PART II OF II: IMPROVED PARENTERAL CONTAINERS THROUGH PLASMA DEPOSITION OF HIGH PURITY GLASS

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1 PART II OF II: IMPROVED PARENTERAL CONTAINERS THROUGH PLASMA DEPOSITION OF HIGH PURITY GLASS In this article, the second part of a two-part series, Chris Weikart, Director of R&D, and Peter Sagona, Vice-President and Secretary, both of Medical Products, and Shawn Kinney, consultant to Medical Products, showcase the chemical, mechanical, and thermal performance stability of vials and syringes coated with an ultra-thin, high-purity glass barrier coating system. Performance stability studies were conducted with a wide range of liquid formulations intended to simulate what primary containers may experience under long-term aging (i.e. more than two years). Parenteral containers were filled with challenge solutions meant to represent the extremes of pharmaceutical and biological formulations. Dr Shawn Kinney Consultant to Medical Products INTRODUCTION Part I of this article series appeared in the October 2013 issue of ONdrugDelivery Magazine. 1 In the first article, Medical Products introduced plastic primary containers with a glass-like, barrier coating system. Furthermore, the patented plasma technology used to deposit the glass layer and some description of the coating composition, architecture, and function were detailed. Data were presented on the barrier coating system thickness uniformity, composition, and surface energy using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and contact angle measurement. Here in Part II, we focus on the performance stability of vials and syringes coated with this ultra-thin coating system and report the results. The barrier coating system incorporates a thin silicon oxide (glass) barrier layer and a crosslinked organosiloxane top layer. The high-purity glass barrier coating system is flexible because of its ultra-thin thickness of several hundred nanometers, and covers the entire interior surface of the primary container. The drug contact top layer protects the underlying silicon oxide layer from hydrolytic attack over the drug s shelf life, especially at higher ph conditions. BACKGROUND ON LIQUID SOLUTION SELECTION A range of liquid solutions were used to evaluate the barrier-coated parenteral containers, including extremes of ph (i.e. 3.5 citrate buffer and 8.0 phosphate buffer), water for injection (WFI), and high osmolality phosphate buffered saline solution (~600 mosm/kg, ph = 7.4) with a surfactant. These liquid solutions were selected because they simulate a range of standard pharmaceutical and biological formulation conditions that are known to provide challenges to glass containers, as follows: Citrate has a low acid dissociation constant (referred to as pka ) and is known to chelate metals, as demonstrated by its use in passivation. However, citrate can present a delamination challenge to standard borosilicate glass. ph 8.0 is an upper range found in typical parenteral drugs. Higher ph solutions increase Dr Christopher Weikart Director of R&D Mr Peter Sagona Vice-President and Secretary Medical Products 350 Enterprise Drive Auburn, AL United States T: E: sio2-info@sio2med.com 18

2 50 the silicon dissolution of glass containers. Phosphate is a widely-used buffer with biologics and has an acid dissociation constant (pka) well-suited for ph 8.0. Water for injection (WFI) is known to be an aggressive solvent to containers and is commonly the solvent of choice for parenterals, especially for small-molecule drugs. A high osmolality phosphate buffer solution (PBS) and WFI will demonstrate the ability of the coatings to withstand from low WFI to high osmolality solutions. Tween, a common surfactant in biological formulations, was also included in this study at a concentration of 0.2%, which is considerably higher than typical biological formulations. CHEMICAL STABILTY The shelf-life of barrier-coated plastic cyclic olefin polymer (COP) vials was evaluated through chemical stability studies involving various liquid formulations, as identified above. Barrier-coated 5ml vials were filled with the formulations, incubated at 4ºC, 25ºC, and 40ºC, and tested at various time points for critical performance parameters, including oxygen transmission rates (OTR), amount of dissolved Si, and particulates. If coating debonding was occurring, an elevated dissolved Si and particulates would be expected. If the barrier coating on the coated vials was being dissolved, an increase in OTR and dissolved Si would be expected. 