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

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Risk M

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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.