USP Chapter Emphasizes Problems With Revision Process

The United States Pharmacopia has been recognized for years as an authoritative compendium on drug standards. In recent years, it has paid increasing attention to "microbial purity," i.e., freedom from and control of objectionable bacteria and fungi and included writings on the theory and practice of antimicrobial agents. A reading of Chapter ‹1072› in current USP 29 (Antiseptics and Disinfectants), however, reveals inaccuracies in organic chemistry, proper selection of agents, and ingredient concentrations. Although these errors or inaccuracies do not affect drug purity, they are evidence of a revision process that fails to circulate early drafts to the right people.

Item No. 1: The remarks following Table 3 in Chapter ‹1072› discuss the ionization of weak acids such as phenol and acetic acid, both rarely used in the pharmaceutical plant as microbicides. It is correctly stated that phenol is more active in killing microorganisms below pH 7.0 because it is mostly un-ionized. The same common ion effect would be obtained for acetic acid as well, but the author reverses the equation and states that "acetic acid will be more effective at a pH below 4.0 where it is ionized" (1). The equation is

The pKa of acetic acid is 4.55. By the rule of 2-above-2-below, at pH 6.55 the acid is highly ionized and at pH 2.55 it is practically all un-ionized. At pH 4.0, as cited by the author, it cannot be said to be "ionized;" as a matter of fact, about 90% is just the opposite. Thus, fungi and a few aciduric bacteria will be killed rapidly because the molecule exists mainly as HOAc un-ionized. This pH-dependant lethality is, we believe, what the author tried to convey. But if what is said is not clear, it should not be said.

Item No. 2: Table 2 misspells glutaraldehyde, and Table 4 mistakenly lists glutaraldehyde as an oxidizing agent. Glutaraldehyde exerts its effect by covalent bonding to amino groups or other susceptible sites on nucleic acids or polypeptide chains. In chemistry, a nucleophile (literally, "nucleus lover") is a reagent that forms a chemical bond to its reaction partner (the electrophile) by donating both bonding electrons. Its mechanism is the same as formaldehyde but it is less toxic. No manufacturer of this germicide has ever claimed glutaraldehyde to be an oxidizing agent, like chlorine, nor will any textbook of organic chemistry so state. A common definition of an oxidizing agent is a substance that gains electrons in a redox chemical reaction.

In this same table, ethylene oxide is listed as an oxidizing agent. For classification purposes, it should be grouped with formaldehyde and glutaraldehyde. It is an alkylating agent. Alkylating agents increase the size of a molecule, oxidizing agents generally degrade them.

Item No. 3: In Table 2, "General Classification of Antiseptics, Disinfectants, and Sporicidal Agents," benzalkonium chloride is listed at a use concentration of 200 μg/g. This single concentration does not fit any of the standard marketed products now available that might include this agent. For example, it is too low for use as a disinfectant, for first-aid preparation, or for cosmetic use (the usual range is 1000–3000 μg/g for these uses) and it is too high to be used as an ophthalmic preservative, for which the range is 30–100 μg/g.

Item No. 4: Table 4 lists two germicides that essentially have been banned or restricted since the 1970s: mercuric chloride, an environmental hazard, and hexachlorophene, a toxic antiseptic. The listing of these toxicants, even as informational material, should include a statement of their restricted status, lest someone in the future ascribe USP sanction to these agents. Better examples are available. Furthermore, mercurials are cited as attacking either "-SH groups" or "thiol" groups, but they are both the same. Any compound that contains a functional group consisting of a sulfur and hydrogen atom (R-SH) traditionally is known as mercaptan.

Item No. 5: Chapter ‹1072› in the section entitled "Theoretical Discussion of Disinfectant Activity" presents an intriguing but, in context, useless series of mathematical equations for the purpose of "... picking the use-dilution of different disinfectants." In legal and regulatory terms, the use-dilution is simply what the Environmental Protection Agency allows on the label after a manufacturer provides data or whatever the user decides to use based on in-house experiments with organisms isolated in the plant. Q-10 values, rate constants, and discussions of first-order reactions and linear or sigmoid plots are not required to sanitize, disinfect, or sterilize a pharmaceutical plant.

USP has at its service some of the finest microbiologists and chemists in the world. It has been honored by the scientific, regulatory, and legal communities. These comments on the work of a single chapter are not meant to diminish the classic writing in the chapters about sterility, antibiotics, microbial limits, or any others. We merely point out a series of questionable scientific statements in a USP chapter that reflect a proofreading or revision process that requires adjustment and that, if not corrected, could lead to serious problems in the future. There is an old saying: "What you tolerate becomes your standard." USP must not allow incorrect or misleading statements to become its standard.

Herbert Prince, PhD, is scientific director and founder, and Daniel Prince, PhD,* is president of Gibralter Laboratories, Inc., 122 Fairfield Rd., Fairfield, NJ 07004, tel. 973.227.6882 ext. 519, fax 973.227.0812, danielprince@gibraltarlabsinc.com

*To whom all correspondence should be addressed.

Reference

1. United States Pharmacopeia 29—National Formulary 24, Chapter ‹1072› (US Pharmacopeial Convention, Rockville, MD, 2006).