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Microbiological aspects of heat sterilization of drugs

III. Heat resistance of spore-forming bacteria, isolated from large-volume parenterals

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Abstract

In order to calculate the minimum sterilization process conditions to obtain the generally accepted sterility level (less than 1·10−6 probability of microbial survival), we determined the bioburden and its heat resistance of 500 ml large-volume parenteral bottles over a period of 5 years. For the bioburden determination 1,832 bottles were examined by the membrane filtration method. Mean bioburden was 9.36 colony-forming units/bottle. Of the colony-forming units isolated 118 were heat resistant (0.69%). These were spore-formingBacillus species. Of the isolatedBacillus species heat resistance was determined in 5% glucose, 0.9% sodium chloride and 8% amino acids solution.D values greater than 1 min at 105°C were found for 2, 5 and 4 differentBacillus species in glucose 5%, sodium chloride 0.9% and amino acids 8%, respectively. 2Bacillus species showed aD value over 2 min at 105°C in all three media.D values at 110°C in sodium chloride 0.9% for these 2Bacillus species were 1.8 and 2.6 min and in amino acids 8% 0.9 and 1.7 min, respectively. The minimum sterilization process time at 110°C, calculated with the experimentally determined bioburden andD values is less than 25 min. When introducing reduced exposure times/temperatures, each individual manufacturer should assess the bioburden. The time-consuming determination of the heat resistance of bioburden isolates is not always necessary. By dividing the isolated colony-forming units in a ‘heat-resistant’ group and a ‘not-heat-resistant’ group, changing from standard overkill sterilization procedures to processes with lowerF 0 values is possible.

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References

  1. Boom FA, Paalman ACA. Microbiologische aspecten van het steriliseren van geneesmiddelen door middel van hitte. I. Het afsterven van micro-organismen onder invloed van vochtige hitte [Microbiological aspects of heat sterilization of drugs. I. The destruction of micro-organisms by heat]. Pharm Weekbl 1979;114:157–65.

    Google Scholar 

  2. Anonymous. Technical Monograph No. 1. Validation of steam sterilization cycles. Philadelphia: Parenteral Drug Association, 1978:1–36.

  3. Anonymous. Nederlandse Farmacopee. Ed. IX. 's-Gravenhage: Staatsuitgeverij, 1983:505–8.

  4. Anonymous. British Pharmacopoeia. London: Her Majesty's Stationery Office, 1988:A208–10.

  5. Anonymous. United States Pharmacopeia. Ed. XXI. Easton: Mack Publishing Company, 1985:1347–9.

  6. Van Asten J, Dorpema JW. A new approach to sterilization conditions. The IMO concept. Pharm Weekbl [Sci] 1982;4:49–56.

    Google Scholar 

  7. Boom FA, Paalman ACA, Stout-Zonneveld A. Microbiological aspects of heat sterilization of medicines. II. A method for the determination of the effectiveness of a sterilization process using the bioburden and the bioburdens heat resistance. Pharm Weekbl [Sci] 1984;6:209–15.

    Google Scholar 

  8. Nash RA. A method for calculating thermal sterilization conditions based upon process parametrics. J Parenter Sci Technol 1985;39:251–6.

    PubMed  Google Scholar 

  9. Pflug IJ, Odlaug TE. Biological indicators in the pharmaceutical and medical device industry. J Parenter Sci Technol 1986;40:242–8.

    PubMed  Google Scholar 

  10. Boom FA, De Flines EW, Graatsma BH. Bereidingsvoorschriften voor parenterale voeding. II [Formulations for parenteral nutrition solutions]. Mededelingen NVZA 1980:488–90.

  11. Boom FA. Microbiologische contaminatie tijdens de bereiding van parenteralia [Microbiological contamination during the production of parenterals]. Pharm Weekbl 1980;115:170–81.

    Google Scholar 

  12. Kooiman WJ, Geers JM. Simple and accurate technique for the determination of heat resistance of bacterial spores. J Appl Bacteriol 1975;38:185–9.

    PubMed  Google Scholar 

  13. Strumbo CR, Murphey JR, Cohren J. Nature of thermal death time curves for P.A. 3679 andClostridium botulinum. Food Technol 1950;9:321–6.

    Google Scholar 

  14. Pflug IJ, Holcomb RG. Principles of thermal destruction of microorganisms. In: Block SS, ed. Disinfection, sterilization and preservation. Philadelphia: Lea and Febiger, 1983:751–810.

    Google Scholar 

  15. Caputo RA, Odlaug TE, Wilkinson RL, Mascoli CC. Biological validation of a sterilization process for a parenteral product-fraction exposure method. J Parenter Drug Assoc 1979;33:214–21.

    PubMed  Google Scholar 

  16. Jones AT, Pflug IJ.Bacillus coagulans, FRR B666, as a potential biological indicator organism. J Parenter Sci Technol 1981;35:82–7.

