Section 7 - Parenterals 1 Flashcards
What does parenteral mean?
- Administration by injection
- Main routes are subcutaneous, intramuscular, and intravenous
What are the advantages to parenterals?
- Rapid onset of action
- Complete and predictable bioavailability
- Avoidance of GI tract
- Reliable route for comatose, very ill, and uncooperative patients (who are experiencing preventable side effects)
- Allows high dose medication
What are disadvantages to parenterals?
- Frequent dosing
- Pain
- Cost
- Medications errors difficult or impossible to reverse
Which drugs is a parenteral route useful for?
Drugs showing unreliable GI absorption, inactivation or destruction by GI tract (extensive first-pass or mucosal metabolism)
Which patients is a parenteral route useful for?
Patients that require rapid, assured high blood levels or constant blood levels
Which health care professional has the greatest amount of information regarding parenteral products?
Pharmacists
What is a syringe?
A device for measuring injectable products
What can a syringe be made of? What does it consist of? What are the sizes of syringes?
- Can be made of glass or plastic
- Consists of barrel and plunger
- Range from 1-60 mL
What should a syringe be made of if the drug is to be stored in syringe for a protracted period of time?
Glass
Why are disposable syringes almost always used?
- Cost
- Danger of cross-contamination w/ AIDS or hepatitis
What are needles made of?
Stainless steel
As the gauge of a needle increases, what happens to diameter?
Decreases
What determines the selection of needle gauge and length?
- Site of administration
- Nature of product being injected
What are the 2 variations of needles?
1) Butterfly for pediatrics
2) Teflon or silastic cannulas for long-term use
What does a basic IV administration set consist of?
- Spike
- Drip chamber
- Tubing
- Roller clamp
- End fitting compatible w/ hub of a needle or cannula
When is a vented IV administration set needed? When is a non-vented set needed?
- Vented = rigid glass bottles
- Non-vented = flexible plastic bags
What is the function of a spike?
To allow entry into the closure of the container
What is the function of a drip chamber?
To allow the flow rate to be set
What is the function of a roller clamp?
To allow the flow rate to be adjusted
Why are filters sometimes attached to the end of the IV administration set?
- To protect the patient from particulate material
- Some sets (Buretrol) are specifically designed for drug administration
When is the subcutaneous route used?
- Vaccines
- Insulin
- Scopolamine
What is the max volume for a subcutaneous injection?
2 mL
What are the typical body sites of subcutaneous injections?
Arms, legs, abdomen
What should be done if ongoing injections are needed?
Rotate sites
Does IV or IM have a faster onset?
IV
Intramuscular injections are injected into _____
Striated muscle fibers
What are the usual sites of intramuscular injections?
Deltoid, lateral or gluteal muscles
What is the usual volume of intramuscular injections?
1-3 mL (use multiple sites if greater than 5 mL)
What does the release rate of an intramuscular injection depend on?
- Vascularization
- Formulation
- Drug solubility in water
What are advantages to IV administration?
- Direct into lumen of vein
- Extremely rapid predictable response
- Avoids tissue irritation and GI tract
What is a disadvantage to IV administration?
Difficult or impossible to reverse if error occurs
What is the normal volume and rate of IV injections?
- Volume = 1-100 mL
- rate = 1 mL/10-20 seconds
When are volumes larger than 100 mL administered by IV?
Fluid and electrolyte replacement
What is an intrathecal administration?
Drug administered directly into CSF
What characteristics are needed of the drug to be administered intrathecally?
High purity, preservative-free, and free of particles
Which drugs should never be given intrathecally and why?
- Antineoplastic vincristine
- This route bypasses the BBB
Are intrathecal and epidural administrations the same?
No, intrathecal is administered into CSF and epidural is injected outside the dural membrane w/in the boney spinal caudal canals
Intra-ocular products must be of similar quality to ____
Intrathecal
Death of cells often appear to follow ____ order process
First
What does it mean when cell death follows a first order process?
The time interval required to bring about one decimal reduction (90% reduction) is constant
How is sterility determined?
Sterility testing of entire batch
What is sterility assurance level (SAL) expressed as and what does this mean?
- Expressed as log10 probability of survival
- SAL of 6 means 1 in 1,000,000 units contaminated
What is an acceptable SAL value for critical items?
6 (1 in 1,000,000)
How is a SAL of 6 achieved?
Apply process to reach log (10^0) then safety factor to deliver extra 6 log reduction
What is the D-value?
- Decimal reduction time
- Time for population to decrease by 1 log unit
When do you need to state temperature for D-value?
When heat sterilization processes are used
What is a Z-factor?
- Temperature increase needed to provide a decimal reduction time
- Generally as temp increases, need shorter exposure times
What does it mean if a D-value is 20 and a Z-factor is 9?
