Facility Biocontainment and Inactivation a Risk-management Case Study Part 3

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Facility biocontainment and inactivation a risk-management case study (Part 3)

Stephen Brooks Richard Creekmore Ted Frank Brian Hasselbalch Kristin Murrayand Kwame Obeng

Pharmaceutical Technology 359 (Sept 2011) p74

Case study

Full Text COPYRIGHT 2011 Advanstar Communications InchttpwwwadvanstarcomFull Text

This case study on facility biocontainment and inactivation is the third of eight in a series put together by theProduct Quality Research Institute Manufacturing Technical Committee (PQRI-MTC) risk-management workinggroup The series is meant to advance the understanding and application of the International Conference onHarmonization (ICH) Q9 Qualify Risk Management guideline by providing actual examples of risk-managementassessments used by the biopharmceutical industry The introductory article and first case study on definingdesign space appeared in the July 2011 issue of Pharmaceutical Technology (1)

When a manufacturer produces two or more drug substances in the same manufacturing facility the facility isconsidered to be multiproduct The facility designs operations and controls related to the use for multiple productsshould provide for appropriate measures to prevent cross-contamination between products These controls includethe containment procedures used to prevent the release of hazardous agents within the facility

There are numerous facility design and operational attributes that may significantly affect the quality of productsbeing manufactured These attributes include but are not limited to area classifications open versus closedprocessing utility-system design cleaning validationclean-in-place systems rules regarding equipment sharing andcritical flows throughout the facility Facility designs and operations should provide for appropriate segregation ofproducts to prevent cross-contamination For facilities with multiple products or processes the impact of potentialprocess or product failures on the other operations in the same facility should be evaluated

The following case study on facility biocontainment and inactivation is the third of eight in a series put together bythe Product Quality Research Institute Manufacturing Technical Committee (PQRI-MTC) risk-managementworking group The series is meant to advance the understanding and application of the International Conference onHarmonization (ICH) Q9 Quality Risk Management guideline by providing actual examples of risk-managementassessments used by the biopharmceutical industry The introductory article explaining the history and structure ofthe series as well as the first case study on defining design space appeared in the July 2011 issue ofPharmaceutical Technology (1) The second study addressed functional equivalence for equipment replacement (2)

In the current case study two existing manufacturing suites were proposed to be remodeled to accommodate andcontain manufacturing operations involving bacterial fermentation through viable cells of Streptococcuspneumoniae a pathogenic Biosafety Level 2 (BL2) organism These suites were separate

manufacturing areas located adjacent to mammalian cell culture manufacturing-processing areas Regulatoryguidance requires BL2-Large Scale (LS) waste and residues to be inactivated prior to exiting the manufacturing area(3) An inactivation autoclave was identified during the initial risk assessment as one of the primary means ofinactivation of BL2 waste and process equipment prior to exiting the fermentation suite The risk-review step in therisk-management process identified that there was only one inactivation autoclave in the fermentation suite and thatalternative backup inactivation procedures were desired to maintain continuity of manufacturing operations duringautoclave preventive- and corrective-maintenance activities

This case study describes the evaluation of various backup inactivation procedures for operational feasibility andincludes a demonstration of an appropriate level of in-activation of the BL2 waste and equipment

Risk question and risk-assessment method

The risk question developed for the subject case study is What are the appropriate backup inactivation methods(ie procedures) that are operationally feasible and provide an appropriate level of decontamination capability thatcan be utilized in the fermentation suite to inactivate BL2 waste and equipment when the inactivation autoclave is



unavailable

Selection of a backup inactivation procedure is a precise exercise requiring an objective evaluation of theeffectiveness of proposed procedures at inactivating the BL2 organism along with demonstration of consistentexecution of these procedures each time they are performed

Hazards analysis and critical control points (HACCP) is a risk-assessment tool that can be proactively used toidentify and implement process controls that consistently and effectively prevent hazards from occurring HACCPinvolves evaluation of critical procedural limits and determination of how they will be achieved routinely Because itis essential that the backup inactivation procedures prevent the release of the BL2 organism outside of thefermentation suite HACCP was selected as the risk-assessment tool to use to determine the appropriate preventativecontrols

Risk identification and analysis

For this evaluation there was only one hazard to consider the BL2 organism The HACCP process wassignificantly streamlined to control for operator safety and the high level of regulatory requirements for pathogenicBL2 organisms The hazard was always considered to be significant in this case study (see Table I)

