Manufacturing of water for injection

Introduction and process of preparation and quality control of sterile water according to industries.

1. MANUFACTURING OF WATER FOR INJECTION PRESENTED BY: Arun Agarwal Bpharm (2011-2015) Invertis Institute Of Pharmacy, Invertis University, bareilly

2. CONTENTS Origin of word “ parenteral ”. Introduction of parenteral products. Advantages of parenterals . Disadvantages of parenterals . Standards for route of parenterals administration. Parenteral dosage forms. Formulation of parenteral products. Vehicles. Water for injection. Pyrogenicity . References.

3. ORIGIN OF PARENTERAL English Para- Beside Greek Eteron Intestine English -al Parenteral 20 th century

4. INTRODUCTION OF PARENTERAL PRODUCTS  Physiology Located outside the alimentary canal(GIT). The first official injection (morphine) appeared in the British pharmacopoeias of 1867. Parenteral administration of drugs by intravenous (IV), intramuscular(IM), or subcutaneous(SC) routes is now established and essential part of medical practice.

5. ADVANTAGES… Rapid onset Predictable effect Nearly complete bioavailability Avoidance from biotransformation It provide reliable drug administration in very ill and comatose patient

6. DISADVANTAGES.. Frequent pain and discomfort Psychological fears associated with “the needle”. The realization that an incorrect drug or dose is often harder or impossible to counteract when it has been given parenterally (particularly intravenously), rather than orally.

7. REASONS FOR INCREASING GROWTH OF PARENTERAL PRODUCTS.. New and better parenteral administration techniques. Increasing number of drugs that can be administered only by a parenteral route. The need of simultaneously administration of multiple drugs in hospitalized patient receiving IV therapy. New forms of nutritional therapy, such as IV lipids, amino acids and trace metals. The extension of parenteral therapy into the home

8. Standards for route of parenterals administration.

9. Standards for route of parenterals administration. cont..

10. Parenteral dosage forms Solutions ready for injection. Dry, soluble products ready to be combined with a solvent just prior to use. Suspension ready for injections. Dry, insoluble products ready to be combined with a vehicles just prior to use. Emulsions Liquids concentrates ready to dilution prior from administration.

11. FORMULATION OF PARENTERAL PRODUCTS Vehicles The active drug Anti- oxidents Anti-microbial agents Buffers Chelating agents Inert gasses Solubilizing agents and surfactants Tonicity adjustment agents Protectants

12. VEHICLES It present in the high proportion in the preparation. It has no therapeutic activity and is non-toxic. Absorption occurs most rapidly and completely when drug is presented as an aqueous solution. Modification of vehicles with water miscible liquids and other water immiscible liquids normaly decrease the rate of absorption.

13. Types Of Vehicles Aqueous vehicles Water miscible liquids Non-aqueous vehicles

14. AQUEOUS VEHICLES Certain aqueous vehicles are recognized officially because their valid use in parenterals . They are used as isotonic vehicles to which a drug may be added at a time of administration. The additional osmotic effect of the drug may not be enough to produce discomfort when administered. These vehicle include sodium chloride injection, Ringer’s injection, dextrose and sodium chloride injection, lactated Ringer’s injection.

15. WATER MICSIBLE VEHICLES These vehicles are reviewed by “Spiegel and Noseworthy ”. These vehicle used to effect solubility and to prevent hydrolysis of drugs. The most important solvents of this class are: ethyl alcohol, polyethylene glycol, propylene glycol . Ethyl alcohol is particularly used in the preparation of solution of cardiac glycosides. Glycols are used to prepare the solutions of barbiturates, certain alkaloids and certain anti- biotics . These preparation are used for IM administration.

16. NON-AQUEOUS VEHICLES The most common group of this type of vehicle is fixed oil. The USP provide specifications for such vehicles: fixed oil should be from vegetable origin so that they will be metabolized. It should be liquid at room temperature. They should not rancid at room temperature. Fixed vehicles are used particularly for certain hormone preparations. Examples: corn oil, cottonseed oil, peanut oil, sesame oil.

17. WATER FOR INJECTION (WFI)

18. WATER FOR INJECTION (WFI)   A clear and colorless liquid; odorless. Water for injections is pyrogen -free. It contains no added substance. Water for injections is obtained from potable or Purified water by distillation in an apparatus. The distillate is collected and stored in conditions designed to prevent growth of microorganisms and to avoid any other contamination.

19. MANUFACTURING OF WFI USP specified distillation and reverse osmosis as methods to prepare water for injection. Only these two methods is it possible to separate adequately various liquids, gas and solid containing substances from water.

20. FACTORS INFLUENCE PRODUCTION OF WFI The quality of feed of water for distillation will effect the quality of distillate. The size of the eveporator . The baffles (condensing surface) determine the effectiveness of refluxing. Volatile impurities. Contamination of vapor and distillate from the metal part of the still can occur.

21. MANUFACTURING OF WFI The source water usually must be pretreated by one or a combination of following treatment: Chemical softening, filtration, deionization, carbon absorption, or reverse osmosis purification. There are three types of distillation still to produce water for injection. Compression distillation Multiple-effect still Reverse osmosis

22. COMPRESSION DISTILLATION Cont.. Vapor compression still is primarily designed for the production of large volumes of high purity distillate with low consumption of energy and water. Vapor compression processes produce water 5 to 10 times more cost effectively than multiple effect distillers and 25-40 times more cost effectively than conventional, Vapor compression still are available from 50 to 2800 gal/hr (1 US gallon = 3.78541 lit.)

