Parenteral Products

Introduction
• Parenteral refers injectable route of
administration. It derived from Greek words Para
(Outside) and enteron (Intestine). So it is a route
of administration other than the oral route.
• This route of administration bypasses the
alimentary canal.
• Parenteral preparations are sterile preparations
containing one or more active ingredients
intended for administration by injection, infusion
or implantation into the body. They are packaged
in either single-dose or multidose containers.
 Advantages
• The IV route is the fastest method for delivering systemic
drugs preferred administration in an emergency situation
• It can provide fluids, electrolytes, and nutrition.
• Patients who cannot take food or have serious problems
with the GI tract
• It provides higher concentration of drug to bloodstream or
tissues
• Advantageous in serious bacterial infection.
• IV infusion provides a continuous amount of needed
medication
• Infusion rate can be adjusted, to provide more or less
medication as the situation dictates.
 Disadvantages
• Chances of introducing Toxic agents, Microbes, Pyrogens
• Impossible to retrieve if adverse reaction occurs as injected
directly into the body
• Correct syringe, needle, and technique must be used
• Skilled person needed for injection.
• Pain on injection
• Sensitivity or allergic reaction at the site of injection.
• Requires strict control of sterility & non pyrogenicity than
• other formulation.
• More expensive and costly to produce.
 PARENTERAL ROUTES
• Intravenous
• Intramuscular
• Subcutaneous
• Intradermal
• Intra-arterial
• Intracardiac
• Intrathecal
• Intracisternal
• Peridural
• Intraarticular
• Intracerebral
Intravenous Intramuscular
• The injection of a drug • Drugs are injected deeply
directly into the patient's into muscle tissue. If the
veins, resulting in the most drug is in aqueous (water)
rapid onset of action solution, absorption is
rapid. However, if the drug
is in an oily liquid or in the
form of a suspension, it can
prolong the release of the
drug.
 Intravenous
• Fast-acting route because the drug goes
directly into the bloodstream often used in
the emergency department and in critical care
areas
• Commonly used for fluid and electrolyte
replacement to provide necessary nutrition to
the patient who is critically ill
• Intravenous (IV) injections are administered at
a 15- to 20-degree angle
• The drug is injected as a bolus (venipuncture) or infused slowly over hours (venoclysis)
in one of the superficial veins (generally medial basilic vein). Drug must be administered
through this route slowly because irritation or an excessive drug concentration at
sensitive organs such as the heart and brain (drug shock) may occur. The duration of
action of a drug depends on the pharamcokinetic parameters (rate of distribution and
elimination)
Advantages:
• The drug directly reaches the blood stream and effect is produced immediately, hence,
this route can be used in emergencies.
• The inside of the veins is insensitive (because no nerve endings are there) and drug gets
diluted with blood quickly, therefore, even highly irritant drugs can be injected
intravenously.
• Large volumes can be infused (e.g. normal saline).
• It is useful in unconscious patients.
• Desired blood concentration can be achieved.
Disadvantages:
• Drugs that precipitate in the blood cannot be administered. Only aqueous solution can
be administered.
• If the needle puncture the vessel (i.e. extra vasation) then thrombophlebitis of the
injected vein and necrosis of the adjoining tissues may occur.
• No drug can be given in depot form - so the action is not prolonged compared to other
parenteral administrations.
• Untoward reactions if occur are immediate.
• Once administered, withdrawal of the drug is not possible
 Intramuscular
• Care must be taken with deep IM injections to
avoid hitting a vein, artery, or nerve
• In adults, IM injections are given into upper, outer
portion of the gluteus maximus large muscle on
either side of the buttocks
• For children and some adults, IM injections are
given into the deltoid muscles of the shoulders
• Typical needle is 22- 25 gauge ½- to 1-inch needle
• IM injections are administered at a 900 angle
volume limited to less than 3 ml
• Body sites of injection: Deltoid (upper arm), gluteal (buttock),
vastus lateralis (lateral thigh) msucles.
• It is important to aspirate before injection to ensure that the
needle does not enter into a vein.
Advantages:
• Muscle is less richly supplied with sensory nerves, hence mild
irritants can be injected.
• Muscle is more vascular hence absorption is faster (onset of
action 15 to 30mins) than subcutaneous route.
• It is less painful.
• Depot preparations can be injected by this route and the action
of the drug may be prolonged.
Disadvantages:
• Since deep penetration is needed hence self-medication is not
possible.
• Large volume cannot be given. e.g. Low volume injections -
Vitamin A, hydrocortisone acetate, tetanus toxoid, antibiotic etc.
Subcutaneous Intradermal
• The injection of the drug • The drug is injected into the
under the skin into the top few layers of the skin.
fatty layer, but not into the Ideally, the drug is placed
muscle. Absorption of the within the dermis. Used for
drug is rapid. Eg; insulin diagnostic agents.
 Intradermal
• They are made into the skin between the inner layer or dermis,
and the outer layer, or epidermis. The skin of the front of the left
forearm is usually selected.
• The drug is injected into the dermis of skin raising a bleb (e.g. BCG
vaccine, sensitivity testing of drugs) or scarring / multiple puncture
of the epidermis through a drop of the drug (small pox vaccine) is
done.
• This route is employed for testing of allergen, such as pollens, dust
or microorganisms (tuberculin or histoplasmin).
• Absorption is very small from this site because very small number
of blood capillaries are present. The site should not be massaged.
• Body sites of injection: Usually on the outer surface of the left
forearm
 Subcutaneous
• These injections are made under the skin, into the subcutaneous tissue.
The drug is deposited in the loose subcutaneous tissue which is richly
supplied by nerves (so irritant drugs cannot be injected) but is less
vascular (so absorption is slower).
• Care must be taken to ensure that the needle is not in a blood vessel. This
is checked by lightly pulling back the syringe plunger (a method known as
aspiration) before making an injection. If the needle has pierced into a
vessel then blood will appear in the syringe and in that situation the
injection should not be made.
• Sometimes dextrose and electrolyte solutions are given subcutaneously in
amounts from 250 to 1000mL. This technique is called hypodermoclysis.
This method is used when veins are not available in a patient or are
difficult to use for further medication. In this case the hyalouronidase is
co-administered with the large volume injection (LVP) that helps in
hydrolysis of hyalouronic acid (the cell-cementing material that binds the
cells of the tissues), increases the absorption of the liquid and decrease
tissue distension.
• Body sites of injection: Usually on the most portions of arms, legs and
abdomen.
 Subcutaneous cont…

