Water for Injection WFI

The Water for Injection (WFI) is produced by an XYZ multi-effect water still (type 300-S), which is intended to produce pure, pyrogen-free distilled water from pretreated feed water by evaporating and condensing the feed water (i.e., DI Water). The water still consists of pressure vessels, five columns, and a condenser. The piping between the pressure vessels is stainless steel (S.S.) 316L. 

The WFI distribution system (storage tanks, circulation pumps, pipework) is steam sterilized. The sterilization cycle is controlled and monitored by temperature indicators located at critical points. 

---

Water for injection (WFI) is the most widely used solvent for parenteral preparations. The USP requirements for WFI and purified water have been recently updated to replace the traditional wet and colorimetric analytical methods with the more modern and cost-effective methods of conductivity and total organic carbon. Water for injection must be prepared and stored in a manner to ensure purity and freedom from pyrogens. The most common means of obtaining WFI is by the distillation of deionized water. This is the only method of preparation permitted by the European Pharmacopoeia (EP). In contrast, the USP and the Japanese Pharmacopeias also permit reverse osmosis to be used. The USP has also recently broadened its definition of source water to include not only the U.S. Environmental Protection Agency National Primary Drinking Water Standards, but also comparable regulations of the European Union or Japan. 

Purified water (PW) is used for cleaning and preparation of nonsterile drug compounds whereas water-for-injection (WFI) is used for the final rinse and preparation of sterile materials. Refer to Section 9.6.1. 

CDS of surfaces/equipment coming into direct contact with the product requires special consideration. While CDS procedures of guaranteed efficiency must be applied, it is imperative that no trace of the CDS agents subsequently remain on such surfaces, as this would result in automatic product contamination. The final stage of most CDS procedures, as applied to such process equipment, involves exhaustive rinsing with highly pure water (water for injections WFI). This is followed if at all possible by autoclaving. 

Two of the more recent such approvals are that of Ovitrelle and Luveris. Ovitrelle is the trade name given by Serono to its recombinant hCG-based product. The producer is an engineered CHO cell line that has been co-transfected with the genes coding for both the hCG a- and P-subunits. Downstream processing entails a combination of several chromatographic and ultrafiltration steps and the final product is presented in freeze-dried form. Each vial of product contains 285 fig of active substance (hCG) and the product has been assigned a 2 year shelf-life. It is reconstituted with water for injections (WFI) immediately before use. 

To provide the guideline for the validation of water for injection (WFI) to be maintained in compliance with USP 24 monograph... 

Water systems. The water systems at ABC Pharmaceutical Industries are monitored per manufacturing site SOP for Microbiological Monitoring of Water. The levels of water tested are city water, purified water (deionized water), and water for injection (WFI). Manufacturing site SOP describes the procedures for obtaining samples, sampling frequencies, test procedures, and acceptance criteria (alert and action limits). 

Place the container of stoppers on a laminar flow bench along with a container of sterile, nonpyrogenic water for injection (WFI). Don a fresh pair of sterile gloves. 

Even when water comphes with quality parameters as a raw material, it can present some impurities after being turned into a pharmaceutical product. Table 6 presents the level of some contaminants found in water for injection (WFI). Since the raw material should have passed in the quality test, contaminants either were below the allowed concentration level or were introduced after packaging. Contaminants introduced after packaging most Ukely originate from the packaging materials. Section 6.1.3.2 discusses containers as sources of contamination. 

An action guideline of not more than 10 CFUs/100 ml for bacteriological purity is suggested. As with the purified water system, the sampling and testing frequency for the water for injection (WFI) system is defined in the protocol and can be reduced after the system is qualified and validated. 

Grades of water specified in the Pharmacopeia (USP) are summarized in Table 1. Water for injection (WFI) is the most purified water, and careful attention should be paid to the validation of its manufacturing process. 

The cleaning agents used are mostly demineralized water (DE) and water for injections (WFI). The use of cleaning media and detergents will depend on the components of the product. 

Table 5.2. Standards for the quality of purified water (PW) and water for injection (WFI) (Slabicky, 1994)...

In tangential filtration, membranes are used as filter media. Membranes are defined as barriers of reduced thickness, across which physical and/or chemical gradients are established to facilitate the preferential migration of one or more components from a given mixture, promoting their separation (Klein, 1991). They are usually made of polymers or inorganic materials, such as ceramic or sintered steel. In the biopharmaceutical industry, membranes find various applications, such as production of water for injection (WFI), sterilization of culture media, buffer solutions and gases, separation of cells and cell debris, and purification and concentration of proteins. 

