shiseido Capceil Pak C8 DD 3 μ m 4.6 x 100 mm (Lot No. BLAA01015)
Temperature : 40°C Detection : 230 nm Flow rate : approx. 1.0 mL/min Infusion : 10 μ L
Mobile phase A : 0.01 M Ammonium acetate water solution Mobile phase B : Acetonitrile
A : B = 65 : 35 (0 min)  5 : 95 (30 min) 65 : 35 (30.01 min)  65 : 35 (40min)
IDNo.
ASB17061(#EA1 02) 9-10 steps for measurement condition
Date and time of 11/15/2010, 09 : 12 : 00
measurement
Infusion 1/1
Method name ASB1 7061 (#EA1 02) 1-5Process temperature constant conditions
VWD : Absorbance

21.091 3.394 0.588 0.155 % 0.106 minutes
minutes
21.475 15.514 2.162 0.612 % 0.111 minutes
minutes
22.965 BTTN 1281.989 183.318 60.607 % 0.107 minutes
minutes
23.994 35.410 4.462 1.398 % 0.116 minutes
minutes
25.430 BETN 1196.374 171.457 47.228 % 0.106 minutes
minutes
Total 253.210 361.986
Page 1 of 1 2010/11/15 9 : 53 : 38
2010/11/15 9 : 09 : 27
Device 　　(税行子田) 　　　(茂魔樹田)
　　　　　　2010.11.15 2010.11.15
G1312A DEVICE 1 BINARY PUMP
Solvent A : 0.01M AcONH4 Ratio : 65.0 % Stroke : Automatic Compression rate : 100 µbar^-1
Solvent B : CH3CN Ratio : 35.0 % Stroke : Automatic Compression rate : 115 µbar^-1
Flow rate : 1.000 mI/min maximum flow lamp : 100.0 mI/mm
Pressure range : 0 bar ~ 400 bar
Stop time : 40.000 minutes Delay time : 0.000 minutes
time B ratio Flow rate Pressure

rate
0.000 35.0 1.000 400
30.000 95.0 1.000 400
30.010 35.0 1.000 400
40.000 35.0 1.000 400
Contact point 1 : open < Contact point 2 : open < Contact point 3 : open < Contact point 4 : open <
Event # Time : Contact point 1 Contact point 2 Contact Contact point 4

point 3
(The table is empty)
G1314A VWD DEVICE 1

Analog zero : 5.00 % Analog attenuation : 1000 mAU
Wavelength : 230 nm Peak width : More than 0.1 minutes
Balance mode : Automatic Negative absorbance margin : 100 mAU
Stop time : No limitation Delay time : 0.000 minutes
Time Wavelength Balance

Event # Time Contact point 1 Contact point 2 Contact point 3 Contact point 4
G1316A DEVICE 1 TCC
Page 1 of 2
2010/11/15 9 : 09 : 27
Left compartment Right compartment
Temperature : 40.00 °C 40.00 °C
Preparation temperature : 0.80 °C 0.80 °C
Individual heat exchangers : one (税行子田) 　　　(茂魔樹

田)
Stop time : No limitation Delay time : 0.000 minutes 　　　2010.11.15 2010.11.15
Time Left Right Column valve

temperature temperature
G1329A DEVICE 1 ALS

Infusion count volume : 10.0 μ L Discharge speed : 200 μ l/mm
Suction position : 0.0 Suction speed : 200 μ l/mm
Cleaning location : 91
Infusion mode : Washing
Event # Time Contact point 1 Contact point 2 Contact point 3 Contact point 4
Injector program
Command
Page 2 of 2
2010/11/15 None 9 : 09 : 27
Minute product ASB17061 (# EA102) 9-10 steps for measurement condition (17)
Created on : 06/07/2010, 10 : 40 : 20
Modified on : 10/15/2010, 08 : 21 : 349
(税行子田) 　　　 (茂魔樹田)
　　　　　　　　2010.11.15 　　2010.11.15
Common initial minute product event
Tail peak skim height ratio : 0.0000
Front peak skim height ratio : 0.0000
Skim valley ratio : 20.0000
Baseline correction : Classical
Tangent skim mode : Standard
Peak / Valley Ratio : 500.0000
VWD EVENT
Area rejection : 2.000
Slope sensitivity : 5.000
Peak width : 0.040
Shoulder detection mode : Invalid
Height rejection : 0.500
VWD EVENT
Event # Event time Event Event value

1 0.0000 minutes Product minutes off N/A
2 1.5000 minutes Product minutes on N/A
Page 1 of 1
　　　 (税行子田) 　　　 (茂魔樹田)
2010.11.15 2010.11.15
Sample name BETN PROCESSProcess control test－4Confirmation by of the infusion reproducibility n-1
Analysis conditions ASB17061 (9-10 steps ) Repeatability measurement terms
力ラム : Shiseido Capcell Pak 08 DD 3 μ m 4.6 x 100 mm (Lot No. BLAA1015)
Temperature : 40 °C Detection : 230 nm Flow rate : approx. 1.0 mL / min Infusion: 10 μ L
Mobile phase A : 0.01 M Ammonium acetate aqueous solution Mobile phase B : Acetonitrile
Date and time of A : B = 65 : 35 11/15/2010, 09 : 56 : 26
measurement
Infusion 1/1
Method name ASB17061(#EA1 02) 9-10 Process reproducibility measurement condition
VWD : Absorbance

2.851 1261.728  150.852 100.000 % 0.128
minutes minutes
Total 1261.728 150.852
Page 1 of 1 2010/11/15 10 : 04 : 02
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　(税行子田) 　　　 (茂魔樹田)　　　
2010.11.15 　　2010.11.15
Sample name BETN PROCESS Process control test－4Confirmation by of the infusion reproducibility n-2
力ラム : Shiseido Capcell Pak CS DD 3 μ m 4.6 x 100 mm (Lot No. BLAA01015)
Temperature : 40 °C Detection : 230 nm Flow rate : approx. 1.0 mL/min Infusion : : 10 μ L
A : B = 65 : 35
Date and time of 11/15/2010, 10 : 04 : 06
measurement
Infusion 1/1
Method name ASB17061 (#EA102) 9-10 Process reproducibility measurement condition
VWD : Absorbance

2.854 1266.262  151.105 100.000 % 0.128
minutes minutes
Total 1266.262 151.105
Page 1 of 1 2010/11/15 10 : 11 : 43
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　(税行子田) 　　　 (茂魔樹田)
　　　
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　2010.11.15 2010.11.15
Sample name BETN PROCESS Process control test－4Confirmation by of the infusion reproducibility n-3
力ラム : Shiseido Capcell Pak C8 DD 3 μ m 4.6 x 100 mm (Lot No. BLAAO1015)
Temperature : 40 °C Detection : 230 nm Flow rate 約 1.0 mL/min Infusion : 10 μ L
A : B = 65 : 35
Date and time of 11/15/2010, 10 : 11 : 46
measurement
Infusion 1/1
Method name ASB17061 (#EA102) 9-10 Steps Process reproducibility measurement condition
VWD : Absorbance

2.856 1265.570  150.920 100.000 % 0.128
minutes minutes
Total 1265.570 150.920
Page 1 of 1 2010/11/15 10 : 19 : 24
Device setting value 1/1

ページ
　　　　　　　2010.11.15 　　2010.11.15
Device
Solvent A : 0.01M AcONH4 Ratio : 65.0 % Stroke: Automatic Compression rate : 100 µbar^-1
Solvent B : CH3CN Ratio : 35.0 % Stroke: Automatic Compression rate : 115 µbar^-1
Flow rate : 1.000 mI/mmn 最大 Flow rate ランプ : 100.0 mI/mm
Time : B ratio Flow rate Pressure

rate
Contact point 1 : open < Contact point 2 : open < Contact point 3 : open < Contact point 4 : open
<
Event # Time : Contact point 1 Contact point 2 Contact point 3 Contact point 4
G1314A VWD DEVICE 1

アナログゼ口 : 5.00 % Analog attenuation : 1000 mAU
Time Wavelength Balance


point 3
G1316A VWDDEVICE 1 TCC

file : //￥￥cdmssrv01￥ cerityreports￥temp￥rad642FD.tmp￥default.htm 2010/11/15
Device setting value 2/2 Page
Individual heat exchangers : one (税行子田) 　　　(茂魔樹田)

Stop time : No limitation Delay time : 0.000 minutes 2010.11.15 2010.11.15
Time : Left Right Column valve

G1329A DEVICE 1 ALS

Infusion count volume : 10.0 μ L Discharge speed : 200 μ l/min
Suction position : 0.0 Suction speed : 200 μ l/min
Injector program
Command
file : //￥￥cdmssrv01￥ cerityreports￥temp￥rad642FD.tmp￥default.htm 2010/11/15

2010/11/15 None 9 : 45 : 05
Product minutes ASB17061 (# EA102) 9-10 steps for measurement

condition (19)
Created on : 06/07/2010, 10 : 40 : 20
Modified on : 11/15/2010, 8 : 21 : 16
2010.11.15 2010.11.15
Tangent skim mode : standard
Peak / Valley ratio : 500.0000
VWD1AEvent
Peak width : 0.040
VWD1A DEVICE

Page 1 of 1
Production instructions・Record No. : 秤量記録 1/1
Sample weighing record
Process control test name : ASB17061BETN steps for Trans-Stem Appropriate Compatibility Test
Date of testing : : 2010.11.15 Lot No. : EA102 - U

Balance control No. : EB062-HAP Confirmed by : Akira Yano
Tested by : Sutekuro-shō eru
(税行子田) (税行子田) (税行子田)

ASB17061 BETN steps 経． ASB17061 BETN steps 　
ASB17061BETN steps 経． System Appropriate Comprehensive Sostem Appropriate Comprehensive
System Appropriate Comprehensive Examination BETN ( # TC-204) Examination
Examination BETN (# EA 101) ツ性 Test No. : ド o キン映を蔵メ付し
15 Nov 2010 9 : 01 ( # STL3498)
15 Nov 2010 8 : 59 Operator : 　E. Yukita
　　　　　　　　　　　　　Operator : Operator AX205DR 15 Nov 2010 9 : 38
Operator E. Yukita Tenbin EB062-HAP Operator : E. Yukita
　　　　　　　　　　　　　AX205DR Operator AX205DR
Tenbin EB062-HAP 5.35 mg Tenbin EB062-HAP
5.23 mg 15 Nov 2010 9 : 02 10.28 mg

1-Operator 　　E. Yukita
15 Nov 2010 8 : 59 　　　　　　　　　　　　　AX205DR 15 Nov 2010 9 : 40
1-Operator Katashiki EB062-HAP 1-Operator 　　E.
E. Yukita 0.0 Tenbin Yukita
Katashiki AX205DR mg Katashiki EB062-HAP
Tenbin EB062-HAP Tenbin 　　　 EB062-HAP
0.0 mg 0.0 mg
(税行子田). (茂魔樹田)． (税行子田).(茂魔樹田) 　　　 (税行子田).(茂魔樹田)
2010.11.15 2010.11.15 2010.11.15
Production instructions・Record No. : 10HA-SM010

Test No. : 16/43
Test data sheet ② ASB17061　BETN steps　 Production

Manager
Process control test 一 4 Confirmation of reaction (茂魔樹田）.

