Case StudyJoint Risk Assessment DuringTechnical TransferA framework for donor and recipient companiesto jointly analyze and document the technical andbusiness risks associated with a technical transferEvery technical (tech) transferis different, with companiestaking different paths towardreaching their goal. Eachone presents a unique set ofchallenges. These challengesare most often technical, butat times they may also bebusiness related. Howeverall donors (the outsourcingpartner) and recipients(the contract manufacturer)have the same overallgoal – to achieve a quick,efficient transfer of processand knowledge that meetsall necessary quality andregulatory requirements.To help drive the tech transfer of partnerproducts, Alkermes sought to developa risk assessment framework thatinvolved both the donor company andthe Alkermes transfer team in jointlyassessing the tech transfer risks. Thisframework would address not just theusual technical challenges but also, whereappropriate, the business challenges. Thiscase study provides an overview of theimplementation of this framework in arecent real-world tech transfer.BackgroundA large pharmaceutical company wishedto outsource to Alkermes the commercialmanufacture of a solid oral dose product,which had been in commercial productionfor over five years. Alkermes had previousexperience in the core technologies andprocesses involved. This was the donor’sfirst major tech transfer to Alkermes.The ChallengeThe donor’s desire was to minimizeregulatory changes, which meant thedonor equipment train would need to bereplicated wherever possible. This requiredthe purchase, installation and qualificationof new equipment at the Alkermes Athlone,Ireland site. Some of this equipment was ata working scale new to Alkermes. ExistingAlkermes equipment was to be employedfor one core unit operation. This requireda process scale change from the donorsite. A lean approach to the tech transferwas agreed i.e., only one active engineeringbatch was to be manufactured prior toprocess validation. Minimal developmentdata or product history was shared with therecipient site.The Approach – Joint RiskAssessmentThe first round of risk assessment wasperformed based on the Partner’stransfer plan and process knowledge atAlkermes. First the risks were identifiedvia brainstorming. The risks were thenanalyzed and evaluated via a risk rankingprocess and the use of Failure Mode,Effects and Criticality Analysis (FMECA).As part of this process, the joint team (ofdonor and recipient members) started toconsider the controls that should be put inplace or the additional data and/or studiesrequired to mitigate the risks identified.To reduce the time associated withworking risks through the full FMECAprocess, Alkermes introduced a sub-process between risk ranking and theFMECA stage – referred to as the “silverbullet” step. Here, unanimous agreementof both teams can render the riskacceptable based on existing knowledge.It is important that the justificationfor applying the silver bullet step bethoroughly documented.It was agreed that all risks identified mustbe closed out by one of the followingmeans prior to proceeding to processvalidation:• Donor and Alkermes deem the risks tobe acceptable.• Donor and Alkermes deem additionaldata is required. Donor to provide/facilitate data gathering.• Donor and Alkermes deem additionaldata is required. Donor has existingsupporting data. Donor declares the riskis acceptable.• Alkermes deems the risk isunacceptable. Donor prepared to acceptrisk. • Donor and Alkermes deem the risk to beunacceptable. Further work is requiredto close out.
