Sterility pharmaceutics

Potential sources of contamination

Materials used in compounding

Evniroment (airborne and surface)

Personnel (inadvertent touch or shedding/spewing)

Potential sources of contamination

material used in compouunding

ingrediantes (particulate matter)

supplies/devices

Potential sources of contamination

Environment (airborne and surfaces)

airborne contaminants controlled via HEPA filtraton, both LAFW and total room air, positive pressure cleanrooms

surface contaminants controlled via cleaning and sanitaiton programs for products, facilities, equipment

restricted access/activity in critical areas

Potential sources of contamination

Personnel (inadvertent trouch or shedding/spewing)

contaminants controlled via training, monitoring, and testing or personnel

1. scrubbing and gowning techniques

2. hygiene

3. established workflow and SOPS

4. aseptic technique

LAFW

Laminar Flow

clean air, shoots the air down and pushes it out

BSC

Biological Safety Cabinett

recirculate air

hepa air comes in from the opening or front, pulled up, filtered, and comes down

CAI

Compounding Aseptic Isolator or Barrier Isolator

Methods of drug product sterilization

autoclaving

Dry heat

Filtraton

Ionizing gamma radiaton

autoclaving

steam 121 C 15PSI for 20-60min

for heat stable aqueous solutions

will inactivate all fungi, bacteria, viruses and also bacterial spores

will not necessarily elimate all prions (infection agent composed primarily of protien eg, BSE, cruetzfiled jakod disease in humans)

1. can be elimated by 2 hours in 0.09 NaOH followed by 1hr autocolave

Dry heat

oven at >160C for much longer period of time than steam (variable depending on material)

for sealed glass and metal containers, powders, heat stable

Filtration

0.22uM porosity sterile membranes

for known heat labile drugs and compound when heat stability is not known

Ionizing gamma radiation

for powders, ointments, large molecules/particles that cant be filtered

Pyrogens or bacterial endotoxins

Non living lipopolysaccharides

1. part of the cell wall of gram negative bacteria

Wide size range, typically >10kD

water soluble

stable to autoclaving

Pass through 0.22 uM pores in sterilizing filters

Retain potency for months to years in dry state on clean containers and tubing

Bacterial endotoxins testing and limits

1 EU (endotoxin unit)= 0.1-0.2 mg/ml

1. 5EU/kg of body wieght for any route of administration other then intrathecal (for which 0.2 Eu/Kg of body weight)

Injecting rabbits with a sample and observing their body temperature Pryogen (response)

LAL (limulus amebocyte lysate) test

1. water soluble enzyme extracted from blue amebocyte blood cells of horseshoe crabs

USP 85 Bacterial Endotoxin Test

How to avoid, remove, and destroy pyrogens

To avoid: use freshly distilled water to make injecitons (pyrogens are non volatile)

To remove or destroy

1. Ultrafilitraton: membrane with 10,000 daltons cut off limit (product-liquids)

2. Heating, 250C for 30 min denature

USP 797 is

Practice Standards for Stelire compounding

Issue with USP 797

Pharmacy linked to Multiple state outbreak of Serratia infection

1. magnesium sulfate intravenous solutions made by a compouding pharmacy linked to 18 caes of Seerratia marcenens bloodstream infection in five states

New England compuding center

1. outbreak of fungal meningitis

2. Sterility Issues of Methylprednisolone sued for epidural injection

3. Over 100 people died

USP 797 Pharmaceutical Compounding Sterile prepartions definition

Enforceable sterile preparation compounding standard that applies to healtchare insitutionns, pharmacies, physcian practice facilities, and other facilities in which CSPs are prepared, stored, and dispensed

USP 797 Pharmaceutical Compounding Sterile prepartions requirements

Requirements must be followed to minimize harm, including death, to human and animal patients that could result from

1. microbial contamination (nonsterility)

2. excessive bacterial endotoxins

3. variability from the intented strengh of correct ingrediadients\

4. Physical and chemical incompatibilities

5. chemical and physical contaminants

6. Use of ingredients of inapproprate quality

USP chapter 797 foundation

pharmacist is ultimately responsible for sterility and accuracy of compound sterile preperations CSP

Divided CPPs into three categories based on the state of enviromental control, probablity for microbial groth, and time period of use.

The BUDs for CSPs are based primarly on factors that affect the acheivement and maintencance of sterility, which include but are not limited to the following

1. conditions of the enviroment in which the CSP is prepared

2. Aseptic processing and sterilization method

3. Starting components (eg sterile or nonsterile ingredients)

4. whetehr or not sterility testing is performed

5. Storage condiitions (eg packaging and temperature

Category 1

Least controlled environmental conditons, BUD 12> no more than 24 hour refrigerated.

Category 2

more control of enviroment

cat 3

Requires sterilty testing, endotoxin testing, stringent enviromentmental/personel control. Assigned longer BUDs