completion
2010.11.15
Lot No. EA102 – U
Date of testing : : Year 2010 Month 11 Day 15
Tested by : Sutekuro-shō eru Confirmed by : Akira Yano．
HPLC control NO. : HPLC059-HAP
reaction 終点確認管理値: BTTN /BETN 0.010 or more.
Chart No. reaction time BTTN area BETN area BTTN /BETN Decision
10111505 1.0 h 423.972 1932.387 0.2194  0.219 Appropriate

Not appropriate
10111506 2.0 h 127.424 2293.896 0.0555  0.056 Appropriate
Not appropriate
10111507 3.0 h 38.457 2409.826 0.0159  0.016 Appropriate
Not appropriate
10111508 4.0 h 11.930 2405.173 0.0049  0.005 Appropriate
Not appropriate
h Appropriate
Not appropriate
h Appropriate
Not appropriate
< BTTN /BETN CALCULATION FORMULA >

BTTN area
BTTN / BETN= BETN area (Rounded to the fourth decimal place)
Decision
Decision criteria : BTTN / BETN IS 0.010 OR LESS
 Appropriate : reaction time h BTTN / BETN IS 0.010 OR LESS at the time, so move to the next operation.
 Not appropriate : BTTN / BETN exceeds 0.010 then follow the instructions provided for by the Production Manager.
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　（税行子田） (茂魔樹田)
2010.11.15 2010.11.15
Sample name BETN PROCESS Process control test－4 reaction 1.0h

Analysis conditions ASB17061 (9-10 steps ) 狽'1 定 Condition
column : Shiseido Capcell Pak C8 DD 3 μ m 4.6 x 100 mrn (Lot No. BLAA01015)
Temperature : 40 °C Detection : 230 nm Flow rate : approx. 1.0 mL/min Infusion : 10 μ L
Mobile phase A : 0.01M Ammonium acetate aqueous solution Mobile phase B : Acetonitrile
A : B = 65 : 35 (0 min)  5 : 95 (30 min) → 65 : 35 (30.01 min)  65 : 35 (40 min)
Date and time of 11/15/2010,13 : 16 : 28

measurement
Control No. ID No. HPLC059-HAP (Formerly known as ID No. 30235-205)
Infusion 1/1
Method name ASB17061 (#EA102) 9-10 steps for measurement condition
VWD : Absorbance

2.515 26.100 4.603 1.049 % 0.088
minutes minutes
21.505 13.479 1.763 0.542 0.114
minutes minutes
23.000 BTTN 423.972  60.404 17.047 0.107
minutes minutes
23.976 67.404 8.752 2.710 0.114
minutes minutes
25.462 BETN 1932.387  276.755 77.699 0.106
minutes minutes
26.552 5.360 0.806 0.216 0.101
minutes minutes
27.467 18.327 1.710 0.737 0.167
minutes minutes
Total 2487.030 354.792
Page 1 of 1 2010/11/15 13 : 58 : 03
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　（税行子田） (茂魔樹田)
2010.11.15 2010.11.15
Sample name BETN PROCESS Process control test－4 reaction 2.0h

Analysis conditions ASB17061 (9-10 steps ) Confidence condition
Equipment No. : HPL0059-HAP
力ラム : Shiseido Capcell Pak 08 DD 3 μ m 4.6 x 100 mm (Lot No. BLAA01015)
Mobile phase A : 0.01 MAmmonium acetate aqueous solution Mobile phase B : Acetonitrile
A : B = 65 : 35 (0 min)  5 : 95 (30 min) →65 : 35 (30.01 min)  65 : 35 (40 min)
Date and time of 11/15/2010. 14 : 15 : 51
measurement
Infusion 1/1
Method name ASB17061 (#EA102) 9-10 steps Process measurement condition
VWD : Absorbance

2.520 26.099 4.595 0.021 % 0.088
minutes minutes
20.110 5.135 0.646 0.201 % 0.117
minutes minutes
20.912 4.927 0.595 0.193 % 0.131
minutes minutes
21.134 4.028 0.546 0.158 % 0.118
minutes minutes
21.516 14.304 0.964 0.560 % 0.111
minutes minutes
22.603 4.782 0.663 0.187 % 0.117
minutes minutes
23.005 BTTN 127.424  18.285 4.987 % 0.107
minutes minutes
23.982 68.749 8.716 2.691 % 0.116
minutes minutes
25.467 BETN 2293.896  327.938 89.776 % 0.106
minutes minutes
26.556 5.779 0.893 0.226 % 0.100
minutes minutes
Total 2555.121 364.840
Page 1 of 1 2010/11/15 14 : 57 : 26
　　　（税行子田） (茂魔樹田)
2010.11.15 2010.11.15
Sample name BETN PROCESSProcess control test－4 reaction 3.0 h

Analysis conditions ASB17061 (9-10 steps ) Measurement condition
力ラム : Shiseido Capcell Pak C8 DD 3 μ m 4.6 x 100 mm (Lot No. BLAA01015)
A : B = 65 : 35 (0 min)  5 : 95 (30 min)  65 : 35 (30.01 min)  65 : 35 (40 min)
Date and time of 11/15/2010, 15 : 17 : 47
measurement
Infusion 1/1
VWD : Absorbance

2.519 26.230 4.621 1.013 % 0.088
minutes minutes
20.107 5.620 0.730 0.217 % 0.115
minutes minutes
20.907 8.241 0.996 0.318 % 0.130
minutes minutes
21.130 4.340 0.591 0.168 % 0.119
minutes minutes
21.511 14.924 2.063 0.576 % 0.111
minutes minutes
22.599 6.149 0.816 0.238 % 0.119
minutes minutes
22.999 BTTN 38.457  5.569 1.485 % 0.107
minutes minutes
23.977 69.144 8.693 2.671 % 0.116
minutes minutes
25.461 BETN 2409.826  344.250 93.086 % 0.106
minutes minutes
26.552 5.889 0.910 0.227 % 0.100
minutes minutes
Total 2588.820 369.239
Page 1 of 1 2010/11/15 15 : 59 : 23
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　（税行子田） (茂魔樹田)
2010.11.15 2010.11.15
Sample name BETN PROCESSProcess control test4 reaction 4.0 h

Analysis conditions ASB17061 (9-10 steps ) Process measurement condition
Column : Shiseido Capcell Pak C8 DD 3 μ m 4.6 x 100 mm (Lot No. BLAA01015)
Temperature : 40 °C Detection : 230 nm Flow rate : approx. 1.0mL/min Infusion : 1 μ L
A : B = 65 : 35 (0 min)  5 : 95 (30 min)  65 : 35 (30.01 min)  65 : 35 (40 min)
Date and time of 11/1 5/2010, 16 : 17 : 13
measurement
Infusion 1/1
VWD : Absorbance

2.518 26.074 4.595 1.018 % 0.888
minutes minutes
20.110 6.151 0.794 0.240 % 0.116
minutes minutes
20.910 10.839 1.307 0.243 % 0.129
minutes minutes
21.315 4.623 0.624 0.181 % 0.124
minutes minutes
21.516 15.878 2.190 0.620 % 0.111
minutes minutes
22.604 6.6716 0.874 0.260 % 0.120
minutes minutes
23.004 BTTN 11.930  1.756 0.466 % 0.106
minutes minutes
23.980 67.829 8.524 2.648 % 0.116
minutes minutes
25.464 BETN 2405.173  343.562 93.912 % 0.106
minutes minutes
25.553 5.920 0.910 0.213 % 0.100
minutes minutes
Total 2561.086 365.135
Page 1 of 1 2010/11/15 15 : 58 : 48
Product name : ASB17061 Production instructions・Record No. : 10HA-SM010 1/1
batch No EA102-U Equipment Washing 14/19
BETN PROCESS
製造茸任者
[Equipment cleaning 一 14] reaction kettle (K201) Washing (At the same time, it also cleans the wood
(茂魔樹田)
used.) 2010.11.25
1. Purpose : Washing between steps reaction kettle : K201 hose Tag. No. : 2B608
2. Contents of use 2010.11.22 2010.11.22

Before cleaning the contents of use : reaction 4-1 Start date and time : 14 : 00 End date and time :
After cleaning the contents of use minute liquid in ASB17061 14 : 15
steps Confirmed by : Ka. N.
3. Cleaning effect confirmation by test 2010.11.22 2010.11.22

visual Confirmation by test, dissolution test (Follow the 4-2 Start date and time : 14 : 24 End date and time :
cleaning evaluation test between BETN steps) 15 : 00
4. Cleaning method
2010.11.24 2010.11.24
4-1 Nitrogen substitution the inside of the kettle, hang it with 4-3 Start date and time : 9 : 18 End date and time :
metal to wash it, and then wash it with running water. 9 : 33
Confirmed by : Y. SN.
4-2 Enter the kettle (L), use a cleaning tool to wash the kettle
wall, large flange, agitated horse chestnut 1/7) with running 2010.11.24 2010.11.24
water. 4-4 Start date and time : 9 : 18 End date and time :
9 : 33
4-3 Remove the bottom valve from the hook at the affairs Visual Confirmation by test Decision : Appropriate.
section. Confirmed by : Y. S.
4-4 Clean the bottom valve of the hook and visually check it. 2010.11.24 2010.11.24
4-5 Restore the bottom valve at the Construction Department. 10 : 00
4-6 Perform a leak test (nitrogen pressurization 0.1 MPa).
2010.11.24 2010.11.24
4-7 After Nitrogen substitution in the kettle, metal with a 4-6 Start date and time : 10 : 05 End date and time :
nominal capacity of about 10% is sent from the outlet side of 10 : 45
the reflux line via C denser and refluxed for 30 minutes or Confirmed by : Ka. N.
more. ,the valve is also filled and washed.
2010.11.24 2010.11.24
4-8 After cooling, perform Sun 701 rug and discharge. When 4-7 Start date and time : 13 : 05 End date and time :
discharging, visually check for foreign matter and coloring 13 : 55
(If visual confirmation by testis not appropriate, then follow Confirmed by : Ka. N.
the instructions provided for by the Production Manager)
2010.11.24 2010.11.24
4-9 Perform dissolution test for the sampled liquid. (If the 4-8 Start date and time : 14 : 10 End date and time :
dissolution test is not appropriate, then follow the instructions 14 : 18
provided for by the Production Manager) Visual Confirmation by test Decision : Appropriate．
4-10 Inside the kettle, dry the wood soup and visually check
after drying. 2010.11.24 2010.11.24
15 : 10
Confirmed by : Y. S.
2010.11.25 2010.11.25
20 : 00
Confirmed by : Y. S.
Remarks: None
Operator’s 中た AppropriateKa. N.Appropriate 天田釆えＹ.Ｓ

remarks with
signature
BETN (Dissolution)
Measurement result data sheet

HPLC ID No. : HPLC057-HAP
Electronic balance ID No. : EB062-HAP
Device name : K201, hose （1 stock） sampling : 1 Time
internal area of the equipment : 27.028 m2 Tolerance limit : 0.05 mg / 100 cm2 : mg
2010.11.24 Y. S.
Formula 1: Residual concentration C (mg/L) =[ (C 1-C2) X (Qt-Qs) / (QS1-QS2) + C1] ASB17071

