Aaron Schieving is Corporate Director of Sales & Marketing for Texas-based Lifecycle Biotechnologies, parent company to Chata Biosystems, a chemical and reagent manufacturer, aschieving@lifecyclebio.com.

Aaron Schieving

	Manufacturing of pharmaceuticals, medical devices, biologics, cell- and tissue-based products, and many other medical products requires significant volumes of water. The author outlined the different types of water and their most common applications in a 

 (1). These different water types are determined based on the various testing performed. The following definitions can help navigate these complexities through a deeper understanding of the analytical and microbiology testing based on the requirements set forth in the 

 (TOC) testing is performed as a means for screening for organic molecules introduced from source water, from purification and distribution system materials, and from biofilm growing in the system.

testing is performed to measure the ion-facilitated electron flow through the water. Water molecules dissociate into ions as a function of pH and temperature and result in a predictable conductivity. Conductivity can be affected by the presence of carbon dioxide and inorganic dissolved solids, such as chloride, nitrate, sulfate, phosphate anions, sodium, magnesium, calcium, iron, and aluminum cations.

 also referred to as pyrogen testing, is a test that uses Limulus Amebocyte Lysate, a reagent derived from the blood of the horseshoe crab (Limulus polyphemus), to detect the presence of bacterial endotoxin in the water. Bacterial endotoxin is found in the cell wall of gram negative bacteria and causes a fever in mammalian species.

 testing is performed on the water to determine the presence or absence of viable microorganisms on products or portions thereof.

 testing allows quantitative enumeration of mesophilic bacteria and fungi that may grow under aerobic conditions. These tests are designed primarily to determine whether the water complies with an established specification for microbiological quality.

 testing is of particular concern in injections and parenteral infusions consisting of extraneous mobile undissolved particles, other than gas bubbles, unintentionally present in the solutions. Water designated for use in injectable products requires this testing to ensure the source water is not adding particulate matter into the final product that could be introduced intravenously.

 testing demonstrates the effectiveness of antimicrobial protection. Antimicrobial preservatives are toxic substances added to non-sterile dosage forms to protect them from microbiological growth or from microorganisms that are introduced inadvertently during or subsequent to the manufacturing process. In the case of sterile articles packaged in multiple-dose containers, antimicrobial preservatives are added to inhibit the growth of microorganisms that may be introduced from repeatedly withdrawing individual doses.

testing evaluates the negative log of the activity of the hydrogen ion in the water.

 are all qualitative tests to determine the amounts of these substances in the water.

	Having a robust understanding of each different test will provide a roadmap for how water impacts each product. Using a less stringent type of water for a product based on its intended use could be a costly mistake. Similarly, using a more stringent type of water, when not required, could result in increased costs. Add in the increased scrutiny of the ever-changing regulatory landscape, and it becomes crucial to have a complete understanding of the water a process requires. 

	The final piece is knowing which tests are required for each type of water. Table I summarizes the requirements needed to claim a particular water type.  

	Water types and testing variables can be a complicated process. Knowing the specifics of the water used for processing is crucial to ensure optimal patient care. Water may seem ordinary, but the impact it has on patients’ lives is proof of its tremendous need and value.

		A. Schieving, “Understanding USP <1231> Water for Pharmaceutical Use,” May 1, 2017, 

understanding-usp-water-pharmaceutical-use.	

 <1231> Water for Pharmaceutical Purposes (Rockville, MD, March 8, 2017).


	Aaron Schieving is Corporate Director of Sales & Marketing for Texas-based Lifecycle Biotechnologies, parent company to Chata Biosystems, a chemical and reagent manufacturer, 

Articles

USP  describes analytical and microbiology testing required for different types of pharmaceutical water.