Advantages:
• Self injection is possible because deep penetration is not required.
• Oily solutions or aqueous suspensions can form a depot which will release
drug slowly for a prolonged period.
Disadvantages:
• Since skin is richly supplied by nerve-endings hence irritant drugs cannot
be injected.
• Drugs administered in this route produce slower onset of action than i.m.
or i.v. route.
• This route should be avoided in shock patients. e.g. Insulin injection.
• Given at a 45-degree angle, 25- or 26-gauge needle, 3/8 to 5/8 inch length
• No more then 1.5 ml should be injected into the site to avoid pressure on
sensory nerves causing pain and discomfort
Intra-arterial Intracardiac
• Injections given directly to • Given in heart muscles or
arteries ventricle in emergency
condition only
 Intra-arterial
• The intra-arterial route involves injecting a drug
directly into an artery. It is important that the artery
not be missed, since serious nerve damage may occur
to the nerves lying close to the arteries.
• Dose given through this route must be minimum and
given gradually, since, once injected, the drug effect
cannot be neutralized.
• This route of injection is used to administer
radiopaque contrast media for viewing an organ, such
as the heart or kidney, or to perfuse an antineoplastic
agent at the highest possible concentration to the
target organ.
Intrathecal Intracisternal
• These are given in • Given between 1st and 2nd
subarachanoid space that cervical nerve.
surrounds the spinal chord. • Used for diagnostic puspose
Used in spinal anasthesia
 Intrathecal
• The intrathecal route is employed to administer a drug
directly into the cerebrospinal fluid at any level of the
cerebrospinal axis. This route is used when it is not
possible to achieve sufficiently high plasma levels to
accomplish adequate diffusion and penetration into
the cerebrospinal fluid. Intrathecal, intraspinal, and
intracisternal routes must be formulated at
physiologic pH, must be isotonic and must not contain
any preservatives in order to minimize nerve damage.
• Local anaesthetic drugs are injected through this
routes.
Peridural Intraarticular
• These are given in between • These are given in the
duramater & inner aspect of articulating ends of bone
vertebra. joints.
• Used for lubricating the
joints
 Intracerebral
• Given in cerebrum.
 Classification
• Small volume parenterals (SVP): An injection
that is packed in containers labelled as
containing 100 ml or less.
• Large volume parenterals (LVP): LVP are
parenterals designed to provide :-
– Fluid
– Calories (dextrose solution )
– Electrolytes
– Volume 101- 1000 ml
 Difference between LVP & SVP
Parameter SVP LVP
volume 100 ml or less 101-1000 ml
Routes IV, IM & SC IV- LVP & non IV- LVP
Dosage unit Single or multiple Single
preservative Used Not used
Buffers Used Not used
Formulation Soln, emulsion, Soln & o/w nutrient
suspension Emulsion
Isotonicity Not essential Must
Pyrogenicity Not essential Must
Use Therapeutic & diagnostic Nutrition, detoxification
& during surgery
 Small volume parenterals
• SVIs include solutions, suspensions, emulsions, and solids.
• Most of SVIs are ready to use solution forms and the next
frequent type of forms are the lyophilized or powder filled
dosage forms. The third forms are suspensions, emulsions,
and other dispersed systems.
Solutions – ready to use products or can be liquid
concentrates to be diluted in a small container or in a IV
fluid. Aqueous solutions are water based or combined
with water miscible organic solvents such as ethanol,
polyethylene glycol, glycerin or propylene glycol.
Nonaqueous solutions contain vegetable oils such as
soybean, sesame, and cottonseed as the vehicle. Oil
solutions must be administered by the IV.
 Suspensions
Macro- or micro-sized solids dispersed in a
suitable vehicle, water or oil. Insulin, vaccines,
and microsphere are delivered as suspensions.
Suspensions are not administered by the IV.
 Emulsions
Dispersed systems combined with an oil phase and an
aqueous phase. It could be either oil-in-water emulsion or
water-in-oil emulsion, but most injectable emulsions are
oil-in-water emulsions. Liposomes are emulsified
spherical vesicles composed of a phospholipid bilayer with
an aqueous inner phase. Drug can be incorporated in
either the liquid or aqueous phases. Parenteral emulsions
are milky white in appearance and have an average
globule size of 1 – 5 micrometer. Globules larger than 5
micrometer should be less than 0.05% of the total
volume. Propofol and oil soluble vitamins are examples.
 Solids
• Primarily prepared by lyophilization as amorphous solids
are very difficult to fill accurately due to their lack of
density. Some solid formulation that can be crystalized
and powder filled. Sterile solids are reconstituted prior
to injection with a suitable diluent.
 Large volume parenterals
LVIs include electrolytes, carbohydrates, proteins, fatty emulsions,
dialysis solutions, and irrigating solutions.
Electrolyte solutions – 0.9% NaCl isotonic solutions, 0.45% or 3%
NaCl, 20-40 mEq/L KCl, Ringer’s lactated Ringer’s, etc.
Carbohydrate solutions – Dextrose 5% in water (D5W)
Nutritional proteins: 2.5 – 10% synthetic amino acid mixtures used
on patients with starvation, renal, hepatic failure or other
conditions.
Fatty Emulsions: serve as a source of nutrient fat. Composed of
10-20% soybean oil, water and 1.2% egg yolk phospholipids, and
2.5% glycerin.
Peritoneal Dialysis: dialysis solution contains large volumes of
dextrose to remove waste such as urea and potassium from the
blood.
• Irrigating (washing) solutions – they come in
various formulations and differ from
injectable solutions with the package closure.
Irrigating solutions have a screw cap that
twisted open. Irrigating solutions must be
sterile, pyrogen and particulate free.
Sustained or controlled release injectable
systems
• Sustained or controlled release injectable
systems are desirable for increased duration
of release, reduced number of injections, and
increased compliance, localized delivery in the
case of cancer therapy and vaccinations, and
protection against in vivo degradation of the
active ingredient.
Polymeric implants – sterile, solid drug
products manufactured by compression,
melting or sintering processes. They have
drug and a biodegradable or replaceable
polymeric system which controls the
sustained or prolonged drug delivery.
Norplant (birth control implant) is shown in
the picture below.
• Microspheres: injectable suspensions
containing particles of diameters of 1 – 100
micrometer. Prior to injection, the particles
are mixed with an appropriate vehicle,
dispersed and administered. Drug release