Calculation Formula 2: Residual value (mg/100 cm ) = (Residual concentration C (mg/L) ) x Solvent quantity (L)
2
/{ (internal area of the equipment (m 2) x 100} 60.4 kg

C (mg/L) : In the sample solution Residual concentration of (BETN, related material)
C1 (mg/L) : Standard solution－1 BETN concentration C2 (mg/L) : Standard solution－2 BETN concentration
30.2 g
Qs1 : Standard solution－1 BETN Peak area Qs2 : Standard solution－2 BETN Peak area
Qt : In the sample solution BETN Peak area and Peak area calculated values of related substances
Solvent quantity (L) : Solvent quantity used for cleaning
Chart No.
Blank solution 10112405 Standard solution 10112403 Standard solution 10112404

－1 －2
Standard solution
standard product lot W (mg) F (%) Qs1 Qs2

No.
TC-204 21.83 100 76.890 7.616
C1 (mg/L) : W x (F/100) ｘ (1/4) W : standard product sampling quantity (mg)
C2 (mg/L) : C1 x (1/10) F : Total standard product content (%)
C1 (mg/L) = (W) 21.82 ｘ ( (F) 100 /100) /4 = 5.455  5.46 mg/L
C2 (mg/L) = (C1) 5.46 ｘ 1/10 = 0.546  0.55 mg/L (Rounded off to the third place of the decimal point)
Formula 1 : Residual concentration C (mg/L) ※ Usage of quantitative limit concentration Formula 0.05
(mg/L)
Sample solution Solvent quantity Qt Formula 1 : C (mg/L)

chart No. (L) BETN Related BETN Related
substances  Usage of substances
quantitative limit (Reference
concentration value)
10112406 150 27.596 12.020 1.966  1.97 0.862  0.86
Formula 2 : Residual quantity (mg/100cm2) 1.97 mg/L x 150 L = 295.5 mg 残雄量

・BETNResidual quantity = C 1.97 (mg/L) x 150 (L) / { 27.028 (internal area of the equipment (m 2) ) x 100 }
0.109  0.11 (mg/100 cm2)
(Rounded to the third decimal place)
・Related substancesResidual quantity (Reference value) = C 0.86 (mg/L) x 150 (L) / { 27.028 (internal area
of the equipment (m2) ) x 100 }
= 0.047  0.05 (mg/100 cm2)
The residual concentration C (mg / L) of BETN is below the limit of quantification, or ND. In the case of, the limit concentration
(*) for quantification is used as the residual concentration, and the residual amount (mg / 100 cm?) Of formula 1: C (mg / L) is
calculated.

 Usage of quantitative limit concentration Residual quantity = C ________ (mg/L) x (L) / { Production
(internal area of the equipment (m2) ) x100 } Manager
= (mg/100 cm2) (茂魔樹田)
Decision
 Tolerance limit or less (residual value) ≤ 0.05mg/100 cm2) Therefore, the post-cleaning is completed. 2010.11.24
 Tolerance limit (Residual value > 0.05 mg/100 cm 2) Since it exceeds the above, perform re-cleaning..
6
　　　　　　　　　　　　　　　　　　　　(税行子田) 　　　 (茂魔樹田)　
2010.11.24 2010.11.24

Sample name BETN process steps during cleaning evaluation test of the sample solution (K201, hose)
Analysis conditions BETN process steps during cleaning evaluation testAnalysis conditions
力ラム : Cadenza CD-C18 (3.0f x 50 mm, 3 μ m #JC16A9L)
Sample cooler temperature : 10 °C Mobile phase A : MeCN : water＝9 : 1
Date and time of 11/24/2010, 14 : 44 : 36
measurement
Control No. ID No. HFLCOS7-HAP (Formerly known as ID No. 30235-203)
Infusion 1/1
Method name BETN (#EA102-U) process steps during cleaning evaluation test
VWD : Absorbance

0.447 3.324 0.649 6.545 % 0.082
minutes minutes
0.623 2.304 0.864 4.537 % 0.042
minutes minutes
0.742 3.331 0.644 6.559 % 0.096
minutes minutes
0.869 6.998 1.063 13.779 % 0.091
minutes minutes
1.570 3.162 0.322 6.226 % 0.221
minutes minutes
2.531 4.074 0.356 8.021 % 0.184
minutes minutes
2.825 BETN 27.596  3.973 54.335 % 0.106
minutes minutes
Total 50.789 7.870
Page 1 of 1 2010/11/24 14 : 52 : 09
BETN (Dissolution)
Qt value [Related substances] Calculation sheet (blank correction calculation)

Device name : K201, hose Sampling : 1st time
(税行子田) (茂魔樹田)
2010.11.24 2010.11.24

1 0.447 3.324 1.871 1.453
(signed)
2010.11.24
E. Y.
2 0.623 2.304 2.793 0
3 0.742 3.331 0 3.331
4 0.869 6.998 9.500 0
5 1.570 3.162 0 3.162
6 2.531 4.074 0 4.074

If the Qt value is (1: minus), enter “Ui” in the Qt value field..
Production
Manager
(茂魔樹田)
2010.11.24
5
( 税行子田) (茂魔樹田 l)
2010.11.24 2010.11.24
Sample name BETN process steps during cleaning evaluation testBlank solution
Analysis conditions BETN process during cleaning evaluation testAnalysis conditions
Temperature : 40 °C Detection: 225 nm Flow rate : approx. 0.5 mL/min Infusion : 5 μ L Sample cooler
temperature : 10 °C
Date and time of 11/24/2010, 13 : 38 : 18
measurement
Infusion 1/1
VWD : Absorbance

0.436 1.871 0.381 11.983 % 0.065
minutes minutes
0.622 2.793 0.972 17.889 % 0.045
minutes minutes
0.871 9.500 0.969 60.847 % 0.089
minutes minutes
1.196 1.449 0.141 9.281 % 0.264
minutes minutes
Total 15.612 2.463
Page 1 of 1 2010/11/24 13 : 45 : 49
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　(税行子田) 　　　 (茂魔樹田)
2010.11.24 2010.11.24
(explanatory note)2010.11.24 E. Y.
Sample name BETN System compatibility test Standard solution－2

Analysis conditions BETN process steps during cleaning evaluation testAnalysis conditions
Temperature : 40 °CDetection : 225 nm Flow rate : approx. 0.5 mL/min Infusion : 5 μ L
Sample cooler temperature10 °CMobile phase A : MeCN : water ＝ 9 : 1
Date and time of 11/24/2010, 12 : 28 : 23
measurement
Infusion 1/1
Method name BETN (#EA1 02-U) process steps during cleaning evaluation test
VWD : Absorbance

0.440 2.579 0.448 11.901 % 0.074
minutes minutes
0.626 3.167 1.046 14.614 % 0.047
minutes minutes
0.877 8.311 0.970 38.345 % 0.083
minutes minutes
2.858 BETN 7.616  1.103 35.140 % 0.107
minutes minutes
Total 21.673 3.568
Page 1 of 1 2010/11/24 12 : 35 : 57
Washing between steps 秤量記録 1/1
Sample weighing record 1/1
Date of testing : : 2010.11.24 Lot No. : EA102 – U

Balance control No. : EB062-HAP Confirmed by : Akira Yano．
Tested by : ステムロ　小える.
(税行子田)
ASB17061
BETN PROCESS goods (# TC-204)
24. Nov 2010 11 : 20

Operator 　　　　　　　　　E. Yukita
Katashiki AX205DR
Tenbin　　　　　　　　　EB062-HAP　　　　　　　
21.82 mg
24 Nov 2010 11 : 21
Operator E. Yukita
Katashiki AX205DR
Tenbin EB062-HAP
0.0 mg 
(税行子田) 　　　 (茂魔樹田)　
2010.11.12
BETN (Dissolution)
BETN process steps during cleaning evaluation test (Dissolution Test)
1.Purpose :
BETN process steps during cleaning evaluation test.

2-1 Minute analysis
GMP Equipment Registered High Performance Liquid Chromatography (Hereafter, HPLC is used. The operation is
performed according to the standard Operation procedure manual..
column : Cadenza CD-C18 (3.0 ϕ x 50 mm, 3 μ m Intakt ( stock) Made by )
column tempreatur : 40 °CConstant temperature in the vicinity
Mobile phase : MeCN / Water mixture (9 : 1)
Flow rate : Approximately 0.5 mL / min (BETN Retention time : approx. 2.8 minutes)
Detection : 225 nm
Minute analysis time : 6 min
Minute analysis parameter : Make an appropriate strict setting for the HPLC and measurement conditions used

1) Mobile phase
Mix MeCN with distilled water or ultrapure water at a volume of 9: 1.
2-4 Chart numbering
Enter the Chart No. on all HPLC measurement charts.
Chart No. indicates the 8-digit number of the Christian era (last 2 digits) + Infusion month and day (4 digits) + same day serial
number (2 digits).
Example) In the case of the third Infusion on the xx day of XX month of 20 △△, the numbering will be [△△ 〇〇 x x 03].

3-1 Expiration date of System compatibility test
The result of the System compatibility test is valid as long as the HPLC Appropriated to the System compatibility test is
continuously in the steady operation state. The end of the "steady operation state" here means the following state.
3) While replacing the force ram
3-2 Confirmation of retention time
1) Weigh about 20 mg of standard BETN in a 100 mL volumetric flask, dissolve in Sample dissolution solution, and
measure up.
2) Accurately weigh the solution of 1) with a 5 mL measuring pipette, transfer to a 20 mL measuring flask, and measure
up with a Sample dissolution solution.
3) Weigh the solution of 2) accurately with a 5 mL measuring pipette, transfer it to a 50 mL measuring flask, and
measure it with Sample dissolution solution to make a measurement solution.
4) Infuse 5 μL of the prepared measurement solution into HPLC and perform minute analysis under 1 rule condition of
2.2-2. Enter the obtained Retention time in System compatibility test data sheet 1) and retention time. Make sure that is within
the decision criteria.
1
BETN (Dissolution)

1) From the measurement results for which the retention time was confirmed in 3-2, enter the obtained retention time and peak
height of 50% in the system Appropriate compatibility test No.: Data sheet 2), obtain the theoretical plate (N), and N is 1000.
Confirm that it is the above.
2) If N is less than 1000, measure again after the baseline stabilizes, or replace the force ram and mobile phase according to the
instructions of the Production Manager, and then measure again.
Theoretical plate (N) = TR = ＝Retention time

W0.5 ＝Peak width 50 %

1) The measurement result in which the theoretical plate was confirmed in 3-3 and then the measurement solution of 10 μL was
repeatedly infused into HPLC twice in succession.
2. Perform minutes analysis under the Measurement condition of 2-2 (Measurement repeated 3 times in a row in total). 2)
System compatibility test data sheet of the obtained peak area.
Fill in 3), determine the Relative standard deviation ((RSD), and confirm that the RSD is 2.0% or less. 3) If the RSD exceeds
2.0%, measure again after the baseline stabilizes, or Production. After exchanging the force ram and mobile phase according to
the instruction of the manager, measure again.
Relative standard deviation (RSD) = n = Number of measurements

