Nutritional supplements and herbal medicines are also tested to determine the microbiological quality of the raw materials and formulations [51]. Because of the continuous health-related claims of these products, regulatory agencies are currently recommending the application of GMP to their manufacturing and quality control. This is done to control the quality, efficacy, and safety of these products. A wide variety of nutritional supplements are based upon the use of natural ingredients such as botanicals and mineral oils. These materials contain large number of microorganisms.
The test methods are based upon the same requirements and methods described for nonsterile pharmaceutical products [1]. However, these tests are not mandatory since the chapter is part of the informational sections of the USP [51]. The only difference between the nonsterile test and the supplements is that yeast and mold are required to be part of the preparatory test (vali- dation test), while nonsterile pharmaceuticals do not require these two microorganisms to be part of it.
9. CONCLUSION
Validation of microbiological testing for nonsterile pharmaceuticals provides a reliable way to determine the potential risk of high microbial bioburden and
objectionable microorganisms in finished products and raw materials. Be- cause a bioburden is allowed in nonsterile pharmaceutical products, their microbiological risk is based upon the nature of the product, intended use, and route of application. Monitoring of critical areas such as facilities, equipment, raw materials, air, and water must be part of a testing plan to determine the efficacy of process control to minimize microbial contamina- tion and the presence of objectionable microorganisms. A good microbio- logical program for nonsterile pharmaceuticals relies on cGMP practices to provide safe, stable, and efficacious products.
REFERENCES
1. United States Pharmacopeial Convention. Microbial limit test. In U.S. Phar- macopoeia. Rockville, Maryland: United States Pharmacopeial Convention, 2002:1873–1878.
2. Federal Register of the United States of America. Code of Federal Regulations. Subpart F: Production and Process Control, 21 Part 211.113: Control of mi- crobiological contamination. Rockville, Maryland, 1996.
3. Underwood E. Ecology of microorganisms as its affects the pharmaceutical in- dustry. In: Hugo WB, Russell AB, eds. Pharmaceutical Microbiology. 6th ed. Oxford, England: Blackwell Science, 1998:339–354.
4. Reich RR, Miller MJ, Paterson H. Developing a viable environmental program for non-sterile pharmaceutical operations. Pharm Technol 2003; 27:92–100. 5. Mestrandrea LW. Microbiological monitoring of environmental conditions for
non-sterile pharmaceutical manufacturing. Pharm Technol 1997; 21:59–74. 6. European Pharmacopoeial Convention. Microbiological examination of non-
sterile products. European Pharmacopoeia. 3rd ed. Strasbourg, France: Council of Europe, 2001:70–78.
7. The Japanese Pharmacopoeia. Microbial Limit Test. 13th ed. Tokyo, Japan: The Society of Japanese Pharmacopoeia, 1996:49–54.
8. Baird R. Contamination of non-sterile pharmaceuticals in hospital and com- munity environments. In: Hugo WB, Russell AD, eds. Pharmaceutical Micro- biology. 6th ed. Oxford, England: Blackwell Science, 1998:374–384. Chapter 19.
9. FDC Reports. Quality control reports ‘‘The Gold Sheet.’’ 1997; 31, Number 1. 10. FDC Reports. Quality control reports ‘‘The Gold Sheet.’’ 1998; 32, Number 1. 11. FDC Reports. Quality control reports ‘‘The Gold Sheet.’’ 1999; 33, No. 8. 12. FDC Reports. Quality control reports ‘‘The Gold Sheet.’’ 2000; 34, No. 2. 13. FDC Reports. Quality control reports ‘‘The Gold Sheet.’’ 2001; 35, No. 3. 14. FDC Reports. Quality control reports ‘‘The Gold Sheet.’’ 2002; 36, No. 3. 15. Desvignes A, Sebastien F, Benard J, Campion G. Etude de la contaminacion
microbienne de diverses preparations pharmaceutiques. Ann Pharm Fr 1973; 31:775–785.
farmaceutici orally e topici col metodo delle membrane filtranti. Farmaco 1970; 26:224–229.
17. Zani F, Minutello A, Maggi L, Santi P, Mazza P. Evaluation of preservative effectiveness in pharmaceutical products: The use of a wild strain of Pseudomonas cepacia. J Appl Microbiol 1997; 43:208–212.
18. Palmieri MJ, Carito SL, Meyer J. Comparison of rapid NFT and API 20E with conventional methods for identification of gram-negative nonfermentative bacilli from pharmaceutical and cosmetics. Appl Environ Microbiol 1988; 54:2838–3241.
19. De La Rosa MC, Medina MR, Vivar C. Microbiological quality of pharma- ceutical raw materials. Pharm Acta Helv 1995; 70:227–232.
20. Abdelaziz AA, Ashour MSE, Hefnai H, El-Tayeb OM. Microbial contamination of cosmetics and personal care items in Egypt-shaving creams and shampoos. J Clin Pharmacol Ther 1989; 14:29–34.
21. Archibald LK, Corl A, Shah B, Schulte M, Arduino MJ, Aguero S, Fisher DJ, Stechenberg BW, Banerjee SN, Jarvis WR. Serratia marcescens outbreak asso- ciated with extrinsic contamination of 1% chlorxylenol soap. Infect Control Hosp Epidemiol 1997; 18:704–709.
22. Baird R, Shooter RA. Pseudomonas aeruginosa infections associated with use of contaminated medicaments. Br Med J 1976; 2:349–350.
23. Ferguson A, Patel A, Bair RM. A comparison of two incubation temperatures for the isolation of gram negative contaminants from raw materials and non- sterile pharmaceuticals. J Clin Pharmacol Ther 1987; 12:249–254.
