session 4: methods of sterilization

what is the most common filter size?

0.2 micrometers because this is the size of the smallest bacteria (pyrogens can still pass through)

what's included in 797?

1. establishing beyond use dates 2. compounding radiopharmaceuticals and allergen extracts 3. characteristics of a quality assurance program 4. verification of compounding accuracy and sterility 5. finished preparation release checks and test 6. elements of quality control

disadvantages of EtO gas sterilization

1. excessively long cycle 2. safety concerns: carcinogenic to humans 3. toxicity issues: toxic residues on surgical instruments and tubing 4. flammable 5. requires special room conditions, safety equipment and separate ventilation system 6. relatively high cost for maintenance, servicing and consumables

disadvantages of filtration

1. fragility of the membrane may result in being ruptured during filtration process (due to assembly, sterilization, or use) 2. filtration of large volumes are often time intensive especially when filtering viscous liquids 3. can only be used for solutions 4. filter can remove drug and reduce the activity/potency of some drug products

advantages of ionizing radiation

1. irradiation does not cause a significant rise in temp and induces no radioactivity in the final product --> used on heat sensitive materials 2. gamma and beta rays have good penetrative power 3. short exposure time

advantages of EtO gas sterilization

1. low temp 2. high efficiency --> destroys microorgs including resistant spores 3. large sterilizing volume/chamber capacity 4. non-corrosive to plastic, metal and rubber materials

injection containers

1. single dose containers: hermetic container; cannot be resealed --> ex: ampules and single dose vials 2. multiple dose containers: hermetic container that permits withdrawal of successive portions of the contents without changing the strength, quality or purity of the remaining portion

advantages of filtration

1. speed in filtration of small quantities of soln 2. ability to sterilize thermolabile/heat sensitive materials 3. relatively inexpensive equipment 4. complete removal of living and dead microorganisms and other particulate matter

packaging and labeling of injections

USP 23 labels must state: 1. name of the prep 2. % content of drug or amount of drug in a specified volume (for liquids) 3. amount of active ingredient present and volume of liquid to be added (for dry) 4. route of admin 5. statement of storage conditions and expiration date 6. name of manufacturer and distributor 7. lot number capable of yielding complete manufacturing history of the specific package each monograph for the official injection states the type of container permitted, type of glass preferred, exceptions to usual package size limitations and special storage instructions

quality assurance

USP 797 guidelines provide the minimum practice and quality standards for compounded sterile preparations applies at all times to those who compound sterile preps facilities for compounding CSPs are designed and controlled to minimize airborne contamination through use of laminar workbenches, compounding aseptic isolators and aseptic containment isolators and biological safety cabinets hazardous drugs must be compounded under conditions that protect the health care professionals: with the use of PPE, training for all personnel who come into contact with the material, verification of compounding techniques must be done annually

biological indicators

a characterized preparation of specific microorganisms resistant to a particular sterilization process used to monitor a sterilization cycle and/or periodically revalidate the process generally spores that are used to assess sterilization procedure --> spores can be added to a carrier or representative units of the product being sterilized

traditional pyrogen test

admin of the sample to lab rabbits whose body temp is monitored for a period of time thereafter if no rabbit shows a rise in temp of 0.5C or more the product meets the requirement for absence of pyrogens very well established

when is steam useful?

aqueous solns in sealed containers, bulk solns, glassware, surgical dressings and instruments

pyrogen

bacterial endotoxin fever producing organic metabolic products arising from microbial contamination responsible for many of the febrile reactions in patients following injection the febrile reaction/pyrexia is caused by LPS/endotoxin may remain after sterilization by autoclaving or bacterial filtration thermostable and water soluble product that passes sterility test may not pass pyrogen test more heavily contaminated with bacteria a product becomes during manufacturing --> more pyrogenic it is likely to be at end of process

disadvantages of ionizing radiation

can effect a number of materials: polyethylene, polypropylene, silicone rubber, teflon, glass

membrane filter materials

cellulose acetate, cellulose nitrate, fluorocarbonates, acrylic polymers, polycarbonate, polyester, PVC, nylon, polytef (teflon)

sterilization

destruction or complete removal of all living organisms and their spores from a pharmaceutical preparation

sterilization by filtration

effectiveness depends on physical removal of microorganisms by adsorption on the filter or by sieving used for heat-sensitive solutions medical preps sterilized this way must undergo extensive validation and monitoring filters produced with a variety of pore size specifications --> filters are very uniform with high degree of porosity --> pore sizes 0.025 to 14 micrometers pore size is most important but also consider electrical charge on filter and microorganism, pH of soln, temp and pressure or vacuum applied to the system.