kinetics are controlled by polymer
degradation and diffusion.
• Liposomes - a spherical vehicle having at least
one lipid bilayer. The liposome can be used as
a vehicle for administration of nutrients and
drugs.
 Formulation factors
• The formulation of injections involves careful
consideration of the following factors:
• The route of administration
• The volume of injection
• The vehicle in which the medicament is to be
dissolved or suspended.
• The osmotic pressure of the solution. (6.8atm)
• The need for a preservative
• The pH of the solution
• The stability of the drug
 Routes Usual volume Needle commonly Types of medication dministered
(ml) used
Primary parenteral routes
Small volume
parenterals
Subcutaneous 0.5-2 5/8 in., 23 gauge Insulin, vaccines
Intramuscular 0.5-2 1½ in., 22 gauge Nearly all drug classes
Intravenous 1-100 1½-in., 20-22 gauge Nearly all drug classes
Large volume 1000 and 1½ in., 18-19 gauge Nearly all drug classes like
parenterals larger (infusion electrolytes and nutrients to
units) restore blood volume & to prevent
tissue dehydration.
 Routes Usual Needle Types of medication
Volume commonly administered
(ml) used
Other parenteral routes
Intra-arterial: directly into an artery 2-20 20-22 gauge Radiopaque media,
(immediate action sought in peripheral antineoplastic,
area) antibiotics
Intrathecal (intraspinal) 1-4 24-28 gauge Local anesthetics,
analgesics; neurolytic
agents
Intraepidural (into epidural space near 6-30 5 in., 16-18 Local anesthetics,
spinal column) gauge narcotics, steroids
Intra-articular: directly into the joint, 2-20 1.5-2 in., Morphine, local
usually for a local effect there, as for 18-22 gauge anesthetics, steroids,
steroid anti-inflammatory action in NSAIDs, antibiotics
arthritis
Intracardial: directly into the heart when 0.2-1 5 in., 22 Cardiotonic drugs,
life is threatened gauge calcium
Intrapeural: directly into the pleural cavity 2-30 2-5 in., Local anesthetics,
or a lung (also used for fluid withdrawal) 16-22 gauge narcotics,
chemotherapeutic
agents
 Volume of injection
• Usually the volume of an injection depends on the route of administration.
Only the intravenous route is really suitable for large volume parenterals
(LVP).
• In subcutaneuous route generally 0.5-2ml volume may be injected. Some
times veins of a patient are unavailable.
• In those cases instead of intravenous infusion large volume parenterals
(250 to 1000ml) may be injected subcutaneously. This technique is called
hypodermoclysis.
• In most of this case the injection is given along with hyalouronidase an
enzyme that hydrolyses the hyalouronic acid, the viscous cell-cementing
agent. It helps in rapid absorption of the injection and reduces tissue
distension.
• The hydrolysis is reversible and the acid is reformed in about 20minutes
after completion of the injection.
• The volume must be convenient to administer. Less than 20ml is suitable
for injection with a syringe and more than 250ml injections are given as
infusion.
FORMULATION OF
PARENTERALS
 Preformulation
• The important properties with reference to
preformulation of parenterals includes
solubility, pKa, pH, solid state characteristics,
chemical modification of drug and
polymorphism
 Solubility /pKa/pH
• Solubility is one of the important parameter in preformulation
of parenterals most of the parenterals dosage form exist in
solution form so it should maintain its properties, consistency
and stability in liquid form.
• Solubility is a function of hygroscopicity, chemical nature and
pKa of the salt.
• In general term we state that if the pKa is at least two units
lower than the pH of the medium, complete dissolution can
be achieved; the opposite holds true for basic compounds.
• Other considerations like dilution prior to administration, and
the rate of administration (dilution factor) should also be
simulated using in vitro techniques. Thus, by determining and
manipulating the solubility, pH and pKa one can develop a
parenteral dosage form with its stability and safety.
• When a drug substance is dissolved in a liquid it gets dissociated in ionized and
unionized form. The unionized substances are lipid soluble thus dissolve in lipid
material of the membrane and transported by passive diffusion and their
absorption is rapid. Whereas, the ionized substances are a lipid insoluble therefore
their permeation is slow and absorption is poor.
• The percentage of ionization can be calculated as-
• For Acidic compounds: = PH=pKa+log ionized drug/un-ionized drug
• For Basic compounds: PH =pKa + log un-ionized drug/ionized drug
• For acidic drugs pKa ranges from3-7.5. for basic drugs pKa ranges from7-11. Beside
it pH plays a vital role in stability of solution and suspension type of parenteral
products.
• pH value for parenteral products:
– Ideal pH 7 pH of blood
– Above pH 9 Tissue necrosis
– Below pH 3 Extreme pain at site of injection
• The methods used to increase solubility are change in pH, cosolvency, dielectric
constant, solubilization by surfactant, complexation, hydrotropy, and chemical
modification of drug, etc. Care must be taken when using co solvents although
they increases the solubility but as they are conjugate acid base systems there
may be a shift of pKa of the buffer or salt results and it may affect the integrity of
the formulation like there may be precipitation or degradation of salt.
 Solid state characteristics
• Crystalline characteristics are analyzed by microscopy and
X-ray powder diffratctometry (XRPD).
• So the combination of crystalline and amorphous form of a
same drug may provide a dosage form with combined
benefits of rapid onset and prolonged duration of action.
• Moreover, the crystalline form of the drug can withstand the
high thermal stress (dry heat for several hours) as compared
to amorphous form (e.g. Pencillin G).
Chemical Modification of the Drug
• Chemical modification like preparation of an ester, salt, or any other form
of the parent drug sometimes increases stability, alter drug solubility,
enhance depot action, avoid formulation difficulties and possibly, to
decrease pain on injection.
• Compounds for both IV and IM solutions may require high solubility in
order for the drug to be incorporated into acceptable volumes for bolus
administration.
• Sodium and potassium salts of weak acids and hydrochloride and sulfate
salts of weak bases are widely used in parenterals requiring highly soluble
compounds, based on their overall safety and history of clinical
acceptance.
• If the solubility of a drug is to be reduced to enhance stability or to
prepare a suspension, the formulator may prepare water insoluble salts.
Ex: Procaine Penicillin G: decrease solubility (7mg/ml) of which, when
compared with the very soluble penicillin G potassium, is utilized to
prepare stable parenteral suspensions.
• Apart from this we need to analyze the following factors
before formulation of a parenteral dosage form
• Melting point
• Thermal profile
• Particle size and shape
• Hygroscopicity potential
• Ionization constant
• Light stability
• Optical activity
• pH solubility profile
• pH stability profile
• Polymorphism potential
 Vehicle
AQUEOUS VEHICLE :
• WATER FOR INJECTION (WFI) USP : Highly purified
water used as a vehicle for injective preparations
which will be subsequently sterilized. USP requirement
include not more than 10 parts per million of total
solids.
• Sterilization at this stage may be omitted, provided
that the preparation is subject to terminal sterilization.
• pH of 5.0 – 7.0 .
• WFI may be prepared by either distillation or reverse
osmosis.
• Stored in chemically resistant tank
• Water for Injections is water that is pre-treated to render it
suitable for subsequent treatment and then purified by
distillation or by reverse osmosis and it meets all of the
chemical requirements stated under Purified Water
• It is not intended to be sterile but should comply with the
test for a limit of bacterial endotoxins (2.2.3), or as
appropriate, with the test for pyrogens (2.2.8). It must be
produced, stored and distributed under conditions designed
to prevent production of endotoxins or pyrogens.
• The equipment and procedures used by the system to
purify, store and distribute Water for Injections must be
designed to minimise or prevent microbial contamination
and also remove incoming endotoxin from the starting
water.
• Water for Injections systems must be validated to reliably
and consistently produce and distribute this quality of
water.
 Methods of preparation
• Water for Injection can be prepared by distillation or by membrane
technologies (i.e., reverse osmosis or ultrafiltration).
• The EP (European Pharmacopeia) only permits distillation as the process
for producing WFI. The USP and JP (Japanese Pharmacopeia) allow all
these technologies to be applied.
• Distillation is a process of converting water from a liquid to its gaseous
form (steam). Since steam is pure gaseous water, all other contaminants
in the feedwater are removed.
• A conventional still consists of-
– Boiler or evaporator, containing feed water.
– Source of heat to vaporize the water in the evaporator
– Headspace above the level of feed water, with condensing surfaces for refluxing
the vapor, thereby returning nonvolatile impurities to the feed water.
– Provision for eliminating volatile impurities before the hot water vapor is
condensed.
– Condenser for removing the heat of vaporization, thereby converting the water
vapor to a liquid distillate.
 Storage and Distribution
As per USP
• WFI should be stored at 80°C for prevention of any
contamination When the water cannot be used at 80°C,
heat exchangers must be installed to reduce the
temperature at the point of use
• The USP also permits the WFI to be stored at room
temperature but for a maximum of 24 hrs requires frequent
sanitization to minimize the risk of viable microorganisms
• WFI is stored in stainless-steel storage tanks. These tanks
are connected to a welded stainlesssteel distribution loop
supplying the various use sites with a continuously
circulating water supply.
 STERILE WATER FOR INJECTION
• SWFI containing one or more suitable
bacteriostatic agent.
• multiple – dose containers not exceeding 30 ml.
• They are permitted to contain higher levels of
solid than WFI because of possible leaching.
• Used for washing wounds , surgical incisions, or
body tissues.
• The Sterile Water for injection (SWFI)
requirements differs in that since it is a final
product, it must pass USP sterility test.
 Sterile Water for Injections
• Sterilised within 12 hours of collection and
distributed in sterile containers.
• It is intended mainly for use as a solvent for
parenteral preparations such as powders for
injection that are distributed dry because of
limited stability of their solutions.
• It should be packaged only in single dose
containers of not larger than 1-litre size
 BACTERIOSTATIC WATER FOR
INJECTION
• This type of water used for making parenteral
solutions prepared under aseptic conditions
and not terminally sterilized.
• Need to meet USP sterility test.
• It can contain an added bacteriostatic agent
when in containers of 30 ml or less.
 WATER MISCIBLE VEHICLES
• The number of solvents that are miscible with
water has been used as a portion of a vehicle.
• Primarily to affect solubility of drugs and to
reduce hydrolysis.
• Example: Ethyl alcohol, Liquid propelene
glycol, Glycerine Ethyl alcohol used in the case
of cardiac glycoside
 NON – AQUEOUS VEHICLES
• Fixed oils (vegitable origin, liquid, and rancid
resistance,unsaturated, free fatty acid
content) Peanut oil, Corn oil, Cotton seed oil
(depo-testosterone), Sesame oil, Soyabean oil,
Ethyl oleate, Isopropyl myristate.
 Examples of Parenteral Additives
Additives Examples Usual concentration (%)
Antimicrobials (Protect a Benzalkonium chloride 0.01
preparation against the Benzyl alcohol 1-2
growth of microorgan- Chlorobutanol 0.25-0.5
isms) Metacresol 0.1-0.3
Butyl p-hydroxybenzoate 0.015
Methyl p-hydroxybenzoate 0.1-0.2
Propyl p-hydroxybenzoate 0.2
Phenol 0.25-0.5
Thimerosal 0.01
Antioxidants Ascorbic acid 0.01-0.05
Cysteine 0.1-0.5
Monothioglycerol 0.1-1.0
Sodium bisulfite 0.1-1.0
Sodium metabisulphite 0.1-1.0
Tocopherols 0.05-0.5
Buffers (Enhance the Acetates 1-2
chemical stability of a Citrates 1-5
solution) Phosphates 0.8-2.0
Chelating agents Salts of 0.01-0.05
ethylenediaminetetraacetic
acid
Protectants Prevents loss Sucrose 2-5
of activity of drug caused Glucose 2-5
by stress or adsorption Lactose 2-5
Maltose 2-5
Solubilizing agent Ethyl alcohol 1-50
Glycerine 1-50
Surfactants Sorbitan mono oleate 0.05-0.25
Tonicity adjusting agent Dextrose 4-5
Sodium chloride 0.5-0.9
 Isotonicity
• The most important thing with respect to
parenterals is maintaining the isotonisity of
product as to avoid any swelling and contraction
of blood cells.
• 0.9% of NaCl is said to be isotonic and used as a
standard in pharmaceutical preparations.
Methods of adjusting tonicity:-
• Freezing point depression and Sodium chloride
equivalent method
• White-Vincent method and Sprowls method
Freezing point depression method
• In this method any substance is added to lower f.p of
solution to -0.52º.
• FP of blood and tears is - 0.52º, so any solution having FP
0.52º is isotonic.
• The formula for calculating the amount of adjusting
substance to make isotonic solution is

