Water is most widely used ingredient or solvent in pharmaceutical industries for manufacturing of different products and dosage forms like oral solid dosage form (tablets by wet granulation), oral liquid dosage forms, sterile products, semi-solid and other products.
Water is also used in the washing of pharmaceutical equipment. Water used for the manufacturing of sterile products is called wfi or water for injection and is produced by the process of distillation.
Water used for oral solid dosage forms and oral liquid dosage and other non-parenteral dosage forms is prepared by RO or reverse osmosis process. RO is a process which uses semi-permeable membranes to remove undesired molecules, ions and particles from water.
Purified water in the pharmaceutical industry for manufacturing purpose is produced and stored in a storage tank from where it is supplied to different areas for use. It is commonly observed that stagnant water promotes the growth of microorganism and microorganism form a layer inside the piping of the distribution system, this layer of microorganism is called biofilm.
Biofilm formed inside piping is the major source of contamination of water.
Reasons for biofilm formation
There are many reasons which may cause the formation of biofilm but some key factors are as follow
- Stagnant water
- laminar flow
- Dead legs in piping
- Leakage of piping
- Cold temperature
It is observed that stagnant water is a major cause of biofilm formation. Laminar flow also promotes microbial growth in piping. A dead leg is an area inside piping where water velocity is less or water is stagnant.
Dead legs may be reduced by using turbulent flow, maintaining the velocity of water in piping at 1-2 meter per second or usually at 1.5 meters/second.
According to WHO TRS 970 dead leg should not be more than 3 times the internal diameter of the pipe.
Reynold number also play an important role in the reduction of dead leg and biofilm formation, Reynold no is the measure of the flow pattern of water or liquid that either it is laminar or turbulent flow.
Reynold number below 2300 is considered as laminar and this number promote biofilm formation. Reynold number 2300-4000 is in between laminar and turbulent and value above 4000 is turbulent flow. So in a loop system, Reynold number should be over 4000 to prevent biofilm formation.
Leakage of piping promotes proliferation of microorganisms inside the water and this may form a biofilm.
So to avoid biofilm formation water should remain in continuous motion and recirculation. For this, a circulation loop system is used for water distribution from the storage tank.
Water storage and Distribution System
Water storage and distribution system consist of the following components.
- Storage tank
- SS pipes or Loop system
- centrifugal pump
- Heating System/Heat Exchanger
- Temperature sensors
- Conductivity sensors
Purified water produced from RO plant is stored in a storage tank. The storage tank is available in different capacities depending upon the usage of water. The storage tank is made of Stainless Steel 316L. This is usually double jacketed to prevent corrosion and for heating purpose. The water is filled in the tank through spray ball which sprays water inside all surface of the tank.
The tank is fitted with 0.22-micron vent filter. The storage tank should be equipped with a system that allows its heat or chemical sanitization and should also have sampling points for validation samples. The interior surface of the tank should be smooth because irregular surfaces allow the growth of microbes by adhering the irregular surfaces.
SS pipes or loop System
To supply water from the storage tank to the user endpoint loop system is used. Loop system is piping system consisting of stainless steel pipes of 316L. This loop system recirculates the water means water remains in continuous motion in the loop system. Stagnant water promotes biofilm formation so recirculated water prevents biofilm formation.
Flow in the loop system is kept turbulent because turbulent flow prevents dead leg formation. The flow of water in the loop system is also kept at a specific velocity that is 1-2 meter per second or is usually at 1.5 meters per second.
Centrifugal pump is used to re-circulate the water in a loop system.
Valves are installed in the loop system at different points where water is required for usage. The valve should not produce any dead leg. The conventional type of ball valve is not used because they produce a dead leg that promotes biofilm formation. Generally, the valves are used which supply water under the effect of gravity. Now a days zero dead leg valves are used.
There should not be any dead point in the loop circulation system. The dead point means any valve which is not in use because this can result in dead leg and biofilm formation.
Heating System/Heat exchangers
It is a reality that recirculating water in the loop system prevents the development of biofilm, but along with recirculation heating of water is also very important to prevent the development of biofilm. For this purpose, water is heated up to 65-80 degree centigrade. This temperature kills microbes and thus prevent biofilm formation in the loop.
The heat exchanger is installed which bring the water temperature to normal temperature at user end before use. The heat exchanger installed should not affect the quality of water.
Heat sensors are installed at different points which monitor the temperature of the water and indicate it on the control panel if the temperature drops below limits at any point.
Flow meters are also installed which monitor the flow of purified water.
Conductivity sensors are installed which monitors the conductivity of water.
Sampling of water
Samples of purified water are taken from different points at specific time intervals according to the validation plan.
Sanitization of loop system/Storage tank
Sanitization or removal of biofilm of water loop system can be done using steam or chemicals. In the steaming process steam generated at 121-degree centigrade is circulated in a loop system for 10-15 minutes. Sanitization or biofilm removal is also done using different types of chemicals for example ozone, sodium hydroxide, peracetic acid and chlorine.
The concentration depends upon the nature of the chemical used for the sanitization process.