Parenteral Products

Definition
Parenteral products are sterile preparations containing one or more
active ingredients intended to be administrated directly into the
systemic circulation by injection, infusion or implantation into the
body. They are packaged in either single‐dose or multi dose
containers.

The preparation and handling of parenteral products requires

extraordinary care to maintain the potency, microbial and particulate
standards assigned to these drugs.
Routes of Parenteral Administration

The choice of route is governed by the purpose of the

treatment and the volume of medicine to be administered.
The major routes are:

• Intravenous (IV)
• Intramuscular (IM)
• Subcutaneous routes (SC)
• Intradermal
• Intra‐arterial
• Intrathecal
• Epidural
• Intra‐articular routes
Parenteral Administration Routes
Reasons for Choosing Parenteral Administration

1. The intravenous route of injection is routinely used to

administer medication to the unconscious patient who is
unable to swallow. This route is also employed in conscious
or unconscious patients if the gastrointestinal tract is not
working.

2. Intravenous injection delivers the drug directly into the

circulatory system, where it is then rapidly distributed
around the body.

3. Many medicines are administered parenterally simply

because the drug molecule itself would be rapidly broken
down in the gastrointestinal tract and would thus become
inactivated before it could be absorbed into the circulatory
system. Good examples of this are aminoglycoside
antibiotics, such as gentamicin.
4. By choosing to administer a drug by intramuscular
injection, the release of the medicine from the injection
site into the circulation can be delayed and prolonged.

5. Bioavailability is 100% when administered

intravenously

6. The injectable route may be chosen to provide a

highly localized effect. E.g., injection of steroids into
joint spaces (intra‐articular injection), intra‐ocular
injections to treat eye diseases or intrathecal injections
where medicines are administered into the spinal
column to deliver drugs into the cerebrospinal fluid.
Hazards Associated with Parenteral Therapy
• Caution must be taken to prevent introduction of air into
intravenous products and administration devices because the
injection of a few millilitres of air into a vessel can obstruct blood
flow (air embolism).
• Certain devices such as catheters and in‐dwelling needles are prone
to clot formation, if dislodged, can be harmful to patients.
• Drug solutions at high or low pH or highly concentrated hypertonic
solutions will damage the cells lining the vein and cause localized
pain and inflammation (thrombophlebitis).
• Hemolysis may occur when hypotonic solutions are used.
• If drug solution leaks through the vessels, a problem called
extravasation, it can cause serious damage to the surrounding
tissues, particularly if the drug is cytotoxic.
 Intravenous Injections and Infusions
• Intravenous (IV) injections and infusions are administered into an easily
accessible prominent vein near the surface of the skin, typically on the
back of the hand or in the internal flexure of the elbow.

• IV placed on smaller peripheral veins, if the drug therapy is short term

and non‐irritating, and a larger, central vein for hypertonic drugs or long
term therapy.
Intravenous Injections and Infusions
• The volumes administered can range from 1 mL for an
intravenous injection, up to several liters for an intravenous
infusion.

• Medicines administered by intravenous injection (or intravenous

bolus dose) will rapidly increase the concentration of the drug in
the plasma and produce a rapid effect.

• The use of 500 mL to 1 L bags of solutions for IV infusion is

commonplace in the hospital. These solutions, containing such
agents as nutrients, plasma volume expanders, electrolytes,
amino acids, and other therapeutic agents, are administered
through an indwelling needle or catheter by continuous infusion.
The infusion or flow rate may be adjusted according to the
needs of the patient. Generally, flow rates for IV fluids are
expressed in milliliters per hour and range from 42 to 150 mL/h.
Intravenous Injections and Infusions

• Injections which are formulated either as water in oil emulsions

or suspensions must not be administered by the intravenous
route. This is because the suspended drug particles can physically
block blood capillaries and the oil phase of a water‐in‐oil
injection could cause a fat embolism, again blocking blood
vessels.
 Three methods of injection into the vein
2. The Intermittent Infusion administrations
1. Direct intravenous injection,
also called IV bolus or IV push. include 50‐200ml over 20‐60 min, at a
A relatively small volume of evenly spaced intervals if the dose is to be
drug solution is administered repeated.
over a short period of time 3. Continuous infusion are 250‐1000ml
(less than 5 mins). The drug parenteral that are slowly infused into a
reaches the plasma rapidly and vein over 8‐24hr. This method of infusion
then typically declines produces constant blood levels of the drugs
exponentially. and reduces irritation to vein because the
drug is diluted and usually isotonic.

