impact of the vial capping process on residual seal force ... · seal force and container closure...
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1 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015
Impact of the Vial Capping Process on Residual
Seal Force and Container Closure Integrity
Roman Mathaes
AAPS NBC
Boston | 05/16/2016
Pharma&Biotech
2 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015
Roche Project
Head of Roche PTDE-P
Roche PTDE-PPrimary Packaging
Roche PTDE-PEstablished Product Support
Roche DP Fill&Finish Sites Roche DP MSAT Teams
Roche PTDUProcess Development
Roche PTDE-DVDevice Verification
3 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015
Outline
Introduction
Capping,
Regulatory
Framework
Lab scale
experiments
RSF, CT,
He-Leak
GMP
Manufacturing
Large Scale
capping
equipment
Conclusion
Process
parameter
setting
4 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015
Motivation
1. The capping process can impacts container
closure integrity (CCI) and can cause
cosmetic defects.
2. Authorities increasingly recognize the
criticality of the vial capping process (USP
<1207.3> revision).
3. Across the clinical and commercial
manufacturing sites a variety of capping
techniques and packaging configurations
are implemented.
4. Capping equipment independent methods
are insufficiently described.
Mathaes et al., The pharmaceutical vial capping process: Container closure systems, capping equipment, regulatory framework, and seal quality tests, EJPB, 2015
5 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015
Capping Associated Issues
Examples of defects
Scratches on vial neck, crimp cap wrinkles, scratches
on the crimp cap
Partially crimped vials
Dimpling rubber stoppers
Removal of the crimp cap upon flip-off button removal
CCI failure because of low stopper compression
Time consuming validation process
Subjective visual inspection of capped vials
Dimpling:
Partially crimped vials:
6 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015
Residual Seal Force
The RSF tester measures the force / distance
curve (green line).
The RSF (56 N, yellow line) is derived from the
minimum of the 2nd derivative of the force /
distance curve.
RSF
7 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015
Aim of the Project
• Define and investigate key capping process parameters
• Establish a capper independent method (residual seal force (RSF)
tester) to monitor the capping process
• Define a safe and robust RSF range for container closure systems
(CCS)
Improve the robustness of the capping process less risk for major
and minor defects
Standardize capping simplify the capping equipment validation
8 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015
Experiment Setup: Lab Scale
13 mm
20 mm
Serum D777-1
Serum D713
Lyo D777-1
Lyo D713
Datwyler
Datwyler
Datwyler
Datwyler
Datwyler
Datwyler
West
West
West
West
Vial neck Rubber stopper Crimp Cap
Serum West 50
Lyo West 50
13 mm
20 mm
Integra West Capper:
9 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015
Capping Equipment Settings
Key capping parameters
1. Capping force
2. Capping plate height
Setting No. Capping
plate to
plunger [mm]
Force [N]
1 9.19 44.48
2 8.86 44.48
3 8.48 44.48
4 8.35 75.62
5 7.98 222.41
1.
2.
Capping equipment settings
10 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
RSF 20mm Neck Vials
• Increased RSF with increased rubber
stopper flange height (West vs.
Daikyo).
• The rubber stopper shore A hardness
had only a minor effect (D777 vs.
D713).
Different rubber stopper types
1 2 3 4 50
20
40
60
80
100120140160180
*
RS
F [N
]
Capper Setting
D777 serum / Datwyler cap
D713 serum / Datwyler cap
W4432-50 serum / Datwyler cap
n=20
* *
* **
*
* **
**
RSF tester
Mathaes, R., Impact of Vial Capping on Residual Seal Force and Container Closure Integrity, PDA, 2016
11 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015
• The rubber stopper design had
only a minor effect.
