Preventing Contamination: Aseptic Processing Risk Factors

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Preventing Contamination Aseptic Processing Risk
Factors

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

10/22/02 OPS Advisory Committee/ Aseptic
Processing
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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

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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.

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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

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Aseptic Processing Line D/M
Process -personnel flow -material
flow -layout
Facility Room D/M
Personnel

Daily Sterility Assurance
QA/QC
HVAC/ Utilities
Media Fills
Response to Deviations Environmental
Control Trends
Disinfection Procedures Practices

• D Design
• M Maintenance

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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

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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

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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

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DESIGN ENVIRONMENTAL CONTROL Sterility
Link BFS Air Shower Setting
-1
10
Configuration A
Challenge Concentration 5 x 104 spores m-3
?
-2
10
Fraction Contaminated
-3
10
?
?
?
-4
10
0
1
2
3
4
Air Velocity (m s-1)
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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.
• FDAs 1987 Guideline on Sterile Drug
  Products Produced by Aseptic Processing

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Design, Environment, Personnel Link to
Sterility

• Widely accepted that each of the following is
  crucial to assuring sterility
• Design
• Environment
• Personnel
• Thats 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.

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Case Study Media Fill Failure

• Media Fill Failure
• Approx. 60 contaminated
• Considered spurious. Corrections made to firms
  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.

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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.

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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

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Sources of Contamination Investigation
Conclusions (e.g.)

• New lines 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.

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Five Topics for Discussion

• Sterilization Options
• Aseptic Processing Design, Evaluation and
  Contamination Prevention
• Media Fills
• Environmental Monitoring
• Personnel Issues

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CGMPs in the 21st CenturyScience 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

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Summary

• Weve 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!