Fig: Plasma drug concentration versus time

curve for an IV bolus injection
 Intramuscular Injections
• Intramuscular (IM) injections are preferably
administered into the tissue of a relaxed muscle.
• IM injections are administered into three larger
muscles:
1. The Deltoid in the upper arm
2. The Lateral thigh muscles
3. The Gluteal muscles of the buttock
• The drug mixed with interstitial fluids and is absorbed
into the blood supply of the muscles before it begins to
distribute.
• IM injections are easier to administer than IV and
formulation can be varied to modify onset and
duration.
• Aqueous or oily solutions or suspensions can be
administered in volumes of up to 4 mL and they are
called Depot dosage forms.
• More slowly absorbed from the injection site into the
systemic circulation compared to those administered
by the subcutaneous route
 Subcutaneous Injections
• Subcutaneous (SC, also called hypodermic) injections are
administered into the loose connective and adipose tissues
immediately beneath the dermal skin layer.
• Typical injection sites are the abdomen, upper arms and
upper legs.
• The drug mixes with or dissolve in the interstitial fluid and is
absorbed via the subcutaneous blood supply.
• Subcutaneous tissue is largely adipose tissue and poorly
perfused.
• Volumes of up to 1 mL can be administered comfortably.
• Aqueous solutions or suspensions of drugs are
administered by this route.
• Like IM injections, the formulation can be varied for rapid
onset (aqueous solution) and longer durations
(suspension/implants) Suspensions produce continued
absorption from the injection site (depots) and can maintain
blood levels for hours to days.
• A common example of a drug administered by
subcutaneous injection is Insulin.
Intradermal Injections

• Intradermal injections are given into the skin between the epidermal
and dermal layers. This procedure requires a very small volume
(0.1ml) and absorption from the intradermal injection site is slow.
• The solution used must be isotonic.
• This route is used primarily for local effects, vaccines and
administering antigens for allergic reaction testing.
• Example: BCG vaccine for tuberculosis is administered by intradermal
injection.
Intra‐arterial Injections
• Essentially same as intravenous administration except that the drug is
administered into an Artery rather than a vein.

Disadvantages:
• Arteries are not as readily accessible as veins
• This technique is much more invasive, and carries a greater risk than simple
intravenous administration and prone to embolism, arterial occlusion and
local drug toxicity. For this reason it is seldom used.
Uses
• Intra‐arterial administration is sometimes used when intravenous access
cannot easily be established, such as in very premature infants, due to the
very small size of their veins in relation to the catheter tubes used to
maintain vascular access.
• Intra‐arterial administration has also been used in the treatment of some
cancers (such as liver cancer) where the anti‐cancer medicines are injected
into an artery upstream of the tumour site to ensure the maximum amount
of drug reaches the tumour before distribution elsewhere around the body.
However, the benefits of this method of administration do not appear to
outweigh the risks to any significant degree.
Intra‐cardiac Injections
• Intra‐cardiac injections are
used to administer a drug (a
common example being an
aqueous solution of adrenaline)
directly into either cardiac
muscle or into a ventricle of
the heart.
• This is undertaken only in life
threatening emergencies to
produce a rapid, local effect in
the heart during a heart attack
or in circulatory collapse.
 Intra‐spinal injections
• Intra‐spinal injections are given between the
vertebrae of the spine and the area of the spinal
column.
• Only drugs in aqueous solution are administered by
this route.
• Intrathecal (IT) injections are administered into the
cerebrospinal fluid (CSF) in the subarachnoid space
between the arachnoid mater and the pia mater.
• Volumes up to 10 mL can be administered by
intrathecal injection.
• Uses:
• For spinal anaesthesia,
• To introduce drug substances into the CSF that would
otherwise not diffuse across the blood brain barrier.
Typically this could be antibiotics to treat meningitis
or anticancer agents such as methotrexate or
cytarabine.
 Intra‐spinal Injections

