Revisions to the USP's General Information Chapters in Pharmaceutical Microbiology

By Robert Friedel

In the 1999 March-April issue of Pharmacopeial Forum (Pharmacopeial Previews section), the USP Microbiological Subcommittee has renamed General Information Chapter <1111>, "Microbiological Attributes of Nonsterile Pharmacopeial Articles." Two very important statements regarding preservation and subsequent microbiological quality are listed in the chapter, including:

• "Nonaqueous, or dry dosage forms do not support microbial growth due to low water activity." As a result, the microbiological quality is a function of the microorganisms introduced by the raw materials and during processing.
• "The concentration of added antimicrobial preservative can be minimized if the formulation has intrinsic antimicrobial activity (i.e., antimicrobial ingredients, hostile pH, high osmotic pressure, and low water activity)." This has long been recognized by food industry microbiologists and is known as the "hurdle effect."

There are several interesting developments regarding the proposed revision of this informational chapter. The first affects those pharmaceutical articles not covered by individual monographs. In this particular instance, the USP has provided a specific microbiological target of not-more-than (NMT) 1000 cfu/g or mL for raw materials, excipients and drug substances. When the article is not cited as having microbiological specifications, USP has provided a novel decision tree designed to evaluate the need to test for the absence of a particular pathogen.

The decision regarding the inclusion of an "objectionable" organism(s) will be based upon the dosage form's route of administration (e.g., inhalations, vaginal, [nasal, otic, or topical], rectal, liquid oral, and solid oral), nature of the product (aqueous vs. non-aqueous, multiple-use vs. single-use) and potential hazard to the user (count levels). Of course, there are exceptions to the rule and these are addressed as required.

Traditionally, the microbiologist has applied a somewhat limited number of analytical techniques to evaluate the microbiological profile of a particular substance. Many techniques used today have not changed since the time of Pasteur. In today's world, however, all techniques involving the cultivation of microorganisms from materials containing inimical, antimicrobial compounds, whether they be preservatives or antibiotics, contain one common goal—the accurate recovery of indigenous bioburden. Techniques used to achieve this include the addition of a chemical neutralizer, dilution, and rinsing (membrane filtration).

To ascertain the ability of the method to recover viable microorganisms, the antimicrobial effect of the material undergoing analysis must be neutralized in the recovery medium. This is accomplished by eliminating what is known in the laboratory as "antimicrobial carryover." More importantly, the diluent used to neutralize the antimicrobial (e.g., parabens) must demonstrate a lack of toxicity to the organism(s) the microbiologist is attempting to recover.

The USP/NF Supplement 10 (issued May 15, 1999) contains the new General Information Chapter <1227> "Validation of Microbial Recovery from Pharmacopeial Articles"*. This chapter provides the microbiologist with information regarding the conditions and methodologies necessary to ensure accurate recovery of microorganisms from dosage forms containing antimicrobial chemicals. The chapter is applicable to: <61> Microbial Limit Tests, <51> Antimicrobial Effectiveness Testing, and <71>Sterility Tests. The information included in the new chapter was published previously by the American Society for Testing and Materials (ASTM document E1054 "Standard Practices for Evaluating Inactivators of Antimicrobial Agents Used in Disinfectant, Sanitizer, Antiseptic or Preserved Products") and has been present in the industrial microbiological literature for quite some time.

USP is taking the correct steps in providing guidelines for microbiological recovery where none have existed previously or which were limited in scope.

*N.B.—The Chapter <1227> "Validation of Microbial Recovery From Pharmacopeial Articles" which was published in Supplement # 10 of USP, was not the intended version. The chapter <1227> that became official on May 15, 1999 is shown in the March-April 1999 issue of Pharmacopeial Forum.

References

1. Russell, A.D. et al. "A Review: Microbiological Applications of the Inactivation of Antibiotics and Other Antimicrobial Ingredients", J. Appl. Microbiol., 46:207-245, 1979.
2. Dabbah, R. "USP Update", Parenteral Drug Association Letter, May 1999.

Robert Friedel is Quality Assurance Manager, Laboratory Research & Analysis Groups, at Perritt Laboratories. Perritt is an FDA-registered, independent testing laboratory specializing in pharmaceutical and cosmetic microbiological testing using both standard and custom assays.

For more information: Robert R. Friedel, Perritt Laboratories Inc., 145 South Main St., Hightstown, NJ 08520. Tel: 609-443-4848. Fax: 609-443-5293. Email: rfriedel@perrittlab.com.