484-437-2654

RhoTau on LinkedIn 

Water Quality for Pharmaceutical Applications – Does It Matter?

RJTimko

Water is composed of two atoms of hydrogen and one atom of oxygen.  Water comprises about 50-70% of the human body. It is essential for life.  From a pharmaceutical perspective, it is a key component in the development, manufacture and stability of a variety of dosage forms.  It may serve as a solvent and vehicle in liquid dosage forms, non-sterile and sterile, oral, parenteral – intravenous, intramuscular, and subcutaneous, otic, ocular, and topical. It may also have applicability in the preparation of solid dosage forms as a massing aid, or to deliver a drug substance onto a solid carrier or as a tablet coating aid. Further, it can impact the stability of the dosage form from chemical and/or physical perspectives.

 

One question that often arises is what water quality is required for use in the development, manufacture and testing of pharmaceutical dosage forms. 

 

The United States Pharmacopeia (USP) defines the various types of component waters used in Pharmaceutical Products. However, the USP is not considered a regulatory document itself, it is a set of standards that are recognized and enforced by regulatory agencies like the FDA, meaning manufacturers are expected to adhere to these standards when producing drugs. These standards can be used as evidence of compliance with regulations.  The current version of USP standards for water are deemed official by the USP are enforceable by the U.S. Food and Drug Administration (FDA) for medicines manufactured and marketed in the United States.

 

According to the USP, there are various quality designations that can be applied to water:

  • Non-potable
  • Potable (drinkable) water
  • USP purified water
  • USP water for injection (WFI)
  • USP sterile water for injection
  • USP sterile water for inhalation
  • USP bacteriostatic water for injection
  • USP sterile water for irrigation

 

The USP compendia designations mean that the water is the subject of an official monograph in the current USP with various specifications for each type. The latter four waters (USP sterile water for injection, USP sterile water for inhalation, USP bacteriostatic water for injection, and USP sterile water for irrigation) are “finished” products that are packaged and labeled as such and need not be of concern during an inspection outside of plants which actually produce these products.

 

The USP purified water and the USP WFI are components or “ingredient materials” as they are termed by the USP; intended to be used in the production of drug products. USP WFI may be made only by distillation or reverse osmosis.

 

But what about potable water as a component in a drug product? Is it required to undergo routine sampling and testing before use in production? 

 

Potable water is obtained primarily from municipal water systems but may also be drawn from wells, rivers, or ponds. According to the preamble to the Current Good Manufacturing Practice regulations (CGMPs), no acceptance testing is required for potable water unless it is obtained from sources that do not control water quality to Environmental Protection Agency (EPA) standards. It is important to know that potable water may not be used to prepare USP dosage form drug products or for laboratory reagents to test solutions. Potable water may be used to manufacture drug substances (also known as bulk drugs or bulk pharmaceutical chemicals).

 

While there are no absolute microbial standards for water (other than water intended to be sterile), the GMP regulations require that appropriate specifications be established and monitored. The specification must take into account the intended use of the water; i.e., water used to formulate a product should contain no organisms capable of growing in the product. Action or alert limits must be based upon validation data and must be set low enough to signal significant changes from normal operating conditions.

 

In toxicology studies, USP water is normally used as the primary vehicle for administering test substances to animals, ensuring a high level of purity and consistency that minimizes the introduction of extraneous chemicals which could potentially interfere with the study results, allowing for accurate assessment of the toxicity of the test substance alone. 

 

Key points about using USP/NF water in toxicology studies are as follows:

  • High Purity: USP/NF water meets strict standards for contaminant levels, including metals, organic compounds, and microorganisms, which is critical for accurately evaluating the toxicity of a test substance without confounding factors from impurities in the water. 
  • Consistency: By using a standardized water source, researchers can ensure consistency across different experiments and laboratories, facilitating comparison of results. 
  • Regulatory Compliance: Most regulatory agencies require the use of USP/NF grade water for toxicological studies, as it provides a reliable guarantee of quality. 
  • Applications: USP/NF water is used in various aspects of toxicology studies, including:
    • Dosing solutions: Preparing test substance dilutions for oral, dermal, or inhalation administration. 
    • Vehicle controls: A control group receiving only the vehicle (USP/NF water) is often included to assess the effects of the vehicle itself. 
    • Tissue preparation: Preparing solutions for tissue homogenization and analysis. 

 

Other Important considerations for toxicology studies are:

  • Depending on the study design and route of administration, specific USP/NF water specifications may need to be followed, such as conductivity or total organic carbon (TOC) levels. 
  • Also, it is important to validate the water purification system used to ensure it consistently produces USP/NF grade water. 

