Background

Earlier this year (2024), the USP published Pharmacopeial Forum 50(2), which introduced proposed changes to the General Notices section of the USP for public comment. Among the changes is a modification to the Foreign Substances & Impurities language, replacing the term “Foreign Substances” with “Impurities & Contaminants.” By introducing the term “Impurities & Contaminants,” the testing requirements for objectionable materials are clarified to include those from any source of contamination, not just those introduced from external sources.

As the General Notices section of the USP is binding and relevant to all monographs in the compendium, USP Purified Water and WFI are subject to the existing prescribed language and any modifications that may be adopted. Although the official text will not be released until 2025, the modifications regarding “Impurities & Contaminants” in official USP articles may change how testing and monitoring for contamination in pharmaceutical waters is viewed and regulated.

Testing and Monitoring Requirements

The proposed USP language includes two important points regarding the testing requirements for official articles. First, it notes that it is not practical to include a test for every potential contaminant in each monograph. For USP waters such as Purified Water and Water for Injection (WFI), the monograph tests are limited to a few broad water quality parameters. These include conductivity, Total Organic Carbon (TOC), and endotoxin for WFI. Not specifically included in the USP bulk water monographs, but also mandated, is the monitoring and testing for total viable bacteria. These tests represent the minimum required testing standards, and additional tests should be established based on the nature of the product for which the water is used.

The second important addition is the proposed language stating that “appropriate tests and acceptance criteria for detecting and controlling such impurities and contaminants, where reasonably expected to be present, are expected to be employed in addition to the tests provided in the individual monograph.” This text further suggests that additional testing is warranted when there is a sufficient risk that these impurities may be present. This proposed language aligns with the language in the EP General Notices section, which states:

“The requirements are not framed to take account of all possible impurities. It is not to be presumed, for example, that an impurity that is not detectable by means of the prescribed [monograph] tests is tolerated if common sense and good pharmaceutical practice require that it be absent.”

The language in both pharmacopeias clearly places the responsibility for determining the risk of impurities that may be present, and whether additional testing may be required, directly on the drug manufacturer. It forces the manufacturer to review the feed water source, identify any likely impurities, evaluate additional sources of contamination, and develop a plan to manage potential impurities. Simply testing the product water without developing a contamination control strategy is not sufficient.

Impurities in Pharmaceutical Waters

There are certain impurities we expect to be present in pharmaceutical waters, even if the water quality is within specification. At the concentrations typically encountered, these may pose little or minimal risk to the product. Common, yet often acceptable, impurities in pharmaceutical waters may include the following:

• Carbon Dioxide and Ammonia – Gases often introduced into the system via the vent filtration systems on atmospheric storage tanks. These will increase the conductivity of deionized water when absorbed and ionized.
• Gram-Negative Bacteria & Endotoxins – Presence originating from the feed water, and should be controlled throughout the generation and distribution systems.
• Low Molecular Weight Organics, including THMs – Difficult-to-remove species that generally constitute most of the Total Organic Carbon (TOC) in high-purity waters.
• Inert Gases – Gases such as oxygen and nitrogen that are naturally present in water at low concentrations unless specifically reduced during the treatment process.
• Trace Metals and Organics – Impurities that may be absorbed in pharmaceutical waters from contact surfaces such as 316LSS and polymeric elastomers. Generally, their presence is at parts-per-million concentrations or lower, which is acceptable for most products.

The level of acceptable risk depends on the nature of the product, the route of administration of the drug, and whether the water is used in a product that undergoes further downstream purification steps. A risk assessment (RA) process can be used to identify sources of contamination, determine their potential impact on the water treatment process itself, and ultimately on product water quality. Certain impurities may be undesirable because they impact process components but are not necessarily detrimental to product quality (e.g., dissolved silica). Contaminants that may pose additional product risk and may be unacceptable include, but are not limited to, the following:

• Particulates – especially concerning for parenteral products.
• Nitrosamines (and their precursors) – a class of compounds that are known or suspected carcinogens.
• Nucleases – relevant for molecular biology applications and PCR products.
• Specific Microbiological Impurities – including objectionable organisms.
• Heavy Metals – may be of greater concern for biological products.
• Emerging Contaminants – generally synthetic compounds that may adversely affect human health.

Contamination found in final product waters can come from a variety of sources, but most likely from the starting material or feed water. With an unlimited number of possible impurities and continuously varying composition, feed waters to pharmaceutical water treatment systems are uniquely challenging. Contamination may stem from process additives—chemicals or other compounds used during the water treatment process. Additionally, contamination could include extractables from water contact materials, be generated within the system (e.g., microbial-based contamination), or originate externally. A complete evaluation of all potential sources of contamination should be carried out, and a strategy for minimizing, controlling, and monitoring impurities should be adopted.

Path Forward

Bulk pharmaceutical waters are not pure, nor are they sterile. Impurities and contamination will be present, even if only at trace levels. Users must determine which impurities are reasonably expected to be present and whether or not they are objectionable, using RA tools. Adjustments to system design, operation, procedures, or testing requirements are made to mitigate the identified risks. Ultimately, testing and monitoring requirements for each Purified Water and WFI system may be unique.

Note: The content of this post was adapted in part, from the author’s presentation at the ISPE Critical Utilities Conference on November 13-14, 2024.