Presentation from 2010 Stoppers and Elastomers Consference in Cologne, Germany

1. Siliconization
of Stoppers
Aaron Mertens
Atec Pharmatechnik
Sörup, Germany

2. Presentation Overview
• Stopper Types
• Stopper Processing Steps and
Performance Requirements
• Stopper Processing Equipment Types
• Siliconization Process Details
• Challenges in Siliconization of Stoppers

3. Stopper Types
• Serum stoppers
• Freeze dry stoppers
• Plungers

4. Stopper Processing Steps
• Washing
• Rinsing
• Siliconization
• Sterilization
• Drying / Cooling
• Transport / Storage
• Transfer to Filling Line

5. Washing
• Goal: Endotoxin and particle reduction
• Process: Use WFI and detergent (if required)
to remove contaminants.
• Performance Requirements (endotoxin):
3 log reduction of endotoxin.
• Performance Requirements (particulate):
Use USP limits for product particle levels.

6. Rinsing
• Goal: Remove residual detergent, final
removal of endotoxin and particles.
• Process: Same as Washing, without
detergent.
• Performance Requirements: Demonstrate
complete removal of detergents from rinse
water.

7. Siliconization
• Goal:
 Evenly coat surfaces of the stopper with
silicone oil.
 Smooth transfer of stoppers to filling line.
 Smooth processing on the filling line.
 Correct stopper insertion into product vial or
expression of syringe plungers.
Syringe
Freeze dry

8. Siliconization (cont)
• Processing Method 1:
 Silicone oil is measured and added directly
to the stopper load.
 Addition to stoppers prior to filling with WFI.
 Addition during WFI filling.
 Rotation or tumbling of stoppers.
 Drain WFI and surplus silicone.

9. Siliconization (cont)
• Processing Method 2:
 Silicone oil and WFI are added to an
intermediate vessel for mixing into an
emulsion.
 Emulsion is added to the process and
stoppers along with WFI.
 Sparge with pharmaceutical air (filtered) to
agitate and move stoppers.
 Drain WFI and surplus silicone.

10. Siliconization (cont)
• Performance Requirements: Stoppers must work
well on filling line. Stoppers must form a seal with
container (pass Container/Closure Integrity Testing).
• Verification Testing:
 Line trials for stopper handling on the filling line.
 Container / Closure Integrity Testing.
 Extraction from stoppers using methyl isobutyl
ketone and quantified using Atomic Absorption.
 Micro Flow Imaging (MFI)
 Infrared Spectroscopy

11. Sterilization
• Goal: Sterilize all surfaces of the stoppers.
Sterilize piping used for drying and cooling of
stoppers.
• Process: Saturated clean steam (temperature
121-123°C) for 20 minutes is a typical cycle.
• Performance Requirements: Validated
sterilization cycle for stoppers and piping, per
standard regulatory requirements.

12. Drying
• Goal: Remove moisture from stoppers.
• Process: Alternating pulses of vacuum and
pressure are used to dry the stoppers.
• Performance Requirements: Final moisture
content of the stoppers depends on the final
intended use.

13. Cooling
• Goal: Reduce the temperature of the stopper
load.
• Process: Cold, sterile filtered air flows through
the stopper mass until the target temperature
is achieved.
• Performance Requirements: Typically the
cooling process continues until a final
temperature of 35 °C is achieved.

14. Transport / Storage
• Goal: To maintain the quality of the stoppers until time
of use at the filling line.
• Methods: Depending on the stopper processing
equipment used, different transport and storage
methods are possible.
 Sealed vessel with overpressure
 Intermediate container
 Bags
• Performance Requirements:
 Stoppers must remain sterile and endotoxin free
until insertion into vial.
 Minimal clumping / sticking

15. Transport / Storage Methods
Bags
(with and without port)
Intermediate container
Pressurized vessel

16. Transfer to Filling Line
• Goal: Transfer stoppers to filling line (RABS or isolator) without
introducing contaminants.
• Methods: Depending on the stopper processing equipment used,
different transfer methods are possible.
 Through rapid transfer port (RTP)
 Pass through addition using intermediate container
 Manual addition to line through glove ports
• Performance Requirements:
 Stoppers must remain sterile and endotoxin free until insertion
into vial.
 Stoppers must flow from storage container into filling line

17. Transfer Methods
Transfer to filling line
through RTP
Using glove ports
RTP docked vessel

18. Stopper Processing Equipment
• Autoclave – siliconization NOT possible
• Rotating Drum
• Process Station with Mobile Vessels

19. Rotating Drum
Processing System Internal Drum

20. Rotating Drum Processor
Key Features
• Silicone addition by tumbling stoppers through
the silicone bath
• Uses a cleaning cycle with specific detergent
to help remove silicone between batches

21. Process Station with Vessels
Process Station Detachable / mobile
vessel on trolley

22. Process Station with Vessels
Key Features
• Silicone emulsion
• Emulsion added to WFI supply during filling
• Uses a cleaning cycle with specific detergent
to help remove silicone between batches
• Can dedicate vessels for siliconized and
nonsiliconized stoppers

23. Silicone Process Detail
• Silicone dosing
 Pump and pressure switch
 Overpressure and flow meter
• Silicone mixing
• Silicone addition to stoppers
• Pharm air sparge
• Vessel rotation
• Draining

24. Siliconization Equipment (with pump)
Storage Tank Mixer
Emulsion Tank
Pressure switch
Dosing Pump

25. Silicone Dosing

26. Silicone Mixing

27. Siliconization

28. Sparging

29. Siliconization Equipment
Storage Tank
Mixer
Dosing Pump
Emulsion Tank

30. Challenges
• Residual silicone remaining in the processing
equipment
• Applying a consistent amount of silicone
 Distribution within a batch
 From one batch to the next
• Measuring siliconization effectiveness
 Positive correlation between silicone
amount added to process and amount
applied to stopper

31. Challenges (cont)
• Too much silicone
 Stoppers do not stay inserted
 Contamination of product
• Too little silicone
 Stoppers do not insert properly
 Clumping / stickiness
 Poor processing on filling line

32. Conclusions
• Stopper siliconization is part of an integrated
process
• Stopper processing is regulated
• Siliconization is not regulated
• Siliconization process must be predictable
• Siliconization process must be reproducible
• Two types of stopper processing equipment

33. Questions?