WATER FOR PHARMACEUTICAL PURPOSES

INTRODUCTION:- Water is one of the major commodities used by pharmaceutical industry.  It may be present as an excipient, or used for reconstitution of products, during synthesis, during production of finished product or as cleaning agent for rinsing vessels, equipment, primary packaging material etc.

Different grades of water quality are required depending upon the different pharmaceutical uses. Control of quality of water , in particular, the microbiological quality is a major concern and the pharmaceutical industry devotes considerable resource to the development and maintenance of water purification system.

Different types of water are there which are used for their specific purposes and they are given as follows.

  • Non-potable.
  • Potable (drinkable) water – required FDA starting point.
  • Purified water.
  • Highly purified water.
  • Water for injection (WFI).
  • Sterile water for injection.
  • Sterile water for inhalation.
  • Bacteriostatic water for injection.
  • Sterile water for irrigation.

APPLICATION OF WATER IN PHARMACEUTICAL INDUSTRY:-  Different applications of different types of water are discussed here under.

Table-1-  Sterile medicinal products:-

Sterile Medicinal Products Minimum Acceptable Quality Of Water
Parenteral WFI
Ophthalmic Purified water
Haemofiltration solution

Haemodiafiltration solution

WFI
Peritoneal dialysis solution WFI
Irrigation solution WFI
Nasal/ear preparation Purified water
Cutaneous preparation Purified water

 

Table-2-  Non-Sterile medicinal products:-

Non-Sterile Medicinal Products Minimum Acceptable Quality Of Water
Oral preparation Purified water
Nebulizer Purified water
Cutaneous preparation Purified water
Nasal/ear preparation Purified water
Rectal/vaginal preparation Purified water
capsules Purified water
Creams Purified water
Gels Purified water
lotion Purified water
Mouth paints Purified water

 

Table-3-  Water used during the manufacture of active pharmaceutical ingredients.

Type Of Manufacture Product Requirement Minimum Acceptable Quality Of Water
Synthesis of all intermediates of API prior to final isolation and purification steps. No requirement for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used. Portable water
Fermentation media No requirement for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used. Portable water
Extraction of herbals No requirement for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used. Portable water
Final isolation and purification No requirement for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used. Portable water
Final isolation and purification API is not sterile, but is intended for use in a sterile, non-parenteral product. Purified  water
Final isolation and purification API is sterile and not intended for parenteral use. Purified  water
Final isolation and purification API is not sterile, but is intended for use in a sterile, parenteral product. Purified  water with an endotoxin limit of

0.25 Eu/ml

Final isolation and purification API is sterile and apyrogenic. WFI

 

Table-4-  Water used during the manufacture of medicinal products which is not present in the final formulation

Manufacture Minimum Acceptable Quality Of Water
Granulation Purified water
Tablet coating Purified water
Used in formulation prior to non-sterile  lyophilisation Purified water
Used in formulation prior to sterile  lyophilisation WFI

 

Table-5: Water used for cleaning/rinsing:

Cleaning/Rinsing Of Equipment, Container And Closures Product type Minimum Acceptable Quality Of Water
Initial rinse Intermediates and API Portable water
Final rinse API use same quality of water as used in the API manufacture
Initial rinse including clean in place(CIP) of equipment, container and closures if applicable. Pharmaceutical products

non-sterile

Portable water
Final rinse including CIP of equipment, container and closures if applicable. Pharmaceutical products

non-sterile

Purified water or use same quality of water as used in medicinal product, if higher quality than purified water.
initial rinse including CIP of equipment, container and closures if applicable. Sterile Products Purified water
Final rinse including CIP of equipment, container and closures if applicable. Sterile non-parenteral products Purified water or use same quality of water as used in medicinal product, if higher quality than purified water.
Final rinse including CIP of equipment, container and closures if applicable. Sterile parenteral products WFI

 

Treatment of source water for use in pharmaceuticals:

Source water for pharmaceuticals generally contain the following types of water

  • Borewell water.
  • Municipal water.

Treatment comprises of the following steps.

  • Filtration
  • Dual media filter.
  • Pressure Media Filter.
  • Sand filter.
  • Slow sand filter
  • Rapid gravity sand filter
  • Activated carbon filter.
  • Granular Activated Carbon (GAC)
  • Solid Block Activated Carbon (SBAC)
  • Softening of water.
  • Filtration
  • Dual media filter
  • Pressure Media Filter:- This comprises of sand and anthracite as filtering media and polishing media respectively. Internally it is fitted with inlet distributor and a bottom collecting system. Externally, it is fitted with frontal pipe work and isolation valves. Sand is used for removing the suspended particles and anthracite removes the odor and colour etc to make the water fit for various application. Pebbles and gravels are provided to support to both the media. This filter is to be backwashed after accumulation of suspended solids over the cycle; however, before carrying out the backwash, air scouring (optional) is also to be done for loosening of dirt and suspended solids. Limit for the backwash in these filers is governed by differential pressure across the filter.
  • Sand filter
  • Slow sand filter:- Slow sand filters may be used where there is sufficient land and space as the water must be passed very slowly through the filters. These filters rely on biological treatment processes for their action rather than physical filtration. The filters are carefully constructed using graded layers of sand with the coarsest sand, along with some gravel, at the bottom and finest sand at the top. Drains at the base convey treated water away for disinfection. Filtration depends on the development of a thin biological layer, called the zoogleal layer or Schmutzdecke, on the surface of the filter. An effective slow sand filter may remain in service for many weeks or even months if the pre-treatment is well designed and produces water with a very low available nutrient level which physical methods of treatment rarely achieve. Very low nutrient levels allow water to be safely sent through distribution system with very low disinfectant levels thereby reducing consumer irritation over offensive levels of chlorine and chlorine by-products. Slow sand filters are not backwashed; they are maintained by having the top layer of sand scraped off when flow is eventually obstructed by biological growth. A specific ‘large-scale’ form of slow sand filter is the process of bank filtration, in which natural sediments in a riverbank are used to provide a first stage of contaminant filtration. While typically not sufficiently clean enough to be used directly for drinking water, the water gained from the associated extraction wells is much less problematic than river water taken directly from the major streams where bank filtration is often used.

 

  • Rapid gravity sand filter:- Either single or dual grade sand is filled up in the top-open filter boxes. Under the filter media, the filter box is fitted with inlet distributor and a bottom collecting system. Externally, it is fitted with isolation valves and backwash water collection system. Pebbles and gravels are provided as the bottom layer under the sand bed of uniform size to support the sand bed. This filter removes mainly suspended impurities from the water source. Suspended impurities get trapped within the sand media when water having suspended impurities is passed through the sand bed and clear water comes out as the product. Backwash of the filter is to be carried out to remove these entrapped impurities from the filter, once it reaches to its maximum limits. This limit is governed by differential pressure across the filter.
  • Activated carbon filters:- Activated carbon (AC) is particles of carbon that have been treated to increase their surface area and increase their ability to adsorb a wide range of contaminants – activated carbon is particularly good at adsorbing organic compounds.  You will find two basic kinds of carbon filters Granular Activated Carbon (GAC) and Solid Block Activated Carbon (SBAC).

Contaminant reduction in AC filters takes place by two processes, physical removal of contaminant particles, blocking any that are too large to pass through the pores (obviously, filters with smaller pores are more effective), and a process called adsorption by which a variety of dissolved contaminants are attracted to and held (adsorbed) on the surface of the carbon particles. The characteristics of the carbon material (particle and pore size, surface area, surface chemistry, density, and hardness) influence the efficiency of adsorption.

AC is a highly porous material; therefore, it has an extremely high surface area for contaminant adsorption. One reference mentions “The equivalent surface area of 1 pound of AC ranges from 60 to 150 acres (over 3 football fields)”.

AC is made of tiny clusters of carbon atoms stacked upon one another. The carbon source is a variety of materials, such as peanut shells, coconut husks, or coal. The raw carbon source is slowly heated in the absence of air to produce a high carbon material. The carbon is activated by passing oxidizing gases through the material at extremely high temperatures. The activation process produces the pores that result in such high adsorptive properties.

The effectiveness of carbon filters to reduce contaminants is affected by the factors affecting adsorption listed above and three additional characteristics of the filter, contact time between the water and the carbon material, the amount of carbon in the filter, and pore size.
The length of contact time between the water and the carbon material, governed by the rate of water flow and the amount/volume of activated carbon, has a significant effect on adsorption of contaminants. More contact time results in greater adsorption. The amount of carbon present in a cartridge or filter affects the amount and type of contaminant removed. Less carbon is required to remove taste and odor-producing chemicals than to remove trihalomethanes. Because of the filter characteristics discussed above, the most effective Point of Use activated carbon filters are large SBAC filtration systems, and the least effective are the small, pour-through pitcher filters.

  • Activated carbon filter cartridges will, over time, become less effective at reducing contaminants as the pores clog with particles (slowing water flow) and the adsorptive surfaces in the pores become filled with contaminants (typically not affecting flow rate). There is often no noticeable indication that a carbon filter is no longer removing contaminants, so it is important to replace the cartridge according to the manufacturer’s instructions. The overall water quality (turbidity or presence of other contaminants) also affects the capacity of activated carbon to adsorb a specific contaminant.
  • Granular Activated Carbon (GAC):– In this type of filter, water flows through a bed of loose activated carbon granules which trap some particulate matter and remove some chlorine, organic contaminants, and undesirable tastes and odors.  The three main problems associated with GAC filters are: channeling, dumping, and an inherently large pore size.  Most of the disadvantages discussed below are not the fault of the activated carbon filtration media, rather, the problem is the design of the filters and the use of loose granules of activated carbon.

The advantages of GAC filters include:

  • Simple GAC filters are primarily used for aesthetic water treatment, since they can reduce chlorine and particulate matter as well as improve the taste and odor of the water.
  • Loose granules of carbon do not restrict the water flow to the extent of Solid Block Activated Carbon (SBAC) filters.  This enables them to  be used in situations, like whole house filters, where maintaining a good water flow rate and pressure is important.
  • Simple, economical maintenance.  Typically an inexpensive filter cartridge needs to be changed every few months to a year, depending on water use and the manufacturer’s recommendation.
  • GAC filters do not require electricity, nor do they waste water.
  • Many dissolved minerals are not removed by activated carbon.  In the
    case of calcium, magnesium, potassium, and other beneficial minerals, the taste of the water can be improved and some (usually small) nutrient
    value can be gained from the water.

The bottom line is that GAC filters are effective and valuable water treatment devices, but their limitations always need to be considered.  A uniform flow rate, not to exceed the manufacture’s specifications, needs to be maintained for optimal performance, and the filter cartridge must be changed after treating the number of gallons the filter is rated for.

