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Preparation of large volume and small volume parenteral
1. Large and Small Volume
Parenteral
Mr. Sangram Maskar.
Ashokrao mane college of Pharmacy, Peth Vadgaon.
2. Parenteral
The term of Parenteral derived from Greek words:
Para means : Outside
Enteron: Intestine
Denotes route of administration other than Oral route
Sterile
3. Introduction
Definition Of Large Volume Parenteral:
The large Volume solution applies to an Injection that is intended for
intravenous use and is packed in container holding 100 mL or more
(As per USP).
“LVP”s Means sterilized aqueous phase drug products packed in
single dose container with a capacity of 100 mL or More.
Definition Of Small Volume Parenteral: An Injection that is packed
in container labeled as containing 100 mL or less.
5. Parameter SVP LVP
Volume 100 mL or less 101-1000 mL
Routes IV, IM and SC IV-LVP & Non IV-LVP
Dosage Unite Single or Multiple Single
Perseverative Used Not used
Buffer Used Not used
Formulation
Solution, Emulsion &
Suspension
Solution and O/W
nutrient emulsion
Isotonicity Not essential Must
6. GENERAL PROCEDURE
Dispending of Material
Cleaning and Washing of Container, Closures
Preparation of Solution
Sterilization (Filtration)
Filling
Packaging
7. Formulation of parenteral product
In preparation of Parenteral product the following substance are
added to make stable preparation:
The Active drug
Vehicles
• Aqueous vehicles (Water for Injection, Water for Injection free from
Co2)
• Non aqueous vehicles ( Ethyl alcohol, propylene glycol, almond oil)
Antimicrobial Preservative:
• Maintain the stability of the product during storage
• e.g Chlorobutanol 0.5%
8. pH Buffer system Conc %
3.5-5.7 Acetic acid - acetate 0.22
2.5-6.0 Citric acid- citrate 0.5
6.0-8.2
Phosphoric acid –
phosphate
0.8-2
8.2-10.2
Glutamic acid-
Glutamate
1-2
Buffer:
Added to maintain pH results in stability of drug against hydrolytic
degradation or enhance the solubility of drug in solution.
9. Antioxidant:
• Antioxidant function by preferentially with molecule Oxygen and minimize or
terminate the free radical auto-oxidation
e.g. Reducing agent : Ascorbic acid,0.002-0.1%, Thiourea 0.005 %
Tonicity Adjuster:
• Electrolytes : Nacl
• Non electrolytes: Dextrose Injection 5 %
• Tonicity can measurement by “Osmometer”
Other Ingredient:
Bulking agent: For freeze dried preparation eg Mannitol, dextrose, Lactose sucrose.
Suspending agent: Carboxy methyl cellulose, sorbitol
Emulsifying agent: Polysorbate 80
12. Production Facilities of Parenterals:
The production area where the parenteral preparations
are manufactured can be divided into five section:
Clean up area:
• It is not aseptic area
• All the parenteral products must be free from foreign particles and
microorganism
• Clean up area should be withstand moisture, dust & detergent.
• This area should be kept clean so that contamination may not carried out into
aseptic area.
13. Preparation area:
• In this area the ingredients of the paracentral preparation are mixed &
preparation is made for filling operation.
• It is not essentially aseptic area but precaution are required to prevent ant
contamination from outside.
Aseptic area:
• The parenteral preparation are filtered filled into final container & sealed
should be in aseptic area.
• The entry of personal into aseptic area should be limited & through an
air lock.
• Celling, wall & floor of that area should be sealed.
14. • The air in the aseptic area should be free from fiber, dust & microorganism.
• The High efficiency particulate air filter (HEPA) is used for air.
• UV lamp are fitted in order to maintain sterility.
