Parenterals 1 Flashcards
What does parenteral refer to? What are the main routes?
- refers to administration by injection
- the main routes are SC, IM, and IV
What are the advantages of using parenterals?
- rapid onset of action, complete and predictable bioavailability and avoidance of the GI tract
- reliable route for comatose, very ill and uncooperative patients. Allows a high dose of medication
What are the disadvantaged of parenterals?
- frequent dosing, pain, cost, and medication errors difficult or impossible to reverse
In what cases are parenterals useful?
- parenteral route useful for drugs showing unreliable GI absorption, inactivation or destruction by the GI tract, extensive first pass or mucosal metabolism
- heparin, insulin, EPO and some antibiotics
- useful route when patient requires rapid, assured high blood levels or constant blood levels
- lidocaine for arrhythmias
Syringes, needles and administration sets
syringe is needed for measuring injectable products
- may be glass or plastic
- consists of a barrel and plunger
- glass preferred if it is to be stored in syringe for a protracted period of time
- graduations on barrel allow for measurement
- sizes - 1-60 mL
Why are syringes always disposable?
- cost
- cross contamination with AIDS or hepatitis
Describe the needs on the syringe?
- used for penetrating the skin
- are hollow, made from stainless steel
- have a hib at one end for attaching a syringe and usually have a sharp beveled tip at the other end
- lengths vary from 3/8 - 6 inches and outside diameter ranges form 10-27 gauge with larger gauge value referring to smaller diameter
What does the selection of needle gauge and length depend on?
What do the variations of needles include?
- site of administration
- nature of the product being injected
- variations include butterfly needles for pediatrics and teflon or silastic cannulas for long term use
What does an IV administration set consist of?
- basic set consists of spike, drip chamber, tubing, roller clamp, end fitting compatible with hub of a needle or cannula
- vented needed for rigid glass bottles; non-vented for flexible plastic bags
- many variations such as Buretrol
Describe the subcutaneous route of administration
- for vaccines, insulin
- volume smaller than 2 mL and short, fine needle used
- usual body site arms, legs and abdomen
- rotate sites
- hypodermoclysis is variation where 250-1000 mL may be given when veins are not available
Describe the intramuscular route of administration
- injected into striated muscle fibres
- usual sites are deltoid, lateral or gluteal muscles
- usual volume 1-3 mL; if > 5 mL use multiple sites
- take care not to enter a vein
- needle usually 19-21 G and 1 inch
- risk of nerve damage
- allows controlled release or sustained release with oil vehicles
Describe the intravenous rote of administration
- direct into lumen of vein
- extremely rapid predictable response
- avoids tissue irritation and GI tract
- difficult or impossible to revers if error occurs
- care to avoid extravasation and too rapid a rate
- drugs with short 1/2 life give loading dose and then a maintenance dose
- volumes usually 1-100 mL and rate 1mL/10-20 sec although for some drugs rate specific to avoid toxicity or irritation
- drugs need to be in solution for this route although emulsions can also be used
- large proximal veins are generally used for rapid dilution of drugs
What happens to drug volumes larger than 100 mL?
- they are LVP and are used for fluid and electrolyte replacement
What are the options for adding drugs that are used for intermittent infusion?
- piggybacking them into the IV or giving them by push through a device like Buretrol
Describe the intrathecal route of administration
- drug administered directly into the CSF
- product must be of high purity, preservative free and free of particles
- since route bypasses the BBB, some drugs like the antineoplastic vincristine must never be given this way
- this is DIFFERENT from epidural where the drug is injected outside the dural membrane and within the boney spinal caudal canals
- inta-ocular product must be of similar quality to intrathecal (ITH)
When microbial populations are exposed to heat, radiation or antimicrobial death of cells follow what process?
- first order process
What is the ‘D value’?
- the time interval known as the decimal reduction time
- its the time interval required to bring about 1 decimal reduction of the microbial population (1000 to 100, for example) - works out to being a 90% reduction
What is sterility?
the absence of viable microorganisms - can only be determined by sterility testing of the entire batch (sterility assurance level is more practical)
What sterility assurance level is acceptable?
SAL is 6 is acceptable
What is the Z factor?
- the temperature increase needed to provide a decimal reduction time
(generally as temperature is higher, need shorter exposure times)
What would a non-linear plot of log survivors be caused by?
- cell clumping
- mutations more resistant to process
- populations of mixed species
What are some common sources of microbial contamination?
- atmosphere (microorganisms associated with particulates- often generated by people)
- water (esp pseudomonas sp)
- raw materials (controlled by USP microbial limits testing)
- packaging (mold spores from paper)
- people
What are the 5 methods of sterilization that the USP recognizes?
