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8 | IN THE MEDIA

Pharmaceutical Engineering } August 2015

Skyrocketing Drug Prices Leave Cures Out of Reach for Some Patients

USA Today, 15 June 2015, Liz Szabo

Sophisticateddrugsareopening thedoor, scientists say, toaneraof “precisionmedicine.” They’re also ushering in an ageofastronomical prices. New cancer drugs are routinely priced at morethan$100,000ayear–nearlytwicetheaveragehouseholdincome. Experimental cholesterol drugs – widely predicted to be approvedthissummer–couldcost$10,000ayear.Adrugforasubsetofpeoplewithcysticfibrosis,alungdiseasethat kills most patients by their early 40s, commands morethan$300,000ayear.Evenwith insurance,patientsmightpaythousands of dollars a month out of pocket.www.usatoday.com/story/news/2015/06/14/rising-drug-prices/71077100

Op-Ed: Don’t Weaken the FDA’s Drug Approval ProcessThe New York Times, 11 June 2015, Gregg Gonsalves, Mark Harrington and David A. Kessler

Duringtheearlydaysof theAIDSepidemic in the1980s, therewere no effective treatments againstHIV, the virus that causesthe disease. Because of this, many thousands of people diedlingering deaths. The desperation of those times led to the rise of an activist movement that took to the streets and pressed governmentofficialstoexpediteresearchondrugstotreatAIDS.The danger of faster drug approval was that a devil’s bargain would bestruck:quickeraccesstoexperimentaldrugsbutwithoutfirstdetermining whether these drugs were safe and would improve health and extend life.www.nytimes.com/2015/06/11/opinion/dont-weaken-the-fdas-drug-approval-process.html?emc=edit_tnt_20150611&nlid=33652061&tntemail0=y&_r=0

Drugmaker Sues FDA over Right to Discuss Off-Label Uses

The New York Times, 7 May 2015, Katie Thomas

Drugmakers have long argued they should have the right to talk to doctorsaboutunapprovedusesfortheirproducts,aslongastheyarebeingtruthful.And insomecases,courtshaveagreed.Butthefederalgovernmentstillfrownsonthepracticeand,inrecentyears,hasfineddrugcompaniesbillionsofdollarsfortalkingtodoctorsaboutso-calledoff-labelusesfortheirmedications.On[7May2015],AmarinPharmatooktheunusualstepofsuingthe US Food and Drug Administration, arguing that it has aconstitutional right to share certain information about its products withdoctors,eventhoughtheagencydidnotpermitthecompanyto do so.www.nytimes.com/2015/05/08/business/drugmaker-sues-fda-over-right-to-discuss-off-label-uses.html

India Takes First Step Towards Regulating Medical DevicesReuters, 12 June 2015, Zeba Siddiqui

Indiaplanstosetuparegulatortooverseethecountry’s$4billionmedicaldeviceindustry,accordingtoadraftpolicyreleasedthis

month,thecountry’sfirstefforttoregulateanindustrythatcoverseverything from thermometers to prostheses.Thepolicydocument,welcomedbymanyintheindustrydespiteconcernsoveralackofdetail,alsooutlinesplanstoboostlocalmanufacturing and reduce reliance on imports.www.reuters.com/article/2015/06/12/india-healthcare-regulations-idUSL3N0YW4QK20150612

Public Rarely Knows Full Reason FDA Rejects New DrugsReuters, 16 June 2015, Lisa Rapaport

Drug companies generally don’t disclose all the reasons new medicines fail to win US marketing approval, even thoughregulators often reject treatments over concerns about safety or effectiveness,astudyfinds.Researchers compared the details companies made public in pressreleaseswithconfidentialdocumentsfromtheUSFoodandDrugAdministration(FDA)knownascompleteresponseletters,which explain why a new medicine can’t be sold.Often, companies made no announcement when a drug wasrejected or omitted most of the reasons the FDA cited for denying approval,thestudyfound.www.reuters.com/article/2015/06/16/us-drug-approvals-fda-letters-idUSKBN0OW2NX20150616

Venezuelans Can’t Get Even the Most Basic Lifesaving Medical SuppliesWashington Post, 29 April 2015, Diederik Lohman

As Yamila’s three-month-old daughter was recovering from heartsurgeryatoneof the leadingpublichospitals inCaracas,Venezuela,doctorstoldhersheneededtogooutandbuybasicmedical supplies for her baby that the hospital had run out of. They gaveheralistthatincludedcatheters,needlesforadministeringIV fluids, antibiotics, and othermedications, themother told aHuman Rights Watch researcher in November.Leavingherdaughter’sside,Yamilawentonafranticsearchformedical supplies so basic that no hospital – let alone one of the country’s largest teaching hospitals – should ever run out of them. But none of the hospitals or pharmacies she visited had themin stock. In the end,despite concerns about thequality of thesupplies,andunsurewhethershehadthecorrectcathetersandneedlesforanewborn,Yamilahadnooptionbuttobuywhatevershecouldfindontheblackmarket–withnoqualityguarantees.www.washingtonpost.com/posteverything/wp/2015/04/29/venezuelans-cant-get-even-the-most-basic-lifesaving-medical-supplies/

Generic Drugs: Much Ado about SomethingThe Economist, 30 April 2015 (print)

The plot is worthy of a Shakespearean comedy. Teva is in pursuit ofMylan.ButMylandislikesitssuitorandrunsawaytodeclareitslove for Perrigo while seeking a poison pill in case it is forced to marryTeva.Perrigo,though,rebuffsMylan.www.economist.com/news/business/21650151-worries-are-growing-about-effects-dealmaking-among-generics-firms-much-ado-about?zid=318&ah=ac379c09c1c3fb67e0e8fd1964d5247f

COVER STORY } 13

August 2015 } Pharmaceutical Engineering

EVERY PATIENT, EVERY TIMEAssessing and Planning for Biologics Supply Chain Risks

Andrew D. Skibo Head of Global Biologics Operations & Global Engineering, MedImmune/AstraZeneca, and Chairman of the Board of Directors, ISPE

The ISPE/FDA/PQRI Quality Manufacturing Conference was held in early June in Washington, DC. Andrew D. Skibo, gave a keynote address titled “Biologics Supply Chain Risks: Point and Systemic Risks”. This article is based on his presentation.1

Consider this hypothetical scenario: A healthy woman gives birth prematurely, at 34 weeks term. Although she is distressed to have her newborn transferred to the neonatal intensive-care unit (NICU), she is comforted to know that theNICUathercountyhospitalisdesignedtodealwithpreemiesthisage and even much younger. Her son’s vital signs are monitored constantly. He is susceptible to infection by a virus called RSV because his lungs aren’t fully developed. He should be given a vaccine that is routinely administered to preemies during RSV season to prevent this infection.

Unfortunately, there isashortageof theRSVvaccine–asole-asset-in-class product – due to a supply chain problem at our manufacturingplant.Thesupplybaseisnarrow.Bulkmammaliancell drug substance production is always at risk of sporadic but lengthy interruptions due to particularly difficult to clearcontaminations such as murine retroviruses. The drug that could savethisbaby’slifeisatriskofbecomingunavailable.Fortunately,we know our supply risks and we manage accordingly. In this instance we maintain enough inventory to bridge a full season’s worthofproductionofthisveryspecializedproduct.

I know that the market for a drug like this cannot be shorted. In this case, themath representing human health outcomes isimplacable. I don’t ever want to wake up in the morning having to do that math. I don’t take risks managing its supply chain.

TAKING OUR INDUSTRY’S HISTORYThe Risks To Quality Of Cost-CuttingThreeyearsago,whilethinkingaboutthegeneralriskstosupplyinour industry, Iwasreadingareviewbyaleadingconsultancythat recommended that pharma could learn from the supply chainmodelsandsupplychainefficienciesofthebigautomotive

companies. They noted one manufacturer in particular as a best inclassexample.IalsohappenedtohavetheBusinessSectionofthat Sunday’s Washington Post on my desk. The headline article highlighted the despair of key auto suppliers in Japan that were havingtomoveproductionoffshoretooffsetthecostpressuresand just-in-time scheduling being mandated by this very same automobile manufacturer. These suppliers could no longer ensure that their products would be produced to the standards of quality that were historically associated with their family name.

The juxtaposition of these two articles startled me. One suggested we learn from the auto industry while the other demonstrated the adverse effects that this manufacturer’s relentless cost cuttingwas having on supplier quality.

Fifteen yearsago,pharma industry supplychainswere fat.Wehadlargelyinternalproduction,controlledthequality,maintaineddeepinventory,andhadanaverageutilizationofonly54%.Whatfollowed was streamlining and cost-cutting by all of big pharma. Concomitant with this, drug shortages and quality alerts bothwent up significantly. Many firms with previously stellar qualityrecordswerehavingqualityissues,nearmissesandunpleasantconversations with the FDA. Had pharma’s attempts to streamline oursupplychainscreatedadifferentproblem?

We at first thought of these as disconnected events. I wouldargue that they were not. Like those Japanese automotivemanufacturers, aswe streamlinedour supply chains to reducecosts did we increase the risks of being able to manage quality or supply product?

The Risks to Supply of Cost-CuttingAsanindustry,therewasnodoubtthatwehadtostreamlineournetworks,butinretrospectwerewestumblingintorisksthatweweren’t aware of? We were migrating from a supply chain that relied on three or four internal sources and end-to-end internal sourcing – in plants that had been making pharmaceuticals in our home bases for 15 years. If there was a challenge in one of those plants–anoldpieceofequipmentthatwentdown,forexample– the market never saw it. You could move production around in therestofyournetwork,whichwastotallyunderyourcontrol.Youhad deep inventory. There was incredible resilience in the supply chain as it existed then.

Startingin2010,drugshortagesdoubledinjustovertwoyears.TheFDAbelievedthiswasconnectedtoqualitycontrol.In2013,it started a quality metrics and drug shortage initiative with major supportfromtheISPE.Thethinkingwasthat, ifwecouldgetahandleonthequalitymetricsofanyoneplant,wewouldhaveasense what the risk might be of product shortages from that plant.

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Butthiswasgenerallynottherootcauseissue,asdemonstrated by two hypothetical scenarios. First, consider a perfect plant,theposterchildforqualitymetrics.Yetitoperatesat95%capa-city, thesupplychainmaintainsonlytwomonthsof inventory, itismanufacturingasole-asset-in-class,SpecialtyCare,pharma-ceutical,anditislocatedinadifficultpartoftheworld.Thisisahigh-risk scenario for drug shortage despite the plant’s superb quality metrics.

Alternatively,considertheexampleofthesameproductmanufac-tured in three older plants in our home base. The plants are fully in compliance but rely on equipment that is 20 years old. There are threenodes,allinternal,operatingat54%capacity,andwith14months of inventory. I’d argue that’s a much lower overall product supply risk situation even though anyone of those older plants might have a higher probability of an equipment failure.

DIAGNOSING THE STATE OF THE SUPPLY CHAIN TODAYThe Perfect StormAconfluenceoffactorsaccountedforthisfocusoncost.We’veseen increases in:} Patent expirations.} Drug development costs–Inthemid-‘80s,itcost$75-100

million to get a drug from concept to approval. Today that numberis$1.8billion,ormorethan$7billionifyoufactorinthe cost of unsuccessful products.} Regulatory uncertainty – Regulators are becoming more conservative,especiallyforlifestyledrugsora“metoo”productsuchasathird-generationproduct,forwhichtheapproval data would need to be impeccable.} The bar for reimbursement and access is high – The pool

of insurance company money is limited and a product has to offeramaterialadvantageoverwhat’salreadyonthemarket,for it to be reimbursable.

These have been accompanied by decreases in:} R&D productivity – The success rate for small molecule launches15yearsagowasabout6%.Today,thatnumberisunder2%(10%forbiologics).Thisisnotafundablebusinessmodel,werewerequestingventurecapitaltostartourbusiness today.

Many supply chain leaders in pharma came to the industry from highmanufacturingcost,must-be-efficientsupplymarketssuchasapparel, footwearorautomotive.Theyusedtheirexperienceandmetthisperfectstormoffactors,streamliningoperationsandreducing costs through:} Outsourcing – An increased reliance on CMOs (contract manufacturingorganizations).Manybigpharmasbragthatthey’veachieved100%outsourcingforAPIs(active pharmaceuticalingredients).60%ormoreofallAPIsare currently outsourced to emerging markets.} Increased utilization ratestochemicalcompanylevels,approaching85%-90%.

} Reduced inventories,sometimesbyasmuchasafactoroffive.} Reduced investments in internal networks

This focus on supply chain cost was absolutely necessary. Since1990,R&Dandall other costs except formanufacturingoperations have come close to doubling. If supply chain leaders hadn’tstrippedout40%ofcostbystreamliningthesupplychain,the rising expenses of the rest of the business would have made earnings go down in relation to revenue.2

THE INDUSTRY PROGNOSISThere’s a Growth Spurt, Especially Within BiologicsWeareenteringanewera inwhichnewBLAs(biologic licenseapplications) are being submitted at an historic rate and approvals are doubling from what they were a few years ago. Nine of the top 10drugsareforecasttoreachover$1billioninsalesintheUSfiveyears post launch.3Growthofthepharmamarketisexpectedtogrow,yearonyear,until2020whensalesareexpectedtoreach$1trillion,whichisdoublethatof2006.4 This growth is coming from a few markets.

Large moleculeThereiscleargrowthinthebiologicsspace.R&Dproductivityishigh.With15%-20%oftotalR&Dgoingintobiooverthelast15years,largemoleculesrepresenthalfofthepipelineintheindustry.On a sales basis the portion of revenues for bio is expected to grow from 14% in 2006 to 27% in 2020.5 Some projections suggestthat70%-80%ofthepipelinein2020willbebiologics.

OncologyThe oncology space shows the largest and fastest growth,especiallyimmune-oncologyproductstargetingthePD-1/PD-L1pathway.6 These breakthrough therapies see pipeline acceleration ofasmuchasfiveyears,whichisenormous.

BiosimilarsWe used to think that biosimilars would merely replace the bio-novels and that the capacity of one would decline while the other increased. That has turned out not to be true.7 Among other reasons,biosimilarswillbeused inco-therapieswithnovels,atleast in the oncology space. The value demand for a bio product doesn’t collapse after a patent expires as it frequently can for small molecules.

Emerging MarketsSoutheast Asia and Latin America are expected to lead thegrowthinpharmaceuticalsalesamongemergingmarkets,whichwillgrowfrom30%to40%ofworldwidesalesby2017.8 These are markets we can no longer ignore.

Personalized drugsThepredictivepersonalizeddrugmarket isexpected todoublefrom2013to2019,whichiswhatispartiallydrivingtheoncologyspace.9

COVER STORY } 15


Impacts of Cost-Cutting and Projected Growth on the Supply ChainAsmentionedearlier,asan industrywehavemadeourphamasupply chain lean. We are now at a low point of capacity agility and resilience.10 Our industry’s overall agility to support a return to growth with new products may be constrained. This is particular true for biologics, where there are at least 17 large bio drugsubstance plants in development right now. It takes five yearsto design, build, and commission one of these plants. As anindustry, we are clearly facing potentially constrained bio drugsubstance supply until this wave of new plants are commissioned and licensed. 2017 through 2020 will be years to watch with caution as we plan for bio supply.

Forthepast10-15yearsbigpharmahasoperatedwithamature,product portfolio focused more so on Primary Care rather than SpecialtyCaremarkets.Weoperatedintheefficient/matureendof the supply curve.

