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Parenteral
Mr. Kailash Vilegave
1
Products:
Mr. Kailash Vilegave
M Pharm (Research Scholar)
Shivajirao S jondhle college of pharmacy
Asangaon.
Mr. Kailash Vilegave 2
• Introduction
• History
Why parenteral?
Necessary condition of parenteral
• advantages/ disadvantages
• Methods of preparation
• Quality control
• Packaging
• Types of parenteral products
• Routes of administration
• advantages/ disadvantages
• conclusion
History:
Mr. Kailash Vilegave 3
 1657: first recorded injection in animals- SirChristopher
Wren
 1855: first subcutaneous injection of drugs using hypodermic
needles - Dr.Alexander wood
 1920:proof of microbial growth resulting in infections
- Dr. Florence Seibert
 1926: inclusion in the national formulary
 1931: commercial intravenous solution(Baxter)
 1946:organization of parenteral drug association
 1965:development of total parenteral nutrition
Why parenteral?
Mr. Kailash Vilegave 4
Mr. Kailash Vilegave 5
Necessities of parenteralpreparations:
• Sterility (must)
• Free from pyrogen (must)
• Free from particulate
matter
• Clarity (must)
• Stability (must)
 Isotonicity (should)
 Solvents and vehicles used
must meet special purity and
other standard
 Do not use coloring agents
 Must be prepared under
aseptic conditions
 Specific and highquality
packaging
DEFINATION:
Mr. Kailash Vilegave 6
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
Pyrogens, fever-producing substances, primarily
lipopolysaccharide product of metabolism of microorganism;
they may be soluble, insoluble, or colloid.
Advantages of the Parenteral Route
Mr. Kailash Vilegave 7
 T h e IV route is the fastest method for delivering systemicdrugs
preferred administration in an emergencysituation
 I t can provide fluids, electrolytes, and nutrition.
patients who cannot take food or have serious problems withthe
GI tract
 I t provides higher concentration of drug to bloodstream or
tissues
advantageous in serious bacterial infection.
 I V infusion provides a continuous amount of needed medication
infusion rate can beadjusted.
 t o provide more or less medication as the situation dictates
Drug action can be prolonged by modifying the formulation.
Mr. Kailash Vilegave 8
Advantages of Parenteral Administration
1. Useful for patients who cannot take drugs orally
2. Useful for drugs that require a rapid onset of action
(primarily iv admin)
3. Useful for emergency situations
4. Useful for providing sustained drug delivery (implants, im
depot injections)
5. Can be used for self-delivery of drugs (subcutaneous)
6. Useful for drugs that are inactivated in the GIT or
susceptible to first-pass
7. Useful for injection of drugs directly into a tissue (targeted
drug delivery)
8. Useful for delivering fluids, electrolytes, or nutrients
(TPN) Useful for providing precise drug delivery by iv
injection or infusion utilizing pharmacokinetic techniques
9. Can be done in hospitals, ambulatory infusion centers,
and home health care
Disadvantages of the Parenteral Route
Mr. Kailash Vilegave 9
Traumatic injury from the insertion of needle
Potential forintroducing:
Toxic agents
Microbes
Pyrogens
Impossible to retrieve if adverse reactionoccurs
injected directly into thebody
Correct syringe, needle, and technique must beused
Rotation of injection sites with long-termuse
prevents scarring and other skinchanges
 can influence drugabsorption
Mr. Kailash Vilegave 10
Disadvantages of Parenteral Administration
1. More expensive and costly to produce.
2. Potential for infection at the site of injection,
thrombophlebitis, fluid overload, air embolism,
extravasation, sepsis
3. Psychological distress by the patient
4. Require specialized equipment, devices, and techniques to
prepare and administer drugs.
5. Potential for pain upon injection
6. Potential for tissue damage upon injection
7. Risk of needle stick injuries and exposure to blood-borne
pathogens by health care worker.
8. Increased morbidity associated with long-term vascular
access devices.
9. Disposal of needles, syringes, and other infusion devices
requires special consideration.
Routes of Administration of parenteral
products
Mr. Kailash Vilegave 11
Various types of route of administration of parenteral products are:










Subcutaneous (Hypodermis) injection
Intramuscular injection
Intravenous injection
Intradermal injection
Intra-arterial injection
Intracardiac injection
Intrathecal injection
Intracisternal injection
Peridural injection
Intra- articular injection
5
Subcutaneous Injections
Mr. Kailash Vilegave 12
• Administer medications below the skin into the subcutaneous fat
outside of the upper arm
top of the thigh
lower portion of each side of the abdomen
not into grossly adipose, hardened, inflamed, or swollen tissue
• Often have a longer onset of action and a longer duration of action
compared with IM or IV injection
Given at a 45-degreeangle
 25- or 26-gauge needle, 3/8 to5/8
inch length
 N o more then 1.5 ml should be
injected into the site
 t o avoid pressure on sensory nerves
causing pain and discomfort
Intramuscular Injections
Mr. Kailash Vilegave 13
Care must be taken with deep IM injections to avoid hitting a
vein, artery, or nerve
 I n adults, IM injections are given into upper, outer portion of the
gluteus maximus
large muscle on either side of thebuttocks
 Fo r 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
Intravenous Injections or Infusions
Mr. Kailash Vilegave 14
Fast-acting route because the drug goes directly intothe
bloodstream
often used in the emergency department and in criticalcare
areas
Commonly used
 for fluid and electrolytereplacement
 t o provide necessary nutrition to the patient who is
critically ill
• Intravenous (IV) injections are
administered at a 15- to 20-degree
angle
Intra-arterial injection
The inaction are given directly in to the artery
Intracardiac injection
These are given into the heart muscle or
ventricle at the time of emergency only.
Intrathecal injection
These are given into the subachonoid space the
surround the spinal cord. This route is used for
spinal anesthesia.
Mr. Kailash Vilegave 15
Intracisternal injection
These are given in b/w first & second cervical nerve.
Used for CSF for diagnosticpurpose.
Peridural injection
These are given in b/w the dura matter & inner
aspect of vertebra.
Used for giving spinal anesthesia.
Intra- articular injection
These are given into the articulating ends of bones
in a joint.
Used for lubricating the joints.
Intracerebral injection
These are given into the cerebrum.
Mr. Kailash Vilegave 16
Official types of injections
Mr. Kailash Vilegave 17
Injection: Liquid preparation of drug substance or drug
solution e.g. insulin injection USP.
 Fo r injection: Dry solid that upon addition of suitable vehicles
yield solutions confirming in all respect to the requirements to
the injection. e.g. Cefuroxime injection USP.
Injectable emulsions: Liquid preparation of drug substance
dispersed in a suitable emulsion medium. e.g. Propofol USP.
Injectable suspension: Liquid preparation of solid suspended
in a suitable medium. e.g. Methyl Prednisolone Acetate
Suspension USP.
 Fo r injectable suspension: Dry solid that upon addition of
suitable vehicle yields preparation confirming in all respect
to the requirements for Injectable suspension.
e.g. Imipenem
11
General requirements of parenteral preparations
Mr. Kailash Vilegave 18
 Stability
 Sterility
 Free from Pyrogens
 Free from foreign particles
 Isotonicity
 Specific gravity
 Chemical purity
 Clarity (must)
 Solvents and vehicles used must meet special
purity and other standard
 Do not use coloring agents
 Must be prepared under aseptic conditions
 Specific and high quality packaging
Formulation of parenteralpro ducts
Mr. Kailash Vilegave 19
wing In the preparation of parenteral products, the follo
substances are added to make a stable preparation:
 The active drug
 Vehicles
 Aqueous vehicle (e.g.water for injection, water for inj. free from CO2)
 Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil)
 Adjuvants
 Solubilizing agents (e.g. Tweens & polysorbates)
 Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol)
 Buffering agents (e.g. citric acid, sodium citrate)
 Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol)
 Chelating agents (e.g. EDTA)
 Suspending, emulsifying & wetting agents (e.g. MC, CMC)
 Tonicity factor (e.g. sodium chloride, dextrose)
Processing of parenteral preparation
Mr. Kailash Vilegave 20
Following steps are involved in the processing of
parenteral preparation:
1) Cleaning of containers, closures & equipments
2) Collection of materials
3) Preparation of parenteral products
4) Filtration
5) Filling the preparation in final container
6) Sealing the container
7) Sterilization
8) Evaluation of the parenteral preparation
9) Labeling & packaging
1. Cleaning of containers, closures & equipments: Thoroughly cleaned with
detergents with tap water distilled water finally rinsed
with water for injection.
Mr. Kailash Vilegave 21
Rubber closures are washed with 0.5% sod. pyrophosphate in water.
