PREPARATION OF
PACKAGING COMPONENTS
FOR STERILE DOSAGE
FORMS
• Improper handling of packaging materials in the
preparation stage is one of the greatest sources of
contamination by particulate matter.
• A sterile package consists of primary and secondary
packaging components.
• Primary packaging components are in direct contact
with the sterile product, such as ampoules, vials,
syringes, syringe cartridges, squeeze bottles and rubber
or plastic stoppers.
• The primary components must be clean and sterile.
There are numerous methods for cleaning primary
packaging components.
Containers
• All containers for sterile preparations must be
sterile, free of both particulate matter and
pyrogens.
• These containers should not interact physically
or chemically with formulations to alter their
required strength, quality, or purity.
• Containers must also permit inspection of
their contents.
Packaging Construction Materials
• Glass
• Rubber
• Plastic
Glass Containers
•
•
•
•
•
•
•
Glass is the most popular material for sterile preparation containers.
USP classifies glass as:
Type I (borosilicate glass),
Type II (soda-lime-treated glass),
Type III (soda-lime glass), or
NP (soda-lime glass unsuitable for parenteral containers).
Different glass types vary in their resistance to attack by water and
chemicals.
• For pharmaceutical containers, glass must meet the USP test for
chemical resistance.
• Because most pharmacy personnel do not have the time or facilities
to perform glass chemical interaction studies, they should use only
Type I glass to minimize sterile preparation compatibilities.
• Glass containers received in cardboard and chipboard
boxes contain dust generated by these packaging
materials.
• This dust and other particulate matters are difficult to
eliminate, frequently, the empty glass are vacuumed
before washing.
• Another approach to reduce troublesome particulates
have been the use of Shrink wrapping.
• Groups of empty glass containers are wrapped tightly
together with plastic films before shipment, thus
eliminating the contact of the glass with the cardboard
cartons.
• The glass containers are passed through a number
of cycles in automatic washing equipment.
• The air and water entering the washer should be
filtered to reduce particulate contact with the
containers during washing.
• A 0.22 μm cartridge is the most common porosity,
although 1 to 5 μm sizes are being used to give
high flow rate.
• Hot, pyrogen- free distilled water is used as the
washing and rinsing fluid.
• A typical wash cycle, allowing 1 minute for each step,
would be:
• Inside wash: hot filtered pyrogen- free water
• Outside wash: hot filtered pyrogen- free water
• Inside: filtered air
• Inside wash: hot filtered pyrogen- free water
• Outside wash: hot filtered pyrogen- free water
• Inside: filtered air
• Inside wash: hot filtered pyrogen- free water
• Inside: filtered air
• Outside: filtered air
• The vials or ampoules are then removed in tray
for sterilization.
• There are continuous washing system in which
the vials/ampoules are washed, sterilized, filled
and sealed in one continuous operation.
• After washing the glass components are sterilized
by dry heat.
• The sterile, depyrogenated glass containers are
stored in covered stainless steel trays in a cool,
humidity-controlled, clean-area under laminar
airflow.
• Siliconization is necessary to:
• Facilitate the draining of solid products from
the walls of the containers. This drainage
factor may help improve the appearance of the
product as well as help the dose uniformity by
inhibiting drying of the solid portion of a
suspension on the vial wall, resulting in a
reduction of the solids delivered per volume of
suspension.
• Siliconization is carried out with freshly prepared
aqueous emulsion of silicon which is sprayed into
the vials via a standard vial washing machine.
• The siliconized vials are then backed in a dry wall
oven at 250 C° for 5 hours.
• This backing procedure bakes the silicone onto
the surface of glass container.
• This procedure is done last in the processing step,
so that it serves as a depyrogenating step as well.
PLASTIC CONTAINERS
• Plastic polymers can be used as sterile preparation
containers but present three problems:
• 1. Permeation of vapors and other molecules in either
direction through the container.
• 2. Leaching of constituents from the plastic into the
preparation.
• 3. Sorption of drug molecules onto the plastic.
• Plastics must meet USP specifications for biological
reactivity and physiochemicals.
• Most plastic containers do not permit ready inspection
of their contents because they are unclear. Most plastics
also melt under heat sterilization.
• Plastic containers, such as ophthalmic dispensers, are
usually, washed in much the same manner as glass but
are sterilized by means requiring low temperature
because of the low melting point of the plastic used.
• Polypropylene or high- density polyethylene parts, such
as caps, can be steam sterilized.
• Low density polyethylene plastics used for flexiblewalled ophthalmic packaging can’t be steam-sterilized,
due to the distortion encountered during the normal
autoclaving cycle. So they are usually sterilized with
ethylene oxide.