Now we are moving into the agile end of the supply chain curve: new product launches, more Specialty Care products, highlyvariable and unpredictable, first years demand. Variables suchasthenumberofpatients,thedoseperpatient,andproductiontiter dictate a wide range of potential plant capacities that may be required. For new oncology products, the launch volumesrequiredarenotoriouslydifficulttoprojectandcanvarybyafactorofasmuchas17.Howdoyouplanforthat?Agilityandflexibilityare key.

As we said before, it takes about five years to design, build,commission, and license a big biologics manufacturing facility.The product development cycle used to be approximately 7-9 years. Now we see product developments cycles of three years. Yetitstilltakesfiveyearstobuildaplantifyouneedone.Suddenlywe’re in a position where we are risk mapping for products we don’t even have yet because they will come before you can get thatplantdesigned,built,andlicensed.It’saverydifferentworld.

Itcosts$750-$800milliontobuilda4x15,000lplanttoday.Ifyoudon’t have the capacity, and you’re not able to share capacitywith another big pharma – a previously common occurrence – youcouldendupwithasignificantshortage.More importantly,we’renot in this just fordollars; therearepatientson theotherendofthatsupplychain.Ifweshortastatin,itwillbemeaningfulintermsoflostrevenuetoourcompanies,butnopatientsuffersbecause there are other suppliers. If we short a PD-1/PD-L1product, patients suffer.Many of these breakthrough therapiesare saving lives, yet there is not 5X surplus capacity for theseproducts available in the marketplace. If we get the launch / earlyyearvolumesversussupplywrong,therewillbehealthcareconsequences,notjustdollarconsequences.

THE WAY FORWARD – SUPPLY CHAIN MODELINGSupplychainagilityisnowabuzzwordintheindustry,11 with over three-quarters of businesses in big pharma agreeing that they needtochangetheirsupplychainmodel.Tellingly,only7%havecompleted that change.12

Two years ago at AstraZeneca, we developed a proprietarycapacity model for our biologics products. We run this model for hundreds of demand scenarios to assess whether the actual capacity of our current network needs to be augmented, tomeet future demand. The model allows us to tell our executive committeeandourBoard,notonlywhatwe’reasking them tobuild tomeet future capacity, but very importantly what is thewhitespaceabovethat,forwhichwearenotplanningtobuild.Iftheextremeupsidedemandhitsandwe’renotprepared,asacompany we need to understand what we may not be able to providethatcapacityonshortnotice,giventheconstraintsintheindustry. We can’t build to all the upsides – there aren’t enough very large plants available or the dollars to build them. How much of the wide-range of potential demand that we are planning to supplyshouldbeanexecutivedecision,not justasupplychaindecision.

Modeling Supply Chain RiskWhenwe change amanufacturing process in our industry,weroutinely do a quality risk assessment. Since supply chain risk hasasmuchimpactondrugsupplyasqualityrisk,weneedtobe doing the same risk assessment for the supply chain. For this reason we are developing a model to assess supply chain risks.

Supply chain management requires mental thinking that is like nine-dimensional chess. If you’re good at it you can see that,whenyoumakeachange here,andput thatconstraint inoverthere,thensomewhereelseinthematrixsomethinghappensthatmaycreaterisk.Understandingthissubjectivelyishelpful.WhenyouapproachyourBoardandask for$800Mtocure that risk,Board’sexpectmorethansubjectivejudgement.Boardslikehardnumbers.

Our model allows us to quantify risks so we can go to our CFO withactualprojectionsofriskmitigationversuscost.Quantificationallows us to sell objective modeling instead of appearing to base need on personal preference.

Modeling also helps us identify risks that we may not subjectively see.Asanexample,inourfluvaccinefranchise,weareverygood

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aboutprojectingincomingrawmaterialneeds,understandingtheplant capacities, packaging, and shipping and in-house testingneeds.Butwemissedtheriskassociatedwithlimitedcapabilitiesof outside testing labs. Missing that risk could have had the same consequence for us as not ordering the raw material. We hadbackupplans that fortunatelymitigated the issue.But thatconceptual miss was one of the issues that made it clear that weneededanend-to-endriskmodelthatwouldflagariskifwedidn’t see the risk ourselves.

Eventually themodelwill responddynamically,be liveandself-correcting,andoffersolutionstoidentifiedrisks.

What Determines Risk?Supply chain risk is determined by: inventory policy,network utilization,redundancy,andvisibility.

Inventory policyIf inventory isreducedtofreeupcash,whilesomeoneelseisreducingutilizationandsomeoneelseisoptimizingthenumberofnodesinthesupplychain,wecouldcollectivelybebuildinga weak supply chain.

Network utilizationWith95%utilization,thereislittleroomforequipmentmalfunc-tionorotherrisks.With50%utilization,productionisinefficientand expensive. How do you balance these options?

RedundancyRemember our example of 15 years ago. Three plants in our homebase,primarilyinsourcedunderourcontrolwithourqualitysystems,lowutilization,andhighinventories.Theredundancyof this network leads to virtually no risk to the supply chain. Compare that to today – do we have that redundancy in our supply chain?

VisibilityOutsourcing means that we can’t shine a spotlight on production the way we could when all plants were under our control. If we treat these supply contracts as commodity purchase orders, we have no visibility into our true supplychain. We discover a risk only when there is a problem. We may haveadualsourcestructure,butsupposebothsuppliersusethe same intermediate material supplier for a key step. What looksliketwooutsourcednodesis,inreality,onlyone.Whatifoneofthemisinadifficultpartoftheworld,operatingat95%utilization,andwehavegreatlyreducedinventory.Thisisahighsupply risk that we may not see.

Thesevariableshavetobeconsideredtogether.Optimizingthemindependently puts the drug supply at risk. Understanding therisksassociatedwithasingleproductionsite(i.e.,qualitymetrics)alone is of marginal value in evaluating overall supply risk. It’s not correct to think that a company with outstanding quality metrics needn’t worry about supply chain risks. Takeaway: Quality metrics do not equal supply chain risk metrics.

Anticipating Supply Chain Risks – Two Real-Life ExamplesWefind that theoutput fromour riskmodelhashigh value formeasuring risks such as what impact would the failure of a particular node have on on-time delivery. Here are two examples where we used the model to successfully anticipate supply risks.

We had two supply sources providing DP for a key clinical material,one internalandoneexternal.Theexternal supplierunexpectedly received a warning letter and had to close its plant. At the time it was our planned sole source of this clinical trial material. This could have materially affected our trials.However, we never eliminated the internal node. When thewarningletterhit,wewereabletoeasilycallupontheinternalnode. We produced the drug product internally with less than threeweeksnotice.Becausewehadplannedforthatpotentialrisk we averted an issue on a major clinical program.

As another example, increasing volumes of a frozen supplychainproductleadtopotentialconstraintsonairshipment,thehistorical method of choice. We planned to move to ocean ship for the next year. Ocean ship startup proved to be less robust thanexpected.Fortunately,ourriskmodeltoldusthatthiswasapotentialriskand,insteadofcancellingtheairshipmentoption,we had held it in reserve. It was reactivated it immediately with no interruptions to supply.

What will supply chain risk assessment allow?Modelingthesupplychainriskensurestwothings:first,weseetherisk;second,thatwehaveharddatatosupportrequestsorplans that will add cost to our network to mitigate the risk.

The supply chain doesn’t operate in a vacuum. We need to communicatewithourcolleagues inclinical,finance,regulatory,commercial,R&D, andmanufacturing to understand thewholenetwork. Then we can make these decisions together. We really want our executive committee to be aware of what we’re doing.

Cost-to-benefit analysis of de-risking is easier to implementbeforeashortage,buthardertoselltotheCFOwithoutconcretefacts. Modeling tells us these costs versus benefits. Solutionsmayincludewhitespaceinplant.A70%utilizationaddsflexibilityacross products without adding inventory. This is especially true if we’reintheagile,orgrowth,partofthesupplycurve.Itdoesaddcost.Isthebalance,right?

Moving Beyond EfficiencyUntil recently, most texts and journal articles regarding supplychain structures focused only upon efficiencies. Supply chainefficiency toolssuchassimplification,higherutilization,and the3 Vs (visibility, variation and velocity) were discussed in depth.Many of the early texts about supply chain modeling are full of complicated formulas, focused upon these issues. There arefactors for the number of nodes, leanness, and inventory. Butmostofthetexts,mostofthemath,includednofactorsforrisk.We weren’t measuring risk; we were measuring how lean wecould make the supply chain.

ISPE UPDATE } 21


METRICS AND SUPPLY CHAIN COMMAND ATTENTION

2015 ISPE/FDA/PQRI Quality Manufacturing Conference, Washington, DC. 1-3 June

Hosted by the ISPE, the US Food andDrug Administration (FDA), and theProduct Quality Research Institute (PQRI), the annual Quality Manufactu-ring Conference celebrated its fourth anniversary from 1–3 June 2015 at the Mayflower Renaissance Hotel in Wash-ington,DC.Theevent featuredover76speakers from industry and government in more than 38 education sessions and panels. The three-track confe-rence covered manufacturing innova-tions, quality systems advances, and regulatory insights, with topics thatincluded modernization, continuousmanufacturing, facilityoperations,drug-shortage prevention, foundations forquality, life-cycle knowledge manage-ment,anddataintegrity.

The last day of the conference was dedi-cated to regulatory issues, a feature thatconferenceCo-chairandISPEBoardViceChairJoeFamulare,VicePresidentofGe-nentech,hailedas“unique.”Discussionsatthese sessions were led by representatives fromANVISA,theMedicines&HealthcareproductsRegulatoryAgency(MHRA),andtheFDA,withafocusoninspectiontrendsandglobalharmonization.

In addition to education sessions and regulatory discussions, participants dis-covered cutting-edge technologies from 21exhibitors,withproductsandservicesdesigned to improve processes and main-tain compliance.

Conference highlights were keynote pres-entations that focused on each of the three conference tracks and updates on three ISPE initiatives: results of the ISPE Quality MetricsPilotProgramWave1 report, thedevelopment of a benchmark drug-shor-tage-prevention gap analysis tool, and apromising partnership with the Pew Cha-ritable Trusts to explore additional causes

of drug shortages. The gathering also in-cluded the 2015 Facility of the Year Award banquet.

Keynote PresentationsJanet Woodcock, MD, Director of theCenter for Drug Evaluation and Research (CDER)attheFDA,beganthefirstsessionwith a much-anticipated presentation on the agency’s quality initiatives. She noted that while the FDA is transitioning to a newparadigm,mergingdepartmentfunc-tions and creating new ones, momen-tum and progress continue. The agency released established conditions draft guidance in May 2015 and hopes to issue its quality metrics draft for review and comment soon.

The FDA plans to place more emphasis on quality by design, training, and riskassessment and will audit how well it ad-dressestheseinitsassessments.“Thisisoneofourmostimportantinitiatives,”said

Woodcock. Turning to regulatory conver-gence, she noted the urgent need forcommon standards around the world. The FDA is pursuing mutual reliance with the EuropeanUnionondrugmanufacturing–thefirstinwhatshehopeswillbeaseriesof agreements with international regulatory agencies.

Although the agency’s transition is a challenge, Woodcock remains optimisticabout the industry as a whole. We must resolve the problems of the past, shesaid, tobenefit from futureopportunities.“It’simportant,”sheconcluded.“It’saboutscience,technology,engineering,andma-nufacturing. Science and technology will get us out of the conundrum we’re in. We need a revolutionary change in manufactu-ringaswellastherapy.”

Inhiskeynoteaddress,JuanAndres,Glo-bal Head of Technical Operations (Manu-facturing and Supply Chain) at Novartis Pharma, encouraged the audience tocreateacultureofquality,developadeepunderstandingofproductsandprocesses,and invest in new technologies.

“Medicine has evolved faster than tech-nology,” Andres observed. “We keepproducing new drugs on old platforms.”Continuousmanufacturing,hesaid,coulddrastically change the landscape.

InBasel,Switzerland,amultipurposepilotfacilitythesizeofatenniscourt istestinga number of new process technologies,approaches, and process-control stra-tegies. “Wewanted tobreak the traditio-nal chemical operations in pharma,” hesaid,callingthenewplanta“toolbox”forupstream and downstream technologies. Thechallenges,hesaid,arejustasbigasthe potential.

The conference’s final keynote addresswasdeliveredbyAndrewSkibo,HeadofGlobalBiologicsOperationsandRealEs-tate for AstraZeneca’s MedImmune. The industry’s“perfectstorm”ofrisingpatientexpirations,drugdevelopmentcosts,andregulatoryuncertainty,hesaid,combinedwith declining revenue andR&Dproduc-tivity,createdpressuretostreamlineope-rations and reduce costs. “We are now

ISPE UPDATE } 25


BENCHMARKING HOLDS COURT

2016 ISPE Europe Annual Conference, Frankfurt, Germany 14-16 March 2016

The ISPE will host its third annual Europe Conference14−16March2016 inFrank-furt,Germany.Asalways, theconferencewill showcase innovations and trends in pharmaceutical manufacturing, with anexecutive forum and education tracks dedicated to operational excellence. In the past,theconferencehasproventobeanexcellent platform for dialogue between processexperts,mid-levelandseniorma-nagement, regulators, industry suppliers,and academics.

The 2015 conference was met with glowing reviews from the 300 attendees and 15 regulators. Some highlights included:Executive ForumThis pre-conference forum was an open session that enhanced the dialogue between the shop floor,middle-manage-ment experts and senior management. The focus this year was on benchmar-king, with speakers from the Benchmar-king European Medicines Agencies (EMA) Secretariat, McKinsey and the Develo-ping Countries Vaccine Manufacturers Network. Special presentations by spea-kers from Porsche Consulting (auto) and Nestlé (food) highlighted how to measure and manage complexity in other process industries that depend on individualizedproducts,quality,andintegrity.

Keynote PresentationsSanofi provided a look into the future ofbiopharmaceuticals, which represent thefastest growing sector within pharmaceu-tical drugs. Merck highlighted the chal-lenges posed for quality and compliance by the need for data integrity on all levels of the value chain. Pfizer completed thepicture of industry challenges by descri-bing the need for a new quality culture in companies that includes all employees in a comprehensive quality team.

Conference TracksThe conference itself provided a plat-formfor the latest techtrends, regulatory

updates,anddevelopmentsinproductionfacility design. Regulators and legislators fromtheMedicines&HealthcareproductsRegulatory Agency (MHRA) and EMA were present. Conference attendees could choose between four education tracks.

Regulatory Trends and Developments in Europe and Beyond provided a forum for industry and regulators to discuss the implications of the revised European Com-mission’s GMP Guidelines, in particularAnnex1“ManufactureofSterileMedicinalProducts.”Thesestandardsandrules formanufacturing drugs in aseptic conditions are among the most complex regulations for our industry, with the most stringentprovisions and highest impact on cost and quality oversight. This track also delved deeply into the hot topic of drug shortages and included an update on the ISPE Drug Strategy Prevention Plan (DSPP), whichwas created to address the manufacturing

and quality issues that cause shortages. The development from guidelines to im-plementation is an iterative process, anddiscussions like these are helpful for both engineersandregulators,whoareabletolearn about daily industry practice.

Managing Quality Under the New Pa-radigm addressed the state of life cycle CMC management and its role in quality systems,includinginspections,audits,fin-dings,bestpractices,andhowtorespondtoanauditoraUSFoodandDrugAdmi-nistration (FDA) warning letter. There was a good discussion on the growing role of what is known as “quality by design” asthe standard for new drug development and also within the life-cycle management of legacy drug products.

Facilities of the Future was popular with process engineers and production teams. Innovations in process technology were discussed,suchascontinuousmanufac-turing,advancedasepticprocessing,leanGMP operations, and quality by design.Highlights included discussions on how to make facilities flexible and implementleanproduction;theimpactsofregulationsonfacilitydesign;theincreaseinmid-sizeproductionfacilities;andtheriseofsingle-use technology, which complements therapidly growing biotech sector.