Xi = i-th measurements
XAVE =Average value
4. Cleaning evaluation test
1) 3. 3-4 The final measurement result used to calculate the Confirmation by of the infusion reproducibility is defined as
standard solution-1.
2) 3. 3-1 Accurately weigh the measurement solution prepared in 1 with a 5 mL measuring pipette, transfer to a 50 mL
measuring flask, and dissolve the sample.
Use a volumetric flask to make a standard solution-2.
3) Infuse the prepared Standard solution-25 μL into HPLC and perform minutes analysis under the Measurement
condition of 2.2-2.
Standard solution concentration C1, C2 and the BETN peak area value in the standard solution Qs 1, Qs2.
W : standard product of the BETN sampling quantity C1 (mg/L) F : Standard product BETN quantity (%)
Standard solution－1 BETN concentration C1 (mg/L) = W x (F/100) x (1/4)
Standard solution－2 BETN concentration C2 (mg/L) = C2 x (1/10)
4-2 Blank solution minute analysis
1) Sampling solvent used for cleaning.
2) Weigh this solution with a 10 mL volumetric pipette, transfer to a 100 mL eggplant flask, and concentrate and dry..
3) Sample dissolution solution を 10 rn1LWeigh with a whole pipette), and irradiate ultrasonic waves as needed.
4) Infuse 5 μL of this solution into HPLC and perform minute analysis under the Measurement conditions of 2.2-2.
4-3 Minute analysis of the sample solution
1) Sampling the cleaning solution for the dissolution test.
2) Weigh this solution with a 10 mL volumetric pipette, transfer to a 100 mL eggplant fresco, concentrate and dry.
3) Weigh 10 mL of the test solution with a 1 hole pipette and irradiate with ultrasonic waves as necessary.
4) Infuse 5 μL of this solution into HPLC and perform minute analysis under Measurement conditions of 2.2-2.
5. Test calculation of results

The Qt value is shown in the Test :chart, BETN is peak area value, related substances are all peaks except BETN.
The Qt value of related substances is the area value of of the sample solution other than BETN and the area value of
Blank solution. Qt value [Related substances]
Fill in the calculation sheet (blank correction calculation), obtain the Qt value, and post it to the related substancesat in
the Measurement result data sheet.
Each at value = Peak area value of of the sample solution - Peak area value of Blank solution 2
BETN (Dissolution)
Enter each value in the measurement result data sheet and perform the Calculation of results according to the following
Formula ..
Calculation Formula 1 Residual concentration C (mg/L) = [ (C 1-C2) x (Qt-Qs1) / (Qs1-Qs2) +C1]
C (mg/L) : In the sample solution Residual concentration of (BETN, related material)
C1 (mg/L) : Standard solution－1 BETN concentration
C2 (mg/L) : Standard solution－2 BETN concentration
Qs1 : Standard solution－1 BETN peak area
Qs2 : Standard solution—2 BETN Peak area
Qt : Calculated peak area of BETN and related substances in sample solutionResidual value C' of
related substances is calculated as reference value.
Formula 2 Residual value C' (mg/100 cm2) = [BETN C (mg/L) ] x Amount of Solvent (L) / (internal area of the equipment (m 2)
x100)
Solvent quantity (L) ＝ Solvent quantity used for cleaning
If BETN's residual concentration C (mg / L) is less than or equal to the capacity limit value'or N.D., use the capacity limit
concentration as the residual concentration .
Formula :
1 : C (mg/L) of Shelf: Check. The Formula below Check the fence and BETN's residual quantity (mg/100 cm 2)
and calculate it.
Residual value C' (mg/100 cm2) ＝ Quantitative limit concentration C (mg/L) x Solvent quantity (L) / { (internal area of
the equipment (m2) ) x 100 }
Solvent quantity (L) ＝Quantity of solvent used for cleaning
6. Decision
The residual value of BETN is ASB17061 製造量に対 0.05 % Make sure it is less than the Measurement result data
sheet
Tolerance limit ______________ Check the fields below to complete the cleaning.
If the residual value of BETN is 0.05% or more, it is equal to or more than the Tolerance limit of the Measurement result data
sheet. Check the box and perform re-cleaning according to the order of Operation Hand 1.
3
BETN (Dissolution)
System compatibility test data sheet

Tested by Confirmed
HPLC ID. No. HPLC057-HAP Balance management ID No. : EB062-HAP by
BETN　Lot No. TC-204 column lot No. : JC16A9L (税行子田) (茂魔樹田)

System compatibility test 2010.11.24 2010.11.24
Retention time and confirmation of the theoretical plates Chart No. 10112401
Retention time Peak area Peak width 50 %

(2.52 ~ 3.08 min)
BETN 2.843 77.339 0.108 ✓
< BETN の Theoretical plate >
(Rounded to the 4th significant digit)
. Decision criteria : more than 1000 Decision :  Appropriate  Not appropriate
3) Infusion reproducibility
Peak area value Measurement solution Average value : 77.130 

chart No.
n=1 : 77.339 10112401 RSD : 0.3 %
n=2 : 77.161 1011202 Decision :  Appropriate (less than 2.0 ％)  Not appropriate
n=3 : 76.890 10112403
Formula
く Average value>
Ｘ = ( 77.339 + 77.161 + 77.890 ) / 3 = 77.1300   77.130 
く Relative standard deviation (RSD) >
= 0.29   0.3  %
Decision
 Appropriate : Since this minutes analysis system is in a state of being prepared as a system, Preparation of sample solution
and minutes analysis are started.
Production
 Not appropriate : Since this minutes analysis system is in an undeveloped state as a system, the Manager
following Operation is performed.
(茂魔樹田)
Not appropriate content  Remeasured after seeing the stability of the baseline.
2010.11.24
 Replace Columns, or re-arrange the Mobile phase, etc..
 Miscellaneous ( _________________________________________ )
4
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　(税行子田) 　　　　　(茂魔樹田)
Sample information Lot No. 10112401 　2010.11.24 2010.11.24
Sample name BETN System compatibility test of the theoretical plate as well as confirmation by of the infusion
reproducibility n-1
BETN process steps during cleaning evaluation testAnalysis conditions
Analysis conditions 力ラム : Cadenza CD-C18 (3.0f x 50 mm, 3 μ m #JC16A9L)
Date and time of 11/24/2010, 12 : 05 : 36
measurement
Control No. IDNo. HPLCOS7-HAP (Formerly known as ID No. 30235-203)
Infusion 1/1
VWD : Absorbance

0.439 3.035 0.594 3.066 % 0.068
minutes minutes
0.624 2.976 1.014 3.007 % 0.046
minutes minutes
0.874 13.488 1.230 13.628 % 0.102
minutes minutes
1.366 2.143 0.341 2.156 % 0.087
minutes minutes
2.843 BETN 77.339  11.136 78.143 % 0.108
minutes minutes 
Total 98.971 14.316
Page 1 of 1 2010/11/24 12 : 13 : 09
　　　　(税行子田) 　　　(茂魔樹田)
Sample information Lot No. 10112402 　　　　2010.11.24 　　

2010.11.24
Sample name BETN System compatibility test confirmation by the infusion reproducibility n-2
Analysis conditions 力ラム : Cadenza CD-C18 (3.01 x 50 mm, 3 μ m #JC16A9L)
Temperature : 40 °C Detection : 225 nm Flow rate 約 0.5mL/min Infusion : : 5 μ L Sample cooler
temperature : 10 °C
Date and time of 11/24/2010,12 : 13 : 11
measurement
Infusion 1/1
VWD : Absorbance

0.441 2.234 0.402 2.285 % 0.072
minutes minutes
0.627 3.004 1.017 3.073 % 0.046
minutes minutes
0.878 13.201 1.224 13.506 % 0.101
minutes minutes
1.369 2.142 0.342 2.191 % 0.086
minutes minutes
2.851 BETN 77.161  11.124 78.944 % 0.107
minutes minutes 
Total 97.742 14.109
Page 1 of 1 2010/11/24 12 : 20 : 44
Sample name BETN System compatibility test confirmation by the infusion reproducibility n-3
Analysis conditions 力ラム : Cadenza CD-Cl 8 (3.0f x 50 mm, 3 μ m #JC16A9L)
Mobile phase A : MeCN : water＝ 9 : 1
Date and time of 11/24/2010,12 : 20 : 47
measurement
Infusion 1/1
VWD : Absorbance

0.439 1.491 0.224 1.539 % 0.086
minutes minutes
0.626 2.975 1.008 3.070 % 0.046
minutes minutes
0.877 12.278 1.233 13.705 % 0.102
minutes minutes
1.369 2.253 0.344 2.325 % 0.088
minutes minutes
2.839 BETN 76.890  11.083 79.361 % 0.107
minutes minutes
Total 96.887 13.892
Page 1 of 1 2010/11/24 12 : 28 : 21
2010/11/24 12 : 07 : 12
Device (税行子田) 　　　(茂魔樹田)　
　　2011.11.24 　　2011.11.24

Solvent A : H2O Ratio : 10.0 % Stroke: Automatic Compression rate : 100 μ bar^-1
SolventB : MeCN Ratio : 90.0 % Stroke: Automatic Compression rate : 105 μ bar^-1
Flow rate : 0.500 mI/min Maximum Flow rate lamp: 100.0 mI/min
Time B ratio Flow rate 圧力

rate

point 3
G1314A VWD DEVICE 1

Analog zero : 5.00 % Analog attenuation : 1000 mAU
Time : Wavelength Balance


point 3
G1316A DEVICE 1 TCC

Page 1 of 2
2010/11/24 12 : 07 : 12
Individual heat exchangers : one (税行子田) 　　　(茂魔樹田)　
Stop time : No limitation Delay time : 0.000 minutes 　　2010.11.24 　　2010.11.24
Time : Left Right Column valve

G1329A DEVICE 1 ALS

Infusion count volume : 5.0 μ L Discharge speed : 200 μ l/mm
Suction position : 0.0 Suction speed : 200 μ l/mm
Injector program
Command
Page 2 of 2
2010/10/25 None 9 : 14 : 57
BETN minute product (# EA102-U) process steps during

cleaning evaluation test (8)
Created on : 06/07/2010, 10 : 40 : 20
Modified on : 10/24/2010, 12 : 02 : 56
2010.11.24 2010.11.24
Tangent skim mode : standard
Peak / Valley Ratio : 500.0000
VWD1AEvent
Peak width : 0.100
VWD EVENT

Page 1 of 1
Product name : ASB17061 Production instructions・Record No.： 10HA-SM010 Preparation 14/16
batch No: EA102-U Preparation amount calculation list
ASB16726 steps
BETN Preparation weight (kg) = 91.60 kg
< 4M HCI/Production of EtOAc > Preparation of calculation standard of BTTN Gross weight standard
Operation <*2 > EtOAc ( x 5.1 vol )
BTTN weight Preparation (kg) x 5.1 = 91.60 x 5.1 = 467.1  467 L
Operation < *4 > HCI ( x 18 eq)
BTTN weight Preparation (kg) x

HCI molecular weight x 18
91.60 x 36.46
= 799.33 x 18 = 75.207  75.21 kg
Drafted by Confirmed by Production

