Seminar On

Small Volume Parenterals

Presented by
M. Venkata Ramana Reddy
M. Pharmacy

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A BRIEF ABOUT PARENTERALS :

• para: outside
enteron: intestine (i.e. beside the intestine)

• Any drug or fluid whose delivery does not utilize the alimentary canal for entry into body tissues.

• Drugs applied topically to the eye, ear & skin or even inhaled may be broadly interpreted as parenterals.

• Parenteral products are injected through the skin or mucous membranes into the internal body
compartments.

• These are the preparations which are given other than oral routes.

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History of parenterals :

• 1657: First recorded injection in animals - Sir Christopher Wren

• 1855: First subcutaneous injections of drugs using hypodermic
needles
Dr. Alexander Wood
• 1920s: Proof of microbial growth resulting in infections - Dr.
Florence Seibert
• 1926: inclusion in the National Formulary
• 1933: Application of freeze drying to clinical materials
• 1944: Discovery of ethylene oxide
• 1946: Organization of Parenteral drug Association.
• 1961: Development of laminar air flow concept
• 1965: Development of Total Parenteral nutrition(TPN)

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 CONTENTS

• Definition
• Introduction
• Advantages
• Disadvantages
• Routes of administration
• Formulation of product (SVP)
• Manufacture of SVP
• Packaging
• Sterilization
• Quality assurance
• Quality control
• Conclusion

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 DEFINITION

• According to USP :
“ an injection that is packaged in containers labeled as
containing 100 ml or less”

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 INTRODUCTION

• All the sterile products packaged in vials, ampoules, cartridges,

syringes, bottles or any other container that is 100ml or less fall
under the class of SVP.

• Ophthalmic products packaged in squeezable plastic containers,

although topically applied to the eye rather than administered by
injection, also fall under the classification of Small Volume Injections
(SVI) as long as the container size is 100ml or less.
• SVP aqueous solutions can be administered by intravenous route
because of local irritation.

• Small volume parenteral products can be formulated and packaged in

several ways and include a wide variety of products like :

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• Pharmaceutical products.
• Biological products.
• Diagnostic agents.
• Allergenic extracts.
• Radiopharmaceutical products.
• Dental products.
• Genetically engineered or biotechnology products.
• Liposome and lipid products.

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ADVANTAGES
• Quick onset of action

• Suitable for the drugs which are not administered by oral route

• Useful for unconscious or vomiting patients.

• Useful for patients who cannot take drugs orally

• Useful for emergency situations

• Duration of action can be prolonged by modifying formulation.

• Can be done in hospitals, ambulatory infusion centers, and home

health care

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DISADVANTAGES
• Pain on injection.

• Difficult to reverse an administered drug’s effects.

• Sensitivity or allergic reaction at the site of injection.

• Requires strict control of sterility & non pyrogenicity than other

formulation.

• Only trained person is required

• Require specialized equipment, devices, and techniques to prepare and

administer drugs.

• More expensive and costly to produce.

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 ROUTES OF
ADMINISTRATION
Three primary routes of parenteral administration are commonly employed :

• Subcutaneous
• Intramuscular
• Intravenous

Other routes :
• Intra – arterial
• Intrathecal
• Intraepidural
• Intracisternal
• Intraarticular
• Intracardial
• Intrapleural
• Intradermal

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 Formulation of SVP

Aqueous vehicle :
Water For Injection(WFI) USP :
• Highly purified water used as a vehicle for injectable preparations which will be
subsequently sterilized.
• USP requirement include not more than 10 parts per million of total solids.
• pH of 5.0 to 7.0
• WFI may prepared by either distillation or reverse osmosis.
• Stored for less than 24hr at RT or for longer times at specific temperatures.
• Should be meet USP pyrogen test
• It may not contain any added substances.
• Stored in chemically resistant tank.

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Bacteriostatic Water for Injection (BWFI) :

• This type of water used for making parenteral solutions prepared under
aseptic conditions and not terminally sterilized.

• Need to meet USP sterility test.

• It can contain an added bacteriostatic agent when in containers of 30ml or

less

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Sterile Water for Injection USP

• SWFI containing one or more suitable bacteriostatic agents.

• Multiple-dose containers not exceeding 30 ml.

• They are permitted to contain higher levels of than WFI because of the
possible leaching of glass container.

• Sterile Water for Irrigation.

• Wash wounds, surgical incisions, or body tissues.

Types of Water described in USP
Water-miscible vehicles :
• primarily to effect solubility of drugs and/or reduce hydrolysis
Non-aqueous vehicles :
Fixed oils (vegetable origin, liquid, and rancid resistance,
unsaturated, free fatty acid content)
– Peanut oil
– Corn oil
– Cotton seed oil (depo-testosterone)
– Sesame oil
– Soybean oil (source of fat in intralipid)
– Ethyl oleate
– Isopropyl myristate
 Additives in parenteral products :

Antibacterial Agents
• Required to prevent microorganism growth
• Limited concentration of agents
- Phenylmercuric nitrate and Thiomersol 0.01%
- Benzethonium chloride and benzalkonium chloride 0.01%
- Phenol or cresol 0.5%
- Chlorobutanol 0.5%

Buffers
• Added to maintain pH
• Results in stability
• Effective range, concentration, chemical effect
– Citrate and Acetate buffer
– Sodium benzoate and benzoic acid
– Sodium titrate and tartaric acid
– Phosphate buffer
 Tonicity Agents Chelating agents
• Reduce pain of injection – ethylenediamine
tetraacetic acid
• Can include buffers
- Sodium chloride
- Potassium chloride Inert
Gases
- Dextrose N2 (gentamycin
sulfate injection)
- mannitol
- sorbitol CO2 (sodium bicarbonate
injection)
Surfactants
polyoxyethylene sorbitan monooleate
sorbitan monooleate
MANUFACTURING OF SVP
 packaging

