Contamination and Beyond - cbinet.com IVT 05Jun16_FINAL...growth/gross contamination Visual...
Transcript of Contamination and Beyond - cbinet.com IVT 05Jun16_FINAL...growth/gross contamination Visual...
Contamination and Beyond
Hilary Chan
QC Sr. Scientist
Shire
Lynn Johnson
QC Scientist
Shire
IVT Microbiology Week
June 7-9, 2016
Detection, Remediation, Control, and the
Integral Role of the Microbiologist
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Session Outline
Objective and Introduction
Building Blocks of an Effective Contamination Investigation
Interactive Exercise Part I – Investigation Case Study
Contamination Control – Microbial Risk and CAPA
Interactive Exercise Part II – CAPAs
Contamination Control - Preparedness
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• How to detect, investigate, and respond effectively to a
contamination
• Tools for improved lab support for investigation
• Tactics for continual improvement of contamination
response and investigation
Objective
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Introduction
• Determining the root cause of a microbial contamination
can be time consuming and difficult
• Potential product loss
• Production down time
• Unique circumstances/“uncharted territory”
Patient safety is #1 priority
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Scrambling around to figure out what to do
No time for lengthy studies
Difficult to pinpoint root cause
Shotgun approach to mitigation
Rely on contamination response “formula”
Scope and risk may be unclear
Microbiologist may be left out of early stages of investigation
Common Pitfalls
Goal:
A systematic approach for investigating
microbial contaminations
Ideal Scenario
Introduction
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• Aseptic vs. non-sterile/low bioburden
• aseptic facility – a finished product free of any microorganisms
• non-sterile or low bioburden facility - a microorganism presence may
be expected/allowed, but the type and number are tightly controlled
• Intrinsic vs. extrinsic sources of microbial contamination
Introduction
• Examples - bacterial contamination from raw material, biofilm in water system
Intrinsic
• Example - bacterial contamination from poor gowning practices, HEPA failure
Extrinsic
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• What constitutes a “contamination” at a non-sterile/low
bioburden facility?
• “Gross” contamination/out of specification or action-level result
• A more subtle loss of microbiological control
• Trend (product, EM, utility)
• Recovery of microorganism that is considered “of concern” or
high risk due to characteristics and sample source
Can be more difficult to detect and investigate
Can progress and severely impact your process/product
Introduction:
Signs and Symptoms of Microbial Contaminations
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Introduction:
Signs and Symptoms of Microbial Contaminations
Endospores: Bacterial (typically Gram positive) spores form in stressful environments and are prime for dispersal in the environment
Ultramicrobacteria: The ability of microorganisms to reduce in size as a means of starvation survival, and at the same time, allow them to pass through traditional 0.45um and 0.2um membrane filters
Mold: Spores are ubiquitous in nature and can readily grow in diverse environments; concern surrounds pathogenicity, mycotoxin production, allergic reactions, and invasiveness in the facility
Endotoxin: Lipopolysaccharide complex associated with the outer membrane of Gram negative bacteria. Can indicate the presence of Gram negative bacteria and elicit inflammatory responses in humans
Biofilm: Microorganism creates an enclosed environment and adheres to surfaces under nutrient limited conditions
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Susceptible Systems Signs of Contamination Detection Mode Contamination
Type
Nutrient-rich
environments (e.g., cell
culture, media)
System parameter shifts (e.g.,
pH, DO), loss of host cell viability
Indirect High-level
growth/gross
contamination
Visual turbidity, microbial cells
visible on slides, odor
Direct
Steps with open
processing
Recurring low level bioburden
recovery
Direct bioburden
detection, indirect
trend detection
Low level
bioburden trend
Water systems, nutrient-
poor environments
Sporadic bioburden recovery,
similar/reoccurring isolates,
endotoxin
Indirect Biofilm
Areas with lower
environmental
classification/ transition
points (e.g., gowning
rooms, airlocks)
Similar/reoccurring isolates
(especially spore-forming bacilli
and fungi), frequent excursions
Direct EM trend
Production operations
with heavy personnel
reliance
Similar/reoccurring isolates
(especially G+c), frequent
excursions specific to operator(s)
Direct Personnel trend
Introduction:
Signs and Symptoms of Microbial Contaminations
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BUILDING BLOCKS OF AN EFFECTIVE
CONTAMINATION INVESTIGATION
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Building Blocks of an Effective Contamination Investigation:
Introduction
The role of the microbiologist is not limited to testing and
reporting of data; the impact a microbiologist has is best
summarized in the statement below:
“The mission of a microbiologist is to develop in the pharmaceutical
organization a foundation for understanding of microbial origin, and
parameters for proliferation and survival; to continuously improve/
embed the concepts for protection, exclusion, reduction, removal or
destruction of contaminating microbiological entities.”