Rubber stopper design (lyo vs. serum)
1 2 3 4 50
20
40
60
80
100120140160180 D777 serum / Datwyler cap
D777 lyo / Datwyler cap
n=20
RS
F [N
]
Capper Setting
*
*
*
*
RSF tester
Mathaes, R., Impact of Vial Capping on Residual Seal Force and Container Closure Integrity, PDA, 2016
RSF 20mm Neck Vials
12 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
RSF - Influence of the Flip-off Button
RSF without flip-off button RSF with flip-off button
2 3 4 2 3 40
20
40
60
80
100
120
140
LyoSerum
RS
F [
N]
West cap, without flip-off button
2 3 4 2 3 40
20
40
60
80
100
120
140
LyoSerum
RS
F [
N]
West cap, with flip-off button
10 20 30 40 50 600
20
40
60
80
100
120
140
160
180
200
Fo
rce
[N
]
10 20 30 40 50 60-10
-5
0
5
10
15
20
25
30without flip-off button
De
riva
tive
s
Distance (unitless)
RSF
10 20 30 40 50 600
20
40
60
80
100
120
140
160
180
200
Fo
rce
[N
]
10 20 30 40 50 60-10
-5
0
5
10
15
20
25
30with flip-off button
De
riva
tive
s
Distance (unitless)
13 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
RSF - Influence of the Flip-off Button
Measuring with flip-off button vs. without flip-off button
Mathaes, R., Impact of Vial Capping on Residual Seal Force and Container Closure Integrity, PDA, 2016
14 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
Extended characterization: Stopper Compression
Stopper compression as a function of RSF
CT measurements: Vial height measurements:
Stopper compression = Flange height before capping
Flange height before capping – Flange height after capping
15 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
Stopper Compression 20 mm Neck Vials
1 2 3 4 50
20
40
Sto
pper
Com
pre
ssio
n [%
]
Capper Setting
D777 Liquid / Datwyler
D777 Lyo / Datwyler
D713 Liquid / Datwyler
W4432-50 Liquid / Datwyler
W4432-50 Lyo / Datwyler
D777 Liquid / West
D777 Lyo / West
n=20
Rubber stopper compression is a function of RSF.
CT and vial height measurements showed good correlation.
CT measurements Vial height measurements
1 2 3 4 50
20
40 D777 Liquid / Datwyler
D777 Lyo / Datwyler
D713 Liquid / Datwyler
W4432-50 Liquid / Datwyler
W4432-50 Lyo / Datwyler
D777 Liquid / West
D777 Lyo / West
n=1
Sto
pper
Com
pre
ssio
n [%
]
Capper Setting
Mathaes, R., Impact of Vial Capping on Residual Seal Force and Container Closure Integrity, PDA, 2016
16 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
Rubber Stopper Defects
CT measurements: Visual inspection:
All formats were measured with CT and were visually inspected
Worst case Capper setting 6, D777-1 liquid, RSF = 101 N
The soft D777-1 liquid rubber stopper showed dimpling.
Mathaes, R., Impact of Vial Capping on Residual Seal Force and Container Closure Integrity, PDA, 2016
17 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
Defining an Adequate RSF Range for a CCS
• Vials capped with different capping equipment settings
• Measure RSF and use extended characterization methods
• Define a safety margin
• Define a secure RSF range for each CSS configuration
• Run commercial capping equipment in the secure RSF range
CCI or microorganism
tightness not assured
Partially folded crimp
cap
Secure RSF range Stopper dimpling /
rupture
Wrinkled crimp cap
?N 40 N 60 N 80 N ?N20 N
18 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
Example: Defining an Adequate RSF Range
0 N 40 N 60 N 80 N 100N20 N
1 2 3 4 5
• Vials capped with RSF 16 N – 101 N
• No vials showed helium leakage, vials with RSF 101 N showed dimpling
• Define a safety margin of e.g. 10 N
• Acceptable RSF range of 26 N – 66 N
• Capping equipment RSF set value 46 N
120N
13 mm Neck Vial, D777-1 liquid rubber stopper, West crimp cap
6
19 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
• Different process parameter
• Different formats
• Different capping equipment
Describe the key capping parameters for the
commercial capper
Ensure that commercially produced vials correlate
to the lab scale data
Experimental Setup: Drug Product Manufacturing
20 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
Capping Process Parameters
Commercial capping
equipment
Key capping parameter
1. Capping force
2. Capping plate height
3. Rotation speed of the turntable
1.
2.
