Sterile manufacturing in hospital

Dr.S.Balamurugan.,BPharm,PharmD.,
ASSISTANT PROFESSOR,
KMCH-COP
 STERILITY

Absence of living microorganism

 Sterile products

These are the products or preparations

free from living microorganisms
 Sterile
manufacture

Manufacturing of sterile products

 STERILE MANUFACTURE
• All parenteral products are applied on mucus membrane,
open wound or products for ophthalmic purpose must be
sterile.
• The parenteral products bypasses the body's natural defence
system and enters directly into the blood, and so they must
be free from viable microbes and pyrogens.
• Pyrogens are the metabolic products of microorganisms and
if they enter the blood along with parenteral products, they
cause fever and worsen the condition of the patients.
STERILE PRODUCTS
Parenteral
products

Ophthalmic
products

Eardrops,nasal
drops ,etc
 PARENTERAL PRODUCTS
Small volume • Solution<100ml in
parenteral(SVP) volume

Large volume • solution>100ml in

parenteral (LVP) volume
 In Hospitals
• Daily consumption of large volume parenteral and
small volume parenteral is very high and so they be
manufactured in hospitals itself to maintain the
quality and to reduce the cost of the products.
 Importance
parenteral preparations
A.IV ADMIXTURES
• These preparations consist of one or
more sterile drug products added to an
IV fluid(Dextrose and NACL alone or in
combination.
• These are used for drug intended for
continuous infusion and for drugs that
may cause irritation or toxicity when
given via direct IV Injection.
 B.FLUIDs AND
ELCETROLYTES
Fluids used in the preparation and administration
of parenteral products.

They serve as vehicles in IV admixtures ,provide a

means for reconstituting sterile powders, and serves
as the basis for the correcting body fluid and
electrolyte disturbances and for administering
parenteral nutrition.
Dextrose 5% in Water (D5W)
• Dextrose 5% in water is injected into
a vein through an IV to replace lost
fluids and provide carbohydrates to
the body.
• Dextrose 5% in water is used to treat
low blood sugar (hypoglycemia),
insulin shock, or dehydration (fluid
loss).
• Dextrose 5% in water is also given for
nutritional support to patients who
are unable to eat because of illness,
injury, or other medical condition.
Dextrose 5% in Water (D5W)

• Dextrose 5% in water is used to

treat low blood sugar
(hypoglycemia), insulin shock, or
dehydration (fluid loss).
• Dextrose 5% in water is also
given for nutritional support to
patients who are unable to eat
because of illness, injury, or
other medical condition.
Dextrose 5% in Water (D5W)

• Ph ranges from 3.5 to 6.5

instability may results if it is
combined with an acid sensitive.
• Dextrose 10% in water is also
given for nutritional support to
patients who are unable to eat
because of illness, injury, or
other medical condition.
B.SODIUM CHLORIDE-0.9%
• Normal saline solution contains 0.9
percent sodium chloride (salt), which
is similar to the sodium concentration
in blood and tears.
•  Saline solution is usually
called normal saline, but it's
sometimes referred to
as physiological or isotonic saline.
SODIUM CHLORIDE-0.9%

A solution of
0.45% Nacl
Half –normal
saline
Sterile NACL For Injections
• It used as vehicle in IV
admixtures and for fluid and
electrolyte replacement.
• In smaller volumes, it is suitable
for the reconstitution of various
medications.
BACTERISTATIC SODIUM CHLORIDE
INJECTION
• Each mL contains: Sodium
chloride 9 mg; methylparaben
0.12%; propylparaben 0.012%;
Water for Injection q.s. 
• Hydrochloric acid and/or sodium
hydroxide may have been added
for pH adjustment (pH 4.5-7.0).
BACTERISTATIC SODIUM CHLORIDE
INJECTION
• It is intended solely for multiple
reconstitutions.
• It contains an agent that inhibits
bacterial growth ,allowing its
use in multiple –dose
preparations.
 C.WATER

STERILE WATER FOR BATERIOSTATIOC

INJECTION WATER FOR
INJECTION

It is used for reconstitution and for dilution of such

IV solutions as dextrose and sodium chloride
Water for Injection
• Sterile Water for Injection, USP,
is sterile, nonpyrogenic,
distilled water in a single dose
container for intravenous
administration after addition of a
suitable solute.
• It may also be used as a
dispensing container for diluent
use.
 BACTERIOSTATIC WATER FOR
INJECTION
• Bacteriostatic Water for Injection,
USP is a sterile, nonpyrogenic
preparation of water for injection
containing 0.9% (9 mg/mL) of
benzyl alcohol added as a
bacteriostatic preservative.
• It is supplied in a multiple-dose
container from which repeated
withdrawals may be made to dilute
or dissolve drugs for injection.
• The pH is 5.7 (4.5 to 7.0).
D.RINGER SOLUTIONS

