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Advanced In-Process Monitoring & Traceability for Primary Container
ManufacturingProf. Robert Langer and Dr. Christopher Weikart
1
Presentation Overview
Technology & Coating Description Manufacturing Processes Process Controls & In-line Inspection Case Studies
– Zoledronic Acid Leachables Study– Lyophilization Study– Silicone Oil-free Lubricant
2
TECHNOLOGY & COATING DESCRIPTION
3
4
Technology Overview Molded Primary Containers
• Medical Grade Cyclic Olefin Polymer (COP)• Customizable designs (vials, syringes, cartridges) • Optically clear & impact resistant• High barrier to water vapor
Interior Coating System • Silicon-based plasma deposited coating• High barrier to oxygen• Barrier to label adhesives & polymer additives/oligomers• Optically clear
Exterior Coating System• Hybrid cross-linked coating• Scratch & impact resistant• Static charge resistant• Optically clear
Internal Coating ArchitectureCoated COP containers have an oxygen barrier approaching glass and blocks potential leachables into the drug product. A silicone oil (PDMS) free lubricant with low particulates & forces.
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Top pH Protective Layer
Barrier to Oxygen & Leachables
Adhesion to COP
SiO2
SiOxCyHz
Protective
Barrier
Plastic Container
Adhesion
Lubricant
<0.7
5µm
Silicone Oil Free Lubricant
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External Coating ArchitectureAnti-scratch/anti-static coating enables COP containers to be processed on standard glass container filling equipment without imparting scratches or static charge.
Hybrid Cross-linked Coating
Nanocluster (10-15µm)
Nanocluster (10-15µm)
Nanocluster (10-15µm)
Organic Cross-links
Inorganic Network
Plastic Container
Anti-scratch/Anti-static5µ
m
MANUFACTURING PROCESSES
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Differences in Manufacturing Practices
Current Industry
Containers made of one material (either all glass or all plastic)
Glass composition varies from batch to batch due to natural origin and high dimensional variability
Manufacturing traceability by batch
Different levels of quality by product segmentation (AQL Sampling)
SiO2 Medical Products, Inc.
Engineered polymer with inherently low composition & dimensional variation
100% checks on all parts for Critical Quality Attributes: chemistry, coating presence, functionality, dimensions and particles
Manufacturing traceability by individual container and batch (unique ID)
A hybrid material container leveraging the properties of each material to its function
One level of quality – six sigma - 100% process monitoring and inspection
100% checks on tubing dimensions and cosmetic defects on top tier offerings
• A unique identification code on each container– Manufacturing record is unique to container &
batch• 25 in-process 100% inspection & control systems
– All Critical Quality Attributes (CQA)
SiO2™ Manufacturing Processes
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Raw Materials
Molding
Barrier Coating
Packaging
Sterilization
Final Product
Inspection
Inspection
Inspection
Unique ID Added
• Fully automated container manufacturing– For molding, coating, and packaging unit operations
• Coating process in ISO Class 5 over the product– All processes in an ISO Class 7 environment
Silicone Oil Free
Lubricant
Inspection
Syringe Injection Molding Process
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1. Needles loaded in magazine and blade picks up
2. Needle transferred from blade into robot via
vacuum
3. Robot delivers needle to mold
5. Needle mechanically
bonded to syringe
4. Syringe molded around the
needle
Gripper Needle held by vacuum
Mold Cavity
Mold Cavity
COPResin
Needle Magazine
Blade
Melted and delivered to injection mold
Mol
ding
No Adhesive or Tungsten Contaminants
A Unique Identification on Every Container
• Individual unit serialization and tracking
• Electronic records for each unit provide step manufacturing process data
