DDS Lecture 14 Content

General Manufacturing Process

1. Procurement and selection of components and containers

2. Product preparation: in sterile environment (aseptic)

3. Quality assurance (stability testing, pyrogen testing)

4. packaging and labeling

Components of Parenterals

• vehicles

• solutes

Parenteral Vehicle

• non-irritating

• non-toxic

• no pharmacologic activity

• no effect on active ingredient

• physical properties: stability at various pH, temperatures, viscosity, miscibility with body fluid

Aqueous Vehicles

• isotonic

• drugs may be added

• 0.9% Sodium Chloride injection

• Dextrose

• Lactated Ringers

Water-Miscible Vehicles

• used to affect solubility and reduce hydrolysis

• propylene glycol (phenytoin)

Non-aqueous vehicles

• fixed oils of vegetable origins

• ex. soybean oil (used for propofol), amphotericin B liposomal

Parenteral solutes

• antimicrobial agents: thimerosal 0.01%, benzethonium chloride 0.01%

• buffers: citrates, acetates, phosphates

• antioxidants: sodium bisulfite 0.1%

• other added substances: sodium benzoate

Parenteral containers

• no container is totally insoluble

• should avoid

  • leaching

  • permeation

  • adsorption

• selection of containers:

  • glass

  • plastic polymers: polyethylene, polypropylene, polyvinyl chloride (PVC)

  • rubber polymers- butyl, silicone, natural rubber

Plastic containers

• Do not break

• weight reduction (very light)

• flexible (dropper)

• risk of permeation, leaching, adsorption: must carefully select drugs

• not clear: difficult to inspect contents

• melts under thermal sterilization

Glass container

• glass composition: silicon dioxide and other oxides

• oxides loosely bound to silicon oxide tetrahedron

• 4 main types, 3 used in containers

Type I Glass

• silicon dioxide and boric acid

• neutral glass

• preferred

• low levels of migratory oxides, low leaching

• suitable for all products

• more expensive

Type II Glass

• sodium oxide and calcium oxide

• soda-lime glass with high hydrolytic resistance

• melt at lower temperatures

• lower concentration of migratory oxides than type III

• treated with sulfur dioxide to dealkalize interior surface of glass

• best used for solutions with pH < 7 or is buffered

Type III glass

• sodium oxide and calcium oxide

• soda-lime glass with moderate hydrolytic resistance

• highest concentration of migratory oxides

• best used for dry substances, non-aqeous preparations

Industrial Preparation of Parenteral Products

1. Compounding

2. Filtration

3. Filling/Sealing

4. Sterilizing

Methods of Sterilization

• steam

• dry heat

• filtration

• gas

• ionizing radiation

Steam Sterilization

• equipment used: autoclave

• with moisture, bacteria coagulate and are destroyed at lower temperature (vs. without moisture)

• bacterial cells with large % of water killed more easily (spores difficult)

• mech of action: denaturing and coagulation of bacteria’s essential protein

• ideal for preparations that can withstand required temperatures, but not affected by moisture

• usually method of choice is feasible

• widely used settings: 15 lbs pressure, 121.5 C (250 F), 20 minutes

• used for solutions sealed in ampules or vials, surgical instruments, bulk solutions

Dry Heat

• electric or gas “ovens”

• dry heat is less effective in killing than moist heat

• mechanism of destruction is dehydration

• conducted at 150-170 C (302-338 F) for 2-4 hours

  • higher temp, longer than steam

• effective for substances not effectively sterilized by moist heat

• ex.

