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Characteristics and Requirements for Large Volume Parenterals (LVPs) USP Workshop on Thresholds and Best Practices for Parenteral and Ophthalmic Drug Products Bethesda, MD February 22 and 23, 2011 Presenter Gregory A. Sacha, Ph.D. Large Volume Intravenous Solution A single-dose injection that is intended for intravenous use and is packaged in containers labeled as containing more than 100 mL. © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 2 Characteristics of LVPs Packaged in glass bottles or in large volume flexible containers. May contain greater than 100 ml to greater than 1 or 2 L Sterile Pyrogen-Free Essentially free of particulate matter No anti-microbial agents Isotonicity © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 3 Types of Large Volume Intravenous Solutions Electrolytes Carbohydrates Nutritional Solutions – Proteins – Lipid Emulsions Peritoneal Dialysis Irrigating Solutions © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 4 Route of Administration Intravenous – Direct Injection – Infusion Subcutaneous Intramuscular Intradermal Intraspinal Intrathecal Intra-arterial Others © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 5 Methods of Delivery for LVPs 6 Peripheral Vein – if solution with low osmolality – Hyper or hypotonicity can irritate the vein - phlebitis Central Vein – Subclavian Vein A B A. From http://www.hsc.wvu.edu/mbrcc/bmt/siteImages/centralVenousCatheter.jpg B. From http://www.nursinghomesabuseblog.com/uploads/image/picc.png © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. Methods of Delivery for LVPs 7 Peritoneal Dialysis – Dialysis membrane assisted hemodialysis – Continuous ambulatory dialysis • Patient warms solution to body temperature • Injects into abdominal cavity • Exchanges solution 4 to 5 times daily A A. From http://www.wirralchesterkidney.nhs.uk/images/principle.jpg © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. Preparation and Hospital Practice Ready to use solutions stored on nursing units for easy access. Saline and Dextrose solutions. Medications can be added to the large volume containers in the pharmacy. – Prepared when ordered or in batches every 8 to 12 hours, labeled, and delivered to the nursing unit. – Typically expire after 24 hours Some drugs prepared in LVPs as ready to use – Propofol – Ciprofloxacin – Lidocaine HCl © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 8 Preparation of Parenteral Nutrition Formulations Custom formulation designed for each patient in US Use Automix and Micromix compounders to transfer quantities of each additive to sterile, empty Viaflex containers. © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 9 Materials of Construction Basic Types of Plastics – Thermoplastics • Polymers that soften upon heating and solidify upon cooling • Most parenteral packaging – Thermosets • Chemically reactive polymers in the fluid state • Harden irreversibly by cross-linking • Epoxies, melamine resins, cross-linked polyesters and phenolics © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 10 Most Common Polymers for Sterile Products Polyethylene (PE) Polyvinylchloride (PVC) Polypropylene (PP) Polyamide (Nylon) Polycarbonate (PC) Ethylene vinyl acetate (EVA) Polyolefin (mixtures of low density PE, high density PE, PP, and EVA) © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 11 Large Volume Flexible Containers Advantages – Durable and light weight – No air interchange. The bag collapses as it empties. © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 12 Large Volume Flexible Containers 13 Disadvantages – Permeation of vapors and other molecules in either direction through the walls. • Resolved by overwrapping the containers. – Leaching of constituents from the plastic into the product. • Plasticizers and anti-oxidants – Sorption of drug molecules or ions on the plastic material. • Proteins, warfarin sodium, diazepam © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. Types of Flexible Containers PVC – polyvinylchloride was the first polymer used for collapsible containers. – Performs best with respect to collapsibility and transparency – May leach DEHP (di (2-ethyl hexyl) phthalate • Banned by countries such as Germany, Sweden, France, Canada, and others. – Produces dioxin when incinerated © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 14 Types of Flexible Containers Ethylene vinyl acetate films (EVA) – Developed to improve compatibility and moisture permeation characteristics – However, moisture permeation is poor and film requires overwrap Combinations – Multilayer films developed to reduce moisture permeation – Ethylene vinyl alcohol can be used as core film for its high gas barrier properties. – Physically bonded between two layers of EVA © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 15 Comparative Properties of Polymers © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 16 Sterilization of Flexible Containers 17 Thermal Sterilization – Many plastics will soften or melt. Ethylene Oxide (EtO) – May be used for the empty container and then aseptically filled. – Must evaluate possible residues and degradants from EtO. © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. Sterilization of Flexible Containers Gamma Radiation – May affect the appearance of the plastic and the stability of the product – PVC can change color from clear to yellow, possible pH shifts, increases in extractables © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 18 Possible Extractables Plastics – Antioxidants: BHT, thioesters, phosphates – Lubricants: silicones, polyethylene waxes – Plasticizers: phthalates Glass – Major extractables: silicon and sodium – Minor extractables: K, Ca, Ba, Al – Trace extractables: Fe, Mg, Zn – Dependant upon pH, buffer, and other components in formulation © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc. 19 Summary 20 Contain >100 mL, no antimicrobial agents Typically simple solutions – NaCl, Dextrose, other nutritional solutions Available in glass and flexible containers Trend toward multi-chamber bags Available for infusions, dialysis, irrigation Plastic films chosen based on flexibility, resistance to moisture permeation, ability to sterilize © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc.