Water Treatment

Dr. Majed FeddahPharmaceutical Dosage

Forms and Calculations

Drinking Water

2

Dissolved and unresolved organic matters

Sod

ium

,

Potassium

Magnesium Ir

on

Ch

lori

des

sulf

ates

Bicarbonates

Clear, colorless, odorless, neutral,

The use in pharmaceutical industries

Microorganisms

Why Purification of Water

1. Although reasonably pure, it is always

variable.

2. Seasonal variations may occur in water.

3. Some regions have very poor quality water.

4. Must remove impurities to prevent product

contamination.

5. Control microbes to avoid contaminating

products 3

There is no pure water in nature, as it can contain large no of possible unacceptable contaminants

Contaminant groups:1. Inorganic compounds2. Organic compounds3. Solids 4. Gases5. Micro-organisms

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Why Purification of Water

Contamination in Water

Problem minerals

1. Calcium and magnesium

2. Iron and manganese3. Silicates4. Carbon dioxide5. Hydrogen sulfide6. Phosphates

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Contamination in Water

Further problem minerals 1. Copper2. Aluminum3. Heavy metals

Arsenic, lead, cadmium4. Nitrates

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Microbial Contamination

Micro-organisms – Biofilm1. Algae2. Protozoa

Cryptosporidium Giardia

3. Bacteria Pseudomonas Gram negative, non-fermenting bacteria Escherichia coli and coliforms

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Pyrogens and endotoxins

Any compound injected into mammals which gives rise to fever is a “Pyrogen”.

Water Types:There are essentially four types of water that are of interest to the pharmaceutical industry:1) Potable water: Feed water, public water

supply, service water, city water, drinking water, National Primary Drinking Water

2) Purified water: Aqua purificata, demineralized water, deionized water.

3) Water for injection: Aqua ad iniectabilia, ultra pure water, distilled water

4) Highly purified water: Aqua valde purificata, low endotoxin water, reverse osmosis water

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Purified Water filled into containers (Packaged Purified Water)

If purified water is filled into containers for dispensing, it is a final product. In this case, additional tests for purity must be carried out. Purified water filled in containers must also pass the following tests: 1. Test for acidic or alkaline substances,

oxidizable substances, chlorides, sulfates, ammonium.

2. Microbial purity.

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Application of purified water in bulk

Manufacturing for category 2, 3 and 4 products

Manufacturing of WFI. Manufacturing of highly purified water. Cleaning of facilities. Cleaning of containers for category 2, 3 and

4 products. Rinsing of equipment & containers for

category 1 products* Autoclave cooling (only cooling jacket) Autoclave cooling (touching container). Blue bath solution.

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Highly purified waterApplication of highly purified water: Manufacturing of ophthalmic products. Manufacturing of sterile nose/ear

preparations. Manufacturing of sterile preparations forCutaneous use. Final rinsing of equipment, containers and

covers for sterile parenterals, if a later depyrogenation step is carried out.

Highly purified water is made from potable water, by double-step reverse osmosis combined with other suitable procedures such as ultrafiltration or deionization.

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Water for injection

Application of water for injection in bulk:

Manufacturing of parenterals (aseptic manufacturing) Manufacturing of parenterals (final sterilization) Final rinsing of equipment,

containers and caps for category 1 products

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Sterilized Water for Injection

Sterilized Water is produced by filling water for injection into adequate containers which are sealed and sterilized by heat.

Sterilized Water for Injection has to fulfill the test for bacterial endotoxins and must not contain any additives.

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Water for Injection: special USP monographs

The USP also distinguishes between the following types of water for injection, unlike the European pharmacopoeia:

1. Bacteriostatic water for injection2. Sterile water for inhalation3. Sterile water for irrigation4. Water for hemodialysis

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Generation of Purified Water

In order to produce the chemical & microbiological quality water types and at the same time comply with the regulations, certain instruments are required for the generating purified water. The raw water must be:

Pretreated before actual purification.

Thus, a facility for generating purified water consists of several steps, which are described next:

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Air-break In order to protect the public water

supply from contamination, it is necessary to install an air-break between the first processing step in the generation of purified water and the feed of potable water.

This is in order to prevent reverse contamination in the public water supply. The systems can be separated in various ways.

1) Install a supply separation container.

2) Use a supply or non-return valve.17

Softener

The potable water is first coarsely filtered, then the scale (calcium, magnesium, sulfate, carbonate) is removed in a first stage.

