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Process Risk Assessment to Ensure Microbial
Contamination Control
Process Risk Assessment to Ensure Microbial
Contamination Control
Presented by Lucia Clontz
Director, MicrobiologyDiosynth Biotechnology
March 16, 2006North Carolina Biotech Center
Topics AddressedTopics Addressed
Regulatory requirements & expectationsPotential sources and types of microbial contaminationRisk analysis tool applied to contamination control
Control of ContaminationControl of ContaminationIncludes:– Microbial contamination– Cross-contamination– Particulates and other impurities
Covers:– Facility– Personnel– Equipment– Process
Today’s focus: Microbial Contamination
Why Worry About Microbial Contamination?Why Worry About Microbial Contamination?
Must ensure product quality and safety!
- Life-threatening health risk to a patient- Product spoilage- Lost product batches
Microbial control is a regulatory requirement
- FDA 483- Client observations/lost business
CFR 21- 211.113 (a)CFR 21- 211.113 (a)Control of Microbiological Contamination
“Appropriate written procedures, designed to prevent objectionable organisms in drug products not required to be sterile, shall be established.”
Control of bioburden Absence of objectionable organisms
CFR 21- 211.113 (b)CFR 21- 211.113 (b)Control of Microbiological Contamination
“Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.”
Control of bioburden pre-sterilized bulkReduction of bacterial endotoxin
FDA Inspection - Risk ApproachFDA Inspection - Risk ApproachPlant tour – look for the obvious!
Leaking valves, vessels, pipes, spillsEquipment corrosionPoor employee practicesPersonnel gowning/trainingCleaning/sanitization practicesSterilization of glassware
More than 65% of FDA-483s within the past year had some comment about microbial contamination or issues with sanitization & cleaning practices
Kip Priesmeyer, FDA/Team Biologics - ISPE Webinar, April 6, 2005
What is Contamination Control?What is Contamination Control?
Science and Applied Technologythat interacts continuously with all products, processes, materials, equipment, and personnel entering the manufacturing areas.
Risk Assessment RequirementsRisk Assessment Requirements
FDA Guidance for Industry – Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations (09/04)ICH Q9 (draft), Quality Risk Management(08/05)
Risk Assessment ToolRisk Assessment Tool
HACCP methodology can be applied to pharmaceutical/biotech processes to reduce risk of microbial contamination
Sources of Microbial ContaminationSources of Microbial Contamination
Raw Materials/ExcipientsEquipment and ProcessEnvironment/FacilityPersonnel
Bacteria gram (+) rods - environment, soil, RMgram (+) cocci - personnel, RMgram (-) rods - water, soil, RM
Fungi- Yeast
personnel, RM- Mold (filamentous fungi)
environment, soil, RMRisks: biofilm formation and release of toxins/toxic productsControls: humidity, temperature, flow, water activity, etc.
Types of Microbial ContaminationTypes of Microbial Contamination
Shift in ParadigmShift in Paradigm
Current Desired
• Reactive Mode• Quality by Inspection• Blind Compliance• Corrective/Preventive
Actions prompted byinvestigations
•Proactive Mode•Process Understanding•Quality by Design•Continuous Improvement
Hazard Analysis Critical Control Point (HACCP)Hazard Analysis Critical Control Point (HACCP)
Developed in the 1970s – food safetyPrinciples apply to other industriesSystematic, proactive, and preventative tool to identify, assess and prevent/reduce potential risks that can occur at specific steps in a process.