2. Collection of materials: All raw material of preparation should be collect
from warehouse after accurate weighed.
Water for injection should be Pyrogens free.
3. Preparation of parenteral products: The parenteral preparation must be
prepared in aseptic conditions.
The ingredients are accurately weighed separately and dissolved in
vehicle as per method of preparation to be followed.
4. Filtration: The parenteral preparation must be filtered by
ba0c5t/0e2/r1i7aproof filter suH.cPh.IRaisshi,RfaimltPearrajculaindle, membranefilter.
15
5. Filling the preparation in final container: The filling
operation is carried out under strict aseptic precautions.
6. Sealing the container: Sealing should be done immediate after
filling in aseptic environment.
7. Sterilization: For thermostable substances the parenteral
products are sterilized by autoclaving method at different temp.
& pressure.
 Heat sensitive or moisture sensitive material are sterilized by
exposure to ethylene oxide or propylene oxide gas .
8. Evaluation of the parenteral preparation: The following tests
are performed in order to maintain quality control:
1. Sterility test
4. Pyrogen test
2. Clarity test 3. Leakage test
5. Assay
9. Labeling & packaging.Mr. Kailash Vilegave 22
Evaluation of Parenteral
products
Mr. Kailash Vilegave 23
 Sterility testing
 Particulate matter monitoring or Clarity Test
 Faulty seal packaging or leakage test
 Pyrogen testing:
Rabbit Test
LAL Test
MAT
Assay or drug content uniformity
Sterility testing
Mr. Kailash Vilegave 24
• DEFINITION:
• Sterility Testing: It is a procedure carried out to detect and
conform absence of any viable form of microbes in or on
pharmacopeial preparation or product.
• PRINCIPLE : If the microorganism are present in the product can
be indicated by a turbidity in the clear medium.
• OBJECTIVE OF STERILITY TESTING:
For validation of sterilizationprocess.
To check presence of microorganisms in preparation which are
sterile.
05/0T2/1o7 prevent issuHe.P.IoRfishciRoanmtPaaramjuliinatedproduct in market.
18
STEPS INVOLVED IN STERILITY TETESTING
Mr. Kailash Vilegave 25
1) Sampling
2) Selection of the quantity of the product to be used
3) Method of sterility testing
i ) METHOD 1 Membrane filtration method
ii) METHOD 2 Direct inoculation method
1) Observation and interpretation Must be carried out under
aseptic condition.
H.P.I Rishi Ram Parajuli05/02/17 19
Sampling
Mr. Kailash Vilegave 26H.P.I Rishi Ram Parajuli
• The sample must be representative of the whole of the bulk
material & a lot of final containers.
• MAINLY FOLLOWED BY TWO RULES:
 A fixed percentage of the final container are selected.
 A fixed number of container are taken independent of the lot or
batch size.
According to Indian Pharmacopoeia following guidelines for
determining the minimum number of items are:
05/02/17 20
Method of sterility testing
Mr. Kailash Vilegave 27
Membrane filtration method (METHOD 1):
Membrane filtration Appropriate for : (advantage)
Filterable aqueouspreparations
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 Laminar
Flow Hood
05/02/17 H.P.I Rishi Ram Parajuli 21
Membrane filter 0.45μ porosity
Mr. Kailash Vilegave 28
Filter the test solution
After filtration remove the filter
Cut the filter in to two halves
First halves (For Bacteria) Second halves (For Fungi)
Transfer in 100 ml culture media
(Fluid Thioglycollate medium)
Incubate at 30-350 C for not less then 7 days
Transfer in 100 ml culture media
(Soyabeans-Casein Digest medium)
Incubate at 20-250 C for not less then 7 days
05O/0b2s/1e7rvethe growth in the media Observe the growth in the med22
ia
Suitable for samples with small
volumes
volume of the product is not
more than 10% of the volume of
the medium
suitable method for aqueous
solutions, oily liquids, ointments
an creams
Direct inoculation of the culture
medium suitable quantity of the
appropriate culture medium
preparation to be examinedis
transferred directly into the
&
incubate for not less than 14 days.
H.P.I Rishi Ram Parajuli
Direct inoculation method (METHOD 2):
Mr. Kailash Vilegave 2905/02/17 23
Observation and results
Mr. Kailash Vilegave 30
Culture media is examined during and after at the end of incubation. The
following observations are possible:
1) No evidence of growth Pass the test for sterility.
2) There is evidence of growth(preserved) Re-testing is performed same
no. of sample, volume & media as in original test No
evidence of growth Pass the test for sterility.
3) There is evidence of growth isolate & identify the organism.
Same as in preserved fail .Diff Re-testing is performed
with twice no. of sample if:
No evidence of growth Pass the test for sterility.
T05h/02e/1r7eis evidence of growth Fail the test for sterility 24
leakage testing
Mr. Kailash Vilegave 31
 T h e sealed ampoules are subjected to small cracks which occurdue
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.
Clarity Test:
Mr. Kailash Vilegave 32
Performed to ensure that the parenteral productsare
free from foreign particles.
Method: Visual Method,
Coulter Counter Method
Filtration Method
Particle Size (μm) equal to
or large than
Max. no. o f particlesper
ml
10 50
25 5
50 nill
Pyrogen Testing
Mr. Kailash Vilegave 33
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.
Stable to at least 175oC; steam sterilization ineffective
Water soluble; monomer unit of LPS can be 10,000 Daltons (1.8
nm) so endotoxins can easily pass through 0.22μm filters
Sources: Water (main), raw materials, equipment, process
environment, people, and protein if using gram negative ba cteria.
Biological properties of endotoxin
:
Mr. Kailash Vilegave 34
Pyrogen elevate the circulatory levels of inflammatory
cytokines which may be followed by fever, blood coagulation,
hypotension
Low doses of Pyrogen: asymptomatic inflammationreaction
Moderate doses: fever & changes in plasma composition
High doses:
vasoconstriction,
cardiovascular dysfunction,vasodilation,
endothelium dysfunction, multiple organ
failure & finally death.
Elimination of pyrogens
Mr. Kailash Vilegave 35
 Dry heat sterilization : For glass wares, metal equipments,
powders, waxes, oils, heat stable drugs
650 o C temp - 1 min
250 o C temp - 30 min
180 o C temp - 240 min
Ultra filtration
 Reverse osmosis : RO membrane is composed of cellulose
acetate phthalate/ polyamide
Distillation
Adsorption method
Rabbit PyrogenTest:
Mr. Kailash Vilegave 36
Rabbits are used to perform this test because their body temp
increases when pyrogen are introduced into their bodies by
parenteral route
3 healthy adult rabbits of either sex, each weighing NLT 1.5 kg are
selected
Do not use anyrabbit
having a temp higher than 39.8 oC
o CShowing temp variation >0.2 between two successive
reading in the determination of initial temp
Sham test is performed within 7 days of actual test
oAnimal showing temp increase over 0.6 C should beremoved
from pyrogen testing
• 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 earvein
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
Mr. Kailash Vilegave 37
Interpretation of results
Mr. Kailash Vilegave 38
Bacterial endotoxin (LAL) test )
Mr. Kailash Vilegave 39
 To detect or quantify endotoxins of gram-ve bacterial origin
 Reagent: amoebocyte lysate enzyme from horseshoe crab
(Limulus polyphemus or Tachypleus tridentatus).
 The name of the test is also Limulus amebocyte lysate (LAL)
• Mteecshtanism of LAL Test:
The test is based on the gelling properties of enzyme extracted
from the horseshoe crab of Limulus polyphemus.
enzymes when come in contact with bacterial endotoxin
Gelling
Degree of Gelling related to amount of Endotoxin present
05/02/17
H.P.I Rishi Ram Parajuli
33
• Test performance (short)
Avoid endotoxin contamination
– Before the test:
– interfering factors should not be present
– equipment should be depyrogenated the sensitivity of the
lysate should be known
Test:
– equal Volume of LAL reagent and test solution (usually 0.1 ml
of each) are mixed in a depyrogenated test-tube
– Incubation at 37°C, 1 hour
– remove the tube - invert at (180°) observe the result
H.P.I Rishi Ram Parajuli0–5/0p2/1a7ss-failtest 34Mr. Kailash Vilegave 40
LAL test
Mr. Kailash Vilegave 41
Three differenttechniques:
1. The gel-clot technique - gel formation
2. The turbidimetric technique - the development of Turbidity
after cleavage of an endogenous substrate
3. The chromogenic technique - the development of color after
cleavage of a synthetic peptide- chromogen complex
• Advantages of LAL test
Fast - 60 minutes vs. 180 minutes
Greater Sensitivity ,Less Variability
Much Less False, Positives ,Much Less Expensive
 Alternative to Animal Model, cheaper,
particularly useful for:
Radiopharmaceuticals and cytotoxic agents
Blood products
Water for injection
35
MAT (Monocyte Activation
Test)
Mr. Kailash Vilegave 42
 D u e to its greater sensitivity replaces LAL Test.