The disadvantages of GAC filters include:

  • Water flowing through the filter is able to “channel” around the carbon granules and avoid filtration.  Water seeks the path of least resistance. When it flows through a bed of loose carbon granules, it can carve a channel where it can flow freely with little resistance.  Water flowing through the channel does not come in contact with the filtration medium.
  • Pockets of contaminated water can form in a loose bed of carbon granules.  With changes in water pressure and flow rates, these pockets can collapse, “dumping” the contaminated water through the filter into the “filtered” flow.
  • Since the carbon granules are fairly large (0.1mm to 1mm in  one popular pitcher filter), the effective pore size of the filter is relatively  large (20 – 30 microns or larger).  GAC filters, by themselves, can not bacteria.
  • As described above, hot water should NEVER be run through a carbon filter
  • Also, if you think of a bed of charcoal that traps an occasional bacterium, picks up a bit of organic material, and removes the chlorine from the water, you can see how these filters might become breeding grounds for the bacteria they trap. You will see warnings about GAC filters suggesting you run water through them for a few minutes each morning to flush out any bacteria. Unless the filter plugs up or you notice an odor in the “filtered water”, it may be difficult to know when the filter has become saturated with contaminants and ineffective. That is why it is necessary to change filter cartridges according to the manufacturer’s recommendation.
  • Solid Block Activated Carbon (SBAC):- Activated carbon is the primary raw material in solid carbon block filters; but instead of carbon granules comprising the filtration medium, the carbon has been specially treated, compressed, and bonded to form a uniform matrix.  The effective pore size can be very small (0.5 – 1 micron).  SBAC, like all filter cartridges, eventually become plugged or saturated by contaminants and must be changed according to manufacturer’s specifications.  Depending on the manufacturer, the filters  can be designed to better reduce specific contaminants like arsenic  MTBE, etc. (an example)

The advantages of SBAC filters include:

  • Provide a larger surface area for adsorption to take place than Granular Activated Carbon (GAC) filters for better contaminant reduction.
  • Provide a longer contact time with the activated carbon for more complete contaminant reduction.
  • Provide a small pore size to physically trap particulates. If the pore size   is small enough, around 0.5 microns or smaller, bacteria that become trapped in the pores do not have enough room to multiply, eliminating problem common to GAC filters.
  • Completely eliminate the channeling and dumping problems associated with GAC filters.
  • SBAC filters are useful in emergency situations where water pressure and electricity might be lost.  They do not require electricity to be completely effective, and water can even be siphoned through them.
  • SBAC filters do not waste water like reverse osmosis.
  • Many dissolved minerals are not removed by activated carbon.  In the case of calcium, magnesium, potassium, and other beneficial minerals, the taste of the water can be improved and some (usually small) nutrient value can be gained from the water.
  • Simple, economical maintenance.  Typically, an inexpensive filter cartridge needs to be changed every few months to a year, depending on water use and the manufacturer’s recommendation.

This combination of features provides the potential for greater adsorption of many different chemicals (pesticides, herbicides, chlorine, chlorine byproducts, etc.) and greater particulate filtration of parasitic cysts, asbestos, etc. than much other purification process available. By using other specialized materials along with specially prepared activated carbon, customized SBAC filters can be produced for specific applications or to achieve greater capacity ratings for certain contaminants like lead, mercury, arsenic, etc.

The disadvantages of SBAC filters include:

  • SBAC filters, like all activated carbon filters, do not naturally reduce the levels of soluble salts (including nitrates), fluoride, and some other potentially harmful minerals like arsenic (unless specially designed) and cadmium.  If these contaminants are present in your water, reverse osmosis would usually be the most economical alternative followed by distillation.
  • As described above, hot water should NEVER be run through a carbon filter.
  • As SBAC filters remove contaminants from the water they gradually lose effectiveness until they are no longer able to adsorb the contaminants.  There is no easy way to determine when a filter is nearing the end of its effective life except that the ‘filtered’ water eventually begins to taste and smell like the unfiltered water.  The manufacturer’s guidelines for changing filter cartridges should always be followed.
  • Softening of water.

Water softening: –When water contains a significant amount of calcium and magnesium, it is called hard water. Hard water is known to clog pipes and to complicate soap and detergent dissolving in water. Water softening is a technique that serves the removal of the ions that cause the water to be hard, in most cases calcium and magnesium ions. Iron ions may also be removed during softening. The best way to soften water is to use a water softener unit and connect it directly to the water supply.

Water softener: – A water softener is a unit that is used to soften water, by removing the minerals that cause the water to be hard.

Importance of water softening:Water softening is an important process, because the hardness of water in households and companies is reduced during this process.
When water is hard, it can clog pipes and soap will dissolve in it less easily. Water softening can prevent these negative effects. Hard water causes a higher risk of lime scale deposits in household water systems. Due to this lime scale build-up, pipes are blocked and the efficiency of hot boilers and tanks is reduced. This increases the cost of domestic water heating by about fifteen to twenty percent. Another negative effect of lime scale is that it has damaging effects on household machinery, such as laundry machines. Water softening means expanding the life span of household machine, such as laundry machines, and the life span of pipelines. It also contributes to the improved working, and longer lifespan of solar heating systems, air conditioning units and many other water-based applications.

Water softener work: – Water softeners are specific ion exchangers that are designed to remove ions, which are positively charged. Softeners mainly remove calcium (Ca2+) and magnesium (Mg2+) ions. Calcium and magnesium are often referred to as ‘hardness minerals’.
Softeners are sometimes even applied to remove iron. The softening devices are able to remove up to five milligrams per liter (5 mg/L) of dissolved iron. Softeners can operate automatic, semi-automatic, or manual. Each type is rated on the amount of hardness it can remove before regeneration is necessary. A water softener collects hardness minerals within its conditioning tank and from time to time flushes them away to drain. Ion exchangers are often used for water softening. When an ion exchanger is applied for water softening, it will replace the calcium and magnesium ions in the water with other ions, for instance sodium or potassium. The exchanger ions are added to the ion exchanger reservoir as sodium and potassium salts (NaCl and KCl).

Water softener last:- A good water softener will last many years. Softeners that were supplied in the 1980’s may still work, and many need little maintenance, besides filling them with salt occasionally.

Softening salts::- For water softening, three types of salt are generally sold:

Rock salt, Solar salt,Evaporated salt
Rock salt:- Rock salt as a mineral occurs naturally in the ground. It is obtained from underground salt deposits by traditional mining methods. It contains between ninety-eight and ninety-nine percent sodium chloride. It has a water insolubility level of about 0.5-1.5%, being mainly calcium sulphate. Its most important component is calcium sulphate.

Solar salt:- Solar salt as a natural product is obtained mainly through evaporation of seawater. It contains 85% sodium chloride. It has a water insolubility level of less than 0.03%. It is usually sold in crystal form. Sometimes it is also sold in pellets.

Evaporated salt:- Evaporated salt is obtained through mining underground salt deposits of dissolving salt. The moisture is then evaporated, using energy from natural gas or coal. Evaporated salt contains between 99.6 and 99.99% sodium chloride.

Rock salt contains a lot of matter that is not water-soluble. As a result, the softening reservoirs have to be cleaned much more regularly, when rock salt is used. Rock salt is cheaper than evaporated salt and solar salt, but reservoir cleaning may take up a lot of your time and energy.

Solar salt contains a bit more water-insoluble matter than evaporated salt. When one makes a decision about which salt to use, consideration should be given to how much salt is used, how often the softener needs cleanout, and the softener design. If salt usage is low, the products could be used alternately.

If salt usage is high, insoluble salts will build up faster when using solar salt. Additionally, the reservoir will need more frequent cleaning. In that case evaporated salt is recommended.

It is generally not harmful to mix salts in a water softener, but there are types of softeners that are designed for specific water softening products. When using alternative products, these softeners will not function well. Mixing evaporated salt with rock salt is not recommended, as this could clog the softening reservoir. It is recommended that you allow your unit to go empty of one type of salt before adding another to avoid the occurrence of any problems.

Salt is usually added to the reservoir during regeneration of the softener. The more often a softener is regenerated, the more often salt needs to be added. Usually water softeners are checked once a month. To guarantee a satisfactory production of soft water, the salt level should be kept at least half-full at all times. Before salt starts working in a water softener it needs a little residence time within the reservoir, since the salt is dissolving slowly. When one immediately starts regeneration after adding salt to the reservoir, the water softener may not work according to standards. When the water softening does not take place it could also indicate softener malfunction, or a problem with the salt that is applied.

Softeners maintenance:

When does a softener resin need replacement:- When the water does not become soft enough, one should first consider problems with the salt that is used, or mechanical malfunctions of softener components. When these elements are not the cause of the unsatisfactory water softening, it may be time to replace the softener resin, or perhaps even the entire softener.
Through experience we know that most softener resins and ion exchanger resins last about twenty to twenty-five years.

Does a softener brine tank need cleaning:- Usually it is not necessary to clean out a brine tank, unless the salt product being used is high in water-insoluble matter, or there is a serious malfunction of some sort. If there is a build-up of insoluble matter in the resin, the reservoir should be cleaned out to prevent softener malfunction.

What is ‘mushing’ and why should we avoid it:- When loosely compacted salt pellets or cube-style salt is used in a resin, it may form tiny crystals of evaporated salt, which are similar to table salt. These crystals may bond, creating a thick mass in the brine tank. This phenomenon, commonly known as ‘mushing’, may interrupt brine production. Brine production is the most important element for refreshing of the resin beads in a water softener. Without brine production, a water softener is not able produce soft water.

SPECIFICATIONS OF DIFFERENT TYPE OF WATERS:

Source water (IN HOUSE):

Sr no..
Parameters
Specification
01 Description A clear, colourless, odourless and tasteless liquid.
02 pH (at 25°C) 6.5 to 8.5
03 Free Chlorine Not more than 0.2 ppm
04 Chloride Not more than 250 ppm
05 Hardness Not more than 300 ppm
06 Total dissolved solids Not more than 500 ppm
07 Total aerobic Microbial count

Pathogens :

Escherichia coli

Salmonella

Pseudomonas aeruginosa  Staphylococcus aureus

Not more than 500 cfu / ml

 

Should be Absent / 100 ml

Should be Absent / 100 ml

Should be Absent / 100 ml               Should be Absent / 100 ml

SPECIFICATIONS OF DIFFERENT TYPE OF WATERS ACCORDING TO IP:

Purified water IP:

Sr no. Test Test method Specification
1. Description/Characteristics A clear, colourless, odourless and Tasteless liquid. Should comply
2.

