Risk-MaPP A cGMP Driver for Contained Equipment and Facility Design Risk-Based Manufacture of Pharmaceutical Products

Risk-MaPPA cGMP Driver for Contained Equipment and Facility Design

Risk-Based Manufacture of Pharmaceutical Products

Paul RichardsCRB Consulting EngineersPharmaForum 2011 - Portland, OR

PharmaForum 2011 - Portland, ORWho am I?I am not an Industrial HygienistI am a Chemical Engineer who is PASSIONATE about containmentSenior Process Engineer for CRB Consulting Engineers 23+ years in chemical and pharmaceutical industriesFormerly Sr. Principal Engineer with Pfizer (11+ years)Extensive capital project experience in API and OSD manufacturing facilitiesDesigned, installed, and tested many successful containment systemsSteering Committee - ISPE Containment CoPBoard of Directors ISPE New England Chapter BS Chemical Engineering / MS Management

What is Risk-MaPPHow Risk-MaPP relates to ContainmentPractical solutions

PharmaForum 2011 - Portland, ORTopics of Discussion

What is Risk-MaPP?PharmaForum 2011 - Portland, ORA guide to managing risks associated with cross contaminationISPE Baseline Pharmaceutical Engineering GuideRolled out in Fall of 2010Six years in developmentFDA and EMA reviewed and approvedmeant to assist pharmaceutical manufacturers in the design and construction of new and renovated facilities that are required to comply with the requirements of the US FDA.

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PharmaForum 2011 - Portland, ORIntent of Risk-MaPPRisk-MaPP provides a scientific risk-based approach, based on ICH Q9, to manage the risk of cross contamination in order to achieve and maintain an appropriate balance between product quality and operator safety. Focus on science based risk analysis to design and operation versus emotional reactions

PharmaForum 2011 - Portland, ORcGMP Focus of Risk-MaPPProtecting the PATIENT through quality systems to manage the risk of cross contamination

PharmaForum 2011 - Portland, ORFDA Focus on Sound Risk Assessments

PharmaForum 2011 - Portland, ORExposure RoutesMix-upCross contamination by using wrong API, excipients, product contact materials, equipment, etcEquipment Retention / Residue CarryoverMaterial that remains in product contact after cleaning due to failure or inadequate cleaningMechanical TransferParticulate transfer on clothing/feet from operators and equipment alternating between 2 or more processing areasAirborne TransferCross contamination via airborne migration of particulates

PharmaForum 2011 - Portland, ORProper Control is Critical

PharmaForum 2011 - Portland, ORRisk-MaPP and ContainmentcGMP versus Industrial HygienePatient versus the OperatorDifferent exposure routes / pathwaysIH monitoring targeted at worker exposure not cross contaminationHow do you meaningfully correlate IH data from an air sampling pump and filter?How do you validate containment if it is a cGMP control?

PharmaForum 2011 - Portland, ORThe Relationship Exists between cGMP and Containment Sterile ManufacturingRABSIsolators

Highly hazardous (potent) compoundsContainment is effective to protect workers as well as to reduce risks of cross contamination via mechanical transfer or airborne transfer

PharmaForum 2011 - Portland, ORReducing the Risk of Cross Contamination from Mix-upRedundant electronic verification of materialsRedundant manual checksColor codingBar coding and RFID of materials & equipmentLocked cages to store APIs with chain of custody Transfer and utility connect technologies that are unique to the processProcess Analytical Technologies (ie. NIR)Separate dispensary areasSeparate raw material staging areas

Clean to set limitsBase limits on science, risk assessment, statistical analysisCleaning validationEquipment designed for CIPOn-line monitoring / PATDisposable product contact partsDedicated product contact partsPharmaForum 2011 - Portland, ORReducing the Risk of Cross Contamination from Residue Carryover