Uses monocyte obtained from Human volunteeror
blood bank
Detects pro-inflamatory and pyrogenic
contaminants.
Used or Qualitative and Quantitativedetection.
Production facilities of parenterals
Mr. Kailash Vilegave 43
preparation are The production area where the parenteral
manufactured can be divided into five sections:
 Clean-uparea
 Preparation area
 Aseptic area
 Quarantine area
 Finishing & packaging area
 Clean-up area:
44
 It is not aseptic area.



All the parenteral products must be free from foreign particles &
microorganism.
Clean-up area should be withstand moisture, dust & detergent.
This area should be kept clean so that contaminants may not be carried
out into aseptic area.
 Preparation area:


In this area the ingredients of the parenteral preparation are mixed &
preparation is made for filling operation.
It is not essentially aseptic area but strict precautions are required to
prevent any contamination from outside.
 Aseptic area:
Mr. Kailash Vilegave 45
 The parenteral preparations are filtered, filled into final
container & sealed in aseptic area.
 The entry of personnel into aseptic area should be limited &
through an air lock.
 Ceiling, wall & floor of that area should be sealed & painted.
 The air in the aseptic area should be free from fibers, dust
and microorganism.
 The High efficiency particulate air filters (HEPA) is used for
air.
 UV lamps are fitted in order to maintain sterility.
 Quarantine area:
 Parenteral products are properly labelled and packed.
 Properly packing is essential to provide protection
against physical damage.
 The labelled container should be packed incardboard or
plastic container.
 Ampoules should be packed in partitioned boxes
Mr. Kailash Vilegave 46



After filling, sealing & sterilization the parenteral product are
held up in quarantine area.
Randomly samples were kept for evaluation.
The batch or product pass the evaluation tests are transfer in
to finishing or packaging area.
 Finishing & packaging area:




Lyophilization or freeze drying
Mr. Kailash Vilegave 47
Lyophilization or freeze drying is a process in which water is
removed from a product after it is frozen and placed under a
vacuum, allowing the ice to change directly from solid to vapor
without passing through a liquid phase.
 T h e process consists of three separate, unique, and interdependent
processes;
Freezing,
Primary drying (sublimation),and
Secondary drying (desorption).
 T h e advantages of Lyophilizationinclude:
Ease of processing a liquid, which simplifies aseptichandling
Enhanced stability of a drypowder
Removal of water without excessive heating of theproduct
Enhanced product stability in a drystate
Rapid and easy dissolution of reconstitutedproduct
Disadvantages of Lyophilization include:
Increased handling and processing time
Need for sterile diluent uponreconstitution
Cost and complexity ofequipment
Mr. Kailash Vilegave 48
Mr. Kailash Vilegave 49
Containers for parenteral
1.Glass
2. Plastic
3.Rubber closers
SELECTION CRITERIA FOR PACKAGING MATERIAL
• The product or pack contents
• The application of the product
• Content stability, and the need of protection form any
environmental factors
• Content reactivity (with relevant to the packaging material)
• Acceptability of the pack to the consumer or user
• The packaging process
• Regulatory, legal and quality issues
Characteristics of packaging material
• They must protect the preparation from environmental
conditions.
• They must not be reactive with the product.
• They must not impart to the product tastes or odors.
• They must be nontoxic.
• They must be FDA approved.
• They must meet applicable tamper-resistance
requirements.
• They must be adaptable to commonly employed high
speed packaging equipment.
List of packages for sterile dosage forms
• All types of parental
ampoules
vials
i.v. infusion (small vol. + large vol.)
s.c injections
intra thecal inj.
intramuscular inj.
• Oral vaccines
tripsules
• Ophthalmic product
drops
ointment
Using of packaging material
vaccine storage,I)Glass - ampule, vials, syringe, SVI, LVI,
dropper (primary packaging)
II) Metals - vials (primary packaging)
III)Rubbers – vials, syringe’s plunger, vaccine closer (primary
packaging)
IV)Plastics - ampule, vials, syringe, SVI, LVI, vaccine storage,
dropper, tripsules, (primary packaging as well as secondary
packaging)
V)Fibrous mater- all types of secondary packaging
VI)Films, Foils and laminates –all types of secondary packaging
GLASS:
• Glass has been widely used as a drug packaging material.
• Glass is composed of sand, soda ash, limestone,& cullet.
• Si, Al, Na, K, Ca, Mg, Zn & Ba are generally used into preparation of glass
 Advantages
• They are hygienic and suitable for sterilization
• They are relatively non reactive ( depending on the grade chosen)
• It can accept a variety of closures
• They can be used on high speed packaging lines
• They are transparent.
• They have good protection power.
• They can be easily labeled.
 DISADVANTAGES
• It is relatively heavy
• Glass is fragile so easily broken.
• Release alkali to aqueous preparation
TYPES OF GLASS:
Type I ( Neutral or Borosilicate Glass)
Type II ( Treated Soda lime glass)
Type III ( Soda lime glass)
Type IV ( General purpose soda lime glass)
 TYPE I GLASS
• Least reactive.
more sensitive• Higher ingredients and processing cost therefore used for
pharmaceutical products such as parenteral or blood products.
• Mostly ampoules and vials are made up of Type I glass.
 Type II glass:
pe I. Higher chemical resistance but not as much as ty
 Cheaper than Type I.
 Acceptable for most products accept blood products and
aqueous pharmaceutical with a pH less than 7
Type III glass
 Have similar composition and are distinguished from each
other on the basis of their hydraulic resistance
 it has average or slight better than average resistance and is
suitable for non- aqueous parenterals and non parenteral
products.


Type III glass containers are normally dry
sterilized before being filled.
 Type IV glass:
lowest hydraulic resistance and is suitable for solid
products, some liquids and semi solids and not for
parenteral.
Mr. Kailash Vilegave 58
1. Glass:
• Highly Resistant Borosilicate Glass
• Treated Soda lime Glass
• Regular Soda Lime Glass
• N.P (Non-parenteral) Glass
Type 4 is not used for parenteral packaging,
others all are used for parenteral packaging.
 Plastic
 Thermoplastic polymers have been established as
packaging materials for sterile preparations such
60
as large-volume parenteral's,
solutions and increasingly,
ophthalmic
small-volume
parenteral's.
 Three principal problem areas exist in using these
materials:
1. Permeation of vapours and other molecules in either
direction through the wall of the plastic container.
2. Leaching of constituents from the container to the product.
3. Sorption(absorption and/or adsorption) of drug
molecules or ions on the plastic materials.
 Plastic polymers used for parenteral
packages include polyvinylchloride (PVC) and
polyolefin.
 PVC is flexible and nonrigid.
 Polyolefin is semirigid; unlike PVC, it can be
stored upright.
 Both types of plastic offer several advantages
over glass, including durability, easier
storage and disposal, reduced weight, and
improved safety.
61
Mr. Kailash Vilegave 62
Plastic containers are used but they face following problems
• Permeation
• Sorption
• Leaching
• Softening
Rubber:
To provide closure for multiple dose vials, IV fluid bottles, plugs for
disposable syringes and bulbs for ophthalmic pipettes, rubber is the
material of choice.
Problems associated with rubber closures are
• Incompatibility
• Chemical instability
Closure:
• Characteristics of Good Pharmaceutical rubbers
• Good ageing qualities
• Satisfactory hardness and elasticity
• Resistance to sterilization conditions
• Impermeable to moisture and air
•
•
•
•
•
• Examples:
Butyl Rubbers
Natural Rubbers
Neoprene Rubbers
Polyisoprene rubbers
Silicone Rubbers
Tests for
Glass
Plastics and
Rubbers
Mr. Kailash Vilegave 64
WATER ATTACK TEST
• This test is used only with containers that have been
exposed to sulphur dioxide fumes under controlled humidity
conditions. Such a treatment neutralizes the surface alkali.
Now the glass becomes chemically more resistant. The
principle involved in the water attack test is to determine
whether the alkali leached form the surface of a container is
within the specified limits or not. Since the inner surface is
under test entire container (ampoule) has to be used. The
amount of acid that is necessary to neutralize the released
alkali from the surface is estimated, the leaching of alkali is
accelerated using elevated temperature for a specified time.
Methyl red indicator is used to determine the end point. The
basic is acid-base titration.
