The production of pharmaceuticals, medical devices, biologics, cell and tissue products and many other medical devices requires significant amounts of water. Water is more complicated than most people think. The two main categories are bulk water (i.e., manufactured on-site if used from an internal water system) and packaged water (i.e., manufactured elsewhere, packaged, sterilized to maintain microbial quality throughout the shelf life of the package, and purchased). Whether water or packaged water, the type of water is then determined by the tests performed, as defined in the United States Pharmacopoeia (USP) (1). Purified water. Purified water is most often used as a diluent in the manufacture of non-sterile products for injection, infusion or implantation, the cleaning of equipment and the cleaning of non-sterile components in contact with the product. Ultrapure water systems must be validated to consistently produce and distribute water of acceptable chemical and microbiological quality. However, they may be sensitive to biofilms, unwanted levels of viable microorganisms or endotoxins, which means frequent disinfection and monitoring to ensure adequate quality at sites of use. RO and EDI systems are disinfected with hot water as needed after membrane cleaning. The disinfection cycle consists of three basic steps: heating, holding and cooling, as described in Chapter 2. The water is usually heated to 80 °C with the steam heat exchanger and recirculated in the RO/EDI system circuit during the heating stage. Once the water temperature reaches 80°C, it usually flows back into the RO/EDI loop for one hour during the holding step. After an hour, the steam stops and the cooling phase begins when the chilled water circulates again in the RO/EDI circuit and is sent to the drain.
The system continues to flush the water to drain it until the water temperature drops below 30°C. With nine different types of water, each with specific requirements and test applications, it`s critical to understand how they can impact products. Using a less demanding type of water for a product based on its intended use could be a costly mistake. Similarly, using a stricter type of water when not needed could result in higher costs. Add to that the increasing scrutiny of the ever-changing regulatory landscape, making it even more important to have a complete understanding of the water that requires a process. Case study. The case study describes an ultrapure water system similar to the one shown in Figure 3.46. The water treatment plant supplies 9 m3/h of purified water USP to a drug manufacturing facility in the United States. Purified water is used in the manufacture of topical and oral medications.
The hybrid membrane installation consists of a pre-treatment section, a two-pass RO unit with intermediate booster pump and a post-treatment section similar to that shown in the figure above. Raw (urban) feedwater has pH = 7.6 and TDS = 140 mg/l with the following main components: bicarbonate = 19 mg/l; chloride = 19 mg/l; sulphate = 47 mg/l; silicon dioxide = 7 mg/l; calcium = 9 mg/l; magnesium = 4 mg/l; sodium = 30 mg/l). In April 2017, PhEur 9.1 0169 was revised to allow WFI production with a purification process equivalent to distillation and harmonize its rules using USP and JP methods. This change allowed the qualification of membrane-based processes for the production of WFIs, with particular attention to the safety guarantees for microbial control required in the European Medicines Agency (EMA) Q&A monitoring guidelines and Annex 1 of GMP. Membrane-based production is called “membrane WFI” or “ambient WFI”. Although there is no defined WFI environment process, a two-pass IO, ion exchange, and ultrafiltration (UF) approach is becoming increasingly common. Back to front: • UF is used for retention of up to 4 log endotoxins/pyrogens. Pharmaceutical UFs are typically designed for a molecular threshold weight (MWCO) of 10,000 to 20,000 daltons, with 6,000 Da MWCO required for certain applications. • Continuous electrodeionization (CEDI) is an ion exchange process that uses direct current to regenerate in-line resins and is typically used in place of interchangeable or chemically regenerated systems that pose a risk of contamination. CEDI is a polishing technology that reduces all residual minerals, CO2, NH4, SiO2 and TOC left by the RO process.
• While single-pass RO is allowed, two-pass RO provides “additional assurance to maintain the quality of the produced water” according to the EMA`s Q&A document, as the second membrane is a barrier for microorganisms that make their way through the membrane or O-ring defects or grow behind the first pass. In addition, pH adjustment is often used in conjunction with the second pass to release excess CO2 and ensure reliable operation of CEDI modules downstream. A typical RO PW process includes sediment filtration, water softening, and activated carbon filtration upstream of the RO system to prevent particulate pollution and mineral deposits and remove community-added chlorine, which irreversibly damages most RO membrane elements.