PharmaForum 2011 - Portland, ORHealth Based Cleaning Limit

PharmaForum 2011 - Portland, ORReducing the Risk of Cross Contamination from Mechanical TransferLimit transfer of compounds between suitesie. High Shear Granulation, Milling, and Drying in same suite Segregate work areas to a single productContain at the SourceClose process systemsRoom airflowAirlocksGowning proceduresWipe down protocols for mobile equipmentClean mobile equipment in processing roomMisting showersCleaning bays with dirty / clean pass through

PharmaForum 2011 - Portland, ORReducing the Risk of Cross Contamination from Airborne TransferContain at the SourceClose process systemsRoom airflowAirlock separation to corridorGowning proceduresWipe down protocolsMisting showersRoom differential pressuresHigh room air change rates

Containment Design 101

Contain at the sourceAvoid technique dependant systemsFocus on transfer systemsDesign below the OEL / ADEConsider ergonomics, cleaning, sampling, waste, material compatibilityProvide redundancy / secondary containmentEngineer out the reliance on PPE

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PharmaForum 2011 - Portland, ORContainment at the SourceDispensing

Avoid Technique Dependent Systems

PharmaForum 2011 - Portland, ORFocus on Transfer SystemsThe Key to Success

Typical Containment Levels

OEL (g/m3)

Local exhaust ventilation

Crossflow boothDownflow boothCone ValveSplit Butterfly ValvesSplit Butterfly (Glatt SKS / Buck TC)

Rapid Transfer Ports (RTPs)10,0001,000100501010.10.01

Bag TechnologyOEB VOEB IOEB IIOEB IIIOEB IV

Split Butterfly Valves with air extraction

HicoFlex / EziDock CSV4

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Rapid Transfer Ports (RTPs)Well proven in industryPerformance: < 0.1 g/m3 Consists of an alpha (active) port attached to an isolator and a beta (passive) port connected to the portable containerThe beta is docked and locked to the alpha by rotation before the door can be openedRequires an isolatorVendorsLa CalheneApplied Containment EngineeringCentral Research Labs

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Rapid Transfer Ports (RTPs)

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Rapid Transfer Port Demo

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Rapid Access Port (RAP)Same basic technology at RTP, but passive attaches to equipmentActive fitted with a purpose made glove bagActive made in HDPE to keep light weightPassive flange or boltedAdapt passive with sight glassPressure cap provides 6 bar-g designActive $12,000Passive $ 6,000 (SS)Vendor Heaton Green Containment

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Rapid Access Port (RAP)

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Split Butterfly ValvesPrimary VendorsGEA Buck Valve Charge PointGlattAndocksystemeTypes of Split Butterfly ValvesStandard With air extraction shroudAir or Liquid Wash systemsPressure rated or notPrimary concern with split butterfly valves!material on the faces of the valves after undocking

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Split Butterfly Valves

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PharmaForum 2011 - Portland, ORSplit Butterfly Valve Demo

PharmaForum 2011 - Portland, ORFlexible Solutions to Reduce Risk

PharmaForum 2011 - Portland, ORRisk AssessmentFailure Modes Effect Analysis (FMEA)Perform risk assessment to identify steps and controls, prioritize level of risk, and determine corrective actionsFMEA format for risk assessmentSeverity the impact on the patientOccurrence how often this effect takes placeDetection how easily the failure can be detected

Multiply each factor for a resulting risk priority number (RPN)S x O x D = RPNSet limits for RPNsAcceptableInvestigate and remedyRequires immediate attention

PharmaForum 2011 - Portland, ORFMEA Risk Scoring Example

PharmaForum 2011 - Portland, ORFMEA Example

PharmaForum 2011 - Portland, ORSummaryThe FDA is on board with Risk-MaPPThe regulations have not changed, but the FDA will expect all manufacturers to Show us your scientifically sound assessment to prevent cross contamination and to justify the level of controlsThere are many common engineering controls to reduce risks of potential cross contamination and operator exposureUnderstand and document your risks and your controls

PharmaForum 2011 - Portland, ORQuestions?