1. Particle Reduction Guidance From Industry (West Pharmaceutical Services):
Background:
Maintaining a high level of quality for all primary product contact surfaces is critical,
specifically for the final container and closure for injectable drug products. The container
and closure must meet GMP requirements for sterility, endotoxin and particulate limits.
Case Study:
This case study focuses on developing a component (closure) processing cycle that
effectively reduces endotoxin and sterilizes the components, while minimizing particulate
generation during the process. Developing an efficient processing cycle was especially
challenging given the sometimes aggressive nature of the processing steps.
Nevertheless, these components are required to be endotoxin and particulate free, sterile
and must function smoothly on the filling line. Processing steps, such as washing,
sterilization and drying, had to be carefully designed in order to meet the GMP
requirements, while avoiding over processing which resulted in particle generation,
damage to the components and potential improper function on the filling line.
Particle Reduction During Component / Closure ProcessingParticle Reduction During Component / Closure Processing
Lifting Device:
• Automated lift system
• Programmable paths for vessel docking to
filling line
• Compatible with different vessel sizes and
isolator configurations
• Ergonomic
Process / Transfer Vessel:
• Perforated diffusion plate
• Variable sizes (10-300 liter volumes)
• Sealed upon process completion
• Compatible with lift system
• Butterfly valve for transfer to isolator
• Beta port flange for RTP connection at filling line
GMP Requirements for Components:
• Endotoxin free – validated for > 3-log
reduction of bacterial endotoxin
• Sterile – validated for a Sterility
Assurance Level of > 10-6 , Spore
Log Reduction > 12
Replicate cycles including:
• Vessel filling with WFI
• WFI overflow
• WFI / pharmaceutical air flow
• Vessel draining
Critical Parameters:
• WFI Temperature
• WFI flow rate
• Pharm air bubbling pressure
• Time
Challenges:
• Meeting GMP requirements for
endotoxin reduction and sterility without
generating particles
• Defining the requirements for particle
reduction
Solution:
Using a detachable vessel component processor, a cycle
was developed for the components which included slow
vessel rotation and gentle pharmaceutical air bubbling during
the wash process, thus preventing damage to the
components. Slow vessel rotation and pulsed vacuum /
pressure helped to minimize particle generation during the
drying and cooling process steps.
Cycle development using specialized component processing
equipment was critical, given the requirements and risks
involved. Unique parameters for washing, sterilization,
siliconization, drying and cooling were 100% configurable,
allowing for optimizatioin of the cycle during development.
These configurable parameters include filling under vacuum,
rotation speed / angle / frequency, pharmaceutical air flow
(bubbling pressure) and pulsed drying pressure /
temperature.
Wash / Rinse Sterilization
• Pre-vacuum pulses
• 123oC steam
• 30 minutes steam exposure
Critical Parameters:
• Pressure
• Temperature
• Time
• Rotation speed / frequency
Drying
Alternating pulses including:
• Vacuum
• Pressure
• Continuous addition of hot,
dry, sterile filtered air
Critical Parameters:
• Air removal
• Steam quality
• Time
• Temperature
Critical Parameters:
• Temperature
• Time
• Rotation speed / frequency
Cooling
Alternating pulses including:
• Continuous addition of cool,
dry, sterile filtered air
Process Trend
Unclassified
Cleanroom
Grade C or D
Vessel
Process Station
Transfer Lift at
Filling Line
Loading Station
Component Processing Equipment Features
Process Station:
• Clean utilities (WFI, clean steam,
pharmaceutical air)
• Rotates process vessel
• Detergent and silicone capabilities
• PLC with customizable programs
Reporting Category Enhanced Specification
(particles / 10cm2)
PCI < 2.5
> 25µm but ≤ 50µm < 13
> 50µm but ≤ 100µm < 3.5
> 100µm < 0.9
Proved Clean Index Particle Count
Component Flow:
Remove Foreign Particles and Minimize Particle Generation
Stopper Inoculation:
• Artificially inoculate stoppers with
particles of known quantity and size
(rubber, plastic, aluminum, hair)
• Process stoppers
• Recover inoculated stoppers
• Inspect for particulate material
• Recover 100% particulate material in
drain filter
Particle Counting (Rinse Water):
• Liquid particle counter installed in processor drain
piping, recording in real time
• Overflow water – smaller, lower density particles
are removed
• Drain water – larger, higher density particles are
removed
• Information used to develop cycle parameters
(overflow time and replicate filling/draining cycles)
Particle Counting (Processed Stopper):
• Conducted in laboratory under laminar
air flow with validated methodology
• Standard Operating Procedures
• Sample stoppers after processing and
recover particles
• Count particles by filtering and viewing
filter under a microscope or with a
liquid particle counter
Inoculated
Components
Example:
0.5 mm
aluminum
particle
2.5 mm
hair
25-50 µm 50-100 µm >100 µm PCI
Total Particles 83 17 4 NA
Particles per 10cm2 8.3 1.7 0.4 1.6
Specification ≤ 13 ≤ 3.5 ≤ 0.9 ≤ 2.5
Particle Load
Assessment
Example: