1. Dr. Majed Feddah Pharmaceutical Dosage Forms and Calculations
Water Treatment
Dr. Majed Feddah
Pharmaceutical Dosage
Forms and Calculations

2. Drinking Water Clear, colorless, odorless, neutral, Potassium Sodium,
Magnesium
Microorganisms
Bicarbonates
Iron
Chlorides
sulfates
The use in pharmaceutical industries
Dissolved and unresolved organic matters

3. Why Purification of Water
Although reasonably pure, it is always variable.
Seasonal variations may occur in water.
Some regions have very poor quality water.
Must remove impurities to prevent product contamination.
Control microbes to avoid contaminating products

4. Why Purification of Water
There is no pure water in nature, as it can contain large no of possible unacceptable contaminants
Contaminant groups:
Inorganic compounds
Organic compounds
Solids
Gases
Micro-organisms

5. Contamination in Water
Problem minerals
Calcium and magnesium
Iron and manganese
Silicates
Carbon dioxide
Hydrogen sulfide
Phosphates

6. Contamination in Water
Further problem minerals
Copper
Aluminum
Heavy metals
Arsenic, lead, cadmium
Nitrates

7. Microbial Contamination
Micro-organisms – Biofilm
Algae
Protozoa
Cryptosporidium
Giardia
Bacteria
Pseudomonas
Gram negative, non-fermenting bacteria
Escherichia coli and coliforms

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

9. Water Types:
There are essentially four types of water that are of interest to the pharmaceutical industry:
Potable water: Feed water, public water supply, service water, city water, drinking water, National Primary Drinking Water
Purified water: Aqua purificata, demineralized water, deionized water.
Water for injection: Aqua ad iniectabilia, ultra pure water, distilled water
Highly purified water: Aqua valde purificata, low endotoxin water, reverse osmosis water

10. 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:
Test for acidic or alkaline substances, oxidizable substances, chlorides, sulfates, ammonium.
Microbial purity.
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. In the Ph. Eur., the specifications for purified water, filled in containers apply.
Purified water filled in containers must also pass the following tests:
Test for acidic or alkaline substances, oxidizable substances, chlorides, sulfates, ammonium (maximum 0.2 ppm), calcium/magnesium, residue on evaporating (0.001 percent) and microbial purity.

11. 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.

12. Highly purified water Application of highly purified water:
Manufacturing of ophthalmic products.
Manufacturing of sterile nose/ear preparations.
Manufacturing of sterile preparations for
Cutaneous 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.

13. Water for injection Application of water for injection in bulk:
Manufacturing of parenterals
(aseptic manufacturing)
(final sterilization)
Final rinsing of equipment, containers and caps for category 1 products

14. 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.

15. Water for Injection: special USP monographs
The USP also distinguishes between the following types of water for injection, unlike the European pharmacopoeia:
Bacteriostatic water for injection
Sterile water for inhalation
Sterile water for irrigation
Water for hemodialysis

16. 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:

17. Air-break Install a supply separation container.
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.
Install a supply separation container.
Use a supply or non-return valve.
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 only requirement for this is the physical separation of the two systems.
The systems can be separated in various ways.
It is possible to install a supply separation container or use a supply or non-return valve.

18. 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.
The potable water is first coarsely filtered, then the scale (calcium, magnesium, sulfate, carbonate) is removed in a first stage. Softened water is the
prerequisite for the next stage in the manufacturing of purified water, as otherwise there could be scaling of magnesium and calcium sulfates on the
downstream equipment, such as membranes of the reverse osmosis units, deionization devices, and distillation units. 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. Figure 5.B-1 illustrates this operation.

19. Na+
Exchanger
materials

20. As the resins have to be regenerated periodically, such facilities are operated discontinuously. Once exhausted, the ion exchanger is rinsed with a saline solution. In order to assure a continuous softened water supply for the subsequent processes, two ion exchangers are often operated in reciprocating mode. The softened water generated is monitored by means of a hardness measurement. In order to counteract a biological fouling of the resins, the facility should be dimensioned so that the ion exchangers can be regenerated every 24 to 36 hours. Figure 5.B-2 and Figure 5.B-3 show the
operating and regeneration phases of a facility. The medium flow and the valve settings should also be illustrated.