 

 

Acidity and Alkalinity To 10ml, freshly boiled and cooled in borosilicate glass flask add 0.05ml of methyl red solution.

To 10ml, freshly boiled and cooled in borosilicate glass flask add 0.1ml of bromothymol blue solution.

 

The resulting solution is not red with methyl red solution and resulting solution is not blue with bromothymol blue solution.
3. Ammonium To 20 ml add 1ml of alkaline potassium mercuric iodide solution and allow to stand for 5 minutes. When viewed vertically, the solution is not more intensely coloured than the solution prepared at the same time by adding 1ml of alkaline potassium mercuric iodide solution to a mixture of 4.0 ml of ammonium standard solution(1ppm NH4) and 16 ml of ammonia free water(0.2ppm)

 

Test solution is not more intensely coloured than standard solution.
4. Calcium and Magnesium To 100 ml add 2ml of ammonia buffer pH 10.0. 50mg of mordant black ll mixture and 0.5 ml of 0.01M disodium edetate.

 

A pure blue colour is produced.
5. Chlorides To 10 ml add 1 ml of 2M nitric acid and 0.2 ml of 0.1M AgNO3. The appearance of the solution does not change for at least 15 minutes.

 

 

6. Nitrates To 5 ml in a test tube immersed in ice and 0.4ml of a 10% w/v solution of potassium chloride0.1 ml of di phenylamine solution, and drop wise with shaking 5ml sulphuric acid. Transfer the tube to a water bath    at 500C and allow to stand for 15 minutes.

 

Any blue colour produced in the sample solution is less intense than a solution prepared at the same time and the same manner using a mixture of 4.5 ml of nitrate-free water and 0.5ml of nitrate standard solution(2ppm)(0.2ppm)
7. Heavy Metals Evaporate 150ml to 15 ml on a water bath.(Use lead standard solution (1ppm pb) to prepare the standard.) 12ml of the solution complies with the limit test for heavy metals.
8. Sulphates To 10ml add 0.1ml of 2M HCl and 0.1ml of barium chloride solution. The appearance of the solution does not change for at least 1 hour.
9. Oxidisable substances To 100ml add 10 ml of 1M sulphuric acid and 0.1 ml of 0.02M KMnO4 and boil for 5 minutes; The solution remains faintly pink.
10. Residue on Evaporation Evaporate 100ml to dryness on a water bath and dry to constant weight at 1050C. The residue weighs Not more than 0.001%.
11. Aluminium Determined using the following solution.

Test solution: To 400ml of water under examination add 10 ml of acetate buffer solution pH 6.0 and 100 ml of distilled water.

Reference solution: mix 2 ml of aluminium standard solution (2ppm Al ) 10 ml of acetate buffer solution pH 6.0 and 98 ml of distilled water.

Blank solution: Mix 10 ml of acetate buffer solution pH 6.0 and 100 ml of distilled water.

Not more than 10 ppb
12. Bacterial endotoxins   Not more than 0.25 endotoxin unit per ml

 

Water for injection in bulk IP:

Sr no. Test Test method Specification
01 Description/Characteristics A clear, colourless, odourless and Tasteless liquid.  
03

 

 

Acidity and Alkalinity To 10ml, freshly boiled and cooled in borosilicate glass flask add 0.05ml of methyl red solution.

To 10ml, freshly boiled and cooled in borosilicate glass flask add 0.1ml of bromothymol blue solution.

The resulting solution is not red with methyl red solution and resulting solution is not blue with bromothymol blue solution.
04 Ammonium To 20 ml add 1ml of alkaline potassium mercuric iodide solution and allow to stand for. When viewed vertically, the solution is not more intensely coloured than the solution prepared at the same time by adding 1ml of alkaline potassium mercuric iodide solution to a solution containing 2.5ml of dilute ammonium chloride solution and 7.5 ml of liquid under examination.

 

Test solution is not more intensely coloured than standard solution.
05 Calcium and Magnesium To 100 ml add 2ml of ammonia buffer pH 10.0. 50mg of mordant black ll mixture and 0.5 ml of 0.01M disodium edetate.

 

A pure blue colour is produced.
06 Chlorides To 10 ml add 1 ml of 2M nitric acid and 0.2 ml of 0.1M AgNO3. The appearance of the solution does not change for at least 15 minutes.
07 Nitrates To 5 ml in a test tube immersed in ice and 0.4ml of a 10% w/v solution of potassium chloride 0.1 ml of di phenylamine solution and, drop wise with shaking 5ml sulphuric acid. Transfer the tube to a water bath    at 500C and allow to stand for 15 minutes.

 

 

Any blue colour produced in the sample solution is less intense than a solution prepared at the same time and the same manner using a mixture of 4.5 ml of nitrate-free water and 0.5ml of nitrate standard solution(2ppm)(0.2ppm)
08 Heavy Metals Evaporate 150ml to 15 ml on a water bath. (Use lead standard solution (1ppm pb) to prepare the standard.) 12ml of the solution complies with the limit test for heavy metals.
09 Sulphates To 10ml add 0.1ml of 2M HCl and 0.1ml of barium chloride solution. The appearance of the solution does not change for at least 1 hour.

 

10 Aluminium For water for injections intended for use in manufacture of dialysis  solution,

Determined using the following solution.

Test solution: To 400ml of water under examination add 10 ml of acetate buffer solution pH 6.0 and 100 ml of distilled water.

Reference solution: mix 2 ml of aluminium standard solution (2ppm Al) 10 ml of acetate buffer solution pH 6.0 and 98 ml of distilled water.

Blank solution: Mix 10 ml of acetate buffer solution pH 6.0 and 100 ml of distilled water.

 

Not more than 10 ppb.
11 Bacterial endotoxins   Not more than 0.25 endotoxin units per ml.
12 Total organic carbon   Not more than 0.5 mg per litre.
13 Conductivity   Meets the requirement of the test.

 

Sterile Water for injection IP:

Sr no. Test Test method Specification
01 Description/Characteristics A clear, colourless, odourless and Tasteless liquid.

Practically free from suspended particles.

Should comply.
02

 

 

Acidity and Alkalinity To 20ml, add 0.05ml of phenol red solution. If the solution is yellow, it becomes red on the addition of 0.1 ml of 0.01 M sodium hydroxide; if red it becomes yellow on the addition of 0.15 ml of 0.01 M hydrochloric acid. Should comply.
03 Ammonium To 20 ml add 1ml of alkaline potassium mercuric iodide solution and allow to stand for. When viewed vertically, the solution is not more intensely coloured than the solution prepared at the same time by adding 1ml of alkaline potassium mercuric iodide solution to a solution containing 2.5ml of dilute ammonium chloride solution and 7.5 ml of liquid under examination.  
04 Calcium and Magnesium To 100 ml add 2ml of ammonia buffer pH 10.0. 50mg of mordant black ll mixture and 0.5 ml of 0.01M disodium edetate. A pure blue colour is produced.
05 Chlorides To 10 ml add 1 ml of 2M nitric acid and 0.2 ml of 0.1M AgNO3. The appearance of the solution does not change for at least 15 minutes.
06 Nitrates To 5 ml in a test tube immersed in ice and 0.4ml of a 10% w/v solution of potassium chloride 0.1 ml of di phenylamine solution and, drop wise with shaking 5ml sulphuric acid. Transfer the tube to a water bath    at 500C and allow to stand for 15 minutes. Any blue colour produced in the sample solution is less intense than a solution prepared at the same time and the same manner using a mixture of 4.5 ml of nitrate-free water and 0.5ml of nitrate standard solution(2ppm)(0.2ppm)
07 Heavy Metals Evaporate 150ml to 15 ml on a water bath. (Use lead standard solution (1ppm pb) to prepare the standard.) 12ml of the solution complies with the limit test for heavy metals.
08 Sulphates To 10ml add 0.1ml of 2M HCl and 0.1ml of barium chloride solution. The appearance of the solution does not change for at least 1 hour.
09 Oxidisable substances Boil 100 ml with 10 ml of 1M sulphuric acid, add 0.4 ml of 0.02M potassium permanganate (for sterile water for injection in containers with fill volume of less than 50 ml) or 0.2ml of 0.02M potassium permanganate(for sterile water for injection in containers with fill volume of less than 50 ml) and boil for 5 minutes. If a precipitate forms, cool in an ice bath to room temperature and filter through a sintered glass filter (porosity no 3). The pink colour of the solution does not disappear completely.
10 Residue on Evaporation Evaporate 100ml to dryness on a water bath and dry the residue to constant weight at 1050C. For containers with a nominal volume of 10 ml or less the residue weighs not more than 4mg (0.004 percent).

For containers with a nominal volume of greater than 10 ml the residue weighs not more than 3mg (0.003 percent).

11 Bacterial endotoxins   Not more than 0.25 endotoxin units per ml.
12

 

 

13

particulate contamination   Complies with the requirements of method 1 and method 2.

 

sterility   Complies with the test of sterility

SPECIFICATIONS OF DIFFERENT TYPE OF WATERS ACCORDING TO BP:

Purified water in bulk production BP:

Sr no. Test Test method specification
1. Appearance Clear and colourless liquid Should comply
2. Nitrates Place 5 ml in a test tube immersed in iced water, add 0.4 ml of a 100g/L solution of potassium chloride R, 0.1 ml of diphenyl amine solution R and, dropwise with shaking, 5ml of nitrogen free sulphuric acid R. Transfer the tube to a water bath at 500C. after 15 minutes any blue colour in the solution is not more intense than that in a reference solution prepared at the same time in the same manner using a mixture of 4.5 ml of nitrate free water R and 0.5ml of nitrate standard solution  (2 ppm NO3. )R. Maximum 0.2ppm
3. Aluminium If intended for use in manufacture of dialysis  solution,

Prescribed solution: To 400ml of water under examination add 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

Reference solution: mix 2 ml of aluminium standard solution (2ppm Al) R, 10 ml of acetate buffer solution pH 6.0 R and 98 ml of distilled water R.

Blank solution: Mix 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

 

Not more than 10 ppb.
4. Heavy metals Heat 200 ml in a glass evaporating dish on a water bath until the volume is reduced to 20 ml. 12 ml of the concentrated solution complies with limit test A. prepare the standard using 10 ml of lead standard solution (1 ppm Pb) R. Maximum 0.1ppm.
5. Bacterial endotoxins Less than 0.25 IU/ml, if intended for use in the manufacture of dialysis solution without a further appropriate procedure for removal of bacterial endotoxins. Not more than 0.25 IU/ml.

