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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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• 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)

History of parenterals :

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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

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 Test

General Use

I

II

III

NP

Highly resistant

Borosilicate

Treated Soda Lime glass

Soda lime glass

General purpose Soda lime

Powdered Glass

Water Attack

Powdered Glass

Powdered Glass

Buffered and unbuffered aqueous solutions All other uses

Buffered aqueous solutions pH<7.0, Dry powders, Oleaginous solutionsDry powders, Oleaginous solutions

Not for Parenterals. For tablets, oral solutions and suspensions, ointments and external liquids

Plastic containers : Closures :

Thermoplastic

ThermosettingPolyethylene (Polyethene)High Density

Polyethene Polyvinyl chloride (PVC)

Poly methyl methacrylate Polystyrene

Polypropylene

Polyamides

Polycarbonates

Phenol Formaldehyde

Urea Formaldehyde

Melamine Formaldehyde

Pharmaceutical rubbers Butyl Rubbers

Natural Rubbers

Neoprene Rubbers

Polyisoprene rubbers

Silicone Rubbers

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