TESTS CONTAINER VOL.OF 0.02N H2SO4
Powdered glass test Type I
Type II
Type III
1.0
8.5
15.0
Water attack test
Type II(100ml or below)
Type II(above 100ml)
0.07
0.02
QUALITY CONTROL TESTS FOR GLASS CONTAINERS:
CHEMICAL RESISTANT OF GLASS CONTAINERS
A) POWDERED GLASS TEST :
It is done to estimate the amount of alkali leached from the powdered glass
which usually happens at the elevated temperatures. When the glass is
powdered, leaching of alkali is enhanced, which can be titrated with 0.02N
sulphuric acid using methyl red as an indicator .
o Step -1 : Preparation of glass specimen : Few containers
are rinsed thoroughly with purified water and dried with stream of clean
air. Grind the containers in a mortar to a fine powder and pass through
sieve no.20 and 50.
o Step -2 : Washing the specimen : 10gm of the above
specimen is taken into 250 ml conical flask and wash it with 30 ml
acetone. Repeat the washing, decant the acetone and dried after which it is
used within 48hr.
 Procedure :
10gm sample is added with 50ml of high purity water in a 250ml flask. Place
it in an autoclave at 121⁰C±2⁰C for 30min.Cool it under running water.
Decant the solution into another flask, wash again with 15ml high purity
water and again decant. Titrate immediately with 0.02N sulphuric acid
using methyl red as an indicator and record the volume.
2) HYDROLYTIC RESISTANCE OF GLASS
CONTAINERS:
• Rinse each container at least 3times with CO2 free water
and fill with the same to their filling volume. Also fill &
Cover the vials and bottles and keep in autoclave. Heat to
100⁰C for 10min and allow the steam to issue from the vent
cork. Rise the temp from 100⁰C to 121⁰C over 20min.
Maintain the temp at 121⁰C to 122⁰C for 60min.Lower the
temp from 121⁰C to 100C over 40min venting to prevent
vacuum.
• Remove the container from autoclave, cool and combine
the liquids being examined. Measure the volume of test
solution into a conical flask and titrate with 0.01M HCl
using methyl red as an indicator. Perform blank with
water and the difference between the titration represents
the volume of HCl consumed by the test solution.
3) ARSENIC TEST:
• This test is for glass containers intended for aqueous
parenterals. Wash the inner and outer surface of container
with fresh distilled water for 5min.Prep test as described in
the test for hydrolytic resistance for an adequate no.of
samples to produce 50ml.pipette out 10ml solution from
combined contents of all ampoules to the flask.
• Add 10ml of HNO3 to dryness on the water bath, dry the
residue in an oven at 130⁰C for 30min cool and add 10ml
hydrogen molybdate reagent .Swirl to dissolve and heat under
water bath and reflux for 25min. Cool to room temp and
determine the absorbance at 840nm.
• Do the blank with 10ml hydrogen molybdate. The absorbance
of the test solution should not exceed the absorbance obtained
by repeating the determination using 0.1ml of arsenic
standard solution (10ppm) in place of test soln.
4 ) THERMAL SHOCK TEST:
• Place the samples in upright position in a tray.
Immerse the tray into a hot water for a given
time and transfers to cold water bath, temp of
both are closely controlled. Examine cracks or
breaks before and after the test. The amount of
thermal shock a bottle can withstand depends on
its size, design and glass distribution. Small
bottles withstand a temp differential of 60 to
80⁰C and 1 pint bottle 30 to 40⁰C.A typical test
uses 45C temp difference between hot and cold
water.
The test bottle is filled with water and
placed inside the test chamber
A scaling head is applied and the
internal pressure automatically raised
by a series of increments each of which
is held for a set of time
The bottle can be checked for
predetermined pressure level and the
test continues unteil the container finally
bursts.
INTERNAL BURSTING PRESSURE TEST
• The most common instrument used is American glass
research increment pressure tester .
6 ) LEAKAGE TEST:
• Drug filled container is placed in a container
filled with coloured solution (due to the addition
of dye)which is at high pressure compared to the
pressure inside the glass container so that the
coloured solution enters the container if any
cracks or any breakage is present.
Place a 4ml of water in each of 12 clean vials. Close a vial with
closure and secure caps for 16 hrs.
Pierce the closure with 21 SWG hypodermic needle. Repeat the
operation 4 times for each closures.
Count the number of fragment visible on the rubber . Total
number of fragment should not be more than 10 except butyl
rubber
QUALITY CONTROL TESTS FOR RUBBERS :
• Fragmentation test for rubber closures :
QUALITY CONTROL OF CLOSURES
• PREPARATION OF SAMPLE (SOL.-A) :
Wash closures
in 0.2%w/v of
anionic
surface active
agents for
5min.
Rinse 5 times with dist
water and add 200ml water
and is subjected to
autoclave at 119 to 123⁰C
for 20 to 30min covering
with aluminum foil.
Cool and
separate
solution from
closure (soln-A)
1) STERILITY TEST:
• When treated closures are subjected to
sterilization test at 64-66⁰C and a pressure of
about 0.7 KPa for 24hr.
2) Fragmentation test
For closures for aqueous place a vol of water corresponding to the
nominal vol minus 4 ml in each of 12 clean vials.
close the vials with the ‘prepared’ closures & allow to stand for 16
hours.
For closures for dry preparations close 12 clean vials with the
‘prepared’ closures.
Using a hypodermic needle with an external diameter of 0.8 mm
inject 1 ml of water into the vial and remove 1 ml of air.
Carry out this operation 4 times with new needle each time Pass the
liquid in the vials through a filter with a pores size of 0.5 µm.
No. of fragments is NMT 10 except in the case of butyl rubber
closures where the total no. of fragments is NMT 15
3)Self – sealability test:
• This test is applicable to closures intended to be used
with water close the vials with the ‘Prepared’ closures
• For each closure, use a new hypodermic needle with an
external diameter of 0.8 mm & pierce the closure 10
times, each time at a different site.
• Immerse the vials upright in a 0.1% w/v solution of
methylene blue & reduce the external pressure by 27KPa
for 10 min.
• Restore the atmospheric pressure and leave the vials
immersed for 30 minutes. Rinse the outside of the vials.
None of the vials contains any trace of coloured solution.
4 ) PH OF AQUEOUS EXTRACT:
• 20ml of solution A is added with 0.1ml
bromothymol blue when it is added with a small
amount of 0.01M NaOH which changes the
colour from blue to yellow. The volume of NaOH
required is NMT 0.3ml and if it is done with
HCl, the volume of HCl needed should NMT
0.8ml.
5 ) LIGHTABSORPTION TEST:
• It must be done within 4hrs of preparing
solution A. It is filtered through 0.5μ filter and
its absorbance is measured at 220 to
360nm.Blank is done without closures and
absorbance is NMT 2.0.
6 ) REDUCING SUBSTANCES:
20ml of solution A is added with 1ml of 1M
H2SO4 and 20ml of 0.002M KMnO4 and boil
for 3min then cool and add 1gm of potassium
iodide which is titrated with sodium thio-
sulphate using starch as an indicator. Blank is
done and the difference between titration
volumes is NMT 0.7ml.
7 ) RESIDUE ON EVAPORATION:
• 50ml of solution A is evaporated to dryness at
105⁰C.Then weigh the residue NMT 4mg.
TEST FOR PLASTIC CONTAINERS:
• 1.For non-injectable preparations:
Leakage test / Collapsibility test : Applicable to
containers which are to be squeezed in order to
remove contents. yield 90%of its contents at
required rate of flow at ambient temp. Fill 10
containers with water Fit with closures Keep them
inverted at room temp. 24hrs No signs of leakage
CLARITY OF AQUEOUS EXTRACT:
• Clarity of aqueous extract Select unlabelled portion
from a suitable containers Cut these portions into
strips Wash it with extraneous matter by shaking with
two separate portions of distilled water Transfer to
flask – previously washed with chromic acid Rinse
with distilled water add 250ml d.w. Cover the flask
autoclave at 121Ċ, 30min Colourless , free from
turbidity
NON VOLATILE RESIDUE TEST:
• Non volatile residue test 2. Injectable
preparations: a. Leakage test b. Collapsibility
test C. Transperancy: Fill 5 containers with dil.
Suspension. The cloudiness of of the diluted
suspension in each container is detectable when
viewed through the containers as compared with
a container of the same type filled with water
Evaporate 100ml extract Allow it to dry at 105Ċ
Residue weighs not more than 12.5mg
WATER VAPOUR PERMEABILITY:
• Fill 5 containers with nominal volume of water
and heat seal the bottles with aluminium foil.