Supply chain integrity presentations outlined the provisions that regulators and legislators have taken to protect the sup-plychainfromcounterfeitmedicines,inclu-ding,forexample,theuseof2-Dbarcodesonproducts,whichcanbereadataphar-macy or at any stage of dispensing.

Looking Ahead to March 2016At theconference in14−16March2016,attendees can expect to gain insight into emerging developments in regulations and their practical implementation via good engineeringandprocesstechnology,inno-vationtechnology,andqualitycontrolthatwill enhance productivity. The conference will have an executive forum, high-levelkeynotespeakers, theconferencetracks,apostersession,andoptionalplanttours.AsusualatISPE,youwillmeetexhibitorspresenting innovative solutions for process technology and engineering.

INDUSTRY HIGHLIGHTS } 33


Consultant Amanda Bishop McFarland Joins ValSourceValSource, LLC, 16 June 2015

ValSourceannouncedthatAmandaBishopMcFarlandhasjoinedNorth America’s largest independent validation services company as a consultant. Prior to joining ValSource, Bishop McFarlandspentfiveyearswithGenzyme,mostrecentlyservingasSeniorContinuous Process Improvement Analyst.BishopMcFarlandcomments,“ValSourceprovidesme[with]theperfect opportunity to share my QRM [quality risk management] and microbiology knowledge to influence change in ourindustry.” She specializes in quality riskmanagement, programimplementation, partnership development, and contaminationcontrol.

Roche Employees Unite to Raise Funds for Children in NeedRoche Group, Media Relations, 16 June 2015

Roche employees participated in the 2015 Roche Children’s Walk at more than 131 company sites across the world. The funds raisedthroughtheeventwillbeusedtosupportchildreninneed,eitherinthelocalcommunityorinMalawiinSoutheastAfrica,oneof the world’s least-developed countries.“The Roche Children’s Walk is a key event in our company’scalendar,” saysSeverinSchwan,CEOofRoche. “It representsour firm conviction that support for social and humanitarianprogrammes should be long-term and foster sustainable solutions. Over the years, the funds raised have improved thelives of many vulnerable children. We will again match the money raisedbyemployees.”

GEA Launches New Group Structure GEA Group Aktiengesellschaft, 12 June 2015

GEAhaslaunchedtheoptimizednewGroupstructuredevelopedaspartofits“Fitfor2020”initiative,markingafundamentalshiftin both its internal structure and organization and its externalcustomer relations.Starting immediately, theGroup isbundlingand reporting the development and manufacturing of products and the provision of process solutions in two new business areas: “Equipment”and“Solutions.”

Honeywell Technology Modernizes Mill for Europe’s Largest Forest Industry CompanyHoneywell Technology, 11 June 2015

Honeywell Process Solutions (HPS) today announced that Europe’s largest pulp, board and paper manufacturer will useHPS process automation, safety system, and manufacturingoptimization technologies tomodernizeoneof itskeymillsandhelp it meet rising demand for renewable packaging board.Stora Enso Oyj is implementing Honeywell’s technologies as partof amodernizationandoptimizationeffort at itspapermillinVarkaus,Finland.HeadquarteredinHelsinki,StoraEnsoisthelargestpulp,board,andpaperproducerinEuropeandoneofthelargest in the world.

Janssen Supply Chain Expands Collaboration with Rutgers School of Engineering with $6 Million Funding Arrangement to Implement Continuous Manufacturing InitiativeRutgers University, 11 June 2015

Janssen Supply Chain has furthered its strategic partnership with theRutgersUniversitySchool of Engineeringbyprovidingover$6 million to expand ongoing research efforts supporting thecompany’s introduction of continuous manufacturing techniques for pharmaceuticals. The funds from Janssen, part of the Janssen PharmaceuticalCompanies of Johnson & Johnson, will increase research anddevelopmenteffortsattheRutgersEngineeringResearchCenterfor Structured Organic Particulate Systems (C-SOPS) over the next several years. The Center is helping Janssen transition several products to continuous manufacturing, including developinga specially designed manufacturing line at a Janssen facility in Puerto Rico.

Shire Appoints Olivier Bohuon to Its Board of DirectorsShire plc, 11 June 2015

Shire plc announces the appointment ofOlivier Bohuon to theShireBoardofDirectorsasaNon-ExecutiveDirector.Bohuonwillalso be amember of theScience& TechnologyCommittee oftheShireBoard.Bothappointmentswillbeeffectivefrom1July2015. BohuonhasservedasChiefExecutiveOfficerofSmith&Nephewplc,aglobalmedical technologycompany,since2011.Hehasextensive international business and leadership experience across a number of pharmaceutical and health-care companies inEurope,theMiddleEast,andUnitedStates.HealsoservesasaNon-ExecutiveDirectorofVirbacGroupSA.

New Synexus Board Gears Up for Expansion through Organic Growth and AcquisitionSynexus, 9 June 2011

FollowingthecompletionofthemanagementbuyoutofSynexus,thenewboardconfirmsitsintentiontoexpandthefootprintofthecompany through organic growth and acquisition.Synexus, already the world’s largest multinational companydedicated to the recruitment and running of clinical trials at its own research centers across the globe, intends to become amajorplayerintheUnitedStates,continuetoexpanditsexistingnetworkofsitesinEuropeandAfrica,anddevelopapresenceinAsia and South America.The new board members of Synexus are Charles Woler,Chairman,andBenjaminHarrild,HywelEvans,GedGouldandSimonBraham,allnon-executives.ChristopheBerthoux,CEOofSynexus,andPaulChambers,FinancianDirectorofSynexus,willremain on the board.

INDUSTRY HIGHLIGHTS } 35


Allied Minds Names Kevin Sharer, Former Chairman and CEO of Amgen, to Board of DirectorsAllied Minds, 5 June 2015

Allied Minds, an innovative US science and technologydevelopmentandcommercializationcompany,todayannouncedthe appointment of Kevin Sharer, former Chairman and ChiefExecutiveOfficerofAmgen,toitsBoardofDirectors.Sharer led Amgen for two decades, starting as President andChiefOperatingOfficerin1992andtheneventuallytakingoverasChiefExecutiveOfficerandChairman.AmgenhascreditedSharerwith an expansion that resulted in operations in 55 countries and a more than fourfold increase in revenue to almost $16 billion. Duringhistenure,thecompanyreceivedregulatoryapprovalfordrugs, including Neulasta, for preventing infections in cancerpatients undergoing chemotherapy; Prolia, for osteoporosis;and Xgeva, for the prevention of bone complications, such asfractures,forcancerpatients.

Körber Medipak Systems Opens New Location in São PauloKörber Medipak Systems, 19 May 2015

Körber Medipak Systems has opened a new location in SãoPaulo.DuetogrowingpopulationsinLatinAmerica,withcurrentfiguresatover600millionpeople,thepharmaceuticalindustryisrecordingstronggrowth in the region,particularly inBrazil.Theservices of the new location are meeting the increasing need for solutions for thepharmaceutical andbiotech industries inLatinAmerica,fromMexicotoArgentina.

Change in Roche Board of DirectorsRoche, 8 May 2015

RocheannouncedtodaythatDeAnneJulius(66),memberoftheBoardofDirectorssince2002,hasdecidedthatshewillnotstandforre-electiontotheBoardofDirectorsattheAGMin2016.TheBoard decided that Julie Brown (53), Chief Financial Officer ofSmith & Nephew plc, will be nominated for election as a newmemberoftheBoardofDirectorsbytheAGMin2016.ChristophFranz,ChairmanofRoche:“AsaBoardmemberandChairman of the Audit Committee, DeAnne Julius has madeimportant contributions to the success of Roche. On behalf of the Board,Iwanttoexpressmyprofoundgratitudeforhervaluableservicesandwishherallthebestforthefuture.”Franzadded:“Iamverypleased thatwithJulieBrownweareable toproposea leader with significant international commercial and financialexperience in the health-care industry to be elected as a new memberoftheBoard.”

Finnish DNA Diagnostics Company Genoscoper to Partner with Mars VeterinaryGenoscoper Laboratories, 5 June 2015

Finland-basedGenoscoperLaboratoriesandMarsVeterinary,adivisionofMarsPetcare,teamuptocombineproprietarygenometechnologies and DNA-based product solutions to advance the well-being and relationship between pets, pet owners andveterinarians through valuable insights into pets as individuals. Genoscoper Laboratories, a Finland-based DNA diagnosticslaboratory,specializesinhighlydevelopedDNAtestingandisthefirst laboratory in theworld to introduceacaninegenome-widepanel-testing method that combines disease gene testing with advanced genetic diversity measurement. Mars Veterinary will integrateaspectsoftheGenoscoperMyDogDNAtestingplatforminto its existing DNA veterinary products that are sold through affiliateMarsPetcarebusinesses,RoyalCaninandBanfieldPetHospital.

AmpliPhi Biosciences Announces Scott Salka as New CEOAmpliPhi BioSciences Corporation, 1 May 2015

AmpliPhiBioSciencesCorporation,agloballeaderindevelopingbacteriophage-based antibacterial therapies to treat drug-resistantinfections,todayannouncedthatScottSalkahasbeenappointed as the new CEO. Salka will replace Jeremy Curnock Cook,InterimCEOandChairmanofAmpliPhi,effectiveMay18.Curnock Cook will remain in his role as Chairman.“Mr. Salka’s leadership will enable AmpliPhi to execute on itsmission to develop innovative therapeutic solutions aimed at the growing problem of combating antibiotic-resistant bacterial infections,” said Curnock Cook. “His extensive experiencein building biotech companies with a focus on technology development and discovery will accelerate the progress of our bacteriophage candidates towards the clinic, and his skill set,combinedwithover25yearsofexperience,willfurtherstrengthenAmpliPhi’spositioninthisexcitingfield.”

38 | REGULATORY COMPLIANCE


SCIENTIFIC AND REGULATORY CONSIDERATIONS FOR IMPLEMENTING MATHEMATICAL MODELS IN THE QUALITY BY DESIGN (QbD) FRAMEWORK (PART 2)

Theodora Kourti, John Lepore, Lorenz Liesum, Moheb Nasr, Sharmista Chatterjee, Christine M.V. Moore and Evdokia Korakianiti

This article is the second of a two-part series and presents points to consider for building and using models in the regulated pharmaceutical industry and offers examples of how models can play a part in the Quality by Design (QbD) framework.

A model, in general, is an alternative representation of reality. A mathematical model is a description of a system using mathematical language. Mathematical models are used extensi-vely in process industries to describe the chemical and physical phenomena taking place during production.

The Quality by Design (QbD) framework for drug development and manufacturing is a science and risk based approach that beginswithpredefinedobjectivesformeetingthedesiredclinicalperformance and emphasizes product andprocess understan-dingandprocesscontrol. In theQbDframework,mathematicalmodelscanbeutilizedateverystageofproductdevelopmentandmanufacturing. Models have been implemented in pharmaceuti-cal industry for developing and controlling processes and have appeared in regulatory submissions. Models can also be indis-pensable for the implementation of continuous manufacturing processes.Overall,applicationofmodelsthroughoutaproduct’slife cycle from development through manufacturing can enhance processandproductunderstanding.Ingeneral,thesemodelingapproaches,somewell-established inother industries26,27,28,arestillevolvinginthepharmaceuticalindustry.3,4,7,14,16

Therearemanyconsiderationsinthedevelopment,validationandmaintenanceofmodelsdependingontheiruse.Thefirstpartofthisseriesgaveanoverviewofmodelsandshowedhowtheyfitin the QbD framework. The second part gives examples of model use in aQbD framework, provides points for consideration forthe building and use of models in the regulated pharmaceutical industry.

Examples of Models in QbD FrameworkExample 1: Mechanistic Model of an Epimerization ReactionThis example summarizes an experimental program intendedto achieve a mechanistic understanding for an epimerizationreaction used to produce a key building block of a drug substance molecule. The methodology is based on using a combination of riskassessment,mechanistic,empiricalandstatisticalapproachesto develop a robust design space.

Prior knowledge coming into this study includes the reaction mechanism,potentialreactionpathways,andariskassessmentof what attributes in drug substance may be important to understand.

This information was used to develop an Ishikawa (fishbone)diagram,whichprovidesagoodlinkageofdesiredattributeswiththe parameters thatmay influenceproduct quality. In Figure 5,blue boxes were understood to not have interactions with other factors.Inthesecases,explorativeexperimentswereconductedto achieve process understanding, and where there wasuncertaintyaboutthedetermination,DOEwasusedtoconfirmtheabsence of interactions. The orange boxes were determined to havevariableswithasignificantpotentialtointeract,andinthesecases,DOEwasusedtoachievegreaterprocessunderstanding.

The remainder of this discussion focuses on the epimerizationreaction. The epimerization changes the stereocenter on theprimary amine in the reaction scheme shown in Figure 6. It is importanttocontrolthecisstartingmaterial,soreactionconversionrequiresthoroughunderstanding.Further,downstreamprocessingrequires a cis:trans ratio of 19 or higher in order to achieve target purity and maintain target productivity. The conditions in the downstreamcrystallizationofthefinalintermediatecanbetunedto accommodate variable cis:trans ratios, but 19 was chosenas a minimum optimal point for productivity purposes. Factors influencingreactionoutcomearealsoshownintheFigure6.

The sensitivity analysis was conducted via a 2 6-2 (1/4 fraction)factorial design with three center points (19 total runs) to study the epimerization.Therangesselectedfortestingwereinformedbypriorexperiencewiththereaction(i.e.,provenacceptableranges)with the interest inprovidingmaximummanufacturing flexibility.TheresultsareshowninFigure7.Notethatinthiscase,HNBandtemperaturewereidentifiedasthemostsignificantfactors.

Furtheranalysisandeffortstofitthestatisticalmodelwithreactiondata (including center oints) showed that there was significantcurvature in the model - Figure 8. The analysis of the temperature as a variable revealed significant non-linearity, as the predictedbehavior (see trend lines in Figure 8) did not align with the data observed (see individual data points in Figure 8). Given thattemperaturewasasignificantfactor,andthatchemicalreactiontheory holds that reactions run at lower temperatures require longerperiodsoftimetoachieveequilibrium,thecurvaturewashypothesizedtobeaconsequenceofthetime-temperatureeffecton conversion. Note that the DOE could have been established using criteria that could have addressed the curvature issue;however,analternativecoursewastakenhereasanillustrationofhowfirstprinciplesandDOEcanbeusedincombination.

In this case, a chemical kinetics model was designed and fitwith commercially available kinetic modelling software. This modelinitiatedonfirstprinciplesallowedexplanationofthetimetemperature issue noted above:

REGULATORY COMPLIANCE } 45


Scale-Up and Transfer ConsiderationsWhen the objective is to implement a model that was developed at pilot or laboratory scale to commercial scale or to transfer a PATcalibrationmodeltoanotherinstrument,thescale-up/transferissues may be addressed in one or more of the following ways:

Scale-Up of Design Space Models: a scale-up approach can include,butisnotlimitedto:

} Usingappropriatescale-upcorrelations} Definingamodelintermsofscaleinvariantordimensionless

parameters} Implementing an enhanced monitoring/testing scheme of sufficientdurationtoverifythequalityofproductmanufacturedwhenmovingtoareasofdesignspacenotpreviouslyverifiedat commercial scale.

PAT Models: A calibration model developed at the laboratory instrument and process equipment should be verified whentransferring to the commercial scale. For situations where commercial conditions cannot be simulated in laboratory or pilot scaledata,themethodshouldbedevelopedbasedonfullscaledata.