A choice procedure would be softening using ion exchange technology.

A sodium exchanger can be used for this purpose.

The magnesium and calcium ions present in the water are deposited in the resin in exchange for sodium ions.

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Na+

Exchanger

materials

Exchanger

materials

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Removal of chlorine Only potable water can be used to

generate pharmaceutical water. However, the composition can vary greatly

and it is possible that the potable water may have been chlorinated.

As the raw water must be free from oxidation media, de-chlorination must be carried out through the use of either:

1. Activated charcoal filters. or2. Sodium bisulfite (Na2HSO3).

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Activated charcoal filter The use of an activated charcoal filter

for de-chlorination of the potable water is a simple & very effective method.

Activated charcoal absorbs low molecular weight organics, such as chlorine and chloramine compounds.

However, when manufacturing ultra pure water the use of activated charcoal could be problematic. The risk of increased microbiological fouling and the formation of a biofilm is very high. 23

Dosage of sodium bisulfite

Sodium bisulfite is added to the raw water. Sodium bisulfite combines with the chlorine, which is then separated through reverse osmosis.

The added quantity must be adjusted.

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Removal of carbon dioxide (CO2) Carbon dioxide represents a problem

when generating purified water via reverse osmosis, as it is not retained by the reverse osmosis membrane and thus leads to increased conductivity. Two methods are used to remove carbon dioxide:

1. Dosage of sodium hydroxide solution: The carbon dioxide is converted into carbonate, which is retained by reverse osmosis.

2. Membrane degassing: Through the creation pressure difference and are rinsed from the membrane using air.

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Reverse osmosis Deionization and removal of

microorganisms can be carried out in the reverse osmosis unit.

Reverse osmosis is a physical operation which takes place on membranes. It reverses the process of osmosis.

A semipermeable membrane retains cations, anions colloidal systems and bacteria.

The membrane lets through water that is almost pure.

With reverse osmosis, more than 98 % of salts and 90 % of organic compounds are retained, as well as bacteria and organisms.

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In order to reverse the process of osmosis, pressure higher than the osmotic pressure must be applied to the concentrate stream in order to push water with a low amount of solids through the membrane.

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Reverse osmosis mechanism

Reverse Osmosis

Remove particles, bacteria, pyrogen, organic, inorganic ions and silica

Reverse Osmosis

Reverse Osmosis

Electro-deionization (EDI, CDI)

Electro-deionization (CDI = Continuous Deionization; EDI = Electro-deionization.

EDI works by coupling the behavior of ions in the electrical field with membrane technology.

The anions wander towards the anode.

The cations are transported towards the cathode in the same manner.

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Advantages of EDI High purification level (>98%) with small

membrane area. Continuous operation through self-

regeneration. No use of chemicals for regeneration or

neutralization. Retention of high pH values through

water division and thus regeneration Optimum carbon dioxide, silicate and TOC

removal Prevention of multiplication of

microorganisms. Low energy consumption (0.1–1.0 KW/m3)

with very low voltage. Minimum space requirement due to

compact design of the module

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Ultra filtration

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Ultra filtration (UF) is a separation technology for separating particles with a size of 0.001 to 0.1 μm.

For ultra pure water production UF hollow fiber membranes are usually used.

The conductivity of the permeate remains nearly the same as that of the feed water.

Ion exchanger

In the ion exchanger (separate bed and mixed bed system) ions are removed from the water. Ion exchangers are filled with special resins which are usually produced from synthetic polymers as balls (particle size 0.3–1.5 mm.

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2. Ion-Exchange The ion-exchange equipment

involves the passage of water through a column of:

Cation and Anion exchangers.Resin is:

Water-insoluble materialssynthetic, polymerized phenolic,

carboxylic, amino, or sulfonated materials high molecular weight.

Types of Resins

1. The Cation or acid exchangers. Which permit the exchange of

Cations +

Na+, Ca++, Mg++, etc, (in solution in the tap water) with hydrogen ion from the resin.

2. The Anion-, or base exchange resins. which permit the removal of anions in solution in the tap water with Cl

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The process is as follows: (M+) indicating the metal or Cation as (Na+) (X-) indicating the Anion as (Cl-)Cation ExchangeH-Resin + M+ + X- + H2O M-Resin + H+ + X- + H2O.

Anion Exchange:Resin-NH2 + H+ + X- + H2O Resin-NH2 . HX + H2O Pure.

