Linking Component Selection to Drug Delivery

Linking Component Selection to Drug Delivery
Strategies in a Highly Competitive Market
West Pharmaceutical Services, Inc., Tibor Hlobik, Global Marketing Director, PFS Platform
Abstract
Companies developing biotechnology products in pre-filled
syringes are faced with a highly competitive market in leading
therapeutic categories. As a result, all players have to implement
new strategies to continuously improve their existing drug
brands as part of lifecycle management or introduce new,
superior products with better patient outcomes. At the same
time, these manufacturers are challenged to reduce total unit
cost, increase quality levels and ensure dose accuracy. Plungers
play a key role in these new strategies and must be carefully
selected especially with auto-injector drug delivery formats.
Costly issues such as particle contamination, high levels of
leachables forming during long term storage, and poor dose
delivery performance can be avoided by selecting the right
plunger product.
Product Overview
A new FluroTec® laminated and B2-coated 1mL long NovaPure®
plunger was industrialized to meet user requirements for 1mL
long staked needle syringes as defined by the International
Standards Organization (ISO) and intended for an auto-injector
device. Specifications and process controls were developed
using Quality by Design (QbD) principles and a defined Quality
Target Product Profile (QTPP).
A development framework was used to commercialize the new
FluroTec® plunger that included Concept Development (voiceof-customer, design options, prototype generation), Product
Development (design verification, validation, small scale testing)
and Industrialization (design transfer, large scale capacity, market
introduction). As shown in reference Figure #1, advanced
characterization techniques were applied for product and process
development that included assigning Critical Quality Attributes
(CQA) specifications, modeling using (FEA) Finite Element
Analysis, fabricating prototype designs and running design of
experiments (DOE). West modern materials (reference Table #1)
that are market proven were selected for the manufacture of the
NovaPure® plunger. Key quality targets for design of the new
plunger included in this study overview are summarized:
• High Process Capability Index (CpK) for rib and overall
height dimensions
• Loose particle control limits for sub-visible and
visible size ranges
• Consistent break loose and gliding forces over
long term storage
• 100% vison verified for dimensional and visual attributes
Figure #1. Product and Process Development Examples
Table #1. Plunger Material Overview
Material
4023/50
Gray
Description
Plunger Attribute
Bromobutyl
Elastomer Formula
- Complies to global Pharmacopeia
- Low potential extractables profile
FluroTec
Fluoropolymer
Laminate Film
- Minimizes leachables formation
- Low drug adsorption and absorption
B2
Cross-linked
Silicone Oil
- Low particle levels in sub-visible range
- No need for added silicone oil
®
Study #1. Dimensional Analysis
Methodology: To develop process capability data, production
batches of the 1mL long NovaPure® plunger were collected for
dimensional analysis and analyzed by a SmartScope® image
analysis that includes solid state illumination sources, camera,
supporting touch probe, laser scanner and micro-probes and
using West test method FTM033-3 “Operation of Smartscope®”.
• Custom fixture and preprogrammed for configuration
• Test 50 samples total from each batch
• Calculate values once all dimensional results are recorded
• Report average, maximum and minimum for CpK values
Results: All plunger batches tested showed very consistent
dimensional control for ribs 1, 2 and 3 and overall plunger
height as calculated by CpK (reference Table #2) for attributed
studied and met release criteria for >1.33 CpK.
Figure #2. Plunger Design
Table #2. Process Capability
Dimensional
Attributes
Average
CpK
Minimum
CpK
Maximum
CpK
1st Rib Diameter
2.74
2.06
3.59
2nd Rib Diameter
3.47
3.09
3.67
3rd Rib Diameter
3.23
2.85
3.59
Overall Height
2.11
1.82
2.53
Study #2. Particle Analysis
Methodology: Baseline particle data was established on
production batches of the 1mL long NovaPure plunger. Samples
were steam sterilized in a ready to use (RU) format and evaluated
for sub-visible and visible loose surface particulates. The particles
were collected on membrane filters, measured, counted along
with shapes analyzed by a Clemex image analysis system and
according to West test method Particle-21 “Determination of
Sub-visible and Visible Particles on Rubber Closures by Clemex.”