1. Gas Barrier Properties - Oxygen Transmission Rate An effective method of evaluating the oxygen ingress or oxygen transmission rate (OTR) into a container can be conducted by monitoring the oxygen partial pressure inside the container over time after the oxygen inside is replaced by nitrogen. To understand the impact of the glass coating on OTR better, all of the non-wall sources of oxygen ingress (i.e. stoppers and tip-caps) were eliminated. For a vial, this was accomplished by sealing the vial opening with a glass slide and epoxy. An oxygen-sensitive sensor inside nitrogen-purged vials was used to measure the oxygen partial pressure over time. A plot of the oxygen partial pressure over time for 5ml uncoated COP vials, barrier system coated COP vials, and borosilicate glass vials is shown in Figure 1. The data illustrate Partial Pressure (mbar O2) 45 Borosilicate Glass Coated COP 40 Uncoated COP Time (days) Figure 1: Partial pressure of oxygen inside vials. Dissolution Rate ( Si/day) Figure 2: The top-layer reduces silicon extractables from the glass coating compared with traditional borosilicate glass at high ph. that the glass coating improves the barrier to oxygen significantly and approaches the barrier provided by borosilicate glass. Comparing the relative OTR of the uncoated and coated COP shows at least 30 times lower OTR through the coated COP wall. Oxygen barrier performance is maintained over the product shelf life by protecting the silicon oxide layer from chemical attack and dissolution. The OTR, described in this section, is an important performance parameter for the stability of the barrier coating system. The barrier coating system has remained intact, Silicon Dissolution Rate Comparison (ph 8 phosphate buffer at 40ºC) Coated COP Vial which is further supported by additional data (presented later in this article). 2. ph Stability - Silicon Dissolution Rate The chemical stability of the barrier coating system was also interrogated by monitoring the THE HIGH-PURITY GLASS BARRIER COATING SYSTEM IS FLEXIBLE BECAUSE OF ITS ULTRA-THIN THICKNESS OF SEVERAL HUNDRED NANOMETERS, AND COVERS THE ENTIRE INTERIOR SURFACE OF THE PRIMARY CONTAINER 8.4 Glass Vial amount of silicon dissolved over time in vials filled with the liquid formulations that were outlined previously. Silicates are well known to dissolve readily in high ph solutions by hydrolytic attack, which is further accelerated at high temperature. 2 In a high ph environment, a several hundred nanometer thick layer Copyright 2014 Frederick Furness Publishing Ltd 19

3 Silica ( ) Glass Multi-Component Silicate Glass Surface 10 Å bulk yellow Si red 0 puroke Na blue 0 green H Figure 3: Illustration of pure glass surface versus a surface of a multi-component glass. of silicon oxide or amorphous glass will completely dissolve quickly at 40 C. The purpose of the top layer is to protect the underlying silicon oxide barrier layer for the duration of the product shelf life. The top layer s unique combination of siloxane content, carbon content, and cross-link density provides a barrier to hydrolytic attack by the solution. The silicon concentration was measured by inductively coupled plasma optical emission spectroscopy (ICP-OES) in each solution at various time points. The change in silicon concentration over time was converted into a silicon dissolution rate in units of micrograms per day. Figure 2 shows an 80-fold reduction in silicon dissolution rate for vials coated with the barrier coating system compared with borosilicate glass filled with ph 8 solution at 40 C. Further, there was no observed increase in particulates with any of the solutions studied. Ion exchange reactions, a prevalent mechanism for chemical attack of borosilicate glass (Figure 3), are non-existent in a plasma-deposited barrier coating system because of the absence of alkaline ions and oxides. Consequently, Si dissolution in vials coated with the barrier coating system is not accompanied by the B, Ca, Al, and Na ions known to be a leading cause of glass delamination. 3. Extractables Characterisation Extractables characterisation was conducted on COP vials that had been coated with the barrier coating system to quantify potential extractable chemical species from the coating. Both coated and uncoated vials were subjected to reflux extraction in WFI, water at ph4, water at ph8, and isopropyl alcohol (IPA). Volatile SIO 2 MEDICAL PRODUCTS BARRIER COATING SYSTEM APPLIED TO PLASTIC PRIMARY CONTAINERS IS ROBUST UNDER CHEMICAL, THERMAL, AND MECHANICAL CONDITIONS REPRESENTING THE EXTREMES impurities and residual solvents were characterised using headspace gas chromatography-mass spectrometry (HS GC-MS) with electron ionisation, and semi-volatile compounds were characterised using gas chromatography-mass spectrometry. Non-volatile polar compounds were characterised using high-performance liquid chromatography-ultraviolet-mass spectrometry with positive and negative atmospheric pressure chemical ionization. Chemical species attributed to the coatings were not observed in any of the extracts at levels exceeding the analytical evaluation threshold (AET) of 0.13 μg/g and 1 μg/g for volatiles from headspace analysis. MECHANICAL STABILTY Barrier-coated 5ml plastic (COP) vials were evaluated through a variety of mechanical challenges to determine the robustness of the barrier coating system to maintain barrier properties after the application of simulated forces that a vial may be exposed to during processing. 