Manager
2010.11.12 2010.11.12 2010.11.12
(明兵野) (茂魔樹田) (茂魔樹田)

Crystal formation name : ASB17061 Production instructions / records of Haraku clinical trial フロ– 52/52
batch No：ＥＡ１０２－Ｕ Document No.: 10HA-SM010
ASB16726 steps Date of working : 2010.11.16 ~ 2010.11.22
< 4 M HCl /Production of EtOAc >
Standard calculation of BTTN gross weight quantity Preparation
1000 L　GL reaction kettle (K203) < *1 > Time : 16 ： 20
Oxygen concentration : 0.5 % ( ≤ 5%)
[Nitrogen substitution] < *1 > .............................................................. Confirmation by ：A． Y． Ka.
Oxygen concentration 5% or less N.
ＡｃＯＥｔＡ 467 L  [Note] < *2 > < *2 >
( Standard standard 481L) < x 5.1 vol > Time Internal Internal Internal Remarks
[ °C ] [ °C ] SV [ °C ]
[Holding pressure cooling] < *3 16 : 31 17.2 17.9 —

5 °C 以下：40 17.2 17.9 —
...................................................... Confirmation by ：A． Y． Ka. N.
HCl 75.21 kg  [Addition] < *4 > < *3 >
(standard 77.42 kg) < x 1.8 eq > 5 °C 以下 Time Internal Internal Internal Rotatio Remarks
temperature temperature temperature n speed
Process control test – 10 [ °C ] [ °C ] SV [ rpm ]
　　　　　　HCl concentration measurement [ °C ]
HCl concentration is 4.0 ~ 4.4 M (mol/L) 9 : 05 17.1 17.9 -5.0 30
15 : 19 -3.2 -5.0 -5.0 60
4 M HCl /EtOAc :
........................................................... Confirmation by ：A． Y． Ka. N.
< *４> ２０１０．１１．１６
15:20　Internal temperature of HCl main blown air start　－3.2 °C
=50 Internal temperature of HCl bowed in air = 0.5℃ HCl book ＝ 10.50 kg
＝５５ HCl 2nd blown start internal temperature 1.5℃
１６＝２８ Internal temperature of the blowed in air = 1．6℃ HCl quantity＝１０.４８ k ｇ
Ｔｏｔａｌ＝２０．９８ｋｇ.
＝３５ HCl Internal temperature of the 3rd blowed in air start = 0.5 ℃
１７＝１０ Internal temperature of the blowed in air = 2.2 ℃
HCl quantity ＝１１．１３ｋｇ
Ｔｏｔａｌ＝３２．１１ｋｇ
＝１５ HCl Internal temperature of the 4th blowed in air = 0.8 ℃
=49 Internal temperature of the end of blowed in air = 2.4 ℃
HCl quantity＝１１．５２ｋｇ
Ｔｏｔａｌ＝４３．６３ｋｇ
１８＝１５ HCl Internal temperature of the 5th blowed in air start = 2.3 °C
Instructions ＝４６　Internal temperature of the blowed in air = 0.4 ℃
Production HCl quantity＝１０．６１ｋｇ
Ｔｏｔａｌ＝５４．２４ｋｇ
Manager ＝５５ HCl ６ Internal temperature of the blowed –n air start = 1.9℃
１９＝２９ Internal temperature of the blowed in air end = 0.3 ℃
(茂魔樹田) HCl quantity＝１０．５０ｋｇ
Ｔｏｔａｌ＝６４．７４ｋｇ
＝４０ Internal temperature = 2.1 ℃ Internal temperature = 5.5 ℃
2010.11.15 supporting group
２０１０－１１－１７
１３＝３０ HCl Internal temperature of the 7th blowed in air = 4.6 ℃
＝５１ Internal temperature of the blowed in air end = 2.0 ℃
HCl quantity＝６．６３ｋｇ
Ｔｏｔａｌ＝７１．７３ｋｇ
＝５６ HCl Internal temperature of the 8th blowed in air = ２．８℃
１４＝０７ Internal temperature of the blowed in air end = 1.9 ℃
HCl quantity＝３．８８ｋｇ
Total＝７５．２５ｋｇ
approx. 3.9 Ｎ
　　　　　　ｘｘｘｘｘｘｘｘｘｘｘｘｘｘｘ
１６＝００ HCl Internal temperature of the 9th blowed in air start = 4.5 ℃
＝１５ Internal temperature of the blowed in air end = 2.8 ℃
HCl quantity＝４．５ｋｇ
Ｔｏｔａｌ＝７９．７６ｋｇ
=３０ Internal temperature = 4.1℃ Internal temperature = 5.0 ℃
Internal SV temperature＝10.0 supporting group
approx.4.0 N .............. Additional quantity : 79.76 kg
　　　　　　　　　　　　　　　　　　Confirmation by ：A． Y． Ka. N.
Process control test－１０ HCl concentration measurement
Confirmation Measurement result Decision Decision
time value
１４：４０４．0 M (mol/L) ４.0 ~ ４.４ Appropriate.
※ Until the Decision value is satisfied, repeat < *4 >
Operator’s signature Akira YanoA.Y 中たゆ xxxKa. N.太田蔵樹Ａ．Ｙ

with remarks
Product name : ASB17061 Lot No. ：EA102-U No. ：10HA-SM010 Test No. : １/３
ASB17061. ASB16726 steps
HCL concentration measurement
Process control test 一 10 Test data sheet ①
1. Purpose :
In the Preparation of 1-HCl / EtOAc used in ASB16726 steps, measure the HCl concentration in EtOAc and confirm the end point
of HCl absorption.
2. Minute analytical instrument condition

1) Burette
① Well-cleaned and undamaged.
②Capacity: approx. 50 ml
③Minimum scale：0.1 mI
2) Condition
The external air temperature is a nearly constant temperature of 10 to 30 ° C.
3. Preparation of test solution

1) 1.0 mol / L sodium hydroxide solution
Commercial product, capacity with actor indication minutes for analysis.
2) Dilute ethanol
Ethanol (special grade 95%) Water-1: 1
3) Bromothymol blue solution
① Dissolve bromothymol blue (Bromothymol blue) 0.1 g in 100 ml of rare eta / l.
② Appropriate if necessary.
4) Dilute ethanol
Ethanol (special grade 95%) Water-1: 1
4. Sample collection and measurement

1) Sample collection
①After absorption of HCl, collect EtOAc from the reaction kettle by using a sampler.
②Collect approx. 20 ml of the sample in a sample bottle and seal it immediately.
2) Sample measurement
① Fill the burette with 1.0 mol/L sodium hydroxide solution.
(2) Weigh 60 ml of the sample diluent with a measuring cylinder and put it in a 200 ml triangular flask.
③ Weigh the sample with a 5 ml whole pipette and add it to the Erlenmeyer flask of ②.
 Add a few drops (5-10 drops) of bromthymol blue solution to the solution with a pasteur pipette (the solution will
become yellowish.
⑤Titration with 1.0 mol / L sodium hydroxide solution (change from yellow to green, drop amount is described in the test
data sheet ①.
⑥Repeat the titration of the sample 3 times in total, and describe the amount of 1.0 mol / L sodium hydroxide solution
dropped in the test data sheet ①.
Crystal formation name : ASB17061 Lot No. : ＥＡ１０２－Ｕ
Production instructions・Record No. : 10HA-SM010 Test No. : 2/3
5. HCI concentration (mol / L) sample calculation

1) Calculate HCl concentration (mol / L) by using formula 1 and describe it in the test data sheet ① (rounding down to
the 4th place below a few points).
1.0 x FNaOH x NaOH dropping quantity (ml)
Calculation formula 1 - HCl concentration of sample (mol/L) = 5
FNaOH .1.0 mol/L sodium hydroxide factor
2) Calculate the difference between the maximum and minimum values of HCI concentration (mol / L) from formula-2 and
describe it in the test data sheet ①.
Calculation formula－2 Difference in HCl concentration (mol / L) sample ＝Maximum — Minimum
3) Calculate the average value of HCI concentration (mol / L) by using Formula-3 and describe it in Test data sheet ① (round
down to the third decimal place, round to the second decimal place)) .
M1 + M2 + M3
Calculation formula－3 HCL concentration sample (mol/L) = 3
M1 ~ M3 : Each calculation result of concentration (mol / L)
6. Decision for measurement end confirmation and HCI absorption end point
1) Confirmation of measurement completion The HCl concentration (mol / L) of each calculation result is in the range of 4.000 to
4.400, and the difference in HCl concentration (mol / L) (maximum value / minimum value) is within 0.050.
2) Decision for HCI absorption end point
HCI concentration average value (mol/L) If it is betweem 4.0 to 4.4, HCI absorption is completed and a question is added to the
column.
HCl concentration average value (mol/L) If it is out of the range of 4.0 to 4.4, it is considered that HCI absorption is insufficient,
check the column B and follow the instructions of the person in charge of production.
Product name : ASB17061 Lot No. : RA102-U
Production instructionsRecord No. : 10HA-SM010
Test data sheet ① Test No. : 3/3
　　　　　　　　　　　　 <ASB17061. ASB16726 >
Production
HCl concentration measurement
Manager
Lot No. EA102-U
(茂魔樹田)
Date of testing : : 2010 Year 11 Month 19 Day
Tested by : Akira Yano Confirmed by :
2010.11.19
1.0 moL / L Sodium Hydroxide Lot No.STL 3094 Factor : 1.000
(All displayed values have been recorded)
Sample measurement
Drop quantity (ml) ① Drop quantity (ml) ② Drop quantity (ml) ③
20.00  20.0 19.0  19.9 19.80  19.8
(Example, rounded to the second place with a

few points or less (eye minute amount))
HCI concentration sample (mol/L)
1.0 x FNaOH x NaOHDrop quantity (ml)
HCl concentration sample (mol/L) 5
=
FNaOH . 1.0 mol/L Sodium hydroxide factor

M1 = 1.0 x 1.000 x 20.0 (ml) /5 = 4.0000  4.000
M2 = 1.0 x 1.000 x 19.9 (ml) /5 = 3.4800  3.480
M 3 = 1.0 x 1.000 x 19.8 (ml) /5 = 3.9600  3.960
(Rounded down to the fourth decimal place)
Confirmation of measurement completion

Decision criteria : The HCl concentration ((mol / L) of each calculation result is in the range of 4.000 to 4.400 and HCI
concentration (rnol/L) difference (maximum value - minimum value) is within 0.050.
(Maximum value) 4.000 — (Minimum value) 3.960 = 0.040
 Appropriate : The measurement is completed

 Not appropriate : Carry out the re-measurement.
Decision for HCl absorption end point

Decision Criteria: Average HCI concentration samples (mol/L) = 4.0 ~ 4.4 mol/L
(M1 4.000 + M2 3.980 + M3 3.980 ) /3
= 3.980  3.98  4.0 mol/L
(Round down to the third decimal place and round to the second decimal place)
 HCI absorption completed : HCl concentration (mol/L) is 4.0 mol/L.