Weigh accurately each container and allow to
stand for 14 days humidity- 60±5% temp. 20Ċ
and 25Ċ. Reweigh the containers. Loss in wt in
each container is NMT 0.2% Specifications and
tests of plastic container materials: Barium
Heavy metals Tin zinc 19
Quality test is designed to achieve-
1. Consistency
2. Purity
3. Stability
And to avoid-
1. Damage
2. Contaimination
3. degradation
Laboratory Analysis
• Visual inspection
• Identification test
• Dimentional test
• Physical test
• Chemical test
• Microbiologcal test
• Permormance measurements
Mr. Kailash Vilegave 88
Thank You …. For your kind
attention

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Parenterals products by Kailash vilegave

  • 1. Parenteral Mr. Kailash Vilegave 1 Products: Mr. Kailash Vilegave M Pharm (Research Scholar) Shivajirao S jondhle college of pharmacy Asangaon.
  • 2. Mr. Kailash Vilegave 2 • Introduction • History Why parenteral? Necessary condition of parenteral • advantages/ disadvantages • Methods of preparation • Quality control • Packaging • Types of parenteral products • Routes of administration • advantages/ disadvantages • conclusion
  • 3. History: Mr. Kailash Vilegave 3  1657: first recorded injection in animals- SirChristopher Wren  1855: first subcutaneous injection of drugs using hypodermic needles - Dr.Alexander wood  1920:proof of microbial growth resulting in infections - Dr. Florence Seibert  1926: inclusion in the national formulary  1931: commercial intravenous solution(Baxter)  1946:organization of parenteral drug association  1965:development of total parenteral nutrition
  • 5. Mr. Kailash Vilegave 5 Necessities of parenteralpreparations: • Sterility (must) • Free from pyrogen (must) • Free from particulate matter • Clarity (must) • Stability (must)  Isotonicity (should)  Solvents and vehicles used must meet special purity and other standard  Do not use coloring agents  Must be prepared under aseptic conditions  Specific and highquality packaging
  • 6. DEFINATION: Mr. Kailash Vilegave 6 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 Pyrogens, fever-producing substances, primarily lipopolysaccharide product of metabolism of microorganism; they may be soluble, insoluble, or colloid.
  • 7. Advantages of the Parenteral Route Mr. Kailash Vilegave 7  T h e IV route is the fastest method for delivering systemicdrugs preferred administration in an emergencysituation  I t can provide fluids, electrolytes, and nutrition. patients who cannot take food or have serious problems withthe GI tract  I t provides higher concentration of drug to bloodstream or tissues advantageous in serious bacterial infection.  I V infusion provides a continuous amount of needed medication infusion rate can beadjusted.  t o provide more or less medication as the situation dictates Drug action can be prolonged by modifying the formulation.
  • 8. Mr. Kailash Vilegave 8 Advantages of Parenteral Administration 1. Useful for patients who cannot take drugs orally 2. Useful for drugs that require a rapid onset of action (primarily iv admin) 3. Useful for emergency situations 4. Useful for providing sustained drug delivery (implants, im depot injections) 5. Can be used for self-delivery of drugs (subcutaneous) 6. Useful for drugs that are inactivated in the GIT or susceptible to first-pass 7. Useful for injection of drugs directly into a tissue (targeted drug delivery) 8. Useful for delivering fluids, electrolytes, or nutrients (TPN) Useful for providing precise drug delivery by iv injection or infusion utilizing pharmacokinetic techniques 9. Can be done in hospitals, ambulatory infusion centers, and home health care
  • 9. Disadvantages of the Parenteral Route Mr. Kailash Vilegave 9 Traumatic injury from the insertion of needle Potential forintroducing: Toxic agents Microbes Pyrogens Impossible to retrieve if adverse reactionoccurs injected directly into thebody Correct syringe, needle, and technique must beused Rotation of injection sites with long-termuse prevents scarring and other skinchanges  can influence drugabsorption
  • 10. Mr. Kailash Vilegave 10 Disadvantages of Parenteral Administration 1. More expensive and costly to produce. 2. Potential for infection at the site of injection, thrombophlebitis, fluid overload, air embolism, extravasation, sepsis 3. Psychological distress by the patient 4. Require specialized equipment, devices, and techniques to prepare and administer drugs. 5. Potential for pain upon injection 6. Potential for tissue damage upon injection 7. Risk of needle stick injuries and exposure to blood-borne pathogens by health care worker. 8. Increased morbidity associated with long-term vascular access devices. 9. Disposal of needles, syringes, and other infusion devices requires special consideration.
  • 11. Routes of Administration of parenteral products Mr. Kailash Vilegave 11 Various types of route of administration of parenteral products are:           Subcutaneous (Hypodermis) injection Intramuscular injection Intravenous injection Intradermal injection Intra-arterial injection Intracardiac injection Intrathecal injection Intracisternal injection Peridural injection Intra- articular injection 5
  • 12. Subcutaneous Injections Mr. Kailash Vilegave 12 • Administer medications below the skin into the subcutaneous fat outside of the upper arm top of the thigh lower portion of each side of the abdomen not into grossly adipose, hardened, inflamed, or swollen tissue • Often have a longer onset of action and a longer duration of action compared with IM or IV injection Given at a 45-degreeangle  25- or 26-gauge needle, 3/8 to5/8 inch length  N o more then 1.5 ml should be injected into the site  t o avoid pressure on sensory nerves causing pain and discomfort
  • 13. Intramuscular Injections Mr. Kailash Vilegave 13 Care must be taken with deep IM injections to avoid hitting a vein, artery, or nerve  I n adults, IM injections are given into upper, outer portion of the gluteus maximus large muscle on either side of thebuttocks  Fo r 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
  • 14. Intravenous Injections or Infusions Mr. Kailash Vilegave 14 Fast-acting route because the drug goes directly intothe bloodstream often used in the emergency department and in criticalcare areas Commonly used  for fluid and electrolytereplacement  t o provide necessary nutrition to the patient who is critically ill • Intravenous (IV) injections are administered at a 15- to 20-degree angle
  • 15. Intra-arterial injection The inaction are given directly in to the artery Intracardiac injection These are given into the heart muscle or ventricle at the time of emergency only. Intrathecal injection These are given into the subachonoid space the surround the spinal cord. This route is used for spinal anesthesia. Mr. Kailash Vilegave 15
  • 16. Intracisternal injection These are given in b/w first & second cervical nerve. Used for CSF for diagnosticpurpose. Peridural injection These are given in b/w the dura matter & inner aspect of vertebra. Used for giving spinal anesthesia. Intra- articular injection These are given into the articulating ends of bones in a joint. Used for lubricating the joints. Intracerebral injection These are given into the cerebrum. Mr. Kailash Vilegave 16
  • 17. Official types of injections Mr. Kailash Vilegave 17 Injection: Liquid preparation of drug substance or drug solution e.g. insulin injection USP.  Fo r injection: Dry solid that upon addition of suitable vehicles yield solutions confirming in all respect to the requirements to the injection. e.g. Cefuroxime injection USP. Injectable emulsions: Liquid preparation of drug substance dispersed in a suitable emulsion medium. e.g. Propofol USP. Injectable suspension: Liquid preparation of solid suspended in a suitable medium. e.g. Methyl Prednisolone Acetate Suspension USP.  Fo r injectable suspension: Dry solid that upon addition of suitable vehicle yields preparation confirming in all respect to the requirements for Injectable suspension. e.g. Imipenem 11
  • 18. General requirements of parenteral preparations Mr. Kailash Vilegave 18  Stability  Sterility  Free from Pyrogens  Free from foreign particles  Isotonicity  Specific gravity  Chemical purity  Clarity (must)  Solvents and vehicles used must meet special purity and other standard  Do not use coloring agents  Must be prepared under aseptic conditions  Specific and high quality packaging
  • 19. Formulation of parenteralpro ducts Mr. Kailash Vilegave 19 wing In the preparation of parenteral products, the follo substances are added to make a stable preparation:  The active drug  Vehicles  Aqueous vehicle (e.g.water for injection, water for inj. free from CO2)  Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil)  Adjuvants  Solubilizing agents (e.g. Tweens & polysorbates)  Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol)  Buffering agents (e.g. citric acid, sodium citrate)  Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol)  Chelating agents (e.g. EDTA)  Suspending, emulsifying & wetting agents (e.g. MC, CMC)  Tonicity factor (e.g. sodium chloride, dextrose)
  • 20. Processing of parenteral preparation Mr. Kailash Vilegave 20 Following steps are involved in the processing of parenteral preparation: 1) Cleaning of containers, closures & equipments 2) Collection of materials 3) Preparation of parenteral products 4) Filtration 5) Filling the preparation in final container 6) Sealing the container 7) Sterilization 8) Evaluation of the parenteral preparation 9) Labeling & packaging
