for Parenteral Syringes and Cartridges Dr. Christopher Weikart - - PowerPoint PPT Presentation

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for Parenteral Syringes and Cartridges Dr. Christopher Weikart - - PowerPoint PPT Presentation

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Next Generation Lubricant Technology for Parenteral Syringes and Cartridges Dr. Christopher Weikart Chief Scientist SiO 2 Medical Products, Inc. 1 2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

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Next Generation Lubricant Technology for Parenteral Syringes and Cartridges

  • Dr. Christopher Weikart

Chief Scientist SiO2 Medical Products, Inc.

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

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 Problems with Silicone Oil

  • Drug Stability
  • Syringe/Device Performance

 Comparison of Silicone Oil and SiO2 Lubricant  How the SiO2 Lubricant is Applied

  • Balancing Performance Attributes

 Plunger Force Performance  Particulate Performance  Extractables – Toxicology Assessment

Overview

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

The Problem with Silicone Oil – Scientific Literature & FDA

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“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] maybe 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).

“Silicone oil-coated syringe components provide a chemical and structural environment on which proteins can denature and aggregate.”

  • Immunogenicity Assessment for Therapeutic Protein Products; US Dept.of Health and Human Services;

FDA, CDER, CBER; Aug 2014.

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

Silicone Oil New Lubricant

Application to Syringe Barrel Spray a solvent or emulsion based solution with polydimethylsiloxane Plasma Enhanced Chemical Vapor Deposition (PECVD) Plunger Force Control Increase molecular weight & cross-link PECVD process parameters (cross-link) Subvisible Particles (<15µm) (Particle Count/ml) Range (30,000 – 50,000) Range (500 - 1,000) Coating Distribution After Aging Migrates over time Stationary until plunger moves Molecular Structure Linear chain polymer - Polydimethylsiloxane Amorphous, crosslinked polymer

Contrasting Silicone Oil & New Lubricant

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

 Measured by optical reflectance spectroscopy

  • Non-destructive
  • Fast (1-2 seconds/measurement)
  • Adaptable for vials, syringes, and cartridges

 Average lubricant coating thickness was 460 nm and its volume estimated at 0.15 µL

  • This is less than half the volume of silicone
  • il on 1mL glass syringes (approximately

0.5 µL)

 Thickness distribution and volume of lubricant can be tailored to virtually any syringe or cartridge size by the PECVD process

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New Lubricant Thickness Distribution Mapping

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

New Lubricant Deposition Process - PECVD

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Octamethylcyclotetrasiloxane

Ar + O2

Plasma Enhanced Chemical Vapor Deposition (PECVD)

Hollow Cathode Plasma + O2 + Ar + CO2+ H2O + Ar Plasma

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

Controlling Lubricant Cross-link Density

7 Lubricant Coating Chemically Resistant Protective Coating Barrier Coating

Plasma Energy Density = Applied Energy Mass of Gas Mixture

How do you characterize and tailor this & why? Plasma Energy Density (KJ/kg) Cross Link Density

High Intermediate Low

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

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Why Tailor Cross-link Density?

Lubricant Cross-link Density

High Intermediate Low

Particles Plunger Force Particles Plunger Force Balance Plunger Force & Particle Loads

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

400 900 1400 1900 2400 2900 3400 3900

Absorbance Wavenumber (cm-1) Si-O-Si Si-CH3 Si-(CH3)x C-H

How to Characterize Cross-link Density? – FTIR Spectroscopy

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Liquid @ RT MW: 296.61g/mol Tbpt :175-176°C Viscosity: 2.5cSt Pvapor :100Torr

Octamethylcyclotetrasiloxane

Monomer for New Lubricant – A Chemical Fingerprint

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

Effect of Lubricant Cross-linking on FTIR Spectra

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

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5 10 15 20 25 30 35 40 10 20 30 40 50 60 Force (N) Displacement (mm)

Silicone Oil on Glass New Lubricant on Coated COP

Plunger Force - Effect of Cross-linking

1ml water ETFE-Coated Plunger

Fi Fm Fi Fm

Constant Applied Force @ 300mm/min After 7 days stored @ RT Initiation Force (Fi): 9±2N Maintenance (Fm): 3±1N Initiation Force (Fi): 10±2N Maintenance (Fm): 4±1N after 2 years after 2 years

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

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  • Filled w/ Citrate Buffer Solution
  • 10min shake @ 1000rpm
  • Solution expressed through

needle into MFI injection port

1ml ETFE-Coated Plunger

*Particle analysis by microflow digital imaging which detects particles between 2 -100 µm.

(Particle Diameter Range: 2-50µm)

Barrier System Coated COP

Particulates – Effect of Cross-linking

Meets USP 788

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

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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 1ml

  • 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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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

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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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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

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Toxicology Assessment of New 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 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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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

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 Silicon-based lubricant  Solid lubricant applied uniformly on syringe barrel by PECVD process  Process highly reproducible  Lubricant balances consistent plunger forces and low subvisible particulates  Low extractables  Safe (Toxicology Assessment)

Summary

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2016 PDAUniverse of Pre-filled Syringes & Injection Devices | October 17-18, 2016 | Hyatt Regency Huntington Beach Resort and S pa | Huntington Beach, CA

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Thank you for your time.

SiO₂ Medical Products, Inc. www.sio2med.com