Large Volume Parenterals:

Use, Handling and Storage

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Contents
o Introduction
 Sterility
 Sterile products

o Large Volume Parenterals

o IV admixtures
 Premises

 Compatibility/Stability

o Storage and Distribution of LVPs

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Objectives
At the end of this training, trainees will be able to:

• Describe unique properties of sterile products-LVPs

• Identify the risks and requirements in IV admixture practices
• Describe good practices in IV admixture
• Describe good practices in storage and transportation of LVPs

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Introduction: Sterility & Sterile Products
• Sterility is defined as complete absence of viable microorganisms.
o Absolute (sterile or non-sterile)

• Certain pharmaceutical products required to be sterile.

o injections, ophthalmic preparations, irrigations solutions, dialysis solutions
• Other requirements of sterile products:
o Pyrogen free
o Particle free (for solutions), (clarity)
o Tonicity

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Introduction: Sterility & Sterile Products
• Two ways of achieving sterility of products
o Sterilization in final container (terminally sterilized)

o Those that cannot be terminally sterilized (aseptically prepared)

• Achieving acceptable sterility assurance level during compounding/admixture is
more difficult
• Sterile medical devices

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Introduction: Sterility & Sterile Products
• Volume of preparation (LVP, SVP)
• Route of administration

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 Large Volume Parenterals (LVPs)
• Parenteral solutions packaged in containers labeled as containing more than 100 mL
• Include IV fluids (injections) & other large volume sterile solutions
o Sterile
o Pyrogen-free
o Essentially free of particulate matter
o Clarity
o No anti-microbial agents
o Tonicity
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Large Volume Parenterals…
o Electrolytes

o Carbohydrates

o Nutritional Solutions

o Dialysis solutions

o Irrigating Solutions

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Large Volume Parenterals…
Containers for LVPs:
Rigid Containers
◦ Glass
◦ “Glass-like” Plastics
Flexible Containers

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Large Volume Parenterals…
• Ready to use solutions stored on nursing units for easy access.
• Medications can be added to the large volume containers.
◦ Prepared when ordered or in batches, labeled and delivered to nursing unit

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Have you ever encountered a quality problem in IV fluids during use,
storage,…?

◦ What was it?

◦ Did you find out the causes?

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Sterile Compounding
• Defined as combining, admixing, diluting, pooling, reconstituting, repackaging, or
otherwise altering a drug product or bulk drug substance to create a sterile
preparation.

• Compounding provides access to medication for patients who may not be able to use
commercially available formulations.

• Advantages of IV admixture?

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Centralized IV Admixture Service
• Economical
◦ Batch preparation

◦ Reduce personnel time

• Enhanced safety with standardized solutions

• Cleaner, more controlled environment

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❑ Describe the practice of IV admixture in your facility!
▪ The premise where you do IV admixing procedures?

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Sterile Compounding…
• Understanding the inherent risks and observing established standards are essential for
patient safety.
• Minimize harm, including death, that could result from:
o microbial contamination [non-sterility],
o excessive bacterial endotoxins,
o variability from the intended strength of correct ingredients,
o physical and chemical incompatibilities,
o chemical and physical contaminants, and/or
o use of ingredients of inappropriate quality.
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Sterile Compounding…

Dose calculation Quality assurance

Considerations in IV
admixture

Facility & Compatibility &

Process Stability

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Sterile Compounding…
• Aseptic techniques must be followed for preparing any sterile medication.
• Processes and procedures must be in place to minimize the potential for contact
with nonsterile surfaces, introduction of particulate matter or biological fluids, and
mix-ups with other products

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Room for IV Admixture
Buffer Room
• Positive pressure room with HEPA filtered air
• Room where ISO Class 5 (Class 100) Laminar Airflow Workbench is placed
• Must be ISO Class 7 (Class 10,000)
• Access is restricted in Buffer area
• Walls, floors, ceiling should be smooth, no cracks and crevices
• Ceilings should be sealed; Floors coved
• No sinks in Buffer area

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Room for IV Admixture (buffer area)…

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Room for IV Admixture…
Ante-Room or Ante-Area
• Room for gowning and hand-washing.
• No food or beverages allowed.
• No carts moving back and forth from buffer zone to ante-area.
• Wipe down of products before introducing into the buffer area.