• Full product traceability and anti-counterfeiting
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Plasma Coating Deposition Process
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+ 12 O2 2 SiO2+ 9 H2O + 6 CO2
Coa
ting
Power System
Vacuum System
Gas System
Ready to Use Packaging• Cyclic Olefin Polymer containers with an internal barrier coating system• Sterilized by ethylene oxide, gamma or e-beam• Endotoxins below detection limit
13Syringes Vials
Pack
agin
g
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Process Controls & In-line Inspection
In-Process Inspection & ControlsIndependent 100% inspection systems (patented) are each six sigma, therefore guaranteeing a six sigma-plus quality level:
1. Process parameter monitoring and controls for molding and coating
2. Finger print identification of plasma – Optical Emission Spectra (OES) &
cameras
3. Barrier Properties – Diffusion measurement differential of coating
4. Particles – Vision system
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Molding & Coating Process Parameter Controls
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Molding (Shot Size) Coating (Monomer Flowrate)
Upper Limit
Lower Limit
Outliers
Lower Limit
Upper Limit
Outliers
Shot
Siz
e (m
m)
(sccm = standard cubic centimeters per minute)
Coating Parameters Tracked(500+)
Molding Parameters Tracked(100+)
Plasma Light Monitoring – Vision & OES Systems • Real-time monitoring and data acquisition of the plasma light using a vision
system and Optical Emission Spectroscopy (OES)• OES analyzes discrete light wavelengths for process control monitoring
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Image Plasma Coating Deposition
Optical Emission Spectra (OES) of Plasma
Plasma Light
Visible Light Spectral Signature of Coating Process
Gas Barrier Performance – Off Gas
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Uncoated
Coated with Defects or too Thin
Coated within Specifications2.00E-07
2.10E-07
2.20E-07
2.30E-07
2.40E-07
-0.0005 0.0005 0.0015 0.0025 0.0035OTR (cc/syringe/day)
0-5 sec
7 Sec
10 Sec
Mas
s Flo
w c
c/C
O2
Transfer
CO2 Adsorption
Air CO2
Measure CO2 Desorption
Head-Space CO2
Adsorbed CO2Process Steps
In spec UncoatedOut of spec
Visible Particle Control Strategy Minimize manual part handling using
automated molding and coating cells
In-process controls at molding and coating to mitigate particle generation and cosmetic defects
Empty container inspection -- Automated, on line particle inspection for empty containers. Detect ≥ 50µm particles
– Acquires 8,000 pixels/column in 25 microseconds– 6,000 columns stitched together– Part rotated at 60rpm 20
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Chemical, Thermal & Mechanical Stability
Chemical Stability• pH 3.5-8.0• Surfactants (e.g. Tween)
Thermal Stability• (-196) – 60°C• Freeze thaw cycling• Freeze drying (Lyophilization)
Mechanical Stability• <1500lbs top down compression• <700lbs side compression
Robust Silica coated COP containers functional over broad range of challenges:
CASE STUDY 1 – ZOLEDRONIC ACID LEACHABLE STUDY
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Zoledronic Acid Leachables Study Filed a Type II variation of a European national marketing authorization for
zoledronic acid packaged in coated 6ml COP vials.
Bisphosphonates (e.g. zoledronic acid), are widely used drugs known to chelate
with residual metal ions present in borosilicate glass resulting in particulates.
Leachables study was performed to examine the potential advantages of silica-
coated COP vials (6ml) for zoledronic acid (4mg/5ml) packaging
• Real-time aging at (250C/60% R.H.)
• Accelerated aging at (400C/75%R.H)
Zoledronic Acid
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SiO2’s engineered, silicon-based coating system is manufactured from gas and does not contain any metals. Avoids metal ion contamination which occurs as a result of delamination in borosilicate glass containers.
