WATER FOR PHARMACEUTICAL INDUSTRY

Water plays an important role in the pharmaceutical industry, serving as an essential component in the development and production of various products. Different types of water are used for different dosage forms such as water for injection, sterile water for injection and purified water. However, if microbiological purification and validation of water treatment systems are not carried out properly, it can have a negative impact on the quality of pharmaceutical products. Regular monitoring, maintenance and inspection of water treatment systems is important to ensure the production of high quality products. In addition, compliance with TOC, inorganic, organic, and microbial limits is critical to USP specifications. This article highlights the importance of testing and maintaining water quality to achieve optimal product quality.

Pharmaceutical water systems must be designed, operated, and maintained appropriately to ensure the production of high-quality water. The USP General Chapter <1231> Water for Pharmaceutical Purposes offers comprehensive information on all aspects of maintaining, validating, and monitoring such systems. Validation is the crucial process of demonstrating that a pharmaceutical water system consistently meets the requirements set by the USP. General Chapter <1231> extensively discusses the life cycle elements necessary to maintain a validated state of control.

Water serves multiple purposes in the pharmaceutical industry, acting as a raw material, ingredient, and solvent in various stages of processing, formulation, and manufacturing. It is utilized in the production of pharmaceutical products, active pharmaceutical ingredients (APIs), intermediates, compendia articles, and analytical reagents. The quality of water used in these processes is of utmost importance to ensure the production of high-quality pharmaceuticals.

Water plays a crucial role in pharmaceutical manufacturing, both directly and indirectly. It is a key component in injectable products and is also used for cleaning manufacturing equipment. As a result, water holds significant value as a raw material in Good Manufacturing Practices (GMP) and in validating the manufacturing process.

TYPES OF WATER USED IN PHARMACEUTICAL INDUSTRY

In the pharmaceutical industry, different types of water are classified based on how they are administered to patients. These include bulk forms such as Purified Water (PW), Highly Purified Water (HPW), Water for Injection, and Water for Hemodialysis. Additionally, there are packaged forms of water, such as Bacteriostatic WFI, Sterile Water for Inhalation, Sterile Water for Injection, Sterile Water for Irrigation, and Sterile Purified Water. Each type of water serves a specific purpose in pharmaceutical applications.

Water Purification Techniques

1. Reverse Osmosis

Reverse osmosis (RO) stands as the most advanced membrane separation technique available. It effectively separates even the tiniest particles or suspended matter, with a particle size of up to 0.001 microns, from a liquid. RO is capable of eliminating metal ions and completely removing aqueous salts. In a reverse osmosis system, water is subjected to pressure and forced through a membrane that filters out minerals and nitrates. These systems are compact, user-friendly, and require minimal labor, making them suitable for small-scale operations and areas with significant fluctuations in water demand.

1. Membrane Ultrafiltration

Membrane ultrafiltration serves as a membrane separation technique that effectively separates very fine particles or suspended matter, ranging in size from 0.005 to 0.1 microns, from a liquid. It has the ability to remove salts, proteins, and other impurities within its specified range. Ultrafiltration membranes possess a nominal pore size of 0.0025 to 0.1 microns.

1. De-chlorination

While chlorine is commonly used for water disinfection, it has its drawbacks. It can react with chloramines and chlorinated hydrocarbons, which are hazardous carcinogens. To address this issue, chlorine dioxide can be employed. Chlorine dioxide acts as a potent biocide, even at concentrations as low as 0.1 ppm and across a wide pH range. It penetrates the bacteria cell wall and reacts with essential amino acids in the cell’s cytoplasm, effectively killing the organism. The by-product of this reaction is chlorite. Extensive toxicological studies have demonstrated that the disinfection by-product of chlorine dioxide, chlorite, does not pose any significant adverse risks to human health.

1. Softening

A widely utilized method for removing calcium and magnesium ions from hard water is through the use of a water softener. This device replaces these ions with other positively charged ions, such as sodium, resulting in softened water.

1. Demineralization

The process of demineralization involves the elimination of minerals and nitrates from water. By employing this method, the hardness of the water can be effectively reduced.

1. Filtration

Filtration is a commonly employed technique for the primary purification of water. This straightforward process utilizes cloth filters, carbon filters, or filters with specific pore sizes to purify various types of water.

1. UV Treatment

In modern times, UV radiation is utilized for disinfection purposes. When exposed to sunlight, UV radiation effectively eliminates germs, prevents the spread of bacteria and fungi, and serves as a natural disinfection process. This method can be optimally applied by controlling the application of UV radiation.

1. Deionization

Deionization is typically achieved through ion exchange. Ion exchange systems consist of tanks containing small beds of synthetic resin that selectively absorb specific cations or anions and replace them with counter-ions. The ion exchange process continues until all available spaces in the resin beds are filled with ions. The ion-exchanging device then needs to be regenerated using suitable chemicals.

1. Ozonization

Ozone has been employed for disinfecting drinking water in the European municipal water industry for over a century. Many water companies utilize ozone generators with capacities reaching up to a hundred kilograms per hour. When ozone encounters odors, bacteria, or viruses, the additional oxygen atom present in ozone destroys them through oxidation. This process eliminates any remaining odors, bacteria, or extra atoms. Ozone not only serves as an effective disinfectant but also ensures safety during usage.

Checking the water supply system:

Verification is the process of obtaining and documenting evidence that provides a high level of confidence that a specific process consistently produces products that meet established quality standards.

Verification programs ensure that the design, installation, operation and performance of the device are certified and documented. For water supply systems, the inspection plan usually includes the following steps:

1. Establish quality standards for both finished and raw water.
2. Determination of appropriate plant operations and their operating parameters to achieve the desired finished water quality characteristics using available raw water.
3. Selection of suitable pipelines, equipment, control and monitoring systems.
4. Development of a table of installer qualifications (IQ). This includes calibration of equipment, verification of accuracy of system drawings, and special testing necessary to ensure the installation meets design requirements.
5. Stage of development of functional qualifications (QA). This includes testing and inspection to verify reliable equipment operation, system warnings and controls, and establishing appropriate warning and action levels.
6. Develop a forward-looking performance qualification (PQ) step to verify compliance with operational limits of critical process parameters.
7. Ensure ongoing monitoring procedures, such as frequency of disinfection, are adequate.
8. Improve your care plan with review. This includes measures to control changes in water supply and planned preventive maintenance, including major equipment repairs.
9. Establish a schedule for formal performance testing and recertification.

By following these steps, a water system inspection can provide the necessary confidence that the system is consistently producing water that meets the required quality specifications.

VALIDATION OF WATER SYSTEMS:

Validation is the process by which evidence is obtained and documented to provide a high level of assurance that a specific process will consistently produce a product that meets established quality standards.

A validation program ensures that the design, installation, operation, and performance of equipment are qualified and documented. In the case of a water system, a validation plan typically involves the following steps:

1. Establishing standards for the quality attributes of both the finished water and the source water.
2. Defining appropriate unit operations and their operating parameters to achieve the desired quality attributes in the finished water using the available source water.
3. Selecting suitable piping, equipment, controls, and monitoring technologies.
4. Developing an Installation Qualification (IQ) stage, which includes instrument calibrations, inspections to verify the accuracy of system drawings, and special tests if needed to ensure that the installation meets design requirements.
5. Developing an Operational Qualification (OQ) stage, which involves tests and inspections to verify the reliable operation of equipment, system alerts, and controls, as well as the establishment of appropriate alert and action levels.
6. Developing a Prospective Performance Qualification (PQ) stage to confirm the suitability of critical process parameter operating ranges.
7. Ensuring the adequacy of ongoing control procedures, such as the frequency of sanitization.
8. Supplementing the validation maintenance program, which includes a mechanism to control changes to the water system and scheduled preventive maintenance, including instrument recalibration.
9. Establishing a schedule for periodic review of system performance and requalification.

By following these steps, the validation of water systems can provide the necessary assurance that the system consistently produces water that meets the required quality attributes.

INSTALLATION QUALIFICATION

During the installation (IQ) process, application requirements must be identified and documented with each piece of equipment and piping These documents should cover various aspects such as surface specifications for ion exchange resins and regeneration chemicals. The IQ format may vary from institution to institution, but generally it should include the following sections:

5. Equipment description and review ensures proper identification of each component and equipment in the system including valves, monitoring devices, filters, filter housings, storage tanks, ports, construction materials, selected suppliers and specifications.
6. Electrical Equipment This section provides specific information about electrical equipment, including panel locations and safety information.
7. Other Utilities This section describes other utilities that may be required for your computer hardware
8. Location of drawings This section specifies where drawings, manuals and technical information provided by suppliers and installers are kept.
9. Calibration Records This section identifies instruments requiring calibration, actual calibration records, and scheduled dates for subsequent calibrations. National Institute of Science and Technology (NIST) standards should include additional information.

