2. PARENTERAL PRODUCTS
Parenteral preparations are sterile,
pyrogen-free liquids (solutions, emulsions,
or suspensions) or solid dosage forms
containing one or more active ingredients,
packaged in either single-dose or multidose
containers.
They are intended for administration by
injection, infusion, or implantation into the
body.
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3. Classifications
Based on volume
1. Small Volume Parenteral
( = or <100ml)
Solutions
Suspensions
Emulsions
Dry powders for reconstitution
as solutions
Dry powders for reconstitution
as suspension
2. Large Volume Parenteral
(>100ml)
Hyperalimentation solution
Cardioplegic solution
Peritoneal dialysis solution
Irrigation solution
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5. 1. VEHICLES
AQUEOUS VEHICLES
Water for injection (WFI)
Sterile water for injection (SWFI)
Bacteriostatic sterile water for injection
(BWFI)
Sodium Chloride injection
Bacteriostatic Sodium Chloride injection
NON AQUEOUES VEHICLES
1. WATER MISCIBLE
Agents like Ethanol, Glycerine and Propylene
glycol are used with water for injection to
promote the solubility and stability.
2. WATER IMMISCIBLE
Fixed oils- corn oil, olive oil, arachis oil, almond
oil, soya oil, poppyseed oil, sesame oil,
cottonseed oil, peanut oil, castor oil
•Ethyl oleate
•Isopropyl myristate
•Benzyl benzoate
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6. 2. Antimicrobial Agents
Antimicrobial agents or preservatives are added to multiple dose containers to
prevent the growth of microorganisms.
Properties of antimicrobial agents used
• Compatible with other ingredients used.
• Non-toxic. Non-irritant and inert.
• Should not be absorbed by rubber or plastic closure.
• Should be thermostable.
Examples: Quaternary ammonium compounds, Phenyl mercuric nitrate,
Phenol, cresol and chlorobutanol, Benzyl alcohol, A combination of methyl
parabens and propyl parabens
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7. 3. Antioxidants
Prevents oxidative degradation of active ingredient by:-
Undergoing oxidation in place of API.
Blocks an oxidative chain reaction
Prevent oxidation by forming a complex.
Example:
Reducing agents: ascorbic acid, sodium bisulphite, sodium metabisulphite.
Blocking agent: ascorbic acid esters, butyl hydroxy toluene (BHT),
tocopherols.
Chelating agents: ethylenediamine tetra acetic acid (EDTA)
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8. 4. Buffering agent
They prevent degradation of API due to change in pH by maintaining
desired pH.
Buffers selected should not affect the pharmacological activity and solubility
of drug.
The most ideal pH of parenteral preparation is 7.4
Example:- acetate buffer, acetic acid buffer, benzoate buffer, sodium
bicarbonate buffer.
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9. 5. Surfactants / solubilizers
These are used to increase the solubility (wetting property) of the drug
or to disperse water insoluble drug.
Examples:
Propylene glycol, povidone, polysorbate 80, PEG 30, glycerine, dioctyl sodium
sulphosuccinate (DOSS)
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10. 6. Chelating agents
These inactivate heavy metals such as copper, iron, lead, mercury, chromium
etc. by forming complexes.
Examples: EDTA ( ethylene diamine tetra acetic acid) and its salts.
Sodium or potassium salt of citric acid .
7. Tonicity modifiers
Parenteral need to be isotonic with body fluids .
Depends on the amount and nature of solute present in it.
Tonicity adjustment is done by 0.9% NaCl , 2.0% Boric acid, 5.0% Dextrose.
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12. 9. WETTING AGENTS
Added to facilitate dispersion
Surfactants with HLB value in the range 7 to 9 show maximum wetting
efficiency
Usual concentration of surfactant varies from 0.05% - 0.5% depending on
the solid content of the suspension
Example-polysorbate 80, polysorbate 20, lecithin
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13. 10.EMULSIFIERS
The oils have hydrophobic surface. For their dispersion in aqueous system,
suitable emulsifying agents are essential.
eg. Natural lecithin :- advantage -it is metabolized in the same way as fat
and is not excreted via kidneys, as are many synthetic agents.
Poloxamers are also promising emulsifiers for parenteral emulsions.
Cholesterol is sometimes added to increase stability of emulsions.
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15. The following equipment's is recommended(as
per schedule-M):
Manufacturing area: -
1. Storage equipment for ampoules, vials
bottles and closures.
2. Washing and drying equipment.
3. Dust proof storage cabinet
4. Water still.
5. Mixing and preparation tanks or other
containers.
6. Mixing equipment where necessary.
7. Filtering equipment.
8. Hot air sterilizer/ Moist heat
Aseptic filling and sealing rooms –
9. Benches for filling and sealing.
10.Bacteriological filters.
11.Filling and sealing unit under laminar
flow work station.
General Room : –
12.Inspection table.
13.Leak testing table.