24. Lambin MS, Desvignes A, Kiger JL, Azaria M. Etude de la contamination microbienne des sirops pharmaceutiques. Ann Pharm Fr 1972; 30:161–168. 25. Na’was T, Alkofahi A. Microbial contamination and preservative efficacy of
topical creams. J Clin Pharmacol Ther 1994; 19:41–46.
26. Oie S, Kamiya A. Microbial contamination of antiseptics and disinfectants. Am J Infect Control 1996; 24:389–395.
27. Wargo EJ. Microbial contamination of topical ointments. Am J Hosp Pharm 1973; 30:332–335.
28. Zembrzuska-Sadkowska E. The danger of infections of the hospitalized patients with the microorganisms present in preparations and in the hospital environ- ment. Acta Pol Pharm 1995; 52:173–178.
29. Bergogne-Berezin E. The increasing significance of outbreaks of Acinetobacter spp.: The need for control and new agents. J Hosp Infect 1995; (suppl):441–452. 30. Parrot PL, Terry PM, Whitworth EN, Frawley LW, Ceble RD, Wachsmuth IK, McGowan JE Jr. Pseudomonas aeruginosa peritonitis associated with intrinsic contamination of poloxamer–iodine solution. Lancet 1982; ii:683–685.
31. Anderson RL, Bland LE, Favero MS, McNeil BJ, Davis DC, Mackel DC, Gravelle CR. Factors associated with Pseudomonas pickettii intrinsic contami- nation of commercial respiratory therapy solutions marketed as sterile. Appl Environ Microbiol 1985; 50:1343–1348.
32. Coyle-Gilchrist MM, Crewe P, Roberts G. Flavobacterium meningosepticum in the hospital environment. J Clin Pathol 1976; 29:824–826.
33. Drelichman V, Band JD. Bacteremias due to Citrobacter diversus and Citrobacter freundii. Incidence, risk factors, and clinical outcome. Arch Intern Med 1985; 145:1808–1810.
34. Hamill RJ, Houston ED, Georghiou PR, Wright CE, Koza MA, Cadle RM, Goepfert PA, Lewis DA, Zenon GJ, Clarridge JE. An outbreak of Burkholderia (formerly Pseudomonas) cepacia respiratory tract colonization and infection associated with nebulized albuterol therapy. Ann Intern Med 1995; 122:762–766. 35. Hawkins RE, Moriarty RA, Lewis DE, Oldfield EC. Serious infections involving the CDC group Ve bacteria Chryseomonas luteola and Flavimonas oryzihabitans. Rev Infect Dis 1991; 13:257–260.
36. Hsueh PR, Teng LJ, Yang PC, Chen YC, Pan HJ, Ho SW, Luh KT. Nosocomial infections caused by Sphingomonas paucimobilis: Clinical features and microbi- ological characteristics. Clin Infect Dis 1998; 26:676–681.
37. Okharavi N, Ficker L, Matheson MM, Lightman S. Enterobacter cloacae endophthalmitis: report of four cases. J Clin Microbiol 1998; 36:48–51. 38. VanCouwenberghe CJ, Farver TB, Cohen SH. Risk factors associated with
isolation of Stenotrophomonas (Xanthomonas) malthophilia in clinical specimens. Infect Control Hosp Epidemiol 1997; 18:316–321.
39. Manu-Tawiah W, Brescia BA, Montgomery ER. Setting threshold limits for the significance of objectionable microorganisms in oral pharmaceutical products. PDA J Pharm Sci Technol 2001; 55:171–175.
40. Dabbah R, Knapp J, Sutton S. The role of USP in the assessment of microbio- logical quality of pharmaceuticals. Pharm Technol 2001; 25:54–60.
41. Parker MT. The clinical significance of the presence of microorganisms in pharmaceutical and cosmetic preparations. J Soc Cosmet Chem 1972; 23:415– 426.
42. Rusin PA, Rose JB, Haas CN, Gerba CP. Risk assessment of opportunistic bacterial pathogens in drinking water. Rev Environ Contam Toxicol 1997; 152:57–83.
43. United States Pharmacopeial Convention. Microbiological attributes of non- sterile pharmaceutical products. In: U.S. Pharmacopoeia. Vol. 25. Rockville, Maryland: United States Pharmacopeial Convention, 2002:2205–2206.
44. European Pharmacopoeial Convention. Microbiological quality of pharma- ceutical preparations. In: European Pharmacopoeia. 3rd ed. Strasbourg, France: Council of Europe, 2001:294–295.
45. United States Pharmacopeial Convention. Validation of microbial recovery from pharmacopeial articles. U.S. Pharmacopoeia, United States Pharmacopeial Convention. Rockville, Maryland, 2000; 25:2259–22261.
46. Cundell AM. Review of the media selection and incubation conditions for the compendial sterility and microbial limit tests. Pharmacop Forum 2002; 28:2034– 2041.
47. Anonymous. Pharmacopeial Reviews. Microbial enumeration tests. Pharmacop Forum 1999; 25:7761–7773.
48. Anonymous. Pharmacopeial Reviews. Microbiological procedures for the ab- sence of objectionable microorganisms. Pharmacop Forum 1999; 25:7774–7784.
49. Anonymous. Pharmacopeial Reviews. Microbiological attributes of non-sterile pharmacopeial articles. Pharmacop Forum 1999; 25:7785–7791.
50. United States Pharmacopeial Convention. Microbiological evaluation of clean rooms and other controlled environments. In: U.S. Pharmacopoeia. Vol. 25. Rockville, Maryland: United States Pharmacopeial Convention, 2002:2206– 2212.
51. United States Pharmacopeial Convention. Microbial limits tests-nutritional supplements. In U.S. Pharmacopoeia. Rockville, Maryland: United States Phar- macopeial Convention, 2003:2659–2663.