It is important to note that equipment is usually calibrated prior to operational qualification (OQ), which must include the calibration conditions.

3. The Installation Qualification Protocol acts as a thorough manual for verifying the installation, labeling, and positioning of each piece of equipment. It is imperative for the IQ protocol to be highly detailed and customized to the specific system being validated. Additionally, it must accurately record that the system has been installed in accordance with the instructions and specifications provided by the manufacturer.
4. The Standard Operating Procedures encompass a compilation of all pertinent procedures, incorporating the most recent revisions throughout the validation process. Generally, these procedures are initially drafted during the Operational Qualification phase and subsequently enhanced during the Performance Qualification phase.
5. The Preventative Maintenance Procedures comprise a comprehensive list of all relevant maintenance procedures, including the most recent revisions at the time of validation. These procedures are typically formulated during the Operational Qualification phase and further refined during the Performance Qualification phase.

OPERATIONAL QUALIFICATION

The Operational Qualification (OQ) is an essential step in the validation process. It is important for the OQ protocol to clearly outline the test functions and specify the items to be inspected and tested. Additionally, the protocol should indicate the number of replicate tests required to verify each parameter being evaluated.

In order to ensure a comprehensive inspection, the OQ protocol should include an introduction that outlines the purpose of the inspection. It should also provide a detailed list of materials, methods, and test functions that will be used during the qualification process.

The test functions should clearly explain the parameter being tested, the purpose of the testing, the acceptance criteria, and the procedure to be followed. It is crucial to include tests that verify various aspects such as adequate flow, low volume of supply water, excessive pressure drop between pressure valves, resistivity drop below set points, temperature drop or increase beyond set levels (for hot WFI systems), operational range of flow rates, and recirculation to minimize intermittent use and low flow.

The first step in the OQ process should be to verify that the operation of the system is properly described in the draft Standard Operating Procedure (SOP). The protocol for system operation should be developed using the vendor manual, as well as other published references for water system validation.

Once the system has been verified, the analyst should proceed to test the system for compliance. This includes checking whether the system is operating according to the written procedure, determining whether critical parameters such as minimum circulating pressure and return pressure are being maintained, and verifying the alarm settings including low water level, resistivity changes, and excessive pressure differentials. It may be advisable to simulate some alarms to ensure the safety of testers and equipment.

Revalidation

The revalidation of the system should have clearly defined and documented periods or conditions, as stated in the Special Edition: Utilities Qualification Bob Elms and Cindy Green. There are several circumstances that may require revalidation, such as changes in system design that could potentially impact flow rates, temperature, storage, delivery, sampling, or water quality. Revalidation may also be necessary if alert and action levels are consistently exceeded, if there are product failures or performance issues caused by water, or if there are changes in sanitizing agents or procedures. While re-validation does not always require a complete repetition of IQ, OQ, and PQ, it is advisable to use previously written protocols as a guide for developing the revalidation protocol. The new protocol should include key inspections and tests to thoroughly evaluate the system’s capabilities. This may involve increased sampling and testing for chemical, endotoxin, and microbial contamination.

FREQUENCY OF VALIDATING WATER SYSTEMS

To ensure that the water system remains under control and consistently produces water of the desired quality, it is crucial to monitor it at regular intervals. Samples should be collected from representative locations within the processing and distribution system. The individual responsible for collecting the samples should have received training in aseptic handling practices. These samples should be tested within a few hours and chilled to a temperature below 8°C, but they should not be frozen. It is important to have well-designed and hygienic sampling points. For sub-systems, deionizers, and reverse osmosis (RO) systems, the sampling points should be located as close to the downstream side as possible. Specifications should include “target,” “alert,” and “action” limits for different sampling locations, and an action plan should be readily available. The sample sizes should be between 100-500ml. The sample container should be inert, securely closable, preferably single-use, and sterile. Proper labeling of the sample container is essential, including the date and time of sampling, sampling location, sampler’s name, and sampler’s signature. The frequency of monitoring should be determined in a way that ensures the water meets the required quality standards.

(1.) For potable water, validation should be conducted once a year, considering both Indian Standards and, if the water source is groundwater located near agricultural land, for pesticides.

(2.) Water from storage tanks should be validated once a month for parameters such as turbidity, dissolved solids, pH value, chlorine content, total organic carbon (TOC), and pathogens.

(3.) Purified water and water for injection should be validated once a week, adhering to the specifications outlined in the Indian Pharmacopoeia (I.P).

(4.) For microbial purity, purified water and water for injection should be validated twice a week.