Model ValidationIn general, validity of a model’s performance needs to beestablished prior to its implementation for decision making purposes.Thegoalofvalidation,whetheritisappliedtoaprocessorananalyticalmethod,istodemonstratethattheprocessorthemethod is suitable for its intended use in the intended process conditions and scale. In this section, the concept of validatingmodels will be discussed, highlighting the different aspects tobe considered. Data considerations for model development and validation are also discussed.

Considerations for first principle models, or phenomenologicalmodels, follow a similar thought process to that developed forempirical modelling, but with a number of major distinctions.When a system can be described accurately with existing tools thatexemplifythermodynamicandratephenomena,thosetoolscan usually be successfully leveraged to describe the system. Asaconsequence,thesemodelswouldnottypicallyrequirethesamelevelofvalidationasanempiricalmodel.Often,thereisnobasis forusingan independentdataset,as theverificationhasbeen done through the prior knowledge and widespread use. Thermodynamicfunctionsarestatebased,andasaresult,tendto be path independent.

Asanexample,indrugsubstanceprocesses,equilibriumprocessconditions are widespread. A phase diagram describing crystal form as a function of composition or temperature is a classic case. The model is developed based on existing equilibrium theory. Duringmodeldevelopment,themodelisoftentestedatextremeconditions,toevaluateitsresponsetosuchconditions;however,once developed, the model would be expected to behave

consistently across scales given compositional control within the range shown to deliver the desired crystal form. A similar case istheuseofkineticmodels,whichbytheirnaturerelatesystemconcentrations,temperatureandtimeandmore.

Internal ValidationIn the development phase, after themodel generation, internalvalidation assessment is typically carried out to verify the performance of the model. The model prediction is compared to actual values with data available at the time of method development.

The data set used for model generation is referred to as the Calibration Set or Model Building Set or Training Set.21 This set should include the variability anticipated in future routine production andisrepresentativeofthecommercialprocess(e.g.,equipment,steps).Whenthemodelisusedforpredictionofaproperty(i.e.,water content or assay), data covering the expected range ofvariability should be used. When the model will be used for MSPC (that is, to detect variability beyond common cause variation),only data of compliant batches which are representative of typical operatingconditionsshouldbeusedtodefinethecontrollimits.

The data used for verifying the model performance during the development form the Internal Validation or Test Set. The confirmation of themodel by these data is referred to asinternal validation. These data are excluded from the dataset available for modelling and are used as an independent data setforaconfirmationofthemodelwithrespecttoaccuracyandrobustness.Forsomeprocesses,theremaynotbesufficientdataavailable to exclude them from the data set for model building sincealldataareneededforestablishingthemodel.Inthiscase,techniques such as cross validation, random (MonteCarlo) re-sampling,orbootstrapping22 can be used.

For mechanistic models, when DOE are performed for thecalculation of constants or coefficients, internal validation alsoshould be performed.

External ValidationExternal validation is performed with an independent data set after themodeliscompletedandfixed.Thisdataset,calledExternalValidationSetorValidationSet,containsdatathatwerenotusedtobuildthemodel.Verificationofthemodelwithanappropriatedataset is especially important to demonstrate robustness –Figure 16.

The experimental procedures, parameters to be validated,andacceptancecriteria thatmustbemetshouldbedefined inadvance.Inacompliantenvironment,theyaretypicallydefinedinavalidationwrittenprotocol,issuedpriortotheexecutionofthevalidation,andmaintainedwithinthefirm’squalitysystem.Sincethemodel physically exists in the form of the digital data, themodelandtherelateddatamethodsaretypically“locked”beforeexternalvalidationtopreventanymodificationofthemethods.



Formechanisticmodels,theextentoftestingwouldbeexpectedto be consistent with the parameter/attribute being modelled and theimportanceofthemodel.Forexample,reactionrate,phasediagram, distribution coefficient, all would have differentmetricand acceptance criteria.

The robustness and stability of the model can be assessed by havingasufficientnumberofdataavailable,whichwereproducedover a longer period of time covering anticipated variability in environmental and process condition, e.g., different batches ofincoming material and seasonal changes in air humidity. Another waycouldbetoassesstheimpactofpotentialfactorsidentifiedpreviously in the frame of a risk assessment on the performance of the model using DoEs.

Implementation PhaseSubsequent to validation, the model is integrated into thecompany’s quality systems and there is on-going evaluation as part of regular maintenance. For example, the implementationof a high impact model in a production environment consists ofverificationatproductionscalephase, release forusageandmaintenance phase.

Verification at Production Scale EnvironmentIn thisphaseofproductionscale verification, themodeloutputis assessed against traditional testing of quality to ensure that it can perform as intended in a production environment. The need and extent of theproduction scale verificationdependson the

variation covered during validation in the intended production conditions and scale. The range covered and the batches required for this purpose depends on the type and purpose of model. This testing phase enlarges the body of data in order to makeastatisticalassessmentofmodelcapabilitypriortothefinalimplementation. For predictive models, this approach includescomparison of the models prediction with the reference method. ForMSPCmodels,theabilitytodifferentiatebetweentypicalandabnormalsituations is tested.Forprocesscontrolmodels (e.g.,feed forward/feedback), this phase makes sure that processcontrol algorithms and procedures deliver the required outcome.

Forpredictivemodels,companiesoftenchoosetotestatornearthetargetoperatingconditionsatthisstage.Alternatively,itisalsopossible to evaluate systematic variation within the design space. Iftestingofthemodeloccursonlyattargetprocessingconditions,a procedure could be included within the production quality system to help assure that the model performs as desired when there is variation (planned and unplanned) in the processing conditions. Some tools that could be used are: MSPC to detect unplanned disturbances and risk assessment to assess performance in planneddisturbances(e.g.,changeofrawmaterial).

MSPC models can and should9betestedofflinepriortorealtimeimplementation,byutilizingprocessdatatoassessTypeIandTypeII errors and to make decisions about real time implementation.

Table A Examples of acceptance criteria for validation of empirical qualitative and quantitative models.

EXAMPLES OF QUALITATIVE MODEL VALIDATION

Validation Parameter Specific Metrics Acceptance/Rejection Principles

Specificity/Selectivity Membership criterion, e.g. Hotelling’s T2 or Residual analysis

Points falling within predefined limits are acceptedPoints falling out of limits are further analyzed for their root cause

Robustness Number of batches, over a certain period of time, large enough to cover typical variability related to raw materials, environmental and process influences

Batches exhibiting the typical common cause variation of the process are accepted by the model

EXAMPLES OF QUANTITATIVE MODEL VALIDATION

Validation Parameter Specific Metrics Acceptance/Rejection Principles

Selectivity/Specificity Testing Model Applicability: check that the new data come from the same population as those used to develop and validate the model

Batches that reveal an unusual situation or are not produced at expected normal operating conditions are flagged and filtered out prior to quantification

Accuracy Root Mean Squared Error of Prediction (RMSEP/BIAS to the reference method)

Comparable to established acceptance criteria for conventional method transfers taking the inherent precision of the two methods, (i.e. the model and the reference into account)

Linearity 1. Distribution of residuals2. Accuracy across the range

1. Are randomly distributed2. Residuals stay within a defined bandwidth over

the complete range

Precision RepeatabilityReproducibility

For batch model, sometimes repeatability or reproducibility is not possible to measure as a batch is unique and multiple measurements are not feasible

Robustness Number of batches over a certain period of time covering environmental and process variability ( e.g. different raw material batches)

Batches exhibiting the normal variability of the process are accepted by the model with no impact on the predictive performance



Release for UsageOncethemodelisreleased,itisusedasanelementintheGMPsystem that warrants routine maintenance.

Model MaintenanceAfter the model is released for usage, the model is generallycheckedperiodicallybasedoncertaincriteria,asdiscussedlaterin in the Maintenance Model section of this article.

Usage, Incident and Change Management ConsiderationsAfterthevalidationofthemodel,proceduresforitsimplementationwithintheproductionsystemshouldbeconsidered;thatis,howto incorporate and integrate the model into the control procedures and release flow of the quality systems. These procedurestypicallyencompass thedefinitionofprocessflow, incidentandchangemanagement,anddefinewhatisseenasanoutofcontrolincident.Fortheseprocedures,itissuggestedtoincludeacleardefinitionofthresholdsandcontrollimits.Onepossibleoutcomeof an incident might be that the applied model is not covering the present variability which could entail an update of the model.

Usage and ImplementationFortheapplicationofamodelinproduction,theautomateddataflow between sensors, the model and the distributed controlsystem is highly essential for a compliant and secure usage. The control metrics and logic should be clearly defined andembedded into the manufacturing recipes. Based on methodspecificparameters, awarningcanbeautomaticallygeneratedif a certain control limit or threshold is exceeded. Examples for suchdeviationscouldincludeacertaincriticalprocessparameter,latent sum variable (as a score) or a residual deviated out of the predefinedacceptableranges.

Furthermore,fallbackscenarioscanbeinplaceincasethatthedataflowmightbreakdown,e.g.,incaseofasensorfailureorabreakageofadataconnectionorserver.Ideally,procedureswouldbe in place to handle such unplanned incidents in a systematic pre-planned manner. In particular, for multivariate models, theevent of having partially missing data could automatically generate alerts to the process expert who can then react.

Incident ManagementFor applying models in the production environment, clearproceduresfortheusageshouldbeestablishedincludingdefiningwhat is seen as an “unusual event.” In MSPC language, an“unusualevent”occursifoperationfallsoutsidetypicallimits,andmayneedtobeanalyzedfurther;thisdoesnotnecessarilymeanabadproduct.Acleardefinitionofthresholdsandcontrollimitcanbe developed in combination with a thorough risk assessment.

Inthecaseofan“unusualevent,”theincidentisusuallycheckedtoassesswhetherthisfindingisbeingescalatedtorealprocessdeviation and whether/when QA needs be informed. The investigation typically includes a thorough examination of all process steps involved, equipment andsensorsandpersonnelengaged to trace back the incident to the root cause of the model outof trendoccurrence. Inparticular,aQCtestingplan for theinvolved material might be considered.

One possible outcome of the incident might be that the applied model is not covering the present variability. This scenario would typically entail an update of the model.

Maintenance of ModelsTypically, models are evaluated periodically and may need tobe updateddue to an instrument or processdrift. Additionally,unaccountedvariability(e.g.,changesinrawmaterial)couldresultin out-of-spec predictions from the model. It is important to monitor the performance of the model over the lifecycle of the product as well as to monitor that the assumptions of the model still hold. An approach for monitoring model performance can include periodic comparison of model prediction with a reference method. Early identificationofmodeldefectsallowsmakingadjustmentstothemodel(e.g.,recalibration)beforefailuresoccur.

For data based models, maintenance has already beendiscussed as a crucial stage in the model lifecycle in the literature. “Continued evaluation of system performance relative to project objectives and the actions taken to ensure ongoing performance are part of system maintenance. Maintenance can encompass many activities including the updating of model parameters and control chart limits. Various methods can be used to maintain model parameters and control limits. These methods can include periodic off-line rebuilding of models, the development of automated model updating methods, or some combination of these activities. In either case, the goal is to ensure that the empirical models used in MVS analysis retain a high degree of fidelity to the process so that client needs continue to be met.21

Having long-term maintenance strategies in place is important in ensuring continuing success.”

“Once a model has been developed, it is often the case that the tacit assumptions underlying its validity are forgotten or neglected.” A discussion onmodel validation and detection ofparameter changes under closed-loop conditions can be found inJiang,etal,(2009).23

Empiricalprocessmodelscanbere-evaluatedatdefinedintervalsas part of an ongoing method evaluation throughout the life cycle of the model and the associated process. The main focuses of planned assessments are:} A reassessment of the accuracy of the method including a comparisonwiththereferencemethod(e.g.,repeatcertainparts of the validation)} Statistical assessment of performance of the model (similar

to Annual Performance Review (APR)/Product Quality Review (PQR))} Listofalldeviationsencounteredintheevaluationperiod} Final assessment of the validity of the method and statement

about the necessity of a model update

The outcome of the method reassessment under regular method maintenance is the conclusion whether the performance of the model is still appropriate and accurate to support further use of themodel.Iftheperformanceisinacceptable,correctiveactions



shouldbe taken.Forexample, themodel couldbedeveloped,takingintoaccountnewdata,processinsightandexperience.

The frequency of checking the adequacy of model performance dependsonthevariability,complexityandthenumberofbatchesproduced per year. An alternative approach to having a fixedtimewouldbetoexecutethiskindofassessmentafteradefinednumberofbatchesproduced,whichissimilartotheconceptoffrequency testing.

Other incidents, such as change in a sensor, change in rawmaterial, or change in manufacturing equipment could triggerreassessment of model relevance, potentially followed by aredevelopment and adaptation of the method.

Regulatory Considerations for Model ImplementationPoints for consideration for regulatory submissions are discussed in this section. These points are additional to the information that isdocumentedunderthefirm’squalitysystem.Forexample,forhigh impactmodels, information in the quality system typicallyincludes: development report, validation report, StandardOperating Procedures (SOPs), release process, maintenance,and incident management.

Considerations of Model Related Information in Regulatory SubmissionsIn accordancewith ICHQIWGPoints toConsider5 section onmodels,thelevelofdetailfordescribingamodelinaregulatorysubmission is dependent on the impact of its implementation in assuring thequalityof theproduct.Additionally,documentationofmodelrelatedinformationinregulatoryfilingsisdependentonthe intended use of the model and the risk associated with it. For example,ifaMSPCmodelisusedformonitoringonlyandnotforcontrolpurposes,itcanberegardedasalowimpact/riskmodel.However, anMSPCmodel used as a part of a RTRT strategycould be considered a high impact model.

The applicant should consider including the following information for various types of models:

I. Low-Impact Models: a discussion of how the models were used to make decisions during process development.

II. Medium-Impact Models:} Model assumptions} Tabular or graphical summary of model inputs and outputs} Relevantmodelequations(e.g.,formechanisticmodels)

either in the submission or via a reference} Statistical analysis where appropriate} Comparison of model prediction with measured data} Discussion of how the other elements in the control strategy helptomitigateuncertaintyinthemodel,ifappropriate

III. High-Impact Models:dataand/orpriorknowledge(e.g.,forestablishedfirstprinciplesdrivenmodels)suchas:

} Model assumptions} Appropriatenessofthesamplesize} Number and distribution of samples} Datapre-treatment(e.g.,variabletransformations,anyfilteringofthedata,spectralpre-treatments)} Justificationforvariableselection(wavelengthselectionfor

spectral data)} Model inputs and outputs} Model equations} Statisticalanalysisofdatashowingfitandpredictionability} Rationale for setting of model acceptance criteria} Model validation (internal and external)} Generaldiscussionofapproachesformodelverification

during the lifecycle.

Other considerations in accordance to regional requirements (e.g.,EMA2014a,b)24,25 could include:} Describing details about the composition of the data sets usedformodeldevelopment(e.g.,numberofindependentbatchesthatwereused,numberofsamplesperbatch,criteriausedforseparatingthebatchesintosets,demonstratingthatthese datasets are representative of the expected process variability in routine production)} Procedures for handling outliers} Forchemometricmodels,therationaleforselectionofnumberofprincipalcomponents,demonstrationofthelinkagebetween the weightings of the variables in the principal componentstotheprocess,methodoferrorestimation,RootMeanSquareErrorofCrossValidation(RMSECV),RootMeanSquareErrorofPrediction(RMSEP),etc.} If data from a reference analytical method is used to generate anempiricalmodel,demonstrationthatthereferencemethodisfitforpurpose(e.g.,fulldescriptionandvalidationofthereference methods).