As shown in Table I each proposed inactivation mechanism or procedure was deemed crucial because they wereproposed as backups for the primary autoclave inactivation method (which was itself deemed crucial) Theevaluation of the effectiveness of the procedures including how they would be controlled to achieve consistencyamong critical parameters is shown in Table II

Risk control

In this case study identifying effective backup inactivation methods to compensate for times when the primaryinactivation autoclave is unavailable for use reduces the risk of a breach of containment in the facility Table IIdemonstrates that the backup procedures identified are effective and can be consistently controlled Table II alsoindicates that additional more detailed procedural controls and more clearly defined functional-area responsibilitiesare required to maintain proper containment of the BL2 organism These additional procedural controls are identifiedin the recommended actions column of Table II

Risk documentation and communication

For this case study the outputs of the risk-assessment process including recommendations for additionalprocedural and functional-area controls were documented in a risk-assessment report This report became part ofthe operating history of the manufacturing facility and the associated product The project team of each functionalarea affected by the results of the risk assessment reviewed and signed off on the results and recommendationsThe project team assumed responsibility for implementing the recommendations that arose from the quality risk-management process

Risk review

In the case study presented it may be appropriate to review the backup procedures as additional detailedprocedures are developed This activity will ensure that the backup procedures are fully effective and controlled inan effort to contain appropriately the BL2 organism

Training Tools

This PQRI risk-management case study series includes online training tools available atPharmTechcomPQRIstudies The PDF trainers include a HAZOP training guide a FMEA training guide aHACCP training guide and a Risk Rank Filter training guide

References

(1) T Frank et al Pharm Technol 35 (7) pp 72-79




(3) NIH Guidelines for Research Involving Recombinant DNA Molecules Appendix K (May 2011)

Ted Frank is with Merck amp Co Stephen Brooks Kristin Murray and Steve Reich are with Pfizer Ed Sanchez iswith Johnson amp Johnson Brian Hasselbalch is with the FDA Center for Drug Evaluation and Research KwameObeng is with Bristol Myers Squibb and Richard Creekmore is with AstraZeneca

To whom all correspondence should be addressed at kristinmurraypfizercom

Table I Hazard analysis worksheet

Categories of Actual and potential Introduced Are anyitems hazards introduced controlled potential controlled or or enhanced safety hazards enhanced at this step significant

Mixed trash Biosafety Level 2 Introduced Yes (BL2) host organism- known infectious pathogen Controlled Yes

Categories of Introduced Justify What preventativeitems controlled response measures were or enhanced applied to prevent the significant hazard

Mixed trash Introduced BI-2 host Place trash bag into organism another trash bag seal for transport and sanitize bag exterior Place bags in a covered container for transport to an external autoclave

Controled BL2 host Inactivation within an organism external autoclave

Categories of Introduced Is this a CCP rationaleitems controlled critical control far both or enhanced point (CCP) Yes and No)

Mixed trash Introduced Yes This CPP is the primary means of containment until inactivation

Controlled Yes This CPP is the primary means of inactivation

Table II HACCP plan form for the evaluation of the effectivenessand control of standard operation procedures (SOPs)RTD is resistance temperature detector EHampS environmentalhealth and safety

CriticalCritical Significant limits Monitoringcontrol hazards or eachpoint preventive What measure

Place trash Biosafety Bag closure Closurebag into Level 2 via tie-knotanother trash (BL2) host



bag seal for organism

transport 70 volvol Ethanoland sanitize concentrationbags for wipe-exterior downPlace bagsin a covered 1 min Ethanolcontainer for contact timetransport to for wipe-an external downautoclave

Complete Ethanol spray coverage coverage of bag

Inactivation BL2 host 12 min Sterilizationwithin organism hold time-external auto set at 90clave minutes

121[degrees]C Sterilization temperature

Critical limits MonitoringCritical or eachcontrol preventivepoint measure How Frequency Who

Place trash Bag closure Visual Once-upon Trainedbag into via tie-knot closure techniciananother trashbag seal fortransport 70 volvol Certificate Once-upon Qualityand sanitize of analysis release ControlbagsexteriorPlace bagsin a covered 1 min Wall-clock Once-upon Trainedcontainer for wipe down techniciantransport toan externalautoclave

Complete Visual- Once-upon Trained coverage ensure wipe down technician surfaces are wetted

Inactivation 12 min Controller Throughout Automatedwithin timer cycle unitexternal auto controllerclave