 

The US Code of Federal Regulations in discussing Test and Control Articles for toxicology studies does not specifically address the components in a toxicology test article, only the test article itself. The term test article can either be the drug substance alone or the drug substance in a carrier vehicle. If the test article involves a carrier vehicle:

  • For each test or control article that is mixed with a carrier, tests by appropriate analytical methods shall be conducted:
  • To determine the uniformity of the mixture and to determine, periodically, the concentration of the test or control article in the mixture.
  • To determine the stability of the test and control articles in the mixture as required by the conditions of the study either:
    • Before study initiation, or concomitantly, according to written standard operating procedures which provide for periodic analysis of the test and control articles in the mixture.
    • Where any of the components of the test or control article carrier mixture has an expiration date, that date shall be clearly shown on the container. If more than one component has an expiration date, the earliest date shall be shown.

 

The United States Code of Federal Regulations does not specify a water quality standard for pharmaceutical applications, but it does indicate water quality for bottled water, flavored effervescent water and soda.

 

So, if a pharmaceutical product uses water that may be considered an effervescent oral liquid product, the water used to make this product may also wish to consider the requirements for a ‘soda-type’ product. 

 

In general, a soda or effervescent water product must meet strict quality standards to ensure it’s free of contaminants and tastes good. It should meet the standards set by the US Environmental Protection Agency (EPA), World Health Organization (WHO), and European Directive EC 98/1983. 

 

The water should be free of microorganisms and sterile. It should be free of any off-tastes or odors. Further the water should be soft to medium soft, with a hardness of less than 50–100 parts per million (ppm) as calcium carbonate (CaCO3). Also, the water should be free of high levels of mineral salts and elements, and have total mineral solids of less than 350 ppm and should be free of dissolved oxygen. 

 

Soda manufacturers often use softened water to remove chlorine residues that can cause off-tastes. They use a variety of techniques and equipment to remove impurities, such as ion-exchange polymers, reverse osmosis, precipitation methods, and chelating agents. 

 

Some reference and guidance documents one may consider when determining the water quality for use in toxicology or clinical studies are available on the FDA website. These documents represent  FDA’s interpretation of what is in the CFR and their current thinking regarding chemistry, manufacturing and controls for clinical dosage forms.

 

Also, possible consideration could be given to the following presentation, “Guidance on CMC for Phase 1 and Phases 2/3 Investigational New Drug Applications,” Charles P. Hoiberg, Ph.D. Executive Director, Pfizer Board Member, FDA Alumni Association , DIA China, Beijing, China May 16-18, 2011, https://www.diaglobal.org/productfiles/25849/20110518/track4/11%20t4-4_chuck%20hoiberg.pdf

 

Further, for an effervescent or ‘soda-like’ product, the following FDA link may be consideration.

 

Some additional references that may be of interest are:

  • United States Pharmacopeia, General Chapter <1231> Water for Pharmaceutical Purposes
  • Guideline on the Quality of Water for Pharmaceutical Use, European Medicines Agency, EMA/CHMP/CVMP/QWP/496873/2018, 20May2020
  • FDA Current Good Manufacturing Practice Regulations, Federal Register, Vol.43, No. 190 – Sept. 29, 1978, I. General Comments and Subpart C, para. 211.48.
  • Water Programs, Environmental Protection Agency, National Interim Primary Drinking Water Regulations, Dec. 16, 1985, 40 Code of Federal Regulations, Part 141, para. 141.14 and 141.21.
  • FDA LETTER TO THE PHARMACEUTICAL INDUSTRY Re: Validation and Control of Deionized Water Systems, – Daniel L. Michels, Bureau of Drugs, Aug. 1981.
  • FDA Inspection Technical Guide, Number 36, Reverse Osmosis, Oct. 1980.
  • FDA Inspection Technical Guide, Number 40, Bacterial Endotoxins/Pyrogens, March 1985.
  • Protection of Water Treatment Systems series, PMA Deionized Water Committee, PHARMACEUTICAL TECHNOLOGY – May, Sept. and Oct., 1983; Sept. 1984, and Nov. 1985.
  • Parenteral Drug Association, Design Concepts for the Validation of a Water for Injection System, Technical Report No. 4, 1983.
  • Monitoring and Validation of High Purity Water Systems with the LAL test for pyrogens, T.J. Novistsky, Pharmaceutical Engineering, March-April, 1984

 

312025rjt

 

Call Now Button