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Laminar Air Flow Workbench (LAFW)
• Provides ISO Class 5 (Class 100) environment.
• Vertical, horizontal design and barrier isolators
• The hood does not provide sterility – just an ultraclean work area.
• Products will be placed in the hood for assembly or compounding that are either
sterilized before hand or will be sterilized by filtration while in the hood.
• Personnel must use techniques to minimize potential contamination.

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Requirements for a good aseptic technique
• Conduct all manipulations inside a properly maintained and certified LAFW.
• Allow the LAFW to operate for at least 30 minutes before use.

• Maintain a designated “clean” area around the hood.

• Remove all jewelry and scrub hands and arms to the elbows with a suitable
antibacterial agent.

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Requirements for a good aseptic technique…

• Sterile gloves are worn in addition to scrubbing.

• Wear lint-free clothing or clothing covers, head and facial hair covers, and a mask.
• Clean all flat surfaces of the hood with 70% isopropyl alcohol, or other
antibacterial scrub such as benzalkonium chloride solution, working from top to
bottom, then from back to front.

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Requirements for a good aseptic technique…
• Assemble all necessary supplies in the hood checking each for packaging damage,
expiration dates, and particulate material.

• Use only pre-sterilized needles, syringes, and tubing for medication transfers.

• Remove the dust covering from supplies before placing them in the hood.
• Swab all surfaces that require entry (puncture) with 70% isopropyl alcohol or other.

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Requirements for a good aseptic technique…

• Give close attention to hand position and the direction of air flow over injection ports
or objects being manipulated. Minimize hand movements within the hood.

• When handling syringes and needles, be sure not to touch any surface that will come
in contact with the sterile solution.

• Only the exterior of the syringe barrel, plunger tip and needle cap or sheath may be
safely handled.

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Requirements for a good aseptic technique…
• Do all manipulations at least 6 inches inside the outer edge of the hood.
• Do not remove the hands from the hood until the compounding procedure is complete
and the final inspection of the formulation has been made.

• Examine all formulations before removing them from the hood.

• Place all syringes and needles in puncture-proof containers and dispose of them
according to institutional procedures.

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Garbing and Hand Hygiene
Garbing
• Special clothing is required
o aprons, sleeves, gloves, hoods, shoe covers, coveralls, head coverings, lab coats,
hats/caps, facemasks, and beard covers

• Entire process of garbing is designed to reduce particle shedding count from

personnel
• Garb worn during aseptic compounding also provides some level of microbial
containment

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Garbing…
• Infected skin (e.g., rashes, cuts, sunburn, and weeping sores) or people with active
respiratory infections shed particles at higher rates.
• When individuals wear cosmetics or makeup, more particles are shed.
▪ Hands must be cleansed carefully and personnel protective equipment worn
correctly in order to minimize the microbial contamination.

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Hand Hygiene
• Most effective method of preventing the transmission of pathogens that cause
infection in the community and in health-care settings .
➔ is an essential component of good compounding practices
• Waterless, alcohol-based hand sanitizers that exhibit persistent activity are among
the most effective products that ensure an appropriate level of hand hygiene during
compounding.
• Most alcohol-based hand antiseptics contain isopropanol, ethanol, N-propanol, or
combination of two of those agents.

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Aseptic Addition of Drug Solution to Large Volume Parenterals

• LVP solutions are used as primary or continuous infusion solutions by administering

them at a slow infusion rate.
• Drug additives can then be introduced directly into LVP, or introduced into LVP at Y-
connection of the administration set, or put in minibags and used as a piggyback on the
LVP.
• All of these scenarios require a syringe and needle to transfer the drug additive solution
into a plastic bag or administration set injection port.

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How To transfer drug additive to LVP/administration set with a needle and syringe
• Remove the protective covering from the injection port.
• Assemble the needle and syringe and aseptically withdraw the necessary volume.

• Swab the injection port with an alcohol swab.

• Inject the drug additive solution.
• Remove the needle.
• Mix and inspect the admixture.

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Aseptically Transferring Drug From a Glass Ampule
To open an ampule:
• Hold the ampule upright and tap the top to remove solution from the head space.
• Swab the neck of the ampule with an alcohol swab.
• Quickly snap the ampule.
• Inspect the opened ampule for any particles of glass that might have fallen inside

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Aseptically Transferring Drug From a Glass Ampule…
To transfer the drug solution from an opened ampule:
• Insert a needle into the ampule taking care not to touch the neck where it is broken.
• Position the needle in such way to avoid pulling glass particles into the syringe.

• Withdraw solution but keep needle submerged to avoid withdrawing air.

