542 - Kwon Sterile product requirement (copy)

KWON

top 10 excipients in injectable products

1. water

2. cosolvent

3. oils

4. surfactant

5. antimicrobial agent

6. buffer

7. antioxidant

8. tonicity agent

9. cryoprotectant/lyoprotectant

10. competitive binding

Top 7 requiremnts of injectable products

1. purity

2. sterility

3. sterile filtration

4. particulates

5. antimicrobial agents (such as perservatives)

6. pyrogens

7. isotonicity

sterility

complete destruction of all living organisms and their spores or complete removal

what sterile products are susceptible to microbial contamination?

• aq solution

• emulsions

• suspensions

D-value

time in mins required to destroy 90% of microbes udner a standard set of conditions

D= 1 min —> 10^6 organisms goes to 10^5 after 1 min

biological indicator

specific microorganisms resistant to a particular method of sterilization

Validation of sterility

add at known level and known D value and sterilize - survival should be 10^-6 or less

List the Sterilization techniques (4)

• steam

• dry heat

• radiation

• Gas

Steam sterilization

heating under pressure in the presence of water to generate steam

• moist heat causes irreversible denaturation of essential proteins

• this can damage oils, proteins, and powders

• D = 1 min at 121 C

Dry heat sterilization

done in sterilizing ovens

• mech of microbial destruction is dehydration, denaturation, and slow burning or oxidation

• D = 5 mins at 160 C

Radiation sterilziation

• gamma radiation

• mech: ejects electrons nad creates free radical that reacts iwth biological macromolecules, esp DNA< leading to cell damage and death

• ionizing radiation can damage biologic drugs

gas sterilization

Ethylene oxide (EO) + heat + moisture

EO = alkylating agent + reacts with amine groups of DNA

Residual EO must be allowed to dissipate after sterilization and before use of sterile product

Sterile filtration

physical removal of particles and microorganisms form solution

Depth filter

substance that trap particles in channels

Screen filter

surface filtration - cellulose esters

Mcirobial filter

0.22uM

particulate - free

particles can be emboli (matters carried in blood) that can get stuck in a BV, obstructing it and resulting in a blockage —> embolism

list antimicrobial agents

benzyl alcohol

• IV can cause death of neonates given preserved saline

• Intrathecal can increase risk of neurological events

• epidural toxicity

Pyrogens

fever causing organic molecules

primary source of pyrogens

water

Sources of microbial contamination (7)

• Raw material

• water

• air

• processing operations

• equipment

• employees

• environment

Approaches to sterility (4)

• initial control

• terminal sterilization (product in primary packaging)

• aseptic processing and sterile filtration for biologics

• antimicrobial agents

Sterility assurance level (SAL)

1/10 ^6

Major factors of mcirobial growth and death (7)

• temperature

• time of storage

• C_o

• Chemical (Nutrients, ph)

• Gaseous environment (oxygen)

• Moisture content

• radiation

Limulus amebocyte lysate test

Type of pyrogen test

• a gel forms in the presence of pyrogen

Rabbit febrile reaction test

type of pyrogen test

• elevation of >0.6 C above normal is the basis for failure of the test (from animals rectal temp

Lipopolysaccharide (LPS)

• cell wall of grame negative bacteria aka endotoxin

• maybe remain thermostable even after steam sterilization or bacterial filtration

List situations where you wouldn’t need an antimicrobial agents

• hydroalcoholic preperations, >15% alcohol

• hypertonic solutions, 67% sucrose in syrups (microorganisms cannot grow)

• pH < 3 (pickling)

• pH >9(too basic)

• multiple dose products

Bacteriocidal

Kills organisms

Bacteriostatic

Prevents growth

Modes of action

Sources of Particulate - free? (7)

• bacteria/fungi

• protein aggregation/ precipitation

• incompletely dissolved drug

• precipitate from incompatible admixtures

• glass particles from ampoules

• particles from rubber stoppers

• particles form plastic

when are incidence of phlebitis reduced?

when IV infusions are filtered (final filter)

Phlebitis

• inflammation of vein

• pain and tenderness along course of vein