Sterile Dosage Forms

and Long Acting

Parenteral Drug
Delivery Systems
Presented by: Jeanne Pauline R. Mabutas, RPh
Definition of Terms
Are sterile, pyrogen-free preparations intended to be
administered parenterally
Refers to

Are used when rapid drug action is desired such as in

emergencies, when the patient is uncooperative,
unconscious or unable to accept or tolerate oral
medication or when the drug itself is ineffective by
other routes
Also called

Are organic metabolic products shed from gram(-)

bacteria which can cause fever and hypotension in
patients when they are in excessive amounts in
intravenous injections
 01
Parenteral Routes
of
Administration
 01 02
Provides effect that are less rapid
Provides rapid action compared with other ROA;
but generally longer lasting than
optimum blood levels may be achieved with
those obtained from IV
accuracy and immediacy not possible by other
administration
routes

03 04
May be used for injection of small Usually for diagnostic determinations,
amounts of medication desensitization or immunization
 02
Official Types of
Injections
 ___________ – liquid
preparations that are drug
substances or solutions
thereof
 ___________– dry solids
that upon addition of
suitable vehicles, yield
solutions conforming in all
respects to the
requirements for injections
 _____________– liquid
preparation of drug
substance dissolved or
dispersed in a suitable
emulsion medium
 _____________– liquid
preparation of solid
suspended in a suitable
liquid medium
 ______________– dry
solid that upon addition of
suitable vehicle, yields
preparation conforming in
all respects to the
requirements for injectable
suspension
 ______________– long
acting injections to reduce
the frequency of injections
 03
Solvents and
Vehicles for
Injections
 _______________– most
frequently used solvent in
the large-scale
manufacturer of injections.
Intended to be use of
injectable products to be
sterilized after preparation
 __________________–
packaged in single-dose
containers not larger than
1L. Intended to be used as
a solvent, vehicle or
diluent for already
sterilized and packaged
injectable medications.
 _______________–
contains one or more
suitable antimicrobial
agents. Usually packed in
prefilled syringes or in
vials containing not more
than 30ml of water.
Employed as a sterile
vehicle in the preparation
of small volumes of
injectable preparations.
 _______________– sterile
isotonic solution of NaCl
in water for injection. May
be used as a sterile vehicle
in solutions or suspensions
of drugs for parenteral
administration
 ________________–
sterile isotonic solution of
NaCl in water for
injection. May not be
packaged in containers
more than 30ml. Must also
carry the warning NOT
FOR USE IN NEONATES
 _________________–
sterile solution of sodium
chloride, potassium
chloride and calcium
chloride in water for
injection. Serves as an
electrolyte replenisher and
plasma volume expander.
 _______________– has
different quantities of the
three salts in ringer
injection, and it contains
sodium lactate. Also serves
as a fluid and electrolyte
replenisher and a systemic
alkalizer.
 04
Non-Aqueous
Vehicles
 Non-Aqueous Vehicles
Must be nonirritating, nontoxic in the amounts
administered, and not sensitizing
Must not exert a pharmacologic activity of its
own, nor may it adversely affect the activity of its
own, nor may it adversely affect the activity of
the medicinal agent
Considerations for
NAVs:
Examples include:
The USP specifies restrictions on the fixed
vegetable oils in parenteral products
They must remain clear when cooled to 10°C to
ensure the stability and clarity of the injectable
product during refrigeration
Must not contain mineral oil or paraffin as these
are not absorbed by body tissues
Most commonly used fixed oils in injections:
 05
Added Substances
 Added Substances
Addition of suitable substances to official preparations
intended for injection to increase stability or usefulness as
long as the substances are not interdicted in the individual
monographs, are harmless in the amounts administered, and
do not interfere with the therapeutic efficacy of the
preparation or with specified assays and tests.
 Added Substances
These added substances are:
 Antibacterial preservatives
 Buffers
 Solubilizers
 Antioxidants

*Coloring agents are strictly prohibited in parenteral

products
 Added Substances
The USP requires that one or more suitable substances be
added to parenteral products that are packaged in multiple-
dose containers to prevent the growth of microorganisms
regardless of the method of sterilization employed, unless
otherwise directed in the individual monograph or unless the
injection’s active ingredients are themselves bacteriostatic.
 Added Substances
These substances are used in concentrations that prevent the
growth of or kill microorganisms.