Every increase of 9 degrees will decrease the D-value by 10 fold (from 20 minutes, to 2 minutes, to 0.2 minutes…)
What could make a plot of loq survivors NOT be linear?
- Cells clumping
- Mutations more resistant to process
- Populations of mixed species
Which processes tend to display a non-linear plot of log survivors?
Chemical processes
What are some sources of microbial contamination?
- Atmosphere
- Water
- Raw materials
- Packaging
- People
Which species are likely to cause microbial contamination through water?
Pseudomonas
Which species are likely to cause microbial contamination through packaging?
Mold spores from paper
How many microorganisms can a person shed per hour?
10-100 cfu, even when properly gowned
What are the 5 methods of sterilization recognized by the USP?
- Steam
- Dry heat
- Filtration
- Gas
- Ionizing radiation
What determines which method of sterilization should be used?
- Nature of product
- Expected bioburden
What is the bioburden for kaolin and which method of sterilization should be used?
- Potentially high
- Dry heat
Which sterilization method should NOT be used for petrolatum and why?
Steam penetration b/c will not penetrate these materials (petrolatum or oil)
What is the definition of sterilization?
Inactivation or removal of all viable microorganisms
Define disinfectant
Substance used on inanimate objects to render them non-infectious
Define antiseptic
Substance used on animate objects to kill microorganisms or prevent them from multiplying
Define bacteriostatic
Substance which prevents multiplication of microorganisms; often used as preservatives
Define terminal sterilization
Process where sterilization is the final procedure
What must be characteristics of the product and container for steam sterilization?
- Product and container not damaged or altered by heat
- Container must be permeable to steam
Are pyrogens affected by steam?
No
What is the normal temperature and pressure of an autoclave?
121 C and 15 psi(g)
What occurs in an autoclave?
- Steam enters from top and displaces air from bottom through traps and valves (gravity displacement)
- Large systems may use a vacuum pump to remove air
Are dry steam or air-steam mixtures more efficient?
Dry steam
What must be considered w/ respect to temperature if liquid material is in an autoclave?
Must allow time for contents to reach 121 C before starting timing
How long is an autoclave normally run?
15-20 minutes
What must be done if a sealed aqueous product is in an autoclave?
Must allow to cool w/ autoclave sealed, otherwise pressure in the container will cause an explosion
What is the method of kill w/ steam sterilization?
Hydrolysis and protein and nucleic acid coagulation and denaturation
What must steam do to kill microorganisms?
Come into direct contact w/ microbial cells and release latent energy
What is dry heat used for?
- Containers and equipment
- Oil and lipid material (as long as not adversely affected by heat)
Is dry heat or steam more efficient, and what does this mean?
Steam, so dry heat requires longer times
Which method is used for destruction of pyrogens and for how long at what temperature?
- Dry heat
- 250 C for 30 minutes
What is the usual temperature and run time of dry heat?
160 C for 2 hours
What is the mechanism of kill for dry heat?
Oxidation
Which gas is used for sterilization and where is it used?
- Ethylene oxide
- Hospitals for plastic devices and some powdered drugs
What is ethylene oxide mixed with and why?
Mixed w/ CO2 or a fluorocarbon to overcome flammability and explosive nature of ethylene oxide
Which parameters are important for gas sterilization?
- Gas concentration
- Temperature
- Humidity
- Exposure time
What is the usual exposure time for gas sterilization?
1.5 hours
What must be done when performing gas sterilization?
Allow venting to allow residual gas to dissipate
What is the mechanism of kill of gas sterilization?
Alkylation of various reactive groups in bacterial cells and spores
What is the sterilant of choice for isolators?
Vapor phase hydrogen peroxide
What temperature does vapor pressure hydrogen peroxide sterilization occur at?
Room temperature
What is the normal exposure time for vapor phase hydrogen peroxide sterilization?
90 minutes (fairly fast acting)
What is the method of kill of vapor phase hydrogen peroxide sterilization?
Oxidation
What are the 2 types of filter medium?
Depth and membrane
What is membrane filter medium used for?
Sterilization
What is the pore size of membrane filter medium?
0.2 um
Does filtration remove pyrogens?
No
What are the various types of membranes and what are they used for?
- Hydrophilic for aqueous
- Hydrophobic for non-aqueous
- Low protein binding
Why is selection of a membrane important?
- To avoid dissolution of filter components into product
- Avoid loss of product due to binding of drug to membrane
- Bubble-point for integrity testing
What is ionizing radiation used for?
Disposable plastic materials and powdered drugs
What must be validated w/ ionizing radiation?
- Radiation dose and exposure time
- Establish that penetration of the product has been achieved and that the product is not altered by exposure
What is a disadvantage of ionizing radiation?
