Earlier pharmaceutical industries used to rely on one time procedures that had a severe impact on the formulations resulting in product recalls often and eventually financial losses. Therefore it was the need of pharmaceutical industry to develop some procedures that eliminates the causes of uncertainty. Hence qualification came into existence.
Qualification in simple terms could be defined as step by step procedure which makes sure that the whether an instrument/ equipment/ system is fit for its intended use.
The manufacturing method is different for different grades of water and depending upon the type of manufacturing method the water system is designed. The grade of water is selected depending upon the its intended use and quality attributes which include microbial count, endotoxins and organic or inorganic impurities. The following flow diagram explains how a particular grade of water is selected for pharmaceutical purpose.
Reference: USP 37, General Information/ <1231> Water for Pharmaceutical Purpose.
Once the selection of water is done according to the requirement it is necessary that water treatment system must be designed in such a way that it produces the required quality of water that meets the predefined parameters as set by the user. The selection of the processing steps (unit operations) and design characteristics are considered which include the quality of feed water, the right technology for subsequent processing steps, water distribution system (extent and complexity) and other additional requirements. The first step is to qualify all the equipments and components to be used in water system so that maintain their sanitary and anti corrosive integrity. Equipment selection is based on URS and finally built into water system.
- Piping: Low carbon stainless steel SS316 or SS304L is generally used for the construction of the pipes for obtaining higher grades of water and also when ozonization is done. It is widely used because of it’s inert nature, ability to resist large range of temperatures and can be easily sanitized. Glass or polycarbonate is utilized when transparency is required, PVC for ambient temperature operations. Whenever hot water is made to run through pipes it may create bends due to stress which may result in leakage. It is also important to remove the “dead legs” to prevent contamination at such spaces and weld all the joints properly.
- Valves: Gate, ball, butterfly and diaphragm are the type of valves utilized in the water systems. For preparing Water for Injection and Purified water diaphragm valve is used because of it’s complete containment for in process materials and it is easy to clean. Plunger valves are used when complete containment is not required and they offer better installation and operational qualities than diaphragm valves. Teflon is picked as material for valve seats when ozone is utilized as sterilant as it is not degraded on repeated applications.
- Pumps: Centrifugal, rotary lobe, peristaltic and diaphragm pumps are commonly used easily cleanable pumps used in pharmaceutical industry. The design of the pumps should be sanitary that prevents any type of contamination.
- Storage Tanks: They are included in the water system to optimize processing equipment capacity. Stainless steel is most commonly used material however HDPE can be used when storage at ambient temperatures is required. The most important feature of storage tanks is vent filter which consist of hydrophobic 1 micron air filter that prevents microbial contamination. New tanks these days have vent filters that prevent condensate or water blocking the hydrophobic filter. Design of storage tanks marks certain essential aspects that include minimize corrosion and development of biofilm, ease in sanitization, extend of mechanical integrity.
- Pressure gauges: Diaphragm style pressure gauges are used commonly and when they are installed in piping the diameter should be less than 6D.
- Heat Exchangers: It is designed to prevent distillate contamination from feed water. Two common types are: Double tube sheet and concentric tube design. Other than these designs the pressure differential should be maintained and monitored in such a way that higher pressure is constantly maintained on the distillate side.
- Filters: Water filters are placed at different steps in water system and everyone has it’s own specific function. Common uses include removal of undissolved solids and bacterial contaminants from feed water. Storage tanks: hydrophobic filters (1 micron), carbon and resin beds filter (10-15 micron), membrane filter (0.2 micron). They should be arranged in proper order so as the water system works efficiently.
- Deionizers: Removes dissolved solids from the feed water. Single bed resins (cationic or anionic) or mixed bed resins (cationic and anionic) are used to removed excess ions that may impose problems in the downstream of the water system.
- Distillation Unit: Used to remove solids that are not removed by deionizers or RO units. These units provide microbial purification through thermal vaporization, mist elimination and condensing. The designs for such system available include single effect, multiple effect and vapor compression. Multiple effect and vapor compression systems have high generating capacity and efficiency therefore used for larger systems. These systems do not need rigorous controls as do the membrane systems. Areas of concern for these systems include carry-over impurities, evaporator flooding, stagnant water, pump and compressor design and conductivity variations during start-up and operation.Control methods include reliable mist elimination, visual or automated high water level indication, use of on-line conductivity sensing with automated diversion of unacceptable quality water to the waste stream.
- Auxiliary Equipment: These include all those units that are connecting links. Prevention of the back flow of water at the points of interconnection, pipelines that are used for transmission of water or final rinse, equipment for seals, gaskets, diaphragms etc.
The installation of all the qualified equipment is done according to the designed water system. It helps in ensuring that validation is not at risk and successful. The techniques used for installation are important as it directly effects the sanitary, corrosive and integrity of the system. The critical factors looked during installation are following:
- Dead Legs: They are resulted due to hot or cold water cycles and in more than 6D diameter of pipeline. Water could get collected in them leading to growth of micro organisms and production of biofilms. It is essential to remove dead legs and complete sanitation should done to assure cleaning and maintenance of the system.
- Slope Verification: Appropriate slopes in pipes should be provided during the time of installation to ensure proper drainage. The ratio of the slope to the length of pipe should not be more than 1:100. Pipe slopes are maintained such that water from the system is drainable to a low point drain.
- Welding Inspection: The joints by welding should not have pinholes, thermal cracking, weld seam color. The appearance for the weld bear must be regular, convex in shape and of uniform thickness and should not be more than 20% of the tube thickness.
- Pressure Test: This test is conducted to ensure that the water system is fit to handle if subjected to extreme pressures. For this the pressure which is at least two time mores than the operation pressure (150 psig or which ever is more) is applied to conduct this test and results are reported.
- Passivization Test: It is done to remove all the materials that could be oxidized.
After finalizing all the installation the description and design drawing of the system should be added into the complete report. It should include all the components and the sampling points.
It ensures that the system that is installed meet the requirements of the designed system. Two main tests are conducted to ensure the quality of the water.
- Water Velocity Test: Conducted to evaluate the quantity of water at the set rated flow. It is done by checking the outlets and verified that the flow velocity should not be less than 1.5m/sec.
- Determination of Reynolds Number: Related to the turbulence created by water in the distribution pipelines. It should be more than 2000 because if not the flow will become laminar that may result in biofilm development.
It ensures that the system will continuously meet the requirements as specified. After the installation and operational qualification, the performance qualification includes three stages of validation:
PHASE I: In this phase following are fixed
- Sampling should be done for 2-4 weeks from defined sampling points (feed water, after each step of purification, each point of use)
- Development of appropriate ranges and finalizing
- Operational parameters
- Cleaning and sanitation procedures
- Frequencies for the above
- Use and define the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting.
- Verify provisional alert and action limits
- Develop and define test failure procedures
This phase is generally the demonstration that the prepared and fixed SOP’s in Stage I are providing the desired water quality when followed. The sampling time period and points are similar to phase I. At this stage water could be utilized for manufacturing purposes.
This is the final phase that is performed over a year to demonstrate:
- Extended reliable performance
- Seasonal Variations
After establishing procedures as per phases 1 and 2 sample locations, sampling frequencies and tests should be reduced to the normal routine pattern.