Many of these are toxic in large amounts or irritating when

parenterally administered special care must be exercised in
the selection of the appropriate preservative agents.
 Added Substances
In addition to the stabilizing effect of the additives, the air
accompanying an injectable product is frequently replaced
with an inert gas, such as nitrogen, to enhance the stability
of the product by preventing a chemical reaction between
oxygen and the drug.
 06
Methods of
Sterilization
 Sterilization
Sterilization, as applied to pharmaceutical preparation, means
destruction of all living organisms and their spores or their complete
removal from the preparation

Five general methods are used to sterilize pharmaceutical products:

 Conducted in an ______________ and employs steam
under pressure
 Usually the method of choice if the product can withstand
the required temperature and are penetrated but not
adversely affected by moisture
 The mechanism is thought to be by denaturation and
coagulation of some of the organism’s essential protein
 It is the hot moisture in the microbial cell that permits
destruction at relatively low temperature
 The greater the pressure applied, the higher the
temperature obtainable and the less time required for
sterilization
 Solutions in ampules are sterilized by this method
 Applicable to bulk solutions, glassware, surgical dressings
and instruments
 Usually carried out in ___________ designed for this
purpose
 Less effective in killing microorganisms than moist heat,
higher temperatures an longer periods of exposure are
required
 Usually conducted at 150°C-170 °C for not less than 2
hours
 Also effective for sterilizing glassware and surgical
instruments
 Method of choice when dry apparatus or dry containers
are required, as in the handling of packaging of dry
chemicals or nonaqueous solutions
 Examples include fixed oils, glycerin, various petroleum
products such as petrolatum, mineral oil and paraffin.
Also heat-stable powders such as zinc oxide
 Depends on the physical removal of microorganisms by
adsorption on the filter medium or by a sieving
mechanism used for heat-sensitive solutions
 May be used in community pharmacy to filter
extemporaneously prepared solutions such as ophthalmic
solutions that must be sterile
Advantages include:
 Speed in the filtration of small quantities of solution
 Ability to sterilize thermolabile materials
 Relatively inexpensive equipment required
 Development and proliferation of membrane filter
technology
 Complete removal of living and dead microorganisms
and other particulate matter from the solution
 Exposure to _________________________ than by other
means
 Used in sterilization of medical and surgical supplies and
appliances such as catheters, needles and plastic
disposable syringes in their final plastic packaging just
prior to shipment
 Sterilization by Ionizing
Radiation
 Use of _______________________
 Limited because of the highly specialized equipment
required and effects of irradiation on the products and
their containers
 07
Validation/
Verfication of
Sterility
________________– a characterized preparation of specific
microorganisms resistant to a particular sterilization process. They may
be used to monitor a sterilization cycle and/or periodically to revalidate
the process.

Mainly of two forms:

 Spores are added to a carrier (i.e. filter paper) packaged to maintain
physical integrity while allowing the sterilization effect
 Spores are added to representative units of the product being
sterilized, with assessment of sterilization based on these samples
 Method of Sterilization Spore used

Steam and Ethylene Oxide

Sterilization

Dry Heat

Ionizing Radiation
 Pyrogen and Endotoxin Testing
______________ – are a subset of pyrogens that come from gram-
negative bacteria. These are the natural complex of lipopolysaccharides
that occur in the outer layer of bilayered gram-negative bacterial cells.
• They are potent, toxic, and very stable and are present in many
pharmaceutical ingredients and on surfaces that come into contact
with preparations formulated for parenteral administration.
• They are water soluble, will pass through filters, and are not
destroyed by autoclaving, and are insoluble in organic solvents.
Inject into an ear vein of each of three Came from the extract from the
rabbits 10ml of the product per kg of blood cells of the
body weight, completing each injection ___________________________
within 10mins of start of administration.
If no rabbit shows an individual rise of that contains an enzyme and
temperature of 0.5 or more, the product protein system that coagulates in
meets the requirements for the absence the presence of low levels of
of pyrogens. lipopolysaccharides.
 08
Industrial
Preparation of
Parenteral Products
 In the preparation of parenteral solutions, the required ingredients are
dissolved according to good pharmaceutical practice in water for injection, in
another solvent, or in a combination of solvents.
 The solutions are usually filtered through a membrane until sparkling clear.
After filtration, the solution is transferred as rapidly as possible and with the
least possible exposure into the final containers.
 The product is then sterilized, preferably by autoclaving, and samples of the
finished product are tested for sterility and pyrogens.