Clean Area
Classification (0.5
um particles/ft3 )
ISO
Designation
> 0.5 µm particles/m3
Microbiological Active Air
Action Level sc (cfu/m3 )
Microbiological
Settling Plates
Action Level sc,d
(diam. 90mm; cfu/4
hours)
100 5 3,520 Less than 1 Less than 1
1000 6 3,5200 7 3
10,000 7 3,52000 10 5
1,00000 8 35,20,000 100 50
15. Quarantine area:
• After filling, sealing & sterilization the parental product are held up in quarantine area.
• Randomly samples were kept for evaluation.
• The batch or product pass the evaluation tests are transfer into finishing or packaging
area.
Finishing & packaging area:
• Parenteral products are properly labelled and packed.
• Properly packing is essential to provide protection against physical damage.
• Ampoules should be packed in partition boxes.
16. Criteria for parenterals
Raw Material testing
In process testing
Semi finished testing
Finished product testing
17. Chemical :
• Physical testing
• Color , Appearance, Clarity.
• Analytical testing
• PH test
• Assay test
• Relative substance, Impurities , Particulate matter, Viscosity, Density, Specific
Gravity, Fill volume, Moisture content, Leak test.
Biological testing
Sterility test
BET
Bioburden test
18. Assay :
• Assay is performed according to method given in the monograph of that parental
preparation in Pharmacopoeia.
• Assay is done to check the quantity of medication present in the parental
preparation.
Sterility Test:
• It is a procedure carried out to detect and conform absence of any viable form of
microbe in or on pharmacopeia preparation or product.
• Method of sterility testing
• Method 1 membrane filtration method
• Bubble point test
• WIT
19. Method 2 Direct inoculation method
• Suitable for samples with small volumes.
• Suitable method for aqueous solution and oily liquids.
• Direct Inoculation of the culture medium suitable quantity to be
examined is transferred directly into the appropriate culture medium &
incubate for not less than 14 days.
20. Clarity Test:
• Particulate matter is defined as unwanted mobile insoluble matter other
than gas bubble present in the product.
• If the particle size of foreign matter is larger than the size of R.B.C. it can
be block the vessel.
• The permit limits of particulates matter as per I.P are follows
Particle size in µm
Maximum number of particles
per mL
10 50
25 5
50 Nil
21. Leakage test:
• The sealed ampoules are subjected to small cracks which occur due
to rapid temperature changes or due to mechanical shocks.
• Filled sealed ampoules.
• Dipped in 1% methyl blue solution under negative pressure in
Vacuum chamber.
• Vacuum released colored enter the ampoules
• Defective sealing
22. Pyrogen test:
• Pyrogen = ‘Pyro” (Greek = Fire) + “Gen” (Greek = Beginning)
• Fever production, metabolic by-product of microbial growth and death.
• Bacterial Pyrogens are called “Endotoxins” Gram negative bacteria produce
more potent endotoxin than gram positive and fungi.
• Limulus amebocyte lysate (LAL) test another method for the determination of
pyrogenic endotoxins.
• In this method, the test solution is combined a cell lysate from the amebocyte
(Blood cell) of horse shoe crab
• Any endo toxin that might be present will be coagulated with protein fraction
of amebocyte & results in the formation of gel.
• This consider to be simple, Rapid and greater sensitivity that the rabbit test.
23. Stability (Reference Q1A R1)
Study Long term Intermediate Accelerated
Storage condition
(For Room temp product)
25°C ± 2°C/60% RH ± 5%
RH
or
30°C ± 2°C/65% RH ± 5%
RH
30°C ± 2°C/65% RH ± 5%
RH
40°C ± 2°C/75% RH ± 5%
RH
Minimum time period
covered by data at
submission
12 months 6 months 6 months
Storage condition (For 2 to
8 °C Product)
5°C ± 3°C NA
25°C ± 2°C/60% RH ± 5%
RH
Minimum time period
covered by data at
submission
12 months NA 6 months
Storage condition (For
freezer Product)
- 20°C ± 5°C NA NA
Minimum time period
covered by data at
submission
12 months NA NA
