By Mike Henley, Ultrapure Water Journal and Industrial Water Treatment
Pharmaceutical water is key to the production of pharmaceutical drug products, many of which require high-purity water. This is water purified according to guidelines as defined by the USP or other pharmacopeias.
There have been a number of technological advancements in high-purity pharmaceutical-grade water. Unlike other industries, however, changes in the use of high-purity water systems have often been in response to compendial and regulatory changes rather than a desire to innovate.
To start, it’s useful to provide some context about pharmaceutical water’s place in the larger water world. The category known as ultrapure water (UPW) itself is used by end users in four main industries: life sciences, microelectronics, power generation, and specialty applications. Each industry’s definition of UPW is unique and their methods to produce this water, and requirements for materials of construction (piping, valves, storage tanks, etc.), vary. Treated UPW that meets requirements for a power station would be unacceptable for a pharmaceutical plant. And purified water meeting pharma plant quality standards does not meet the stricter requirements found in the microelectronics industry.
For pharma, the water treatment guidelines are based around pharmacopeias, of which the USP, European Pharmacopeia (EP), and Japanese Pharmacopeia (JP) are among the most influential. The Indian Pharmacopeia and Chinese Pharmacopeia are also growing in importance. Of course, facilities providing products to other regions follow the pharmacopeias applicable for those markets they sell into. For example, an Indian plant supplying the European market follows EP guidelines when purifying water used to make products sold in that market.
On the regulatory side, the U.S. FDA administers the USP treatment guidelines through inspections to validate system performance, as well as by taking enforcement action when problems are found. Because pharma is a global industry, the FDA sends its staff internationally to nations like India to inspect and validate a treatment system when the plant’s products are sold into the U.S. market.
Water Flows Throughout Pharma
Pharmaceutical water falls under several classifications, based on the final application. Examples include bacteriostatic water for injection, purified water, sterile purified water, and water for injection (WFI). Other examples are listed in Table 1, which also provides an overview of the concerns and uses for pharmaceutical-grade waters. Outside of being used as an ingredient, pharmaceutical water has multiple other applications, including container and equipment cleaning, intravenous fluids, product contact of ingredient, product contact of medical device (cleaning), and reagent or solvent in drug manufacturing (but not in final product).
Table 1 Overview of Pharmaceutical Water and Concerns
Specific water treatment concerns within pharma include chemical/microbial/ endotoxin contamination and case-specific controls for certain types of pharmaceutical water (i.e., aluminum for water for hemodialysis). Life science facilities, including pharma plants, are required to use feedwater that meets drinking water standards as set forth by the U.S. EPA, similar agencies in the country the plant is located, or WHO. Since incoming water is already clean, water pretreatment generally focuses around chlorine removal to protect reverse osmosis (RO) membranes. Common technologies may be activated carbon or metabisulfite.
The main treatment system may include ion exchange (IX), electrodeionization (EDI), RO, distillation, ultrafiltration (UF), microfiltration (MF), ultraviolet (UV), and ozone. The most common material of construction for distribution systems and storage tanks is stainless steel, which can be heat sanitized and carry hot water. Common instruments used to measure water quality are total organic carbon (TOC) and conductivity.
What’s Driving New Water Treatments?
One key factor that drives the choice of water treatment technologies among pharma companies is regulation and changes in the USP guidelines over time. So, unlike other users of UPW, pharma companies tend to move slowly and carefully when adopting new treatment technologies. Many times, innovation in pharmaceutical water systems is driven because of changes in the USP chapters, not because it is the best available technology for a particular need.
One case in point is the use of on-line TOC and conductivity instruments to track water quality. Prior to USP 23, USP called for using wet chemistry testing to measure calcium, sulfate chloride, ammonia, and carbon dioxide. These wet chemistry tests were replaced by the use of conductivity instruments as outlined in USP <645> Water Conductivity (1, 2). The logic behind adopting the conductivity test was that if a plant met the conductivity requirement then it would pass the chemistry tests. Likewise, the Oxidizable Substances test was replaced by <643> on TOC (2).
After implementation, the USP 23 revisions prompted a widespread move among pharmaceutical companies to buy and install TOC and conductivity instruments. For pharmaceutical companies, these new requirements led to innovation to their treatment systems.
A more recent example of how the regulatory approach impacts technology implementation by pharmaceutical companies has been the changes in the acceptable treatment technologies to produce WFI. The USP and JP have permitted the use of non-distillation technologies, while the EP has not.
In 2009, the Japanese Pharmacopoeial Forum recognized RO and ultrafiltration (UF) as an acceptable alternative to produce WFI from either a purified water source or water previously treated by RO or ion exchange, also pointing out that the USP defines WFI as “…water purified by distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms” (3).
While the EP has been slow to change their WFI guidelines, the pharmacopeia had previously set standards for highly purified water (EP 6.3) that actually called for treatments similar to what the USP and JP allowed in their WFI classifications (4). The EP is now prepared, however, to allow for non-distillation technologies to produce WFI [Editor’s Note: Click here for PDA’s comments on the EP revision].
In March 2016, the EP adopted a revised monograph for WFI that allows for the use of technologies equivalent to distillation, such as RO, that are “coupled with appropriate techniques” (5). Appropriate treatment technologies will now include electrodeionization (EDI), UF, or nanofiltration (NF) (6). The change will be effective this April.
The net effect of these changes is that pharmaceutical companies will have greater freedom to produce WFI by either a thermal distillation technology or with membranes. New facilities could opt for either distillation or membrane technologies, while plants with aging stills will also be able to update their plant equipment. Also, since membrane systems operate at ambient temperatures, pharmaceutical facilities opting to use non-distillation technologies could see potential energy and cost savings by changing equipment.
Another important part of this development is that pharmaceutical plants may not need to use distillation to make WFI if their products do not go into markets where the governing pharmacopeia only allows for stills. This change is a part of efforts by the EP, JP, and USP to harmonize different requirements impacting pharmaceutical- grade waters. The benefit is that it simplifies operations for pharmaceutical companies as they make products sold in different global markets.
The adoption of new treatment technologies by pharmaceutical companies is often driven more by changes in pharmacopeia/ regulatory requirements. The pending move by the EDQM to allow for non-distillation treatments will aid the continuing efforts by the EP, JP, and USP to harmonize treatment standards between these pharmacopeias.
The author thanks the following individuals for their help with Table 1: Slava Libman, PhD, Air Liquide-Balazs NanoAnalysis; Anthony Bevilacqua, PhD, METTLERTOLEDO Thornton; William V. Collentro, Water Consulting Specialists; and Brad Buecker, Kiewit Engineering and Design. The author also thanks T.C. Soli, PhD, of Soli Pharma Solutions, and Igor Gorsky of Concordia ValSource for their assistance with this article.
Note: This article originally appeared in the PDA Letter, a publication produced by the Parenteral Drug Association. Jan 31, 2017