 

Purified water in containers BP:

Sr no. Test Test method specification
1. Appearance Clear and colourless liquid Should comply
2. Nitrates Place 5 ml in a test tube immersed in iced water, add 0.4 ml of a 100g/L solution of potassium chloride R, 0.1 ml of diphenyl amine solution R and, dropwise with shaking, 5ml of nitrogen free sulphuric acid R. Transfer the tube to a water bath at 500C. after 15 minutes any blue colour in the solution is not more intense than that in a reference solution prepared at the same time in the same manner using a mixture of 4.5 ml of nitrate free water R and 0.5ml of nitrate standard solution       (2 ppm NO3. )R. Maximum 0.2ppm
3. Aluminium If intended for use in manufacture of dialysis  solution,

Prescribed solution: To 400ml of water under examination add 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

Reference solution: mix 2 ml of aluminium standard solution (2ppm Al) R, 10 ml of acetate buffer solution pH 6.0 R and 98 ml of distilled water R.

Blank solution: Mix 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

 

Not more than 10 ppb.
4. Heavy metals Heat 200 ml in a glass evaporating dish on a water bath until the volume is reduced to 20 ml. 12 ml of the concentrated solution complies with limit test A. prepare the standard using 10 ml of lead standard solution (1 ppm Pb) R. Maximum 0.1ppm.
5. Bacterial endotoxins Less than 0.25 IU/ml, if intended for use in the manufacture of dialysis solution without a further appropriate procedure for removal of bacterial endotoxins. Not more than 0.25 IU/ml.

 

 

 

6. Acidity or alkalinity To 10ml, freshly boiled and cooled in borosilicate glass flask add 0.05ml of methyl red solution R.

To 10ml, freshly boiled and cooled in borosilicate glass flask add 0.1ml of bromothymol blue solution R.

The resulting solution is not red with methyl red solution and resulting solution is not blue with bromothymol blue solution.
7. Oxidisable substances To 100ml add 10 ml of dilute sulphuric acid R and 0.1 ml of 0.02M KMnOand boil for 5 minutes; The solution remains faintly pink.
8. Chlorides To 10 ml add 1 ml of dilute nitric acid R and 0.2 ml of AgNO3 solution R2 the appearance of the solution does not change for at least 15 minutes.

 

9. Sulphates To 10ml add 0.1ml of dilute HCl R and 0.1ml of barium chloride solution R1. The appearance of the solution does not change for at least 1 hour.
10. Ammonium To 20 ml add 1ml of alkaline potassium tetraiodomercurate solution R and allow to stand for 5 minutes. When viewed vertically, the solution is not more intensely coloured than the solution prepared at the same time by adding 1ml of alkaline potassium tetraiodomercurate  solution R  to a mixture of 4.0 ml of ammonium standard solution(1ppm NH4) R and 16 ml of ammonia free water R.

 

Maximum 0.2 ppm.
11. Calcium and Magnesium To 100 ml add 2ml of ammonium chloride buffer solution pH 10.0 R, 50mg of mordant black 11 triturate R and 0.5 ml of 0.01M disodium edetate.

 

A pure blue colour is produced.

 

12. Residue on evaporation. Evaporate 100ml on a water bath and dry in an oven at 100-1050C. Residue weighs a maximum of 1 mg. Maximum 0.001 percent.
13. Microbial contamination Determined by membrane filtration, using agar medium B. Total viable aerobic count not more than 102 micro organisms per milliliter.

 

Water for injection in bulk production BP:

Sr no. Test Test method Specification
1. Appearance Clear and colourless liquid Should comply
2. Nitrates Place 5 ml in a test tube immersed in iced water, add 0.4 ml of a 100g/L solution of potassium chloride R, 0.1 ml of diphenyl amine solution R and, dropwise with shaking, 5ml of nitrogen free sulphuric acid R. Transfer the tube to a water bath at 500C. After 15 minutes any blue colour in the solution is not more intense than that in a reference solution prepared at the same time in the same manner using a mixture of 4.5 ml of nitrate free water R and 0.5ml of nitrate standard solution (2 ppm NO3. ) R. Maximum 0.2ppm.
3. Aluminium If intended for use in manufacture of dialysis  solution,

Prescribed solution: To 400ml of water under examination add 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

Reference solution: mix 2 ml of aluminium standard solution (2ppm Al) R, 10 ml of acetate buffer solution pH 6.0 R and 98 ml of distilled water R.

Blank solution: Mix 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

 

Not more than 10 ppb.
4. Heavy metals Heat 200 ml in a glass evaporating dish on a water bath until the volume is reduced to 20 ml. 12 ml of the concentrated solution complies with limit test A. prepare the standard using 10 ml of lead standard solution (1 ppm Pb) R. Maximum 0.1ppm.

 

 

 

 

 

 

5. Bacterial endotoxins Less than 0.25 IU/ml, if intended for use in the manufacture of dialysis solution without a further appropriate procedure for removal of bacterial endotoxins. Not more than 0.25 IU/ml.

 

 

 

6. Total organic carbon   Maximum 0.5 mg/ml.

 

Sterilised water for injection BP:

Sr no. Test Test method Specification
1. Appearance Clear and colourless liquid Should comply.
2.

 

 

Acidity and Alkalinity To 20ml, add 0.05ml of phenol red solution R. If the solution is yellow, it becomes red on the addition of 0.1 ml of 0.01 M sodium hydroxide; if red it becomes yellow on the addition of 0.15 ml of 0.01 M hydrochloric acid. Should comply.
3. Conductivity Maximum 25 µs-cm-1 for containers with a nominal volume of 10ml or less ; maximum 5µs-cm-1 for containers with a nominal volume of greater than 10ml. Should comply.
4. Oxidisable substances To 100ml add 10 ml of dilute sulphuric acid R and 0.2 ml of 0.02M KMnOand boil for 5 minutes. The solution remains faintly pink.
5. Chlorides Maximum 0.5 ppm for containers with a nominal volume of 100ml or less.

15 ml complies with the limit test for chlorides. Prepare the standard using a mixture of 1.5 ml of chloride standard solution (5ppm Cl) R and 13.5 ml of water R. examine the solutions down the vertical axes of tubes.

Should comply.
6. Nitrates Place 5 ml in a test tube immersed in iced water, add 0.4 ml of a 100g/L solution of potassium chloride R, 0.1 ml of diphenyl amine solution R and, dropwise with shaking, 5ml of nitrogen free sulphuric acid R. Transfer the tube to a water bath at 500C. After 15 minutes any blue colour in the solution is not more intense than that in a reference solution prepared at the same time in the same manner using a mixture of 4.5 ml of nitrate free water R and 0.5ml of nitrate standard solution (2 ppm NO3. ) R. Maximum 0.2ppm.
7. Sulphates To 10ml add 0.1ml of dilute HCl R and 0.1ml of barium chloride solution R1. The appearance of the solution does not change for at least 1 hour.
8. Aluminium If intended for use in manufacture of dialysis  solution,

Prescribed solution: To 400ml of water under examination add 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

Reference solution: mix 2 ml of aluminium standard solution (2ppm Al) R, 10 ml of acetate buffer solution pH 6.0 R and 98 ml of distilled water R.

Blank solution: Mix 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

 

Not more than 10 ppb.
9. Ammonium To 20 ml add 1ml of alkaline potassium tetraiodomercurate solution R and allow to stand for 5 minutes. When viewed vertically, the solution is not more intensely coloured than the solution prepared at the same time by adding 1ml of alkaline potassium tetraiodomercurate  solution R  to a mixture of 4.0 ml of ammonium standard solution(1ppm NH4) R and 16 ml of ammonia free water R.

 

Maximum 0.2 ppm.
10. Calcium and Magnesium To 100 ml add 2ml of ammonium chloride buffer solution pH 10.0 R, 50mg of mordant black 11 triturate R and 0.5 ml of 0.01M disodium edetate.

 

A pure blue colour is produced.

 

11. Heavy metals Heat 200 ml in a glass evaporating dish on a water bath until the volume is reduced to 20 ml. 12 ml of the concentrated solution complies with limit test A. prepare the standard using 10 ml of lead standard solution (1 ppm Pb) R. Maximum 0.1ppm.
12. Residue on evaporation. Evaporate 100ml on a water bath and dry in an oven at 100-1050C. For containers with a nominal volume of 10 ml or less the residue weighs not more than 4mg (0.004 percent).

 

For containers with a nominal volume of greater than 10 ml the residue weighs not more than 3mg (0.003 percent).

13. Particulate contamination. Sub visible particles.

It complies with test A or test B, as appropriate

Should comply.
14. Sterility It complies with the test of sterility Should comply.
15. Bacterial endotoxins Less than 0.25 IU/ml, if intended for use in the manufacture of dialysis solution without a further appropriate procedure for removal of bacterial endotoxins. Not more than 0.25 IU/ml.

 

 

 

 

HIGHLY PURIFIED WATER BP:

Sr no. Test Test method Specification
1. Appearance Clear and colourless liquid Should comply.
2. Nitrates Place 5 ml in a test tube immersed in iced water, add 0.4 ml of a 100g/L solution of potassium chloride R, 0.1 ml of diphenyl amine solution R and, dropwise with shaking, 5ml of nitrogen free sulphuric acid R. Transfer the tube to a water bath at 500C. After 15 minutes any blue colour in the solution is not more intense than that in a reference solution prepared at the same time in the same manner using a mixture of 4.5 ml of nitrate free water R and 0.5ml of nitrate standard solution (2 ppm NO3. ) R. Maximum 0.2ppm.
3. Aluminium If intended for use in manufacture of dialysis  solution,

Prescribed solution: To 400ml of water under examination add 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

Reference solution: mix 2 ml of aluminium standard solution (2ppm Al) R, 10 ml of acetate buffer solution pH 6.0 R and 98 ml of distilled water R.

Blank solution: Mix 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

 

Not more than 10 ppb.
4. Heavy metals Heat 200 ml in a glass evaporating dish on a water bath until the volume is reduced to 20 ml. 12 ml of the concentrated solution complies with limit test A. prepare the standard using 10 ml of lead standard solution (1 ppm Pb) R. Maximum 0.1ppm.
5. Bacterial endotoxins Less than 0.25 IU/ml, if intended for use in the manufacture of dialysis solution without a further appropriate procedure for removal of bacterial endotoxins. Not more than 0.25 IU/ml.

 

 

6. Total organic carbon   Maximum 0.5 mg/ml

 

SPECIFICATIONS OF DIFFERENT TYPE OF WATERS ACCORDING TO USP/NF:

Water for injection USP/NF:

Sr no. Test Test method Specification
1. Bacterial endotoxins. As per USP/NF It contains less than 0.25 USP Endotoxin unit per ml.
2. Total organic carbon. As per USP/NF Maximum 0.50 mg/L.
3. Water conductivity. Perform stage 2, step 4 using a sufficient amount of water to perform the test which is as follows.