Where
– w=conc gm /100mlof adjusting substance
– a= f.p.d of 1% of unadjusted substance
– b = f.p.d of 1% of adjusting substance
 NaCl equivalent method
• NaCl equivalent “E” is the amount of NaCl that is
equivalent to i.e., has the same osmotic effect as 1gm
of drug.
• This method first uses to calculate E NaCl and then
calculate the amount of NaCl to reach 0.9%.
W%= 0.9- (drug% x ENaCl)
Where
– W%= weight of NaCl in gm per 100 ml (to make solution
isotonic)
– Drug%= weight of drug in gm per 100 ml
– ENaCl= NaCl equivalent weight to 1gm of drug
– 0.9 =isotonic solution of NaCl
 White – Vincent method
• This method involves the addition of H2O to
drug to make it isotonic with addition of
isotonic vehicle to bring solution to final
volume
V=w x ENaCl x 111.1
Where,
– V=volume of H2O
– W= weight of drug
– 111.1= 100/0.9
 Sprawl method
• It is a modified white Vincent method in which
total volume is kept constant to 30 ml and the
drug concentration is kept constant to 1% i.e.
0.3g.
• It was done to make it easy for practicing
pharmacist.
FORMULATION AND FACILITIES
• The manufacturing of sterile products is subjected to
special requirements in order to minimize risks of
microbial contaminations.
• General broad guidelines say that that the area should
be kept clean (pyrogen free) and strict precaution is
taken to prevent contamination from outside.
• Ceiling & walls & floors, sealed & painted or treated
with aseptic solution and there should not be any toxic
effect of this treatment.
• High efficiency filter is used (HEPA) which removes
particles up to 0.3 micron and are fitted in laminar air
flow system, in which air is free from dust &
microorganisms flows with uniform velocity. And UV
lamps are fitted to maintain sterility.
 Different areas for production of
sterile products
• Clean- up area: Non-aseptic area, Free from dust, fibers &
micro-organisms and it should withstand moisture, steam &
detergent, washing is done in this area
• Preparation area: The ingredients are mixed & preparation is
prepared for filling, Not essential that the area is aseptic
• Aseptic area: Filtration & filling into final containers & sealing is
done, The entry of outside person is strictly prohibited, To
maintain sterility, special trained persons are only allowed to
enter & work
• Quarantine area: After filling, sealing & sterilization the products
or batch is kept in this area, The random samples are chosen and
given for analysis to QC dept., The batch is sent to packing after
issuing satisfactory reports of analysis from QC, If any problem is
observed in above analysis the decision is to be taken for
reprocessing or others
• Finishing and packaging area
• The preparation of sterile products is carried out
in specialized designed plant layout as to minimize
risks of microbiological and other contaminations.
• It depends on the facilities of plant and on the
skill, training and attitudes of the personnel
involved.
• There are various guidelines by USFDA/ISO/EU.
for manufacture of sterile products
 General guidelines
• The manufacturing of sterile products should be carried out
in clean areas entry to which should be through airlocks for
personnel and/or for equipment and materials. Like three
door air lock system
• The various operations of component preparation, product
preparation and filing should be carried out in separate
areas within the clean area.
• Manufacturing operations are divided in two categories;
– Those where the product is terminally sterilized,
– Those which are conducted aseptically at some or all stages.
• Clean areas for the manufacturing of sterile products are
classified according to the required characteristics of the
environment.
For the manufacture of sterile
medicinal products 4 grades can be
distinguished
• Grade A: The local zone for high risk operations,
e.g. filling zone, stopper bowls, open ampoules
and vials, making aspects connections. Normally
grade A follows all the specifications for
environment control.
• Grade B: For aseptic preparation and filling, this is
the background environment for grade A zone.
• Grade C and D: Clean areas for carrying out less
critical stages in the manufacture of sterile
products
 Personnel
• Only the minimum number of personnel required should be
present in clean area and all persons (including those concerned
with cleaning and maintenance) employed in such areas should
receive initial and regular training in disciplines relevant to the
hygiene and the basic elements of microbiology.
• Staff who have been engaged in the processing of biologicals like
animal-tissue materials or of cultures of microorganisms should
not enter sterile-product areas unless rigorous and clearly defined
decontamination procedures have been followed.
• High standards of personal hygiene and cleanliness are essential,
and personnel involved in the manufacture of sterile preparations.
should be instructed to report any conditions that may cause the
shedding of abnormal numbers or types of contaminants; periodic
health checks for such conditions are desirable.
• The action to be taken in respect of personnel who might be
introducing undue microbiological hazards should be decided by a
designated competent person.
• Outdoor clothing should not be brought into clean areas, and
personnel entering changing rooms should already be clad in
standard factory protective garments.
• Changing and washing should follow a written procedure
designed to minimize the contamination of clean area clothing
or the carry-through of contaminants to clean areas.
• Wristwatches and jewellery should not be worn in clean areas,
and cosmetics that can shed particles should not be used.
• The clothing worn and its quality should be appropriate for the
process and the grade of the working area (workplace). It should
be worn in such a way as to protect the product from
contamination.
• Separate laundry facilities for such clothing are desirable. If
fibers are damaged by inappropriate cleaning or sterilization,
there may be an increased risk of shedding particles. Washing
and sterilization operations should follow standard operating
procedures.
• Grade D:
– The hair and, where relevant, beard and moustache
should be covered.
– Protective clothing and appropriate shoes or
overshoes should be worn.
– Appropriate measures should be taken to avoid any
contamination from outside the clean area.
• Grade C:
– The hair and, where relevant, beard and moustache
should be covered.
– A single or two-piece trouser suit, gathered at the
wrists and with a high neck, and appropriate shoes or
overshoes should be worn.
– The clothing should shed virtually no fibers or
particulate matter.
• Grades A/B:
– Headgear should totally enclose the hair and, where
relevant, beard and moustache.
– A single or two-piece trouser suit, gathered at the wrists
and with a high neck, should be worn.
– The headgear should be tucked into the neck of the suit.
– A face mask should be worn to prevent the shedding of
droplets.
– Appropriate, sterilized, non-powdered rubber or plastic
gloves and sterilized or disinfected footwear should be
worn.
– Trouser bottoms should be tucked inside the footwear and
garment sleeves into the gloves.
