Characteristics and Requirements for Large Volume ...pqri.org/wp-content/uploads/2015/11/Sacha.Characteristics_and...Presenter Characteristics and Requirements for Large Volume Parenterals

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.

Presenter

Presentation Notes

Cover page

Large Volume Intravenous Solution 2

© 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc.

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


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


Electrolytes

Carbohydrates

Nutritional Solutions– Proteins– Lipid Emulsions

Peritoneal Dialysis

Irrigating Solutions

Route of Administration 5


Intravenous– Direct Injection– Infusion

Subcutaneous

Intramuscular

Intradermal

Intraspinal

Intrathecal

Intra-arterial

Others

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.jpgB. From http://www.nursinghomesabuseblog.com/uploads/image/picc.png

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. From http://www.wirralchesterkidney.nhs.uk/images/principle.jpg

A

Preparation and Hospital Practice 8


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


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


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


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


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

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

Types of Flexible Containers 14


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


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


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.

Sterilization of Flexible Containers 18


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


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


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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Characteristics and Requirements for Large Volume ...pqri.org/wp-content/uploads/2015/11/Sacha.Characteristics_and...Presenter Characteristics and Requirements for Large Volume Parenterals