Transfer a sufficient amount of water (100ml or more) to a suitable container, and stir the test specimen. Adjust the temperature, if necessary, and while maintaining it at 25±10C, begin vigorously agitating the test specimen while periodically observing the conductivity. When the change in conductivity (due to uptake of atmospheric carbon dioxide) is less than a net of 0.1 µs/cm per 5 minutes. Note the conductivity.

The conductivity is not more than 25 µs/cm for containers with a nominal volume of 10ml or less at 25±10C.

And not more than 5µs/cm for containers with a nominal volume of greater than 10ml at 25±10C.

 

 

Bacteriostatic water for injection USP/NF:

Sr no. Test Test method Specification
1. Sterility. As per USP/NF If the water under test does not render the medium turbid after 14 days of incubation then the water is found to be sterile.
2. Antimicrobial agents. As per USP/NF Meets the requirement under antimicrobial effectiveness testing, and meets the labeled claim for content of antimicrobial agent, as determined by the method set forth under antimicrobial agents-content.
3. Bacterial endotoxins. As per USP/NF It contains less than 0.5 USP Endotoxin unit per ml.
4. Particulate matter. Method 1- Light obscuration particle count test as per USP/NF.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Method 2- Microscopic particle count test as per USP/NF.

 

 

1-A (Solutions for parenteral infusion or solution for injection supplied in containers with a nominal content of more than 100 ml)-the preparation complies with the test if the average number of particles present in the units tested does not exceed 25/ml equal to or greater than 10µm and does not exceed 3/ml equal to or greater than 25 µm.

 

1-B (Solutions for parenteral infusion or solution for injection supplied in containers with a nominal content of less than 100 ml)-the preparation complies with the test if the average number of particles present in the units tested does not exceed 6000/container equal to or greater than 10µm and does not exceed 600/container equal to or greater than 25 µm.

 

2A-(Solutions for parenteral infusion or solution for injection supplied in containers with a nominal content of more than 100 ml)-the preparation complies with the test if the average number of particles present in the units tested does not exceed 12/ml equal to or greater than 10µm and does not exceed 2/ml equal to or greater than 25 µm.

 

2-B (Solutions for parenteral infusion or solution for injection supplied in containers with a nominal content of less than 100 ml)-the preparation complies with the test if the average number of particles present in the units tested does not exceed 3000/container  equal to or greater than 10µm and does not exceed 300/container equal to or greater than 25 µm.

5. pH As per USP/NF Between 4.5 and 7 in a solution containing 0.3 ml of saturated potassium chloride solution per 100ml of test specimen.
6. Calcium To 100 ml, add 2ml of ammonium oxalate TS. No turbidity should be produced.
7. Carbon dioxide To 25 ml, add 25 ml of calcium hydroxide TS. The mixture should remain clear.
8. Sulphate To 100ml, add 1 ml of barium chloride TS. No turbidity should be produced.

 

Sterile water for inhalation USP/NF:

Sr no. Test Test method Specification
1. Bacterial endotoxins. As per USP/NF It contains less than 0.5 USP Endotoxin unit per ml.
2. Sterility. As per USP/NF If the water under test does not render the medium turbid after 14 days of incubation then the water is found to be sterile.
3. Water conductivity Perform stage 2, step 4 using a sufficient amount of water to perform the test which is as follows.

Transfer a sufficient amount of water (100ml or more) to a suitable container, and stir the test specimen. Adjust the temperature, if necessary, and while maintaining it at 25±10C, begin vigorously agitating the test specimen while periodically observing the conductivity. When the change in conductivity (due to uptake of atmospheric carbon dioxide) is less than a net of 0.1 µs/cm per 5 minutes. Note the conductivity.

The conductivity is not more than 25 µs/cm for containers with a nominal volume of 10ml or less at 25±10C.

And not more than 5µs/cm for containers with a nominal volume of greater than 10ml at 25±10C.

 

4. Oxidisable substances. To 100ml add 10ml of 2N sulphuric acid, and heat to boiling. For sterile water for inhalation in containers having a fill volume less than 50ml, add 0.4 ml of 0.02 M potassium permanganate, and boil for 5 minutes; where the fill volume is 50 ml or more, add 0.2 ml of 0.02M potassium permanganate, and boil for 5 minutes.

If a precipitate forms cool in an ice bath to room temperature and pass through a sintered glass filter.

The pink colour should not completely disappear.

 

Sterile water for injection USP/NF:

Sr no. Test Test method Specification
1. Bacterial endotoxins. As per USP/NF It contains less than 0.25 USP Endotoxin unit per ml.
2. Sterility. As per USP/NF If the water under test does not render the medium turbid after 14 days of incubation then the water is found to be sterile.
3. pH As per USP/NF Between 5 and 7 in a solution containing 0.3 ml of saturated potassium chloride solution per 100ml of test specimen.
4. Particulate matter. Method 1- Light obscuration particle count test as per USP/NF.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Method 2- Microscopic particle count test as per USP/NF.

 

 

1-A (Solutions for parenteral infusion or solution for injection supplied in containers with a nominal content of more than 100 ml)-the preparation complies with the test if the average number of particles present in the units tested does not exceed 25/ml equal to or greater than 10µm and does not exceed 3/ml equal to or greater than 25 µm.

 

1-B (Solutions for parenteral infusion or solution for injection supplied in containers with a nominal content of less than 100 ml)-the preparation complies with the test if the average number of particles present in the units tested does not exceed 6000/container equal to or greater than 10µm and does not exceed 600/container equal to or greater than 25 µm.

 

2A-(Solutions for parenteral infusion or solution for injection supplied in containers with a nominal content of more than 100 ml)-the preparation complies with the test if the average number of particles present in the units tested does not exceed 12/ml equal to or greater than 10µm and does not exceed 2/ml equal to or greater than 25 µm.

 

2-B (Solutions for parenteral infusion or solution for injection supplied in containers with a nominal content of less than 100 ml)-the preparation complies with the test if the average number of particles present in the units tested does not exceed 3000/container  equal to or greater than 10µm and does not exceed 300/container equal to or greater than 25 µm.

5. Ammonia For containers having a fill volume of less than 50 ml, dilute 50 ml of it with 50ml of high purity water, and use this dilution as the test solution; where the fill volume is 50 ml or more use 100ml of it as test solution. To 100ml of the test solution add 2ml of alkaline mercuric-potassium iodide TS. Any yellow colour produced immediately is not darker than that of a control containing 30µg of added ammonia (furnished by adding 1ml of final solution prepared by diluting 3.0 ml of ammonia TS with high purity water to 100ml; 1ml of the solution is further diluted to 100ml) in 100ml of high purity water.

This corresponds to a limit of 0.6 mg/liter for containers having a fill volume of less than 50 ml and 0.3mg/liter, where the fill volume is 50 ml or more.

Should comply.
6. Calcium To 100 ml, add 2ml of ammonium oxalate TS. No turbidity should be produced.
7. Carbon dioxide To 25 ml, add 25 ml of calcium hydroxide TS. The mixture should remain clear.
8. Chloride To 20 ml in a colour comparison tube add 5 drops of nitric acid and 1 ml of silver nitrate TS, and gently mix: any turbidity produced within 10 minutes is not greater than that produced in a similarly treated control consisting of 20 ml of high purity water containing 10µg 0f chloride (0.5mg/liter), viewed downward over a dark surface with a light entering the tubes from the sides.  
9. Sulphate To 100ml, add 1 ml of barium chloride TS. No turbidity should be produced.
10. Oxidisable substances. To 100ml add 10ml of 2N sulphuric acid, and heat to boiling. For sterile water for inhalation in containers having a fill volume less than 50ml, add 0.4 ml of 0.02 M potassium permanganate, and boil for 5 minutes; where the fill volume is 50 ml or more, add 0.2 ml of 0.02M potassium permanganate, and boil for 5 minutes.

If a precipitate forms cool in an ice bath to room temperature and pass through a sintered glass filter.

The pink colour should not completely disappear.

 

Sterile water for irrigation USP/NF:

Sr no. Test Test method Specification
1. Bacterial endotoxins. As per USP/NF It contains less than 0.25 USP Endotoxin unit per ml.
2. Sterility. As per USP/NF If the water under test does not render the medium turbid after 14 days of incubation then the water is found to be sterile.
3. Water conductivity. Perform stage 2, step 4 using a sufficient amount of water to perform the test which is as follows.

Transfer a sufficient amount of water (100ml or more) to a suitable container, and stir the test specimen. Adjust the temperature, if necessary, and while maintaining it at 25±10C, begin vigorously agitating the test specimen while periodically observing the conductivity. When the change in conductivity (due to uptake of atmospheric carbon dioxide) is less than a net of 0.1 µs/cm per 5 minutes. Note the conductivity.

The conductivity is not more than 25 µs/cm for containers with a nominal volume of 10ml or less at 25±10C.

And not more than 5µs/cm for containers with a nominal volume of greater than 10ml at 25±10C.

 

4. Oxidisable substances. To 100ml add 10ml of 2N sulphuric acid, and heat to boiling. For sterile water for inhalation in containers having a fill volume less than 50ml, add 0.4 ml of 0.02 M potassium permanganate, and boil for 5 minutes; where the fill volume is 50 ml or more, add 0.2 ml of 0.02M potassium permanganate, and boil for 5 minutes.

If a precipitate forms cool in an ice bath to room temperature and pass through a sintered glass filter.

The pink colour should not completely disappear.

 

Purified water USP/NF:

Sr no. Test Test method Specification
1. Total organic carbon. As per USP/NF Maximum 0.50 mg/L.
2. Water conductivity. Perform stage 2, step 4 using a sufficient amount of water to perform the test which is as follows.

Transfer a sufficient amount of water (100ml or more) to a suitable container, and stir the test specimen. Adjust the temperature, if necessary, and while maintaining it at 25±10C, begin vigorously agitating the test specimen while periodically observing the conductivity. When the change in conductivity (due to uptake of atmospheric carbon dioxide) is less than a net of 0.1 µs/cm per 5 minutes. Note the conductivity.

The conductivity is not more than 25 µs/cm for containers with a nominal volume of 10ml or less at 25±10C.

And not more than 5µs/cm for containers with a nominal volume of greater than 10ml at 25±10C.

 

 

Sterile Purified water USP/NF:

Sr no. Test Test method Specification
1. Sterility. As per USP/NF If the water under test does not render the medium turbid after 14 days of incubation then the water is found to be sterile.
2. Water conductivity. Perform stage 2, step 4 using a sufficient amount of water to perform the test which is as follows.