  • fixed oils

  • glycerin

  • mineral oil

  • paraffin and zinc oxide

  • thermostable powders

  • glassware, surgical instruments

Filtration

• removal of microbes by adsorption via filter medium

• filters produced according to pore size

  • millpore 14 - 0.025 mcm, smallest bacteria is 0.2 mcm

• electric charge of microbes, pH of solution, temperature

• best used for heat sensitive solutions (thermolabile), low viscosity solutions

Types of Filters

• Candle

• Asbestos

• Sintered Glass

• Membrane (MOST COMMON)

Membrane filter

Bubble Point Test

• tests filter integrity

• minimum pressure required to force liquid out of the capillary space in the membrane

• smaller the pore size, the high the bubble point pressure

• manufacturer gives standards for filter

  • will give certain threshold for pressure

  • should not get pressure lower than standard (means filter is broken)

Gas Sterilization

• use of ethylene oxide or propylene oxide gas

• thought to inhibit bacterial cell wall formation

• extremely flammable when mixed with air

• sterilization with ethylene oxide

  • ~4-16 hours

• con: greater precautions required because variability of time, temperature, gas concentration, and humidity

  • also flammability

• pros:

  • great penetrating qualities useful for powders and heat labile enzyme preparations

    • antibacterials

  • ophthalmic prep

  • vaginal inserts

  • plastic syringes and tubes

Ionizing Radiation

• sterilization via gamma (Cobalt-60), cathode rays, UV lamp

• application limited due to highly specialized equipment and effects of radiation

• thought to destroy vital chemicals and/or structures (ex. chromosomal nucleoproteins)

• used for antibiotics, hormones, sutures, prepackaged, disposable items

Pyrogens

• lipopolysaccharide metabolic products from outer cell walls of gram-negative organisms

• water soluble and thermostable

  • may remain after steam and filtration sterilization

• bacterial endotoxin unit limit (USP)

  • 5 EU/kg/hour for most drugs

  • Intrathecals: 0.2 EU/kg

  • EU = endotoxin units

Pyrogen Testins

• Rabbit Test

• LAL test

Rabbit Testing

1. Instruments heated to 250 C > 30 min

2. heat product to be tested to 37 C ± 2

3. inject product into vein of 3 rabbit’s ears 10 ml/kg and record temperature for 3 hours

4. If no rabbit shows increase in temperature >0.5 C OR sum of 3 rabbits is less than 1.4 C, meets USP standards

5. If one rabbit shows increase in temp more than 0.5 C, repeat test on 5 more rabbits

6. If not more than 3/8 show rise in temperature or 0.5 C, or sum of 8 rabbits is less than 3.3 C, meets USP standards

LAL test

• Limulus Amebocye Lysate Test

• extract blood cells of horseshoe crab (Limulus polyphemus) contains enzyme and proteins that coagulate in presence of low levels of lipopolysaccharides

• aka Gel clot test, photometric test

• Used by USP

• 5-50x more sensitive to endotoxin than rabbit test

• some drugs interfere with test: meperidine, promethazine, oxacillin, vancomycin

Sterility Testing

• USP 71: Must confirm sterility of each sterilized batch by either direct innoculation or filtration

• use culture medium trypticase soy broth (TSB) and fluid thioglycollate medium (FTM)

• medium incubated for 14 days

• does require validation before product shipped

• direct innoculation or membrane filtration test

Direct inoculation sterility test

the product/medical device will be in direct contact with the test media throughout the incubation period

Membrane Filtration Sterility Test

• Test sample effluent is transferred to a cellulose nitrate or cellulose acetate membrane filter capable of retaining microbe

• filter is then transferred to two specific nutrient test mediums and incubation for 14 days

Biological Indiactor

• biological marker

• provides information on whether necessary conditions were met to kill a specific number of microbes for a given sterilization process, providing a level of confidence in the process

• endospores or bacterial spores primarily used in biological indicator

  • microbes considered some of toughest to kill

Steam biological marker

Bacillus stearothermophilus

Gas biological indicator

Bacillus stearothermophilus

Dry Heat Biological Marker

Bacillus subtilis

Ionizing Radiation Biological Marker

• bacillus pumulis

• bacillus stearothermophilus

• bacillus subtilis

USP 797

• USP has 2000 chapters

• 797: minimum practice and quality standards to which sterile preparations should be compounded

• applicable for all settings and all personnel that compound sterile preparations

  • ANY healthcare setting, not just pharmacy

• enforced by state boards of pharmacy and FDA

• was made official in June 2008

Sterile Preparations

• injections (IV, TPN, IM, SC, epidural, IT)

• ophthalmic drops and ointments (ex.

