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Ernest Lee
Senior Manager,
Facilities & Engineering
Except for historical information, the matters contained in this slide presentation
may constitute forward-looking statements that involve risks and uncertainties,
including uncertainties related to product development and clinical trials,
unforeseen safety issues resulting from the administration of antibody products
in patients, uncertainties related to the need for regulatory and other government
approvals, dependence on patents and proprietary technology, the need for
additional capital, uncertainty of market acceptance of Medarexs product
candidates, the receipt of future payments, the continuation of business
partnerships and other risks detailed from time to time in Medarexs filings with
the Securities and Exchange Commission (SEC).
1
Weifeng Frank Zhang
Ernest Lee
BE
B.Eng. (M
(Mechanical
h i lE Eng.),
) MM.Sc.
S (E(Eng. M
Management),
t)
AGENDA
Topic Overview
Two Case Studies
Risk-based Approach
Interactive Exercise
Q&A, Open Discussion
2
Challenges or Common Issues in Validation
Acceptance Criteria!
???
Where to g
grab the magic
g
numbers?
3
Challenges or Common Issues in Validation
Risk-based approach
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Case Study I: How to Set Limits for the Vial Fill
Volume in Aseptic Process
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Case Study I (Continued):
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Case Study I (Continued):
Two Issues
Process Capability
To prove process is capable of meet the fill volume low limit
(10.4 ml) at a certain set point of first tray (10.8 ml) Fill
volume decay was observed during the first tray fill.
Consistency
y
How many runs are enough? (3, 5, 12?)
Engineering Study
Data Analysis
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Case Study I (Continued):
CONTROLLED INPUTS
Cpk Capability
w.r.t External
PROCESS
Specifications
t-Test Internal
Process
EMPTY VIAL Stability
FILLED VIAL
UN-CONTROLLED INPUTS
1st Tray Fill Volume from All Three Sets (Setpoint: 10.8mL)
10 9
10.9
10.8
Fill Volume (mL)
10.7
Set 1
10.6 Set 2
Set 3
10.5
10.4
10.3
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Sample #
Total ~ 220 vials in each tray. Every 10th vials were sampled during the fill.
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Case Study I (Continued):
Trend Analysis
11.00
10.90
10.70
Filll Volume (mL)
10.60
Tray 1 Data
Lst Sqrs
10.50 Approx
10.30
10.20
0 5 10 15 20 25
Sample #
2nd,3rd Tray Fill Volume From All Three Sets (Set point 10.6mL)
10.9
10.8
Fill Volume (mL)
10.3
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Sample #
Total ~ 220 vials in each tray. Every 10th vials were sampled during the fill.
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Case Study I (Continued):
1st Tray Fill Volume from All Three Sets (Setpoint: 10.8mL) 2nd,3rd Tray Fill Volume From All Three Sets (Set point 10.6mL)
10.9 10.9
10.8 10.8
Fill Volume (mL)
10.3 10.3
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Sample # Sample #
Process Capability
Cpk
Consistency
V i
Variance A
Analysis
l i
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Case Study I (Continued):
Process Capability
Average Cpk
10.680 6
10.660 5
10.640 4
Cpk Value
Fill Volum e
10.620 3
10.600 2
10.580 1
10 560
10.560 0
1st Tray 1st Tray 1st Tray The Rest The Rest The Rest The Rest The Rest The Rest 1st Tray 1st Tray 1st Tray The Rest The Rest The Rest The Rest The Rest The Rest
Avg. Avg. Avg. Avg. Avg. Avg. Avg. Avg. Avg. Cpk Cpk Cpk Cpk Cpk Cpk Cpk Cpk Cpk
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Case Study I (Continued):
Cpk Value From the Study
Tray # Cpk
1 (Set 1) 1 47
1.47
1 (Set 2) 1.78
1 (Set 3) 1.47
2 (Set 1) 3.973
3 (Set 1) 4.949
2 (Set 2) 4.449
3 (Set 2) 3.578
2 (Set 3) 5.125
3 (Set 3) 4.930
t-Distribution:
is a probability distribution that arises in the problem of
estimating the mean of a normally distributed population when
the sample size is small.