21 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
Commercial Site: 6 ml Serum Vials
RSF measurements CT measurements
Influence of the capping pre-compression force
0
20
40
60
80
100
RS
F [
N]
8.1 mm 3.4 bar -10 % 6ml serum / Datwyler cap
8.1 mm 4.0 bar -10 % 6ml serum / Datwyler cap
8.1 mm 5.8 bar -10 % 6ml serum / Datwyler cap
n=30
**
0
10
20
30
40
50
Sto
pp
er
co
mp
ressio
n [
%] 8.1 mm 3.4 bar -10 % 6ml serum
8.1 mm 4.0 bar -10 % 6ml serum
8.1 mm 5.8 bar -10 % 6ml serum
The capping pre-compression force had only a minor influencing on RSF.
Mathaes et al., Critical Process Parameters of Capping Equipment used in GMP DP manufacturing, PDA, 2016
22 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
Commercial Site: 6 ml Serum Vials
0
20
40
60
80
100
RS
F [
N]
8.1 mm 4.0 bar -100 % 6ml serum
8.1 mm 4.0 bar -10 % 6ml serum
8.1 mm 4.0 bar -1 % 6ml serum
8.1 mm 4.0 bar +1 % 6ml serum
8.1 mm 4.0 bar +100 % 6ml serum
n=30
0
10
20
30
40
50
Sto
pp
er
co
mp
ressio
n [
%]
A
8.1 mm 4.0 bar -100% 6 ml serum
8.1 mm 4.0 bar -10% 6 ml serum
8.1 mm 4.0 bar -1% 6 ml serum
8.1 mm 4.0 bar +1% 6 ml serum
8.1 mm 4.0 bar +100% 6 ml serum
The rotation speed of the turntable had only a minor influence on RSF.
RSF measurements CT measurements
Influence of the rotation speed of the turntable
Mathaes et al., Critical Process Parameters of Capping Equipment used in GMP DP manufacturing, PDA, 2016
23 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
Commercial Site: 6 ml Serum Vial
0
10
20
30
40
50
Sto
pp
er
co
mp
ressio
n [
%] 8.4 mm 4.0 bar -10 % 6ml serum
8.1 mm 4.0 bar -10 % 6ml serum
7.7 mm 4.0 bar -10 % 6ml serum
The capping plate-plunger distance has a major influence on RSF.
RSF measurements CT measurements
Influence of the capping plate-plunger distance
0
20
40
60
80
100
RS
F [
N]
8.4 mm 4.0 bar -10 % 6ml serum / Datwyler cap
8.1 mm 4.0 bar -10 % 6ml serum / Datwyler cap
7.7 mm 4.0 bar -10 % 6ml serum / Datwyler cap
n=30 * **
Mathaes et al., Critical Process Parameters of Capping Equipment used in GMP DP manufacturing, PDA, 2016
24 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
Conclusion
RSF technology is a reliable and precise tool to characterize the
quality of the capped product in dependence of the capping process
parameters, independent of the used CCS and capping equipment.
Capping pre-compression force is not the only RSF influencing
capping process parameter.
Stopper compression can be measured by CT or vial height
measurements and is a function of RSF.
A secure RSF range can be defined with less risk of major and minor
defects
25 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
References
1. Mathaes, R., et al., The pharmaceutical vial capping process:
Container closure systems, capping equipment, regulatory
framework, and seal quality tests, EJPB, 2015
2. Mathaes, R., et al., Impact of Vial Capping on Residual Seal Force
and Container Closure Integrity, PDA, 2016
3. Mathaes, R., et al., Critical Process Parameters of Capping
Equipment used in GMP DP manufacturing, PDA, 2016
4. Mathaes, R., et al., The Pharmaceutical Capping Process -
Correlation between Residual Seal Force, Torque Moment and Flip-
off Removal Force, PDA 2016
26 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015
RSF - Influence of the Flip-off Button
GenentechRoche
Lonza: Drug Product ServicesHanns-ChristianMahler
www.lonza.com/[email protected]
Holger RöhlJürgen EderSascha DreherMichael LammelYves RoggoAlejandra Nieto