14.Labeling and packing benches.
15.Storage of equipment including cold
storage and refrigerators if necessary.
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21. Clean room
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WHO
(GMP)
United States
(customary)
ISO European
Commission
Grade A Class 100 ISO 5 Grade A
Grade B Class 1000 ISO 6 Grade B
Grade C Class 10 000 ISO 7 Grade C
Grade D Class 100 000 ISO 8 Grade D
An area with defined
environmental control of
particulate and microbial
contamination,
constructed and used in
such a way as to reduce
the introduction,
generation and retention
of contaminants within the
area. GRADE “A”: The local zone for high risk operations. eg. Filling zone,
stopper bowls, open ampules and vials.
GRADE “B”: In case of aseptic preparation and filling, the back
ground environment for grade “A” zone.
GRADE “C” &”D”: Clean areas for carrying out less critical stages
22. 22
(1)Class 100,000 Particle count not to
exceed a total of 100,000 particles per
cubic foot of a size 0.5μ and larger or
700 particles per foot of size 5.0μ and
larger.
(2) Class 10,000 Particle count not to
exceed a total or 10,000 particles per
cubic foot of a size 0.5μ and larger or
65-70 particles per cubic foot of a size
5.0μ and larger.
(3)Class 1,000 Particles count not to
exceed a total of 1000 particles per
cubic foot of a size 0.5μ and larger or 10
particles per cubic foot of a size 5.0μ
and larger.
(4)Class 100 Particles count not to exceed
a total of 100 particles per cubic foot of
a size 0.5μ and larger
The class is directly related to the number of particles per cubic foot of air
equal to or greater than 0.5 micron.
25. PROCESSING OF PARENTERALS
Steps invoved:
1. Cleaning of
containers,
closures and
equipments
2. Collection
of materials
3. Preparation
of parenteral
products
4. filtration
5. Filling the
preparation in
final
containers
6. Sealing the
containers
7. Sterilization
8. Evaluation
of parenteral
preparation
9. labeling and
packaging
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26. Cleaning of containers, closures and equipment
All the containers ,closures and equipment
required during the preparation of parenteral products are thoroughly
cleaned
with detergent and tap water
followed by clean distilled water
finally rinsed with water for injection.
Rubber closures are washed with
hot solution of 0.5 % sodium pyrophosphate in water.
removed from the solution, washed with water
rinsed with filtered water for injection
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27. Collection of materials
Required quantity of ingredients for formulation
are weighed and collected in the preparation room.
The raw materials should be pure.
Water for injection free from pyrogens and microorganisms
The pharmacist should decide the order of mixing and exact method of
preparation to be followed before preparing the parenteral products .
The parenteral preparation must be prepared under strict aseptic
conditions.
The ingredients are accurately weighed separately and dissolved in the
vehicle as per method of preparation to be followed.
Preparation of parenteral product
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28. • The parenteral solutions –
passed through bacteria proof filter - filter
candle, membrane filter and sintered glass
filters.
objective clarify the solution
by removing foreign particles .
• Filtration should be done under strict
aseptic condition to avoid
contamination of filtered solution,
before it is finally transferred into final
container and sealed.
Filtration
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29. Filling the preparation in final containers
On small scale --manually by using hypodermic syringe and needle .
On the large scale -- automatic filling machine.
Sterile Powders -- by individual weighing or by using automatic or semi
automatic devices.
The filtered product is filled into final container
ampoules vials transfusion bottles
single dose multidose transfusion fluids
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30. Sealing the containers
Sealing should be done immediately after filling .
Ampoules
Small scale by rotating the neck of the ampoule in the flame of Bunsen burner.
Sealing of ampoules are done by melting of the portion of the glass neck. There
are two types of sealing:-
Pull –seals
Tip-seals (bead –seals)
Large scale ampoule sealing machine is used.
The vials and transfusion bottles are sealed by
Closing its opening with rubber closures .
The rubber closures are held in place by crimping the aluminum caps
which is done manually or by mechanical means.
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31. Sterilization
The parenteral preparations should be immediately sterilized after
sealing in its final containers.
Thermostable medicament
sterilized by –
autoclaving at the temperature of
115°Cto 116°C for 30 minutes or
121°C for 20 minutes or
in hot air oven at 160°C for 2hours.
Thermolabile preparations
are sterilised by filtration through a
suitable bacteria proof filters. The
process of filtration, filling and
sealing are done under aseptic
conditions.
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32. Evaluation of parenteral preparations
Finished parenteral products are subjected to the
following tests in order to maintain quality
A)Sterility Test
B) Clarity Test
C) Leakage Test
D) Pyrogen Test
E) Assay
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33. Labelling and packaging
• After evaluation of the parenteral preparation, the ampoules, vials
and transfusion bottles are properly labelled and packed.