Singer, D.C. (2012) “A Strategy for Developing Robust Pharmaceutical
Microbiological Control.” American Pharmaceutical Review 15(4)
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Building Blocks of an Effective Contamination Investigation:
Collaborative Contamination Response
Anatomy of a Contamination
Response Team
Key Representatives
Visual Management
Problem Solving
Tools
Participation
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Building Blocks of an Effective Contamination Investigation:
An Overview of a Contamination Investigation - Examples
Immediate actions/containment
Investigation plan
Problem statement
Root cause analysis
CAPA
or
Define
Measure
Analyze
Improve
Control
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Building Blocks of an Effective Contamination Investigation:
Root Cause Analysis
Root Cause Analysis Tools
Checklists, tables,
flowcharts Five Whys
Fishbone/ 6M/Ishikawa
diagram
Contradiction matrix/TRIZ
Is/Is not
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Building Blocks of an Effective Contamination Investigation:
Root Cause Analysis
RCA Tool Benefits Limitations
Checklists, tables,
flowcharts
Customizable, wide range of usage, scope
setting
Unstructured, less efficient
Five Whys Easy to use, no hypothesis testing,
determine relationship between root causes
Higher risk of failure to find root
cause (less comprehensive)
Fishbone Diagram Brainstorming, cause-and-effect,
categories, identifies multiple possible
causes/thorough
Time-consuming, can create
divergence, difficult to
represent interrelatedness
Contradiction Matrix Precedent solutions used to resolve
contradictory elements of a problem,
established matrix reduces analysis time.
Examine facts and causes to see if they are
relevant
Lack of formalization, difficult
to implement as official tool
Is/Is Not Comparative analysis, structured thinking,
can be used when partial knowledge of
situation (determine scope/boundaries),
process of elimination
Focus on differences/changes
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Building Blocks of an Effective Contamination Investigation:
Root Cause Analysis - Example
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• After framing the contamination through initial discussions, a
deeper dive can be taken using one or a combination of the
data collection plan approaches outlined below to help focus the
investigation:
Building Blocks of an Effective Contamination Investigation:
Investigation Tools and Methods
Walk the Process
• GEMBA walk
• Process map
• Material flow diagrams, equipment drawings
• Timeline of sequence of events
• Standard knowledge baseline for all team members on relevant areas of focus
Containment/Scope Setting Sampling
• “Survey” samples to help define scope or problem statement
• Additional process or environmental monitoring locations and/or increased sampling frequency
Hypothesis Testing
• Hypothesis-specific sampling
• Challenge each hypothesis using facts, observations, and data
• Rule in or rule out
• Work cross functionally between functional areas based on topic
• Review data
Laboratory Studies
• Increase knowledge base
• Hypothesis-specific experiments
• Data gathering/ scenario testing
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Building Blocks of an Effective Contamination Investigation:
The Role of the Microbiologist
Recurring contamination? Increasing vs. variable recovery
level? Same microorganisms/strains?
Is endotoxin OOS?
Matrix Evaluation:
What are the microbial growth-
effecting attributes?
Challenge Assumptions:
Is a 0.45µm filter 100% retentive
of a 0.5µm microorganism?
