1. Environmental Control and Developing a Science-based Monitoring Program Richard L. Friedman, M.S. FDA/CDER

2. D= Design M = Maintenance Daily “Sterility Assurance” Media Fills Aseptic Processing Line D/M Response to Deviations & Environmental Control Trends Disinfection Procedures & Practices QA/QC Facility & Room D/M Process -personnel flow -material flow -layout Personnel HVAC/ Utilities

3. Risk-Based Emphasis Concept Paper “Sample timing, frequency, and location should be carefully selected based upon its relationship to the operation performed. Samples should be taken throughout the aseptic processing facility (e.g., aseptic corridors; gowning rooms) using appropriate, scientifically sound sampling procedures, standards, and test limits.” “Locations posing the most microbiological risk to the product are a critical part of the program. It is especially important to monitor the microbiological quality of the aseptic processing clean zone to determine whether or not aseptic conditions are maintained during filling/closing activities.”

4. 1987 Guideline Numbers: No numerical surface limits Critical Surfaces: “Equipment surfaces which contact sterilized drug product or sterilized container/closure surfaces should, of course, be sterile.” Establishing Action Limits: States air monitoring action levels without qualification. ID: “Routine identification of the recovered microorganisms.” Not every every isolate needs to be identified to genus and species; keep a “valid database.” 2002 Concept Paper Numbers: No numerical surface limits Critical Surfaces: “Critical surfaces which contact sterile product should be sterile.” Establishing Action Limits: Provides new latitude for different limits to be established “where justified by nature of the operation.” ID: Essentially the same. Stresses ID in aseptic processing room (as highest product risks are generally present there).

5. Other Environmental Monitoring Issues Trending –Adequate systems to detect emerging or existing problem –When meaningful adverse trend is illuminated by EM data, problem needs to be “promptly” addressed to prevent product contamination (211.42 and 211.113). Interpretation: –No statement indicating that a critical zone positive is a surrogate sterility test. –CGMP expectation is for a holistic batch assessment, with explanation of significance and impact of environmental, or other, deviations.

6. Summary of Risk-Based Program Emphasis on product risk areas –Not just a grid approach… –The nature of the operation determines its criticality. –Strategic collection of meaningful samples, based on understanding of personnel and material flow through the facility Detection of adverse environmental trends –Systems allow detection before there is a product contamination consequence Responsive to identified problems –Corrective action implemented where appropriate