1. Mechanical Stability Glass versus Plastic During filling, packaging, and processing, containers can experience varying applied loading forces from equipment placing stoppers into position, crimp cap placement, labelling, and general handling. Glass vials can tolerate a small amount of deformation before they experience a catastrophic failure and shatter, creating glass particles, which can contaminate other containers in addition to the manufacturing line. Plastic containers such as vials manufactured from COP, can withstand considerably higher compression forces than glass, as shown in Figure 4. Plastic COP containers provide two distinct benefits over glass containers of the same size. The first is due to the visco-elastic properties of COP. Forces applied to the vial below its yield point will allow it to return to its original shape once the force is removed. Vials being deformed with forces beyond the yield point of COP will tolerate permanent deformation without a catastrophic failure or shattering as with glass. A permanent dimensional deformation with COP vials can be screened from the lines with camera systems checking that the dimensions are within tolerance. 2. Barrier Coating Performance Against Vial Deformation A series of compression forces studies were performed on vials and syringes for both topdown (Figure 5) and side-wall forces. In these 20

4 700 Top Compression Force Profile Top Compression Oxygen Transmission Rate (OTR) Profile Permanent vial deformation Top Down Load (lb) Glass Vial Stable COP Vial Stable OTR (cc O 2 /container/day) Maximum capping force Height Deflection (mm) Top Down Load (lb) 700 Figure 4: Deformation of glass vial versus COP vial. Figure 5: Oxygen transmission rate of glass coated 5 ml vials after increasing top down compression loads. studies, increasing forces were applied to the containers and released until a permanent deformation of the container was observed. Both OTR and particulate counts were measured at each applied load prior to the permanent deformation at the yield point. It was observed that the coatings were intact (i.e. no increase in OTR or increase in particulates in the container versus control) up to the yield point of the container. The plasma deposition process produces flexible ultra-thin layers of pure silicon oxide that are several hundred nanometres thick. The extremely thin nature of the coatings enables their ability to tolerate strain that can lead to breakage as seen with conventional glass parenteral containers. THERMAL STABILTY Parenteral containers and the barrier coating system are required to survive an extreme of temperature excursions, from the storing of drugs at cryogenic temperatures to the ability to withstand a steam sterilization cycle, all the while maintaining a barrier coating system that will maintain its optimal performance characteristics. 1. Temperature Excursion Stability Primary parenteral packaging can be exposed to a variety of thermal stresses during processing, including extremes of temperature from -70 C (e.g. frozen storage and lyophilization) to 121 C (e.g. terminal sterilisation). Over these temperature excursions, the barrier coating system integrity must not be compromised. The following temperature exposure investigation was conducted on barrier-coated vials and an uncoated control. A. Environmental exposures: 1. Cryogenic Temperatures: Barrier-coated vials were filled with 5ml of WFI, sealed, and exposed to a number of freeze thaw cycles, from -70 C to room temperature (by freezing in a -70 C freezer and then allowed to sit at room temperature until the contents reached 20 C). 2. Steam Sterilisation Temperatures: Barriercoated vials were filled with 5ml of WFI, sealed, and terminally sterilized by steam at 121 C for thirty minutes, allowed to cool to room temperature, and sterilized for a second time under the same conditions. B. Evaluation conducted on both environmental exposures to the vials coated with the barrier coating system: 1. Vials with the barrier coating system were evaluated for OTR. 2. Solution was evaluated for particulates. 