• Intra‐cisternal injections are given between

the atlas and axis vertebrae into the cisterna
magna.
• This route is also used for antibiotic
administration into the CSF, or to withdraw
CSF for diagnostic purposes.

• Epidural injections or infusions are given into

the peridural space between the dura mater
(the outermost protective membrane covering
the spinal cord) and the vertebrae. This route
is commonly used for spinal anaesthesia, for
example during childbirth.
Intra‐articular Injections

• Intra‐articular (IA) injections are given

into the synovial fluid of joint cavities
such as the knee.

• Aqueous solutions or suspensions can

be administered by this route.

• This route of injection produces a local

effect, and typically anti‐inflammatory
drugs are administered to treat
arthritic conditions or sports injuries.
Ophthalmic Injections
• Ophthalmic injections are administered either around or into the eye; in the latter
case these are referred to as intraocular injections

• Sub‐conjunctival injections usually of 1 mL or less are administered under the

conjunctiva or into the skin surrounding the eye (e.g. inside the eyelid).

• Intraocular injections can be further classified as:

• Intracameral injections into the anterior chamber of the eye (in front of the
lens),
• Intravitreal injections into the vitreous chamber (behind the lens).

• Intracameral injections can be from 0.1 mL to 1 mL in volume depending on

whether the drug is left in the eye. This route has been used to administer during
surgery or local anaesthetics during eye surgery (e.g. cataract surgery).
• Intravitreal injections are used to administer a number of different drugs used to
treat various ocular diseases. Because of the danger caused by raising intraocular
pressure which can damage the retina, a maximum volume of only 0.1 mL can be
administered by the intravitreal route.
General Pharmacopeial Requirements for
Parenteral Products
1. Sterility: All parenteral preparations are sterile preparations. The
requirement for sterility is vital as the method of administration of
these products bypasses the body’s natural defense systems and
barriers (such as the skin or gastrointestinal system), and
introduces the medicine directly into the bloodstream or other
body tissues.

2. Endotoxins and pyrogens: These substances are bacterial

products that may be released from certain types of bacteria when
they are alive, or after they die. When they are injected into a
patient, they can cause fever, and even shock if present in sufficient
quantities. Therefore, parenteral products must comply with the
test for bacterial endotoxins or the test for pyrogens

3. Particulates: They must be free of visible particles and contain

only very low numbers of sub‐visible particles. This is of particular
importance for medicines administered intravenously.
General Pharmacopeial Requirements for
Parenteral Products
4. Excipients
Excipients may be added to parenteral preparations to serve a number of
purposes. They can be added to make the preparation isotonic in relation
to human blood, to adjust the pH, to increase the solubility of the drug
substance, to increase the stability of the drug substance and increase the
shelf life of the product or to act as a preservative. The use of excipients
should not adversely affect the action of the drug substance, or cause any
side effects or toxicity at the concentrations used in a given formulation.

5. Chemical stability
• Drugs with chemical stability problems may be adjusted to an
appropriate pH using buffers or strong acid or base. Antioxidants should
be used to prevent degradation of drugs by oxidation.
• Drug which become unstable if kept in aqueous solution for a long time
are prepared as powders for reconstitution. The term reconstitution is
used because these dosage forms are prepared as solutions, sterilized
by filtration and freeze dried (lyophilized) to remove the water to
provide an extended shelf life.
General Pharmacopeial Requirements for
Parenteral Products

6. Release of drug
The release of drugs from parenteral dosage forms can be prolonged
by the preparation of suspension or oily solution dosage forms and
by the use of parenteral devices such as infusion pumps.