 Insufficient HCI absorption : Because HCl concentration (mol / L) is out of range, follow the instructions provided for
by the Production Manager.
The amount of HCl boiled in this measurement is 4.0 mol / L, which is the number of days for the purpose of use.
It's a good idea to change the regenerative measure before the generation.
Product name : ASB17061 Lot No. ：ＥＡ１０２－Ｕ
Production instructions・Record No. : 10HA-SM010 　　　　Test No. : 3/3
Test data sheet ① Production

Manager
　　<ASB17061. ASB16726 steps > (茂魔樹田)
HCl concentration measurement
ＬｏｔＮｏ．ＥＡ１０２－Ｕ 2010.11.22
Date of testing : : 2010 Year 11 Month 22 Day
Tested by : Akira Yano Confirmed by :
1.0 mol / L sodium hydroxide Lot No. STL 3094 Factor : 1.000
(All displayed values have been recorded)
Sample measurement
Drop quantity (ml) ① Drop quantity (ml) ② Drop quantity (ml) ③
20.0  20.0 20.00  20.0 19.90  19.9
(Rounded off to the second decimal place (Eye minute
amount))
HCl sample thickening (mol/L)

HCI concentration sample (mol/L) = 1.0 x FNaOHDrop quantity (ml)
5
FNaOH : 1.0 mol/L Sodium hydroxide factor
M1 = 1.0 x 1.000 x 20.0 (ｍｌ) /5 = 4.0000  4.000

M2 = 1.0 x 1.000 x 20.0 (ｍｌ) /5 = 4.0000  4.000
M 3 = 1.0 x 1.000 x 19.9 (ｍｌ) /5 = 3.9800  3.980
(Rounded down to the fourth decimal place)
Confirmation of measurement completion

Decision criteria: HCl concentration (mol / L) of each calculation result is in the range of 4.000 to 4.400 and
Difference in HCl concentration (mol / L) (maximum value - maximum value) is within 0.050
(Maximum value) 4.000 — (Minimum value) 3.980 = 0.020

 Appropriate：The measurement is completed
 Not appropriate：Carry out the re-measurement.
Decision for HCl absorption end point

Decision Criteria: Average HCl concentration of samples (mol/L) = 4.0 ~ 4.4 mol/L
(M1 4.000 + M2 4.000 + M3 3.980 ) / 3
= 3.993  3.99  4.0 mol/L
(Round down to the third decimal place and round to the second decimal place)
 End of HCl absorption : HCl concentration (mol/L) is 4.0 mol/L.

 Underabsorption of HCl : Follow the instructions provided for by the Production Manager because HCl
concentration (mol / L) is out of range.
D3HA-D01S06_ Form 2_Production instructions・Procedure for record creation 2010.5.1 Implementation
Production record (3) Weighing record
Clinical trial ASB17061

drug substance
name
Process name ASB16726 steps
1/3 Lot No. ＥＡ１０２－Ｕ
Product name Axis responsibility Lot No. Weighing person G 244160.4 L ✓

source T 243693.2 L ✓
*2 PW for which the 210061 Ka. N. N 467.2 L ✓
ＡｃＯＦｃ instrument number
is abbreviated
Weighing Weighing date Confirmed by
Equipment No.
ＱＴ２０３Ｂ 2010.11.15 Y. S.
Product name Axis responsibility Lot No. Weighing person G
source __________________
T
Weighing Weighing date Confirmed by N
Equipment No.

source __________________
T
Equipment No.

source __________________
T
Equipment No.

source __________________
T
Equipment No.

source __________________
T
Equipment No.

source __________________
T
Equipment No.
Product name Axis responsibility Lot No. Weighing person G ________________

source T
N
Weighing Weighing date Confirmed by
Equipment No.
Remarks: None
D3HA-D01S06_Form 2_Production instructions・Procedure for record creation 2010.5.1 Implementation

drug substance
name
Process name ASB16726

source T 72.67 L ✓
*4 Tsurumi books ( stock) 100731 A. Y. N 10.50 L ✓
HCl (1) Weighing Equipment Weighing date Confirmed by
No.
ＷＥ－２４ 2010.11.16 Ka. N.
*4 source T 73.64 L ✓
Tsurumi books ( stock) 100731 A. Y. N 10.48 L ✓
No.
ＷＥ－２４ 2010.11.16 Ka. N.
*4 source T 70.53 L ✓
No.
ＷＥ－２４ 2010.11.16 Ka. N.
*4 source T 72.19 L ✓
No.
ＷＥ－２４ 2010.11.16 Ka. N.
*4 source T 73.89 L ✓
No.
ＷＥ－２４ 2010.11.16 Ka. N.
*4 source T 72.34 L ✓
No.
ＷＥ－２４ 2010.11.16 Ka. N.
*4 source T 65.71 L ✓
No.
ＷＥ－２４ 2010.11.17 Ka. N.
*4 source T 70.01 L ✓
No.
ＷＥ－２４ 2010.11.17 Ka. N.
Remarks: None

drug substance
name
Process name ASB16726

source T 67.68 L ✓
*4 Tsurumi books 100731 A. Y. N 4.51 L ✓
HCl (9) ( stock)
Weighing Equipment Weighing date Confirmed by
No.
ＷＥ－２４ 2010.11.17 Ka. N.
*4 source T ________________
Tsurumi books N
HCl (1) ~(9) Total ( stock)
No.
A. Y. Ka. N.
source T ________________
Tsurumi books 100731 A. Y. N
HCl (3) ( stock)
No.
ＷＥ－２４ 2010.11.16 Ka. N.
source T ________________
HCl (4) ( stock)
No.
ＷＥ－２４ 2010.11.16 Ka. N.
source T ________________
HCl (5) ( stock)
No.
ＷＥ－２４ 2010.11.16 Ka. N.
source T ________________
HCl (6) ( stock)
No.
ＷＥ－２４ 2010.11.16 Ka. N.
source T ________________
鶴見書達( stock) 100801 A. Y. N
No.
ＷＥ－２４ 2010.11.17 Ka. N.
source T ________________
鶴見書達( stock) 100801 A. Y. N
No.
ＷＥ－２４ 2010.11.17 Ka. N.
Remarks: None
Product name : : ASB17061 Production instructions・Record No.: 10HA-SM010 Preparation 12/16
Lot No. ：EA102-U Preparation amount calculation list  Calculation Formula checked
ASB16726 steps Preparation of calculation standard of BTTN Gross weight standard
BTTN weight preparation（kg) = 91.60 kg
Operation < *1 > Zn( x 6.60 eq)
BTTN weight preparation（Kg) x

Zn molecular weight x 6.60
91.60 x 65.41
= 799.33 x 6.60 = 49.471  49.47 kg 
（Rounded off to the third place of the decimal point）
Operation < *2 > MgSO4 (x 0.1 wt)
BTTN weight Preparation (kg) x 0.1 = 91.60 x 0.1 = 91.60  9.16 kg 

Operation < *4, *5, *6 > 4 M HCl /EtOAc( x 18 eq)
BTTN weight preparation（kg)

BTTN minutes 子量 x 28 x 36.46 = 75.207  75.21 kg  
91.60
799.33 x 18 x 36.46 = 75.207 
75.21 kg  
Process control test－10 HCl molar concentration : 4.0 ｍｏｌ/Ｌ 
HCl quantity in HCl / EtOAc: Mol concentration x HCl minutes = 4.0 x 36.46=145.84  145.84 g/L 
Additional quantity

② x 1000 = 515.7  516 L 
（Rounded off to the first decimal place）

Operation < *12 > ＮａＯＡｃ ( x 18 eq)
BTTN weight preparation（kg) x ＮａＯＡｃ

minutes 子量 x 18
BTTN minutes 子量
91.60 x 82.03
799.33 x 18 = 169.205  164.21 kg 
Manager
2010.11.22 2010.11.22 2010.11.22
明兵野 (税行子田)　　　
(茂魔樹田)
Product name : : ASB17061 Production instructions・Record No.: 10HA-SM010 Preparation 13/16
Lot No. : ＥＡ１０２－Ｕ Preparation amount calculation list
 Calculation formula checked
ASB17061 steps
Operation < *13 > Normal water （x 5.0 voI)

　　　　BTTN weight preparation（kg) x 5.0 = 91.60 x 5.0 = 458.0  458 L 
Operation < *17 > Normal water （x 5.0 voI)

　　　　　BTTN weight preparation（kg) x 5.0 = 91.60 x 5.0 = 458.0  458 L 
Operation < *18 > NaCl（x 5.0 voI)

　　　　　BTTN weight preparation（kg) x 5.0 = 91.600 x 1.0 = 91.600  91.60 kg 
Operation < *22 > AcOAH　（x 2.0 voI)

　　　　　BTTN weight preparation（kg) x 2.0 = 91.60 x 2.0 = 183.2  183 L 
Operation < *23 > IPA（x 4.0 voI)

　　　　　　BTTN weight preparation（kg) x 2.0 = 91.60 x 2.0 = 366.4  366 L 
Operation < *24 > AcOAH　（x 0.5 voI)

　　　　　　BTTN weight preparation（kg) x 0.5 = 91.60 x 0.5 = 45.8  46 L 
Operation < *25 > c.HCl （x 0.0595 wt)

　　　　　　BTTN weight preparation（kg) x 0.0595 = 91.60 x 0.0595 = 5.450  5.45 kg 
Operation < *26 > ASB16726 XX x 0.0001 wt)

　　　　　　BTTN weight preparation（kg) x 0.0001 x 1000 = 91.60 x 0.0001 x 1000 = 9.160  9.16 g 
Operation < *28 > c.HCl （x 0.5355 wt)

　　　　　　BTTN weight preparation（kg) x 0.5355 = 91.60 x 0.5355 = 49.051  49.05 kg 
Operation < *33 > EtOAc（x 1.0 voI)
　　　　　　BTTN weight preparation（kg) x 1.0 = 91.60 x 91.6  92 L 

Manager
2010.11.22 2010.11.22 2010.11.22
（明兵野） (茂魔樹田)
(税行子田)　　　
Product name : : ASB17061 Clinical trial drug substance manufacturing instructions / records フロー 30/52
Lot No. : ＥＡ１０２－Ｕ Document No.: 10HA-SM010
ASB16726 Process Date of working : 2010.11.24 ~ 2010.11.24
Preparation, calculation standard: BTTN Gross weight

< *1 >
Ｚｎ 49.47 kg  [Addition] < *1 > Time Internal Internal Internal Rotation Remarks
(standard 50.93kg) < x 6.60 eq. > temperature temperature temperature speed
[ °C ] [ °C ] SV [ rpm ]
[ °C ]
ＭｇＳＯ 4 9.16 kg  [Addition] < *2 > 9: 0.5 -0.2 -0.2 90
(standard 9.43 kg）< x 0.1 wt > 14
9: 0.5 -0.2 -0.2 90
17
[Holding pressure cooling] < *3 > Additional quantity : 44.47 kg
-20 ~ 5 °C …………. — …………………………………………………….
Confirmation by : Ｙ．Ｓ．Ａ．Ｙ
1000 ＬＧＬ reaction kettle (K203) < *2 >
4 M HCl / EtOAc , x 18 eq > Time Internal Internal Internal Rotation Remarks
516 L temperature temperature temperature speed
Fill in the Instructions column Signed for it [ °C ] [ °C ] SV [ rpm ]
2010.11.22 [Addition] < *4 > [ °C ]
-20 ~ 5 °C 9: 0.5 -0.2 -0.2 90
19
Masahiro Ikeda 9: 0.5 -0.2 -18.0 90
2010.11.22 20
Additional quantity : 9.16 kg
…………. — …………………………………………………….
Confirmation by : Ｙ．Ｓ．Ａ．Ｙ
*7 (K203) *6 (K213) < *3 >
Time Internal Internal Internal Rotation Remarks
Instructions temperature temperature temperature speed
Production [ °C ] [ °C ] SV [ rpm ]
Manager [ °C ]
9 : 21 -1.3 -16.6 -18.0 90 Baffle
(茂魔樹田) meter
9 : 39 -5.0 -18.1 -18.0 90
2010.11.22 :
:
…………. — …………………………………………………….
　　　　　　Confirmation by : Ｙ．Ｓ．Ａ．Ｙ
< *４ > Approximately 4/18 240 min is dropped as a guide. Measured with
OF-16