Silica (Silicon Dioxide) Borosilicate Glass
Zoledronic Acid Leachables Study
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NDNDND ND
Inorganics(ICP-OES: 72hrs in pH 2.5 @ 50°C)
Zoledronic Acid Leachables Study
Extra
cta
ble
s (p
pb
)
ND – Not Detectable
26
Zoledronic Acid Leachables StudyPurpose: Determine amount of leachable compounds in zoledronic acid solution (4mg/5ml) after 6 months real-time aging at 25°C/60%RH
Analytical Methods (after extraction):• Volatile organic compounds (HS-GC/MS)• Semi-volatile organic compounds (GC/MS)• Non-volatile organic compounds (HRAM-UPLC/MS)• Elements (ICP-OES)• Anions (IC)
Fluorinated BromobutylStopper
Coated COP Vial
4mg Zoledronic Acid200mg Mannitol24mg Sodium Citrate5ml WFI
Test Article
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Zoledronic Acid Leachables StudyLeachable Results (6 months real-time)
• Volatile organic compounds: < AET• Semi-volatile organic compounds: < AET• Non-volatile organic compounds: < AET• Elemental Compounds: < limit of quantification• Anions (IC): trace amounts (≤ 0.05µg/ml) of formate and acetate
Silica-coated COP vials are appropriate primary containers for zoledronic acid.
Analytical Evaluation Threshold
AET < 0.15µg/ml or 0.75 µg/vial
No compound identification because amounts are below AET
CASE STUDY 2 – LYOPHILIZATION STUDY –BREAKAGE, PARTICLES & PROTEIN AGGREGATES
28
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Samples Type (6ml):• Silica coated COP Vials• COP Vials• Glass Vials
Set-up:• Lyo-Vials with temperature Sensors
in freeze dryer
9
123
5 4
8 7
6
Lyophilization Study – Experimental Setup
Solution: 7.5% Mannitol in WFI
Tem
pera
ture
(°C
)
Pres
sure
(mba
r)
Time (hours)
temperature
pressure
Lyophilization Study - Breakage
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Vial Type Number of Broken Vials
Type I Glass 13/20
COP 0/20
Silica-coated COP 0/20Silica-coated
COP
Type I Glass
(10% Mannitol Solution/6ml Fill Volume)
Professor Ted Randolph: University of Colorado-Boulder
Lyophilization Study - Particles
31Vial Type
Glass Uncoated COP Trilayer COP
Par
ticle
Con
cent
ratio
n >2
mic
ron
(#/m
L)
0
1000
2000
3000
4000
Before lyophilization After lyophilization
Type I Glass COP Silica-Coated COP
(10% Mannitol Solution/6ml fill Volume)
*Particle analysis by FlowCAM® microflow digital imaging which detects particles between 2 -100 µm.FlowCAM® is a registered trademark of Fluid Imaging Technologies Inc.
Professor Ted Randolph University of Colorado-Boulder
Lyophilization Study - Summary No breakage compared to high breakage in Type I glass No differences were observed on coated COP vials after lyo with:
(1) barrier properties, (2) coating integrity and (3) overall coating thickness
The barrier coating remains fully intact after lyophilization:– Temperature range (-40°C to + 40°C) – Pressure (0.05 to 1000.0 mbar)– Over a time of 65 hours
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CASE STUDY 3 – SILICONE OIL FREE LUBRICANT
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Protein Aggregation with Silicone Oil“We found that the presence of silicone oil microdroplets in OVA formulations caused structural perturbations in the protein which were detected after only relatively short periods of exposure to silicone oil-water interfaces.”
– In Vivo Analysis of the Potency of Silicone Oil Microdroplets as Immunological Adjuvants in Protein Formulations: Chisholm et. al., J. Pharma. Sci., 104, 3681-3690, (2015).
“[Silicone oil] may be responsible for the phenomenon of soluble-protein loss… and the irreversible adsorption of protein may be associated with protein denaturation/aggregation.”
– Mechanistic Understanding of Protein-Silicone Oil Interactions: Li et. al., Pharm. Res., 29, 1689-1697 (2012).
“The most probable explanation for silicone oil induced aggregation is that the oil has direct effects on intermolecular interactions responsible for protein association through interaction with protein surfaces or indirectly through the effects of the solvent.”
– Silicone Oil Induced Aggregation of Proteins: Jones, et. al., J. Pharma. Sci., 94, 4, 918-924 (2005).
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Guidance from The FDA – Aggregates & Immunogenicity“Interactions between therapeutic protein products and the container closure may negatively affect product quality and immunogenicity.”