7. Containers: Containers for parenteral preparations should be

made, wherever possible, from materials that are sufficiently
transparent to allow the contents to be visually inspected for
particles, prior to use. Containers should be made from glass or
plastic materials compatible with the product. Containers should
therefore be airtight and also preferably tamper evident.
Formulation considerations: Importance of
Excipients in Parenteral Preparations
Vehicles for injections
• ‘Water for injections’ is the most common vehicle used for parenteral
products.

• Water for injections is a highly purified grade of water which is subject

to pharmacopoeial standards with respect to production methods and
purity.

• Water is of course well tolerated by the body and it is a solvent for a

wide range of drug substances.

• For those drugs which are poorly soluble in water, water‐miscible non‐
aqueous solvents such as ethanol, glycerol or propylene glycol may be
added as co‐solvents to improve the solubility of a drug substance.

• Water‐insoluble drugs may be administered parenterally by dissolving

the drug in a suitable oil (e.g. arachis oil or sesame oil) and forming an
oil‐in‐water emulsion using a suitable emulsifying agent to stabilize the
emulsion. Droplet size must be controlled and is usually less than 3 μm
in diameter to prevent oil embolisms forming in the blood‐stream.
Preservatives
Antimicrobial preservatives are added to injections which are
designed for multiple use.
Antioxidants
• If the drug substance to be injected is prone to degradation by
oxidation, a number of formulation processes and excipients can be
used to reduce the rate of drug degradation in the product and thus
increase the shelf life or extend the expiry date.
• It is common practice to use pharmaceutical‐grade compressed
nitrogen gas (filtered through a 0.2 µm pore size filter) during the
manufacturing process. Nitrogen is bubbled through the solution
containing the drug before the final packaging is filled. The nitrogen
gas displaces any dissolved oxygen from the drug solution. This
process is known as ‘sparging’.
• An antioxidant may also be included in the formulation.
‐ Ascorbic acid is used in aqueous parenteral products at a concentration
of 0.01% to 0.1% w/v.
‐ For intramuscular injections, butylated hydroxyanisole (BHA) and
butylated hydroxytoluene (BHT) are usually used at a concentration of
0.03% w/v and for intravenous injections, 0.0002% to 0.002% w/v is used.
pH adjustment and buffers

• The physiological pH of plasma and extracellular fluid is 7.4;

therefore, ideally all injectable products should be formulated to
this pH.
• The pH of a parenteral formulation can be adjusted with
acidifying or alkalizing agents. Acidifying agents include
hydrochloric, citric and sulfuric acids. Alkalizing agents include
sodium bicarbonate, sodium citrate and sodium hydroxide.
• Buffers are included in parenteral products to maintain the pH
of the product at the desired optimum value. Changes in pH may
arise because of interactions between an ingredient in the
formulation and the container, or from changes in storage
temperature. The buffer ingredients commonly used in
parenteral products include individual or combinations of citric
acid, sodium citrate, sodium acetate, sodium lactate and
monobasic and dibasic sodium phosphate.
Tonicity adjustment
• Human plasma has an osmolality of between 280–295 mmol per kg.
• An aqueous solution of sodium chloride at a concentration of 0.9%
w/v or 9 g per L has a measured osmolarity of 286 mmol per L and is
isotonic with human plasma.
• Hypotonic solutions when mixed with blood they would cause the
blood cells to swell
• Hypertonic solutions when mixed with blood they would cause the
blood cells to lose water by osmosis and shrink.
• Thus osmolarity adjustment is essential
• Hypotonic injection solutions are made isotonic by the addition of
sodium chloride, dextrose or mannitol.
• Hypertonic injection solutions must be made isotonic by dilution
before administration.
Suspending agents

• Drugs presented as suspensions for injection may require a

suspending agent to ensure that the drug can be readily and
uniformly resuspended before use.

• A water‐soluble cellulose derivative such as methylcellulose can be

used in intramuscular and intra‐articular injectable suspensions.

