Sacha.characteristics and Requirements for Large Volume Parenterals

8/3/2019 Sacha.characteristics and Requirements for Large Volume Parenterals

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Presenter

Characteristics and Requirements for

Large Volume Parenterals (LVPs)USP Workshop on Thresholds andBest Practices for Parenteral and

Ophthalmic Drug Products

Bethesda, MD

February 22 and 23, 2011

Gregory A. Sacha, Ph.D.


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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 forintravenous use and is packaged in containerslabeled as containing more than 100 mL.


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Characteristics of LVPs 3


Packaged in glass bottles or in large volume flexiblecontainers.

May contain greater than 100 ml to greater than 1 or 2 L

Sterile

Pyrogen-Free

Essentially free of particulate matter

No anti-microbial agentsIsotonicity


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Types of Large Volume Intravenous Solutions 4


Electrolytes

CarbohydratesNutritional Solutions

Proteins

Lipid Emulsions

Peritoneal Dialysis

Irrigating Solutions


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Route of Administration 5


Intravenous

Direct Injection

Infusion

Subcutaneous

Intramuscular

Intradermal

Intraspinal

Intrathecal

Intra-arterial

Others


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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


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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.jpgA


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Preparation and Hospital Practice 8


Ready to use solutions stored on nursing units foreasy access. Saline and Dextrose solutions.

Medications can be added to the large volumecontainers 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 9


Custom formulation designed for each patient in US

Use Automix and Micromix compounders to transferquantities of each additive to sterile, empty Viaflexcontainers.


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Materials of Construction 10


Basic Types of Plastics

Thermoplastics

Polymers that soften upon heating and solidify uponcooling

Most parenteral packaging

Thermosets Chemically reactive polymers in the fluid state

Harden irreversibly by cross-linking

Epoxies, melamine resins, cross-linked polyestersand phenolics


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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 densityPE, PP, and EVA)


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Large Volume Flexible Containers 12


Advantages

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


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Large Volume Flexible Containers 13


Disadvantages

Permeation of vapors and other molecules in eitherdirection 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 14


PVC polyvinylchloride was the first polymer used forcollapsible containers.

Performs best with respect to collapsibility andtransparency

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 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 itshigh gas barrier properties.

Physically bonded between two layers of EVA


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Comparative Properties of Polymers 16



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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 fromEtO.


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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, possiblepH shifts, increases in extractables


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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 informulation


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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 tomoisture permeation, ability to sterilize

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Sacha.characteristics and Requirements for Large Volume Parenterals