Considerations for Model VerificationUsually,modelsaredevelopedwithdatageneratedatlaborpilotscale. One of the key points to be discussed in the regulatory submission is the applicability of the model at commercial scale. This can be conveyed by providing evidence of scale independence,availablecommercialscaledata,orbydiscussingplansformodelverificationatcommercialscale.Asalreadystatedabove, the level of detail to be provided for model verificationdepends on the impact of the model on product quality. For example,forahighimpactmodel,suchaplancouldincludetheparametersthatwillbevaried,therangesthatwillbecovered,theCQAsthatwillbetested,theacceptancecriteria,andthenumberof new independent data that will be used.

Considerations for Maintenance of ModelsThe approach of model maintenance and update can be designed relative to the importance of the model in the control strategyanditspotentialtoaffectproductquality.Clearmetrics



About the AuthorsTheodora Kourti,SeniorTechnicalDirector,GlobalManufacturing&Supply,GSK–Correspondingauthoremail:[email protected] Lepore,GlobalPharmaceuticalCommercialization,Merck,WhitehouseStation,NewJersey,USA.Lorenz Liesum,LeadPAT,GlobalPharmaEngineering,NovartisPharmaMoheb Nasr,VP,RegulatoryCMCStrategy,GSKSharmista Chatterjee,ONDQA(OfficeofNewDrugQualityAssessment)/CDER/FDA,SilverSpring,Maryland,USAChristine M.V. Moore,“ActingDirectorforONDQA”/CDER/FDA,SilverSpring,Maryland,USAEvdokia Korakianiti,EMA,London,UnitedKingdom

for model update may be established depending on the impact of themodel.Asdiscussedearlier,modelmaintenanceinformationcould include the following: risk based frequency of comparing modelpredictionwith the referencemethod, triggers formodelupdate, andapproach formodel recalibration.The reportingofmodel updates is according to regional requirements. Details aboutmodelmaintenancearedocumented in the firm’squalitysystem. |

Disclaimers1. ByE.Korakianiti:theviewsexpressedinthisarticlearethepersonalviewsof

the author and may not be understood or quoted as being made on behalf oforreflectingthepositionoftheEuropeanMedicinesAgencyoroneofitscommittees or working parties.

2. Bytherestoftheauthors:theviewsexpressedinthispaperarethepersonalviewsofthecontributingauthorsanddonotnecessarilyreflecttheofficialpositionoftheirrespectiveorganizations.

References1. ICH Q8(R2) – Pharmaceutical Development,August2009,http://www.ich.org/

fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf.

2. Kourti,T.,andDavis,B.,“TheBusinessBenefitsofQualitybyDesign(QbD),”Pharmaceutical Engineering,July/August2012,Vol.32,No.4,www.pharmaceuticalengineering.org.

3. AmEndeD.J.,Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing,Wiley2011.

4. Doyle,FrancisJ.,III,Harrison,ChristopherA.,Crowley,TimothyJ.,“HybridModel-basedApproachtoBatch-to-BatchControlofParticleSizeDistributioninEmulsionPolymerization,”Computers and Chemical Engineering,27(2003)1153-1163.

5. ICH Quality Implementation Working Group (QIWG) Points to Consider(R2),December2011,http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_9_10_QAs/PtC/Quality_IWG_PtCR2_6dec2011.pdf.

6. Uppoor,V.R.S.,“RegulatoryPerspectivesonInVitro(Dissolution)/InVivo(Bioavailability)Correlations,”Journal of Controlled Release,72(2001), pp. 127-132.

7. Nong,K.,Tan,Y-M,Krolski,M.,Wang,J.,Lunchick,C.,Conolly,R.B.,andClewell,H.J.,“BayesianCalibrationofaPhysiologicallyBasedPharmacokinetic/Pharmacodynamic Model of Carbaryl Cholinesterase Inhibition,”J. Toxicol. Environ. Health,71,(20),pp.1361-1381(2008).

8. ISPEGuideSeries:Product Quality Lifecycle Implementation (PQLI®) from Concept to Continual Improvement Part 2 – Product Realization using Quality by Design (QbD): Illustrative Example,InternationalSocietyforPharmaceuticalEngineering(ISPE),FirstEdition,November2011,www.ispe.org.

9. Kourti,T.,“PharmaceuticalManufacturing:theRoleofMultivariateAnalysisinDesignSpace,ControlStrategy,ProcessUnderstanding,Troubleshooting,andOptimization,”DavidJ.amEnde(Editor),Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing,Wiley2011.

10.Duchesne,C.,MacGregor,J.F.,“MultivariateAnalysisandOptimizationofProcessVariableTrajectoriesforBatchProcesses,Chemometrics and Intelligent Laboratory Systems,2000,51:125-137.

11.Kourti,T.,ProcessAnalyticalTechnologyandMultivariateStatisticalProcessControl. Index of Wellness of Product and Process. Part 2. Process Analytical Technology,(2005),Volume2(1),pp.24-28.

12.Flåten,G.R.,Ferreira,A.P.,BellamyL.,andFrake,P.,“PATwithintheQbDFramework:Real-TimeEndPointDetectionforPowderBlendsinaCompliantEnvironment,”Journal of Pharmaceutical Innovation,(2012),7:38-45.

13.Flores-Cerrillo,J.,andMacGregor,J.F.,“ControlofBatchProductQualitybyTrajectoryManipulationUsingLatentVariableModels,”Journal of Process Control,2004,14,pp.539-553.

14.McKeown,R.R.,Wertman,J.T.,Dell’OrcoP.C.,“CrystallizationDesignandScale-Up,”DavidJ.amEnde(Editor),Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing,Wiley2011.

15.AmEnde,MaryT.,andAlfredBerchielli,“AThermodynamicModelforOrganicandAqueousFilmCoating,”Pharmaceutical Development and Technology,10(1),pp.47-58,2005.

16.AmEnde,MaryT.,RahulBharadwajh,SalvadorGarcía-Muñoz,WilliamKetterhagen,AndrewPrpich,andPankajDoshi,“ProcessModelingTechniquesandApplicationsforSolidOralDrugProducts,”DavidJ.amEnde(Editor),Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing,Wiley 2011.

17.García-Muñoz,S.,MacGregor,J.F.,andKourti,T.,“ProductTransferBetweenSitesusingJointY_PLS,”Chemom. Intell. Lab. Syst.,2005,79:pp.101-114.

18.FDA–GuidanceforIndustry:ProcessValidation:GeneralPrinciplesandPractices,GuidanceforIndustry,U.S.DepartmentofHealthandHumanServices,FoodandDrugAdministration,CenterforDrugEvaluationandResearch(CDER),CenterforBiologicsEvaluationandResearch(CBER),CenterforVeterinaryMedicine(CVM),January2011,CurrentGoodManufacturingPractices(CGMP),Revision1.

19.Kourti,T.,“MultivariateStatisticalProcessControlandProcessControl,UsingLatentVariables,”BrownS.,Tauler,R.,Walczak,R.,(Editors),Comprehensive Chemometrics, 2009,Volume4,pp.21-54Oxford:Elsevier.

20.Wold,S.,Kettaneh-Wold,N.,MacGregor,J.F.,andDunn,K.G,“2009BatchProcessModelingandMSPC,”BrownS.,Tauler,R.,Walczak,R.,(Editors),Comprehensive Chemometrics,volume2,pp.163-197Oxford:Elsevier.

21.Miletic,I.,Quinn,S.,Dudzic,M.,Vaculik,V.,andChampagne,M.,“AnIndustrialPerspectiveonImplementingOn-lineApplicationsofMultivariateStatistics,”Journal of Process Control,2004,14(8),pp.821-836.

22.StatSoft,Inc,ElectronicStatisticsTextbook,2011, http://www.statsoft.com/textbook.

23.Jiang,H.,Huang,B.,andShah,S.,“Closed-LoopModelValidationBasedontheTwo-ModelDivergencemethod,”Journal of Process Control,19(4),2009,pp.644-655.

24.EMA(2014a):GuidelineontheUseofNearInfraredSpectroscopybythePharmaceutical Industry and the Data Requirements for New Submissions and variations,27January2014,EMEA/CHMP/CVMP/QWP/17760/2009Rev2,CommitteeforHumanMedicinalProducts(CHMP),CommitteeforVeterinaryMedicinal Products (CVMP).

25.EMA(2014b):AddendumtoEMA/CHMP/CVMP/QWP/17760/2009Rev2:DefiningtheScopeofanNIRSProcedure,5June2014,EMA/CHMP/CVMP/QWP/63699/2014,CommitteeforHumanMedicinalProducts(CHMP),Committee for Veterinary Medicinal Products (CVMP).

26.Kourti,T.,“ProcessAnalyticalTechnologyBeyondReal-TimeAnalyzers:theRoleofMultivariateAnalysis,”Critical Reviews in Analytical Chemistry,2006,36,pp.257-278.

27.Miletic,I.,Boudreau,F.,Dudzic,M.,Kotuza,G.,Ronholm,L.,Vaculik,V.,andZhang,Y.“ExperiencesinApplyingData-DrivenModellingTechnologytoSteelmakingProcesses,”Canadian Journal of Chemical Engineering,2008,86,pp.937-946.

28.Zhang,H.,andLennox,B.,“IntegratedConditionMonitoringandControlofFed-BatchFermentationProcesses,”Journal of Process Control,2004,14, pp.41-50.



CONTENT UNIFORMITY DISCUSSIONS: CURRENT USP <905> DEVELOPMENTS REGARDING <905> AND A COMPARISON OF TWO RELEVANT STATISTICAL APPROACHES TO ASSESS CONTENT UNIFORMITY

James Bergum, William Brown, Jon Clark, Thomas Parks, Thomas Garcia, James Prescott, Charles Hoiberg, Sami Patel, and Ravindra Tejwani

This article compares the performance of two statistical approaches (tolerance interval and ASTM E2709/E2810) to assess dosage unit uniformity. The potential impact that the approaches can have on the USP <905> monograph is also discussed.

AbstractThe ISPE Blend Uniformity and Content Uniformity (BUCU) Group was formed in August 2013 to address the gap resulting from the withdrawal of the draft stratified sampling guidance document. The Group’s proposed modificationsaddress the US Food and Drug Administration’s (FDA’s)concerns,includinginsufficientblendtestingandtheuseofUSP<905>forreleasetesting.TheframeworkdefinedbytheGroupprovidesflexibilityforsamplingplansandstatisticalapproaches/acceptance criteria used for the assessment of dosage unit uniformity. The following article compares the performance of two statistical approaches to assess dosage unit uniformity: One is basedonatoleranceinterval,andtheotheristheASTME2709/E2810 approach. The potential impact that the framework will haveontheUSP<905>monographisalsodiscussed.

IntroductionTheFDAwithdrew thedraftstratifiedsamplingguidancedocu-ment in August 2013 because it wasn’t consistent with its current thinking.1,2,3The reasons for its withdrawal included:

1. The desire to test triplicate blend samples to allow variance component analysis to detect non-uniform locations in the mix

2.TheacceptancecriteriawerebasedonUSP<905>,4 which is insufficientforbatchrelease

3. The desire to use of statistically based sampling plans4.Linkingtheassessmentofblendandcontentuniformitytothe

2011 validation guidance document5

ISPEsponsoredtheformationoftheGroupinJuly/August.TheGroup’s recommendations were published6, 7 and consisted of a framework that could be used to assess blend and content uniformity throughout the three stages of process validation.

Theframeworkprovidesgreaterconfidencethat futuresamplesof dosage units taken from the batch will comply with USP<905>. It also allows flexibility for the use of different samplesizesandstatisticalapproachestoassessdosageunituniformityby inserting them into the appropriate boxes. Figure 1 can be used for both Stage 1 Process Design and Stage 2 Process Qualification,andFigure2containsanapproachthatcanbeusedduring Stage 3 Continued Process Verification. The diagramscontain statistically valid sampling plans that are but one set of plausible sampling plans that can be used. They are for example purposes only and should not be considered firm numbers orrequirements.Justificationforthesamplingplansandacceptancecriteria selected should be based on stage appropriateness,existingproductandprocessknowledge,andtheconsiderationof consumer and producer risks.

Comparison of ASTM E2709/E2810 and Tolerance Interval ApproachesUsingasamplingplan that testsonedosageunit frommultiplelocations, Figure 3 contains operating characteristic (OC)curves that demonstrate the performance of a tolerance interval approach and the ASTM E2709/E2810 approach for the same level of confidence (90 percent) and probability of passing theUSPuniformityofdosageunit(UDU)test(95percent)forvarioussamplesizes.8AllcurvesaretotheleftofthatfortheUSP<905>test. As the sample size increases, estimates of both the truemean and true standard deviation become more precise causing the curves to move to the right (lowering the producer’s risk while maintainingthesame levelofconfidencewithout increasingtheconsumer’srisk).Forthesamesamplesize,thetoleranceintervalcurves are to the right of those for the corresponding (more conservative)ASTME2709/E2810curves.Althoughnotshown,OC curves for other statistical approaches could be generated and compared to the tolerance interval and ASTM E2709/E2810 approaches contained in Figure 3.

Figure 4 contains an approach that can be used for routinereleasetestingduringStage3ContinuedProcessVerificationthatdemonstratestheimpactthatdecreasingtheconfidencefrom90percent to 50 percent (while maintaining a 95 percent probability ofpassingtheUSPUDUtest)hasonthepositionofthecurves.Decreasingtheconfidencelevelto50percentstillresultsincurvesfartotheleftoftheUSPcurve.Theplansaretwo-tieredusing10dosageunitsinthefirststageand20dosageunitsinthesecondstage when needed (referred to as Tier 10:30).

Using a sampling plan that tests more than one dosage unitpersamplinglocation,Figure5showstheOCcurvesforASTME2709/E2810 when the lot mean is 100 percent. OC curves are displayed for both the example validation sampling plans using 20 or 40 locationswith three dosage units tested per location(denoted by 20 x 3 and 40 x 3, respectively) at 90 percentconfidence and the Tier 10:30 routine release sampling plan.Both the validation and routine OC curves are at 50 percentconfidencewitha95percentprobabilityofpassingtheUSPUDUtest.Since theprobabilityofpassing theUSP testdependson

58 | GLOBAL REGULATORY NEWS


ORGANIZATIONS

ASTM InternationalStandard Guide for Application of Conti-nuous Processing in the Pharmaceutical Industry 1

ASTM has released a new guide that in-troduces key concepts and principles to assist in the appropriate selection, deve-lopment,andoperationofcontinuouspro-cessing technologies for the manufacture of pharmaceutical products. Particular consideration is given to the develop-ment and application of the appropriate scientific understanding and engineeringprinciplesthatdifferentiatecontinuousma-nufacturing from traditional batch manu-facturing. Most of the underlying concepts and principles (for example, process dy-namics and process control) outlined in this guide can be applied in both Drug Substance and Drug Product processes. However, it should be recognized that inDrug Substance production, the empha-sis may be more on the chemical behavior anddynamicsinafluidphase,whereasfordrug product manufacture there may be a greater emphasis on the physical behavior and dynamics in a solid/powder format. This guide is intended to apply in the de-velopment of a new process as well as the improvement/redesign of an existing one.

PIC/SPIC/S Revises Annex 15 to PIC/S GMP Guide 2

The PIC/S Committee has adopted, bywritten procedure, the revision of Annex15 of the PIC/S GMP Guide, which willenterintoforceon1October2015,simul-taneously with the EU revision of Annex15. The PIC/S revised Annex 15 can be downloaded at their website.