Any utility in direct product contact is subject to formal qualification through confirmation of the quality of the delivered material at each use point. Water-for-injection (WFI) systems are considered the most critical of all, and the qualification period for WFI is the longest and may be as long as 3 months. The remaining product contact utilities can be qualified more rapidly. Nonproduct utilities requirements can be satisfied by commissioning. 

The most widely used solvent for SVIs is water for injection (WFI), USP. As a solvent, WFI is used in preparing the bulk solution (compounding) and as a final rinse for equipment and packaging preparation. WFI is prepared by distillation or reverse osmosis, although only distillation is permitted for sterile water for injection, USP. Sterile water for injection is used as a vehicle for reconstitution of sterile solid products... 

Ready to Sterilize (RtS) Typically components are washed, then rinsed with Water For Injection (WFI) to reduce bioburden and endotoxin levels, lubricated with silicone oil, and finally packaged in a classified area (Classes 100-10,000) in Tyvek bags that can be steam sterilized by the drug or device manufacturer before use. Alternately polyethylene bags may be used if the end user is utilizing gamma radiation for sterilization. 

The quality attributes of water for injection (WFI) are stricter than for purified water. Consequently, the preparation methods typically vary in the last stage to ensure good control of quality of WFI. Methods for the production of WFI are the subject of current debate. The PhEur 2005 indicates that only distillation would give assurance of consistent supply of the appropriate quality. However, the PhEur 2005 permits distillation, ion exchange, reverse osmosis, or any other suitable method that complies with regulations on water intended for human consumption laid down by the competent authority. 

Water for pharmaceutical use (WPU), purified water (PW), highly purified water (HPW) and water for injections (WFI) systems are all considered to be direct impact, quality critical systems that should be qualified. The qualification should follow the validation convention of design review or design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). 

Several guidelines are available in the literature for the pharmacist who must extemporaneously prepare an ophthalmic solution. The USP contains a section on ophthalmic solutions, as do other compendia and several standard textbooks. Since the pharmacist does not have the facilities to test the product, he or she should dispense only small quantities, with an expiration date of no more than 30 days. Refrigeration of the product should also be required as a precautionary measure. To reduce the largest potential source of microbial contamination, only sterile purified water should be used in compounding ophthalmic solutions. Sterile water for injection (WFI), USP, from unopened rv bottles or vials is the highest-quality water available to the pharmacist. Prepackaged sterile water with bacteriostatic agents should not be used. 

Before execution of the cleaning validation, the cleaning procedures should be in the form of approved standard operating procedures (SOPs). These procedures should be detailed enough to be reproducible. Parameters such as detergent type, detergent concentration, exposure time, rinse temperature/rinse time, and water pressure/flow rate should be included in the procedure. The final rinse is usually performed with water for injection (WFI). The production operators should be trained in these procedures and their training should be documented. 

Water for Injection (WFI) must meet specifications. 10. N2 filter must pass the integrity test. 

Typical UF performance for pyrogen removal with a polymeric and ceramic membrane is shown in Table 13. It can be seen that both types of UF membranes can adequately remove pyrogens. The choice of UF membrane (ceramic or polymeric) will depend on operating conditions or other special process requirements. Ceramic membrane ultrafiltration can achieve a 5 log reduction in pyrogen level. These UF membranes have been validated for the production of water meeting the requirements of pyrogen-free water for injection (WFI) standards.f ... 

USP requires water for injection (WFI) to be produced by distillation or by reverse osmosis. In the pharmaceutical industry however, distillation is currently the preferred method for WFI generation. A double-pass reverse osmosis unit is sometimes used. A single pass RO is not recommended for WFI generation. Water for injection is intended for use as a solvent for the preparation of parenteral solutions and the final rinse of all parenteral product contact surfaces. 

The solutions used for the dissolution of injectable products are prepared by using Water for Injection (WFI) USP that has been made as described in Ch. 13 of this handbook. In some cases, solutions are prepared using organic solvents (e.g., acetone, methanol, ethanol, isopropanol) alone or in combination with WFI. The potential for preventing microbial contamination should dominate the delivery and storage systems for water and solvents. 

---