• A suitable nonionic injectable surfactant such as a polysorbate may

also be included in a suspension formulation to aid the uniform
dispersion of the suspended drug substance
Classification of Parenteral Products
Parenteral products can be divided into 3 general classes according to the
types of packaging
1. Single dose units (ampoules, pre‐filled disposable syringes)
2. Infusion solution
3. Multiple dose units (vials)

Parenteral products can be divided into 2 general classes according to the

volume of the product
1. Small‐volume parenterals (SVP): SVP are 100 ml or less and can be
provided as single‐ or multidose product
2. Large‐volume parenterals (LVP): LVP are intended to be used intravenously
as single‐dose injection and contain more than 100 ml of solution
Example of Components of Small Volume
Parenterals (SVP)
Large Volume Parenterals (LVP) Requirements

1. Sterile, Non Pyrogenic, Free from Particulate matter

2. Volume 101‐1000mL,
3. Single dose unit,
4. No Preservative,
5. Clear solution except Fat Emulsion,
6. Isotonic, but Hypertonic also administered in TPN.
Differences Between SVP and LVP
Quality Control Tests of Final Products

• Sterility test
• Endotoxin test
• Pyrogen test
• Clarity test/Particulate test
• Uniformity of content
• Leak test
 Endotoxin test
Limulus amoebocyte lysate (LAL) test

• The LAL test is an in vitro assay used to detect the presence and concentration of bacterial
endotoxins in drugs and biological products.
• Endotoxins, which are a type of pyrogen, are lipopolysaccharides (LPSs) present in the cell
walls of gram negative bacteria.
• Pyrogens are fever‐inducing substances that can be harmful or even fatal if administered to
humans above certain concentrations.
• The endotoxins in the cell walls of gram negative bacteria reacts with the LAL reagent
derived from the blood of the horseshoe crab, Limulus Polyphemus resulting in the formation
of a gel. The formation of gel indicates the presence of endotoxins in the parenteral
preparation.
• The LAL test is specific for LPSs and is very sensitive.

Procedure:
1. Mix LAL reagent and the test solution in equal parts (0.05ml‐0.2ml) in a pyrogen free assay
tube.
2. Incubate the mixture immediately at 36‐38˚C for 1 hour.
3. Observe the tube for cloudy gel appearance.
4. A spectrophotometer can be used to determine the concentration of endotoxins by measuring
the turbidity caused by the reaction between endotoxin and the lysate
Pyrogen test

Rabbit pyrogen test

• The Rabbit Pyrogen Test in an in vivo test to detect pyrogens qualitatively.

• Rabbits have a similar pyrogen tolerance to humans, so by observing a change
in body temperature in rabbits it is possible to make a determination of the
presence of pyrogens.
• This method can detect non‐bacterial pyrogens as well as bacterial endotoxins.

Procedure
1. Record the initial body temperature of a group of three rabbits
2. Any rabbit showing temp. more than 39 ˚C, should be excluded from the test
3. Inject the sample into the ear vein of each rabbit.
4. Check the temperature after 30 min, 1, 2 and 3 hours.
5. The test is +ve when each rabbit show increase in temperature.
6. If only 2 of the three rabbits show increase in temperature, repeat the test
using group of five, and test will be positive if the four of the five rabbits show
increase in temperature.
Containers
Ampoules

• For small volume parenterals

• Used for single‐use unpreserved products
• Glass ampoules range in size typically from 1 mL up to 10 mL in
volume
• The glass chosen is referred to as Type I or borosilicate glass
• They are open necked containers‐ sealed by fusion after filling.
• The neck has a painted ceramic ring
• Baking process required to fuse the ceramic to the glass makes it a
weak point for easy snapping
Ampoule Sealing
• Ampoules may be closed by melting a portion of the glass neck.

1. Tip Seal:

• Tip seals are made by melting enough glass at the tip of the neck of an
ampoule to form a bead of glass and close the opening. So, it is also called
bead sealing.