• Withdraw needle from ampule and remove all air bubbles from the syringe.
• Transfer the solution to the final container.

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Aseptically Transferring Drug From a Vial

If the drug is already in solution:

• Place the vial on the work area surface and penetrate the vial without coring.
• Inject the air into the vial and withdraw the drug solution.

• Fill the syringe to a slight excess of the drug solution. Remove all air bubbles
from the syringe.
• Transfer the solution in the syringe into a final container, again minimizing
coring.

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Aseptically Transferring Drug From a Vial…
If the drug is a lyophilized powder in a vial:

• Transfer the diluent into the vial containing the lyophilized powder
• Withdraw the needle
• Swirl the vial until the drug is dissolved
• Using a new needle and syringe, withdraw the correct volume
• Transfer the reconstituted drug solution in the syringe into a final container

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 Share challenges you encountered during withdrawing solutions from
vial/ampule and transferring into an IV fluid!

 Any changes you observed?

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Inspection and End Product Evaluation of Admixtures
The compounded formulation should be inspected for:
• container integrity or leaks in flexible containers
• cracks or leaking stoppers in glass containers
• particulate material and properties such as color, odor, fill volume, consistency, etc.
• unexpected precipitation, crystallization, or other physical property changes

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Inspection and End Product Evaluation…
• Visual inspection will show two characteristics of parenteral solutions:
o particulate material and
o stability (any precipitation or crystallization?).
• Presence (or absence) of particulate material is best determined when the parenteral
is held against an illuminated light/dark background.

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Inspection and End Product Evaluations…
• Verify that the product was accurately prepared with respect to:
▪ ingredients (check used vials, ampules, diluents)
▪ quantities (check syringe volumes used)
▪ containers (check final solution container)
▪ instrumentation (check calibration and settings)

• Preparations that are not distributed promptly should be inspected again before
issuance

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Incompatibility and Stability
• Instability is a phenomenon which occurs when an LVP or IV admixture is modified
due to storage conditions (e.g., time, light, temperature, sorption).

• Incompatibility is a phenomenon which occurs when a drug is mixed with others and
produces an unsuitable product by some physiochemical means.”
o New product unsuitable for administration as the “active” drug is been modified (e.g.,
increase in toxicity), or because some physical change (e.g., solubility) has occurred.

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 Do you check for any potential instability/incompatibility issues before preparing
admixtures? What source of information do you use?

 Give examples of medicines which are placed in dark after admixture until they
are given to the patient?

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Incompatibility and Stability…
Types of incompatibility
• Physical incompatibility
o Produces visible change in the appearance of the solution (color, precipitate,…)
• Chemical incompatibility
o Reactions like hydrolysis, oxidation, reduction, decomposition, complexation
o May or may not produce visible change
o Decompose/inactivate active drug or produce toxic matter
• Therapeutic incompatibility

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Give examples of any physical incompatibility you encountered!

Describe any medicines you know which are not mixed into same IV fluid? Why?

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Consequences of IV Admixture Incompatibilities
• Tissue irritation due to major pH changes
• Particulate emboli from crystallization and separation
• The precipitated product may irritate the veins or cause occlusion of vessels
• Toxic decomposition of products
• Therapeutic failure
• Adverse effects of drug incompatibilities extend periods of patients’ hospitalization
and the total costs for hospitals

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Compatibility and Stability…
• If an incompatibility cannot be corrected or prevented, consider the following
administration techniques:
o Administer the preparations separately at staggered times.
o Flush the administration line or set between preparation administrations,
o Use an alternative site of administration.

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Compatibility and Stability…
Common LVP and their pHs
Solution pH
D5W 5.0
0.9% NaCl 5.5
D5/0.9%NaCl 4.5
D5 /Lactated Ringer’s 5.1
Ringer’s injection 5.8
Lactated Ringer’s 6.7

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Compatibility Guide for Combining I.V. Medications. The American Journal of Nursing, Vol. 79, No. 7 (Jul., 1979), pp. 1292-1293+1295

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Compatibility and Stability…
• A product may be stable or soluble only at a pH that is not physiologically safe.
• When added to an infusion, a change in pH could take place and the chance for
precipitation or accelerated chemical degradation increases.

• For example, Potassium Penicillin G contains a citrate buffer, and the injection is
buffered at pH 6.5 when reconstituted. The solution is stable for 24 hours at such
pH; however, it loses activity much faster at a lower pH.

