1. Preventing Contamination: Aseptic Processing Risk Factors Richard L. Friedman, M.S. FDA/CDER 10/22/02 OPS Advisory Committee/ Aseptic Processing

2. TOPICS Risk-based approach Risk-based approach Critical Control Points (CCPs) Critical Control Points (CCPs) –Sources of Variability –Holistic Facility Case studies Case studies –Recurring problems underscore importance of CCPs Latitude & Innovation Latitude & Innovation –New Technology, Automation, Facility Improvements Five Major Issues for Discussion Five Major Issues for Discussion

3. Risk Analysis – FMEA Reducing Risk Severity Factor: “Process changes or product redesign…” including “development of an aseptically produced product into one with terminal sterilization.” “Process changes or product redesign…” including “development of an aseptically produced product into one with terminal sterilization.” Reducing Probability of Occurrence of Risk: “Process automation projects, tighter controls upstream in the process, and new technologies such as isolators” “Process automation projects, tighter controls upstream in the process, and new technologies such as isolators” Probability of Detecting Failures: Validation is “intensified monitoring which should detect flaws or weaknesses, which may not be normally observable. A media fill is a good example of a validation test.” Validation is “intensified monitoring which should detect flaws or weaknesses, which may not be normally observable. A media fill is a good example of a validation test.” [Noble, P., PDA Journal of Pharmaceutical Science and Technology, July/August 2001.]

4. Risk-Based Approach Critical Control Points Causes of Contamination Causes of Contamination –Where are the potential routes of contamination in an aseptic process? Detection of Contamination Problem Detection of Contamination Problem –What measurements are most valuable in indicating sterility assurance? Focus on issues of concern Focus on issues of concern –Influential factors that determine control of the facility and process –Failure to meet CGMP can impact safety or efficacy

5. 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

6. Risk-Based Approach Design Aseptic Processing requires “A strict design regime, not only on the process area, but on the interactions with surrounding areas and the movement of people, materials and equipment so as not to compromise the aseptic conditions.” [ISPE Sterile Manufacturing Facilities Guide, Volume 3, January 1999]

7. Personnel “Continued vigilance throughout the entire manufacturing process” “Continued vigilance throughout the entire manufacturing process” [Avis, K.,“Personnel – An academic Approach,” PDA Journal, Sept-Oct., 1971] “Unstable situations are, in most cases, caused by the influence of arms and hands.” “Unstable situations are, in most cases, caused by the influence of arms and hands.” [Ljungqvist, B., and Reinmuller, B., Clean Room Design: Minimizing Contamination Through Proper Design; Interpharm Press, 1997]

8. Environment Studies have shown that “the level of airborne microorganisms in the filling environment has a profound effect on the level of product contamination.” Studies have shown that “the level of airborne microorganisms in the filling environment has a profound effect on the level of product contamination.” [Ljungqvist, B., and Reinmuller, B., Clean Room Design: Minimizing Contamination Through Proper Design; Interpharm Press, 1997] Researchers found a “definable direct relationship between the fraction of product contaminated and the level of microorganisms in the air surrounding the machine” [Sinclair, C.S., and Tallentire, A., J Pharm Sci Tech, 49 (6), 294-299] Researchers found a “definable direct relationship between the fraction of product contaminated and the level of microorganisms in the air surrounding the machine” [Sinclair, C.S., and Tallentire, A., J Pharm Sci Tech, 49 (6), 294-299]

9. DESIGN & ENVIRONMENTAL CONTROL: Sterility Link DESIGN & ENVIRONMENTAL CONTROL: Sterility Link BFS Air Shower Setting 01234 Air Velocity (m s -1 ) Fraction Contaminated 10 10 -2 10 -3 10 -4 Configuration A Challenge Concentration 5 x 10 4 spores m -3    

10. Environmental Data and State of Line Qualification Environmental Data and State of Line Qualification “It also may be necessary to requalify with acceptable process simulation tests in response to adverse trends or failures in the ongoing monitoring of the facility or process such as: Continued critical area EM results above action/alert limits…” “It also may be necessary to requalify with acceptable process simulation tests in response to adverse trends or failures in the ongoing monitoring of the facility or process such as: Continued critical area EM results above action/alert limits…” [PDA Technical Report #22 “Process Simulation Testing for Aseptically Filled Products,” 1996] “ Facility and equipment modification, significant changes in personnel, anomalies in environmental testing results and end product sterility testing showing contaminated products may all be cause for revalidating the system.” “ Facility and equipment modification, significant changes in personnel, anomalies in environmental testing results and end product sterility testing showing contaminated products may all be cause for revalidating the system.” [FDA’s 1987 “Guideline on Sterile Drug Products Produced by Aseptic Processing”]

11. Design, Environment, & Personnel: Link to Sterility Widely accepted that each of the following is crucial to assuring sterility: Widely accepted that each of the following is crucial to assuring sterility:DesignEnvironmentPersonnel That’s theory, what about actual experiences? That’s theory, what about actual experiences?  The above principle plays out in the many case studies we see throughout each year.  Lack of adherence to CGMP in these areas underlies the vast number of failures in the industry.