It is used for fluid and electrolyte

replacement
HARTMANN'S SOLUTION
• Ringer's lactate solution (RL), also
known as sodium
lactate solution and Hartmann's
solution, is a mixture of sodium
chloride, sodium lactate, potassium
chloride, and calcium chloride in water.
• It is used for replacing fluids and
electrolytes in those who have low
blood volume or low blood pressure.
• Frequently it is combined with
dextrose.
RINGER INJECTION
• Ringer injections differs from lactated
ringers injections in that it does not
contain sodium lactate and has slightly
different concentrations of sodium
chloride and calcium chloride .
• Like lactated ringers injections, it
may be combined in solution with
dextrose.
2.Electrolyte preparations
potassium

Sodium CATIONS Magnesium

Calcium
 Sodium-chief extracellular
• Role in interstitial osmotic pressure.
• Acid –base balance
• Nerve impulse transmission
• Muscle contraction
Parenteral sodium preparations:
• Sodium chloride, sodium acetate and sodium phosphate.
Potassium-chief intracellular cation
• It participate in carbohydrate metabolism, protein synthesis, muscle
contraction and neuromuscular excitability.
• Preparation: acetate, chloride and phosphate
 calcium
• Nerve impulse transmission, muscle contraction, cardiac function.
• Preparations: chloride and gluconate
 Anions Electrolytes

chloride

Anions
phosphat Acetate
e
 Chloride –Extracellular anion
• Along with sodium it regulates interstitial osmotic pressure.
• Control Blood PH
• Preparations: Calcium Chloride, Potassium chloride and sodium
chloride.
Phosphate –major intracellular electrolyte
• Enzyme activities
• Preparations: Potassium and sodium Phosphate .
 Acetate
• It used to provide alkali to assist in the preservation of plasma Ph.
• Preparation : potassium and sodium acetate.
3.DIALYSATES
• The part of a mixture which
passes through the membrane in
dialysis.
• These products remove waste
materials ,serum electrolytes
and toxic products from the
body.
4. Sterile irrigating solutions

• Sterile irrigating solutions are

sterile or nonpyrogenic isotonic
solutions, made under sterile
conditions.
• They are generally used for
washing, irrigation and rinsing
purposes.
 Sterile irrigating solutions

TOPICAL ADMINISTRATION INFUSION OF IRRGATING SOLUTION

 TOPICAL ADMINISTRATION
• It packed in pour bottles that are used in
irrigating wounds, moistening dressings and
cleaning surgical instruments.
INFUSION OF IRRGATING SOLUTION
• This procedure using an
administration set attached to a
foley catheter is commonly used
for many surgical patients.
• Surgeons performing urologic
procedures often use irrigating
solutions to perfuse tissues in
order to maintain the integrity of
the surgical field, remove blood
and provide a clear field of view.
Parenteral antineoplastic agents
• A vertical laminar air flow should
be used during drug preparation
with exhaust directed to the
outside.
Safe antineoplastic handling guide lines
• All syrings and iv tubing should
have luer-lok fittings.
Safe antineoplastic handling guide lines
• Personnel should wear closed
front cuffed surgical gowns and
double-layered latex surgeons
gloves.
• Negative pressure technique should be used during withdrawal of
medication from vials.
• Final dosage adjustment should be made into the vial or ampoule.
• Special care should be taken when iv administration sets are primed.
• Proper procedure should be followed for disposable of materials used
in the preparation and administration of antineoplastics.
Needles should not be clipped or recapped.
Preparations should be discarded in containers that are puncture-
proof, leak proof, properly labeled.
Hazardous waste should be incinerated at a temperature sufficient to
destroy organic compounds(>10000c)
• After removal of gloves, personnel should wash hands thoroughly.
• Personal and equipment should be monitored routinely.
Patient problem during administration of
antineoplastics.
 a. Inflammation of a vein
• Pain • Drug dilution and filtration may
• Swelling eliminate or minimize the risk of
inflammation of a vein.
• Heat sensation
• redness
b.Extravasation
• Infiltration of a drug into
subcutaneous tissues
surrounding the vein.
• It is common with vesicant
properties are administered.
 WORKING ENVIRONMENT
• Socially clean area
• Clean room area
• Aseptically maintained area
 Socially clean area