·L
oose particles were collected from 400 cm2 of plunger
surface area.
· Plungers placed in 200mL of Tween 80 water solution.
· Plungers were agitated in a flask on a rotary shaker.
· Solutions were passed through 0.45 μm membrane filter.
· Blanks were prepared in the same manner.
· Particles on the filters were then evaluated.
Figure #4. Force Profile Syringe Manufacturer 1
Figure #8. Force Profile Syringe Manufacturer 3
Figure 5. S
tatistical Average and Standard Deviations
Syringe Manufacturer 1
Figure #9. S
tatistical Average and Standard Deviations
Syringe Manufacturer 3
Results: All plunger batches analyzed showed very low particle
levels as summarized in Table #3 and well below target specifications for visible particulate levels. Sub-visible (<25.0 µm)
particle results were collected for baseline purpose and to
establish capability for a target specification.
Table #3. Particle Control Limits
Particle Size
Ranges
Specification
(# particles)
Average
Minimum
Maximum
≥5.0 µm but
<10.0 µm
For information
10.8
5.3
14.0
≥10.0 µm but
<25.0 µm
For information
9.6
5.2
12.2
≥25.0 µm but
<50.0 µm
≤ 10.0/10 cm²
1.7
1.1
3.0
≥50.0 µm but
<100.0 µm
≤ 1.6/10 cm²
0.4
0.2
0.6
≥100.0 µm
≤ 0.4 /10 cm²
0.1
0.1
0.2
Study #3. Functional Analysis
Methodology: Syringe performance analysis as measured by
break loose and gliding forces was completed using autoclave
steam sterilized, ready-to-use plungers assembled with water
filled 1mL long ISO staked needle 27G ½” syringes from three
manufacturers. Test parameters and conditions included
• Vacuum plunger placement with KT Manufacturing Co.,
Ltd. Machine (see Figure #3)
• Filled units stored in syringe tubs with needle facing down
• Filled units stored at real-time condition (23°C ± 3°C)
• Testing time 0, 6, 12, and 24 months
• 30 samples tested for each syringe manufacturer
per condition
• West method Instron-43: Determination of Breakfree and
Extrusion Forces for Prefilled Syringes. - Test speed 304.8
mm/min for a distance of 30mm
Results: The study showed that the 1mL Long NovaPure
plunger 4023/50 Gray performed statistically similar (@ 0-5mm,
14mm and 28mm extension points) within the three syringe
manufacturers. Overall the NovaPure plungers exhibited very
consistent, smooth gliding force profiles and maintained the
profile during the 2 year test period. See Figures #4 thru #9.
Figure #6. Force Profile Syringe Manufacturer 2
Conclusion
Critical quality attributes and specifications of NovaPure®
plungers are intended to minimize risks associated with particle
contamination, leachables formation, visual defect rejections
and variability of high injection forces in a syringe. The new
plunger design in combination with statistical process control
of rib and overall height diameters result in very consistent
break loose and gliding forces between 3-5 newtons (average
with water) as studied over a 2 year period with glass barrels
from three manufacturers. Most spring activated auto-injector
devices rely on predictable break loose and extrusion forces for
repeatable dose time accuracy.
Figure #3. KT Stoppering Machine View
A 1mL long plunger NovaPure® developed using QbD principles
in 4023/50 Gray FluroTec® plunger was industrialized to meet
user requirements for biologic drugs in a 1mL long staked
needle syringe and drug delivery strategies that include an
auto-injector device for brand differentiation. The knowledge
gained throughout the QbD process can be used on an ongoing
basis to maintain continuous improvement by the manufacturer.
Acknowledgements
Figure #7. S
tatistical Average and Standard Deviations
Syringe Manufacturer 2
Alexis Kopp, Sr. Specialist, Technical Support of
West Pharmaceutical Services, Inc.
Simon Cote, Technical Support Engineer of
West Pharmaceutical Services, Inc.
FluroTec®, NovaPure® and West and the diamond logo are registered trademarks of
West Pharmaceutical Services, Ltd., in the United States and other jurisdictions.
FluroTec® and B2-coating technologies are licensed from Daikyo Seiko, Ltd.
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