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.

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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

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Types of Large Volume Intravenous Solutions

Electrolytes Carbohydrates Nutritional Solutions Proteins Lipid Emulsions Peritoneal Dialysis Irrigating Solutions

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Route of Administration
Intravenous Direct Injection Infusion Subcutaneous Intramuscular Intradermal Intraspinal Intrathecal Intra-arterial Others
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Methods of Delivery for LVPs

Peripheral Vein if solution with low osmolality Hyper or hypotonicity can irritate the vein - phlebitis Central Vein Subclavian Vein

A. From http://www.hsc.wvu.edu/mbrcc/bmt/siteImages/centralVenousCatheter.jpg B. From http://www.nursinghomesabuseblog.com/uploads/image/picc.png

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Methods of Delivery for LVPs

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
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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
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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.

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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

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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)

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Large Volume Flexible Containers

Advantages Durable and light weight No air interchange. The bag collapses as it empties.

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Large Volume Flexible Containers

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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

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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

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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
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Comparative Properties of Polymers

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Sterilization of Flexible Containers

Thermal Sterilization Many plastics will soften or melt.

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Ethylene Oxide (EtO) May be used for the empty container and then aseptically filled. Must evaluate possible residues and degradants from EtO.

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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

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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

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Summary
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

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