AFRICAEAC Secretariat Hosts African Medicines Regulatory Harmonization Round Table 3

The East African Community (EAC) Se-cretariat hosted the EAC-Africa Medicines Regulatory Harmonization Round TableDonors Conference at its headquarters in Arusha, Tanzania. The Round Table Do-norsConference exploredways of finan-cing the African Medicines Regulatory Har-monizationInitiativeatatimewhenmany

countries are struggling to streamline me-dicine registration processes and systems. The conference also looked at plans for the future and expansion into other Regio-nal Economic Communities.

GhanaMinister of Health: “Good Governance of Pharma Sector Critical to Sustain Health Insurance Scheme” 4

Kwaku Agyeman-Mensah, Ghanaian Mi-nisterofHealth,saidthathisgovernmentiscommitted to putting the necessary mea-sures in place to ensure the sustainability of the National Health Insurance Scheme. SpeakingataforumorganizedbytheMe-dicines Transparency Alliance, a UnitedKingdom Department for InternationalDevelopment-funded initiative to improve sustainable access to medicines through increased transparency in the pharma-ceutical sector, theMinister said that themedicines component for the reimburse-ment is a burden and a key challenge and addressing it requires a multi-stakeholder approach.

NigeriaNAFDAC’s Drug Control Lab Gets International Accreditation 5

MichaelT.Harvey,theUSAgencyforInter-nationalDevelopment’sDirectorinNigeria,presented the International OrganizationforStandardizationqualitycertificatetotheNational Agency for Food and Drug Admi-nistration and Control (NAFDAC) Central DrugControl Laboratory in Yaba, Lagos.NAFDAC becomes the third national qua-lity control lab in Africa to achieve ISO 17025 accreditation with support from the Promoting the Quality of Medicines pro-gram.

AUSTRALIAConsultations on Adoption of European Union Guidelines in Australia 6

Following consultation within the Thera-peutic Goods Administration (TGA) andrelevant external stakeholders, includingindustryandconsumergroups,ending22May 2015, several European Union/ICHguidelineshavebeenadoptedbytheTGA,effective 25May 2015.More informationontheseguidelinescanbefoundatTGA’swebsite.

Australia Publishes TGA Reforms: A Blueprint for TGA’s Future — Progress Report 7

TGA Reforms: A Blueprint for TGA’s Future: Progress Report as at 31 December 2014 is a six-month progress report on reforms to the Therapeutic Goods Administration(TGA)toensurethat itremainsadaptableto community and industry expectations. The reportoutlines theTGA’sprogress inaddressing reforms recommended in TGA Reforms: A Blueprint for TGA’s Future (the Blueprint). The report provides an overview oftheTGA’sprogressinrespondingtotheblueprintrecommendations,including:

} Progressto31December2014(recommendationscompleted,inprogress,andthosewithpotentialdelays)} Expectedbenefitsfromtheblueprint

reforms} Major outputs delivered to 31 December2014andoutputstobe delivered in the six months to 30June2015,foreachblueprintrecommendation

TGA Makes GMP Clearance Application Process Improvements 8

The Therapeutic Goods Administration(TGA) has experienced a significant in-crease in the totalnumberofGMPClea-rance Applications, from approximately2,500 in 2010 to more than 4,000 in2014/2015. This has placed significantpressureontheTGA’sexistingresources;as a result, it is currently not able toconsistently meet target timelines. To im-proveitsabilitytomeetdemand,theTGAis reforming some processes, includingthecollectionofperformancedata,whichwill enable it to better understand ineffi-ciencies. This information will be used to inform consultation with stakeholders.

ASIAChinaCFDA Issues 90 Industry Standards for Medical Devices 9

The China Food and Drug Administration (CFDA) recently issued Announcement Number8of2015,whichreleased90in-dustrystandardsformedicaldevices,such

GLOBAL REGULATORY NEWS } 59


as “Water for Hemodialysis and RelatedTherapies.” These standards contain 14mandatory industry standards and 76 re-commendedindustrystandards,includingimplants for surgery, medical electricalequipment, in vitro diagnostic reagents,and dentistry. The issuance of these stan-dards will further improve the medical de-vicestandardssystemofChina,help im-provethequalityofmedicaldevices,andpromote the sound development of the medical device industry.

IndiaBar Coding of Drugs Becomes Mandatory 10 The government has mandated the bar coding of mono cartons of drugs shipped out of India beginning in July as an addi-tional measure to ensure that medicines manufactured illicitly in other countries are notpassedoffasmade in India.Thebarcoding ofmono cartons,which hold pri-marypacksofdrugs,willenable themtobe traced back to the source. Drugmakers will also have to maintain evidence in a central portal controlled by the Indian go-vernment.

India Considers Joining PIC/S 11

The Indian Commerce Ministry called a meeting with small- and medium-sizedpharmaceutical companies to decide whether India should become part of mul-tinational regulatory regime PIC/S. Many fear that stricter standards necessitated by membership could drive up costs and make them uncompetitive, but being apart of the new system could make it ea-sierforIndianfirmstoaccesslucrativeex-port markets.

South KoreaKim Seung-hee to Lead Food and Drug Safety Ministry 12

Cheong Wa Dae appointed Kim Seung-hee as the new minister for food and drug safety.Priortothisappointment,Kim,61,served as vice minister.

EUROPEEuropean UnionPreventing Medication Errors in the European Union 13

TheEuropeanMedicinesAgency, onbe-

half of the European Union (EU) Regu-latory Network, has released two draftgood-practice guides that aim to improve the reporting, evaluation, and preventionof medication errors by regulatory au-thorities and the pharmaceutical industry throughouttheEU.

New EU Rules on Human Tissues and Cells Increase Patient Safety 14

The European Commission has adopted two sets of rules for human tissues and cells to protect patients in the European Union (EU) by ensuring high-quality andsafety standards.The first setsout tech-nical requirements that facilitate the tra-cing of all tissues and cells from donor to recipient and vice versa. This will happen viaaSingleEuropeanCodeandEUCom-mission-hosted IT platform that will gua-rantee the uniform labeling of all tissues andcellsdistributedintheEU.Inthecaseofasafetyalert,thislabelwillensurethatall those who received tissues and cells from the same donor can be traced and treated as needed. It will also allow for unused tissues and cells to be discarded. The second directive covers imports and sets out procedures for making sure that tissues and cells from emerging economy countries meet the same safety and quality standardsasthoseprocured,processed,anddistributedintheEU.Theimplemen-tation of these rules will ensure that, re-gardlessof theirorigin, thesetissuesandcellsaresafeforEUrecipients.

EMA Issues Reflection on Chemical Structure and Properties to Be Considered for the Eva-luation of New Active Substance Status 15

The European Medicines Agency (EMA) has releasedadraft reflectionpaper thatoutlines the chemical structure and pro-perties criteria to be considered by its Committee for Medicinal Products for Hu-manUsefortheevaluationofanewactivesubstance status. The paper also outlines the elements that applicants are required to include intheirmarketingauthorizationapplications in support of their new active substance status claims. Stakeholders have until 24 July 2015 to provide theircomments to [email protected].

EMA Publishes 2014 Annual Report: Progress in Science, Medicines, Health 16

The annual report published by the Euro-pean Medicines Agency (EMA) focuses on its key priorities, including the evaluationof medicines and supporting the research and development of new and innovative medicines. In 2014, the EMA recom-mended 102 new medicines for marketing authorization, both for human (82) andanimal (20) use. The number of applica-tions for orphan designation increased by 63percentandrequestsforscientificad-vice for human medicines by 16 percent compared to 2013. Developers of medi-cines are making more and better use of the EMA’s tools aimed at helping patients getaccesstoeffectiveandsafemedicinesmore quickly.

New Service Will Improve Safety Monitoring of Medicines and Simplify Pharmacovigilance Activities for Companies17

The European Medicines Agency has pu-blished a list of active substances and a re-ference to the journals that will be covered by its new medical-literature monitoring service. This service will start with a limited number of active substances on 1 July 2015 and be fully rolled out in September 2015.Aguide,atrainingvideo,andado-cument detailing the inclusion and exclu-sion criteria to be used when screening the literature are also available on a dedicated website.

EU Publishes Inspection of Tissue and Cell Procurement and Tissue Establishments: Operational Manual for Competent Authori-ties 18

This manual is intended to support member states that are establishing such regulato-rysystemsforthefirsttime.Itshouldalsopromote standardization of regulatorysystems that are already well established intheEuropeanUnion(EU).Thescopeofthis manual reflects these related direc-tives on the quality and safety of human tissues and cells used for transplantation or in assisted conception. This manual has been established for information purposes only. It has not been adopted or in any way approved by the European Commission. It is not legally binding.



EMA Solicits Comments on Concept Paper on New Guidance for Importers of Medicinal Products 19

The increased complexity of supply chains and the observation that most GMPnon-compliance statements uploaded to EudraGMDPpertain to third-countryma-nufacturers have created new areas where further guidance is desired by both the regulatorsandthe industry; this includes,in particular, the requirements applicableto importers of medicinal products and concerningtheapplicationofGMPrequi-rements,whicharetraditionallyorientedtoactivities performed at true manufacturing sites. In response, the GMP/GDP IWGagreedtodraftaspecificguidanceforim-portauthorizationholders.Thisdocumentmost likely would take the form of a new annex (Annex 21). The scope of the project will be focused on importation activities not addressedindetailintheGMPguideandannexes, taking intoconsideration recentchangesinGMPchaptersandannexesaswell as changes in other regulatory docu-ments.

FinlandFimea Presents Opinion on Interchangeability of Biosimilars 20

Finnish Medicines Agency (Fimea) has presented its position on interchangeabi-lity of biosimilars licensed in the European Union.Theposition isarecommendationto the local health care system. It has been argued that a switch from an original biolo-gical medicinal product (reference product) to its biosimilar copy is risky. The recom-mendation of Fimea concludes that:

} Switches between biological products are common and usually not problema-tic (in the context of hospital tendering processes,forexample).} Forthetimebeing,thereisnoevidenceofadverseeffectsduetotheswitchfrom a reference product to a biosimilar.} The theoretical basis of such adverse effectsisweak.} Theriskofadverseeffectscanbe

expected to be similar to the risk asso-ciated with changes in the manufactu-ring process of any biological product.

} Automatic substitution at the pharma-cy level is not within the scope of this recommendation.

Therefore,thecurrentpositionofFimeaisthat biosimilars are interchangeable with their reference products under the super-vision of a health-care person.

NORTH AMERICACanadaHealth Canada and US Food and Drug Administration Joint Public Consultation on International Conference on Harmo-nisation Guidelines for Registration of Pharmaceuticals for Human Use 21

Prime Minister Stephen Harper and USPresidentBarackObamaannounced thecreationoftheCanada-UnitedStatesRe-gulatory Cooperation Council (RCC) to better align the two countries’ regulatory approaches, where possible. Under theRCCinitiative,HealthCanadaandtheUSFood and Drug Administration (FDA) are holding joint public consultation meetings on International Conference on Harmoni-sation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Hu-manUseguidelinescurrentlyunderdeve-lopment. The aim of this initiative is to hold public consultation meetings prior to each biannual ICH face-to-face meeting in order to seek input on areas of current regulato-rydisharmonyandwhereharmonizedICHguidelineswould be beneficial. Stakehol-der input received through this initiative will be considered in current or future guideline development. Health Canada also intends to use these opportunities to better un-derstand areas where Canadian require-mentsmaydifferfromthoseinplaceintheUnited States, with a view to minimizingthesedifferences.

Guidance Document on the Application for a Certificate of a Pharmaceutical Product 22

Health Canada has issued a document that clarifies the requirements to bemetfortheissuanceofaCertificateofaPhar-maceutical Product (CPP) and describes the procedure for the request of a CPP. A CPP is issued for human drugs (pharma-ceutical, biological, and radiopharmaceu-tical) as well as veterinary drugs (food-pro-ducing animals and non-food-producing

animals). Since the Food and Drugs Act and Regulations apply also to veterinary pharmaceuticals intended for non-food-producinganimals, theymustbe fabrica-tedaccordingtoGMPrequirements,and,consequently,HealthCanadachooses toissue CPPs for these pharmaceutical pro-ducts. Products falling under the Natural Health Products (NHP) framework are ex-cluded from the scope of this document.

Minister Ambrose Launches New Drug and Health Product Inspections Database, Underlines Commitment to Transparency 23

Health Minister Rona Ambrose today launched the Drug and Health Product Ins-pectionsDatabase,anewonlineresourcedesigned to provide ready access to infor-mation on inspections of companies that manufacture and sell drug products for the Canadian market. Canadians can search the site for information on inspection fin-dings, includingwhichcompanieshaveagood history of meeting safety and qua-lity standards and which do not. The tool provides centralized access to plain-lan-guage, timely informationon inspections.Canadians can use this information to have a better understanding of how Health Canada is enforcing – and how companies are meeting – Canada’s high standards for drug safety and quality.

Health Canada Updates Guidance on Medical Device Compliance and Enforcement 24

HealthCanadahasupdateditsGuidanceon Medical Device Compliance and Enfor-cement. This document outlines the stra-tegy and provides guidance for the medi-cal-device industry on Health Canada’s compliance and enforcement activities. This version of the document includes updated Web links and the incorporation of changes to the establishment of licen-sing provisions, which recently occurreddue to the cost-recovery initiative.

United StatesRisk Evaluation and Mitigation Strategies: Modifications and Revisions Guidance for Industry 25

The US Food and Drug Administration(FDA) has issued a guidance document that provides information on how it will de-fineandprocesssubmissionsfromappli-



5. Develop and improve predictive modelsofsafetyinhumans,includingnonclinical biomarkers.

6. Improve clinical-trial statistical analyses forsafety,includingbenefit-riskassessment.

7.Investigateclinicalbiomarkersofsafety,includingstandardsforqualification.

The Federal Register notice requests that interested parties submit descriptions of their ongoing research and initiatives re-lated to the seven areas of need, espe-cially the identified priority projects, andindicate their interest in working with the FDA to address these needs. Comments can be submitted to the docket and this email address: [email protected].

FDA Releases New Biosimilar Guidance to Help Manufacturers Develop More Treatment Options 28

The US Food and Drug Administration(FDA) released four guidance documents for industry – useful tools to help manu-facturers navigate the new terrain of bio-similar development. “Scientific Conside-rationsinDemonstratingBiosimilaritytoaReferenceProduct”assistscompanies indemonstrating that a proposed product is indeed biosimilar to an existing biologic product and intended to provide clarity to manufacturers about the expectations for abiosimilardevelopmentprogram.“Qua-lity Considerations inDemonstratingBio-similarity of a Therapeutic Protein Product to a Reference Product” focuses on theanalytical studies that demonstrate that theproduct is “highly similar” to anexis-tingbiologicalproduct,whichsupportsthedemonstrationofbiosimilarity.“Biosimilars:Questions and Answers Regarding Imple-mentationoftheBiologicsPriceCompeti-tionandInnovationActof2009”answerscommon questions about the biosimilar development and application process and contains information intended to provide a better understanding of the law that allows biosimilar development. A fourth,still in draft form, “Biosimilars: AdditionalQuestions and Answers Regarding Imple-mentationof theBiologicsPriceCompeti-tionandInnovationActof2009,”answersa variety of additional questions that have

arisen regarding the biosimilar development process.

FDA Withdraws 37 Guidance Docs that Were Never Finalized 29

The US Food and Drug Administration(FDA) isannouncingthewithdrawalof47draft guidance documents that published before31December2013,andhavene-verbeenfinalized.TheFDA is taking thisactiontoimprovetheefficiencyandtrans-parency of the guidance development process. The names of the withdrawn guidance documents can be found in the Federal Register notice announcing this action.