- steam
- dry heat
- filtration
- gas
- ionizing radiation
In what way is kaolin sterilized?
potentially high bioburden
In what way is petrolatum sterilized?
- steam penetration
Drug subject to hydrolysis has stability issues related to ___
heat
What is a disinfectant?
- substance used on inanimate objects to render them non-infectious
What is an antiseptic?
- substance used on animate objects to kill microorganisms to prevent them from multiplying
What is bacteriostatic?
-a substance that prevent multiplication of microorganisms-often used as preservatives
What is terminal sterilization?
a process where sterilization is the final procedure
What is steam sterilization?
- widely used procedure that is efficient, quick and inexpensive
- product container must be permeable to steam
- product and content not damaged or altered by heat
- pyrogens are NOT affected by steam
Describe how an autoclave works?
- operations at 121 degrees and 15 psi
- steam enters from the top and displaces air from the bottom through traps and valves (gravity displacement)
- large systems may use a vacuum pump to remove air
- air steam mixtures not as efficient as DRY steam
What is the method of kill with steam sterilization?
hydrolysis and protein and nucleic acid coagulation and denaturation (loss of tertiary and secondary structure)
What must happen in order for steam sterilization to occur?
steam must come into direct contact with the microbial cell and latent energy must be released
What is dry heat sterilization used for?
- useful for containers and equipment, oil and lipid material provided not adversely affected by heat
- less efficient than steam so longer times are needed
- effective method for destruction of pyrogens (250 degrees x 30 minutes)
- time temperature relationship and usual condition is 160 degrees x 2 hours
What is the mechanism of kill in dry heat sterilization?
oxidation
What gas is frequently used as a sterilant in hospitals?
ethylene oxide
What is ethylene oxide a combination of?
- carbon dioxide or a fluorocarbon - overcomes flammability and explosive nature of ethylene oxide
What 4 factors are important to ensuring the efficacy of gas sterilization?
- gas concentration
- temperature
- humidity
- exposure time (1.5 hrs)
What process is very important to allow for to let residual gas to dissipate?
venting
- gas is very toxic and dissolved into plastics
What is gas sterilization frequently used for?
used for plastics
What is the mechanism of kill of gas sterilization?
alkylation- gas must come into contact with the microbe
What is vapour phase hydrogen peroxide used for?
- sterilant choice for isolators
- effective, relatively safe and environmentally friendly
- sterilization occurs at room temperature
- fairly fast acting needing about 90 minutes to sterilize an isolator
What are the 2 types of filter mediums used in filtration sterilization?
- depth and membrane filters
- - membrane types is used for sterilization
Does filtration remove pyrogens?
NO
What is filtration sterilization most useful for?
extratemporaneous compounding of sterile products
Membrane and housings are available in a variety of material for filtration sterilization. They are:
- hydrophilic for aqueous
- hydrophobic for non aqueous
- low protein binding
Why is selection of a membrane in filtration important?
- avoids dissolution of filter components into the product
- avoids loss of product dude to binding of drug to membrane
- bubble point for integrity testing
What is ionizing radiation?
- electromagnetic radiation (UV, gamma)
- particulate radiation (beta particules, high energy electrons produced by linear accelerator)
- efficient process used for disposable plastic materials and powdered drugs
Why must you validate the use of ionizing radiation?
must validate to determine radiation dose and exposure time, establish that penetration of the product has been achieved and that the product is not altered by exposure
The process of ionizing radiation is ___ and only practical for ____
expensive
large production runs
Why is the use of UV radiation very limited?
penetration is a problem and energy levels are often not high enough to be effective
What does validation include?
- involved ensuring that equipment meets required performance specification and that personnel have understanding of process and equipment
- record keeping is an important concept
- -sterilization can challenge processes through the use of resistant viable cells
What are some simple things that can be done for QA?
- placement of thermocouples at different locations in the load
- maintaining records of temperature time for each batch
- using temperature indicators like autoclave tape and chemical indicator tape for EtO sterilization are all simple things that can be done
- membrane filters can be checked for integrity by resistance to air passage while wet
- environment can be monitored by bioburden by use of settle plates and rodnac plates
What is the purpose of sterility testing?
- to determine the probable sterility of a specific batch of product
What are the two basic methods of sterility testing?
- direct inoculation of the test material into culture medium
- membrane filtration of test material followed by incubation of the membrane in suitable media
What is the confidence of sterility testing dependent on? (test alone provides no guarantee that the entire batch is sterile)
- batch has been subjected to a sterilization process of proven effectiveness
- records have been maintained
- process has been validated and shown to be robust
- staff, facilities and equipment have been validated
A statistical method of sampling for sterility that does not exhaust the supply of product is needed. Explain.