    PubMed  Google Scholar 

  17. Reich RR.Bacillus stearothermophilus spores suspensions: effect of storage conditions and time on viability and moist heat resistance. J Parenter Sci Technol 1981;35:74–7.

    PubMed  Google Scholar 

  18. Friesen WT, Anderson RA. Effects of sporulation conditions and cation-exchange treatment on the thermal resistance ofBacillus stearothermophilus spores. Can J Pharm Sci 1974;9:50–3.

    Google Scholar 

  19. Russel AD. The destruction of bacterial spores. In: Hugo WB, ed. Inhibition and destruction of the microbial cell. London: Academic Press, 1971:451–612.

    Google Scholar 

  20. Gould GW. Methods for studying bacterial spores. In: Norris JR, Ribbons DW, eds. Methods in microbiology. Part VIA. London: Academic Press, 1971:327–81.

    Google Scholar 

  21. Pflug IJ, Smith GM. Survivor curves of bacterial spores heated in parenteral solutions. In: Pflug IJ, ed. Microbiology and engineering of sterilization processes. Philadelphia: Parenteral Drug Association, 1978:17–57.

    Google Scholar 

  22. Gautier CA, Smith GM, Pflug IJ. Effect of fosfate buffer concentration on the heat resistance ofBacillus stearothermophilus spores suspended in parenteral solutions. Appl Environmental Microbiol 1978;36:457–64.

    Google Scholar 

  23. Pflug IJ, Smith GM, Scheyer M, Chapman PA. Thermal resistance ofBacillus stearothermophilus spores suspended in parenteral solutions. Bull Parenter Drug Assoc 1976;30:128–38.

    PubMed  Google Scholar 

  24. Wang YJ, Leesman GD, Lipstein ME, Basch HI, Monkhause DC. Optimization of autoclave cycles and selection of formulation for parenteral products. Part III. Effects of formulation variables on sporicidal kinetics. J Parenter Sci Technol 1984;38:78–82.

    PubMed  Google Scholar 

  25. Stolar MH. Assuring the quality of intravenous admixture programs. Am J Hosp Pharm 1979;36:605–8.

    PubMed  Google Scholar 

  26. Parenteral Drug Association. Technical Report. Bioburden recovery validation. J Parenter Sci Technol 1990;44:324–31.

    Google Scholar 

  27. Uotila JA, Santasalo NF. New concepts in the manufacturing and sterilization of LVP's in plastic bottles. J Parenter Sci Technol 1981;35:170–5.

    PubMed  Google Scholar 

  28. Anonymous. Formularium der Nederlandse Apothekers. 's-Gravenhage: Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie, 1989: Parenteralia.

  29. Anonymous. Martindale. The extra pharmacopoeia. 29th ed. London: The Pharmaceutical Press, 1989.

  30. Wang YJ, Leesman GD, Dahl TC, Monkhouse DC. Optimization of autoclave cycles and selection of formulation for parenteral products. Part I. Identification of autoclave conditions by a nonisothermal approach. J Parenter Sci Technol 1984;38:68–72.

    PubMed  Google Scholar 

  31. Kirk B, Hambleton R, Hoskins HF. A method for predicting the stability of autoclaved Pharmaceuticals using real time computer integration techniques. J Parenter Sci Technol 1985;39:89–98.

    PubMed  Google Scholar 

  32. Boom FA, Graatsma BH, Oremus EThHGJ. Bereiding van parenteralia in ziekenhuisapotheken. III. Toetsing aan de hand van het produkt [Production of parenterals in hospital pharmacies. III. Testing the product]. Pharm Weekbl 1981;116:724–30.

    Google Scholar 

  33. Boom FA, Lie-A Huen L. Manufacturing drugs in Dutch hospital pharmacies. Ziekenhuisfarmacie 1987;3:77–81.

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, Hospital de Heel, P.O. Box 210, 1500, EE Zaandam, the Netherlands

    F. A. Boom

  2. ACF Chemiefarma NV, Straatweg 2, 3604, BB Maarssen, the Netherlands

    M. A. E. Van der Heijden Van Beek

  3. Department of Pharmacy, Slotervaart Hospital, Louwesweg 6, 1066, EC Amsterdam, the Netherlands

    A. C. A. Paalman

  4. Department of Medical Microbiology, Slotervaart Hospital, Amsterdam

    A. Stout-Zonneveld

Authors
  1. F. A. Boom
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  2. M. A. E. Van der Heijden Van Beek
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  3. A. C. A. Paalman
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  4. A. Stout-Zonneveld
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Boom, F.A., Van der Heijden Van Beek, M.A.E., Paalman, A.C.A. et al. Microbiological aspects of heat sterilization of drugs. Pharmaceutisch Weekblad Scientific Edition 13, 130–136 (1991). https://doi.org/10.1007/BF01981530

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