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.

5

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

6

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

7

8

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

9

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

10

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

11

Plasma Coating Deposition Process

12

+ 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

15

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

16

Molding & Coating Process Parameter Controls

17

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

18

Image Plasma Coating Deposition

Optical Emission Spectra (OES) of Plasma

Plasma Light

Visible Light Spectral Signature of Coating Process

Gas Barrier Performance – Off Gas

19

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

21

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

22

23

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

24

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

25

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

27

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

29

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

30

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

32

CASE STUDY 3 – SILICONE OIL FREE LUBRICANT

33

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).

34

35

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

36

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

37

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

38

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.

39

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

40

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

41

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

42

Thank you for your time.

SiO₂ Medical Products, Inc.www.sio2med.com