“Silicone oil-coated syringe components provide a chemical and structural environment on which proteins can denature and aggregate.”
“Leached materials from the container closure system may be a source of materials that enhance immunogenicity, … , including the following:…”
• “Organic compounds with immunoglobular activity may be eluted from container closure materials by polysorbate-containing formulations…”
• “Metals that oxidize and aggregate therapeutic protein products” … “have been found in various products contained in prefilled syringes and vials.”
Immunogenicity Assessment for Therapeutic Protein Products; US Dept.of Health and Human Services; FDA, CDER, CBER; Aug 2014.
Silicone-Free Oil Lubricant – System Solution
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Enabling “Lubricant” Features:
• No silicone Oil
• Applied to the syringe barrel by plasma deposition (PECVD) as a solid material
• Consistent Plunger Forces
• Lubricant supports the use of all standard industry plungers
• Low extractables
• Low particles: < 2000 (2-50µm size)
Buty
lR
ubbe
r
Top
Lubricity Coating
BarrierAdhesion
Plastic Container
Plasma Lubricant Coating
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Silicone Oil on Glass New Lubricant on SiO2 Coated Syringe
Plunger Force Profile & Consistency Comparison1ml water
ETFE-Coated Plunger
Fi FmFi Fm
Initiation Force (Fi): 9±2N Maintenance (Fm): 3±1N
Initiation Force (Fi): 10±2NMaintenance (Fm): 4±1N
0
10
20
30
40
0 10 20 30 40 50 60
Forc
e (N
)
Displacement (mm)
0
10
20
30
40
0 10 20 30 40 50 60
Forc
e (N
)
Displacement (mm)
after 2 years after 2 years
Constant Applied Force @ 300mm/min
After 7 days stored at RT
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Particulates – Microflow Imaging (MFI)(Particle Diameter Range: 2-50µm)
• Filled w/ Citrate Buffer Solution• 10min shake @ 1000rpm• Solution expressed through
needle into MFI injection port
1ml
ETFE-Coated Plunger
Meets USP 788 & 789
*Particle analysis by FlowCAM® microflow digital imaging which detects particles between 2 -100 µm.FlowCAM® is a registered trademark of Fluid Imaging Technologies Inc.
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Analytical Experiments:• Solvents: H2O, H2O (pH 4), H2O (pH 8), IPA• Spiked Solvents: 4 different siloxane compounds • Procedure: whole article, boiled under reflux for 24 hours. Five (5) syringes in
200 mL, 50-mL aliquot concentrated to 1 mL.• Semi-volatile compounds: (GC-MS w/ EI)• Non-volatile Polar compounds: (HPLC-UV-MS w/ APCI)• Volatile Impurities & Residual Solvents: (HS GC-MS)
Extractables Testing
200ml
Heat
Extraction Test Setup
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Aqueous extractions: • No compounds exceeding AET (0.75µg/syringe)• No peaks were attributable to extracted siloxane compounds
IPA extractions (rigorous): • Peaks associated with siloxane compounds were found in extracts• Specific siloxane compound identification was not conducted because
each compound was below the AET (0.75µg/syringe) Spiked Extract Identification:
• None of the four spiked siloxanes were recovered from aqueous extracts• All four siloxanes were recovered from IPA extracts
Extractables Testing
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Toxicology Assessment of Silicone Oil Free Lubricant
Report Title: Literature-Based Toxicological Assessment of Siloxane Leachable Targets
Report: No. MCS-SR001A, October 13, 2013 Prepared by: SciScout LLC Summary: Siloxane leachable targets extracted from the device, at the
maximum possible exposure concentrations, do not pose a significant concern for human health risk, from pediatric through geriatric populations for local or systemic exposures to the leachable targets that may occur during the suggested clinical use of the device.
No siloxane compounds exceeding maximum exposure concentrations
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Thank you for your time.
SiO₂ Medical Products, Inc.www.sio2med.com