22. Removal of chlorine Activated charcoal filters. or
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:
Activated charcoal filters. or
Sodium bisulfite (Na2HSO3).
When designing a facility for generating purified water, the individual circumstances of the generation location must also always be taken into account. In
addition to dimensioning the facility in line with the water volumes to be provided, it is important to pay attention to the quality of the raw water used.
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, dechlorination must be carried out through the use of activated charcoal
filters or sodium bisulfite (Na2HSO3).

23. 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.
The use of an activated charcoal filter for dechlorination of the potable water is a simple and very effective method that should only be used for purification of potable water.
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. Due to the large inner surface of the activated charcoal (500–1 600 m2/g) and the large supply of nutrients for microorganisms, the risk of increased microbiological fouling and the formation of a biofilm (see Chapter 5.C.4 Formation of biofilms) is very high. Impregnation of the activated charcoal with elementary silver reduces the microbial load of the activated charcoal. Due to the oligodynamic effect of silver, it kills microorganisms in the water.

24. 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.

25. 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:
Dosage of sodium hydroxide solution: The carbon dioxide is converted into carbonate, which is retained by reverse osmosis.
Membrane degassing: Through the creation pressure difference and are rinsed from the membrane using air.
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. In practice, two methods are used to remove carbon dioxide.
■Dosage of sodium hydroxide solution: By adding small quantities of sodium hydroxide solution (pH value increase), carbon dioxide is converted
into carbonate, which is retained by reverse osmosis.
■Membrane degassing: The gases dissolved in the water are diffused through a membrane through the creation of a particle pressure difference
and are rinsed from the membrane using air.

26. 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.
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 known from the animal and plant world.
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.

27. 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.

28. Reverse osmosis mechanism

29. Reverse Osmosis Reverse Osmosis Remove particles, bacteria,
pyrogen, organic, inorganic ions and silica

30. Reverse Osmosis

31. 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.
Electro-deionization (CDI = Continuous Deionization; EDI = Electro-deionization) is a desalination process based on electro-dialysis and mixed bed technology. EDI works by coupling the behavior of ions in the electrical field with membrane technology. The anions wander towards the anode and pass an ion-selective membrane which transports the anions but not the cations or electrically charged particles. The cations are transported towards the cathode in the same manner. Electro-deionization is illustrated schematically in Figure 5.B-5.
Figure 5.B-5 Schematic diagram of electro-deionization

32. 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

33. Water qualities with a conductivity of less than 0
Water qualities with a conductivity of less than 0.1 μS/cm cannot be achieved with an EDI/CDI module alone. In order to achieve these conductivities, the feed water must be pretreated. If, for example, an upstream reverse osmosis produces a permeate with a conductivity of <50 μS/cm, which feeds the
EDI/CDI module, conductivities of μS/cm are possible (theoretical minimum conductivity).
For a water feed with a TOC content (Total Organic Carbon) of less than 0.1 ppm, a TOC content of less than 5 ppb can be achieved during continuous processing.
This very good TOC removal with EDI/CDI technology is due to two mechanisms: After hydrolysis, the ions are transported through the membrane and removed. Other molecules are polarized, superficially electrically charged and then pass the membrane. A positive side effect of the EDI/CDI process is that electrochemical membrane processes, and thus also the EDI/CDI, are antibacterial due to the electric field. The advantages are summarized in Figure 5.B-6.

34. Ultra filtration
Ultra filtration (UF) is a separation technology for separating particles with a size of 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.
Ultra filtration (UF) is a separation technology for separating particles with a size of to 0.1 μm. For ultra pure water production UF hollow fiber
membranes are usually used. As a UF membrane cannot retain salts, the conductivity of the permeate remains nearly the same as that of the feed
water. The operational costs of a UF facility are lower than those of a reverse osmosis unit due to the lower operating pressure (lower energy
consumption). Another advantage over reverse osmosis is the temperature tolerance of the membranes. The working temperature can reach 80 °C and
steam sterilization is possible in modern UF membranes up to 128 °C.
Ultra filtration is often seen as an alternative to microfiltration plants. Often, older microfiltration plants which are used as pretreatment sections for
reverse osmosis are replaced by ultra filtration modules. This means a higher flux and a longer life can be achieved with the reverse osmosis modules.
The problem of biofilm formation (see Chapter 5.C.4 Formation of biofilms ) can also be displaced from the reverse osmosis membranes to the UF
membranes. This is advantageous, as UF membranes are significantly easier to clean.
5.B.1.7 Ion exchanger
In the

35. 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.

