Download Characteristics and Requirements for Large Volume Parenterals

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
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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
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Methods of Delivery for LVPs
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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
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
© 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
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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
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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.
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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
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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
© 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc.