Large & Small Volume Parenteral

Large & Small Volume Parenteral

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  LARGE & SMALLVOLUME PARENTERAL Submitted to Dr. Dhananjay Kumar Singh Assistance Professor School of Health Science Presented by Mr. Sree Prakash Pandey (CUSB2006122010) M.Pharm 1st year (1st Sem) Department – Pharmacuetics School of Health Science Central University of South Bihar, Gaya 1
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  CONTENTS Introduction-Definition Advantages & Disadvantage Generalrequirements for Parenteral Classification of Parenteral preparation Physiological consideration Formulations consideration Manufacturing process Evaluation References 2
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  Introduction DEFINITION:  Parenteral preparationsare pyrogen-free preparations intended to be administered other than oral routes.  The term parenteral is derived from two Greek words, Para outside ; enteron intestine (i.e. beside the intestine).  An injection is a preparation in the from of sterile drug, solution, suspension or emulsion intended for parenteral administration either directly or after constituting or diluting prior to administration.  Route of administration for parenteral such as – i.v. i.m. s.c. commonly used. 3
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  Advantages  Quick onsetof action.  Useful for unconscious or vomiting patients.  Duration of action can be prolonged by modifying formulation.  Suitable for nutritive like glucose and electrolyte.  Suitable for the drugs which are inactivated in GIT or HCL (GI fluid) Disadvantage Once injected can not controlled (retreat). Injection may cause pain at the site of injection. Only trained person is required. Difficult to save patient if overdose. Sensitivity or allergic reaction at the site of injection. 4
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  GENERAL REQUIREMENTS FORPARENTERAL DOSAGE FORM 1. Container: Containers used for packing parental are classified as –  Well -closed containers: A well- closed container protects the contents from loss during transportation, handling, storage or sale.  Single dose containers: These container are used to supply only one of medicament and hold generally Parenteral products. E.g. Ampoules & Vials  Multidose containers: Hold a quantity of the material that will be used as two or more doses. E.g. multiple dose vial or the plastic tablet bottles. 5
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  2. TYPES OFGLASS USED IN PARENTERALS Glass type General description Test method Uses TYPE 1 Highly-resistant borosilicate glass Powdered Glass test For buffered and unbuffered aqueous solution , powders TYPE 2 Treated (sulphur dioxide fumes) soda lime glass Water attack test For buffered aqueous solution with ph below 7 and for dry powders TYPE 3 Soda lime glass Powdered Glass test For dry powders and oleaginous solutions, not for aqueous preparations 6
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  3. Closures • Closuresfor parenteral preparation containers should be equipped with a firm seal to prevent entry of microorganisms and other contaminants. • They should not be made of components that react with the contents , nor should they allow foreign substances to diffuse into the preparation. 7
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  4. Aseptic area: •The parenteral preparation are filtered , filled into final container & sealed should be in aseptic area. • Ceiling, wall & floor of that area should be sealed & painted. • The High Efficiency Particulate Air filters (HEPA) is used for air . • The air in the aseptic area should be free from fibers, dust & microorganism. Classification of Clean Room 8 Grade Maximum permitted no of particles/m3 At Rest At Operation 0.5µm 5µm 0.5µm 5µm A 3,520 20 3,520 20 B 3,520 29 352,000 2,900 C 352,000 2,900 3,520,000 29,000 D 3,520,000 29,000 Not defined Not defined
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  Classifications of Parenteralpreparation Based on volume classified parenteral into two parts such as :  Small Volume Parenterals (SVP) : According to U.S.P “an injection that is packaged in containers labeled as containing 100 ml or less”.  Large Volume Parenterals (LVP) : They are given in multi-dose and volume 100ml or more than . Generally, these provides electrolytes nutrition to the body. E.g. dextrose(5-50%), body fluids. 9
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  COMPARISON Parameters SVP LVP Volume≤ 100 ml 101- 1000ml Route i.m, i.v, s.c. i.v. Dosage unit Single / multiple Multiple Preservative Used Not used Buffer Used Not used Isotonicity Not essential Must Uses As therapeutic agent, diagnostic agent As Nutrition, Detoxification, Aid during surgery. 10
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  PHYSIOLOGICAL CONSIDERATION 1. pH:The main step in selection of pH in a formulation. For the maximum Physiological acceptability, the target pH is approx pH 7.4. 2. Buffer: Important for parenteral dosage form because due to alteration of pH in formulation. E.g, Potassium phosphate, tartaric acid, dibasic sodium benzoate. 3. Tonicity: All parenteral product should be isotonic ,due to risk of hemolysis. Tonicity adjustment agent such as gelatin, manitol, sorbitol, NaCl etc. 4. Stabilizer: To prevent the degradation of the drug substance i.e. glycine , sodium saccharine, etc. 5. Antimicrobial: Against microbes and prevent i.e. Benzalkonium chloride, Benzethonium chloride, Propyl paraben, etc. 11
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  FORMULATIONS CONSIDERATION Parenteral preparationcontains – solution, suspension, emulsion, powder of injection, gels injection. Required for parenteral preparation : 1. Active drugs 2. Solvent : i. Water : WFI, SWFI, Bacteriostatic WFI. ii. Aqueous vehicle : i.e, Ethyl alcohol, PEG iii. Non-aqueous vehicles: i.e. Fixed oils (corn oil, peanut oil) 3. Surfactants: Surface active agents enhance drug solubility to the required concentration to achieve solution clarity. e.g. Tweens, Poloxamers, Sorbiton monooleate. 12
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  4. Polymers: Hydrophilicpolymers to enhance drug solubility by complexation (polyvinyl alcohol) , PEG, Pectin, Gelatin, CMC. 5. Preservatives: As a bacteriostatic to inhibit any microbes accidentally introduced while doses are being withdrawn. e.g. benzalkonium chloride, benzyl alcohol, methyl & propyl paraben, phenolic compound. 6. Buffer: Parenteral formulation should not vary significantly from physiological pH (about 7.4) e.g. acetates citrates phosphates. 7. Tonicity adjusters: An isotonic solution is one that exhibits the same effective osmotic pressure as blood serum. Eg, Sodium Chloride(0.9%). 8. Antioxidant: Ascorbic acid, sulfur dioxide, metabisulfite and sulfite are the most common antioxidant used in aqueous parenteral. 9. Chelating agents: Disodium EDTA and metalic salts. 10. Inert gases : Inerts gases enhancing the product intregity of Oxygen sensitivity medicaments is by displacing the air solution with Nitrogen or Argon. 13
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  MANUFACTURING PROCESS Following stepsare involved in the processing of parenteral preparation: 1. Cleaning of containers, closures & equipments :Thoroughly cleaned with detergents with tap water → distilled water →finally rinsed with water for injection. • Rubber closures are washed with o.5% sodium pyrophosphate in water. 2. Collection of materials: All raw material of preparation should be collect from warehouse after accurate weighed. water for injection should be pyrogens free. 3. Preparation of parenteral products: The parenteral preparation must be prepared in aseptic conditions. • The ingredients are accurately weighed separately and dissolved in vehicle as per method of preparation to be followed. 14
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  4. Filtration :The parenteral preparation must be filtered by bacteria proof filter such as filter candle, membrane filter . 5. Filling the preparation in final container : The filling operation is carried out under strict aseptic precautions . 6. Sealing the container : Sealing should be done immediate after filling in aseptic environment. 7. Sterilization: For thermostable substances the parenteral products are sterilized by autoclaving method at different temperature & pressure. • Heat sensitive or moisture sensitive material are sterilized by exposure to ethylene oxide or propylene oxide gas . 8. Evaluation of the parenteral preparation: Sterility testing, Clarity test, Leakage test, Pyrogen testing and Assay. 15
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  Process Flow Chart 16 Ingredients vehiclesadditives Compounding Filteration Washing Packing material STERILIZATIO N Packing & Labeling Finished making product Storage Equipment container s closures Sterilization WFI Containers Equipments Finished Product Aseptic filling & sealing
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  Storage : Store ina sterile, airtight , tamper- proof container. Labeling: The term labeling designates all labels and other written, printed or graphic matter on in any package or wrapper in which it is enclosed. Materials used in labeling The following types of labels are, such as –  paper  foil  Fabric 17
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  EVALUATIONS 1. Sterility testing 2.Clarity test (Particulate matter monitoring) 3. Leakage test (Faulty seal packaging) 4. Pyrogen testing i. Rabbit test ii. LAL test 5. Assay 18
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  Sterility Testing Definition:  SterilityTesting: It is a procedure carried out to detect and conform absence of any viable from of microbes in or on pharmacopoeial preparation or product .  Principle: If the microorganism are present in the product can be indicated by a turbidity in the clear medium . Objective of sterility testing : • For validation of sterilization process. • to check presence of microorganisms in preparation which are sterile . • To prevent issue of contaminated product in market . 19
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  Steps involved insterility testing : 1. Sampling 2. Selection of the quantity of the product to be used 3. Method of sterility testing i. Membrane filtration method ii. Direct inoculation method METHOD OF STERILITY TESTING A. Membrane filtration method : Membrane filtration appropriate for (advantage) • Filterable aqueous preparation • Alcoholic preparations • Oily preparations  All steps of this procedure are performed aseptically in a Laminar flow. 20
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  B. Direct inoculationmethod :  Direct inoculation of the culture medium suitable quantity of the preparation to be examined is transferred directly into the appropriate culture medium & incubate for not less than 14 days . Clarity test:  Performed to ensure that the parenteral product are free from foreign particles . • Method : 1. Visual Method 2. Coulter Counter method 3. Filtration method 21 Particle Size (µm) equal to or large than Max. no. of particles per ml 10 50 25 5 50 nil
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  Leakage testing : Thesealed ampoules are subjected to small cracks which occur due to rapid temperature change or due to mechanical shocks. filled & sealed ampoule Dipped in 1% Methylene blue solution under negative pressure in vacuum chamber Vacuum released colored solution enter into the ampoule Defective sealing  Note : vials & bottles are not suitable for this test because the sealing materials used is not rigid. 22
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  Pyrogen testing  Pyrogen= “Pyro” (Greek = Fire)+ “gen”(Greek = beginning)  Fever producing metabolic by- product of microbial growth and death.  Bacterial pyrogen are called “Endotoxins” . Gram negative bacteria produce more potent endotoxins than gram+bacteria and fungi.  Endotoxins are heat stable lipopolysaccharides (LPS) present in bacterial cell walls.  Stable at least 1750 C; steam sterilization ineffective  Source: Water (main), raw materials, equipment, process environment, people and if using gram negative bacteria. 23
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  Biological properties ofendotoxin :  Pyrogen elevated the circulatory levels of inflammatory cytokines which may be followed by fever, blood coagulation , hypotension  Low doses of pyrogen: asymptomatic inflammation reaction  Moderate doses: Fever $ changes in plasma composition  High doses : cardiovascular dysfunction, Vasodilation, vasoconstriction • Elimination of pyrogens:  Dry heat sterilization : for glass wares, metal equipments, powder ,waxes, oils, heat stable drugs.  650C temp- 1 min  350C temp- 30 min  180 C temp -240 min  Ultra filtration  Distillation 24
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  Rabbit Pyrogen Test: Rabbit are used to perform this test because their body temp. increase when pyrogen are introduced into their bodies by parenteral route  3 healthy adult rabbits of either sex, each weighing 1.5kg are selected  Do not use any rabbit  having a temp higher than 39.8 ̊C  Showing temp variation >0.2 ̊C between two successive reading in the determination of initial temp  Shame test is performed within 7 dayes of actual test  Animal showing temp increase over 0.6 ̊C should be removed from pyrogen testing 25
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  Method:  Dissolve thesubs being examined in, or dilute it with a pyrogen free saline solution  warm the liquid being examined to approx. 38.5 ̊C temp before injection  The volume of injection is 0.5 ml & 10ml/ kg of body weight  Withhold water during test  Clinical thermometer is inserted into the rectum of rabbit to record body temp  2 normal reading of rectal temp are should be taken prior to the test injection at an interval of half an hr& its mean is calculated- initial temp  The solution under test is injected through an ear vein  Record the temp of each rabbit in an interval of 30 min for 3 hrs  The difference between initial temp &maximum temp is recorded – taken as response 26
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  NOTE: If abovetest not passes perform the test again If above test not passes, the sample is said to be pyrogenic or go through the source of contamination of pyrogen. No . Of Rabbits Individual temp. Rise C Temp. Rise in group (0C) Test 3 rabbits o.6 1.4 passes If above not passes 3+5=8 rabbits o.6 3.7 passes 27
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  Bacterial endotoxin (LAL)test:  To detect or quantify endotoxins of gram – ve bacterial origin.  Reagent: amoebocyte lysate enzyme from horseshoe crab (Limulus polyphemus or Tachypleus tridentatus). • The name of the test is also Limulus amebocyte lysate (LAL) Mechanism of LAL Test :  The test is based on the gelling properties of enzyme extracted from the horseshoe crab of Limulus polyphemus.  Enzyme when come in contact with bacterial endotoxin. Gelling Degree of Gelling related to amount of endotoxin present. 28
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  Test: 1. Equal volumeof LAL reagent and test solution (usually 0.1ml of each ) are mixed in a test –tube 2. Incubation at 370 ̊C, 1 hrs depyrogenated 3. Remove the tube –invert at (180) observe the result 4. Pass or otherwise fail test Three different techniques: 1. The gel-clot technique- gel formation 2. The turbidimetric technique- the development of Turbidity after cleavage of an endogenous substrate 3. The chromogenic technique- the development of color after cleavage of a synthetic peptide- chromogen complex 29
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  Advantages of LALtest  Fast-60 min vs. 180min  Greater Sensitivity, Less variability  Less expensive  Particularly useful for: • Blood products • Cytotoxic agents • Water for injection 30
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  REFERENCES  Lachman Leon;Liberman Herbert A.; Kanig Joseph L.; “The Theory and Practice of Industrial Pharmacy”; Third Edition; Indian Edition; Varghese Publishing House; Dadar Bombay 400114, 1987; Page No. 639.  Fox Shelley Chambers; “Pharmaceutics”; Remington Education; Published by Pharmaceutical Press;1 Lambeth High Street, London SE1 7JN, UK; Royal Pharmaceutical Society of Great Britain, 2014; Page No. 189-216. 31
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