It mainly contains the deifnation,routes of adminstration and Evaluation of Parenteral Products.

1. Parenteral
Products:
Rishi Ram Parajuli
Department of PAQA
M. Pharm (2nd
Sem)
16HMPA03
H.P.I Rishi Ram Parajuli05/02/17 1

2. DEFINATION:
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.
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3. Advantages of the Parenteral Route
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
Drug action can be prolonged by modifying the formulation.
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4. Disadvantages of the Parenteral Route
Traumatic injury from the insertion of needle
Potential for introducing:
Toxic agents
Microbes
Pyrogens
Impossible to retrieve if adverse reaction occurs
injected directly into the body
Correct syringe, needle, and technique must be used
Rotation of injection sites with long-term use
prevents scarring and other skin changes
can influence drug absorption
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5. Routes of Administration of parenteral
products
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
 Intracerebral injectionH.P.I Rishi Ram Parajuli05/02/17 5

6. Subcutaneous Injections
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
H.P.I Rishi Ram Parajuli
• 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
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7. Intramuscular Injections
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
H.P.I Rishi Ram Parajuli
• 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
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8. Intravenous Injections or Infusions
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
H.P.I Rishi Ram Parajuli
• Intravenous (IV) injections are
administered at a 15- to 20-degree
angle
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9. Intra-arterial injection
Intracardiac injection
Intrathecal injection
These are given into the subachonoid space the
surround the spinal cord. This route is used for
spinal anesthesia.
H.P.I Rishi Ram Parajuli
These are given into the heart muscle or
ventricle at the time of emergency only.
The inaction are given directly in to the artery
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10. Intracisternal injection
These are given in b/w first & second cervical nerve.
Used for CSF for diagnostic purpose.
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.
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11. Official types of injections
Injection: Liquid preparation of drug substance or drug
solution e.g. insulin injection USP.
For 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.
For 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 and Cilastatin injectable suspension USP.H.P.I Rishi Ram Parajuli
05/02/17 11

12. General requirements of parenteral preparations
 Stability
 Sterility
 Free from Pyrogens
 Free from foreign particles
 Isotonicity
 Specific gravity
 Chemical purity
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13. Formulation of parenteral products
In the preparation of parenteral products, the following
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)
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14. Processing of parenteral preparation
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
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15. 1. Cleaning of containers, closures & equipments: Thoroughly cleaned with
detergents with tap water distilled water finally rinsed
with water for injection.
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
bacteria proof filter such as, filter candle, membrane filter.H.P.I Rishi Ram Parajuli05/02/17 15

16. 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 2. Clarity test 3. Leakage test
4. Pyrogen test 5. Assay
9. Labeling & packaging.H.P.I Rishi Ram Parajuli05/02/17 16

17. Evaluation of Parenteral products
 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
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18. Sterility testing
• 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 sterilization process.
To check presence of microorganisms in preparation which are
sterile.
To prevent issue of contaminated product in market.H.P.I Rishi Ram Parajuli05/02/17 18

19. STEPS INVOLVED IN STERILITY TE TESTING
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.
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20. Sampling
• 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.
H.P.I Rishi Ram Parajuli
According to Indian Pharmacopoeia following guidelines for
determining the minimum number of items are:
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21. Method of sterility testing
Membrane filtration method (METHOD 1):
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 Laminar
Flow Hood
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22. 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) 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
Observe the growth in the media Observe the growth in the media05/02/17 22

23. 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
preparation to be examined is
transferred directly into the
appropriate culture medium &
incubate for not less than 14 days.
H.P.I Rishi Ram Parajuli
Direct inoculation method (METHOD 2):
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24. Observation and results
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.
There is evidence of growth Fail the test for sterility05/02/17 24

25. leakage testing
The sealed ampoules are subjected to small cracks which occur
due to rapid temperature changes or due to mechanical shocks.
Vials & bottles are not suitable for this test because the sealing
material used is not rigid.
H.P.I Rishi Ram Parajuli
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
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26. Clarity Test:
Performed to ensure that the parenteral products are
free from foreign particles.
Method: Visual Method,
Coulter Counter Method
Filtration Method
H.P.I Rishi Ram Parajuli
Particle Size (μm) equal to
or large than
Max. no. o f particles per
ml
10 50
25 5
50 nill
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27. Pyrogen Testing
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 175o
C; 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 bacteria.
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28. Biological properties of endotoxin :
Pyrogen elevate the circulatory levels of inflammatory
cytokines which may be followed by fever, blood coagulation,
hypotension
Low doses of Pyrogen: asymptomatic inflammation reaction
Moderate doses: fever & changes in plasma composition
High doses: cardiovascular dysfunction, vasodilation,
vasoconstriction, endothelium dysfunction, multiple organ
failure & finally death.
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29. Elimination of pyrogens
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
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30. Rabbit Pyrogen Test:
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 any rabbit
having a temp higher than 39.8 o
C
Showing temp variation >0.2 o
C between two successive
reading in the determination of initial temp
Sham test is performed within 7 days of actual test
Animal showing temp increase over 0.6 o
C should be removed
from pyrogen testing
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31. • 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
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32. Interpretation of results
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33. Bacterial endotoxin (LAL) test )
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)
test
H.P.I Rishi Ram Parajuli
• Mechanism 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
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34. • 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
– pass-fail test H.P.I Rishi Ram Parajuli05/02/17 34

35. LAL test
Three different techniques:
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
H.P.I Rishi Ram Parajuli
• 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
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36. MAT (Monocyte Activation
Test)
Due to its greater sensitivity replaces LAL Test.
Uses monocyte obtained from Human volunteer or
blood bank
Detects pro-inflamatory and pyrogenic
contaminants.
Used or Qualitative and Quantitative detection.
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37. Production facilities of parenterals
The production area where the parenteral preparation are
manufactured can be divided into five sections:
 Clean-up area
 Preparation area
 Aseptic area
 Quarantine area
 Finishing & packaging area
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38.  Clean-up area:
 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.
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39.  Aseptic area:
 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.
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40.  Quarantine area:
 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:
 Parenteral products are properly labelled and packed.
 Properly packing is essential to provide protection against
physical damage.
 The labelled container should be packed in cardboard or
plastic container.
 Ampoules should be packed in partitioned boxes
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41. Lyophilization or freeze drying
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.
The process consists of three separate, unique, and
interdependent processes;
Freezing,
Primary drying (sublimation), and
Secondary drying (desorption).
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42. The advantages of Lyophilization include:
Ease of processing a liquid, which simplifies aseptic handling
Enhanced stability of a dry powder
Removal of water without excessive heating of the product
Enhanced product stability in a dry state
Rapid and easy dissolution of reconstituted product
Disadvantages of Lyophilization include:
Increased handling and processing time
Need for sterile diluent upon reconstitution
Cost and complexity of equipment
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43. Thank you for listening me………
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