3. Solution was evaluated for dissolved Si. C. Results of the temperature extremes investigations for both exposures: 1. No change in OTR from the control vials. 2. No increase in particulates from control vials. 3. Insignificant increase in the amount of dissolved Si from the control vials. The integrity of the barrier coating system post-exposure to cryogenic temperatures is seen in Figure 6 below. Ruthenium-based solution is used to stain plastics, but will not stain glass that is used to construct the barrier coating system. PLASTIC CONTAINERS WITH THE BARRIER COATING SYSTEM OUTPERFORM BOTH PLASTIC AND TRADITIONAL GLASS CONTAINERS IN TERMS OF THE SELECTED CHALLENGE CHEMICAL INTERACTIONS The clear vial shows no evidence of staining to the inside of the plastic vial because the barrier coating system has remained intact/uncompromised, compared with the uncoated control vial (as seen in Figure 6). Figure 6: Clear vial indicates uncompromised barrier coating system after cryogenic shock followed by a Ru stain. Copyright 2014 Frederick Furness Publishing Ltd 21

5 SUMMARY The results from performance stability studies demonstrate that Medical Products barrier coating system applied to plastic primary containers is robust under chemical, thermal, and mechanical conditions representing the extremes of pharmaceutical and biotech drug formulations and processing. These studies confirm that the plastic container and the barrier coating system maintain mechanical integrity during processing and normal use and that the coating system remains intact when experiencing forces incurred during production, handling, and use. The results from chemical studies indicate that plastic containers with the barrier coating system outperform both plastic and traditional glass containers in terms of the selected challenge chemical interactions. ABOUT SIO 2 : Medical Products is a privately held company founded and supported by CV Holdings, LLC, an organisation with 90 years of worldwide experience in development and manufacturing of diagnostic and food packaging. SiO s pilot R&D and manufacturing facilities are professionally staffed with fully equipped analytical and mechanical laboratories. In Q1 2014, SiO will open its additional newly constructed 160,000 sq ft headquarters in Auburn, AL, US, where the state-of-theart facility will feature three 10,500 sq ft ISO Class 7 clean rooms dedicated to SiO s glass coating and packaging lines. Plans are in place to build a second manufacturing plant in Strasbourg, France, to provide duplicate manufacturing capabilities. REFERENCES 1) Kinney S, Turney K, Sagona P, Part I of II: Improved Parenteral Containers Through Plasma Deposition of High Purity Glass. ONdrugDelivery Magazine (October 2013), Issue 45, pp ) Swift R, Glass Containers for Parenteral Products. Chapter 11 in Pharmaceutical Dosage Forms: Parenteral Medications, 3rd Ed (2010), Vol 1. (Informa Healthcare). ABOUT THE AUTHORS: Christopher Weikart: Director of R&D, Dr Weikart is responsible for development of plasma coating processes to support product development, and coordinates development activities of the in-house technical staff and external consultants. Dr Weikart has a PhD in Chemical Engineering from the University of Missouri. Prior to joining, he was R&D Manager for the energy and materials business at the Dow Chemical Company, where he served for 11 years. Shawn Kinney: A consultant to on the parenteral drug market, Dr Kinney is the founder of Hyaluron, a contract manufacturer of injectable therapeutics. Dr Kinney has presented at many conferences and authored numerous articles relating to prefilled syringes. He provides technical and marketing assistance to regarding the design of parenteral containers, secondary packaging, and coating stability. He holds a Doctorate in Chemistry from the University of Massachusetts at Amherst, MA, US. Peter Sagona: SiO Vice-President and Secretary, Mr Sagona is responsible for programme and IP strategy. Prior to joining, Mr Sagona spent 11 years with CV Holdings, and seven years at SmithKline Beecham managing automation development projects. Mr Sagona received a MS in Engineering Management from Drexel University, PA, US. Visit at PDA Parenteral Packaging Show in Brussels, Table 16 Extractables & Leachables USA 2014 es A E&L USA will be coming to Silver Spring, MD on May 7-9, 2014 and will bring together the complete pharmaceutical supply chain to discuss the latest research in minimizing the risks associated with extractables and leachables. E L RING, Extractables & Leachables USA delivering pharmaceuticals safely MAY , SILVE R P S MD, USA Find out more at Reader Offer Save 10% quote code OD10AD 22