Transfer a sufficient amount of water (100ml or more) to a suitable container, and stir the test specimen. Adjust the temperature, if necessary, and while maintaining it at 25±10C, begin vigorously agitating the test specimen while periodically observing the conductivity. When the change in conductivity (due to uptake of atmospheric carbon dioxide) is less than a net of 0.1 µs/cm per 5 minutes. Note the conductivity.

The conductivity is not more than 25 µs/cm for containers with a nominal volume of 10ml or less at 25±10C.

And not more than 5µs/cm for containers with a nominal volume of greater than 10ml at 25±10C.

 

3. Oxidisable substances. To 100ml add 10ml of 2N sulphuric acid, and heat to boiling. For sterile water for inhalation in containers having a fill volume less than 50ml, add 0.4 ml of 0.02 M potassium permanganate, and boil for 5 minutes; where the fill volume is 50 ml or more, add 0.2 ml of 0.02M potassium permanganate, and boil for 5 minutes.

If a precipitate forms cool in an ice bath to room temperature and pass through a sintered glass filter.

The pink colour should not completely disappear.

 

Water for haemodialysis USP/NF:

Sr no. Test Test method Specification
1. Microbial enumeration test and absence of specified micro organisms. As per USP/NF Total viable count should not exceed 100cfu/ml.
2. Bacterial endotoxins. As per USP/NF It contains less than 2 USP Endotoxin unit per ml.
3. Water conductivity. Perform stage 2, step 4 using a sufficient amount of water to perform the test which is as follows.

Transfer a sufficient amount of water (100ml or more) to a suitable container, and stir the test specimen. Adjust the temperature, if necessary, and while maintaining it at 25±10C, begin vigorously agitating the test specimen while periodically observing the conductivity. When the change in conductivity (due to uptake of atmospheric carbon dioxide) is less than a net of 0.1 µs/cm per 5 minutes. Note the conductivity.

The conductivity is not more than 25 µs/cm for containers with a nominal volume of 10ml or less at 25±10C.

And not more than 5µs/cm for containers with a nominal volume of greater than 10ml at 25±10C.

 

4. Oxidisable substances. To 100ml add 10ml of 2N sulphuric acid, and heat to boiling. For sterile water for inhalation in containers having a fill volume less than 50ml, add 0.4 ml of 0.02 M potassium permanganate, and boil for 5 minutes; where the fill volume is 50 ml or more, add 0.2 ml of 0.02M potassium permanganate, and boil for 5 minutes.

If a precipitate forms cool in an ice bath to room temperature and pass through a sintered glass filter.

The pink colour should not completely disappear.

 

Pure steam USP/NF:

Sr no. Test Test method Specification
1. Bacterial endotoxins. As per USP/NF It contains less than 0.25 USP Endotoxin units per ml (when used in the production of parenterals.)
2. Total organic carbon. As per USP/NF Maximum 0.50 mg/L.

Condensate should meet the requirement.

3. Water conductivity. Perform stage 2, step 4 using a sufficient amount of water to perform the test which is as follows.

Transfer a sufficient amount of water (100ml or more) to a suitable container, and stir the test specimen. Adjust the temperature, if necessary, and while maintaining it at 25±10C, begin vigorously agitating the test specimen while periodically observing the conductivity. When the change in conductivity (due to uptake of atmospheric carbon dioxide) is less than a net of 0.1 µs/cm per 5 minutes. Note the conductivity.

The conductivity is not more than 25 µS/cm for containers with a nominal volume of 10ml or less at 25±10C.

 

And not more than 5µS/cm for containers with a nominal volume of greater than 10ml at 25±10C.

 

Condensate should meet the requirement.

 

Generation of pharmaceutical waters:

Generation of following types of pharmaceutical waters is described hereunder.

PURIFIED WATER:

Purified water is water from any source that is physically processed to remove impurities. Distilled water and deionized water have been the most common forms of purified water, but water can also be purified by other processes including reverse osmosis, carbon filtration, microporous filtration, ultrafiltration, ultraviolet oxidation, or electrodialysis. In recent decades, a combination of the above processes have come into use to produce water of such high purity that its trace contaminants are measured in parts per billion (ppb) or parts per trillion (ppt). Purified water has many uses, largely in science and engineering laboratories and industries, and is produced in a range of purities.

All the above mentioned processes are described here-under.

  • Distillation:- Distilled water is often defined as bottled water that has been produced by a process of distillation and total dissolved solids of less than 10 mg/L. Distillation involves boiling the water and then condensing the steam into a clean container, leaving most solid contaminants behind. Distillation produces very pure water but also leaves behind a leftover white or yellowish mineral scale on the distillation apparatus, which requires that the apparatus be frequently cleaned. Distillation does not guarantee the absence of bacteria in drinking water; unless the reservoir and/or bottle are sterilized before being filled, and once the bottle has been opened, there is a risk of presence of bacteria. For many applications, cheaper alternatives such as deionized water are used in place of distilled water.
  • Deionization:- Deionized water, also known as demineralised water is water that has had its mineral ions removed, such as cations from sodium, calcium, iron, copper and anions such as chloride and bromide. Deionization is a physical process which uses specially-manufactured ion exchange resins which bind to and filter out the mineral salts from water. Because the majority of water impurities are dissolved salts, deionization produces a high purity water that is generally similar to distilled water, and this process is quick and without scale buildup. However, deionization does not significantly remove uncharged organic molecules, viruses or bacteria, except by incidental trapping in the resin. Specially made strong base anion resins can remove Gram-negative Deionization can be done continuously and inexpensively using electrodeionization. Deionization does not remove the hydroxide or hydronium ions from water. These are the products of the self-ionization of water to equilibrium and therefore are impossible to remove.
  • Reverse osmosis:- Reverse osmosis is a membrane separation process for removing solvent from a solution. When a semi permeable membrane separates a dilute solution from a concentrated solution, solvent crosses from the dilute to the concentrated side of the membrane in an attempt to equalize concentrations. The flow of solvent can be prevented by applying an opposing hydrostatic pressure to the concentrated solution. The magnitude of the pressure required to completely impede the flow of solvent is defined as the “osmotic pressure”. If the applied hydrostatic pressure exceeds the osmotic pressure (see figure below), flow of solvent will be reversed, that is, solvent will flow from the concentrated to the dilute solution. This phenomenon is referred to as Reverse Osmosis. The figure illustrates the concepts of osmosis, osmotic pressure and reverse osmosis schematically.

Fig: Osmosis and reverse osmosis.

Overview of osmosis and reverse osmosis:- In order to use reverse osmosis as a water purification process, the feed water is pressurized on one side of a semi permeable membrane. The pressure must be high enough to exceed the osmotic pressure to cause reverse osmotic flow of water.

If the membrane is highly permeable to water, but essentially impermeable to dissolved solutes, pure water crosses the membrane and is known as product water. As product water crosses the membrane, the concentration of dissolved impurities increases in the remaining feed water (a condition known as concentration polarization) and, as a consequence, the osmotic pressure increases.

A point is reached at which the applied pressure is no longer able to overcome the osmotic pressure and no further flow of product water occurs. Moreover, if the applied pressure is increased in an attempt to gain more product water, a point is reached at which the membrane becomes fouled by precipitated salts and other undissolved material from the water.

Therefore, there is a limit to the fraction of feed water which can be recovered as pure water and reverse osmosis units are operated in a configuration where only a portion of the feed water passes through the membrane with the remainder being directed to drain (cross-flow configuration).

The water flowing to drain contains concentrated solutes and other insoluble materials, such as bacteria, endotoxin and particles, and is referred to as the reject stream. The product water to feed water ratio can range from 10% to 50% for purification of water depending on the characteristics of the incoming water as well as other conditions.

Fig: Reverse Osmosis Equipment

Types of Reverse Osmosis Membranes

A reverse osmosis membrane must be freely permeable to water, highly impermeable to solutes, and able to withstand high operating pressures. It should ideally be tolerant of wide ranges of pH and temperature and should be resistant to attack by chemicals like free chlorine and by bacteria.

Ideally, it should also be resistant to scaling and fouling by contaminants in the feed water. There are three major types of reverse osmosis membranes: cellulosic, fully aromatic polyamide and thin film composite.

Cellulosic Membranes: The concept of reverse osmosis was first demonstrated in the late 1950s with cellulose acetate membranes. These membranes are asymmetric, composed of a thin dense surface layer (0.2 to 0.5 ~m ) and a thick porous substructure. Solute rejection is accomplished by the thin dense layer and the porous substructure provides structural strength. Cellulose acetate membranes can be cast in sheets or as hollow fibers.

Cellulose acetate membranes are inexpensive and easy to manufacture but suffer from several limitations. Their asymmetric structure makes them susceptible to compaction under high operating pressures, especially at elevated temperatures.

Compaction occurs when the thin dense layer of the membrane thickens by merging with the thicker porous substructure, leading to a reduction in product flux.

Cellulose acetate membranes are susceptible to hydrolysis and can only be used over a limited pH range (low pH 3 to 5 and high pH 6 to 8, depending on the manufacturers). They also undergo degradation at temperatures above 35°C.

They are vulnerable to attack by bacteria.

Cellulose acetate membranes have a high water permeability but reject low molecular weight contaminants poorly.

Cellulose triacetate membranes have been developed with improved salt rejection characteristics and reduced susceptibility to pH, high temperature and microbial attack. However, cellulose triacetate membranes have a lower water permeability than cellulose acetate membranes. Blends of cellulose triacetate and cellulose acetate have been developed to take advantage of the desirable characteristics of both membranes.

Aromatic polyamide membranes:- Aromatic polyamide membranes were first developed by DuPont in a hollow fiber configuration. Like the cellulosic membranes, these membranes also have an asymmetric structure with a thin (0.1 to 1.0, um) dense skin and a porous substructure.

Polyamide membranes have better resistance to hydrolysis and biological attack than do cellulosic membranes. They can be operated over a pH range of 4 to 11, but extended use at the extremes of this range can cause irreversible membrane degradation. They can withstand higher temperatures than cellulosic membranes. However, like cellulosics, they are subject to compaction at high pressures and temperatures.

They have better salt rejection characteristics than cellulosic membranes as well as better rejection of water soluble organics.

A major drawback of polyamide membranes is that they are subject to degradation by oxidants, such as free chlorine.

Thin film composites: As the name indicates, these membranes are made by forming a thin, dense, solute rejecting surface film on top of a porous substructure. The materials of construction and the manufacturing processes for these two layers can be different and optimized for the best combination of high water flux and low solute permeability.

