Presenter

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
Gregory A. Sacha, Ph.D.
Large Volume Intravenous Solution 2
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A single-dose injection that is intended for
intravenous use and is packaged in containers
labeled as containing more than 100 mL.
Characteristics of LVPs 3
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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
Types of Large Volume Intravenous Solutions 4
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Electrolytes
Carbohydrates
Nutritional Solutions
Proteins
Lipid Emulsions
Peritoneal Dialysis
Irrigating Solutions
Route of Administration 5
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Intravenous
Direct Injection
Infusion
Subcutaneous
Intramuscular
Intradermal
Intraspinal
Intrathecal
Intra-arterial
Others
Methods of Delivery for LVPs 6
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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
Methods of Delivery for LVPs 7
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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. From http://www.wirralchesterkidney.nhs.uk/images/principle.jpg
A
Preparation and Hospital Practice 8
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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
Preparation of Parenteral Nutrition Formulations
9
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Custom formulation designed for each patient in US
Use Automix and Micromix compounders to transfer
quantities of each additive to sterile, empty Viaflex
containers.
Materials of Construction 10
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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
Most Common Polymers for Sterile Products 11
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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)
Large Volume Flexible Containers 12
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Advantages
Durable and light weight
No air interchange. The bag collapses as it empties.
Large Volume Flexible Containers 13
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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
Types of Flexible Containers 14
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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
Types of Flexible Containers 15
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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
Comparative Properties of Polymers 16
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Sterilization of Flexible Containers 17
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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.
Sterilization of Flexible Containers 18
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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
Possible Extractables 19
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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
Summary 20
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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