12. Case Study Media Fill Failure Media Fill Failure: Media Fill Failure: –Approx. 60% contaminated –Considered spurious. Corrections made to firm’s satisfaction. FDA Guideline (and PDA #22): 3 Lots for Revalidation FDA Guideline (and PDA #22): 3 Lots for Revalidation –First Media Fill Batch = No contamination –Second Media Fill Batch = Over 95% contaminated (over 5000 vials) –Third Media Fill Batch = No contamination If one batch was run, a firm would return to production/release of commercial lots without knowledge non-sterility problem still existed. If one batch was run, a firm would return to production/release of commercial lots without knowledge non-sterility problem still existed. Root Cause: Root Cause: –Personnel / Aseptic Connection Isolates in both failures were common skin-borne microbes Isolates in both failures were common skin-borne microbes Only Partially Gowned, Skin Exposed, Aseptic Technique questionable. Only Partially Gowned, Skin Exposed, Aseptic Technique questionable. Corrections to resolve these issues: Full sterile gown donned and enhanced personnel/environmental monitoring performed in near term. Equipment later modified to allow for SIP. Corrections to resolve these issues: Full sterile gown donned and enhanced personnel/environmental monitoring performed in near term. Equipment later modified to allow for SIP.

13. Case Study Sterility Failures and Environmental Trend Management failed to require follow-up on sterility failures with both mold and bacterial contaminants. Batches were released upon re-testing, with each of these failures attributed to inadvertent contamination while performing the sterility test. There was little or no data to support these conclusions. Investigations failed to adequately address possible manufacturing causes (e.g., microorganism correlation). Mold was found on multiple occasions in cleanrooms, and these mold detections exceeded established cleanroom action levels. Management failed to require follow-up on sterility failures with both mold and bacterial contaminants. Batches were released upon re-testing, with each of these failures attributed to inadvertent contamination while performing the sterility test. There was little or no data to support these conclusions. Investigations failed to adequately address possible manufacturing causes (e.g., microorganism correlation). Mold was found on multiple occasions in cleanrooms, and these mold detections exceeded established cleanroom action levels.

14. Sources of Contamination: Investigation Conclusions (e.g.) Aseptic practices: Aseptic practices:  Personnel returned after long winter shutdown  Operator reached over open vials to remove fallen vial on line with gloved hands  Poor personnel flow Poor aseptic connections Poor aseptic connections Poor Sanitization: Procedures deficient, or poorly executed Poor Sanitization: Procedures deficient, or poorly executed Construction in another room on the same floor caused increased airborne contamination (sporeforming bacteria) in facility Construction in another room on the same floor caused increased airborne contamination (sporeforming bacteria) in facility Poor gown design: Introduced new gown component, but then found it was contamination source Poor gown design: Introduced new gown component, but then found it was contamination source

15. Sources of Contamination: Investigation Conclusions (e.g.) New line’s HVAC installation: Approved as qualified, but media fill demonstrated inadequate HEPA seal (over 90% vials contaminated) New line’s HVAC installation: Approved as qualified, but media fill demonstrated inadequate HEPA seal (over 90% vials contaminated) Velocity through HEPA Filters: Variable velocities between filters. Inadequate laminar flow resulted. Low or undetectable velocity at work surface. Had monitored volume thru filter but did not detect problem. Media Fill: 11 positives in approximately 18,000 vials. Velocity through HEPA Filters: Variable velocities between filters. Inadequate laminar flow resulted. Low or undetectable velocity at work surface. Had monitored volume thru filter but did not detect problem. Media Fill: 11 positives in approximately 18,000 vials. Mechanical failure of filling tank; main pump failure; cooling system leaks at joints/pinholes. Mechanical failure of filling tank; main pump failure; cooling system leaks at joints/pinholes.

16. Five Topics for Discussion Sterilization Options Sterilization Options Aseptic Processing Design, Evaluation and Contamination Prevention Aseptic Processing Design, Evaluation and Contamination Prevention Media Fills Media Fills Environmental Monitoring Environmental Monitoring Personnel Issues Personnel Issues

17. CGMPs in the 21 st Century Science and Innovation New technology, automation, facility improvements. Concept paper acknowledges advantages of: Reducing direct personnel involvement in aseptic operations through isolation technology and barrier concepts Well-conceived design (e.g., airlocks) Advantage: Increased automation Liberalizing some old standards e.g., velocity (FPM) setting Latitude: e.g., BFS microbial standards stressed over particulate levels Firms who follow sound CGMP operating procedures and have defined good process metrics will benefit most

18. Summary We’ve been listening We’ve been listening Risk-based Approach Risk-based Approach –Emphasis on product risk areas –CGMP systems should detect trends before there is a product contamination consequence Theoretical and practical basis Theoretical and practical basis We look forward to your comments! We look forward to your comments!