Asking the right questions in order to determine the
appropriate tools and test methods to use
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Gram positive spore forming or Gram negative bacilli that are ubiquitous in nature
Microorganisms that persist in areas that are inaccessible to cleaning processes
Microorganisms that are capable of surviving in stressful conditions
Building Blocks of an Effective Contamination Investigation:
Assessment of Microbial Risk
Typical characteristics of a pharmaceutical contamination
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Examples of manufacturing environments associated with contaminating
microorganisms
Building Blocks of an Effective Contamination Investigation:
Assessment of Microbial Risk
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Building Blocks of an Effective Contamination Investigation:
Investigation Tools and Methods
Situation Studies Purpose
Contaminant found in a
tank or “pool” sample
Growth kinetics study
using process isolate,
matrix, and maximum
process hold time
Use growth curve to determine
doubling time in order to back-
calculate point of entry
Same species
recovered in other
steps/batches/WFI/EM
or investigational (e.g.,
swab) sampling
Strain type analysis of
isolates
Strain relatedness to determine
common source
Recurring
contamination with
variable recovery levels
Biofilm formation and
disinfection
Determine if isolate(s) form
biofilm on manufacturing surfaces
and determine effective method
of eradication
High levels of endotoxin
with low bioburden
Combined
endotoxin/growth
kinetics study
Evaluate microbial growth kinetics
and relationship to endotoxin
production
Hypothesis testing Investigational sampling
or scenario testing
Rule in/out
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Objective of Part I: teams will form hypotheses based on clues
provided by instructors and rule in/out for root cause
1. Break into teams
2. Instructors will guide the teams in performing a mock
contamination investigation based on an actual case study
• Instructors are a resource representing all SMEs required for the
investigation, providing any requested information or data to the
team
• Reference session material as needed
Interactive Exercise Part I: Instructions
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• Form investigation team
• List any critical immediate actions
• Determine problem statement
• Perform root cause analysis
• Establish CAPAs (Interactive Exercise Part II)
Interactive Exercise Part I: Investigation Plan
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• Low level (1-2 CFU/mL, below action limit) mold (Acremonium
kiliense) was detected from in-process bioburden samples for
two sequential drug substance purification batches
• In-process data review revealed increased frequency in purification bioburden recovery over prior two months, including:
• Stenotrophomonas maltophilia (Gram negative bacilli)
• Microbacterium lacticum and Microbacterium species (Gram
positive bacilli)
• Ralstonia pickettii (Gram negative bacilli)
Interactive Exercise Part I: Background
http://jcm.asm.org/content/49/6/2342.full
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• Form investigation team
• List the areas/departments that will be represented as part of the
investigation team
• Immediate actions
• Risk assessment for continued production to ensure controls in place
contained issue
• Confirming scope – walkthrough with survey sampling
• Purification production hold
• Full facility sporicidal cleaning and VHP disinfection
• Equipment cleaning
• Problem statement
• “Increased frequency of low level bioburden recovery from drug
substance purification over a two month period of time, including
recovery of mold”
Interactive Exercise Part I: Step 1
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Root cause analysis strategy:
• Identify RCA tools and activities
• Comparative analysis “Is/Is Not” tool
• Fishbone diagram
• Investigational sampling of equipment and environment
• Strain typing
• Generate hypotheses based on clues from RCA
Interactive Exercise Part I: Step 2
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An atypically large quantity of equipment was returned to the facility
from offsite warehouse storage
• Storage in uncontrolled/unclassified area at warehouse
• Inadequate cleaning process for moving equipment into the manufacturing facility permitted an increased microbial challenge to the purification suites
Interactive Exercise Part I: RCA Clue #1
Equipment Transfer into Facility
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Interactive Exercise Part I: RCA Clue #2
Cabinet Design
• In preparation for facility sporicidal deep clean, discoloration of floor and wall was discovered behind purification cabinetry
• The edges of the cabinetry where they met the walls and floor were sealed, generating a niche area inaccessible for routine facility cleaning
• No backing on the cabinet, which created an area behind and underneath the cabinets that was routinely exposed to the environment when drawers were opened/closed
• Small parts used on the chromatography skid stored in these drawers
Exposed Floor
and Wall
Section after
Drawer
Removal
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Interactive Exercise Part I: RCA Clue #3
Condensate on Wall in Purification Room • During the prior year facility shutdown, a freezer insulation project caused a
change in temperature between the purification and adjacent freezer room,
resulting in areas of the wall having a lower temperature
• Condensate formed on the lower part of the wall, confirmed by moisture mapping
• Cabinet from prior slide located on this wall
Temperature Difference
(~20°C)
Highest Level of Moisture (%)
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Interactive Exercise Part I: RCA Clue #4
Difficult to Clean Parts in Equipment
• Incomplete welds and rouging of internal chromatography skid
surfaces observed
• Check valves on skid difficult to clean due to design
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• Test hypotheses
• Detailed observations (e.g., borescoping)
• Hypothesis-specific investigational sampling
• Strain typing
• Rule in/out hypotheses