23. Construction

24. PROCEDURE Step 1: In a Vapor Compression still, the boiling process begins with both heating elements turned on. As the water in the boiling chamber reaches near boiling temperatures, the compressor turns on. Step 2: In the compressor, the steam is pressurized, which raises the steam's temperature before it is routed through a special heat exchanger located inside the boiling chamber. Step 3: The pressurized steam gives off its heat to the tap water inside the boiling chamber, causing this water to boil, which creates more steam. Step 4: While the pressurized steam is giving up its latent heat, the steam will condense. One of the heating elements will cycle on and off periodically as needed. Step 5: At this stage, the condensed steam is considered distilled water but is still very hot--only slightly cooler than boiling temperature.

25. 2. MULTIPLE EFFECT STILL It is also designed to conserve energy and water usage. In principle, a series of single effect stills running at different pressures. A series up to seven effect may be used, with the first effect operated at a highest pressure and the last effect at atmospheric pressure. The capacity of still can be increased by adding effects. The quantity of distillate will also be affected by inlet steam pressure. A 600gal/hr unit designed to operate at 115 psig steam pressure could be run at approx. 55 psig and would deliver about 400gal/hr. (  1  atmosphere is approximately 14.696  pounds per square inch gauge. ) They are available in capacities from about 50 to 700gal/hr.

26. CONSTRUCTION

27. PRODEDURE Steam from the external source is used in the first effect to generate steam under pressure from feed water, it is used as a power source for second effect. The steam used to drive the second effect condenses as it gives up its heat of vaporization and forms a distillate. The process continues until the last effect, when the steam is at atmospheric pressure and must be condense at the heat exchanger.

28. REVERSE OSMOSIS The natural process of selective permeation of molecule through a semi-permeable membrane separate two aqueous solutions of different concentration is reversed. Pressure, usually between 200 to 400 psig, is applied to overcome and force pure water to penetrate through the membrane. Membrane composed of cellulose esters or polyamides. It provide effective rejection of contaminant molecules in raw water. Sodium chloride is most difficult to remove. Reverse osmosis systems are available in the range of production sizes( ex. Aqua chem , Finn-aqua, Meco , Milipore etc. )

29. STORAGE AND DISTRIBUTION Distillate is collected in holding tanks for subsequent use. The USP requires that the WFI be held at a temperature too high for microbial growth normally this temperature is constant 80 F. USP also permit the storage of WFI at room temp. maximum for only about 24hr. When the water can not be used at 80 F, heat exchangers must be installed to reduce the temperature at the point of use.

30. PURITY The only physical and chemical test remaining are the new total organic carbon (TOC), with a limit of 500ppb, and conductivity , with a limit of 1.3 microS /cm at 25 or 1.1 microS /cm(s- Siemens). The pH requirement is 5 to 7. Biological requirements is not more than 10 CFUs/ml.

31. PYROGENICITY

32. PYROGENS Pyrogens are product of metabolism of micro-organisms. The gram negative bacteria produces most potent pyrogenic substances as endotoxins . Chemically, pyrogens are lipid substances associated with a carrier molecule, which is usually a polysaccharide but may be peptide. About 1 hour after injection into man, pyrogens chills, body aches, cutaneous vasoconstriction and a rise in arterial blood pressure. Anti pyretics eleminates the fever, but not the other systemic effect of pyrogens .

33. SOURCE AND ELIMINATION OF PYROGENS The most likely sources are contaminated water, contaminated solutes and containers. Opened containers of solutes, capable of supporting the growth of micro-organisms. Containers may be rendered free from pyrogens by adequete cleaning and heating. Usually at 210 C for 3 to 4 hr. Pyrogens sometimes can be removed from solutions by adsorption on the surface of select adsorbents. E.g. qualitative and quantitative tests for the presence of ions such as copper and iron.

34. EVALUATION OF PYROGENS One pyrogen test is a qualitative biological test based on the fever response of rabbit. If a pyrogenic substance is injected into the vein of rabbit, a temperature elevation will occur with in three hours. Many imitative medical agent will also cause a fever. A preferred method for the ditection of pyrogen is the limulus amebocyte lysate (LAL) test . A test sample is incubated with amebocyte lysate from the blood of the horseshoe crab. Limulus polyphemus . A pyrogenic substance will cause a gel to form. This result of the clottable protien from the amebocyte cell reacting with the endotoxins . This test is more sensitive, more rapid, and easier to perform than the rabbit test.

35. REFERENCES Lachman l. lieberman A. Herbert “the theory and Practice of industrial pharmacy”, special Indian edition 2009, CBS publishers & distributors PVT. LTD., page no 639- 677. Florence T. Alexander, sieperman jurgen “Modern Pharmaceutics”, vol. I “Basic principles and systems” fifth edition, published by informa health care; page no. 665-607. Alfonso R. Gennaro “Remington: the science and practice of pharmacy” 20 th edition, published by Pheladelphia college of science and pharmacy; page no. 780- 806.