• This can be made rapidly by high T‐gas oxygen flame. To form a uniform
bead, heat must be applied evenly on all sides. This may be clone by rotating
the ampoule in a single flame or by means of burners on opposite sides of
stationary ampoule. The ampule is constantly spinning during the sealing
process to create a rounded, hemispherical seal.

• Care must be taken to properly adjust the flame temperature and the
interval of heating to obtain complete closing of the opening with a bead of
glass. This can be carried out both normally & by automatic machine.
Ampoule Sealing
• Ampoules may be closed by melting a portion of the glass neck.

2. Pull Seal:

• Pull seals are made by heating the neck of a stationary ampoule

below the tip, then pulling away the tip to from a small, twisted
capillary just prior to being melted, heated. The seal is pointed at the
tip, irregular, sometimes a bead of glass is sharp or hanging.

• Pull sealing methods are commonly used for containers filled with
powder as they require a large opening.
• More skill is required for pull sealing than tip sealing.
Ampoules: Disadvantages

• Fragility: can be solved by using robust secondary packaging

• Potential for deposition of glass particles into the drug product on
opening: Glass particles can be removed by drawing up the contents
of the ampoule through a filter straw or quill into a syringe.
• The potential for injury to the fingers of the person opening the
ampoule.

Ampoules: Advantages
• Low cost
• Low interaction between the product and the container (if type I
glass is used)
 Vials
• Usually made of Type I borosilicate glass with a re‐
usable synthetic rubber closure.
• Sealed with a bromobutyl or chlorobutyl synthetic
rubber closure (elastomer) held in place by an
aluminium seal crimped around the neck of the
glass vial.

• Advantages:
• they permit multiple withdrawals and
• are made in sizes usually ranging from 5 mL to 100 mL.
• Disadvantage
• puncturing the rubber closure can cause large rubber
particles to be introduced into the drug product.
Infusion bags and bottles

• Large Volume Parenterals can be packed in:

• Glass bottles
• Collapsible plastic bags
• Semi‐rigid plastic bottles
• Volume range is 100 mL to 1000 mL (upto 3000 mL are also available
for parenteral nutrition)
SEALING OF BOTTLES, CATRIDGES AND VIALS

• In the sealing of these containers with ruler closure, the closure must
fit strongly into the opening of the container to produce an airtight
seal.

• Generally, the closures are coated with silicone to facilitate the

introduction into the vial opening. This can be accomplished
manually or automatically by machine.

• Aluminum caps are placed over rubber closure to hold in place and
for its protection. This cap possesses a center hole that is turn away
at the time of use to expose rubber closure.
BFS (Blow Fill Seal) Technology for Parenteral
Preparation
• Blow‐Fill‐Seal (BFS) technology was developed in the early 1960s and
was initially used for filling many liquid product categories, for
example, nonsterile medical devices, foods, grocery and cosmetics.
The technology has been developed to an extent that today BFS
systems are used to aseptically produce sterile pharmaceutical
products such as respiratory solutions, ophthalmic, Biological and
wound‐care products throughout the world.

• The basic concept is formation, filling and sealing of plastic

containers in aseptic environment.
The BFS cycle can be divided into following main steps:

• Step 1: Parison extrusion

Firstly, pharmaceutical plastic resin is vertically heat extruded through
a circular throat and forms a tube called Parison.

• Step 2: Container molding

The extruded tube is then enclosed within a two part mold and then
the tube is cut above the mold.

• Step 3: Container filling

The mold is transferred to sterile filling zone where filling needles
called mandrels are lowered and used to inflate the flat to form
container within the mold.

• Step 4: Container sealing

The mandrel is used to fill the container with solution, following filling,
mandrels are removed and secondary top mold seals the container.

The Mold is then opened and the filled and sealed containers are
then conveyed to labelling and packing sections.
References

• Aulton's Pharmaceutics‐The Design and Manufacture of

Medicines by Michael E. Aulton, Kevin M.G. Taylor (Chapter 36)

• Remington Education: Pharmaceutics by Shelley Chambers Fox

(Chapter 8)