Hazard Analysis Critical Control Point (HACCP)Hazard Analysis Critical Control Point (HACCP)
Process specificTechnical and scientific principles to identify critical control points (CCP)Output – risk management information that facilitates monitoring of CCP in the manufacturing processMust be performed by a multidisciplinary team
Q9A ModelQ9A ModelRisk AssessmentRisk Identification
Risk Analysis
Risk Evaluation
Risk ControlRisk Reduction
Risk Acceptance
Output/Results
Risk Management and Monitoring of CCPs
Ris
k C
omm
unic
atio
n
Risk M
anagement T
ools
Seven Principles of HACCPSeven Principles of HACCP1. Conduct a risk analysis2. Determine CCPs3. Establish critical limit(s)4. Monitor each CCP5. Establish corrective actions when
deviations occur6. Establish verification procedures7. Establish record keeping system
Understanding the Process –Sources of Microbial Contamination
Understanding the Process –Sources of Microbial Contamination
Raw Materials and ExcipientsRaw Materials and ExcipientsComponents
natural vs synthetic productswater activity levelcontainers (cardboard boxes)
Water Systems (Purified Water, WFI)Biofilm
•
Schematic representation of processes involved in biofilm formation
Equipment and ProcessEquipment and ProcessDesignMaterial/SurfaceUnprotected storage tanksBack flowPerforated heat exchangersChrom columnsUnsanitary pumps
Carbon filtersMembrane filtersSampling/transfer hosesValvesDead legsUF/DF skidsSeals/gaskets
Facility and MaintenanceFacility and Maintenance
Undesirable facility designInadequate air handling systemsInadequate construction materialsInadequate sanitization proceduresInadequate maintenance (standing water, dust, rust, etc.)Ineffective EM Program
PersonnelPersonnelMajor potential source of
microbial contamination
Exposed skin (flakes, oils) Exposed HairExposed Clothing DirtCosmeticsTobacco smokeBehavior
PeoplePeopleSkin
- We lose 1,000 particles/minute- 1,000,000 bacteria can live on 1 cm2 skin
Saliva
- Bacteria project 2-3 feet from talking- Bacteria project 4-6 feet from coughing- Bacteria project 10-15 feet @ 200 mph
Source: ITW Texwipe
Application of HACCP to Microbial ControlApplication of HACCP to Microbial Control
Ideally should be done during product and process development - potential risks are designed outPlanned and carried out for specific products – generic plans should be used only as a guideDifferences between pilot and scaled-up process should be considered.Re-assess after significant changes
Application of HACCP to Microbial ControlApplication of HACCP to Microbial Control
Team prepares a flow diagram of the processOn-site confirmation of flow diagram production siteList potential risksPrepare questions to assess level of risk
Example Considerations During AssessmentExample Considerations During Assessment
Qualitative/quantitative evaluation of risksPossibility of survival/proliferation of organismsPotential for production of microbial toxins/toxic productsEvaluate materials and ingredientsEvaluate equipment and process stepsEvaluate equipment sanitization proceduresEvaluate personnel involvement/open process
Example Process Flow DiagramExample Process Flow DiagramBulk Material
Pegylation
UF/DF Step
Chrom Step
Sterile Filtration
Facility
Raw Materials
Equipment
Personnel
Parts/Materials
Process Design/Parameters
Sterilization Processes
Cleaning/Sanitization
Practices
Example Risk Analysis –PEG Addition StepExample Risk Analysis –PEG Addition Step
PEG addition
Does PEG pose potential risk of microbial contamination?
YesNo No risk – no CCP
Can subsequent step reduce contamination?
No
PEG addition is a CCP
Yes No risk – no CCP
Example Risk Analysis –Open Process StepExample Risk Analysis –Open Process Step
Peg Addition/Open Process
Is Open Step a potential risk of microbial contamination?
YesNo No risk – no CCP
Open process step is a CCP
PEG Addition Step - a CCPPEG Addition Step - a CCPCritical control limit for PEG – bioburden limit for PEG raw materialBioburden/microbial limit program for PEG raw materialPortable HEPA and additional gowningCorrective Actions - describe in HACCP plan actions when bioburden exceeds limitsVerification system – include bioburden testing for the PEGylated sample Record keeping – ensures data trending and availability in case of process modifications
Portable HEPA Hood –Clean AirPortable HEPA Hood –Clean Air
Example of HACCP Work SheetExample of HACCP Work SheetCCP Risk Control
MeasuresCCPLimit
CCP Monitoring
Corrective Actions
PEG Raw Material
High Bioburden Vendor Qualification
Bioburden Limit
MLT, Vendor audits, shipping records
Investigation
Open Process Step
Environment/Personnel contamination
Portable HEPA, Extra Gowning
EM Alert/Action Levels
EM, Personnel Monitoring (if applicable)
Investigation
Create a Summary ReportCreate a Summary Report
Concentrate on High and Medium Risks Need to prioritize!Risk Control: decision making to reduce or accept risks
HACCP Doesn’t Replace GMPs!HACCP Doesn’t Replace GMPs!
HACCP applied to control contamination introduced mainly from equipment, process, and raw materials.GMPs must be followed to ensure control of contamination introduced from people and facility.Used in conjunction with company SOPs, HACCP can be a powerful toolto prevent microbial contaminationin process operations.
What’s wrong with this picture?What’s wrong with this picture?
What’s wrong with this picture?What’s wrong with this picture?
Final ThoughtsFinal Thoughts
PDA TR#13“Personnel are a primary source ofcontamination in an aseptic environment. It is therefore essential that all employees entering an aseptic environment be carefully selected and adequately trained so they can perform their required tasks in a well-disciplined manner.”
Final Thoughts (continued)Final Thoughts (continued)
Microbial control is not simply a task!- It is a continuous effort involving all
parts of the facility, all aspects of the process, and every individual who enters the manufacturing environment.
Final Thoughts (continued)Final Thoughts (continued)
The success of HACCP depends on educating and training personnel in the importance of their role in microbial control.