– The protective clothing should shed virtually no fibers or
particulate matter and should retain particles shed by the
body.
 Premises
• All premises should, as far as possible, be designed to avoid the
unnecessary entry of supervisory or control personnel.
• Grade B areas should be designed so that all operations can be observed
from outside.
• In clean areas, all exposed surfaces should be smooth, impervious and
unbroken in order to minimize the shedding or accumulation of particles
or microorganisms and to permit the repeated application of cleaning
agents and disinfectants, where used.
• To reduce the accumulation of dust and to facilitate cleaning, there should
be no uncleanable recesses and a minimum of projecting ledges, shelves,
cupboards and equipment. Doors should be carefully designed to avoid
uncleanable recesses; sliding doors are undesirable for this reason.
• False ceilings should be sealed to prevent contamination from the space
above them.
• Pipes and ducts and other utilities should be installed so that they do not
create recesses, unsealed openings and surfaces that are difficult to clean.
• Sinks and drains should be avoided wherever possible and should be
excluded from grade A/B areas where aseptic operations are carried out.
• Where installed, they should be designed, located and maintained so as to
minimize the risks of microbiological contamination; they should be fitted
with effective, easily cleanable traps and with air breaks to prevent
back-flow.
• Any floor channels should be open and easily cleanable and be connected
to drains outside the area in a manner that prevents the ingress of
microbiological contaminants.
• Changing rooms should be designed as airlocks and used to separate the
different stages of changing, thus minimizing particulate and
microbiological contamination of protective clothing.
• They should be effectively flushed with filtered air.
• The use of separate changing rooms for entering and leaving clean areas
is sometimes necessary.
• Hand-washing facilities should be provided only in the changing rooms,
not in areas where aseptic work is done.
• Airlock doors should not be opened simultaneously. An interlocking
system and a visual and/or audible warning system can be installed to
prevent the opening of more than one door at a time.
• A filtered air supply should be used to maintain a positive pressure
and airflow relative to surrounding areas of a lower grade under
all operational conditions; it should flush the area effectively.
• Adjacent rooms of different grades should have a pressure
differential of approximately 10–15 pascals.
• Particular attention should be paid to the protection of the zone
of greatest risk, i.e. the immediate environment to which the
product and the cleaned components in contact with it are
exposed.
• The various recommendations regarding air supplies and pressure
differentials may need to be modified where it becomes necessary
to contain certain materials, e.g. pathogenic, highly toxic,
radioactive or live viral or bacterial materials or products. The
decontamination of the facilities and the treatment of air leaving a
clean area may be necessary for some operations.
• It should be demonstrated that airflow patterns do not present a
contamination risk; for example, care should be taken to ensure
that particles from a particle-generating person, operation or
machine are not conveyed to a zone of higher product risk.
• A warning system should be included to indicate
failure in the air supply.
• An indicator of pressure difference should be
fitted between areas where this difference is
important, and the pressure difference should be
regularly recorded.
• Consideration should be given to restricting
unnecessary access to critical filling areas, e.g.
grade A filling zones, by means of a physical
barrier.
 Equipment
• A conveyor belt should not pass through a partition
between a grade A or B clean area and a processing area of
lower air cleanliness, unless the belt itself is continuously
sterilized (e.g. in a sterilizing tunnel).
• Whenever possible, equipment used for processing sterile
products should be chosen so that it can be effectively
sterilized by steam or dry heat or other methods.
• As far as possible, equipment fittings and services should be
designed and installed so that operations, maintenance and
repairs can be carried out outside the clean area.
• Equipment that has to be taken apart for maintenance
should be re-sterilized after completing reassembly,
wherever possible.
• When equipment maintenance is carried out within a clean area,
clean instruments and tools should be used, and the area should
be cleaned and disinfected again, where appropriate, before
processing recommences if the required standards of cleanliness
and/or asepsis have not been maintained during the maintenance
work.
• All equipment, including sterilizers, air-filtration systems, and
water treatment systems, including stills, should be subject to
planned maintenance, validation and monitoring; its approved
use following maintenance work should be documented.
• Water-treatment plants and distribution systems should be
designed, constructed and maintained to ensure a reliable source
of water of an appropriate quality. They should not be operated
beyond their designed capacity.
• Consideration should be given to include a testing programme in
the maintenance of a water system. Water for injection should be
produced, stored and distributed in a manner which prevents the
growth of microorganisms, e.g. by constant circulation at a
temperature above 70 °C or not more than 4 °C.
 Overview of Parenteral Drug
Manufacturing
• The parenteral drug manufacturing (Drug Product Manufacturing)
process includes compounding, mixing, filtration, filling, terminal
sterilization, lyophilization, closing, and sealing, sorting, and
inspection, labeling, and final packaging for distribution.
• The manufacturing process is complicated, requiring organization
and control to ensure the product meets the quality and the
specifications.
• Aseptic processing requirement adds more complication but
assures that all dosage forms manufactured are free from any
contamination of microbial, endotoxin, and visible particulate
matter.
• The manufacturing process initiates with the procurement of
approved raw materials (drug, excipients, vehicles, etc.) and
primary packaging materials (containers, closures, etc.) and ends
with the sterile product sealed in its dispensing package.
 Clean room classified areas
• Manufacturing areas have standard criteria for the acceptable
maximum limit of airborne particles greater than or equal to
0.5 micron per cubic foot or meter.
• Air Classification Systems – accordance with the FDA and EU
guidelines
• Particle counts must be measured during filling and closing
operations.
• Grade A/B or Class100 clean room must have 90-100
ft/min+20% airflow determined by smoke tests (using glycerol
based fog generator).
• All HEPA filters should be integrity tested twice a year using
poly-alpha-olefin (PAO) aerosol. This aerosol is polydispersed,
nontoxic liquid that possessed a light scattering droplet with
0.7 micrometers.
 • Clean Rooms & Microbiology –
• Activities vs. Particles Generated