The water flux and solute rejection characteristics are predominantly determined by the thin surface layer, whose thickness ranges from 0.01 to 0.1 micrometers.

Several types of thin film composite membranes have been developed, including aromatic polyamide, alkyl-aryl poly urea/polyamide and polyfurane cyanurate. The supporting porous sub layer is usually made of polysulfone.

Polyamide thin film composites, like polyamide asymmetric membranes, are highly susceptible to degradation by oxidants, such as free chlorine. Consumers must be consistent in their maintenance of the TFC systems, particularly the carbon pre filtration element which is present to remove free chlorine (and other oxidative organics) and prevent damage and premature destruction of the TFC membrane

Although the stability of these membranes to free chlorine has been improved by modifications of the polymer formulation and the processing technique, exposure to oxidants must be minimized.

Applications: Reverse osmosis membranes reject dissolved inorganic solutes, larger organic solutes (molecular weight greater than 200), a portion of microbiological contaminants such as endotoxin, viruses and bacteria, and particles. Because of this broad spectrum of solute rejection, reverse osmosis is an important process in a wide variety of water treatment processes.

  • Other processes:
  • Microporous filtration:– Microfiltration/Microporous filtration is generally referred to the filtration at less than 1 Micron level.  Depth filters of the conventional type are available in 0.5, 0.2, 0.1 Microns and other sizes.  Most Microfilters use membrane materials.

Spiral wound microfiltration membranes allow a cross-flow type of microfiltration.  Feed water at a relatively high flow is pumped at a pressure of 10-50 psi along the membrane surface.  A small amount (5-10%) of the water goes through the membrane.  The balance of water goes to the next membrane element or is recycled back.  In addition, a small amount of concentrate is removed from the system.

This cross-flow process helps minimize the fouling of the surface of the microfiltration membrane.  Many different materials have been used for Microfiltration but most common are Polysulfone and Polyvinylidine Fluoride. Membranes in both of these materials are available from Applied Membranes, Inc.

Membranes with a pore size of 0.1 – 10 µm perform micro filtration. Microfiltration membranes remove all bacteria. Only part of the viral contamination is caught up in the process, even though viruses are smaller than the pores of a micro filtration membrane. This is because viruses can attach themselves to bacterial biofilm. Micro filtration can be implemented in many different water treatment processes when particles with a diameter greater than 0.1 mm need to be removed from a liquid.

Examples of micro filtration applications are:

Cold sterilization of beverages and pharmaceuticals.

Clearing of fruit juice, wines and beer

Separation of bacteria from water (biological wastewater treatment)

Effluent treatment

Separation of oil/ water emulsions

Pre-treatment of water for nanofiltration or Reverse Osmosis.

Solid-liquid separation for pharmacies or food industries.

  • Ultra filtration:- Ultrafiltration or UF is a pressure driven membrane separation process that separates particulate matter from soluble components in the water. UF membranes typically have pore sizes in the range of 0.001 – 0.10 µm and have a high removal capability for bacteria and most viruses, colloids and silt (SDI). The smaller the nominal pore size, the higher the removal capability. Most materials that are used in UF are polymeric and are naturally hydrophobic. Common polymeric materials used in UF include: Polysulfone (PS), Polyethersulfone (PES), Polypropylene (PP), or Polyvinylidenefluoride (PVDF). Although these materials can be blended with hydrophilic agents, they can reduce the membranes ability to be cleaned with high strength disinfectants such as hypochlorite that impacts removal of bacterial growth.

The DOW™ Ultrafiltration module utilizes a double-walled hollow fiber (capillary) PVDF membrane which has a very small nominal pore diameter for PVDF material that allows for the removal of all particulate matter, bacteria and most viruses and colloids. Despite the small pore diameter, the membrane has a very high porosity resulting in a flux similar to that of micro-filtration (MF) and can effectively replace MF in most cases.

Systems designed with DOW™ Ultrafiltration use an outside-in flow configuration which allows for less plugging, higher solids loading, higher flow area and easy cleaning. The primary flow design is dead-end filtration but the module can be operated using a concentrate bleed. Dead-end filtration uses less energy and has a lower operating pressure than the concentrate bleed, therefore reducing operating costs.

Typically, DOW™ Ultrafiltration is operated at a constant permeate flow. The transmembrane pressure (TMP) will naturally increase over time and the module can be cleaned periodically by back flushing and air scouring to remove the fouling layer. Disinfectants and other cleaning agents can be used to fully remove and prevent performance loss due to biological growth as well as other foulants.

Fig: Ultrafiltration equipment

  • Ultraviolet oxidation:

 Description:- Ultraviolet (UV) oxidation is a destruction process that oxidizes organic contaminants in water. It works by the adding oxidizing agents such as ozone (O3) or hydrogen peroxide (H2O2) to the contaminated groundwater. The contaminated solution is passed through a chamber where it is exposed to intense UV radiation. UV radiation is provided by UV light bulbs Oxidation of target contaminants is caused by direct reaction with the oxidizers (for example, see description of Peroxzone), and through the action of UV light in combination with ozone and/or hydrogen peroxide.

Limitations and Concerns:- A major success factor is how well UV light is transmitted to dissolved contaminants. High turbidity (e.g., cloudiness) of the water would cause interference.

The water should be relatively free of heavy metal ions and insoluble oil or grease to minimize the potential for fouling of the lights.

This system does not destroy some volatile organics such as trichloroethane (TCA). Instead, the contaminants may be vaporized and would need to be treated in an off-gas system.

Energy requirements are very high, and this is a large drawback to this technology.

Handling and storage of hydrogen peroxide requires special safety precautions.

Applicability:- UV treatment is used to destroy VOCs and UXO (explosive compounds such as TNT) in groundwater. Typically, easily oxidized organic compounds, such as those with double bonds (e.g., TCE, PCE, and vinyl chloride), as well as simple aromatic compounds (e.g., toluene, benzene, xylene, and phenol) are rapidly destroyed in UV/oxidation processes.

Technology Development Status:- The UV/oxidation technology is a commercially available groundwater treatment technology that has been used for more than 10 years. A majority of these applications are for groundwater contaminated with petroleum products or with a variety of industrial solvent-related organics such as TCE, DCE, and vinyl chloride. Its use for destroying explosive compounds has been more limited. The US Army Environmental Center (AEC) evaluations have shown it to be 99.9% effective in destroying common explosives in groundwater.

  • Electrodialysis:– Electrodialysis is an electromembrane process in which ions are transported through ion permeable membranes from one solution to another under the influence of a potential gradient. The electrical charges on the ions allow them to be driven through the membranes fabricated from ion exchange polymers. Applying a voltage between two end electrodes generates the potential field required for this. Since the membranes used in electrodialysis have the ability to selectively transport ions having positive or negative charge and reject ions of the opposite charge, useful concentration, removal, or separation of electrolytes can be achieved by electrodialysis.

Ion Permeable Membranes:The ion permeable membranes used in electrodialysis are essentially sheets of ion-exchange resins. They usually also contain other polymers to improve mechanical strength and flexibility. The resin component of a cation-exchange membrane would have negatively charged groups (e.g., -SO3-) chemically attached to the polymer chains (e.g., styrene/divinylbenzene copolymers). Ions with a charge opposite to the fixed charge (counter ions) are freely exchanged at these sites. The concentration of counter ions (e.g., Na+) is relatively high; therefore, counter ions carry most of the electric current through the membrane. The fixed charges attached to the polymer chains repel ions of the same charge (co-ions), in this case the anions. Since their concentration in the membrane is relatively low, anions carry only a small fraction of the electric current through a cation permeable membrane. Attachment of positive fixed charges (e.g., -NR3+ or C5H5N+R where commonly R = CH3) to the polymer chains forms anion permeable membranes, which are selective to transport of negative ions, because the fixed -NR3+ groups repel positive ions. This exclusion, as a result of electrostatic repulsion, is called Donnan exclusion. Ion-exchange polymers such as polystyrene sulfonic acid are water soluble, so crosslinking is needed to prevent dissolution of ion permeable membranes. Divinylbenzene is used to cross link polystyrene chains. The degree of cross-linking and the fixed-charge density affect the membrane’s properties in opposite ways. Higher crosslinking improves selectivity and membrane stability by reducing swelling, but it increases electrical resistance. High charge density reduces resistance and increases selectivity, but it promotes swelling and thus necessitates higher crosslinking. A compromise between selectivity, electrical resistance, and dimensional stability is achieved by proper adjustment of cross linking and fixed-charge densities.

Bipolar Membranes:- Bipolar membranes consist of an anion-permeable membrane and a cation permeable membrane laminated together. When this composite structure is oriented such that the cation-exchange layer faces the anode it is possible, by imposing a potential field across the membrane, to spit water into proton and hydroxyl ions. This results in the production of acidic and basic solutions at the surfaces of the bipolar membranes. Multiple bipolar membranes along with other ion permeable membranes can be placed between a single pair of electrodes in an electrodialysis stack for the production of acid and base from a neutral salt. There are substantial advantages to water splitting with bipolar membranes. Since there are no gases evolved at the surface or within the bipolar membranes, the energy associated with conversion of water to O2 and H2 is saved, and the power consumption is about half that of electrolytic cells. Compared to the electrodes used in conventional electrolytic cells, the bipolar membranes are inexpensive. Where dilute (e.g., < 1 M) acids or bases are needed, bipolar membranes offer the prospect of low cost and minimum unwanted byproducts.

Water for injection:- Water for injection is water purified by distillation or a purification process that is equivalent to or superior to distillation in the removal of chemicals and microorganisms.

The source water for production of WFI may be-

  • Purified water.
  • Water for human consumption.

Process of production of water for injection may be described as follows.

  • Distillation: Distillation involves boiling the water and then condensing the steam into a clean container, leaving most solid contaminants behind. Distillation produces very pure water but also leaves behind a leftover white or yellowish mineral scale on the distillation apparatus, which requires that the apparatus be frequently cleaned. Distillation does not guarantee the absence of bacteria in water; unless the reservoir and/or bottle are sterilized before being filled, and once the bottle has been opened, there is a risk of presence of bacteria.
  • Double-distillation:- Double-distilled water is prepared by double distillation of water. Historically, it was the de facto standard for highly purified laboratory water for biochemistry and trace analysis until combination methods of purification became widespread.
  • Multicolumn distillation:- By Multi Effect Distillation method significant energy (75% approx) is saved when compared to the conventional method.