: temperature temperature temperature speed
[ °C ] [ °C ] SV [ rpm ]
[ °C ]
9 : 40 -5.1 -18.2 -18.0 90
11 : 05 -3.8 -18.0 -18.0 90 HCl /
EtOAc
30.7 L
11 : 40 -2.4 -17.0 -18.0 90 46.9
Attendant.
13 : 10 -2.5 -17.0 -18.0 90 97.2 L
Attendant.
13 : 26 -2.1 -17.4 -18.0 90 115.3 L
Attendant.
:
:
Additional quantity: Approx. 4/18

Confirmation by : Ｙ．Ｓ．A. Y.
Operator’s signature 木ミ田性え Y.S.失面部明 A. Y.た田形材 S.H...．Ｓ．Ｔ中た Ka. N..

with remarks
ASB16726 エ桂 Date of working : 2010.11.24 ~ 2010.11.25

*7 (K203)  [Note] < *5 > < *5 > Drop about 4/18 amount with 120 as a guide. Weigh with OF-
-20 ~ 5 °C 16
Time : Intern Intern Intern Rotati Remarks
[Note] < *6 > al al al on
-20 ~ 5 °C tempe tempe tempe speed
rature rature rature [ rpm ]
[ °C ] [ °C ] SV
[ °C ]
steps 内 Equipment Washing 13 : 31 -2.5 -12.6 -18.0 90
[Equipment cleaning － 16] reaction kettle （ K203) の 14 : 57 -2.7 -17.6 -18.0 90 196.0 L
Washing 15 : 27 -2.3 -17.5 -18.0 90 230.0 L
:
[Stirring] < *7 > Additional quantity : approx. 4/18　　　　
-20 ~ 5 °C 　　　　　　　　　Confirmation by : A. Y.Ｙ.Ｓ.
< *6 > Approximately 10/18 dripping with a volume of 150 min as a
guide. Weighed with OF-16.
[Addition] < *8 > Time : Intern Intern Intern Rotati Remarks
35 ~ 45 °C al al al on
tempe tempe tempe speed
[Stirring] < *9 > [ °C ] [ °C ] SV
35 ~ 45 °C [ °C ]
15 : 34 -3.5 -12.6 -18.0 90 15 : 45 Internal
temperature SV-
*7 (K213) 103 °C
17 : 55 -4.8 -17.0 -18.0 90
:
Additional quantity: 516.0 L
…………. — …………………………………………………….
　　　　　　　　　　　　Confirmation by : Y. S. S. H.
< *7 > -20 ~ 5 °C Liquid agitation
Time : Intern Intern Internal Rotati Remarks
Instructions
al al temperat on
Production tempe tempe ure SV speed
Manager rature rature [ °C ] [ rpm ]
[ °C ] [ °C ]
(茂魔樹田) 17 : 57 -4.9 -16.8 -5.3 50
8 : 45 -4.6 -6.6 -5.3 50
2010.11.22
…………. — …………………………………………………….
Confirmation by : Ａ．Ｙ. Ｙ. S.
< *8 >
Time : Intern Intern Internal Rotati Remarks
al al temperat on
tempe tempe ure SV speed
rature rature [ °C ] [ rpm ]
[ °C ] [ °C ]
8 : 30 -4.5 -5.445.0 70
9 : 30 29.2 45.445.2 70
9 : 44 35.0 45.240.0 70
:
…………. — …………………………………………………….
Confirmation by : Ｙ.Ｓ. Ｓ.Ｈ
< *9 >
Time : Intern Intern Intern Rotati Remarks
al al al on
tempe tempe tempe speed
[ °C ] [ °C ] SV
[ °C ]
9 : 45 35.3 45.1 44.9 70
10 : 45 41.2 41.3 41.3 70
11 : 45 41.5 41.3 41.3 70
12 : 45 42.1 41.3 41.3 70
…………. — …………………………………………………….
Confirmation by : Ｙ.Ｓ. Ｓ.Ｈ
Operator’s signature Akira YanoA.Y 太田蔵樹 SH　中たゆ xxxKa. N.田合 xx ｘｘｘｘ

with remarks
[サン 7.'ルク ] < *10 > < *10 > Sampling 1h after the end of Operation (+9). After that, sampling
every 1h. Reduction / deprotection reaction confirmation of the end point
Process control test－5 Time Process control test－5 Results and Result Remarks
Confirmation of reaction completion decisions confirmatio
条件：中問体/ASB16726 n time
≤ 0.010 10 : 45 Intermediate : 0.157 Appropriate  Not appropriate 11 : 27
1 : 45 Intermediate : 0.030Appropriate  Not appropriate 12 : 28
12 : 45 Intermediate : 0.004Appropriate  Not appropriate 13 : 28
: Intermediate :
: Intermediate :
…………. — ………… 　　Confirmation by : A. Y. Ｙ．Ｓ.
[Holding pressure cooling] < *11 > < *11 >
Tim Internal Internal Internal Rotatio Remark
e temperatur temperatur temperatur n speed s
NaOAc 169.21 kg  [Note] < *12 > e e e SV [ °C ] [ rpm ]
( Standard 174.19 kg) < x 18 eq. > [ °C ] [ °C ]
13 : 40
42.1 41.3 19.9 90
: 45
41.2 31.6 9.8 90
Normal water 458 L  [Note] < *13 > 14 : 05
29.8 8.4 24.8 90
(Standard 472 L) < x 5.0 vol >
…………. — ………………… 　Confirmation by : A. Y. Ｙ．Ｓ.
[ Stirring] < *14 > < *12 >
20 ~ 30 °C Time Internal Internal Internal Remarks
15 min or more temperature temperature temperature
[ °C ] [ °C ] SV [ °C ]
[Stand still] < *15 > 14 : 07 26.9 22.1 24.8
5 min or more : 24 30.8 8.8 10.0
Additional quantity: 169.21 kg
…………. — ……… 　　　Confirmation by : A. Y. Ｙ．Ｓ.
[ minute solution] < * 16 >
< *13 >
Time Internal Internal Internal Remarks
Waste water layer
[ °C ] [ °C ] SV [ °C ]
disposal
14 : 27 29.9 9.6 28.0
*8 (K213) : 35 23.2 28.9 28.0
2010.11.25
(signed)
Instruction
A. Y.
s
Production
…………. — ………………… 　Confirmation by : A. Y.Ｙ．Ｓ.
Manager
< *14 >
(茂魔樹田)
e [ °C ] e [ °C ] e SV [ °C ] [ rpm ]
2010.11.22
14 : 22.9 29.3 28.0 90
36
24.6
: 51 28.0 28.0 90
…………. — …………………… Confirmation by : A. Y.Ｙ．Ｓ.
< *15 >
[ °C ] [ °C ] SV [ °C ]
14 : 52 24.6 28.0 28.0 1540 L
15 : 20 25.4 28.0 28.0
…………. — ………… 　　　Confirmation by : A. Y.Ｙ．Ｓ.
< *16 >
Good quality minute solution
Time Internal Externa Strict Gauge Remarks
tempe- l tempe- internal pressure
rature liquid
rature volume [MPaG]
[ °C ] [ °C ] [L]
15 : 22 25.1 28.0 1540 0.08
: 34 25.4 28.0 940 0.08
Waste water layer of the liquid volume 600 Ｌ　　　ＰＨ
５
There is Azuka Harutsu. Confirmation by : A. Y. Ｙ．Ｓ.
Operaror’s signature Akira YanoA.Y 太田蔵樹 SH　中たゆ xxxKa. N.田合 xx ｘｘｘｘ
with remarks
Product name : : ASB17061 Clinical trial drug substance manufacturing instructions / records
フロー 33/52

Normal water 458 L  [Note] < *17 >
(Standard 472 L) < x 5.0 vol > < *17 >
[ °C ] [ °C ] SV [ °C ]
NaCl 91.60 kg  [Addition] < *18 > 15 : 37 25.5 28.0 28.0
: 43 22.4 28.0 28.0
[Stirring] < *19 > …………. — ……………………… Confirmation by : A. Y. Y. S.
20 ~ 30 °C < *18 >
15 min or more Time : Internal Internal Internal Remarks
[ °C ] [ °C ] SV [ °C ]
[Stand still] < *20 > 15 : 45 22.2 27.8 28.0
: 51 21.8 27.8 28.0
5 min or more Additional quantity: 91.60 kg
…………. — ……………………… Confirmation by : A. Y. Y. S.
< *19 >
[ minute solution] < *21 > > Tim Internal Internal Internal Rotatio Remark
Waste water layer e e e SV [ °C ] [ rpm ]
disposal [ °C ] [ °C ]
AcOH 183 L  [Note] < *22 > 15 : 52
21.8 27.8 28.0 90
(Standard 189 L) < x 2.0 vol > 16 : 08
23.5 27.8 28.0 90
< *20 >
IPA 366 L  [Note] < *23 >
[ °C ] [ °C ] SV [ °C ]
16 : 08 23.5 27.8 28.0
Stirring 46 L  [Note] < *24 > : 25 24.0 28.0 28.0
…………. — ………………………… Confirmation by : A. Y. Y. S.
*9 (K213) < *21 > > Good quality minute solution , Waste water layerpH 4 ~ 5
Time Internal Internal XX XX Remarks
Instruction temperature temperature [L] [MPaG]
s [ °C ] [ °C ]
16 : 47 25.1 28.0 1460 0.07
Production
Manager : 58 25.9 24.4 920 0.07
Waste water layer: liquid quantity is 540 L, PH —
茂魔樹田 …………. — ………………………… Confirmation by : A. Y. Y. S.
2010.11.2 < *22 >
2 Time Internal Internal Internal Remarks
[ °C ] [ °C ] SV [ °C ]
16 : 47 25.1 28.0 25.0
: 58 25.9 24.4 25.0
Additional quantity: １８３３ L
Stirring at 50 rpm Confirmation by : A. Y. Y. S.
< *23 >
[ °C ] [ °C ] SV [ °C ]
17 : 01 25.7 24.8 25.0
: 25 21.4 24.6 25.0
Additional quantity : 366.3 L
矢野 50 rpm Confirmation by : Y. S. Y. S.
< *24 >
[ °C ] [ °C ] SV [ °C ]
17 : 26 21.4 24.6 25.0
: 27 21.4 24.6 25.0
Additional quantity : 46.2 L
Stirring at 50 rpm Confirmation by : A. Y. Y. S.

