Objectionable Microorganisms

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It is important to recognise that pharmacopoeial limits on microbiological contamination in pharmaceutical preparations are not all embracing. Contamination limits can never adequately specify everything present in a pharmaceutical preparation that might risk infection, or lead to patient refusal. Many microorganisms are not specifically restricted from pharmaceutical preparations, but if present — even in numbers well within the quantitative limits — would clearly constitute a risk to the patient.

An example of this is Pseudomonas cepacia, recognized as an important human pathogen, particularly in topical products and inhalations. It would be downright irresponsible to release a preparation to market with (say) a quantitative count of 5 cfu/g versus a limit of not more than 100 cfu/g, if those colonies were identifiable with Pseudomonas cepacia.

The U.S. Food and Drug Administration (FDA) Guide to Inspection of Microbiological Pharmaceutical QC Laboratories (1998) describes Pseudomonas cepacia as objectionable. Clearly, "objectionability" is an important term and concept. FDA in its Guide to Inspection of High Purity Water Systems (1993) defines objectionable microorganisms as "organisms which can cause infections when the drug product is used as directed, or any organism capable of growth in the drug product."

The first part of this definition closely follows the approach of pharmacopoeias to evaluating the risk of infection that microorganisms can create, versus the route of administration of the pharmaceutical preparation to the patient. The second part infers that a microorganism that cannot proliferate in the product is not objectionable unless it can cause infection. In this way, some recovery of low levels of (say) Bacillus spp. from an oral liquid would not typically be expected to be objectionable.

On the other hand an example of an objectionable microorganism in an oral liquid could be Gluconobacter sp. This noninfective microorganism is occasionally found in syrups where it can proliferate and produce slimes and foul odours: its biochemical profile closely resembles that of E. coli but it grows poorly at 37°C, and is more likely to be recovered under conditions designed for yeasts and molds than those designed for recovery of bacteria.

Figure 4.2 shows a decision tree focusing on the issues surrounding objectionability. The first decision points are around known pathogenicity and recourse must be made to a reliable and standard text. Bergey's Manual of Determinative Bacteriology is reliable; the Manual of Clinical Microbiology1 has better focus on pathogenicity.

The second decision point is whether the microorganism has been associated with — but is not necessarily causative of — infectious disease by the administration route, and to the target patient population. Making a decision around this issue is becoming more complicated. If only it were as simple as reaching the conclusion that in a paediatric presentation, any microorganism known to be associated with an infectious illness should be considered objectionable. The number and proportion of the immunodeficient and the immunosuppressed is increasing in the general patient population through greater longevity. (The average life expectancy of a male in the U.K. was 71.7 years in 1985 rising to 75 years in 1999 according to OECD statistics (OECD 2000.)

Increased life expectancy is anticipated for sufferers from HIV/AIDS (34,000 living in the U.K. and 900,000 living in the U.S. in 2001 (UNAIDS/WHO 2000); improved control of diabetes; the progress of transplant surgery; and more

Figure 4.2. Objectionable microorganisms in nonsterile preparations.

successful applications of chemotherapy in cancer treatment. You can still suffer from indigestion, excema, asthma and the common cold while immunosuppressed and immunodeficient.

The capability of a specific type of microorganism to spoil a particular product is also problematic, as it may never have been previously addressed. A preservative efficacy test using the questionable microorganism could be the answer.

For the QA microbiologist it is important to take account of all colonies recovered in microbial limit tests and pay heed to their potential for objectionability. In the author's opinion, all Gram-negative microorganisms (particularly pseudomonads, although recognition of these has become significantly more complicated in recent years by division of the genus into numerous genera such as Burkholderia, Ralstonia, Stenotrophomonas, etc.) isolated from pharmaceutical preparations must be assumed to be objectionable, unless there is compelling evidence to the contrary. Bergey's Manual of Determinative Bacteriology and Murray's Manual of Clinical Microbiology1 are reliable primary sources of information on the infectivity of microorganisms. Other information on current views on the objectionability of particular microorganisms may be obtained from regulatory publications, particularly those from FDA. For instance, a warning letter issued in September 2002 and available on the FDA Web site, indicates quite clearly that FDA considers Serratia liquefaciens and Pseudomonas fluorescens/putida to be objectionable in aqueous nasal spray products.

Table 4.3 Gram-negative Microorganisms That Should be Considered Objectionable as a Result of Infectivity

(NOTE: This list is for guidance; it is not comprehensive. Other microorganisms not listed may also be objectionable through infectivity or other reasons. Absence of any indication of infectivity in a particular range of preparations does not necessarily indicate that it is neither infective nor objectionable.)

Topical Preparations

Liquid Oral Preparations


Pseudomonas (Burkholderia) pseudomallei

Pseudomonas aeruginosa

Pseudomonas (Stenotrophomonas) maltophilia

Pseudomonas (Burkholderia) cepacia

Pseudomonas fluorescens

Causes melioidosis by contact with cut or abraded skin

Opportunistic pathogen of man found in wound infections

Recognised as objectionable by FDA in topical products and nasal solutions

Causes melioidosis by inhalation.

Opportunistic pathogen of man found in the respiratory tract

Pathogen in immunosuppressed patients and those with cystic fibrosis

Recognised as objectionable by FDA in topical products and nasal solutions

Contaminated inhalation solutions recalled in U.S. in 1993

Pseudomonas putida

Acinetobacter spp.

Flavobacterium (Chryseo-bacterium) meningosepticum

Bordetella parapertussis

Contaminated barrier creams recalled in U.S. in 1998

Agents of nosocomial pneumonia

Cause of meningitis and pneumonia in infants

Causative agent of whooping cough (transmitted in aerosols)

01 D

E. coli Shigella spp. Plesiomonas shigelloides Salmonella spp. Klebsiella spp. Enterobacter spp. Edwardsiella tarda

Providencia spp. Infective in wounds and burns

Yersinia spp.

Aeromonas hydrophila

Agent of gastrointestinal disease

Causative agent of bacillary dysentery

Pathogenic in the human intestine

Causative agent of enteric fevers, gastroenteritis, etc.

Associated with respiratory tract infections, pneumonia, etc.

Associated with respiratory tract infections, pneumonia, etc.

Causative agent of a Salmonella-like enteritis

Causative agents of gastrointestinal infections

Causative agent of acute diarrhoea

Table 4.3 contains a limited list of Gram-negative microorganisms versus the types of preparation in which they should be considered objectionable on the basis of infectivity. This is not comprehensive. The fact that Providencia spp. is listed as infective only under topical preparations, does not necessarily mean that it may not be infective or objectionable in other types of preparations. To nonspecialists it may appear curious that some of the better known causative agents of infectious disease, e.g., Campylobacter spp. are not included in this list. This is because there is very little probability of them being isolated from pharmaceutical preparations by the techniques normally recommended and used. Campylobacter spp., for instance, require a microaerobic atmosphere (5% O2, 10% CO2, 85% N2) for optimal recovery.

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