  • 21. 1. Cleaning of containers, closures & equipments: Thoroughly cleaned with detergents with tap water distilled water finally rinsed with water for injection. Mr. Kailash Vilegave 21 Rubber closures are washed with 0.5% sod. pyrophosphate in water. 2. Collection of materials: All raw material of preparation should be collect from warehouse after accurate weighed. Water for injection should be Pyrogens free. 3. Preparation of parenteral products: The parenteral preparation must be prepared in aseptic conditions. The ingredients are accurately weighed separately and dissolved in vehicle as per method of preparation to be followed. 4. Filtration: The parenteral preparation must be filtered by ba0c5t/0e2/r1i7aproof filter suH.cPh.IRaisshi,RfaimltPearrajculaindle, membranefilter. 15
  • 22. 5. Filling the preparation in final container: The filling operation is carried out under strict aseptic precautions. 6. Sealing the container: Sealing should be done immediate after filling in aseptic environment. 7. Sterilization: For thermostable substances the parenteral products are sterilized by autoclaving method at different temp. & pressure.  Heat sensitive or moisture sensitive material are sterilized by exposure to ethylene oxide or propylene oxide gas . 8. Evaluation of the parenteral preparation: The following tests are performed in order to maintain quality control: 1. Sterility test 4. Pyrogen test 2. Clarity test 3. Leakage test 5. Assay 9. Labeling & packaging.Mr. Kailash Vilegave 22
  • 23. Evaluation of Parenteral products Mr. Kailash Vilegave 23  Sterility testing  Particulate matter monitoring or Clarity Test  Faulty seal packaging or leakage test  Pyrogen testing: Rabbit Test LAL Test MAT Assay or drug content uniformity
  • 24. Sterility testing Mr. Kailash Vilegave 24 • DEFINITION: • Sterility Testing: It is a procedure carried out to detect and conform absence of any viable form of microbes in or on pharmacopeial preparation or product. • PRINCIPLE : If the microorganism are present in the product can be indicated by a turbidity in the clear medium. • OBJECTIVE OF STERILITY TESTING: For validation of sterilizationprocess. To check presence of microorganisms in preparation which are sterile. 05/0T2/1o7 prevent issuHe.P.IoRfishciRoanmtPaaramjuliinatedproduct in market. 18
  • 25. STEPS INVOLVED IN STERILITY TETESTING Mr. Kailash Vilegave 25 1) Sampling 2) Selection of the quantity of the product to be used 3) Method of sterility testing i ) METHOD 1 Membrane filtration method ii) METHOD 2 Direct inoculation method 1) Observation and interpretation Must be carried out under aseptic condition. H.P.I Rishi Ram Parajuli05/02/17 19
  • 26. Sampling Mr. Kailash Vilegave 26H.P.I Rishi Ram Parajuli • The sample must be representative of the whole of the bulk material & a lot of final containers. • MAINLY FOLLOWED BY TWO RULES:  A fixed percentage of the final container are selected.  A fixed number of container are taken independent of the lot or batch size. According to Indian Pharmacopoeia following guidelines for determining the minimum number of items are: 05/02/17 20
  • 27. Method of sterility testing Mr. Kailash Vilegave 27 Membrane filtration method (METHOD 1): Membrane filtration Appropriate for : (advantage) Filterable aqueouspreparations 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 Laminar Flow Hood 05/02/17 H.P.I Rishi Ram Parajuli 21
  • 28. Membrane filter 0.45μ porosity Mr. Kailash Vilegave 28 Filter the test solution After filtration remove the filter Cut the filter in to two halves First halves (For Bacteria) Second halves (For Fungi) Transfer in 100 ml culture media (Fluid Thioglycollate medium) Incubate at 30-350 C for not less then 7 days Transfer in 100 ml culture media (Soyabeans-Casein Digest medium) Incubate at 20-250 C for not less then 7 days 05O/0b2s/1e7rvethe growth in the media Observe the growth in the med22 ia
  • 29. Suitable for samples with small volumes volume of the product is not more than 10% of the volume of the medium suitable method for aqueous solutions, oily liquids, ointments an creams Direct inoculation of the culture medium suitable quantity of the appropriate culture medium preparation to be examinedis transferred directly into the & incubate for not less than 14 days. H.P.I Rishi Ram Parajuli Direct inoculation method (METHOD 2): Mr. Kailash Vilegave 2905/02/17 23
  • 30. Observation and results Mr. Kailash Vilegave 30 Culture media is examined during and after at the end of incubation. The following observations are possible: 1) No evidence of growth Pass the test for sterility. 2) There is evidence of growth(preserved) Re-testing is performed same no. of sample, volume & media as in original test No evidence of growth Pass the test for sterility. 3) There is evidence of growth isolate & identify the organism. Same as in preserved fail .Diff Re-testing is performed with twice no. of sample if: No evidence of growth Pass the test for sterility. T05h/02e/1r7eis evidence of growth Fail the test for sterility 24
  • 31. leakage testing Mr. Kailash Vilegave 31  T h e sealed ampoules are subjected to small cracks which occurdue 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.
  • 32. Clarity Test: Mr. Kailash Vilegave 32 Performed to ensure that the parenteral productsare free from foreign particles. Method: Visual Method, Coulter Counter Method Filtration Method Particle Size (μm) equal to or large than Max. no. o f particlesper ml 10 50 25 5 50 nill
  • 33. Pyrogen Testing Mr. Kailash Vilegave 33 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. Stable to at least 175oC; steam sterilization ineffective Water soluble; monomer unit of LPS can be 10,000 Daltons (1.8 nm) so endotoxins can easily pass through 0.22μm filters Sources: Water (main), raw materials, equipment, process environment, people, and protein if using gram negative ba cteria.
  • 34. Biological properties of endotoxin : Mr. Kailash Vilegave 34 Pyrogen elevate the circulatory levels of inflammatory cytokines which may be followed by fever, blood coagulation, hypotension Low doses of Pyrogen: asymptomatic inflammationreaction Moderate doses: fever & changes in plasma composition High doses: vasoconstriction, cardiovascular dysfunction,vasodilation, endothelium dysfunction, multiple organ failure & finally death.
  • 35. Elimination of pyrogens Mr. Kailash Vilegave 35  Dry heat sterilization : For glass wares, metal equipments, powders, waxes, oils, heat stable drugs 650 o C temp - 1 min 250 o C temp - 30 min 180 o C temp - 240 min Ultra filtration  Reverse osmosis : RO membrane is composed of cellulose acetate phthalate/ polyamide Distillation Adsorption method
  • 36. Rabbit PyrogenTest: Mr. Kailash Vilegave 36 Rabbits are used to perform this test because their body temp increases when pyrogen are introduced into their bodies by parenteral route 3 healthy adult rabbits of either sex, each weighing NLT 1.5 kg are selected Do not use anyrabbit having a temp higher than 39.8 oC o CShowing temp variation >0.2 between two successive reading in the determination of initial temp Sham test is performed within 7 days of actual test oAnimal showing temp increase over 0.6 C should beremoved from pyrogen testing
  • 37. • 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 earvein 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 Mr. Kailash Vilegave 37
  • 38. Interpretation of results Mr. Kailash Vilegave 38
  • 39. Bacterial endotoxin (LAL) test ) Mr. Kailash Vilegave 39  To detect or quantify endotoxins of gram-ve bacterial origin  Reagent: amoebocyte lysate enzyme from horseshoe crab (Limulus polyphemus or Tachypleus tridentatus).  The name of the test is also Limulus amebocyte lysate (LAL) • Mteecshtanism of LAL Test: The test is based on the gelling properties of enzyme extracted from the horseshoe crab of Limulus polyphemus. enzymes when come in contact with bacterial endotoxin Gelling Degree of Gelling related to amount of Endotoxin present 05/02/17 H.P.I Rishi Ram Parajuli 33
  • 40. • Test performance (short) Avoid endotoxin contamination – Before the test: – interfering factors should not be present – equipment should be depyrogenated the sensitivity of the lysate should be known Test: – equal Volume of LAL reagent and test solution (usually 0.1 ml of each) are mixed in a depyrogenated test-tube – Incubation at 37°C, 1 hour – remove the tube - invert at (180°) observe the result H.P.I Rishi Ram Parajuli0–5/0p2/1a7ss-failtest 34Mr. Kailash Vilegave 40
  • 41. LAL test Mr. Kailash Vilegave 41 Three differenttechniques: 1. The gel-clot technique - gel formation 2. The turbidimetric technique - the development of Turbidity after cleavage of an endogenous substrate 3. The chromogenic technique - the development of color after cleavage of a synthetic peptide- chromogen complex • Advantages of LAL test Fast - 60 minutes vs. 180 minutes Greater Sensitivity ,Less Variability Much Less False, Positives ,Much Less Expensive  Alternative to Animal Model, cheaper, particularly useful for: Radiopharmaceuticals and cytotoxic agents Blood products Water for injection 35
  • 42. MAT (Monocyte Activation Test) Mr. Kailash Vilegave 42  D u e to its greater sensitivity replaces LAL Test. Uses monocyte obtained from Human volunteeror blood bank Detects pro-inflamatory and pyrogenic contaminants. Used or Qualitative and Quantitativedetection.