• Glass containers :

Type Description Type of General Use

Test
Highly resistant Buffered and unbuffered
I Borosilicate Powdered Glass aqueous solutions All other
uses
Treated Soda Buffered aqueous solutions
II Lime glass Water AttackpH<7.0, Dry powders,
Oleaginous solutions
III Soda lime glass Powdered Glass Dry powders, Oleaginous
solutions

NP General purpose Not for Parenterals. For

Soda lime
Powdered Glass tablets, oral solutions and
suspensions, ointments and
external liquids
 Plastic containers :
Closures : Pharmaceutica
Thermoplastic Thermosetting
Polyethylene Phenol Formaldehyde l
(Polyethene)High
Density
Urea Formaldehyde rubbers
Melamine Formaldehyde Butyl Rubbers
Polyethene Polyvinyl
chloride (PVC) Natural Rubbers
Poly methyl Neoprene Rubbers
methacrylate
Polystyrene Polyisoprene
Polypropylene
rubbers

Polyamides Silicone Rubbers

Polycarbonates
 Sealing Ampoules
• Ampoules are unique in that the primary and secondary seal
are the same.

• Ampoules are sealed by melting a portion of glass in a flame.

• Pull seal – Slow, Reliable, powder or other types with wide

opening

• Roll or Tip seal

Sealing of Bottles, Cartridges and Vials

• Primary seal consisting of a tight rubber or plastic closure

and secondary seal that holds the primary seal in place.

• Secondary seals are usually aluminum caps that are

crimped on to a thread less container.
 STERILIZATION

• Steam sterilization

• Dry heat sterilization

• Sterilization by filtration

• Gas sterilization

• Sterilization by ionizing radiation

 PREFILLED SYRINGES :

• Administration is more convenient for healthcare

professionals and end users.

• Reduction of medication errors, better dose accuracy.

• Better use of controlled drugs such as narcotics.

• easy storage and disposal.

 QUALITY ASSURANCE

• It includes :
- Material management
- Equipment and facility management
- Personnel management
- Documentation control
 QUALITY CONTROL
• STERILITY TESTING
- Membrane filtration
- Direct inoculation of culture media

membrane
filtration
Direct inoculation of the culture medium
 Pyrogen test :

• Pyrogenic - means producing fever

• Pyrogens - fever inducing substances

• Endotoxins Produced mostly by gram-negative bacteria

• Endotoxin - complex of pyrogenic lipopolysaccharide, a protein and

inert lipid.
 LAL test :
• Limulus polyphemus = horseshoe crab
• Limulus - genera of crab
• Amebocyte - crab blood cell from which
active component is derived
• Lysate - component is obtained by separating
amebocytes from the plasma and then lysing them.
• The hearts of mature crabs are
punctured and bled to collect the circulating
amebocyte blood cells.
• Since amebocytes act as activators of the coagulation
mechanism in the crab, an antiaggregating agent must be
added to inhibit aggregation.
• N-Ethylmaleimade is the most commonly

used anti- aggregant .

• LAL test is the combinationof 0.1 ml test sample
with 0.1 ml LAL reagent.
• After 1 hour incubation at 37°C, the mixture is
analyzed for the presence of a gel clot.
• The LAL test is positive, indicating the presence of endotoxin, if
the gel clot maintains its integrity after slow inversion of the test
tube containing the mixture.
 Advantages of LAL
• Greater Sensitivity
• Less Variability
• Much Less False Positives
• Much Less Expensive
• Alternative to Animal Model
• cheaper,
• more accurate than other
• is performed in the pharmaceutical laboratory
• specific for endotoxins of gram-negative origin
• particularly useful for:
– Radiopharmaceuticals and cytotoxic agents
– Products with marked pharmacological or toxicological activity in
the rabbit (e.g. insulin)
– Blood products which sometime give misleading results in the rabbit
– Water for injection where LAL test is potentially more stringent and
readily applied
 Particulate Matter :
• Unwanted mobile insoluble matter other than gas bubbles
present in the given product.
• It may be dangerous when the particle size is larger than
R.B.C. & may block the blood vessel.
• Visual method
• Coulter counter method
• Filtration method
• Light blockage method
LEAKER TEST :
• Immersing the ampoules in a dye solution
• 1% metylene blue
• 25 in (64cm) of vacuum for a minimum of 15 min.
• The vacuum on the tank is then released as rapidly as possible to
put maximum stress on weak seals.
• Defective ampoules will contain blue solution.
 conclusion

• A wide variety of devices and new methods of drug delivery

employed. Each has its advantage and disadvantages,
which have to be carefully considered by the therapist.
• One must understand and appreciate that since parenteral
medications and frequently, body fluids or come into
contact with most parenteral drug delivery devices.
• They must be free of contaminating microorganism,
harmful substances, free of pyrogenic contamination, free
of particulate matter.
• In coming future we can expect much more advance
technology in utilizing parenteral products for safety
desirable effects in human being.
REFERENCES :
• Pharmaceutical Dosage Forms. Lieberman, Herbert A. Vol. 1:
Parenteral Medications.
• Pharmaceutical Dosage Forms. Avis, Kenneth E. Vol. 2:
Parenteral Medications
• Pharmaceutical Dosage Forms. Avis, Kenneth E Vol. 3 : Parenteral
Medications
• Parenteral Quality Control. Michael J. Akers and Daniel S.
Larrimore (Marcel Dekker, second edition.1993).
• Modern Pharmaceutics. Gilbert S. Banker, Christopher T. Rhodes.
Fourth Edition.
• www.google.com
• www.pharmaceuticalonline.com