Pharmaceutical Water Systems

PHARMACEUTICAL WATER SYSTEMS

In general, pharmaceutical water systems employ combinations of technologies described earlier. However, since the objective is unique, we review some of these methods while introducing issues that are specifically related to the pro-duction of different qualities of water (Kuhlman and Coleman, 1995). Table 16.1 summarizes water treatments and uses.

Pretreatment and Sources of Water

Potable (drinking) water is not suitable for pharmaceutical purposes. The United States Environmental Protection Agency limits allow 500 recoverable micro-organisms per milliliter, none of which can be coliform organisms in drinking water. Drinking water requires further treatment to meet the requirements for use in pharmaceutical processes.

Water is pretreated to remove materials likely to be detrimental to the purification equipment. This pretreatment takes many forms. A multimedia bed (different gravels in a carbon steel vessel) is used to remove solids from the municipal water. Common problems include high bacterial or particulate counts in the effluent. This technique is highly inefficient because the container is susceptible to corrosion, the media is porous, and the piping contains dead legs, cracks, and crevices.

Water for Injection

Water for injection (WFI) is prepared following pretreatment and further puri-fication, including ion exchange, distillation, and reverse osmosis (Kuhlman and Coleman, 1995). WFI must contain 50 recoverable bacterial colonies or less per milliliter for immediate use. Its preparation by distillation or reverse osmosis renders it sterile, from which it must be protected from contamination by endotoxins or microorganisms.

TABLE 16.1 Water Treatment

Ion Exchange

Zeolite water softener is an exchanger that replaces calcium ions with magne-sium ions. Regeneration of the resin is necessary and usually conducted with brine. Consequently, chloride ions that attack certain types of composite membranes may enter the feedwater stream. Bacteria may also propagate in this system.

Activated carbon filters employ a carbon steel tank filled with gravel and covered with activated charcoal (anthracite). Again, this is a source of bacteria and chloride ions. Deionized water is produced by passing treated water through a mixed-bed or a two-bed cation/anion exchange resin system. The resulting water is deionized because hydrogen ions replace cations and hydroxyl ions replace anions. Deionized water has little or no bacteria and is easily regenerated. The potential for microbial contamination during some of these purification procedures renders additional steps necessary to prepare water suitable for pharmaceutical processing.

Distillation

Distillation separates water from other soluble and insoluble components by elevating the temperature to that at which vapor forms (100^○C) in a boiling chamber and then condensing the vapor into a receiving vessel. The nature of hydrogen bonding of water imparts a unique property to water. Although it can be raised to 100^○C with a relatively small amount of energy (80 kcal), it takes almost seven times this amount (540 kcal) to break the hydrogen bonds and release the water as steam at the same temperature. Consequently, in the con-densation phase, eight times as much water at 5^○C (refrigeration temperature) is required to condense the water as steam. These large exchanges of heat may be used in an efficiently designed still to heat up water entering a second still. Alternatively, the combined gas law can be utilized by compressing vapor and therefore elevating its temperature (vapor compression still).

Reverse Osmosis

Reverse osmosis units vary in design, construction materials, and membrane type more than any other unit in the pretreatment process. Usually it is a sin-glepass system (may not eliminate chlorides). Transmembrane pressures must be maintained. Osmosis is the process whereby a solution separated from pure water by a semipermeable membrane induces movement of water toward the region of high solute concentration. This would ordinarily give rise to an osmotic pressure. If pressure is applied against the osmotic pressure head, the flow of water can be induced in the opposite direction, thereby reversing osmosis. This process, which may be regarded as a form of filtration, removes materials of sizes down to 200-Da molecular weight in a sequence that usually removes particulates and viable microorganisms and contaminates molecules sequentially according to size (i.e., large particles, bacteria, viruses, pyrogens, and ions). Softened pH-adjusted water is used to maximize the efficiency of ion removal. The ionic radius affects ion removal, with multivalent ions more readily removed than monovalent ions.

Storage and Distribution

The water temperature at the point of use must be such that the water can be handled without risk. A recirculating ambient loop or a heat exchanger at the point of use may be required. A sophisticated system of loops and heat exchangers is required to elevate the water temperature before it returns to a storage tank. One approach is to maintain an ambient loop during the day and heat the water during the night. If the water is maintained at ambient temper-atures for not more than 24 hour, the conditions do not violate current good manufacturing practice (cGMP) regulations.

Quality Control

Conductivity and resistivity are convenient online measures that ensure water quality. As it circulates, water loses resistivity, stabilizing at about 5 MΩ/cm. Some corrosion may take place in the distribution system, which may ultimately lead to adulteration of the water. Endotoxin levels are monitored by sampling. Sampled water may be subjected to the limulus amebocyte lysate test to measure the presence of endotoxin. This in vitro assay was predated by rabbit pyrogen testing, which involves monitoring the rabbit’s core body temperature in response to injection with a water sample. Endotoxin may cause mild immune responses that will be detected by an increase in body temperature.

Validation

Validation of any process is required in pharmaceutical manufacturing. The validation master plan outlines the required content and method of preparing validation documentation. Validation is integral to the start-up of the entire plant. Three major sections of the validation procedure are the following:

1. Installation qualification (IQ): establishes and documents that the unit or system was installed correctly per the manufacturer’s specification

2. Operational qualification (OQ): establishes and documents that the unit or system operates as intended

3. Production qualification (PQ): establishes and documents that the unit or system can fulfill its intended purpose on a reproducible basis when challenged with realistic worst-case conditions

The master plan should include a listing of documentation included in validation files for each system (reference files, vendor data, calibration reports, standard operating procedures, and inventories). Critical path schedules, man-power estimates, operator responsibilities, auditing procedures, and outside validation resources should be included in validation documentation. Outside validation resources should be recruited. They may include purchase of vali-dation protocols from commercial vendors, acquisition of data on validation exercises from equipment vendors, use of testing laboratories for performance qualification, contracting with other qualified agencies to perform water sam-pling, and, in the extreme case, contract with a qualified agency to perform the entire validation exercise (including writing protocols and performing valida-tion testing). The scale of operation and internal resources dictate which option to select.