Introduction

Limited microbiological contamination is tolerated in nonsterile pharmaceutical products such as inhalations, tablets, oral liquids, creams and ointments, etc. The pharmacopoeias and the regulatory bodies responsible for licensing the manufacture of pharmaceuticals may require the numbers of microbiological contaminants per unit volume or weight of these products to be limited, and that specified microorganisms are restricted throughout product shelf life. Compliance with these limits is, in most cases, sufficient to protect the patient from unwanted adverse effects.

The microorganisms for which there are specific restrictions in nonsterile products are only indicators of types that could cause infections when the drug product is used as directed. Naturally there should be no pathogens present, but pharmacopoeial monographs primarily exist as standards against which products are tested. It is recognized that it would be impractical — with existing methodologies — to test pharmaceuticals exhaustively for all potentially pathogenic contaminants.

In the United States Pharmacopeia (USP) XXVI 2003, there are only 95 monographs that include microbial limits. Fifty-one of these require absence of Staphylococcus aureus and Pseudomonas aeruginosa, 20 g or 10 ml, 20 require absence of Escherichia coli or Salmonella spp., or Escherichia coli and Salmonella spp., from 10 g or 10 ml. The restrictions on S. aureus and P. aeruginosa apply to topical products, because these microorganisms are typical of types that could cause infection when products are used on open wounds or abraded skin.

The restrictions on Escherichia coli and Salmonella spp. are applicable to oral products because these microorganisms are typical of types that could cause gastrointestinal infections.

The pharmacopoeial restricted species have been chosen as indicators, at least in part, because of the availability of robust techniques for their isolation and recognition. The possibility of other objectionable microbiological contaminants in nonsterile products cannot be disregarded.

When contamination is discovered, its significance must be evaluated conservatively, considering the formulation of the product, its method of delivery, the contaminant, and the type of patient undergoing treatment. For instance, in 1994 a U.S. company responsibly and voluntarily withdrew 3.6 million units of albuterol sulfate inhalation solution from the market on confirmation of contamination with Pseudomonas fluorescens. Bergey's Manual of Determinative Biology recognizes Pseudomonas fluorescens as being more likely to be associated with soil and water than with specific pathogenicity to humans. A team of independent microbiologists set up at the time of the recall concluded that Pseudomonas fluorescens has "very rarely been found to be the causative agent of illness."

The reason for the recall was concern that this microorganism could cause lung infections, which could be particularly serious in people with cystic fibrosis, chronic obstructive lung disease or with compromised immune systems.

Nonsterile pharmaceutical products are generally formulated to prevent any microorganisms from increasing in number during their shelf lives. This may be intrinsic to the dosage form. An example in solid dosage forms, such as tablets or powder inhalations, is the lack of sufficient water to allow microorganisms to multiply over time. Conversely, nonsterile aqueous dosage forms, in which there is sufficient water to potentially allow microorganisms to multiply, are usually formulated to incorporate antimicrobial preservatives.

In addition to these formulation-related factors, there are regulatory requirements governing the standards of hygiene applicable to the manufacture of nonsterile pharmaceuticals. Such regulations may restrict the numbers and types of microbial contaminants that could be initially present on the product (i.e., at release as distinct from at the end of shelf life). The required standards of hygiene, although exacting and often involving filtration of environmental air, do not normally require manufacture of these products in clean rooms, in the sense that the term "clean room" is understood in the sterile products manufacturing industry.

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