Purified water in this method is named as demineralized or de-ionized water.

Used in any pharmaceutical preparation or prescription.

Purification plants The particular combination of

procedures usually depends on the feed water quality. Usually, the analysis results from the potable water supplier can be used for initial planning regarding which combinations will give the desired result.

There are feed water qualities for which the combination of reverse osmosis with an EDI is sufficient for the generation of purified water. For other feed water qualities, softening, reverse osmosis, CO2-degassing and EDI must be combined to achieve the same result.

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Distilled Water / Distillers

It’s an Instrument used to generate distilled water, by boiling the water and collect the steam in a clean container.

This water which called Distilled water used mainly in the preparation of injectable products such as IV. Solutions, Ampoules, Eye drops, and Liquid Vials.

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Distilled Water

Distilled water is water that has virtually all of its impurities removed through distillation. Distillation involves boiling the water and then condensing the steam into a clean container, leaving most if not all solid contaminants behind.

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Procedure combination for generation purified water

System1

System 2

System 3

System 4

System 5

System 6

Activated charcoal filter

X

Softener X X X X

Mixed bed technology

X X

Ultra filtration

X X

Reverse osmosis

X X X X X

Degassing X X

EDI/CDI X X X 42

Water System

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Softening Reverse Osmosis

Reverse Osmosis

Softening Electro

Deionization

Reverse Osmosis

Pu

rified

Wate

r

Waste Water

Waste WaterWaste Water

Waste Water

Water for injection (WFI) Water for injection (WFI) is required for

the production of sterile medicinal products.

The requirements of manufacturing procedures for WFI are different in the USA, Japan and Europe (see Figure 5.B-9).

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Permissible manufacturing procedure for WFI

Europe Distillation

USP Distillation or other equivalent or superior processes

Japan Ultra filtration or distillation

Pretreatment – schematic drawing

Water is kept circulating

raw water in

« S” trap to sewer

To water softener & DI plant

cartridgefilter

5 micrometers

activatedcarbon

filter

spray ball

break tank

air break to draincentrifugal pump

air filter

floatoperated

valvesand filter

excess water recycledfrom deioniser

Typical de-ionizer

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Cationic column Anionic column

Hygienic pump

Outlets or storage.

Ozone generator

UV light

HCl NaOH

Eluates toneutralization

plant

Air break to sewer

Drain line

from water softener

Water must be kept circulating

12345

6

12345

6

Return to de-ioniser

Cartridgefilter 5 µm

Cartridgefilter 1 µm

Typical 2-Stage RO Schematic

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Branch

Branch

2nd stage buffer tank

Cartridgefilter 1 µm

Second stage RO cartridge

First stage filtrate feeds second stage RO with excess back to 1st stage buffer tank.

1st

stag

e re

ject

co

nce

ntr

ate

Air breakto sewer

Second stage reject water goes back to first stage buffer tank

Second stage RO watermeets Pharmacopoeia

standards Outlets or storage

1st stage buffer tank

Water from softener or de-ioniser

Water returns to 1st stage buffer tank

Hygienic pump

First stage RO cartridge

High pressure pump

Purified Water USP 23

Purified Water is described in the USP 23 monograph as follows:

"Purified Water is water obtained by distillation, ion-exchange treatment, reverse osmosis, or other suitable process.

It is prepared from water complying with the regulations of the U.S. Environmental Protection Agency (EPA) with respect to drinking water. It contains no added substances."

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Purified water USP Purified water is obtained by:

1. Distillation.2. Ion-Exchange.3. Reverse osmosis.4. Other suitable method.

It is prepared from the drinking water.It is more free of solid impurities.When evaporated to dryness, it must not yield greater than 0.001% of residue (1mg of total solids per 100 ml of sample evaporated).Thus it is 100 times more free of solids than the drinking water.

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Water system design (1)There should be no dead legs

Water scours deadleg

If D=25mm & distance X isgreater than 50mm, we havea dead leg that is too long.

Deadleg section

<2D

Flow direction arrows on pipes are important

Sanitary Valve

D

X

Water system design 1.Pipes sloped so water does not

pool and can drain easily2.Sanitary fittings & connections3.Constructed of suitable

materials such as stainless steel

4.Circulate the water5.Incorporate non-return valves

(NRV)

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Sampling There must be a sampling

procedure. Sample integrity must be assured. Sampler training Sample point Sample size Sample container