Transcript packaging
PARENTRALS HINDU COLLEGE OF PHARMACY 1 CONTENTS • • • • • • • • • • • • Introduction Routes of administration Advantages Disadvantages Preliminary stages Formulation Manufacture Filling Packaging Sealing Sterilization Quality control 2 INTRODUCTION DEFINITION “ Introduced other than by way of the intestine” 3 A BRIEF ABOUT PARENTERALS : • para: outside enteron: intestine • Any drug or fluid whose delivery does not utilize the alimentary canal for entry into body tissues. • 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. 4 ROUTES OF ADMINISTRATION Three primary routes of parenteral administration are commonly employed : • Subcutaneous • Intramuscular • Intravenous Other routes : • Intra arterial • Intra athecal • Intra articular • Intra cardial • Intra dermal • Intra pleural • Intra spinal • Intra vascular 5 Parenteral Injection Sites subcutanously intramuscularly intravenously Subcutaneous Route • Absorption depending on blood flow – Constant & slow absorption – Prolonged effect Drugs – Insulin – Heparin Subcutaneous Injection Sites • Abdominal wall • Thigh • Deltoid area Intramuscular Route • Absorption depending on blood flow – Rapid onset & shorter duration – Shock • Drugs – Glucagons – Adrenaline Intramuscular Injection Sites Intravenous Route • • • • Rapid immediate onset Permits titration Administer slowly Drugs – Midazolam Intravenous Injection Sites • Peripheral • Central • Parentrals are classified into two types. They are 1. Small Volume Parenterals (upto 100ml) Primary uses of SVP • Therapeutic injections • Opthalmic products • Diagnostic agents • Allergenic extracts 13 2. Large Volume Parenterals (100-1000ml) Clinical Utilization of LVP • Basic Nutrition • Restoration of Electrolyte balance • Fluid replacement • Blood and blood products • Drug carriers 14 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 15 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. 16 FORMULATION 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. • It may not contain any added substances. • Stored in chemically resistant tank. 17 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 18 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. • Wash wounds, surgical incisions, or body tissues. 19 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 20 OTHER ADDITIVES Antibacterial Agents • Limited concentration of agents - Phenylmercuric nitrate and Thiomersol 0.01% • Required to prevent microorganism growth - 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 21 Tonicity Agents • Reduce pain of injection • Can include buffers Chelating agents – ethylenediamine tetraacetic acid - Sodium chloride - Potassium chloride - Dextrose Inert Gases N2 (gentamycin sulfate injection) - mannitol - sorbitol CO 2 (sodium bicarbonate injection) Surfactants polyoxyethylene sorbitan monooleate sorbitan monooleate 22 MANUFACTURING STEPS • • • • • • • • • 1.clening containers,closures & equipment 2.collection of materials 3.preparation of parentral products 4.filtration 5.filling the preparation in final containers 6.sealing the containers 7.sterilization 8.evalution 9.packing FACILITES • • • • 1.Environmental condition 2.House keeping 3.Air control 4.Surface disentfication FILLING 1. Filling of liquids A. Small volume parentrals Syringe based system Retraction device B. Large volume parentrals By gravity By pressure By vaccum 25 2. Filling of solids Scoop method Machine (Auger) method Problems Stratification Electrostatic charges Air pockets Clumping 26 Types of Filling Equipment Mechanism of filling Types of product filled Piston type (Cozzoli) Liquid products such as solutions, suspensions emulsions and solutions types of package vial, ampoules, plastic containers, bottles syringe cartridges, plastic mini bags ,, ,, Rotary chemical pump Powders Time or pressure type Auger ,, Vacuum Pressure displacement vials, bottles, plastic mini bags. ,, 27 PACKAGING • Glass containers : Type Description Type of Test Highly resistant I Borosilicate General Use Powdered Glass Buffered and unbuffered aqueous solutions All other uses Buffered aqueous solutions pH<7.0, Dry powders, Oleaginous solutions II Treated Soda Lime glass Water Attack III Soda lime glass Powdered Glass Dry powders, Oleaginous solutions NP General purpose Soda lime Powdered Glass Not for Parenterals. For tablets, oral solutions and suspensions, ointments and external liquids 28 Plastic containers : Closures : Thermoplastic Thermosetting Polyethylene (Polyethene)High Density Phenol Formaldehyde Pharmaceutical rubbers Urea Formaldehyde Butyl Rubbers Melamine Formaldehyde Natural Rubbers Polyethene Polyvinyl chloride (PVC) Poly methyl methacrylate Polystyrene Polypropylene Neoprene Rubbers Polyisoprene rubbers Silicone Rubbers Polyamides Polycarbonates 29 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. 30 SEALING 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 31 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. 32 STERILIZATION • Dry heat sterilization • Steam sterilization • Sterilization by filtration • Gas sterilization • Sterilization by ionizing radiation 33 QUALITY CONTROL Sterility testing Pyrogen test Clarity test Leakage test 34 Flow of Materials Through the Production Department Ingredients Vehicles Solutes Processing Equipment Container Components Compounding of Product Cleaning Filtration Solution Sterilization Filling Sealing Packaging Cleaning Sterilization 35 Product storage 1. STERILITY TESTING A . Membrane filtration 36 B. Direct inoculation of culture media 37 2. PYROGEN TEST A. Invivo test (Rabbit 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. 38 The result of pyrogen test No.of Rabbits Individual Tempt. Temperature rise Result rise (°c) in group (°c) 3 rabbits 0.6 1.4 Passes If above not passes 3+5 = 8 rabbits 0.6 3.7 Passes If above test not passes perform the test again If above test not passes, the sample is said to be pyrogenic and the test fails 39 B. Invitro test (LAL) . Limulus polyphemus = horseshoe crab • Limulus - genera of crab • Amebocyte - crab blood cell from which active component is derived • The name of the test is also Limulus amebocyte lysate (LAL) test 40 Mechanism of LAL • The test is based on the primitive blood-clotting mechanism of the horse shoecrab enzymes located with the crab's amebocyte blood cells + endotoxins (pyrogens) ↓ incubated at 37°c initiation of an enzymatic coagulation ↓ proteinaceous gel (with in 60 mins) 41 Commercially derived LAL reagents • 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. 42 3. CLARITY TEST • 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. • It can be done by the following methods. A. Visual method B. Light scattering & Light absorption C. Light blockage method D. Coulter current method 43 4. Leakage Test A. Dye test (Ampoules) • Immersing the ampoules in a dye solution • 1% metylene blue solution • 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. B. Spark tester probe (Vials & Bottles) • Water hammer sound • When the space is evacuated then it releases blue spark 44 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. • Parenteral dosage forms differ from all other drug dosage forms because they are injected directly into body tissues through primary protective systems of human body the skin and mucous membranes. • 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. 45 REFERENCES • Theory and practice of Industrial pharmacy. Lieberman, Herbert A. Vol.1.Lachman, Third edition • Pharmaceutical Dosage Forms. Avis, Kenneth E. Vol. 2: Parenteral Medications • Pharmaceutical Dosage Forms. Avis, Kenneth E Vol. 3 : Parenteral Medications • Pharmaceutical packaging technology. D A Deam , E R Evans, I H Hall • Modern Pharmaceutics. Gilbert S. Banker, Christopher T. Rhodes. Fourth Edition. • www.pharmaceuticalonline.com 46 47