Impact of the Vial Capping Process on Residual Seal Force ... · Seal Force and Container Closure...

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


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


Outline

Introduction

Capping,

Regulatory

Framework

Lab scale

experiments

RSF, CT,

He-Leak

GMP

Manufacturing

Large Scale

capping

equipment

Conclusion

Process

parameter

setting


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


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:


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


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


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:


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


• 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


RSF 20mm Neck Vials


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)



Measuring with flip-off button vs. without flip-off button



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


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


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


W4432-50 Liquid / Datwyler

W4432-50 Lyo / Datwyler

D777 Liquid / West

D777 Lyo / West

n=1

Sto

pper

Com

pre

ssio

n [%

]

Capper Setting



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.



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


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


• 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


Capping Process Parameters

Commercial capping

equipment

Key capping parameter

1. Capping force

2. Capping plate height

3. Rotation speed of the turntable

1.

2.


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



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


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


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 +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.


Influence of the rotation speed of the turntable



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



The capping plate-plunger distance has a major influence on RSF.


Influence of the capping plate-plunger distance

0

20

40

60

80

100

RS

F [

N]




n=30 * **



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


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



GenentechRoche

Lonza: Drug Product ServicesHanns-ChristianMahler

www.lonza.com/[email protected]

Holger RöhlJürgen EderSascha DreherMichael LammelYves RoggoAlejandra Nieto


Thank you

Impact of the Vial Capping Process on Residual Seal Force ... · Seal Force and Container Closure...

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