• aqueous pulmonary inhalations

• baths and soaks

• irrigations for internal body cavities

• implants

Class 5 Environment

• class 100

• no more than 100 particles per cubic foot

• inside hood

Class 7 Environment

• class 10,000

• no more than 10,000 particles per cubic foot

• clean/buffer room

Class 8 Environment

Categories of Compounding sterile preparations

• 4 main categories:

  • Immediate use

  • category 1

  • category 2

  • category 3

• classifications based on potential for microbial, physical, or chemical contamination during compounding

• determined by where the compounded sterile preparation is made and the time period within which it must be used

• if the compounding personnel are unsure, they should go with the more stringent category to ensure safety

Immediate Use CSP

• ISO Class 5 Environment not required

• 7 requirements:

  • Aseptic standard operating procedures and process must be in place

  • Personnel trained and demonstrate facility-specific competency in aseptic technique

  • preparation performed per FDA-approved labeling or evidence-based information

  • preparation limited to 3 different sterile products

  • any unused medication from a single dose vial is discarded

  • administration begins within 4 hours of preparation

    • BUD: 4 hours

  • CSP must be labeled unless it is administered by, or the administration is witnessed by, the preparer

  • ex. prep of epinephrine drip at bedside by nurse of pharmacist for patient in cardiac arrest

Category 1 CSP

• must be compounded in an ISO Class 5 air quality environment or better

  • Class 5/PEC does not have to be located within Class 7 buffer room

  • can be in segregated compounding area (SCA)

  • ex. PEC located directly in regular pharmacy satellite

  • PEC: primary engineering control

• max BUD of 12 hours at room temp, 24 hours in fridge

  • short bc of higher risk for contamination when there’s no buffer or ante room

Category 2 CSP

• preparation compounded in PEC, within buffer room, with ante-room separating the buffer room from the rest of the pharmacy

• assigned BUD based on whether or not they are produced from sterile products only or produced from non-sterile products but terminally sterilized (ex. sterilization after the CSP has been produced using dry heat, steam, irradiation), and whether or not sterility testing has been performed on them

Category 3 CSP

• allows for longest dating

• requirements in addition to those for Cat2 to ensure safety

• additional requirements: increased frequency of aseptic manipulation competency, sterile garbing, increased viable air and surface sampling, and increased frequency of sporicidal applications during cleaning

• BUDs must be supported by stability data obtained using a stability-indicating analytical method

• Sterility testing and endotoxin testing required for all cat3

Multi-dose Vial

• contains preservatives

• max BUD: 28 days after entering with needle or puncturing stopper

• if any type of contamination of multi-dose vial is suspected, discard immediately

Single-dose vial

• max BUD: 12 hours after first entry

• if vial is entered in at least ISO class 5 environment

  • may be removed from ISO class 5 PEC for storage at appropriate temp during 12 hour period

• once ampules have been opened, they must not be stored for any period of time, regardless of air quality

Sources of ISO-Class 5

• Laminar airflow

  • Horizontal

  • Vertical

    • good when drug is hazardous, do not have molecules to flow toward you

  • continuous flow of air through HEPA filter (air filter that removes 99.97% of particles with size of 0.3 microns)

• compounding aseptic isolator

Hazardous drug preparation

• present health risk to compounding personnel

• should be prepared in an ISO class 5 environment in an ISO class 7 negative pressure area physically separated from other prescription areas

  • negative pressure: so air from inside room doesn’t escape; air from outside will come in when person enters

Proper Hygiene and Garbing

• Prior to entering buffer area or segregated compounding area