with remarks

c.HCl 5.45 L  [Note] < *25 > < *25 > [d=1.19]
(Standard 5.61 kg) < x 0.0595 wt > Time Internal Internal Internal Remarks
[ °C ] [ °C ] SV [ °C ]
ASB16726 Stand still 9.16 g  [Addition] < *26 >
(Standard 9.43 g) < x 0.0001 wt. > 17 : 31 21.4 24.4 25.0
: 32 21.8 24.2 25.0
Additional quantity: 5.45 kgL
[Stirring] < *27 > …………. — …………………………………………………….
20 ~ 30 °C Confirmation by : A. Y. Y. S.
60 min or more < *26 >
c.HCl 49.05 kg  [Note] < *28 > temperature temperature temperature
(Standard 50.50 kg) < x 0.5355 wt > more than [ °C ] [ °C ] SV [ °C ]
60 minutes
17 : 34 22.2 24.8 25.0
[Stirring] < *29 > : 35 22.2 24.8 25.0
20 ~ 30 °C Additional quantity: 9.16 g
30 min or more …………. — …………………………………………………….
< *27 >
[Holding pressure cooling] < *30 > Tim Internal Internal Internal Rotatio Remark
0 ~ 5 °C e temperatur temperatur temperatur n speed s
e [ °C ] e [ °C ] e SV [ °C ] [ rpm ]
[Stirring] < *31 > 17 : 22.2 25.0 25.0 50
0 ~ 5 °C 36
8h or more XX 19 : 24.9 25.4 25.0 50
06
…………. — …………………………………………………….
*10 (K213) Confirmation by : A. Y. Y. S.
< *28 > [d=1.19]
Instruction e temperatur temperatur temperatur n speed s
s e [ °C ] e [ °C ] e SV [ °C ] [rpm ]
Production 19 : 07
24.9 25.4 25.0 50
Manager : 23 26.1 25.0 20.5 50
20.09 25.1 20.5 20.5 50
(茂魔樹田) :
Additional quantity: 49.05 kgL
2010.11. …………. — …………………………………………………….
月.日 Confirmation by : A. Y. Y. S.
< *29 > Target temperature = 25 °C
speed
temperature temperature temperature [rpm ]
[ °C ] [ °C ] SV [ °C ]
20 : 09 25.1 20.5 20.5 50
: 40 23.4 20.5 20.5 50
< *30 >
speed
temperature temperature temperature [rpm ]
[ °C ] [ °C ] SV [ °C ]
20 : 40 23.4 20.5 -10.1 50
21 : 40 5.8 -10.2 1.0 50
21 : 46 5.0 -0.8 1.0 50
…………. — …………………………. Confirmation by : A. Y. Y. S.
< *31 > Target temperature = 1 °C
speed
[rpm ]
[ °C ] [ °C ] SV [ °C ]
21 : 47 5.0 -0.4 1.0 50
9 : 08 1.5 1.0 1.0 50
…………. — ………………………. Confirmation by : A. Y. Y. S.

with remarks
Product name : : ASB17061 Clinical trial drug substance manufacturing instructions / records
フロー 35/52
ASB16726 Process Date of working : 2010.11.25 ~ 2010.11.26

1000 L GL reaction kettle (K203) reaction kettle : K213
< *32 > Time : 18 : 43 ~ 18 : 44
[Nitrogen substitution] < *32 > Oxygen concentration : 4.1 % ( ≤ 5%)
Oxygen concentration 5% or less …… — …………………………………………………………….
EtOAc 92 l  [Note] < *33 >
(Standard 94 L) < x 1.0 vol > < *33 > Time : 18 : 45 ~ 18 : 48
Additional quanity: 92.8 L
…… — …………………………………………………………….
EtOAc と 2.0vol 迫力加 Confirmation by : A. Y. Y. S.
する. 184 L
EcOAc is a wash-off. S. H. Keypoint : S202

To send .2V01 minutes to K203 xx, S202. 　 Magic cloth 20226
Tag No.
　　　　　　　　　　　48B Dramatic machine (S202) Backing Available Not
[Nitrogen substitution] < *34 > paper available
　　Oxygen concentration 5% or less
When Appropriate for multiple loads, cobby the book page and
*10 (K213) use it as a production record sheet. At that time, divide the
[遠心演 Appropriate] < *35 > cake cleaning solution for minutes.
*11 K203)
[洗浄] < *36 > < *34 > Time : 9 : 28 ~ 9 : 31
[サン 7 リンク ] < *37 > Oxygen concentration S202: 3.5% (≤ 5% oxygen
concentration (SR202A) : 5.0 % (≤ 5 %)
Process control test 一 6 …… — …………………………………………………………….
品質確認 Confirmation by : A. Y. Y. S.
※Decision 基準は steps 管理 < *35 > K213 XX : 1.5 °C
Test No. : 手順に記載 1 Liquid Time Rotation Liquid Remarks
infusion : speed [ rpm volume
] in the
*12 kettle
Liquid 10 : 4.2 1530
supply 09
start
Instructions End of : 59 4.2 760
Production liquid
Manager supply
　　茂魔樹田 Finished 11 : 0
2010.11.月.日 drainage 14
ｘｘ minutes 量を絡液しな…… — …………………………………
………………………….
< *36 > K213 XX : 12.1 °C
1 Liquid Time : Rotation Liquid Remarks
infusion speed volume
[ rpm ] in the
kettle
Start 11 : 15 402 276
cleaning
Cleanin 12 : 00 402 139
g
finished
Start of 12 : 11 812
liquid
removal
Finished 13 : 03 812 0.04 L/min
drainage
洗浄液使用量：136.6 L
OF-14 In the far-off liquid.
…… — …………………………. Confirmation by : A. Y. Y. S.
< *37 > Time : 13 : 13 ~ 13 : 16
Cake thickness Max. : 25 mm Avg.: 36 mm Min. : 35 mm
Arin with crests from cake Atsumi to the
table………………………………. Confirmation by : A. Y.
Y. S.
Process control test－6 Confirm related substances
Confirmation Measurement Standard Decision

time result
: UK-2 : ________ 0.10 % or
% more
Operator’s signature
with remarks
7D 35/52 -2
Lot No. : ＥＡ１０２－Ｕ Process name : Date of working: Year 2010 Month 11 Day 26 ~ Year 2010 Month
ASN16726 steps 10 Day 26
No. Time Recording of work contents and data Confirmed Confirmed Remarks
by－1 by－2
S202 : 20226 Paper
2 load month
*34 13 : 38 S202 = 3.8 % SR202A 5.0 % Y. S. A. Y.
*35 13 : 42 Painting liquid 417 rpm K213 Kaneuchi 760L Y. S. A. Y.
1.5 ℃
14 : 18 Picture liquid entanglement. K213 Kinnai Y. S. A. Y.
Eima 500L
: 51 Y. S. A. Y.
*36 : 52 Picture liquid 417 rpm K213 Kaneuchi 760L Y. S. A. Y.
1.5℃ = 14.7 °C
15 : 24 45.2 L Y. S. A. Y.
: 30 812 rpm Y. S. A. Y.
: 50 0.04 L/min Y. S. A. Y.
*37 : 55 Y. S. A. Y.
Max. : 10 mm Avg. : 24 mm Min. : 26 mm
S202 20226
30
*34 16 : 35 S202 = 5.0 % SR202A = 5.0 %
*35 : 38 30\99 rpm K213 = 500 L 1.5 °C Y. S. A. Y.
17 : 01 Y. S. A. Y.
: 09 Y. S. A. Y.
*36 : 10 399 rpm K203 = 14.9 °C Y. S. A. Y.
: 27 Y. S. A. Y.
: 32 815 rpm Y. S. A. Y.
18 : 00 0.04 L/min Y. S. A. Y.
*37 : 06 Y. S. A. Y.
Max. : 15 mm, Avg. : 30 mm, Min. : 25 mm
19 : 15 -6 Y. S. E. Y.
＝ UK-2 N.D． 0.10 %
作業者署名

627 - 19 - ASB17061 EBR Lot No EA102-U (201-300) (Japa - Eng Final) )

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(税行子田) (茂魔樹田)

Sample information Lot No. 10111607 2010.11.16 2010.11.16

Retention time Peak area Height Area % Peak width 50 %

Total 76.957 13.243

Qt value [related substances] calculation sheet (blank correction calculation)

Sample solution chart No. : 10111607

Blank solution chart No. : 10111605

sample solution blank solution

Sum of each Qt value 2.712

Sample information Lot No. 10111608 2010.11.16 2010.11.16

Retention time Peak area Height Area % Peak width 50 %

Total 97.055 16.079

Qt value [related substances] calculation sheet (blank correction calculation)

Blank solution chart No. : 10111605

sample solution blank solution

Sum of each Qt value 13.670

If the Qt value is (1: minus), enter “0” in the Qt value field.

Retention time Peak area Height Area % Peak width 50 %

Total 75.245 12.936

Qt value [related substances] calculation sheet (blank correction calculation)

Sample solution chart No. : 10111609

Blank solution chart No. : 10111605

sample solution blank solution

Sum of each Qt value 1.450

If the Qt value is (1: minus), enter “Ui” in the Qt value field.

Retention time Peak area Height Area % Peak width 50 %

Total 20.768 3.431

Retention time Peak area Height Area % Peak width 50 %

Total 74.245 12.871

(batch No): EA102-U Production room cleaning 5/7

BTTN PROCESS (茂魔樹田)

2. Contents of use Production room name : S202 Centrifuge Push

< Changing room > 2010.11.12 2010.11.15

Operator’s 中た AppropriateKa. N.Appropriate 天田釆 S.T

ロ外番号 : EA102-U Production room

1. Purpose : Cleaning between the steps 2010.11.16

2. Contents of use Production room name : D108 乾燥造

Operator’s 中た AppropriateKa. N.Appropriate 天田釆 S.T

TAD process for cleaning evaluation test (dissolution test))

Implementation of cleaning evaluation test between TAD processes.

2. Minute analysis, measurement conditions

2-1 minutes analysis

2-2 Measurement condition

力ラム : Cadenza CD-C18 (3.0 ϕ x 50 mm, 3 μ m Intakt ( stock) 製)

力ラム温度 : 40 °C Constant temperature in the vicinity

Mobile phase : MeCN/Water mixture (2 : 3)

Sample cooler temperature : 10 °C

Minute analysis time : 6 mm

Infusion quantity : 5μL

Sample dissolution solution : MeCN/Water mixture (1 : 1)

Needle cleaning solution : Sample dissolution solution

Follow the instructions provided for by the Production Manager.

Glass vial used : Silane treated brown glass vials used

2-3 How to prepare the test solution

Mix MeCN with distilled water or ultrapure water in a volume of 2 : 3.

2) Sample dissolution solution

Mix MeCN with distilled water or ultrapure water at a volume of 1 : 1.

2-4 Chart numbering

All HPLC measurement charts include Chart numbering filled in.

3. System compatibility test

3-1 Expiration date of system conformity test

1) When the Mobile Phase is stopped

2) While replacing the Mobile phase

(税行子田) 　　　　　(茂魔樹田)