Sterilization decision trees

For sterile products, particular attention should be paid to the choice of an appropriate method of sterilization. Wherever possible a terminal sterilization process should be applied to the product in its final container-closure system, as suggested in the Ph Eur. The preferred options include steam sterilization, dry heat sterilization, and irradiation using the Ph Eur listed conditions (saturated steam at 121°C for 15 minutes dry heat at 160°C for 120 minutes irradiation with an absorbed dose of not less than 25 kGy). Where these cannot be used, the application must include justification for the alternative procedure adopted on the understanding that the highest achievable sterility assurance level should be achieved in conjunction with the lowest practicable level of presterilization bioburden. There is guidance in the form of decision trees as to the preferred options for sterilization method to be applied ... 

For other materials (for instance, equipment and supplies for aseptic manufacture) where the mechanisms of inactivation rely on direct contact between the steam and the item being sterilized and therefore where air removal is matter of importance, the choice of substrate for Bis generally lies between using commercially available paper spore strips and the material itself The decision tree in 4 may be helpful. Regulatory pressure is currently toward use of inoculated product, but commercially available spore strips are more convenient. Tailor-made inoculated product requires substantial amounts of microbiological expertise. The decision tree in Fig. 4 may be helpful in selecting which approach is best in particular circumstances. 

Fig. 19.1 Decision tree for sterilization choices for aqueous products (from CPMP/QWP/054/98).

Fig. 19.2 Decision tree for sterilization choices for non-aqueous liquid, semisolid or dry powder products (from...

European Agency for the Evaluation of Medicinal Products (2000) Decision trees for the selection of sterilization methods. Annex to Note for Guidance on Development of Pharmaceutics. Committee for Proprietary Medicinal Products, London. CPMP/QWP/054/98 Corr. 

All these recommendations are summarized in the Decision trees for the selection of sterilization methods, edited by the EMEA [23] (Fig. 1).Two cases are considered on one hand, the aqueous products and on the other hand, the non-aqueous liquid, semi-solid and dry powder products. Figure 1 shows the order of preference of the sterilization methods for the second group. The terminal ones are ranked in the first place. Among them, thermal sterilization is still referred as the best choice, radio-sterilization ranking right after. Since gas sterilization is excluded and non-terminal methods are listed as the last choice, radiosterilization now precedes all these methods. It is deemed as the recommended alternative method to thermal sterilization. 

According to the decision trees, where it is not possible to carry out terminal sterilisation by heating due to formulation instability, a decision should be made to utilise an alternative method of terminal sterilisation, filtration and/or aseptic processing. If this alternative route is taken, then a clear scientific justification for not using terminal heat sterilisation will be required in the NDA/MAA dossier. Commercial reasons will not be acceptable because terminal sterilisation offers the highest possible level of sterility assurance. 

EMEA Decision trees for the selection of sterilization methods (CPMP/QWP/054/98)... 

---