• Washed plastic components are placed in
polyethylene bag that allow adequate penetration
of the gas for sterilization and proper venting after
sterilization to remove the sterilant.
• Less than 1 ppm of ethylene oxide can be
detected on suitable monitoring equipment.
• Exposure to cobalt- 60 gamma rays or the highenergy electron beam source is another method
for plastic sterilization.
• Plastic syringes: are rarely used to package
unit dosage injection.
• The pharmaceutical industry has not marketed
prefilled plastic syringes.
• This is meanly due to potential plastic
extractives, weight loss by vertue of water
vapor loss, plastic-product interaction.
• Such devices would be sterilized by a gas
sterilant or by exposure to radiation.
Closures
• Rubber closures must be rendered sterile, free from
pyrogens and surface particles. To meet these
specifications, multiple washings and autoclaving are
required.
• Closures are made of natural, neoprene, or butyl rubber.
Thus, the rubber sealing of a vial or the plug in a
syringe is a complex material that can interact with the
ingredients of a formula.
• Rubber closures also are subject to coring.
• Therefore, you should consult the literature standards
when selecting a rubber closure for sterile preparations
• Washing process: to remove dirt and/or surface
contaminants from the rubber.
• Detergents must be used carefully because residual
amounts can be difficult to remove from the rubber.
• Two problems are associated with the ordinary clothes
washers:
• 1- the tumbling action of the washer produces abrasion,
resulting in excess particle formation.
• 2- The gravity drain at the bottom of the washer forces
the dirty effluent liquid to be drained through the clean
stoppers at the end of the wash cycle.
• The problem of gravity drain has been eliminated
by adding an overflow rinse cycle to float dirt and
debris away from the stoppers toward the top of
the liquid surface and out to a separate drain
system. This prevents drainage of wash water
back through the clean bed of closures (HUBER
WASHER).
• One disadvantage of this washer is the tumbling
action of the inner basket. This action may cause
the stoppers to abrade against each other or
against drum.
• CAPSOLUT WASHER:
• Has eliminated both the drain and abrasion problems.
• It gently agitates the stoppers via filtered air, which is
directed toward a basket containing the stoppers.
• The dirt or debris floats to the surface while the tank is
being flushed with clean water from below.
• The debris is removed by overflow through a drain
system at the top of the tank.
• The washing time and temp. of the rinse water will
depend on the type, size and quality of rubber
components being washed/load.
• A 0.22 μm cartridge-type filter is used and the
filter is checked periodically for integrity
and/or clogging.
• After washing the rubber components are
packed in clean glass, polypropylene, nonshedding synthetic bags or stainless steel
containers with sealable tops.
• Sterilization:
• - by autoclaving (moist heat), rapid heat penetration
• -Dry heat (slow heat penetration)may dry and crack the
rubber
• Ethylene oxide may be difficult to release from the
rubber matrix within a practical time period.
• Underheating may not produce an adequate microbial
kill.
• Overheating may cause tackiness or decomposition of
the rubber.
• Siliconization:
• -To facilitate insertion of the rubber
components into container openings via highspeed automatic filling and sealing equipment.
• Without siliconization, shingling or jamp-up of
the rubber stoppers because of the high friction
of untreated rubber.
Cleaning and Sterilization of Vials
• 1. Vials are cleaned and sterilized before filling. Following
procedure is used for cleaning • and sterilization of vials.
• 2. Soak the vial with detergent solution overnight to remove any
sticking particles, grease, etc.
• 3. Wash with tap water three to four times till soap solution is
completely removed.
• 4. Remove surface alkalinity using 1.0% hydrochloric acid solution.
• 5. Again wash the vial using tap water till free from alkalinity.
• 6. Rinse with de-ionized water and finally with distilled water.
• 7. Cleaned vials are sterilized by dry heat sterilization at 200°C for
4 hours.
• 8. Cool sterilized vials at room temperature under the closed
condition prior to filling the vials.
Cleaning and Sterilization of Rubber
closures
• 10. Rubber closures are boiled with 1.0% solution of liquid
detergent for 30 minutes.
• 11. Wash with tap water till free from detergent.
• 12. Boil for 30 min. using 1.0% solution of hydrochloric
acid.
• 13. Wash to make them free from acid.
• 14. Boil the acid washed rubber closures with 1.0% sodium
carbonate solution and wash till free alkali.
• 15. Treat rubber stoppers with double strength bacteriostatic
solution.
• 16. Wash three to four times using pyrogen free water.
• 17. Sterilize by autoclave at 115°C for 30 minutes.