Testing Water for Pharmaceutical Use

	Manufacturing of pharmaceutical products, medical devices, biologics, cell- and tissue-based products, and many other medical products requires significant volumes of water. Water is more complicated than what most people think. The two major categories are bulk water (i.e., produced on-site where used from an internal water system) and packaged water (i.e., produced elsewhere, packaged, sterilized to preserve microbial quality throughout the packaged shelf life, and purchased). Regardless of whether its bulk water or packaged water, the type of water is then determined by the testing performed, as defined by 

	The following definitions can help navigate the complexities of the different types of water and provide a better understanding of their appropriate usages.

Purified water is most commonly used as a diluent in the production of non-sterile products for injection, infusion or implantation, cleaning equipment, and cleaning non-sterile product-contact components. Purified water systems must be validated to consistently produce and distribute water of acceptable chemical and microbiological quality. However, they may be susceptible to biofilms, undesirable levels of viable microorganisms, or endotoxins, which means frequent sanitization and monitoring to ensure appropriate quality at the points of use.

WFI is most often used as an excipient in the production of sterile products and other preparations when endotoxin content must be controlled. Examples are pharmaceutical applications such as cleaning of certain equipment and sterile product-contact components. WFI must meet all the same chemical requirements of purified water with added bacterial endotoxin specifications, because endotoxins are produced by microorganisms that are prone to inhabit water. As with a water system producing purified water, WFI systems also must be validated to reliably and consistently produce and distribute water of acceptable chemical and microbiological quality.

Pure steam is intended for use in steam-sterilizing porous loads and equipment and in other processes, such as cleaning, where condensate would directly contact official articles, containers for these articles, process surfaces that would in turn contact these articles, or materials which are used in analyzing such articles. Pure steam is prepared from suitably pretreated source water, analogous to the pretreatment used for purified water or WFI, vaporized with a suitable mist elimination, and distributed under pressure. 

This type of water is specifically for hemodialysis applications and primarily for the dilution of hemodialysis concentrate solutions. Water for hemodialysis is typically produced and used on site as bulk water. This water contains no added antimicrobials and is not intended for injection.

This water has been packaged and rendered sterile. It is used for preparation of sterile products or in analytical applications requiring purified water when access to a validated system is not practical and only a small quantity is needed. It is also used when bulk packaged purified water is not suitably microbiologically controlled.

This water has been packaged and rendered sterile. This water is for the processing of sterile products intended to be used intravenously. Additionally, it is used for other applications where bulk WFI or purified water is indicated but access to a validated water system is either not practical or only a relatively small quantity is needed. Sterile WFI is typically packaged in single-dose containers that are typically less than 1 L in size.

This water has been packaged and rendered sterile. This water is commonly used when sterile water is required, but when the application does not have particulate matter specifications. Sterile water for irrigation is often packaged in containers that are typically greater than 1 L in size.

This water has been packaged and rendered sterile. This water is usually intended for use with inhalators and in preparation of inhalation solutions. It carries a less stringent specification for bacterial endotoxins than sterile WFI and, therefore, is not suitable for parenteral applications.

This water is sterile WFI to which one or more suitable antimicrobial preservatives have been added. This water is typically intended for use as a diluent in the preparation of sterile products, mostly for multi-dose products that require repeated content withdrawals, such as liquid pharmaceuticals. It may be packaged in single-dose or multiple-dose containers, usually less than 30 mL.

	With nine different types of water, each with specific testing requirements and applications, it is crucial to understand how they can impact products. Using a less stringent type of water for a product based on its intended use could be a costly mistake. Similarly, using a more stringent type of water, when not required, could result in increased costs. Add in the increased scrutiny of the ever-changing regulatory landscape, it becomes even more critical to have a complete understanding of the water a process requires.

<1231> Water for Pharmaceutical Purposes. (Rockville, MD, March 8, 2017).

	Aaron Schieving is Corporate Director of Sales & Marketing for Texas-based Lifecycle Biotechnologies, parent company to Chata Biosystems

The type of water for pharmaceutical use is determined by USP testing.