Added Substances

It may be necessary to supplement certain pharmaceutical preparations to preserve, increase the stability, or improve the efficacy of the active ingredient(s). Except for those formulations defined by USP monographs which specifically prohibit the introduction of “added substances”, additions to final products may be acceptable.   These compounds must not affect the efficacy of the product or integrity of the testing for the preparation’s critical quality attributes. Commonly added substances are excipients, used to stabilize or aid in the delivery of active ingredients to the patient. Added substances differ from “foreign substances and impurities” which often refers to contamination from extraneous sources or raw materials.

Concerns in Pharmaceutical Waters

Added substances, such as antimicrobial agents, are explicitly excluded from use for bulk compendial waters such as USP Purified Water and USP Water for Injection (WFI). For these classifications of water, additions to the final product would also likely affect critical quality attributes such as conductivity and total viable bacteria.

The challenge for these bulk solutions is that high purity water degrades easily, even in closed systems.  This leads to focus on preserving water quality by 

• Minimizing exposure to the environment
• Limiting degradation from contamination from water-contact materials 
• Limiting time between generation and use
• Sound cleaning and sanitization procedures for all water storage and conveyance systems
• GMP system design (temperature, flow rate, hygienic construction, etc.)
• Producing water that exceeds compendial standards

Added substances are compounds introduced to a final drug substance or drug product after its production. However, this does not include substances added during water purification, such as chemicals for pH adjustment, scale control, microbial control, and the removal of residual disinfectants. According to USP guidance, these additives are acceptable as long as they are “removed by subsequent processing steps or are otherwise absent from the finished water.”

Testing for specific impurities introduced during the treatment process may be necessary, especially if they are not detectable through standard assays (e.g., anti-scaling agents that contain uncommon compounds). In such cases, relying solely on conductivity and total organic carbon (TOC) measurements may not suffice. If trace levels of an antiscalant are present while TOC and conductivity values meet specifications, it raises the question of acceptability. Utilizing a risk assessment tool can assist in determining the appropriate level of testing needed.

Concerns regarding added substances likely explain why chemicals are less frequently used in the preparation of pharmaceutical water compared to other types of high-purity water. This rationale may also contribute to the historical preference for heat sanitization in pharmaceutical water treatment systems over ozonation.

Ozone

The most common impurity of concern in pharmaceutical water systems regarding potential violations of the added substance mandate is ozone. This scrutiny arises from the use of ozone for sanitizing pharmaceutical water storage and distribution systems. Typically, ozone gas is continuously introduced into the product water storage tank and is removed before the water is used. If the final product (e.g., Water for Injection) is defined before it reaches the point of use, ozone could be considered an addition to that final product. However, the appropriate designation of the final product occurs at the specific point where the water is utilized. While water quality prior to this point is important, it does not constitute a definitive (compendial) classification upstream in the process.

Another reason for the heightened scrutiny of ozone is its role as an antimicrobial agent. Any residual ozone in the final water product would clearly violate the no added substance mandate. Recently, the USP has provided additional clarification regarding the definition of added substances in pharmaceutical waters in relation to ozone, as follows:

Purified Water and Water for Injection monographs state that the waters “contain no added substance”. In <1231> Water for Pharmaceutical Purposes Section 3, “no added substances” is intended to mean “no added substances that aren’t sufficiently removed”.  Companies are required to reduce the ozone level below a limit of detection prior to use. Every company may perform its individual risk assessment on the use, reduction, and detection of the ozonation process and take action if deemed appropriate.

The overall intent of the guidance is clear: ozone must be removed before the water is used. However, the phrase “sufficiently removed” introduces ambiguity. This wording differs slightly from the earlier reference, which stated that additions should be “absent” from the final water. When considering other impurities, achieving a detection limit of zero for chemical or organic contaminants is generally not feasible. Limits of detection (LODs) vary by specific parameter and test method, and even at these low concentrations, detection accuracy is not 100 percent. Moreover, it is impractical to test for every potential impurity or additive in final product waters. This situation is similar to testing for potable water, where maximum contaminant levels are set for specific carcinogens or toxins. While trace levels of harmful contaminants may still be present, comprehensive testing is not realistic.

Water Treatment By-Products and Other Impurities

Particular attention should be paid to substances that are not intentionally added but can form from naturally occurring materials interacting with purification technologies or chemicals, leading to undesirable compounds. For example, nitrogen-containing compounds like ion-exchange resins may react with chlorine or ozone used in the treatment process, resulting in the formation of nitrosamines—carcinogenic compounds that are currently under scrutiny by regulatory agencies.

One of the most concerning impurities in parenteral products, for which testing is not mandated, is particulate matter. This can include shedding from elastomers, migratory rouge, or colloidal materials eluted from surfaces that come into contact with water. While there may be debate over whether these should be classified as “Added Substances” or “Foreign Substances and Impurities,” there is no doubt that their presence warrants careful examination.

Non-binding Recommendations 

The minimum quality of Purified Water and Water for Injection (WFI) is typically assessed using a limited set of generalized parameters, such as conductivity, total organic carbon (TOC), total viable bacteria, and endotoxin levels. These parameters establish the baseline quality attributes of the product water. The need for testing additional impurities should be determined based on specific product and process requirements. It is not necessary to verify the absence of added substances in final compendial waters if there is no logical basis for the presence of suspected impurities. A risk assessment tool can help quantify the likelihood of such occurrences.

Additional testing for added substances may be warranted in the following scenarios:

• Use of ozone or other continuous sanitization agents in storage and distribution systems
• Introduction of specific chemicals or compounds (not naturally occurring) during the treatment process
• Utilization of treatment technologies or materials that may contaminate products (e.g., amines from ion-exchange resins, migratory rouge from stainless steel)
• Possibility of by-product formation during the treatment process
• Risk of harmful compounds being present (e.g., nitrosamines)

However, excessive testing for specific contaminants should not be required if their presence would not affect the efficacy of the final product or interfere with prescribed tests, particularly when the impurities are indistinguishable from other common compounds. It is impractical to universally test for every potential impurity that could arise from feed water, by-products of water treatment, or leachates from in-process materials. While unofficial tests not mandated by pharmaceutical water monographs may be applied based on risk or product requirements, they should be used judiciously.