Preventing Contamination:

Aseptic Processing Risk

Factors
Richard L. Friedman, M.S.
FDA/CDER

10/22/02 OPS Advisory Committee/ Aseptic Processing

 TOPICS
 Risk-based approach
 Critical Control Points (CCPs)
– Sources of Variability
– Holistic Facility

 Case studies
– Recurring problems underscore importance of CCPs

 Latitude & Innovation

– New Technology, Automation, Facility Improvements
 Five Major Issues for Discussion
 Risk Analysis – FMEA
Reducing Risk Severity Factor:
 “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”
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.”
[Noble, P., PDA Journal of Pharmaceutical Science and Technology, July/August 2001.]
 Risk-Based Approach
Critical Control Points
 Causes of Contamination
– Where are the potential routes of contamination in an
aseptic process?
 Detection of Contamination Problem
– What measurements are most valuable in indicating
sterility assurance?
 Focus on issues of concern
– Influential factors that determine control of the facility
and process
– Failure to meet CGMP can impact safety or efficacy
 Aseptic
Facility & Processing Process
Room Line
Personnel -personnel flow
D/M D/M -material flow
-layout

Daily
QA/QC “Sterility HVAC/
Assurance” Utilities

Response to
Media Fills Disinfection Deviations &
Procedures & Environmental
Practices Control Trends
D= Design
M= Maintenance
 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]
 Personnel

 “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.”
[Ljungqvist, B., and Reinmuller, B., Clean Room Design: Minimizing Contamination Through Proper
Design; Interpharm Press, 1997]
 Environment

 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]
DESIGN & ENVIRONMENTAL CONTROL: Sterility Link
BFS Air Shower Setting
-1
10
Configuration A
Fraction Contaminated

Challenge Concentration 5 x 104 spores m-3

10 -2 

-3
10



10 -4
0 1 2 3
 4
Air Velocity (m s-1)
[Sinclair, C.S., and Tallentire, A., J Pharm Sci Tech, 49 (6), 294-299]
 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…”
[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.”
[FDA’s 1987 “Guideline on Sterile Drug Products Produced by Aseptic Processing”]
Design, Environment, & Personnel:
Link to Sterility
 Widely accepted that each of the following is crucial to assuring
sterility:
Design
Environment
Personnel

 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.
 Case Study
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
– 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.
 Root Cause:
– Personnel / Aseptic Connection
• Isolates in both failures were common skin-borne microbes
• 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.
 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.
 Sources of Contamination:
Investigation Conclusions (e.g.)
 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 Sanitization: Procedures deficient, or poorly executed
 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
 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)

 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.
 Five Topics for Discussion

 Sterilization Options
 Aseptic Processing Design, Evaluation
and Contamination Prevention
 Media Fills
 Environmental Monitoring
 Personnel Issues
 CGMPs in the 21st 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
 Summary

 We’ve been listening

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