• Sitting Quietly Moving Walking

• Particles shed per minute

• 100,000 1 Million 5 Million

• Horseplay 100,000,000
 Parenteral Packaging systems
• Ampoules
• Vials
• Dual chamber vials
• Prefilled syringes and cartridges
• Glass or plastic bottles and plastic bags
 AMPOULES
• A small cylindrical glass / plastic container that
is sealed after filling single dose of
drug/water.
• Most commonly used for supplying WFI.
• They are also used for single dose small
volume parenterals.
 Types of Ampoules
“Rupture-disk" (VIBRAC)
" One-Point Cut Ampoules" (OPC)
• These are named based on facilitator
mechanisms for breaking ampoule safely to
decrease percutaneous injuries and
contamination of contents.
• “Rupture-disk" (VIBRAC):
implies applying a ring of
paint after the
cure/tempera process of
ampoule manufacture.
• It partially penetrates in the
glass, causing fragility of the
area of application.
• This fragility is located at
the strangulation point of
the ampoule (between the
head and body of the
ampoule).
• " One-Point Cut Ampoules"
(OPC)
• A small incision is made in the
strangulation area of the
ampoule.
• A small point of paint is placed
a few millimeters above the
incision.
• This point orients the correct
opening position.
 VIALS
• For single-dose or multi-dose use (contain
preservative).
• Product is easier to remove from vials than
form ampoules
• Eliminate the risk of glass particles
contamination during opening
• The rubber stopper can become cored causing
a small bit of rubber to enter the solution
especially in multi-dose uses.
• DUAL CHAMBER VIALS
• Pfizer’s Act-O-Vial system
• Pressing down on the plastic
activator
• Displaces the center stopper
• Gravity forces the diluent of
upper chamber into the dry
powder in lower chamber
• Suitable for unstable /
hydrolysable drugs.
• Minimizes number of steps in
reconstitution of injection.
PREFILLED SYRINGES AND
CARTRIDGES
• Single-dose medicine
filled in syringe with
fixed needle.
• Plastics / glass
sometimes
• Labeled properly or
done individually for
particular patient in
hospitals.
• Some medicine may be
supplied in pre-filled for
self administration
Pros Cons
• Emergency drugs are available • Component/material may
right away. have extractables and
• Ease of administration (less leachables.
steps involved) .
• Self administration is possible. • Primary packaging materials
• Reduction of medication error / plastics may have an
(right dose always) adverse interaction with the
• Reduction of contamination drugs.
(Assurance of sterility). • Silicone oil (used to
• Less overfill required lubricate the inner surface
(economical for of glass pre-filled syringe) is
biopharmaceuticals)
seen as an “essential evil /
• Good control of controlled
drugs (e.g. narcotics).
interctant.
 GLASS/PLASTIC BOTTLES & PLASTIC
BAGS
• They are used for Large
volume parenterals for IV
administration.
• For the intermittent or
continuous infusion of
fluids or drugs.
• Need special
administration devices to
permit drug administration
 Parenteral packaging Materials
• Glass
– Types I, II, III and surface treatments
• Leachables
• Particulates
• Color (amber)
• Rubber
– Types: unsaturated and saturated elastomers
• Complexity of formulation
• Leachables
• Sorption
• Moisture vapor transmission
• Coring and other physical properties
• Plastic
– Types of polymer
• Leachables
• Air and moisture transmission
 Glass
• Type I: Highly resistant borosillicate glass
– Very little, if any, alkali leachables
– Used for ready-to-use all parenterals
– Most expensive type of glass
• Type II : Treated (sulfar dioxide) soda lime glass
– Sodium sulfate forms on glass (looks like frost)
– (reaction between H2SO4 and sodium ions)
– Used for LVP bottles and acidic/neutral SVPs
• Type III: Soda-lime glass
– About 10x less resistant to alkali than type I
– Used for dry powder SVPs
– Cannot be terminally sterilized with final product
• NP Non parenteral glass
 Factors Affecting Glass Extractables
• Container size and design
• Container processing
– Washing, Drying, Sterilization, Sealing methods
• Product composition
– Type of ions, Concentration, pH
• Storage of filled container
– Time/Temperature, Shipping, Light
 Rubber
• Rubber is used as Closures (container-closure).
• Closures prevent ingress of contamination into a vial once a
needle is inserted (by enabling resealing of the vial after the
needle is withdrawn).
• Hence these are called elastomers.
• Used in vials and bottles closure, syringes and cartridge
plungers, ports on plastic bags and IV administration sets.
• Two primary rubber types elastomers are
– Natural
– Synthetic
• Synthetic rubbers are strongly resistant to permeation by
oxygen or to water vapors.
• Rubber are very complicated with many
components
• Many potential problems are associated with
the use of rubber, especially closures.
• Closures that form part of the
container-closure system are an important
component in the packaging of sterile
products.
• It maintain the sterility of parenteral
pharmaceuticals and prevent ingress of
contamination
Type Autoclavable Additives Water Pot. React.
Vapor with
Permeation product
Butyl Yes Moderat Low Moderate
e
Natural Yes High Moderate High