  • 43. Production facilities of parenterals Mr. Kailash Vilegave 43 preparation are The production area where the parenteral manufactured can be divided into five sections:  Clean-uparea  Preparation area  Aseptic area  Quarantine area  Finishing & packaging area
  • 44.  Clean-up area: 44  It is not aseptic area.    All the parenteral products must be free from foreign particles & microorganism. Clean-up area should be withstand moisture, dust & detergent. This area should be kept clean so that contaminants may not be carried out into aseptic area.  Preparation area:   In this area the ingredients of the parenteral preparation are mixed & preparation is made for filling operation. It is not essentially aseptic area but strict precautions are required to prevent any contamination from outside.
  • 45.  Aseptic area: Mr. Kailash Vilegave 45  The parenteral preparations are filtered, filled into final container & sealed in aseptic area.  The entry of personnel into aseptic area should be limited & through an air lock.  Ceiling, wall & floor of that area should be sealed & painted.  The air in the aseptic area should be free from fibers, dust and microorganism.  The High efficiency particulate air filters (HEPA) is used for air.  UV lamps are fitted in order to maintain sterility.
  • 46.  Quarantine area:  Parenteral products are properly labelled and packed.  Properly packing is essential to provide protection against physical damage.  The labelled container should be packed incardboard or plastic container.  Ampoules should be packed in partitioned boxes Mr. Kailash Vilegave 46    After filling, sealing & sterilization the parenteral product are held up in quarantine area. Randomly samples were kept for evaluation. The batch or product pass the evaluation tests are transfer in to finishing or packaging area.  Finishing & packaging area:    
  • 47. Lyophilization or freeze drying Mr. Kailash Vilegave 47 Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase.  T h e process consists of three separate, unique, and interdependent processes; Freezing, Primary drying (sublimation),and Secondary drying (desorption).
  • 48.  T h e advantages of Lyophilizationinclude: Ease of processing a liquid, which simplifies aseptichandling Enhanced stability of a drypowder Removal of water without excessive heating of theproduct Enhanced product stability in a drystate Rapid and easy dissolution of reconstitutedproduct Disadvantages of Lyophilization include: Increased handling and processing time Need for sterile diluent uponreconstitution Cost and complexity ofequipment Mr. Kailash Vilegave 48
  • 49. Mr. Kailash Vilegave 49 Containers for parenteral 1.Glass 2. Plastic 3.Rubber closers
  • 50. SELECTION CRITERIA FOR PACKAGING MATERIAL • The product or pack contents • The application of the product • Content stability, and the need of protection form any environmental factors • Content reactivity (with relevant to the packaging material) • Acceptability of the pack to the consumer or user • The packaging process • Regulatory, legal and quality issues
  • 51. Characteristics of packaging material • They must protect the preparation from environmental conditions. • They must not be reactive with the product. • They must not impart to the product tastes or odors. • They must be nontoxic. • They must be FDA approved. • They must meet applicable tamper-resistance requirements. • They must be adaptable to commonly employed high speed packaging equipment.
  • 52. List of packages for sterile dosage forms • All types of parental ampoules vials i.v. infusion (small vol. + large vol.) s.c injections intra thecal inj. intramuscular inj. • Oral vaccines tripsules • Ophthalmic product drops ointment
  • 53. Using of packaging material vaccine storage,I)Glass - ampule, vials, syringe, SVI, LVI, dropper (primary packaging) II) Metals - vials (primary packaging) III)Rubbers – vials, syringe’s plunger, vaccine closer (primary packaging) IV)Plastics - ampule, vials, syringe, SVI, LVI, vaccine storage, dropper, tripsules, (primary packaging as well as secondary packaging) V)Fibrous mater- all types of secondary packaging VI)Films, Foils and laminates –all types of secondary packaging
  • 54. GLASS: • Glass has been widely used as a drug packaging material. • Glass is composed of sand, soda ash, limestone,& cullet. • Si, Al, Na, K, Ca, Mg, Zn & Ba are generally used into preparation of glass  Advantages • They are hygienic and suitable for sterilization • They are relatively non reactive ( depending on the grade chosen) • It can accept a variety of closures • They can be used on high speed packaging lines • They are transparent. • They have good protection power. • They can be easily labeled.  DISADVANTAGES • It is relatively heavy • Glass is fragile so easily broken. • Release alkali to aqueous preparation
  • 55. TYPES OF GLASS: Type I ( Neutral or Borosilicate Glass) Type II ( Treated Soda lime glass) Type III ( Soda lime glass) Type IV ( General purpose soda lime glass)  TYPE I GLASS • Least reactive. more sensitive• Higher ingredients and processing cost therefore used for pharmaceutical products such as parenteral or blood products. • Mostly ampoules and vials are made up of Type I glass.
  • 56.  Type II glass: pe I. Higher chemical resistance but not as much as ty  Cheaper than Type I.  Acceptable for most products accept blood products and aqueous pharmaceutical with a pH less than 7 Type III glass  Have similar composition and are distinguished from each other on the basis of their hydraulic resistance  it has average or slight better than average resistance and is suitable for non- aqueous parenterals and non parenteral products.   Type III glass containers are normally dry sterilized before being filled.
  • 57.  Type IV glass: lowest hydraulic resistance and is suitable for solid products, some liquids and semi solids and not for parenteral.
  • 59. 1. Glass: • Highly Resistant Borosilicate Glass • Treated Soda lime Glass • Regular Soda Lime Glass • N.P (Non-parenteral) Glass Type 4 is not used for parenteral packaging, others all are used for parenteral packaging.
  • 60.  Plastic  Thermoplastic polymers have been established as packaging materials for sterile preparations such 60 as large-volume parenteral's, solutions and increasingly, ophthalmic small-volume parenteral's.  Three principal problem areas exist in using these materials: 1. Permeation of vapours and other molecules in either direction through the wall of the plastic container. 2. Leaching of constituents from the container to the product. 3. Sorption(absorption and/or adsorption) of drug molecules or ions on the plastic materials.
  • 61.  Plastic polymers used for parenteral packages include polyvinylchloride (PVC) and polyolefin.  PVC is flexible and nonrigid.  Polyolefin is semirigid; unlike PVC, it can be stored upright.  Both types of plastic offer several advantages over glass, including durability, easier storage and disposal, reduced weight, and improved safety. 61
  • 62. Mr. Kailash Vilegave 62 Plastic containers are used but they face following problems • Permeation • Sorption • Leaching • Softening Rubber: To provide closure for multiple dose vials, IV fluid bottles, plugs for disposable syringes and bulbs for ophthalmic pipettes, rubber is the material of choice. Problems associated with rubber closures are • Incompatibility • Chemical instability Closure:
  • 63. • Characteristics of Good Pharmaceutical rubbers • Good ageing qualities • Satisfactory hardness and elasticity • Resistance to sterilization conditions • Impermeable to moisture and air • • • • • • Examples: Butyl Rubbers Natural Rubbers Neoprene Rubbers Polyisoprene rubbers Silicone Rubbers
  • 65. WATER ATTACK TEST • This test is used only with containers that have been exposed to sulphur dioxide fumes under controlled humidity conditions. Such a treatment neutralizes the surface alkali. Now the glass becomes chemically more resistant. The principle involved in the water attack test is to determine whether the alkali leached form the surface of a container is within the specified limits or not. Since the inner surface is under test entire container (ampoule) has to be used. The amount of acid that is necessary to neutralize the released alkali from the surface is estimated, the leaching of alkali is accelerated using elevated temperature for a specified time. Methyl red indicator is used to determine the end point. The basic is acid-base titration.