121[degrees]C RTD Throughout Automated cycle unit controller

Critical limits or eachCritical preventivecontrol measure Verificationpoint



Place trash Bag closure Bag notbag into via tie-knot accepted ifanother trash not sealedbag seal fortransport 70 volvol Release ofand sanitize ethanol forbags GMP useexteriorPlace bagsin a covered 1 min Placementcontainer for of bags intotransport to airlock onlyan external after ethanolautoclave inactivation performed per SOP

Complete Placement coverage of bags into airlock only after ethanol inactivation performed per SOP

Inactivation 12 min Cycle tapewithin reviewed andexternal auto retained for atclave least 3 years Unit is alarmed if cycle acceptance parameters not achieved

121[degrees]C Cycle tape reviewed and retained for at least 3 years Unit is alarmed if cycle acceptance parameters not achieved Critical limits DocumentationCritical or each Supportingcontrol preventive studies and Recommendedpoint measure records actions

Place trash Bag closure SOP for thisbag into via tie-knot None activity isanother trash required Anybag seal for 70 volvol Validation bags containingtransport reports relabled withand sanitize appropriatebags 1 min Validation external sharpsexterior reports indicator stickersPlace bags to ensure thosein a covered Complete Validation bags are routedcontainer for coverage reports for incinerationtransport to rather thanan external autoclaveautoclave inactivation



Inactivation 12 min Autoclave loads Flow fot thesewithin are challenged materials willexternal auto monthly with need to beclave Bacillus proceduralized stearother- and training of 121[degrees]C mophilus all impacted Electronic functional areas records of the will need to be verifications determined are retained for EMS will need at least 3 to ensure thet years autoclaved gowns are not disposed and are returned for laundering

Frank Ted^Brooks Stephen^Murray Kristin^Reich Steve^Sanchez Ed^Hasselbalch Brian^ObengKwame^Creekmore Richard

Source Citation (MLA 7th Edition)Brooks Stephen et al Facility biocontainment and inactivation a risk-management case study (Part 3)Pharmaceutical Technology Sept 2011 74+ Academic OneFile Web 27 Mar 2013

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unavailable

Selection of a backup inactivation procedure is a precise exercise requiring an objective evaluation of theeffectiveness of proposed procedures at inactivating the BL2 organism along with demonstration of consistentexecution of these procedures each time they are performed

Hazards analysis and critical control points (HACCP) is a risk-assessment tool that can be proactively used toidentify and implement process controls that consistently and effectively prevent hazards from occurring HACCPinvolves evaluation of critical procedural limits and determination of how they will be achieved routinely Because itis essential that the backup inactivation procedures prevent the release of the BL2 organism outside of thefermentation suite HACCP was selected as the risk-assessment tool to use to determine the appropriate preventativecontrols

Risk identification and analysis

For this evaluation there was only one hazard to consider the BL2 organism The HACCP process wassignificantly streamlined to control for operator safety and the high level of regulatory requirements for pathogenicBL2 organisms The hazard was always considered to be significant in this case study (see Table I)

As shown in Table I each proposed inactivation mechanism or procedure was deemed crucial because they wereproposed as backups for the primary autoclave inactivation method (which was itself deemed crucial) Theevaluation of the effectiveness of the procedures including how they would be controlled to achieve consistencyamong critical parameters is shown in Table II

Risk control

In this case study identifying effective backup inactivation methods to compensate for times when the primaryinactivation autoclave is unavailable for use reduces the risk of a breach of containment in the facility Table IIdemonstrates that the backup procedures identified are effective and can be consistently controlled Table II alsoindicates that additional more detailed procedural controls and more clearly defined functional-area responsibilitiesare required to maintain proper containment of the BL2 organism These additional procedural controls are identifiedin the recommended actions column of Table II

Risk documentation and communication

For this case study the outputs of the risk-assessment process including recommendations for additionalprocedural and functional-area controls were documented in a risk-assessment report This report became part ofthe operating history of the manufacturing facility and the associated product The project team of each functionalarea affected by the results of the risk assessment reviewed and signed off on the results and recommendationsThe project team assumed responsibility for implementing the recommendations that arose from the quality risk-management process

Risk review

In the case study presented it may be appropriate to review the backup procedures as additional detailedprocedures are developed This activity will ensure that the backup procedures are fully effective and controlled inan effort to contain appropriately the BL2 organism

Training Tools

This PQRI risk-management case study series includes online training tools available atPharmTechcomPQRIstudies The PDF trainers include a HAZOP training guide a FMEA training guide aHACCP training guide and a Risk Rank Filter training guide

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Facility Biocontainment and Inactivation a Risk-management Case Study Part 3