most commonly recommended gas for pharm prep

ethylene oxide process requires 4-16 hours has bactericidal, fungicidal, virucidal, sporicidal, and protozocidal properties penetrating qualities make it a useful agent in certain special applications 1. medical and surgical supplies and appliances (cathetrs, needles, and plastic disposable syringes) in final plastic packaging 2. heat labile enzyme penetrations--> must be final tested to ensure absence of chemical reaction

gases used

ethylene oxide hydrogen peroxide propylene oxide chloride dioxide peracetic acid ozone

what substances can undergo dry heat?

for substances that are not sterilized by moist heat 1. fixed oils= fatty veggie based oil that doesn't evaporate upon heating (peanut, sesame, mineral) 2. glycerin 3. petrolatum, mineral oil and paraffin 4. various heat-stable powders effective for sterilizing glassware and surgical instruments

pharmaceutical products can be sterilized by which types of radiation?

gamma and beta

industrial sterilization

if sterilization of parenteral soln by autoclaving is impractical because of the nature of the ingredients, the individual components that are heat or moisture labile may be sterilized separately and then aseptically added to the autoclaved sterilized solvent or soln of components integrity of suspensions and emulsions is frequently destroyed by autoclaving so individual components are sterilized separately before being combined

USP bacterial endotoxin unit limit (USP EU)

injections are not pyrogen or endotoxin free but limited

dry heat sterilization

microbial killed by dry heat (dehydration of microbial cell followed by slow oxidation) ovens heated by gas or electricity and are thermostatically controlled dry heat less effective than moist heat --> higher temp and longer exposure required protocol for each product needed --> size, type of product and container all considered --> individual units should be as small as possible usually 150-170C for 2 hours increased temp= shorter time reduced temp= longer time

LAL test

more sensitive to endotoxin than the rabbit test horseshoe crab enzyme and protein system that coagulate in the presence of low level LPSs FDA has endorsed it as a replacement for rabbit test and is used for a number of parenteral products some parenteral products cannot be tested with LAL because active ingredient interferes with with the outcome may overcome interference by diluting product more than two fold

storage of injections

most are stable at room temp and may be stored without special concern most biologics must be stored in fridge individual monograph should be consulted to find proper storage temp and conditions

when is steam not useful?

oils, fats, oleaginous preps, and preps not penetrated by moisture

keeping unwanted particles out

parenteral solutions are usually filtered just before the container is filled the chemically resistant container is cleaned prior to use personnel are trained upon aseptic techniques and are provided with special clothing to prevent contamination all samples are inspected after filling --> any particulate containing samples are rejected large volume parenteral solution orders should be checked for additive compatibility with the original solution

validation

pharm preps required to be sterile must undergo tests to confirm absence of mircoorgs proper documentation/collection of data is necessary--> part of good manufacturing practices

gas sterilization

some heat sensitive and moisture sensitive can be sterilized better by exposure to gas process is a balance of time, temp, humidity and gas conc mech: interference of the metabolisum of the bacterial cell gas can permeate through many polymeric materials and are therefore not limited to just surface applications

industrial prep of injections

some injections are packaged as dry solids because the active ingredient is unstable in liquid --> use dry heat to sterilize reconstitutables generally solvent/vehicle is not provided but product label lists suitable solvents containers must not interact with the prep glass container must be clear and colorless or light amber to permit inspection of contents solutions need to be clear and free of all particulates

methods of sterilization

steam dry heat filtration gas ionizing radiation method chosen determined by nature of preparation and its ingredients final product must pass test for sterility as proof that the method was effective and the equipment and personnel performed correctly

ionizing radiation

two types 1. electromagnetic: gamma rays, x-rays,UV, infrared, microwave, and visible light 2. particulate radiation: alpha rays, beta rays (high speed, high beam electrons or cathode rays), neutrons and protons mech unknown main target site appears to be DNA but damage to RNA, enzyme and cell mems techniques available: gamma rays and cathode rays but limited because highly specialized equipment and irradiation on the products

pyrogen testing

two types 1. traditional test 2. limulus amoebocyte lysate test (LAL)

steam sterilization

usually method of choice if product can withstand the heat and can be penetrated by but not adversely affected by moisture mech: denaturation and coagulation of the organism's essential proteins when moisture is present bacteria coagulate and are destroyed at much lower temps than with no moisture spores have low moisture= destruction is difficult done in an autoclave with steam under pressure --> greater pressure= higher temp= less time to sterilize

when is dry heat the method of choice?

when dry apparatus or dry containers are required (dry chemicals or non-aqueous solutions)