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Compatibility and Stability…
• The solubility of a weak acid or base may depend on pH: amines (dobutamine,
dopamine, epinephrine, morphine) are basic and are generally soluble in acid pH,
whereas carboxylic and other acids (penicillins, cephalosporins, 5-fluorouracil) are
generally soluble in basic pH.

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Ways to Prevent/Minimize Incompatibility
• Mix thoroughly (swirl) when a drug is added to the • Follow established order of mixing.
preparation.
• Administer solution promptly after mixing within
• Minimize number of drugs mixed. the stability window.
• Use fresh components for compounding. • Always refer to compatibility references.
• Develop an incompatibility table or file for
• Verify for correct diluent, drug, and final
frequently compounded preparations.
concentration before compounding.

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Beyond Use Dates

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 Labeling
• Labeling is critical to patient safety.
• At a minimum, include the following:
 Names of active ingredients
 Amounts or concentrations of active ingredients
 BUD and time
 Storage requirements
 Identification of responsible compounding personnel

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LVPs Distribution and Storage
During transportation:
• Ensure that the product identity is not lost, & the cartons and labeling are in good
condition.

• Adequate precaution should be taken against spillage, breakage or theft or other

adverse influences.

• The product and it's pack are secured and not subjected to unacceptable degree of
heat, cold, light, moisture or other adverse influences nor to attack by
microorganisms or pests

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LVPs Distribution and Storage…
• The transporter and loader should be given adequate training from time to
time by manufacturer or distributer to ensure the safety of product during the
loading and transportation.

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LVPs Distribution and Storage…
Truck inspection and acceptance by manufacturer
• The truck should be clean, free of dust and any foreign material
• Should not have holes or should not allow water to come in the
• Should be free of protruding object like ‘’Nail’’ that can damage the product.
• Loading of truck according to the pattern shall be defined in SOP of the
manufacturer.
• Extra caution to be taken to avoid breakage during loading/unloading

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Storage at Distributor’s Warehouse
• The distributor should have approved SOPs and should ◦ Out bound Trailer/ Truck inspection
store the product accordingly. The SOP’s should ◦ Housekeeping, Pest control
cover:
◦ Material inspection, identification and segregation
◦ Warehouse receiving inspection
◦ Monitoring of storage
◦ Product storage
◦ Facility security
◦ Procedure for handling damaged products
◦ Monitoring of temp.
◦ Expiry date [product control]
◦ Shipping requirements

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Good Storage Practices in Hospitals
• Quality, Efficacy and Safety of I.V. Fluids must be maintained after receiving
Premise
• Storage area must be free from unsanitary conditions (Rodents, insects,, litter etc.).
• The floor of the warehouse should be:
◦ hard floor (Concrete /Epoxy) and
◦ in a good state of repair and appearance at all times.
◦ kept clean & free of trash, dirt, slippage water, drain water etc.

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Good Storage Practices in Hospitals…
• The area used for storage of IV fluids should have adequate space and prevent
exposure to direct sunlight.
o Secured area should be available for damaged, rejected and expired goods.
• Ensure adequate pest control program in place
• The Pest control shall cover treatment for Termite and Rodents.

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Good Storage Practices in Hospitals…
Receipt:
• Hospital personnel responsible for receipt should cross check consignment against
order.

• The stocks should be received in intact condition and

• If any deviation observed, products should be separated and informed to the supplier

• If the consignments suspected to be exposed to harsh adverse weather conditions

during transportation should be segregated & informed to the supplier.

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Good Storage Practices in Hospitals…
Storage:
• Products should be stored Batch wise and Product wise on raised platforms.

• The storageshould not hinder the cleaning and should have sufficient space for
movement of stocks and handling.

• Products need to be stored in a manner that prevents damage due to

excessive vertical stacking heights as per manufacturer’s instructions and in
no case not to exceed five stacks.

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 Good Storage Practices in Hospitals (Storage)…
• The products must not get exposed to direct sunlight, rain etc.

• Store the products as per product storage condition (as per label) to prevent
deterioration.

• Monitor and record the temperature of storage area on daily basis.

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Good Storage Practices in Hospitals
Issuance of IV Fluids
• Product label should be free of defacements, tears or cuts
• Products shall be issued on the basis of First Expiry First Out (FEFO)
• Physically inspect before issuance
• Damaged, expired or contaminated product should be segregated from the stock
• Bottles must be carried from stores to ward in a proper trolley or container with
utmost care

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Thank You!

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