 If sterilization by autoclaving is impractical because of the nature of the

ingredients, the individual components of the preparation that are heat or
moisture labile may be sterilized by other appropriate means and added
aseptically to the sterilized solvent or solution of components that can be
autoclaved.
Examples of sterile drugs prepared and packaged WITHOUT pharmaceutical
additives:

Examples of sterile drugs prepared WITH pharmaceutical additives and

intended to be reconstituted prior to injection:
 09
Packaging, Labeling
and Storage of
Injections
A hermetic container holding a quantity
of sterile drug intended for
parenteral administration as a single
dose and when opened, cannot be
resealed with assurance that sterility
has been maintained.
A hermetic container that permits withdrawal
of successive portions of the contents
without changing the strength, quality or
purity of the remaining portion. It is
usually affixed with rubber closures to
permit penetration of a hypodermic
needle without removal or destruction of
the closure.
 Labeling must include:
 The name of preparation
 For a liquid preparation, percentage content of drug or the amount of
drug in a specified volume
 For a dry preparation, the amount of active ingredient present and the
volume of liquid to be added to prepare a solution or suspension
 Route of administration
 A statement of storage conditions and an expiration date
 Name of manufacturer or distributor
 Identifying lot number capable of yielding the complete manufacturing
history of the specific package, including all manufacturing, filling,
sterilizing and labeling operations
 10
Quality Assurance
for the Pharmacy-
Prepared Sterile
Products
• Sterile ingredients are used
• Injecting sterile electrolyte solution in large volume IV bag; reconstituting
lyophilized antibiotic and then transferring the solution to 100ml container

• Sterile ingredients are used

• Compounding parenteral nutrition solutions via automated or manual
methods because of pooling contents from multiple ampules or vials of
sterile products

• Include non-sterile components

• Sterilizing a solution made from a nonsterile bulk powder such as alum or
glutamine
 Facilities
Facilities for compounding CSPs are designed and environmentally
controlled to minimize airborne contamination.

Primary engineering controls (PECs) sources of ISO Class 5 air quality

include:
 11
Small Volume
Parenterals
The USP designation small-volume injection applies to an injection packaged in
containers labeled as containing 100ml or less.

Ready to use systems have not been used much in the pediatric and neonatal
population. In some institutions, the unique dosing and fluid requirements of
pediatric and neonate patients are addressed by making dilutions of medications
to standardized concentrations, filling and capping individual syringes, and
administering these doses through a syringe pump.
 12
Large Volume
Parenterals
The USP designation large-volume IV solution applies to a single-dose injection
intended for IV use and is packaged in containers labeled as containing more
than 100ml.

 They are employed in maintenance therapy for the patient entering or

recovering from surgery and for the patient who is unconscious and unable to
take fluids, electrolytes and nutrition orally.
 May also be used in replacement therapy for patients who have suffered a
heavy loss of fluid and electrolytes.

Examples include:
____________________– is infusion of enough basic
nutrients to achieve active tissue synthesis and growth. It is
characterized by the long-term IV feeding of protein
solutions containing high concentration of dextrose,
electrolytes, vitamins and in some instances, insulin.

____________________– may be administered orally, via

NGT, via feeding gastrosomy or via needle-catheter
jejunostomy.
Special Considerations associated with
Parenteral Therapy
 Standardization of Intravenous Concentrations – different healthcare settings
use different concentrations of IV medications, which foster errors because
pharmacists and healthcare practitioners have to recalculate and recompound
medications for individual patients
 Look Alike Products
 Adsorption of Drugs – some drugs are adsorbed to the inner lining of IV
containers and tubing or administration sets (e.g include proteins and
peptides)
 Absorption (sorption) of drugs – absorption into a plastic material like IV
containers, delivery sets, syringes, filters, and other plastic apparatus can
decrease the amount of drug migration into the material
 13
Irrigation and
Dialysis Solutions
Irrigation and Dialysis Solutions - are not injected into the vein but employed outside of the
circulatory system. Because they are generally used in large volumes, they are packaged in large
containers, generally of the screw cap type, which permits rapid pouring. Dialysis solutions
generally appear similar to IV bags, and irrigation solutions are screw-capped or bagged, so
caution is necessary to avoid selecting the wrong product.

___________________– intended to bathe or wash wounds, surgical incisions or body tissues

____________________– dialysis is separation of substances from one another in
solution by taking advantage of their differing diffusibility through membranes.
 Peritoneal Dialysis solutions – allowed to flow into the peritoneal cavity,
are used to remove toxic substances normally excreted by the kidney.
 Hemodialysis – is employed to remove toxins from the blood.

Solutions are made to be hypertonic (with dextrose) to plasma to avoid absorption of

water from the dialysis solution into the circulation.