Book chapter – Steam Sterilization: A Practitioner’s Guide (Ch.11)
activities associated with conducting cycle development studies necessary for a regulatory filing. The activities associated with developing sterilization technology data for a new or modified drug product require the interaction of several disciplines.
– How Does One Determine Whether the Product Withstands a Thermal Process That Is Encountered in Moist Heat Sterilization?
Generally, pilot plant or bench top laboratory studies are conducted, whereby the formulated product in the intended container/closure system is exposed to maximum anticipated thermal and time conditions. At this point, one would have to speculate on what the maximum conditions of the sterilization process would be. Following thermal exposure per the maximum sterilization cycle conditions, the drug product is tested to ensure that the product remains within the specification limits.
More than one set of cycle parameters may be evaluated, such as variable times and temperature conditions, to determine whether a heat sensitive product is compatible with a terminal sterilization process. These evaluations could be classified as initial R&D stability studies. Further, thermally exposed products should be placed on accelerated 40°C stability studies for at least three months. If the product stability data demonstrate that the initial product specification release limits cannot be maintained, a case exists for aseptically processing the product. These data would have to be included in the NDA or European regulatory submission.
During the review process, questions may arise regarding whether extractables from the container/closure system influenced the drug or product data. Therefore, the developmental data must show whether the system will meet
the USP biological safety testing if the container/closure system is an elastomeric, plastic, or other polymeric material.
Tasks presented in the chapter :
– Expectations of Regulatory Agencies Concerning Sterilization of the Solution and Cycle Selection on the Basis of Solution Selection—Development Studies That Need to Be Conducted
– Defining requirements
– Selection of a moist heat sterilization process
– Container thermal mapping: determining the slowest-to-heat zone
– How much lethality is enough?
– What Is the Purpose of the D- and z-values?
– Determining the Minimum Microbial Lethality
– Determination of the Probability of Survival for Bioburden
– Determination of the required sterilization process time (in minutes of F0) or cycle definition (load probe controlled cycles)
-Required Sterilization Process Time
– Cycle Definition (Product Penetration Controlled Cycles, i.e., controlled by Fo values in solution filled containers)
– The container/closure system
– True Fo cannot be calculated at closure sites
– Regulatory expectations for container/Closure challenge data
– The master solution – biological challenge
– How does one select the Master Solution?
– Special considerations related to the design of the subprocess solution challenge
– Calculation of the required heat history for processes at temperatures other than 121°C
– Fractional or half-cycle developement approaches
– Container closure integrity testing
– The master solution – heat penetration
– The Master Equipment Challeng
– What thermal distribution and penetration data are expected? –
– Heat Penetration (Thermoprobed Product)
– Temperature Distribution Studies
– Time windows
– Cycle Come-Up Time or Heat-Up Time*
– Exposure Time
– Calculation of Cooling Times
– Loading patterns and configurations drying cycles
– Sterilization and integrity of filters
– Cooling water evaluations
Development of an appropriate sterilization cycle is difficult. The development of an efficacious and yet economic sterilization process is one of the most critical phases of a product development process. This chapter is intended to provide some guidance on the topic. However, each site needs to have an established cycle development program that takes into account the facilities and equipment actually used.[…]