Revised Recommendations for Reducing the Risk of Human Immunodeficiency Virus Transmission by Blood and Blood Products: Draft Guidance for Industry 30

ThisguidancedocumentprovidestheUSFood and Drug Administration’s (FDA’s) re-vised donor deferral recommendations for individuals with increased risk for transmit-ting human immunodeficiency virus (HIV)infection. The FDA is also recommending that organizations make correspondingrevisions to donor education materials,donorhistoryquestionnaires,andaccom-panyingmaterials,alongwith revisions todonor requalification and product mana-gement procedures. This document also incorporates certain other recommenda-tions related to donor education mate-rials and testing contained in the memo-randum to blood establishments entitled “Revised Recommendations for the Pre-ventionofHumanImmunodeficiencyVirus(HIV) Transmission by Blood and BloodProducts,” dated 23 April 1992. Whenfinalized,itwillsupersedethe1992bloodmemo. The recommendations contained in this document apply to the collection of blood and blood components, includingsource plasma.

Updated Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use 31

The US Food and Drug Administration(FDA) is amending the regulations appli-cable to blood and blood components,including source plasma, to make thedonor eligibility and testing requirements

more consistent with current practices in the blood industry, to more closely alignthe regulations with current FDA recom-mendations, and to provide flexibility toaccommodate advancing technology. In order to better ensure the safety of the nation’s blood supply and to help protect donorhealth,theFDAisrevisingtherequi-rements for blood establishments to test donors for infectious disease and to deter-mine that donors are eligible to donate and that donations are suitable for transfusion or further manufacture. The FDA is also requiring establishments to evaluate do-nors for factors thatmayadverselyaffectthe safety, purity, and potency of bloodand blood components or the health of a donor during the donation process. Accor-dingly,theseregulationsestablishrequire-mentsfordonoreducation,donorhistory,and donor testing. These regulations also implement a flexible framework to helpboththeFDAandindustrytomoreeffec-tively respond to new or emerging infec-tiousagentsthatmayaffectblood-productsafety.

FDA issues “Established Conditions: Repor-table CMC Changes for Approved Drug and Biologic Products: Guidance for Industry” 32

The US Food and Drug Administration(FDA) has developed a guidance docu-ment to address the lack of clarity with respect to what chemistry, manufactu-ring, andcontrols (CMC) information in amarketing application constitutes an esta-blishedconditionora“regulatorycommit-ment”that,ifchangedfollowingapproval,requiresreportingtotheFDA.Clarificationregarding which elements of the CMC information constitute established condi-tions and where in an application these ele-ments are generally expected to be descri-bed should lead to a better understanding that certain CMC changes can be made solely under the Pharmaceutical Quality System (PQS) without the need to report to the FDA. For those changes that do require reporting, a better understandingof established conditions could allow for a more effective post-approval submissionstrategy by the regulated industry. Speci-fically, thisguidancedocumentdescribesthose sections in a common technical do-cument (CTD): a formatted application that typically contains information that meets

GLOBAL REGULATORY NEWS } 63


thedefinitionofestablishedconditionsandprovides considerations for managing and communicating changes to the approved established conditions over the life cycle of an approved product.

SOUTH AMERICAVenezuela New Program Unveiled to Combat Medicine Shortages in Venezuela 33

VenezuelanHealthMinisterHenryVenturaannounced a new program to improve consumer access to medicines through thecoordinatedparticipationofover7,000pharmacies nationwide. The denominated Integral System for Access to Medicines (SIAMED)prioritizespatientswhohaveill-nessesthatrequireregulartreatment,suchasheartdisease,diabetes,andneurologi-cal disorders.

References1. ASTM,www.astm.org/standards/E2968.htm?A.2. PIC/S,www.picscheme.org/news.php#n79andwww.picscheme.org/bo/commun/upload/document/ps-inf-

11-2015-pics-gmp-revised-annex-15.pdf. 3. PharmaAfrica,www.pharmaafrica.com/eac-secretariat-hosts-african-medicines-regulatory-harmonization-

roundtable.4. PharmaAfrica,www.pharmaafrica.com/ghana-good-governance-of-pharma-sector-critical-to-sustain-

health-insurance-scheme.5. PharmaAfrica,www.pharmaafrica.com/nafdacs-drug-control-lab-gets-international-accreditation.6. AustralianTherapeuticGoodsAdministration,www.tga.gov.au/consultation/consultations-adoption-

european-union-guidelines-australia-outcome-previous-consultation.7. AustralianTherapeuticGoodsAdministration,www.tga.gov.au/publication/tga-reforms-blueprint-tgas-

future-progress-report-31-december-2014.8. AustralianTherapeuticGoodsAdministration,www.tga.gov.au/gmp-clearance-application-process-

improvements.9. ChinaFoodandDrugAdministration,eng.sfda.gov.cn/WS03/CL0757/117359.html.10. TheEconomicTimes,economictimes.indiatimes.com/articleshow/46901956.cms?utm_

source=contentofinterest&utm_medium=text&utm_campaign=cppst.11. TheEconomicTimes,economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/

commerce-ministry-to-talk-to-industry-bodies-to-take-a-call-on-joining-pharma-regulator-pics/articles-how/47066692.cms.

12. TheKoreaTimes,www.koreatimes.co.kr/www/news/people/2015/04/178_176634.html.13. EuropeanMedicinesAgency,www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/

news/2015/04/news_detail_002307.jsp&mid=WC0b01ac058004d5c1.14. EuropeanCommission,ec.europa.eu/health/blood_tissues_organs/docs/20150409_midday_en.pdf.15. EuropeanMedicinesAgency,www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/

news/2015/04/news_detail_002319.jsp&mid=WC0b01ac058004d5c1.16. EuropeanMedicinesAgency,www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/

news/2015/04/news_detail_002320.jsp&mid=WC0b01ac058004d5c1.17. EuropeanMedicinesAgency,www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/

news/2015/05/news_detail_002325.jsp&mid=WC0b01ac058004d5c1.18. EuropeanCommission,ec.europa.eu/health/blood_tissues_organs/docs/manual_11_en.pdf.19. EuropeanMedicinesAgency,www.ema.europa.eu/docs/en_GB/document_library/Scientific_guide-

line/2015/05/WC500187398.pdf. 20. FinnishMedicinesAgency,www.fimea.fi/whats_new/1/0/are_biosimilars_interchangeable.21. HealthCanada,www.hc-sc.gc.ca/dhp-mps/consultation/drug-medic/ich_fda_rcc_ccr_notice_avis-eng.php.22. HealthCanada,www.hc-sc.gc.ca/dhp-mps/compli-conform/licences/directives/gui-0024_doc-eng.php.23. HealthCanada,news.gc.ca/web/article-en.do?nid=962459.24. HealthCanada,www.hc-sc.gc.ca/dhp-mps/compli-conform/info-prod/md-im/gui-0073-eng.php.25. USFoodandDrugAdministration,www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/docu-

ments/document/ucm441226.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery.26. USFoodandDrugAdministration,http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedi-

calProductsandTobacco/CDER/UCM442666.pdf.27. USFoodandDrugAdministration,www.fda.gov/downloads/Drugs/ScienceResearch/UCM438138.pdf.28. USFoodandDrugAdministration,blogs.fda.gov/fdavoice/index.php/2015/05/biosimilars-new-guidance-

from-fda-to-help-manufacturers-develop-more-treatment-options.29. USFederalRegister,s3.amazonaws.com/public-inspection.federalregister.gov/2015-10477.pdf.30. USFoodandDrugAdministration,www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/

document/ucm446580.pdf.31. USGovernmentPublishingOffice,www.gpo.gov/fdsys/pkg/FR-2015-05-22/html/2015-12228.htm.32. USFoodandDrugAdministration,www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor-

mation/Guidances/UCM448638.pdf.33. Venezuelanalysis.com,venezuelanalysis.com/news/11353.

68 | PRODUCTION SYSTEMS


Table A Comparison between stainless steel vessel and single-use freeze-thaw operations

Traditional Bulk Freeze Operation Criteria Single-use Bulk Freeze Operation

Complex vessel tracking system Logistics Simpler vessel tracking system by incorporating one-way logistics

Bioburden potential in long term storage of empty vessels

Sterility BPCs are gamma sterilized by manufacturer and only stored until use

Space requirements for the long term storage of empty vessels

Space Space for carriers and inventory of packaged BPCs prior to use

Extensive labor with preparation of vessel for use (CIP, SIP, etc.)

Operating cost Labor with preparation of carriers and installation of BPCs at use time

Expense and long lead times for purchasing stainless steel vessels

Capital cost Carriers for holding the BPCs have relatively shorter lead times and lower costs

Utility systems to clean and steam in addition to the process water

Capital cost Utility system for process water

Energy and cleaning chemicals Operating cost Maintain inventory of packaged BPCs prior to use

Treatment or disposal of cleaning chemical solutions

Operating cost Disposal of used BPCs

Vessel validation can be inconsistent for older vessels

Quality/change control Change control process for material improvements or manufacturing changes in single-use components and BPCs

Safety concern with vessel handling (size and weight)

Safety Relatively lightweight BPC components

Table B Benefits that can be realized from the use of single-use BPCsEconomic Process Utilities/Waste Validation Other

Advantage } Less Capital} Less Materials} Less Labor} Less Space} Faster builds /

mods

} Reduced down time} Quicker set-up

time} Quicker batch turn} Increased flexibility} Closed systems} Rapid

configuration} Development of

integrated systems

} Less water used} No steam used} Reduced electrical} Reduced waste

water

} No CIP} No SIP

} High level of innovation} Large potential for

improvements} Amenable to Lean

Disadvantages Consumables Scalability Waste treatment – Neutral

E / L studies Supply chain

4.Mitigationofbatchlossesduetoparticulates,foreignobjects,leaksfromgaskets,orvalvesontanks

5. Elimination or reduction of tank management activities globally6. Inventory of single-use containers at drug substance warehouse,resultinginlocalandquickavailabilityforstorageand transport

7. Reduction of lead times for purchase of single-use containers relatedtofabricationandtheinstallationqualification/operationalqualification(IQ/OQ)ofstainlesssteeltanks

As with the implementation of any new technology, there areprecautionary measures that should be considered in order to minimize the risksandgain theadvantages.Possibleconcernsare:

} Howisthesterilityofthesingle-useBPCachievedand maintained?

Single-useBPCsareoftenmanufacturedaspartofaclosed-systemassembly.Manyassembliesaregammasterilized.Oncesterilized,theclosedsystemwillremainsterileunlessit is opened. Since the assemblies typically need to be

PRODUCTION SYSTEMS } 69


connectedtootherprocessequipment,theyincludesterileconnectors that allow one to make these connections and retain the sterility at the connection and therefore for the entire assembly.

} Willexposuretothefreeze-thawconditionscausetheBPCtodevelop leaks that compromise sterility?

Validationofsingle-usecontainersisrequiredtoconfirmtheapplicability of components under operating conditions. While components in single-use systems may seem more limited underextremeconditions,stainlesssteelsystemsoftencontaingasketsandelastomerswithdifferentheating/coolingcharacteristics.Theexpansion/contractioncoefficientsofsteel/plastic interfaces can lead to leaks and sterility issues. Testingoffinalpackagingvs.establishedATSMInternationaland Department of Transportation standards is recommended.

} WillthevalidationofthefilmandothercomponentsoftheBPCdelayprojects?Validation is an important factor that applies in all situations where single-use components are integrated into a process. Validationofcomponentsthatareappliedinfreeze-thawprocesses needs to follow similar protocols. A well-planned implementation program should address the validation issues for material compatibility and applicability of single-use componentsundertheextremeconditionsofthefreeze-thawoperation. Extra care and planning should be taken to study anyeffectsoflight,elastomers,orpHchangesthatoccurduring storage and shipping in single-use containers.

} WhattemperaturescanBPCshandle? Thisishighlydependentonthefilmtype.Mostofthesingle-usefilmsavailabletodayaremultilayered.Theglasstransitiontemperature(Tg)stateofthefilmvariesdependingonthemakeupofthemultilayeredfilm.Typicalsingle-usesystemsare validated for operation at the normal biopharmaceutical operatingtemperaturesranginganywherefrom4ºCto40ºC.Sincemanyfreezeprocessesneedtheproducttobeat-80ºC,itisimportanttoselectcomponentsthatarecompliant and tested at this lower temperature. The polymers thatmakeupthefilmandothersingle-usecomponentsarerecommended to have cold crack temperatures that reach atleast-80ºC.BPCsmadefromfilmsthatcanhandlethesetemperatures are starting to become available for commercial useintheseapplications.Thesecriteriacanbeconfirmedin handling tests where the assemblies go through several 48-hourcyclicprocessesattemperaturecyclesrangingfrom-85ºCto+40ºC.

} WhatpressurescanBPCshandle? ThefilmthatmakesuptheBPCscantypicallyhandleonlyafewpoundspersquareinch(psi)ofpressure.However,thereusablecontainmentvesselforthefilmisdesignedtosupportthefilmandhandlethepressurerequirementsoftheprocess.When these two components are properly designed to work witheachother,thepressurecapabilityismetwitheaseanddoes not cause increased risk.

} Sincegammairradiatedassemblies/BPCshaveaspecificshelflife,howcantheriskofhavingtodisposeofunusedbutexpired products be eliminated?

Normally the shelf life is several times longer than the delivery time for the assembly. The inventory kept on hand in today’s just-in-time environment is usually well within the shelf-life limit.Thecriticalfactorindefiningthelevelofinventoryishowquickly the next order can be delivered. Having an established deliverytimefromyourvendor,byagreement,experience,orboth,isthebestwaytomakesureyouhaveenough(butnottoo much) single-use products for your operation’s needs.

ConclusionsThe freeze-thaw process entails complex operations that aretime-sensitive andcanbe logistically challenging.However, theprocessprovidesflexibilitythatisincreasinglyimportantintoday’sversatile and fast-changing operational arenas. Incorporating a freeze-thawprocesswithmultiple locations isanundertakingthatrequiresexperiencedresources,capital,andawell-executedplan to manage all the interconnected disciplines. The routing and management of reusable stainless steel vessels in the traditionalfreeze-thawprocessrequireasynchronizedoperationthat is very sensitive to deviations. A deviation in one part of the cycle can propagate throughout the whole operation. This can quicklydestabilizeanoperationandrequireimmediateattentionfrom multiple resources. Incorporating single-use disposable equipment helps break the chain of propagating deviations and reliance on sole-sourced tank manufactures. Having a source of ready-to-use single-use freeze-thaw vessels minimizes the riskofdelaysandcontaminationof thebulk freezeprocess.Useofsingle-use technology in the bulk freeze supply chain can leadto smooth and efficient operations while minimizing the costsassociated with reusable stainless steel systems. |

References1. Goldstein,Adam,“FullScaleImplementationforaDisposableBulkFreeze

ApplicationCaseStudy,”CHIPepTalkConferenceheldatPalmSprings,California,24–25January2013.GraphicsarecourtesyofJoeyTeshimaofGenentech,PTSO-SupplyPlanning.

2. Samavedam,R.,Goldstein,A.,andSchieche,D.,“ImplementationofDisposables:ValidationandOtherConsiderations,”American Pharmaceutical Review,2006,Vol.9,No.5,pp.46–51.

3. Bieger,Boris,“DevelopmentandImplementationofDisposableBagswithaFreeze/Thaw-UnitforFastandControlledFreezing/ThawingofDrugSubstance,”8thAnnualBioProcessInternationalConferenceheldatPrague,18–19 April 2012.