- in a pharmaceutical setting, if a product is contaminated, it will be with a low number of organisms
- sacrificing more than 10% of a batch for sterility testing becomes economical
- most consider sterility testing a useful adjunct to fully validated process whose final goal is production of a sterile product
What is defined in the USP <71> concerning test details?
- defines the growth media required, rinding and diluting fluids, test organisms and a general procedure
- quantities or sample size required
When is the membrane technique most useful?
when the product has bacteriostatic or bactericidal properties or where drug is in an oil vehicle or ointment dose form
When should the tests be read for official testing?
- should be read on days 3, 7 and 14
If there is no growth in the test units and growth in the appropriate controls, the ________
requirements of the test are met
If there is growth in the test units but evidence this may be a result of deviation from procedure, _______
the test must be repeated
If growth occurs and there is no documentation of procedural deviation, ____ but number of samples is doubled
test is repeated
What is the luciferin-luciferase test?
- not used pharmaceutically but for water testing
- measure ATP by luminosity
What is the radiocarbon technique?
- use for blood culture
- 14C labeled glucose in medium
- 14C CO2 can be detected if microbes are present
What are pyrogens?
pyrogens are lipopolysaccharide (LPS) components of microorganisms which function as endotoxins (may be soluble, insoluble or colloidal)
What pyrogens are the most potent?
- this produced by gram negative organisms are usually the most potent
Small amounts of pyrogens produce ____ while large doses of pyrogens cause _____
fever and leukopenia
shock and death
Pyrogens provoke an immune response by _____
producing endogenous substances like prostaglandins, pro inflammatory cytokines interleukin 1, interleukin 6 and tumor necrosis factor alpha
Pyrogens are destroyed by autoclaving: true or false
False, they are not
they pass through the membranes used for sterilization
What is the most common source of pyrogen contamination?
water
What are the most likely ways to avoid pyrogen contamination?
- ensure that non are present in starting raw materials, esp water
- strict control of equipment cleanliness, dry heat sterilization of equipment where appropriate, distilling all water used in production or using water for injection and limiting processing times will help to avoid pyrogen contamination
What are the general methods of removing pyrogens?
dry heat, oxidizing agents, adsorption, and ultrafiltration
- distillation of water is effective and is normally used in the production of water for injection
What is the USP <151> test for pyrogens?
- based on the fever response of rabbits
- test carried out using 3 rabbits with stable baseline temperatures
- test material is injected into a marginal ear vein
- body temperature is recorded using a rectal probe and noted at 1, 2 and 3 hours post injection
- requirements met if no individual temp rise exceeding 0.6 degrees is seen and the total temp rise of the 3 rabbits does not exceed 1.4 degrees
(if not met, 5 additional rabbits used)
What is the limulus amoebocyte lysate test (LAL) for pyrogens
- a horseshoe crab has blood cells called amebocytes
- can be lysed to release a protein which reacts with pyrogens
- product of this reaction is a gel and this reaction forms the basis of a quantitative test for pyrogens (endotoxins)
- allowed for testing water for injection and used for testing short lived radioisotopes used in nuclear medicine
- only tests for gram negative bacterial endotoxins
What is the new pyrogen test being developed?
- based on the human fever reaction
- sample to be tested is incubated with blood taken from a healthy donor
- pyrogenic activity induces formation of IL-1B which can be determined by ELISA
What is particulate matter?
- extraneous, mobile, undissolved substances unintentionally present in parenteral solutions
Injectable solutions are to be_______
free from particles which can be observed on visual inspection
What are some sources of particulates?
- raw materials, processing equipment, container, closure and environmental sources
- other sources include human activity, contained/closure interaction, degradation of frug materials and extraction of material from the container
- clinical significance not clear but presence of particulates does severely detract from product elegance and this will cause reduced confidence in product and manufacturer
What are the details of testing procedures presented in USP <788> - particulate matter in injections?
- large volume parenteral contain not more than 12 particles per mL equal to or larger than 10 micrometers and not more than 2 particles per mL equal to or larger than 25 micrometers
- average number of particles is not more than 3000 equal or larger than 10 micrometers and not more than 300 equal to or greater than 25 micrometers per container
What are some common sources of particulates?
- raw materials, processing equipment, container, closure and environmental sources
- other sources include human activity, container/closure interaction, degradation of drug materials and extraction of material from the container
- clinical significance not clear but presence of particulates does severely detract from product elegance and this will cause reduced confidence in the product and manufacturer
