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

1. 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
20th 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
1. Solutions ready for injection.
2. Dry, soluble products ready to be combined with a solvent
just prior to use.
3. Suspension ready for injections.
4. Dry, insoluble products ready to be combined with a
vehicles just prior to use.
5. Emulsions
6. 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.
1. Compression distillation
2. Multiple-effect still
3. Reverse osmosis

22. 1. 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 800 F.
 USP also permit the storage of WFI at room temp.
maximum for only about 24hr.
 When the water can not be used at 800 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 2100 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” 20th edition, published by Pheladelphia
college of science and pharmacy; page no. 780- 806.