Activity on cGMP

Team A
Prashant Gupta (H2018033)
Pratibha Adak (H2018034)

Q. Water system requirements for a tablet manufacturing plant.

DRAWING WATER FROM SOURCE:

The water which is drawn from the source must be in accordance with the standards
defined by the Local Municipality which is in synergy with Pharmacopoeial
specification.
USE OF WATER:

Water drawn and purified (PW) must be utilised for all operations except washing
and cleaning operations where potable water can be used.
STORAGE OF WATER:
Water should be stored in tanks which do not encourage microbial growth and
refrains from affecting the quality of the same.
PRODUCTION OF DRINKING WATER:
Drinking water should be derived from a raw water source (river nearby).\
Typical processes employed for producing drinking water
filtration; softening; disinfection or sanitization (e.g. by sodium hypochlorite
(chlorine) injection); iron (ferrous) removal; precipitation; and reduction of specific
inorganic/organic materials.
WRITTEN PROCEDURE:

A written procedure for operation and maintenance of purified water system shall be
maintained.
MAINTENANCE OF WATER

To avoid the risk of microbial proliferation by methods like re-circulation, UV

treatment, Heat treatment and sanitizing agent. A flushing treatment is done after
sanitization to remove it effectively.
SANITATION

Sanitation records to be maintained periodically and a written procedure for different

water systems to be maintained ibncluding storage tanks, distribution lines, pumps
and other related equipment.
While the public considers municipal water to be “pure”, the pharmaceutical market
considers municipal water (feedwater) just the starting point in producing pure
water. Water is the most widely used excipient in pharmaceutical manufacturing,
and pharmaceutical water is a multi-functional resource, crossing all disciplines in
the pharmaceutical industry. Water is used as a raw material, solvent, ingredient,
reagent, and cleaning agent, and is produced in a variety of “pure” forms.

Purified Water (PW), Highly Purified Water (HPW), and Water for Injection (WFI) used
in pharmaceutical processes are produced on site from the local potablewater, which
has been produced by the treatment of the feedwater.

Today’s pharmaceutical companies have invested considerable capital in state-of-

the-art instrumentation, purification equipment, storage and distribution loops,and
importantly in the calibration and certification of their water systems. By
understanding water, its sources and impurities, and the capabilities and limitations
of purification methods, a water system can be designed to meet not only
pharmaceutical companies’ requirements but to meet global pharmacopeia
regulations.
Source water requirements

The feedwater source for a municipality can be from a surface water or a ground water supply.
The impurities vary in each source and some of the primary differences are shown below:

Because the quality and characteristics of the feedwater supply have an important bearing on the
purification, the pharmacopeia define the source water for the production of PW, HPW, and WFI.
The pharmaceutical facility should communicate regularly with their water provider and request an
annual water test report for the feedwater. To further the understanding of the feedwater and what
technologies are required to purify it, below are the categories of contaminants found in a water
supply.

Contaminants in feedwater:
The impurities found in water can be categorized into six major classes: dissolved ionized solids,
dissolved ionized gases, dissolved non-ionized solids (organics), particulate matter,
bacteria/algae, and pyrogens. Feedwater varies significantly in purity both from one geographical
region to another, and from season to season.

Total dissolved solids (TDS)

A measure of the total of organic and inorganic salts dissolved in water, obtained by drying residue
at 180°C. The sum of all ions in a solution is often
approximated by means of electrical conductivity or resistivity measurements. TDS measurements
are commonly used to assess reverse osmosis unit
performance.

Total ionized solids and gases :

Concentration of dissolved ions in solution, expressed in concentration units of NaCI (sodium
chloride). This determines the operating life of ion exchange resins used in water purification,
and is calculated from measurements of specific resistance. Gases (carbon dioxide and oxygen)
affect the water quality and system performance.

Total solids
Total solids in water include both dissolved and suspended solids. The quantity of total solids is
determined by weighing a sample of the feedwater before and after evaporation.

Microbial
Bacteria, viruses, and pyrogens (endotoxins).

Particulates
Sand, dirt, and decay material.

Organics
Organic matter is a broad category that includes both natural and man-made molecules containing
carbon and hydrogen. All living matter in water is made up of organic molecules. The most common
are by-products of vegetative decay such as tannins, lignins, and humic acid. By knowing the
variety of contaminants in the water and the removal capabilities of the different available
purification processes, a system can be designed that will produce the water quality required for a
pharmaceutical facility. There are a range of purification technologies and we have provided below
a brief description of the major purification technologies.

Major water purification technologies

The chart shown below is a summary of the removal capabilities of different purification
technologies versus the contaminants commonly found in water.
PW, HPW, and WFI for pharmaceutical use are produced via a combination of different purification
technologies. As with the source water, each pharmacopeia defines the methods of production,
but for PW and HPW the technologies utilized is the decision of the system designer, with the only
requirement being that the water meets the pharmacopeia regulations for quality. For WFI, to meet
the pharmacopeia requirements (all pharmacopeias except Japan), the final purification process
must be distillation.
Purifying the feedwater for use in the pharmaceutical industry requires a series of steps. The
objective is to remove the impurities in the feedwater while minimizing additional contamination
from the components of the purification system, the storage tanks, the distribution system, and
from possible biofilm growth. Selection of the correct purification technologies and the
instrumentation to monitor the system are critical to success.

Reverse osmosis
Reverse osmosis is best understood when related to osmosis itself. In one of the experiments
performed by everyone in first year chemistry, a semi-permeable membrane (a membrane that is
permeable to water but not to salt) is used to separate two solutions; a saline solution and pure
water. The pure water will flow through the membrane to dilute the saline solution. This is osmosis.
When pressure is applied to the sa-line solution, the natural process of osmosis can be overcome
and even reversed. With sufficient pressure, pure water can be forced out of the saline solution
through the membrane and into the pure water side of the vessel. This is reverse osmosis.

In reverse osmosis for pharmaceutical water production, a membrane is also used for the
separation of contaminated water. Membranes can be made from cellulose acetate, polyamide,
polysulfone, or a variety of proprietary formulations. Two configurations are common: “hollow fiber”
and “spiral wound”. Hollow fiber membranes look like a group of drinking straws gathered into a
bunch, the spiral wound resemble a helix.

Because the quality of water produced by a reverse osmosis apparatus is directly dependent upon
the quality of the input water and because effective removal of ions rarely exceeds 97%, reverse
osmosis is widely used as a pretreatment process to purify feedwater before introduction into an
ion exchange unit or a distillation system.

Distillation
Distillation is the oldest form of water purification and has been utilized by humans since we first
boiled wa-ter in a cave. It is a unique process because it removes the water via a phase change
and leaves behind the impurities. In distillation, water is heated to itsboiling point and undergoes
the first of two phase changes, from a liquid to a vapor. The solid ionic ma-terials, the particulates,
the microbials, endotoxins, and most of the dissolved organic contaminants are left behind in the
boiler. The pure steam is then passed through a cooling coil where it undergoes a second phase
change from a vapor back to a liquid. For the production of WFI, the pharmaceutical distillation
system is normally fed water that has been pretreated by a variety of other technologies. The
pretreatment is used to reduce the costs of maintenance on the distillation system and to ensure
the quality of the distillate. Distillation is the only purification method that removes 100 percent of
biological materials whether bacterial, viral, or pyrogenic.

Deionization
Deionization or ion exchange is a process also mistakenly called demineralization. The
Encyclopedia of Chemical Technology defines deionization as:
“The reversible interchange of ions between a solid and a liquid phase in which there is no
permanent change in the structure of the solid.”

Deionizers are generally available in two forms: a two-bed and a mixed-bed configuration. In the
two-bed configuration, the cation and anion resins are in two discrete columns or in two discrete
layers in the same column. The advantage of the two-bed deionizer is that it can purify a greater
volume of water than a comparable mixed-bed system; however, they produce lower quality water.

The mixed-bed deionizer contains an integral mixture of anion and cation resins packed in a single
column. Only mixed-bed deionization can produce water with a resistivity of 18.178 million ohms,
which is theoretically ionically pure.

Ion exchange technology is designed to remove ionized or charged material from water. Even
though water will be ionically pure after the deionization process, the water will still contain non-
ionized solid and gaseous materials (organics), bacteria, viruses, and pyrogens. These are not
ionically charged species and cannot be removed by ion exchange processes.

Electrodeionization
Electrodeionization (EDI, also known as EDR, CDI, and CEDI) is a technology that combines ion
exchange resins, ion-selective membranes and an electrical current to remove ionized
contaminants from the water. Reverse osmosis is typically used before EDI to ensure that the EDI
stack is not overloaded with high levels of salts. Usually, reverse osmosis removes about 97% of
ions. EDI will remove 99% of the remaining ions as well as carbon dioxide, organics, and silica. In
electrodeionization, the water passes through multiplechambers filled with ion exchange resins
held between cation or anion selective membranes. Under the influence of an electrical field, the
anions and cations migrate across the membranes to the anode and cathode. Typically, EDI
product water has a resistivity of 11 to 18.2 MΩ-cm (at 25°C) and a total organic carbon (TOC)
content below 20 ppb. Bacterial levels are minimized because the electrical conditions within the
system inhibit the growth of microorganisms.

Carbon adsorption
In adsorption, the organic impurities in water form a low-energy chemical bond with the surface of
activated carbon. Because adsorption is a technique for removing only organics and chlorine, it is
most often used as a pretreatment to remove large amounts of organic impurities prior to other
purification processes. Activated carbon is very effective at removing chlorine and other oxidants
at rates of 2 to 4 times the chemical weight of the oxidant. By removing the oxidants, the opportunity
for microbial growth is increased and must be controlled and monitored.
Ultraviolet light
Ultraviolet light at the 254nm wavelength is used asbactericide. This wavelength disrupts the ability
of bacteria to reproduce. UV at 185nm will break down organic contaminants to CO2 and water for
subsequent removal by ion exchange.

Filtration
Filtration can be performed by one of two methodologies, either depth filtration or membrane
filtration. Depth filters can be made of sand in a container or of fiber wound around a core. Both
methods mechanically strain out sediment and particulate matter.

Membrane filtration, on the other hand, is physical straining by a single layer of membrane material.
The membrane material is produced from man-made resins and can be either hydrophobic or
hydrophillic. The pore size is tightly controlled and therefore absolute removal of particulates with
diameters larger than the pore size can be achieved. In pharmaceutical systems, filtration is
normally limited to the pretreatment section because although filters trap contaminants, it is
possible for bacteria to pass through a membrane filter.

Conclusion
Once the feedwater source is known and the purification technologies have been selected,
knowing what parameters need to be utilized to control and monitor the system are critical. By
understanding feedwater and the water purification system, a consistent supply of Purified Water,
Highly Purified Water or Water for Injection can be ensured.