36. 2. Ion-Exchange
The ion-exchange equipment involves the passage of water through a column of:
Cation and Anion exchangers.
Resin is:
Water-insoluble materials
synthetic, polymerized phenolic,
carboxylic, amino, or
sulfonated materials
high molecular weight.

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

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

39. 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.

40. 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.

41. 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.

42. Procedure combination for generation purified water
System1
System 2
System 3
System 4
System 5
System 6
Activated charcoal filter X
Softener
Mixed bed technology
Ultra filtration
Reverse osmosis
Degassing
EDI/CDI

43. Water System Purified Water Softening Reverse Osmosis Reverse Osmosis
Waste Water
Waste Water
Purified Water
Softening
Reverse Osmosis
Electro Deionization
Waste Water
Waste Water

44. 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).
Permissible manufacturing procedure for WFI
Europe
Distillation
USP
Distillation or other equivalent or superior processes
Japan
Ultra filtration or distillation
According to the United States Pharmacopoeia (USP), distillation must be used for the final unit purification. However, USP allows for the use of other
processes as long as they are at least equivalent to distillation in removing chemical impurities, microorganisms and their components. In Japan WFI
can also be produced via ultra filtration. In Europe, however, based on the requirements in the European pharmacopoeia, WFI must be produced via
distillation
Purified water is used as the feed water for the production of WFI. However, it is also possible to use potable water as the feed water, although this would
significantly reduce the yield of WFI. More costly design of the distillation facility would also be necessary as some of the salts present in potable water
evaporate at the same temperature as water. Therefore, the production of WFI from purified water is preferred.

45. Water is kept circulating
Pretreatment – schematic drawing
raw water in
« S” trap to sewer
To water softener & DI plant
cartridge
filter
5 micrometers
activated
carbon
spray ball
break tank
air break to drain
centrifugal pump
air filter
float
operated
valve
sand filter
excess water recycled
from deioniser
Water is kept circulating
This schematic drawing is shown in handout and illustrates a typical storage and preliminary treatment system for water. Raw water arrives into a buffer or break tank via a level controlled valve. If there are further stages of treatment (such as DI or RO), the tank does not, generally, have to have sophisticated spray balls or air filters.
The water is pumped through a sand filter to remove large particles. This filter must be fitted with a back-flush facility, not shown here. The water then enters an activated carbon (AC) filter which removes organic impurities and chlorine. The AC filter can become heavily contaminated with bacteria. There should be some means of sanitizing it, such as a steam supply. Chemicals are generally not used to disinfect activated carbon filters. The water is then “polished” through a 5 micron filter before it enters the next treatment step. If there is no demand for the water it must be re-circulated to the buffer tank.
Water that is kept constantly circulating is less likely to grow bacteria, because they cannot settle and form a “biofilm”. All equipment such as pumps, pipes and tanks should be stainless steel wherever possible. Plastic should be avoided. Plasticizers may leach and this can result in out-of-specification Total Organic Carbon (TOC) levels. Adhesives used for welding plastic pipes may also leach into the water and cause problems.
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

46. Typical de-ionizer Water must be kept circulating from water softener
HCl
NaOH 1 2 3 4 5 6 1 2 3 4 5 6
Water must be kept circulating
Cationic column
Anionic column
Cartridge
filter 5 µm
Cartridge
filter 1 µm
UV light
Eluates to
neutralization
plant
Ozone generator
Hygienic pump
Return to de-ioniser
Outlets or storage.
Drain line
Air break to sewer

47. Typical 2-Stage RO Schematic
Branch
2nd stage buffer tank
Cartridge
filter 1 µm
Second stage RO cartridge
First stage filtrate feeds second stage RO
with excess back to 1st stage buffer tank .
1st stage reject concentrate
Air break
to sewer
Second stage reject water goes back to first stage buffer tank
Second stage RO water
meets 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

48. 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."

49. Purified water USP Purified water is obtained by: Distillation.
Ion-Exchange.
Reverse osmosis.
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.

50. There should be no dead legs
Water system design (1)
There should be no dead legs
Water scours deadleg
If D=25mm & distance X is greater than 50mm, we have
a dead leg that is too long.
Deadleg section
<2D
Flow direction arrows on pipes are important
Sanitary Valve D X

51. Water system design
Pipes sloped so water does not pool and can drain easily
Sanitary fittings & connections
Constructed of suitable materials such as stainless steel
Circulate the water
Incorporate non-return valves (NRV)

52. Sampling There must be a sampling procedure.
Sample integrity must be assured.
Sampler training
Sample point
Sample size
Sample container