• Where high standards of cleanliness and hygiene are required for the
preparation of oral liquids ,tablets, ointments and non-injectable
sterile water.
Clean room area
• Atmosphere free from small particles(>0.5mm size) is required.
Aseptically maintained area
 colour code of environmental category

• Socially clean area • Black

• Clean room area • White
• Aseptic area • red
MANUFATURE OF PARENTERAL
PREPARATIONS WHICH ARE
TERMINALLY STERILIZED
 A. Clean room
High efficiency particulate air(HEPA)
• The room should undergo 10-15
air charges per hour.
• (High efficiency particulate
air(HEPA) Filters are used to
cleanse the air entering the room.
• HEPA, which stands for High
Efficiency Particulate Air, is a
designation used to describe filters
that are able to trap 99.97 percent
of particles that are 0.3 microns. 
• Positive pressure air flow should be used to prevent contaminated air
from flowing into the clean room. (In order to achieve this the air
pressure inside the clean room should be greater than the pressure
outside the room, so that when a door to the clean room is opened
the air flow is outward).
• Counter in the clean room should be made of stainless steel or
other nonporous, easily cleaned materials.
• Wall and floors should be free from cracks and have rounded corners.
• If the walls or floors are to be painted ,epoxy paint used.
• The air flow should be moved with uniform velocity along parallel
lines. The velocity of the air flow is 90±20feet per minute.
B.LAMINAR FLOW HOODS
• These are used in conjunction with clean rooms and vital to ensure
aseptic preparations.
• Like clean room, laminar flow hoods utilizes HEPA Filters, but the
hoods use a higher efficiency air filter than do clean rooms.
• Hoods are classified as federal class 100(contain no more than
100particles sized 0.5µm or larger per cubic foot of air.
Horizontal laminar flow hoods
• Room air (in red) enters the
system from behind the HEPA
filter; 99.99% particle-free air is
forced in a back-to-front
direction across the work
surface.
Vertical laminar flow hoods
• Room air enters the system from
above the HEPA filter; 99.99%
particle-free air is forced
downward toward the work
surface.
 Inspection and certification
(at least every 6 to 12 months)
• The dioctyl phthalate (DOP) smoke test ensures that no particle
larger than 0.3µm will pass through the HEPA fliter.
• Anemometer is used to determine air flow velocity and a particle
counter is used to determine the particle count.
• Socially clean area is utilized for
a. Storage of used bottles
b. Storage of new bottle and closures.
c. Pre-rinse and delabelling of re-used bottles
d. Washing of new bottles and closures.
Quality control and quality assurance of
parenteral products
 Membrane sterilization method
• An oil or oily preparation
• A non-bacteriostatic solid not readily soluble in culture medium.
• A soluble powder or a liquid that possesses bacteriostaic and
fungistatic properties
• The filtration of the sample through a membrane filter(porosity-
0.45µ and diameter-47mm.
• After the filtration the membrane is removed aseptically from the
metallic holder and divided into two halves.
• The first half is transferred into 100ml of culture media meant for
fungi and incubated at 20 to 25 0C.
• Other half is transferred into 100ml of fluid thioglycollate medium
and incubated at 30 to 35 0C.
• Observe the growth in the media.
Pyrogen testing
Pyrogen testing
• Rabbits are used to perform this test .
•  Clarity is tested by visual inspection of containers under light and
against a black and white background.
• Instrumental methods of evaluation is based on the principles of light
scattering, light absorption and electrical resistance which are used to
count particle and particle size distribution.
• Unwanted mobile insoluble matter other than gas bubbles are present
in the given product.
• It may be dangerous when the particle size is larger than R.B.C. and
may block the blood vessel.
 limulus amebocyte lysate
• The LAL (limulus amebocyte lysate) testing, also known as bacterial
endotoxin testing, is an in vitro assay used to detect the presence and
concentration of bacterial endotoxins in drugs and biological
products, and is an important part of pharmaceutical microbiology.
• Endotoxins, which are a type of pyrogen, are lipopolysaccharides
present in the cell walls of gram-negative bacteria.
• Pyrogens as a class are fever-inducing substances that can be harmful
or even fatal if administered to humans above certain concentrations.
Clarity testing
• Clarity test All the particulate matter is of primary concern with
product given i.vly .
• All parenterals products should be free from insoluble particles.
• The USP has established a limit of 50 particles of 10µm and 5particles
of 25µm and larger per milliliter.
• If the product contain any particulate matter then it is rejected.