Such decision paths are sometimesrequired due to the disparity in theprocess history knowledge betweenthe donor and recipient sites. Thekey here is that the risk is considered,documented and responsibility forthe risk is clearly agreed upon whileallowing an efficient closure of theprocess via a simple declaration by thedonor. Such decisions must always bemade with the quality of the productand safety of patients as the primaryconsideration, regardless of the sourceof the process history knowledge(Figure 1).Risks Identified250 risks were identified at the initialbrainstorming session and presentedto the donor. Of these, 195 weredeemed to be high-risk as they directlyimpacted a Critical Quality Attribute(CQA) at the end of the risk rankingprocess.On completion of the risk ranking andsilver bullet process with the donorcompany, 70 risks retained a high-risk designation and were progressedto FMECA. These risks includedthe risks associated with the singleactive engineering batch approach asrequested by the donor. The FMECAprocess identified that engineeringstudies were required. This included ashort placebo manufacturing campaignto support the lean active engineeringcampaign.The risk assessment was revisited andupdated at the end of the placeboengineering trials i.e., before theactive engineering demonstrationbatch and again on completion of thedemonstration batch. At this point,zero technical and five business risksremained identified as high-risk. Allquality risks had been mitigated viathe additional engineering studies andcontrols identified through the variousiterations of the risk assessment.The remaining business risks were alldeemed acceptable by the donor asthey related to historical process datareadily available to the donor but notshared with the Alkermes team. Thefive business risks were assessed,and it was agreed and documentedthat none of the business risks hadany quality or patient safety impacts(Figure 2). On this basis, it was agreedto progress to validation – Stage 2Process Performance Qualification(PPQ).Figure 1. Risk assessment approach adopted by Alkermes in a tech transfer process.Abbreviations: QS = Quality Systems, CQA = Critical Quality Attribute, KMA= Key Manufacturing Attribute,FMECA= Failure Mode Effects and Criticality Analysis, PPQ = Process Performance QualificationAlkermes Process Brainstorming and Risk RankingStage 1 Process DesignJoint Process Risk AssessmentQuality TargetProduct Profile =Partner QSQualityImpact on CQAsGather additionaldata Manufactureadditional batchesFMECAOverallunacceptableProceed to Stage 2 PPQOverallacceptablePartneracceptablePartneracceptsriskAdditionaldata/workrequiredRiskRankingProgressallhighriskstoFMECA.Documentrationalforparkingalllowandmediumrisks.PartnertoreviewSilverBulletUnanimousagreementnottoprogressManufacturabilityImpact on KMAs
0(0%)5(2%)70(28%)195(78%)250(100%)Conclusion – Successful RiskAssessment CompletionThe time committed to jointly risk-assessing the process played a leadrole in the efficient and successful techtransfer and validation of this product.The framework helped focus bothparties throughout the tech transferand was revisited many times to assistin technical decision-making. The workput into the risk assessment also feddirectly into the development of thevalidation strategy for the product inquestion.The framework was demonstrated tomeet the user requirements suggestedearly in its development – it supportedboth parties in meeting their ICHobligations on risk assessment intech transfers and confirmed theeffectiveness of Alkermes’ Quality RiskManagement (QRM) approach. Thetransfer was deemed to be efficient,and the framework was found to beeasy to use.The tech transfer was deemed to be asuccess by both parties.Lessons Learned• Donor companies find it veryreassuring to have a fullydocumented set of risks andresponsibilities.• By agreeing on the mechanism andareas of responsibility up-front, issuesencountered during transfer can bespeedily resolved.• Alkermes’ experience as this processevolved, is that improved up-frontdetailing of the assumptions thatlie behind the risk assessment canreduce the number of risks thatare dealt with via the silver bulletmechanism and thereby reducethe time associated with theirassessment.• Involving stakeholders on both sidesfrom the outset is invaluable. Theprocess and any differences in theprocesses between the donor andrecipient sites are well understoodlong before the critical processqualification stage. This can makethe review and approval of validationprotocols, master batch records andchange controls much more efficient.• Dedicating time to the riskassessment is key – the first time anew process, piece of equipment ora commercial partner is involved in arisk assessment is time-consuming.Subsequent transfers can leveragethe risk assessments developedin previous transfers. Eventually, alibrary of risk assessments coveringall key unit operations is built.Note – numbers rounded here for illustration purposesFigure 2. Risk ranking process.Total TotalNumber of risks/items identified 250 100%Number of risks/items rated highon completion of risk ranking process195 78%Number of risks/items rated highon completion of silver bullet process70 28%Number of risks/items rated highon completion of FMECA5 2%Number of risks/items not deemedacceptable to proceed to Stage 2 PPQ phase0 0%Case Study Joint Risk Assessment During Technical Transfer“All quality risks had beenmitigated via the additionalengineering studies andcontrols identified throughthe various iterations ofthe risk assessment.”