• Based on hypothesis testing and supporting data
Interactive Exercise Part I: Step 3
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• An atypically large quantity of equipment was returned to the
facility from offsite warehouse storage
• Storage in uncontrolled/unclassified area at warehouse
• Inadequate cleaning process for moving equipment into the manufacturing facility permitted an increased microbial challenge to the purification suites
• Investigative sampling demonstrated one genus level and one
species level match between equipment stored at the warehouse
and the growth behind the cabinet
Interactive Exercise Part I: Hypothesis Testing
Equipment Transfer into Facility
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Interactive Exercise Part I: RCA Clue #2
Cabinet Design
• In preparation for facility sporicidal deep clean, discoloration of floor and wall was discovered behind purification cabinetry and confirmed as microbial growth
• Acremonium kiliense, Microbacterium species, and Stenotrophomonas maltophilia/Stenotrophomonas maltophilia were recovered from this area
• The edges of the cabinetry where they met the walls and floor were sealed, generating a niche area inaccessible for routine facility cleaning
• No backing on the cabinet, which created an area behind and underneath the cabinets that was routinely exposed to the environment when drawers were opened/closed
• Small parts used on the chromatography skid stored in these drawers
Exposed Floor
and Wall
Section after
Drawer
Removal
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Interactive Exercise Part I: RCA Clue #3
Condensate on Wall in Purification Room
• During the prior year facility shutdown, a freezer insulation project caused a
change in temperature between the purification and adjacent freezer room,
resulting in areas of the wall having a lower temperature
• Condensate formed on the lower part of the wall, confirmed by moisture mapping
• The moisture provided an environment that was conducive to growth of microorganisms
Temperature Difference
(~20°C)
Highest Level of Moisture (%)
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Interactive Exercise Part I: RCA Clue #4
Difficult to Clean Parts in Equipment • Incomplete welds and rouging of internal chromatography skid surfaces
observed
• Check valves on skid difficult to clean due to design
• Acremonium kiliense was found in check valves and incomplete welds on skid
• Strain match of Stenotrophomonas maltophilia was found between skid outlet
and the bioburden samples
• Strain match of a different strain of Stenotrophomonas maltophilia was found
between the check valves and from behind the cabinet
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12 Hypotheses Ruled Out: • Increased movement of material, cages and carts
• Column packing room exposure to uncontrolled spaces
• Mold spores/organisms colonizing under floor scales
• Product-specific hose aging
• Exposure of skids to WFI stored during plant shut down
• WFI float installation in WFI storage tanks during plant shut down
• Purified water system preventive maintenance and cleaning
• WFI flow orifices in purification room
• Installation of HEPA fans
• Floor drain repair during plant down
• Pipe insulation can harbor microorganisms
• Upstream material introducing microorganisms to purification
Interactive Exercise Part I: Case Study Hypotheses
• Visual inspections - facility walkthroughs and equipment borescoping
• Investigational sampling - environmental and equipment, scenario testing
• Microbial characterization/strain typing
Hypotheses Testing and Rule In/Out
3 Hypotheses Ruled In: • Equipment transfer from storage with
ineffective cleaning allowed an increased microbial load to facility
• Microorganisms behind cabinet transferred onto bags of small parts stored in cabinet by turbulent airflow from opening/closing of drawers
• Use of contaminated small parts on purification skid led to equipment contamination (biofilm formation on difficult to clean areas)
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Interactive Exercise Part I: Case Study Root
Cause Summary
Hard to Clean Pump Heads / Check Valves
Cabinets
with Small Parts
Mobile
Equipment Warehouse PROCESS
Process
Equipment
Stenotrophomonas
Stenotrophomonas Strain Match
Strain Match
Acremonium Acremonium
Species Match
Species Match Species Match
Facility
Environment
( Typical plant flora )
Species Match
Loss of Control Maintaining Control Process “In Control”
Species / Strain Match
Between Sites
Primary Proposed
Microorganism Transfer
Secondary Proposed
Microorganism Transfer
Microorganism Growth behind the Cabinet in Purification Room
Ingress of Microorganisms from Equipment Shipment
Formation of Biofilm in Chromatography Skid
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• Assessment of microbial risk is the foundation for the determination
of impact to product/process/material
• Allows for evaluation of the impact that microorganisms have on the
quality and safety of the product based on data and scientific
knowledge
• Microorganisms should be evaluated on a case by case basis by
assessing various microbial hazards that may include:
• Number of microorganisms present in the sample
• Downstream endotoxin data
• Downstream bioburden data
• Secondary metabolite/toxin production
• Analytical assays that demonstrate product integrity and product purity
• Considerations such as multiple compounding issues, bracketing data,
limitations of particular process monitoring
Contamination Control:
Assessment of Microbial Risk
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Contamination Control:
Control vs Monitoring
Control
Actively managing contamination
Monitoring
Evaluating the process state of control
Cleaning/Sanitization (facility, equipment) Water monitoring
Sporicidal treatment Air monitoring
Water sanitization Surface monitoring
Physical barriers Personnel
Incoming raw material and in-process
acceptance criteria Raw material and in-process monitoring
Procedures Finished product testing
Sutton, S. (2013) “The Contamination Control Plan in Facility Validation.” Contamination
Control in Healthcare Product Manufacturing, PDA, Bethesda, MD.