Fig: Multicolumn distillation

Operation:- The pre-heated feed water (through condenser) is fed into the first column where 33% of feed water is converted into steam under pressure by outside boiler steam. The pure steam produced in the first column having temperature of 1350C and the remaining feed water goes to the 2nd column. The pure steam is used as a heating media in the 2nd column and converts part of remaining feed water into steam. In the process the steam itself condenses back into water. This process is repeated till the last column each working at low temperature & pressure as compared to the one before it. The steam produced in the last column is condensed in the condenser by feed water as well as cooling water. As external heat is required only to convert the 33% of feed water, the heating energy required is reduced by 67%.

Sterilized water for injection:- This preparation is designed solely for parenteral use only after addition of drugs that require dilution or must be dissolved in an aqueous vehicle prior to injection.

Sterile Water for Injection, USP is a sterile, nonpyrogenic preparation of water for injection which contains no bacteriostatic, antimicrobial agent or added buffer and is supplied only in single-dose containers to dilute or dissolve drugs for injection. For I.V. injection, add sufficient solute to make an approximately isotonic solution.

The source water for production of sterile water for injection is water for injection.

INSTALLATION OF NEW WATER SYSTEM:

For the installation of new water system, user will need to have following documents for proper understanding between manufacturer and user and proper installation and working of water system as per specific requirement.

These documents include:

  • User requirement specification (URS).
  • Design qualification (DQ).
  • Installation qualification (IQ).
  • Operational qualification (OQ).
  • Performance qualification (PQ).

User requirement specification (URS):- It is a documented information about the basic requirement by the user of the water quality for its specific use. The information should be furnished under following headings.

  • Design criteria/system description.
    • Usage of different types of water.
  • System requirement / required quality of purified water.
    • Daily consumption.
    • Material of construction of the system.
    • Sampling points.
    • Other consideration.
    • Design basis.
  • Technical specification.
  • Document approval.

All the above mentioned points are discussed here under.

  • Objective:- To list out specific requirements of water system.
  • Scope:- It describes the water system for which this specification is applicable. (For certain pharmaceutical company).
  • Design criteria/system description:- The design of water system will be based on following information.
  • Daily water requirement of the plant.
  • Source of raw water.
  • Quality of raw water.
  • Different desired processing steps of raw water like.
  • Pre dosing system
  • Post dosing system
  • Softening system.
  • Reverse osmosis system.
  • Electro deionization system.
    • Usage of different types of water:- Usage of different types of waters is described under this heading.
  • System requirement / required quality of purified water:- It contains some parameters and specification that the quality of water should comply with.

It specifies different parameters which are applicable for the different types of water like

  • Description
  • pH
  • conductivity
  • acidity/ alkalinity
  • Calcium& magnesium.
  • Chloride
  • Sulphate
  • Nitrates
  • Residue on evaporation
  • Total bacterial count
  • Fungal count
  • Pathogens
  • And many more.
  • Daily consumption:- It describes the daily generation capacity of the installed water system and daily consumption of the concerned plant.
  • Material of construction of the system:– It describes the desired quality of the material of construction that should be maintained. All components (valve etc.) should be of suitable make so as to obtain water of desired quality consistently.
  • Instruments:- It describes all the required instruments to complete the unit.
  • Controls:– It describes the way of control of the water system whether manual or PLC (Programmable Logical Control).
  • Sampling points:– It describes the places/user points where the sampling points should be present.
  • Documentation:- It describes the list of documents the supplier should provide at least.

These may include-

  • P & I diagram.
  • Calibration certificates for all instruments with national/international traceability.
  • Test and guarantee certificates.
  • Qualification (DQ, IQ, OQ) documentation
  • Individual part certificates
  • Instrument manual.
  • Other considerations:- It describes any other considerations those are necessary in water system.
  • Design basis.
  • Technical specification:- It describes the details and specifications for the instruments of the installed water system.

The instruments may be as follows.

  • Sanitary vent filter.
  • Compound pressure gauze.
  • Safety valve, pressure gauze, air vent valve assembly for jacket.
  • Steam trap assembly.
  • Air evacuated steam valve.
  • Pressure indicator.
  • Spray ball assembly.
  • Temperature controller.
  • Flow transmitter vortex type.
  • Conductivity sensor.
  • Document approval:- This part contains the signatures of the persons who has prepared the URS and who has approved the URS.

Design qualification (DQ):- Based on the URS a basic design is prepared for achieving the technical requirement of desired water. To achieve this design specification, a set of document is prepared under a heading of DQ. This document includes detailed specification of all the major components of water generation and distribution system.

The DQ is described under following headings.

  • Objective:- Objective of design qualification is to finalize the design of the system by comparing it with the required specification for the water system.

To prepare detailed specification for all major components of the water system generation and distribution system to ensure that the user requirement specification and functional requirement specification are achieved.

  • Scope:- This document shall be applicable for design qualification of the water system to be installed for an organization.
  • Selection of vendor:-
    • Preliminary selection of design:- Based on URS, a preliminary design of the system is derived. List of suitable vendors are prepared on the basis of evaluation and called for technical and commercial discussion with the technical team of the company.
  • Assessment of suitable vendor:- During assessment the vendors are evaluated on the basis of their capability of fulfilling the requirement of the company.
  • Final selection of vendor:– Final selection of vendors is done as an outcome of technical discussion and cost consideration.

Note: – Sometimes multiple vendors are selected for multiple purposes like generation, distribution etc.

  • Responsibilities:- Responsibilities of the vendors of the generation system, distribution system and the client are described under different headings.
  • Responsibilities of vendors of generation system.
  • To assure that the system meets the standard as per agreed technical specification.
  • To provide technical specification of all instrument, equipment, and other components to the client.
  • All drawings and lay out of the water system should be prepared & provided to the client.
  • The material of construction should be of SS316L STAINLESS STEEL and where the water is not coming in contact shall be of SS304.
  • Responsibilities of vendors of distribution system:-
  • To assure that the system meets the standard as per agreed technical specification.
  • To provide technical specification of all instrument, equipment, and other components to the client.
  • All drawings and lay out of the water system should be prepared & provided to the client.
  • The material of construction should be of SS316L STAINLESS STEEL and where the water is not coming in contact shall be of SS304.
    • Responsibilities of the Client:-
  • To check and verify all technical documented submitted by the vendor.
  • To provide all the required utility support to the vendors for establishment of the system.
  • To carry out OQ & PQ.
  • Description:- Under this heading the protocol should describe the different component in the water system to be supplied by the vendors. The component will include both generation system and distribution system.
  • Pharmaceutical water generation system:- Complete description of water generation system is given.
  • Pharmaceutical water distribution network:- Complete description of water distribution system is given.
  • Scope of the work:– Under this topic responsibilities of the suppliers of different component of water system should be specified. These responsibilities include design, engineering, supervision, erection, etc.
  • Basis of design:-
  • Water generation system:- Design of water generation system should be based on the raw water analysis report which is furnished to the vendors of water generation system. The water generation system should be designed taking into consideration the higher limits which could occur due to the seasonal variation of source water. The system should be designed to cater the needs of production taking into consideration the operation of plant for 24 hrs.
  • Water distribution network:- Design of the distribution network should be finalized based on the quality of the water generated by the generation system. The water distribution system should be designed in such a manner that, it is capable of maintaining the water quality during the distribution and capable of supplying the water with predetermined pressure and temperature for 24hrs.
  • Design specification:- Design specification for generation system and distribution system shall be verified during IQ.
  • Sampling points:- Sampling points should be feasible for sampling and considering zero dead lags.

The sampling points and their locations are described under this heading.

  • Quality of water to be generated:- Required specification/quality of the water after each treatment is given under this heading.
  • Flow scheme for generation and distribution of purified water:- The whole water generation system and distribution network is given in form of a flow diagram under this heading.
  • Process description of water system:- The detailed process involved in the different steps of the water generation and distribution are described under different headings like pretreatment section, RO system, EDI system, sanitization, water distribution loop etc.
  • Risk analysis:- Limiting factors of operation of the generation system is described. Critical aspects for satisfactory performance of the generation system for purified water are described.
  • Design input for different components of generation and distribution system:– Under this heading the protocol gives the basic design of different components of water system like
  • RO unit
  • EDI unit
  • Rectifier
  • Flow indicator
  • Pressure gauzes
  • Flow meters
  • Conductivity meters etc.

This will include all critical parameters like Material of construction, flow rate, membrane type, operating membrane pressure, etc.

  • List of interlocks
  • Generation system:- Under this heading the interlocks used in the water generation system is listed with their specific purpose and working.

Examples-

  • ORP(oxidation reduction potential) dump valve
  • Conductivity indicator(CI)
  • FIE (flow indicator element) etc.
  • Distribution system:- Under this heading the interlocks used in the water distribution system is listed with their specific purpose and working.
  • Set points of instruments:- Under this heading set points for different instruments like conductivity indicator, pH indicator, flow indicator, pressure switches etc. are given.
  • List of equipments:- The equipments supplied for generation of different grades of pharmaceutical waters are listed with the appropriate material of construction and detailed specifications for each.

These include-

  • Pump
  • RO/EDI block
  • Tanks
  • Instrument list and design specification – control panel/PLC
  • Flow indicator details
  • Conductivity and pH instrument detail
  • Other instruments
  • Control panel and PLCs
  • Water distribution system
  • Conductivity transmitter
  • Pressure gauze
  • Compound pressure gauze
  • Temperature sensor
  • Level transmitter
  • Flow transmitter
  • Intensity monitor etc.
    • Valve details etc.
  • Attachment

Following attachments shall be attached with the installation qualification report.

S.N. DESCRIPTION
1. URS of water system
2. Equipment layout drawing
3. P & I drawing for the water system.
4. Control scheme for instrument cum starter panel
5. RO projections
6. Certificate of MOC of piping network for water whole water system(generation and distribution)
7. Certificates of all the valves used in generation and distribution.
8. Welding drawing as built.
9. Certificate of pressure hydraulic test of piping network
10. Passivation certificate.

 

  • Documentation and raw data:- All the data shall be recorded on the attached annexures and shall be attached with the IQ report.
  • Derivation (if any):– Any deviation from this protocol shall be recorded for necessary corrective action.
  • Summary, conclusion and completion of activity:– All the information should be verified during IQ and completion the qualification. A summary shall be prepared for the complete activity and conclusion shall be drawn for the summary. On the completion of the activity a certificate shall be issued.

FIND MORE AT…

Reference links

http://forums.pharmacyonesource.com/phos/attachments/phos/pharmacy_ops/3975/1/Water%20for%20Pharmaceutical%20Use_1231.pdf

http://www.who.int/medicines/areas/quality_safety/quality_assurance/GMPWatePharmaceuticalUseTRS970Annex2.pdf?ua=1

https://hmc.usp.org/sites/default/files/documents/HMC/GCs-Pdfs/c1231.pdf