 |
 |
 |
 |
 |
 |
 |
|
|
|
|||||||||
|
|||||||||||
Lecturer in Pharmaceutical Microbiology Microbiology Group Department of Pharmaceutics and Centre for Paediatric Pharmacy Research School of Pharmacy University of London 29/39 Brunswick Square London WC1N 1AX UK fax 44 207 753 5868 paul.long{at}ams1.ulsop.ac.uk
Research Fellow in Paediatric Drug Delivery Centre for Paediatric Pharmacy Research School of Pharmacy University of London
Pfizer Paediatric Drug Delivery Lecturer Department of Pharmaceutics and Centre for Paediatric Pharmacy Research School of Pharmacy University of London
Reader and Director of the Centre for Paediatric Pharmacy Research School of Pharmacy University of London Specialist Pharmacist Great Ormond Street Hospital for Children London
Published Online, December 20, 2005. www.theannals.com, DOI 10.1345/aph.1G349
Current editions of the British Pharmacopoeia,3 US Pharmacopoeia,4 and European Pharmacopoeia5 recognize the importance of microbiological quality assurance of raw materials and finished products to prevent medication-borne infection or biodegradation. Pharmacopoeial requirements of low total viable counts for the duration of the manufacture, storage, and shelf life of the product confer no meaningful benefit for non-sterile extemporaneous oral formulations.6 This is because off-label medicines may be prepared with high concentrations of syrup, glycerol, or ethanol, which can have a microstatic preservative effect. Preservative excipients require rigorous evaluation, which is seldom performed on extemporaneous formulations. Many factors can reduce the effectiveness of the preservative including use of contaminated materials, chemical degradation, binding of preservative to suspending agents, incorrect storage, or unhygienic use of the final product. The effectiveness of the preservative in extemporaneous preparations is uncertain, but can remain active during culture-dependent assurance testing, masking true microbial viable counts.
Several methods of inactivating preservatives exist, but since the initial bioburden is not usually known, these are insufficient to be reliably used without potential for a microcidal effect despite use of reference strains during quality assurance testing. Assessment of growth using soya bean casein digest and thioglycollate media is designed for the culture of both aerobic and anaerobic fungi and bacteria. It would be unrealistic to expect these media to support the growth of the wide range of microbes sometimes encountered in pharmaceutical preparations. Also, the health risks presented by viable yet uncultivable microorganisms are now better understood, yet there are no acceptable quality assurance standards sufficient to cater for these microbes in any pharmacopoeia monograph.
An assay using reverse transcriptase–mediated polymerase chain reaction (RT-PCR)7 of 16S or 18S rRNA genes for rapid detection of culture-independent microorganisms would be a useful development for microbiological assurance of pharmaceutical products. Amplification of the rRNA genes would provide a reliable molecular beacon because the presence of rRNA would be present only in total nucleic acid preparations from viable cells. Further, this method is applicable for both quantitative counting of microbes and qualitative tests to ensure the presence or absence of specific organisms in the extemporaneous preparation by applying universal primers.
In this era of cost-containment in the pharmaceutical industry, uncertainty over the assets and limitations of commercial and in-house–developed molecular diagnostic assays has yet to be fully explored. With European regulations expected in late 2006,8 extemporaneous preparation will certainly continue to be a major route by which pediatric oral medicines are prepared. A redrafting of existing bioburden standards to include RT-PCR assays seems well justified based on evidence informed by literature review and expert opinion, which is now very convincing that viable yet uncultivable microorganisms, including a number of emerging pathogens,9 are able to survive in pharmaceuticals.
References
This article has been cited by other articles:
|
|
 |
|
  A. Ghulam, K. Keen, C. Tuleu, I. C.-K. Wong, and P. F Long Poor Preservation Efficacy Versus Quality and Safety of Pediatric Extemporaneous Liquids Ann. Pharmacother., May 1, 2007; 41(5): 857 - 860. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
 |
 |
 |
 |