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Case Study I (Continued):
6
umber of occurance
2
Nu
0
-0.060 -0.040 -0.020 0.000 0.020 0.040 0.060 0.080 0.160
Sample results spread
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Case Study I (Continued):
Histogram from Real Data (2)
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12
umber of occurance
10
4
Nu
0
-0.020 0.000 0.020 0.040
Sample results spread
null hypothesis: The performance of the fill process in all three (3) sets
have no significant difference in filling the vials.
Type I Error
: Probability of Type I Error True
True (significance level) tscore < t((tcrit)
tscore > t (tcrit)
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Case Study I (Continued):
t-Distirbution Table: Compare tactual and t
Confidence level: 1-
when =0.005, 99% confidence level (Two tails)
when =0.025, 95% confidence level (Two tails)
T-Distribution Table.htm
http://www.socr.ucla.edu/Applets.dir/T-table.html
2 1 1
Where, (X = Sp ( + )
B XE )
nB nE
Where, Sp is the variance for the sampling distribution for the difference of samples
means, 2 2
2 (n B 1) S + (n E 1) S
Sp = B E
nB + nE 2
Where, nB and nE are the sample numbers in each set (in this case, nB = nE = 22),
SB and SE are the standard deviations of each set.
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Case Study I (Continued):
Summery of the Study (First Tray)
= 0.005
Group # tscore
t(tcrit)
Since tscore < t(tcrit) , null hypothesis can not be rejected. At 99%
confidence level, there is no significant difference between first tray
from all three (3) sets.
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Case Study II: How to Decide the Acceptance
Criteria for Dynamic EM of Non-viable Particle
Count during Aseptic Fill
EU Updates
At rest In operation
Grade 0.5m 5.0m 0.5m 5.0m
A 3,520 20 3,520 20
B 3,520 29 352,000 2,900
C 352 000
352,000 2 900
2,900 3 520 000
3,520,000 29 000
29,000
D 3,520,000 29,000 Not defined Not defined
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Case Study II (Continued):
Case Review
Set Limits
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Case Study II (Continued):
0.5m 5m
Issue
Industry Standard
AGAIN ???
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Case Study II (Continued):
Alert Limit
Average + 3s (standard deviation)
Action Limit
Binomial distribution
Probability of 3 or more alert limits happen in 10 minutes
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Case Study II (Continued):
Binomial Distribution:
Assume a process is producing some proportion of
non conforming units
non-conforming units.
Application:
Can tell the probability of getting k defectives in a
sample of n units.
The probability of three (3) or more above alert limit readings in 10 minutes
n
Pr (K = k ) = p k (1 P) nk
k
for k = 0, 1, 2, ..., n and where
n n!
=
k k ! ( n k )!
is the binomial coefficient "n choose k"
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Case Study II (Continued):
Choose P Value
From the engineering study fill data, the actual alert limit
conditions (particle count reading >50) happened at each port are:
Port 1: 4 readings from 752 in total; Port 2: 4 readings from 752 in total;
Port 3: 13 readings from 741 in total; Port 4: 8 readings from 746 in total;
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Case Study II (Continued):
Calculate Probability (2)
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Pr (k = 0) = (0.0175)0 (1 0.0175)100 = 0.8382;
0
10
Pr (k = 1) = ( 0 .0175 )1 (1 0 .0175 )10 1 = 0.1493;
1
10
Pr (k = 2) = (0.0175 ) 2 (1 0.0175 )10 2 = 0.0120;
2
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Case Study II (Conclusion):
Risk-based Approach
In compliance
Perform self-motivated risk assessment
Stay continuous and proactive
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Risk-based Approach In Two Case Studies
References
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Special Thanks to:
Bob Wiecenski
Senior Validation Associate, Validation Department
David Lorah
Supervisor, Validation Department
Greg Miles
Manager, Aseptic Fill Operations Department
John R
R. Mosack
Senior Director, Clinical Manufacturing & Validation
Interactive Exercise
Application discussion
Virtual data
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Q &A
Open item
www.medarex.com
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