  • 66. TESTS CONTAINER VOL.OF 0.02N H2SO4 Powdered glass test Type I Type II Type III 1.0 8.5 15.0 Water attack test Type II(100ml or below) Type II(above 100ml) 0.07 0.02
  • 67. QUALITY CONTROL TESTS FOR GLASS CONTAINERS: CHEMICAL RESISTANT OF GLASS CONTAINERS A) POWDERED GLASS TEST : It is done to estimate the amount of alkali leached from the powdered glass which usually happens at the elevated temperatures. When the glass is powdered, leaching of alkali is enhanced, which can be titrated with 0.02N sulphuric acid using methyl red as an indicator . o Step -1 : Preparation of glass specimen : Few containers are rinsed thoroughly with purified water and dried with stream of clean air. Grind the containers in a mortar to a fine powder and pass through sieve no.20 and 50. o Step -2 : Washing the specimen : 10gm of the above specimen is taken into 250 ml conical flask and wash it with 30 ml acetone. Repeat the washing, decant the acetone and dried after which it is used within 48hr.  Procedure : 10gm sample is added with 50ml of high purity water in a 250ml flask. Place it in an autoclave at 121⁰C±2⁰C for 30min.Cool it under running water. Decant the solution into another flask, wash again with 15ml high purity water and again decant. Titrate immediately with 0.02N sulphuric acid using methyl red as an indicator and record the volume.
  • 68. 2) HYDROLYTIC RESISTANCE OF GLASS CONTAINERS: • Rinse each container at least 3times with CO2 free water and fill with the same to their filling volume. Also fill & Cover the vials and bottles and keep in autoclave. Heat to 100⁰C for 10min and allow the steam to issue from the vent cork. Rise the temp from 100⁰C to 121⁰C over 20min. Maintain the temp at 121⁰C to 122⁰C for 60min.Lower the temp from 121⁰C to 100C over 40min venting to prevent vacuum. • Remove the container from autoclave, cool and combine the liquids being examined. Measure the volume of test solution into a conical flask and titrate with 0.01M HCl using methyl red as an indicator. Perform blank with water and the difference between the titration represents the volume of HCl consumed by the test solution.
  • 69. 3) ARSENIC TEST: • This test is for glass containers intended for aqueous parenterals. Wash the inner and outer surface of container with fresh distilled water for 5min.Prep test as described in the test for hydrolytic resistance for an adequate no.of samples to produce 50ml.pipette out 10ml solution from combined contents of all ampoules to the flask. • Add 10ml of HNO3 to dryness on the water bath, dry the residue in an oven at 130⁰C for 30min cool and add 10ml hydrogen molybdate reagent .Swirl to dissolve and heat under water bath and reflux for 25min. Cool to room temp and determine the absorbance at 840nm. • Do the blank with 10ml hydrogen molybdate. The absorbance of the test solution should not exceed the absorbance obtained by repeating the determination using 0.1ml of arsenic standard solution (10ppm) in place of test soln.
  • 70. 4 ) THERMAL SHOCK TEST: • Place the samples in upright position in a tray. Immerse the tray into a hot water for a given time and transfers to cold water bath, temp of both are closely controlled. Examine cracks or breaks before and after the test. The amount of thermal shock a bottle can withstand depends on its size, design and glass distribution. Small bottles withstand a temp differential of 60 to 80⁰C and 1 pint bottle 30 to 40⁰C.A typical test uses 45C temp difference between hot and cold water.
  • 71. The test bottle is filled with water and placed inside the test chamber A scaling head is applied and the internal pressure automatically raised by a series of increments each of which is held for a set of time The bottle can be checked for predetermined pressure level and the test continues unteil the container finally bursts. INTERNAL BURSTING PRESSURE TEST • The most common instrument used is American glass research increment pressure tester .
  • 72. 6 ) LEAKAGE TEST: • Drug filled container is placed in a container filled with coloured solution (due to the addition of dye)which is at high pressure compared to the pressure inside the glass container so that the coloured solution enters the container if any cracks or any breakage is present.
  • 73. Place a 4ml of water in each of 12 clean vials. Close a vial with closure and secure caps for 16 hrs. Pierce the closure with 21 SWG hypodermic needle. Repeat the operation 4 times for each closures. Count the number of fragment visible on the rubber . Total number of fragment should not be more than 10 except butyl rubber QUALITY CONTROL TESTS FOR RUBBERS : • Fragmentation test for rubber closures :
  • 74. QUALITY CONTROL OF CLOSURES • PREPARATION OF SAMPLE (SOL.-A) : Wash closures in 0.2%w/v of anionic surface active agents for 5min. Rinse 5 times with dist water and add 200ml water and is subjected to autoclave at 119 to 123⁰C for 20 to 30min covering with aluminum foil. Cool and separate solution from closure (soln-A)
  • 75. 1) STERILITY TEST: • When treated closures are subjected to sterilization test at 64-66⁰C and a pressure of about 0.7 KPa for 24hr.
  • 76. 2) Fragmentation test For closures for aqueous place a vol of water corresponding to the nominal vol minus 4 ml in each of 12 clean vials. close the vials with the ‘prepared’ closures & allow to stand for 16 hours. For closures for dry preparations close 12 clean vials with the ‘prepared’ closures. Using a hypodermic needle with an external diameter of 0.8 mm inject 1 ml of water into the vial and remove 1 ml of air. Carry out this operation 4 times with new needle each time Pass the liquid in the vials through a filter with a pores size of 0.5 µm. No. of fragments is NMT 10 except in the case of butyl rubber closures where the total no. of fragments is NMT 15
  • 77. 3)Self – sealability test: • This test is applicable to closures intended to be used with water close the vials with the ‘Prepared’ closures • For each closure, use a new hypodermic needle with an external diameter of 0.8 mm & pierce the closure 10 times, each time at a different site. • Immerse the vials upright in a 0.1% w/v solution of methylene blue & reduce the external pressure by 27KPa for 10 min. • Restore the atmospheric pressure and leave the vials immersed for 30 minutes. Rinse the outside of the vials. None of the vials contains any trace of coloured solution.
  • 78. 4 ) PH OF AQUEOUS EXTRACT: • 20ml of solution A is added with 0.1ml bromothymol blue when it is added with a small amount of 0.01M NaOH which changes the colour from blue to yellow. The volume of NaOH required is NMT 0.3ml and if it is done with HCl, the volume of HCl needed should NMT 0.8ml.
  • 79. 5 ) LIGHTABSORPTION TEST: • It must be done within 4hrs of preparing solution A. It is filtered through 0.5μ filter and its absorbance is measured at 220 to 360nm.Blank is done without closures and absorbance is NMT 2.0.
  • 80. 6 ) REDUCING SUBSTANCES: 20ml of solution A is added with 1ml of 1M H2SO4 and 20ml of 0.002M KMnO4 and boil for 3min then cool and add 1gm of potassium iodide which is titrated with sodium thio- sulphate using starch as an indicator. Blank is done and the difference between titration volumes is NMT 0.7ml.
  • 81. 7 ) RESIDUE ON EVAPORATION: • 50ml of solution A is evaporated to dryness at 105⁰C.Then weigh the residue NMT 4mg.
  • 82. TEST FOR PLASTIC CONTAINERS: • 1.For non-injectable preparations: Leakage test / Collapsibility test : Applicable to containers which are to be squeezed in order to remove contents. yield 90%of its contents at required rate of flow at ambient temp. Fill 10 containers with water Fit with closures Keep them inverted at room temp. 24hrs No signs of leakage
  • 83. CLARITY OF AQUEOUS EXTRACT: • Clarity of aqueous extract Select unlabelled portion from a suitable containers Cut these portions into strips Wash it with extraneous matter by shaking with two separate portions of distilled water Transfer to flask – previously washed with chromic acid Rinse with distilled water add 250ml d.w. Cover the flask autoclave at 121Ċ, 30min Colourless , free from turbidity
  • 84. NON VOLATILE RESIDUE TEST: • Non volatile residue test 2. Injectable preparations: a. Leakage test b. Collapsibility test C. Transperancy: Fill 5 containers with dil. Suspension. The cloudiness of of the diluted suspension in each container is detectable when viewed through the containers as compared with a container of the same type filled with water Evaporate 100ml extract Allow it to dry at 105Ċ Residue weighs not more than 12.5mg
  • 85. WATER VAPOUR PERMEABILITY: • Fill 5 containers with nominal volume of water and heat seal the bottles with aluminium foil. Weigh accurately each container and allow to stand for 14 days humidity- 60±5% temp. 20Ċ and 25Ċ. Reweigh the containers. Loss in wt in each container is NMT 0.2% Specifications and tests of plastic container materials: Barium Heavy metals Tin zinc 19
  • 86. Quality test is designed to achieve- 1. Consistency 2. Purity 3. Stability And to avoid- 1. Damage 2. Contaimination 3. degradation
  • 87. Laboratory Analysis • Visual inspection • Identification test • Dimentional test • Physical test • Chemical test • Microbiologcal test • Permormance measurements
  • 88. Mr. Kailash Vilegave 88 Thank You …. For your kind attention