Expensive and only practical for large production runs
What is the method of kill of ionizing radiation?
Damage to nucleic acids, making them non-functional
What are 2 disadvantages to the use of UV radiation?
- Penetration
- Energy levels often not high enough to be effective
What does validation involve?
Making sure equipment meets required performance specifications and that personnel have understanding of process and equipment
What are some simple things that can be done for validation?
- Placement of thermocouples at different locations in the load
- Maintaining temperature-time records for each batch
- Using temp indicators (autoclave tape, chemical indicator tape) for EtO sterilization
- Check membrane filters for integrity by resistance to air passage while wet
- Perform sterile fills
- Monitor environment for bioburden by use of settle-plates and Rodac plates
What is the purpose of sterility testing?
Determine the probable sterility of a specific batch of product
What are the 2 basic method of sterility testing?
- Direct inoculation of test material into culture medium
- Membrane filtration of test material followed by incubation of membrane in suitable media
Which method of sterility testing is more accurate and why?
Membrane filtration b/c has contact w/ all solvent in the media, so any microorganisms will reach the membrane and culturing it will provide an indication of contamination, whereas direct inoculation is only culturing a small portion of the solvent
Does sterility testing provide a guarantee that the entire batch is sterile?
No
What is a negative control used for?
To ensure media is sterile
What is a positive control used for?
To ensure the media can support growth of organisms
What occurs in a main positive control?
Test material is inoculated w/ organism to ensure the product doesn’t adversely affect the test organisms, then the test preparation is run alone
What does USP chapter 71 define?
Growth media required, rinsing and diluting fluids, test organisms, and general procedure for sterility testing
When is the membrane technique of sterility testing more useful?
- Product has bacteriostatic or bactericidal
- Drug is in oil vehicle or ointment dose form
On which days should a sterility test be read and why?
- Days 3, 7, and 14
- Moulds require 14 days to grow
When are the requirements of a sterility test met?
If no growth in the test units and growth in appropriate controls
When should a sterility test be repeated?
If growth in test units, but evidence that it may be from deviation from procedure
When should a sterility test be repeated and the number of samples doubled?
If growth occurs and no documentation of procedural deviation
What is the minimum number of articles to be tested for parenterals less than 100 units?
10% or 4 units, whichever is greater
What is the minimum number of articles to be tested for parenterals between 100 and 500 units?
10 units
What is the minimum number of articles to be tested for parenterals above 500 units?
2% or 20 units, whichever is less
What is the minimum number of articles to be tested for large volume parenterals?
2% or 10 units, whichever is less
What is the minimum number of articles to be tested for ophthalmic preparations less than 200 units?
5% or 2 units, whichever is greater
What is the minimum number of articles to be tested for ophthalmic preparations more than 200 units?
10 units
For sterility testing, quantity of product should not exceed __% of the medium volume
10
What is luciferin-luciferase testing used for?
Water
What is the radiocarbon technique used for?
Blood culture
What are pyrogens?
Lipopolysaccharide components of microorganisms w/ function as endotoxins
Are pyrogens living?
No
Which pyrogens are usually most potent?
Those produced by gram-negative organisms
What do small doses of pyrogens cause?
Fever, leukopenia
What do large doses of pyrogens cause?
Shock and death
What do pyrogens do once in the body?
Provoke an intense immune response by producing endogenous substances like prostaglandins, proinflammatory cytokines interleukin-1, interleukin-6, and TNF-alpha
How can you avoid pyrogen contamination?
Ensure non are present in starting materials, especially water
What is the most common source of pyrogen contamination?
Water
What are some general methods of removing pyrogens?
Dry heat, oxidizing agents, adsorption, and ultrafiltration
How can pyrogens be removed from water?
Distillation
When are requirements met for the USP 151 test for pyrogens and what is done if the requirements aren’t met?
- When none of the 3 rabbits have an individual temp rise over 0.6 C, and the total temp rise of the 3 rabbits is not above 1.4 C
- If not met, 5 additional rabbits are tested
What occurs in the Limulus Amoebocyte Lysate test?
- Amebocytes from blood cells of Horseshoe crabs are lysed to release a protein that reacts w/ pyrogens
- The product will form a gel, which proves pyrogens are present
When in the Limulus Amoebocyte Lysate test used?
- Testing water for injection
- Testing short-lived radioisotopes in nuclear medicine
What is important to note about the Limulus Amoebocyte Lysate test?
Only tests for gram-negative bacterial endotoxins
What is particulate matter?
Extraneous, undissolved substances unintentionally present in parenteral solutions
Are particulates harmful to injections?
Not clear, but detracts from product elegance which reduces confidence in product and manufacturer