• The label should state:-
a) Name of the preparation
b) Quantity of the preparation
c) Mfg. Lic .no.
d) Batch no.
e) Date of manufacture
f) Date of expiry
g) Storage condition
h) Retail price
i) Manufacturer's address
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34. Blow-fill-seal (BFS) technology
Blow-fill-seal (BFS) technology is an automated process by which containers
are formed, filled, and sealed in a continuous operation.
The products can be sterile filled, which makes BFS a cost - effective
alternative for aseptic filling.
It reduced human intervention.
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36. 1. Leakage Test
Leakage test is employed to test the package integrity.
Package integrity reflects its ability to keep the product within and prevent
potential contamination from entering. Leakage test can be done by dye bath
test.
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Performed by immersing the ampules in a vacuum chamber containing dye.
(1% methylene blue)
A vacuum is created for about 15 to 30 min.
The vacuum will create high pressure on the weak points on the ampoule
seal and will also assist the passage of the dye into the leaking ampoule.
Detection: if solution appears blue it confirms leakage
37. 2. Clarity Test
Clarity testing is carried out to check the particulate matter in the
sample.
Detection: In this test transparent particles or white particles observed
against the black background and the black or dark particles observed
against the white background.
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Acceptance criteria: As per USP,
LVP: NMT 25 particles/ mL (size of 10 or more than 10 µm) & NMT 3
particles/mL (size more than 25 µm)
SVP: 6,000 particles/ mL of size 10 µm or greater & NMT 600 particles/
mL greater than 25 µm.
38. 3. Particulate matter in injections
The preparations intended for parenteral use should be free from particulate
matter and should be clear when inspected visually.
Two methods are described by USP according to the filled volume of the
product to be tested.
Large Volume Parenteral (LVP's)
a filtration followed by
microscopical examination
procedure is used.
Small Volume Parenteral (SVP's)
a light obscuration based sensor
containing electronic liquid-borne
particle counter system is used.
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39. SPECIFICATIONS
Volume of
solution
Particle size ≥ 10 μm Particle size ≥25
μm
IP / BP SVP 3000 per container 300 per container
LVP 12 per ml 2 per ml
USP SVP NMT 10,000 particles
per container
NMT 1000 particles
per container
LVP NMT 50 particles per
ml
NMT 5 particles per
ml
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40. 4. Pyrogen test.
♦ The LAL Assay is an in vitro assay used to detect the presence and concentration
of bacterial endotoxins in drugs and biological products.
♦ This test is based upon the gelling property of an enzyme, the limulus
amebocyte lysate extracted from the horse shoe crab, limulus polyphormus.
♦ The enzyme gels in the presence of bacterial endotoxin and the degree of
gelling is related to the amount of endotoxin present
A. Limulus Amebocyte Lysate (LAL) Test
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41. The test is performed using stated amounts of volumes of products,
standard, positive control, negative control of endotoxin.
The tubes are incubated at 37±1o
C for 60 ±2 minutes. When the tubes are
inverted at 180o
C angle.
formation of firm gel confirms positive reaction.
While formation of a viscous gel that doesn't maintain its integrity or
absence of a firm gel confirms negative reaction
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42. 44
This test basically involves the injection of sample solution which is to be
tested into Rabbits which are used as test animals through marginal ear
vein.
The Temperature sensing probe (Clinical Thermometer or similar probe) is
inserted into the rectal cavity of Rabbit at the depth of 7.5 cm, the test
solution must be warmed at 370 C prior to injection.
Then Rectal temperature is recorded at 1, 2, 3 hr subsequent to injection.
B. Rabbit Test
No. of rabbits Individual
temp rise (0C)
Temp rise in a
group (0C)
Test
3 rabbits 0.6 1.4 Passes
If the above
fails
3+5=8 rabbits
0.6 3.7 Passes
If above test not passes the sample is said to be pyrogenic
43. 5. Sterility test
Principle: if micro-organism are placed in a medium that provide optimum
condition of nutrition, moisture, pH, aeration, temperature, they can grow and
their presence will be indicated by the presence of turbidity in clear medium.
A number of culture media are used:
1. Thioglycolate liquid medium: used to support the growth of anaerobic
organisms. It is incubated for 7 days at 35 - 37o C
2. Soybean-casein liquid medium: to support the growth of aerobic
organisms. It is incubated for 7 days at 35 - 37o C.
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44. Membrane Filtration
method
Filtration of sample through filter 0.45
µm whose effectiveness to retain micro-
organisms has been established.
After filtration completion the
membrane is cut into 2 halves
One half is transferred into soyabean
casein digest medium (aerobic bacteria
and fungi)
- Incubated at 20-25°---NLT
seven days.
Second half is transferred into
thioglycolate medium (anaerobic
bacteria)
- Incubated at 30-35°---NLT
seven days
Direct Transfer method
Transfer the quantity of the preparation
to be examined directly into the culture
medium so that the volume of the
product is not more than 10 percent of
the volume of the medium, unless
otherwise prescribed.
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