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• Actions must be complete and thorough (both big picture and specific) to be
effective
Contamination Control:
Key actions following the event
Remediation:
• Actions taken to bring impacted system(s)/area(s) back to normal condition
• E.g., disinfection, passivation
Corrective actions:
• Actions taken to fix specific failure(s) causing a contamination situation
• E.g., fix leak, replace damaged elastomer
Preventative actions:
• Actions taken to reduce risks of repeated failure specific to causes of contamination:
• E.g., implement or improve preventative maintenance program
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• Effective immediate actions
• Interim controls to enable
production to resume
• Long term improvements for
sustainment
• Implement improvements to
bolster detection and monitoring
capabilities
• Examples of CAPAs:
• Improving disinfection and
cleaning program
• Implementing or improving in-
process bioburden/endotoxin
trending
• Effectiveness checks to ensure
CAPAs are successful
Contamination Control:
CAPA
Remediation
Preventative Actions
Effectiveness Checks
Corrective Actions
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CORRECTIVE AND PREVENTATIVE ACTIONS
Interactive Exercise Part II
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• Review:
• Multiple compounding root causes
• Continuation of investigation plan:
• Assessment of microbial risk
• Determine appropriate remediation, corrective, and preventative actions
Interactive Exercise Part II – Corrective and
Preventative Actions
Equipment transfer
from storage/
ineffective cleaning
Organisms behind cabinet
transferred onto bags of small parts
Use of contaminated small parts on
purification skid led to
biofilm
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• General:
• Break into same teams
• Each team will develop remediation and corrective and preventative
actions using the actual case study
• Instructors will function as all SMEs required, providing any requested
information or data
• Reference slide material as needed
• Establish CAPAs (Interactive Exercise Part II) Instructions:
1. List areas of microbial risk (equipment, materials, processes, etc.)
2. Determine appropriate remediation
3. Determine corrective and preventative actions
4. Determine appropriate effectiveness checks
Interactive Exercise Part II – Corrective and
Preventative Actions
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• Perform remediation activities:
• Remove cabinets in purification room and repair/replace wall
• Repair incomplete welds in the chromatography skid
• Treat purification equipment with caustic and a sporicidal disinfectant
(multiple cycles) followed by passivation
Interactive Exercise Part II – Remediation
http://www.atilimkimya.com/paslanmaz-celik-asindirma-ve-pasivasyon-uygulamalari/?lang=en
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Identify CAPAs:
• Implement sporicidal disinfection of equipment and materials
entering manufacturing facility
• Improvements to equipment movement and offsite storage
• Evaluate all fixed cabinetry, replace cabinets with wheeled
cleanroom-approved cabinets, and approve all fixture purchases
• Implement procedures for facility “return to service” from work that
is potentially environmentally disruptive
• Assess check valve/pump design replacement, cleaning
improvements, and improved equipment maintenance
• Improvements to microbial control strategy
• DE testing for equipment cleaning solutions
• Supplemental bioburden challenge recovery with process isolates
• Strategy for in-process bioburden trending
Interactive Exercise Part II – CAPAs
http://www.directindustry.com/prod/bi
oclean/product-121651-
1376205.html
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Implement Effectiveness Checks:
• Prior to resuming production:
• Additional non-routine bioburden and EM sampling
• Confirmatory cleaning process qualifications (CPQ)
Interactive Exercise Part II – Effectiveness Checks
http://microqa.com/wp-content/uploads/2014/08/MQA-Environmental-
Monitoring-Services.jpg
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Contamination Control:
Creating a comprehensive preparedness strategy
Goal: Be proactive and prepared in the event another
contamination occurs
The Benefits: Significantly decrease response time during investigation