Neoprene Yes High Moderate High

Polyisopren Yes High Moderate Moderate

e
Silicone Yes Moderat Veryhigh low
e
 Plastics
• Plastic is a relatively new material for parenteral
packaging.
• As per an estimate, 60–70% of all prefilled syringes in
Japanese market are plastic, rather than glass.
• Issues with glass breakage and delamination are main
concern in the marketplace.
• Glass can break at any time: in production, when used
within a device such as an auto-injector, or even when
in use by the patient or caregiver.
• Silicone oil (Glass lubricant) cause problems such as
the formation of protein/silicone aggregates, which
may alter the integrity of the drug product.
• Polymer or plastic resists breakage extremely well and
is also inert and resistant to broad range of polar
solvents, acids, and bases.
• Plastic offers significant design flexibility and increased
dimensional precision.
• Flexible design and tight dimensional tolerances make
these syringes compatible with various intravenous
connectors , thus ensuring patient safety.
• Plastic is used to produce various types of parenteral
containers such as syringes, cartridges, intravenous
connectors, infusion sets, vials, and ampoules.
• Polyvinyl Chloride – PVC
• Polypropylene – PP
• Ethyl Vinyl Acetate – EVA
• Plastic-drug Interactions hinder its generalized
use.
• For example, diazepam, nitroglycerin, isosorbide
dinitrate, and warfarin sodium, can all be
absorbed by PVC.
• The availability of these drugs is decreased when
they are in plastic containers or administered
through plastic infusion sets.
• Hence plastic packaging options must be
evaluated on a drug-by-drug basis.
• Concerns are scratch sensitivity, inferior barrier
against oxygen and water vapor, and limited
long-term experience
Evaluation of parenteral preparations
• The finished parenteral products are
subjected to the following tests, in order to
maintain quality control
• Sterility test
• Clarity test
• Leakage test
• Pyrogen test
• Assay
 Sterility test
• It is a procedure carried out to detect and
conform absence of any viable form of
microbes in or on pharmacopeia preparation
or product.
Method of sterility testing
• Method 1: Membrane filtration method
• Method 2: Direct inoculation method
 Membrane filtration method
• Membrane filtration Appropriate for :
(advantage)
– Filterable aqueous preparations
– Alcoholic preparations
– Oily preparations
– Preparations miscible with or soluble in aqueous
or oily (solvents with no antimicrobial effect)
• All steps of this procedure are performed
aseptically in a Class 100 Laminar Flow Hood
• Membrane filter 0.45μ porosity
• Filter the test solution
• After filtration remove the filter
• Cut the filter in to two halves
• First halves (For Bacteria)
• Transfer in 100 ml culture media
• (Fluid Thioglycollate medium)

• Incubate at 30-350 C for not less then 7

• Days

• Observe the growth in the media

• Second halves (For Fungi)

• Transfer in 100 ml culture media
• (Soyabeans-Casein Digest medium)

• Incubate at 20-250 C for not less then 7 days

• Observe the growth in the media

 Direct inoculation method
• Suitable for samples with small volumes
• volume of the product is not more than 10% of
the volume of the medium
• It suitable method for aqueous solutions, oily
liquids, ointments and creams
• Direct inoculation of the culture medium suitable
quantity of the preparation to be examined is
transferred directly into the appropriate culture
medium & incubate for not less than 14 days.
 Observation and results
• Culture media is examined during and after at the end
of incubation. The following observations are possible:
• No evidence of growth- Pass the test for sterility.
• There is evidence of growth- Re-testing is performed
same no. of sample, volume & media as in original
test- No evidence of growth- Pass the test for sterility.
• There is evidence of growth -isolate & identify the
organism.
• Re-testing is performed with twice no. of sample if: No
evidence of growth Pass the test for sterility
 Clarity test
• Particulate matter is defined as unwanted mobile
insoluble matter other than gas bubble present in
the product.
• If the particle size of foreign matter is larger than
the size of R.B.C.. It can block the blood vessel.
• The permit limits of particulate matter as per I.P.
Are follows:
 Methods for monitoring particulate
matter contamination
• Visual method
• Coulter counter method
• Filtration method
• Light blockage method
 Leakage test
• The sealed ampoules are subjected to small cracks
which occur due to rapid temperature changes or due
to mechanical shocks.
• Filled & sealed ampoules
• Dipped in 1% Methylene blue solution Under negative
pressure in vacuum chamber
• Vacuum released colored solution enter into the
ampoule
• Defective sealing
• Vials & bottles are not suitable for this test because
the sealing material used is not rigid
 Pyrogen test
• Pyrogen = “Pyro” (Greek = Fire) + “gen” (Greek =
beginning).
• Fever producing, metabolic by-products of
microbial growth and death.
• Bacterial pyrogens are called “Endotoxins”.
• Gram negative bacteria produce more potent
endotoxins than gram + bacteria and fungi.
• Endotoxins are heat stable lipopolysaccharides
(LPS) present in bacterial cell walls, not present in
cell-free bacterial filtrates
Method
• Dissolve the subs being examined in, or dilute it with a pyrogen
free saline
• Solution
• Warm the liquid being examined to approx. 38.5o C temp before
injection
• The volume of injection is NLT 0.5ml/kg & NMT 10ml/kg of body
weight
• Withhold water during test
• Clinical thermometer is inserted into the rectum of rabbit to
record body temp
• 2 normal reading of rectal temp are should be taken prior to the
test injection at an interval of half an hr & its mean is calculated-
initial temp
• The solution under test is injected through an ear vein
• Record the temp of each rabbit in an interval of 30 min for 3 hrs
• The difference between initial temp & maximum temp is
recorded- taken as response
Interpretation of results
 Limulus amebocyte lysate [LAL] test
• Limulus amebocyte lysate (LAL) is an aqueous extract of blood cells
(amoebocytes) from the Atlantic horseshoe crab, Limulus polyphemus. LAL
reacts with bacterial endotoxin lipopolysaccharide (LPS), which is a
membrane component of gram-negative bacteria. This reaction is the
basis of the LAL test, which is widely used for the detection and
quantification of bacterial endotoxins.
• LAL test another method for the determination of pyrogenic endotoxins
• In this method the test solution is combined with a cell lysate from the
ameabocyte [blood cells] of horse shoe crab
• Any endotoxin that might be present will be coagulated with protien
fraction of the ameabocytes and results in the formation of a gel
• This consider to be simple,rapid and of greater sensitivity that the rabbit
test
• Assay is performed according to method given In the monograph of that
parental preperation in the pharmacopoeia
• Assay is done to check the quantity of medicament present in the
parenteral preperation
Thank you