Injectable solutions II - Shih

Steam sterilization

Most effective, preferred choice if product can stay intact

Requires lower temperature than dry heat ~121C vs 170C

Bacteria coagulated and destroyed at lower temperature in the presence of moisture than in the absence of moisture

121C for 20 minutes

When can steam sterilization be used

Aqeuous solutions

Sealed empty vials with small quantity of water inside

Bulk solutions

Glassware

Surgical dressings

Surgical instruments

When is steam sterilization not applicable

Oils

Fats

Materials not penetrated by moisture

Exposed powders that may be damaged by condensed moisture

Sterilization for suspensions and emulsions

Steam sterilization is preferred if the product can withstand it

Autoclaving can affect viscosity, suspend ability and particle size of the product

Can break/destroy the suspension or emulsion

Components may be sterilized individually before combining

Dry heat sterilization

Thermostatically controlled ovens

Dehydrate microorganisms

Less effective than steam

Higher temp for longer periods of time (150-170C for no less than 2 hours)

When can dry heat sterilization be used

Non-aqueous solutions (oil)

Heat stable dry powders

Dry containers

Glassware

Surgical instruments

Sterilization by filtration

Physical removal of microorganisms by absorption on the filter medium or by sieving microorganisms

Used for heat sensitive solutions

Filter pore sizes range: 0.025-14 um

Can use nylon, cellulose acetate, cellulose nitrate, PVC, polyester

Fast filtration of small quantities of solution is relatively inexpensive

Complete removal of dead or living organisms

Applicable in hospitals for small volumes

Difficult for viscous materials, drug can be removed

Gas sterilization

By exposure to ethylene oxide or propylene oxide

Highly flammable - should be mixed with inert gases

Requires specialized equipment

Enhanced by humidity and elevated temp at 50-60C

4-16 hours

Interferes with bacteria metabolism

Gas can penetrate plastic bags

For heat sensitive and moisture sensitive materials

Can remove enzymes and certain bacteria

Sterilization by ionizing radiation

Gamma rays and cathode rays

Destruction of cells by radiation

Limited because of specialized equipment needed and effect of radiation on the product and container

may denature the product

Validation of sterility

Testing to confirm the absence of microorganisms

Biological indicators

A characterized preparation of specific microorganisms resistant to a particular sterilization process. Used to monitor sterilization process, revalidate process. Spores can be added to allow sterilization of act as a representative unit of product being sterilized.

D value

Decimal reduction time. Time required to achieve one log (90%) reduction in microbial population at a sterilization temperature.

Z value

The increase in temperature for steam (under pressure) or dry heat sterilization or the dose of radiation sterilization required to produce one log (90%) reduction in the D value for particular microorganisms

F value

Time required to kill a known population of microorganisms under specified condition. Can be used to compare the lethality of different heat sterilization processes.

Ft equation

Ft = Dt (logA - logB)

Dt= the time for one log reduction in microbial population at temperature T

A = initial population

B = population after a defined time

Sterility Assurance Level

The degree of assurance for a sterilizing process to render a population of products sterile. SAL of 10^-6 or better is required.

Inactivation factor

Measures the reduction in the number of microorganisms of a known D value brought about by a defined sterilization process

IF equation

IF = A/B = 10^t/D

t is contact time with heat or radiation dose

D is the D value appropriate to the process employed

Assumed bacterial inactivation is a first order process

Endotoxins

Are a subset of pyrogens that come from gram negative bacteria

Natural complex of LPS occurring in the outer cell wall of bacteria

Cause fever, irreversible fatal septic shock, hypotension, lymphopenia, neutrophilia, elevated cortisol

They are water soluble and thermostable

Endotoxin elimination

Can be precipitated using potassium permanganate, bactrium hydroxide, followed by distillation in water

Can be eliminated by dry heat 210C for 3-4 hours

or

250C for 30 minutes

650C for 60 seconds

EL

Tolerable endotoxin load per dose

EL equation

EL = K/M

K- threshold of human pyrogenic dose of endotoxin per kg of body weight per hours

M - maximum recommended human dose per kg of body weight that would be administered in a single 1 hour period

Pyrogen testing

A regulatory requirement for release of sterile parenteral drugs

Rabbit pyrogen testing

Measuring rise in temperature of rabbits following IV injection of tested product

Low sensitivity and poor robustness

Limulus Amebocyte lysate test

An extract from RBCs of horseshoe crab contains an enzyme and protein system that coagulates in the presence of low levels of LPS

More heat sensitive

Packaging of parenteral products

Containers cannot interact with preparation

Containers must allow inspection of the components

Single dose containers

A hermetic container holding a quantity of sterile drug intended for parenteral administration as a single dose

When opened it cannot be resealed

Ampules or single dose vials

Multiple dose containers

A hermetic container that permits withdrawal of successive portions of the contents without changing the strength, quality, or purity

Vials or bags