Avoid or reduce time-consuming studies
Easily accessible data and information for immediate reference
Gain familiarity with contamination support tools
Understand impact of process parameters and matrices on microbial growth kinetics and endotoxin production
Understand susceptibility of manufacturing surfaces for biofilm formation and efficacy of routine cleaning cycles and chemistry on biofilms
Data to support specific, effective, remediating actions
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• Compile data and references in a consolidated resource for
accessibility
• Literature searches, published resources
• Build database of relevant in-house data
• Past contaminations
• Evaluation/development/validation studies
• Disinfectant efficacy studies
• Properties of prior contaminants against disinfection, growth properties,
identified source
• Microbial evaluation of site matrices
• Categorize based on likelihood to promote, sustain, or inhibit microbial growth
using attributes such as pH, water activity, nutrient source
Helps identify if the contamination in question is an isolated event or
recurring event that is an indication of insufficient controls
Contamination Control:
Building your knowledge base
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Trending of microorganisms isolated from the process provides
useful detail on:
Contamination Control:
Building your knowledge base
Seasonal shifts in recovery is there an increase in isolate recovery
certain times of the year?
Effectiveness of disinfectant program is there an increase in
recovery of spore forming organisms, necessitating implementation of
a sporicide?
Comparing the type(s) of microorganism recovered: within a specific
product, between products manufactured at the same facility, the
environment and in process steps
Environmental and bioburden levels for a particular process or
atypical growth
Strain information
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• Experimentation to collect data prospectively using
facility isolates and production matrices
• Growth kinetics
• Endotoxin production
• Endospore formation
• Spike/recovery
• Hold time studies
• Biofilm formation
• Disinfectant efficacy
• Filter challenge
Contamination Control:
Building your knowledge base
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Contamination Control:
Building your knowledge base
Contamination Investigation Laboratory Studies update
Type Tool Purpose Strengths Weaknesses
Basic Lab consumables &
equipment (e.g., sterile
flasks & tubes,
incubator)
Microbial growth
kinetics, disinfectant
efficacy, biofilm
formation (certain
surfaces)
Simple &
inexpensive
Can be challenging
to replicate exact
process conditions
Special Bench Scale Bioreactor
(e.g., CelliGen®)
Microbial growth
kinetics, disinfectant
efficacy
More accurately
replicate some
process conditions
Requires expertise,
can be challenging
to maintain sterility
Biofilm Reactor Biofilm formation &
disinfection
Simple & relatively
inexpensive, wide
range of surfaces
Studies can be
lengthy
Strain level
identification (e.g.,
Riboprinter®)
Strain relatedness
between isolates
Can help pinpoint
contamination
source
Higher cost,
expertise
necessary
RMMs Rapid endotoxin,
bioburden, and ID
instruments (e.g., Scan
RDI®, MCS™/PTS™,
MALDI Biotyper)
Rapid testing of
water and in-
process samples
and rapid microbial
identification
Significant
reduction in time
to result, helps
advance
investigation
Some are relatively
expensive and
require expertise
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• Successful contamination control is achieved through
expedient detection, thorough investigation, and effective
actions (mitigate, correct, and prevent)
• A wide range of tools can be utilized for improved
microbiological support for investigations
• Contamination responsiveness/preparedness requires
continuous improvement and a broadening knowledge
base
Summary
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• Singer, D.C. (2012) “A Strategy for Developing Robust
Pharmaceutical Microbiological Control.” American
Pharmaceutical Review 15(4)
• Prince, R., ed. (2008) Microbiology in Pharmaceutical
Manufacturing, Vol. 1, 2nd edition, PDA
• Madsen, R.E. and Moldenhauer, J., eds. (2013) Contamination
Control in Healthcare Product Manufacturing Vol. 1, PDA
References