78 | INFORMATION SYSTEMS


development,andcontrollingRMvariationatthesupplier.Theseinterventionswilltakeplaceinmultiplestagesandaffectmultipleknowledgeelementsbyeffectivelyemployingbigdatacapturingand analytics. |

References1. Lanan,M.“QbDforRawMaterials.”In Quality by Design for

Biopharmaceuticals,editedbyA.S.RathoreandR.Mhatre,255–86.Hoboken:WileyInterscience,2009.

2. Wang,W.,A.A.Ignatius,andS.V.Thakkar.“ImpactofResidualImpuritiesandContaminantsonProteinStability.”Journal of Pharmaceutical Sciences,103,no.5(2014):1315–1330.

3. Ramanan,S.andG.Grampp.“PreventingShortagesofBiologicMedicines.”Expert Review of Clinical Pharmacology,7,no.2(2014):151–159.

4. Zhou,S.,C.Schöneich,andS.Singh.“BiologicsFormulationFactorsAffectingMetalLeachablesfromStainlessSteel.”AAPS PharmSciTech,12,no.1(2011):411–421.

5. Kumar,S.,S.Zhou,andS.K.Singh.“MetalIonLeachatesandthePhysico-ChemicalStabilityofBiotherapeuticDrugProducts.”Current Pharmaceutical Design,20,no.8(2014):1173–1181.

6. Majumdar,S.etal.“EvaluationoftheEffectofSyringeSurfacesonProteinFormulations.”Journal of Pharmaceutical Sciences,100,no.7(2011):2563–2573.

About the AuthorsTing Wang, PhD, is a senior engineer in Process Development at Amgen. She is responsible for implementing an internal raw-material information system to enable automated capture of supplier data as part of the knowledge-management system for Amgen products’ life-cycle management. Collaborating with cross-functional teams,sheprovidesscientificandtechnicalinputintheareasofmultivariateanalysisandpredictivemodelingtowardsunderstandingandmitigatingraw-materialvariationsandrisk.Dr.Wang’sbackgroundisinpharmaceuticalsciences;sheholdsaDoctoratefromtheUniversityofMarylandatBaltimore.Herresearchinpharmaceuticalexcipientvariabilityhasbeenrecognizedthroughseveralawardsandprojects,includingUSPharmacopeia(USP)fellowships(in2011and2012), anOutstandingContributedPaperAward(RegulatoryScience,AAPS,2010),andanInternationalPharmaceuticalExcipientCouncil(IPEC)foundationaward(2012).Dr. Wang is a member of the International Society for Pharmaceutical Engineering (ISPE) and of the American Association of Pharmaceutical Scientists (AAPS).

Bryan LoozeisaseniorengineerwholeadsimplementationoftheReal-TimeMultivariateStatisticalProcessMonitoringprogramforcGMPuseatAmgen’scommercialdrug-substancemanufacturingfacilities.HeholdsaBachelorofScienceinchemicalengineeringfromtheUniversityofMassachusettsandisamemberoftheInstituteofElectricalandElectronicsEngineers(IEEE).Loozesupportsraw-materialdataintegrationandadvancedcontrolmethods,suchasmodelpredictivecontrol.Hehaspublicationswithinthemultivariatemonitoringfield.

Tony WangiscurrentlyaseniorengineerintheDigitalIntegrationandPredictiveTechnologiesgroupatAmgen.Heisresponsibleformultivariatedataanalysis,raw-materialprocessandmethodoptimization,computermodeldevelopment,includingmodelpredictivecontrol,andfurtheringPATwithRamanandNIRtechnologies.Previously,heworkedasacell-cultureengineerinProcessDevelopmentandasaprocessengineerinFacilityEngineeringatAmgen.WangisachemicalengineerbytrainingandalicensedProfessionalEngineer(PE)withAPEGA.HeholdsaBachelorofScienceinchemicalengineeringandaMasterofScienceinbiomedicalengineeringfromtheUniversityofCalgaryinCanada.

Duncan Low, PhD,isscientificexecutivedirectorinMaterialsScience,OperationsTechnology.HejoinedAmgenin2003andisanactivememberofseveralindustrygroupsandscientificadvisoryboards,includingtheISPEExecutiveCommitteeforPAT,theASTME55ExecutiveCommitteedevelopingconsensusstandardsfortheManufactureofPharmaceuticalProducts,andtheExtractablesandLeachablesSafetyInformationExchange(ELSIE).Dr.Lowisco-authoroftheParenteral Drug Association Technical Report 66: Application of Single Use Systems in Pharmaceutical Manufacturing. He holds a Master’s degree in biochemistry fromtheUniversityofCambridgeandaDoctorateinmicrobiologyfromtheUniversityofGlasgow.

Cenk Undey, PhD,leadstheDigitalIntegrationandPredictiveTechnologiesgroupasexecutivedirectorforProcessDevelopmentOrganizationatAmgen.Hisgroupisresponsibleforintroducingtransformationaldatamanagementandmodeling(includingmultivariatestatistical,firstprinciples,computationalfluiddynamics,andfiniteelement)technologiesacrossproductlifecyclestoaccelerateprocessdevelopmentandimprovemanufacturingperformance.Thegroupalsofocusesonraw-material-variation management with suppliers with the goal of identifying and controlling variability. His team has implemented the Real-Time Multivariate Statistical ProcessMonitoringtechnologyincGMPforuseinmanufacturingsupport,aprojectforwhichtheyreceivedtheinternationalCIO100AwardinHealthcarein2013forAmgen.Dr.UndeyisasteeringcommitteememberofthePATindustrygroupPharmaceuticalProcessAnalyticsRoundtable(PPAR)andhasco-authoredtwobooksandmanyarticlesandbookchaptersregardingPATandvariousprocess-modelingtechnologiesinbiotechnologyandpharmaceutical.HeholdsaBachelorofScience,aMasterofScience,andaDoctorate,allinchemicalengineeringfromIstanbulUniversityinTurkey.

7. Seidl,A.etal.“Tungsten-InducedDenaturationandAggregationofEpoetinAlfaDuringPrimaryPackagingasaCauseofImmunogenicity.”Pharmaceutical Research,29,no.6(2012):1454–1467.

8. Sharma,B.“ImmunogenicityofTherapeuticProteins.Part2:ImpactofContainerClosures.”Biotechnology Advances,25,no.3(2007):318–324.

9. Wang,T.etal.“TheCreationofanExcipientPropertiesDatabasetoSupportQualitybyDesign(QbD)FormulationDevelopment.”American Pharmaceutical Review,16,no.4(2013):16–25.

10. Undey,C.etal.“ProcessAnalyticsExperiencesinBiopharmaceuticalManufacturing.”European Pharmaceutical Review,17,no.3(2012):22–29.

11. Wang,T.“UnderstandingandPredictingPharmaceuticalExcipientVariabilityandPerformanceUsingSpectroscopicandMultivariateAnalysisApproaches.”(DoctoralDissertation,UniversityofMaryland,2014).

12. Skibsted,E.“ProcessAnalyticalTechnologyAppliedtoRawMaterials.”In Process Analytical Technology Applied in Biopharmaceutical Process Development and Manufacturing,editedbyC.Undeyetal.127–141.BocaRaton:CRCPress,2012.

AcknowledgementTheauthorswouldliketothankJohnMason,TimHanson,RonForster,ChristopherGarvin,MattDeMonte,andSinemOrukluatAmgenInc.,andDavidKolwyckatBiogenInc. for their contributions at various stages of eData-exchange implementation.

84 | FACILITIES AND EQUIPMENT


1. Cleaning (degreasing) with isopropyl alcohol/water (70/30)2. Complete immersion in the derouging solution at the

temperature indicated in Table C for six hours3.Rinsingwithdemineralizedwater4.Dryinginair

The corrosion rate was calculated after 15 cycles (Figure 5). For all derouging solutions it is smaller than 0.004 mm/a, exceptforsolutionE,whichhasacorrosionrateof0.3mm/a.Neutralsolution D exhibits the smallest corrosion rate, of slightly over0.001 mm/a.

The small corrosion rate of neutral solution D compared with the acid derouging solutions is therefore consistent with the results of thederougingtestsonatesttank(seepart2,sectionon“InfluenceofRougeCoatingsonCleaningEfficiency”).Thismeansthattheneutral solution has higher selectivity and derouging efficiencywhile at the same time causing less material removal.

The metal surfaces before and after the 15 derouging cycles are illustrated in Figure 6 to Figure 10. For themost part, theelectropolished surface was changed only slightly by the treatment: defects and grain boundaries are still clearly discernible. In the caseofsolutionB,whichisbasedoncitricacid,oxalicacidandsulfuricacid,thegrainboundariesareattackedbutnofurtherattackofthegrainsthemselvesisobservedintheinvestigatedzone.

InthecaseofsolutionE,whichisbasedonhydrofluoricacid,thegrains are attacked so intensively that it was no longer possible torelocatethesamesiteafter the15derougingcycles.Locally

grains are completely removed (Figure 10b). The surface exhibits matting.

After the treatmentwith solutions B andD, isolated stains arepresent on the metal surfaces.

AsignificantchangeofsurfaceroughnessasrepresentedbytheRavaluecouldnotbeobservedafterthetreatment,eveninthecaseofthe sample most severely attacked by solution E (Figure 11).

WiththeexceptionofsolutionE,theelectropolishedsurfacewasnot significantly influenced by the other investigated derougingsolutions.

Part 2: Rouged Steel SamplesThecleaningability,theinfluenceonsurfaceroughnessandthecorrosion rate or rate of material removal at various temperatures is investigated by means of various acid solutions. Pipe samples of stainlesssteel1.4404areusedasthematerial.Thepipesamplesaretakenfromasterilizationprocessusingpuresteam.Becauseoftheregularcontactwiththismedium,theyexhibitlightrouging.The acids or acid mixtures that were used are shown in Table D.

The pipeline to be investigated was cut apart longitudinally and samples of approximately 2.5 × 5.5 cm were prepared from the halfshells.Theexposuretime,thetemperatureandthecalculatedcorrosion rate are listed in Table E. The derouging efficiency(cleaning ability) was estimated from an optical comparison with the untreated sample.

An attempt was made to determine the cleaning ability by means ofRamanspectroscopy.Becauseoftheinhomogeneoussignalsandtherougingdistributiononthesurfaces,itwasnotpossible

to evaluate the obtained spec-tra quantitatively. The cleaning ability was therefore estimated only visually.

At room temperature, therouge coating could be com-pletely removed only by 30 mi-nutesof“etching”(20%HNO3+5%HF).Thecorrosionrateunder these conditions was 13.4mm/a.

Table B Change of weight of material sample 212 treated with phosphoric acid and sodium hydroxide solution

Weight before cleaning (mg) 5349.15

Weight after cleaning (mg) 5348.87

Weight decrease (mg) 0.28

Relative weight decrease (%) 0.000052

Table C Ingredients, pH values and temperatures of the investigated derouging solutionsSolution Ingredients pH Values Temperature

A Phosphoric acid; citric acid pH < 1 approx. 70°C

B Citric acid; oxalic acid, sulfuric acid pH < 1 approx. 70°C

C Sulfuric acid; phosphoric acid; citric acid pH < 1 approx. 70°C

D Sodium dithionite, phosphoric acid and potassium hydroxide

pH = 7 approx. 70°C

E Sulfuric acid, hydrofluoric acid, hydrochlo-ric acid

pH < 1 approx. 30°C

Table D Composition and concentration of the investigated solutions

Solution ingredients

20% Nitric acid (HNO3) + 5% hydrofluoric acid (HF)

3% Citric acid

5% Phosphoric acid (H3PO4)

5% Nitric acid (HNO3)


Pharmaceutical Engineering } July/August 2015

About the AuthorsThomas Blitz studiedchemicalengineeringat theUniversityofDarmstadtandholdsaDipl. Ing.Hewas theheadof thematerialsengineering laboratory forMerckKGaA,Darmstadt,Germany,forover10years.Hismainresponsibilitiesincludetheimplementationofmaterialsengineeringstudies(corrosiontests)andtheprocessingofdamages.HeisamemberoftheSocietyforCorrosionProtection(GfKORR).

Ernst Felberwaseducatedasatechnicalglassblower,processengineer(AVOR),anddraughtsman;hereceivedfurthereducationinmaterialengineering.Hehasmanyyearsofpracticalexperienceinengineeringandorganizationofmanufacturingplantsandproductionfacilities(materialmanagement).Heisafieldexpertfor theStateSecretariat forEconomicAffairs (SECO),AccreditationService forpressureequipment.He iscurrentlyheadofTechnicalStandardsdepartmentat F.Hoffmann-LaRocheAGinBasel,Switzerland.

Robert Haas(Dipl.Ing.(FH))graduatedwithadegreeinbioengineeringattheUniversityofAppliedSciencesinMunich.Inhisdiplomathesis,heinvestigatedtheimpactofrougingonbiopharmaceuticalproduction.HehasworkedforRocheDiagnosticsGmbHinPenzbergsince2010.Hisareaofexpertiseincludesmaterialand corrosion related issues in biopharmaceutical production.

18. Coleman,D.C.,andEvans,R.W.,“CorrosionInvestigationof316LStainlessSteelPharmaceuticalWFISystems,”Pharmaceutical Engineering,Vol.11,No.4,1991,pp.9-13,www.pharmaceuticalengineering.org.

19. Collins,S.R,andWilliams,P.C.,“ElectropolishedTubing:AvoidCorrosioninWeldedApplications–IdentifyingOptimumAISI316LComposition,”Chemical Processing,63(12),2000pp.33-36.

20. Tuthill,A.H.,Avery,R.E,andCovert,R.A.,“CleaningstainlessSteelSurfacesPriortoSanitaryService,”Dairy, Food and Environmental Sanitization,17(1997),pp.718-725.

21. R.Greene,CEP,July2002,1522. Coleman,D.C.,andEvans,R.W.,“CorrosionproductsinPharmaceutical/

BiotechSanitarywatersystems,”ProceedingsofUltrapureWaterEXPO´99,Philadelphia,Pennsylvania,USA,8April1999.

23. Suzuki,O.,Newberg,D.,andInoue,M.,“DiscolorationanditsPreventionbySurfaceTreatmentinHigh-PurityWaterSystems,”Pharmaceutical Technology,Vol.22,No.4,1998,pp.66-80.

24. Küpper,J.,Egert,B.,Grabke,H.J.,“EntstehungundAufbaufarbigerschichtenaufrostfreiemstahl:I.VerfärbungenbeimKochenvonNahrungsmitteln,”Material Corrosion,33(1982)pp.669-675.

25. Morach,R.,RougingConferenceConceptHeidelberg,February2007,RougeinpharmazeutischenAnlagenausSichtdesAnwenders.

26. Frantsen,J.E.,T.Mathiesen,J.Rau,J.Terävä,P.BjörnstedtandB.Henkel,“EffectofGasAtmosphereandsurfacequalityonRougingofThreeStainlessSteelsinWFI,”presentedatNACECorrosion2003,Paper03074SanDiego,CA,March2003,www.forcetechnology.com/en/.

27. PIC/SSecretariat,PI 006-3 PIC Recommendations on Validation Masterplan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation,Sep.2007,pp.17-22.

28. EngineeringCommitteederBCI,NichtrostenderStahlnachBN2,2006.

Additional Reading29. Henkel,B.,Mathiesen,T.,etal.,“UsingExposureTeststoExamineRougingof

StainlessSteel,Pharmaceutical Engineering,Vol.21,No.4,July/August2002,www. pharmaceuticalengineering.org.

30. Henkel,G.andHenkel,B.,“Rouging–HinweisezuSchichtbildungenaufOberflächenausaustenitischenEdelstahllegierungen,”FachberichtNr.69,2005.

31. Henkel,G.,andHenkel,B.,“RougebildungaufEdelstahloberflächen316L–MechanismenderBildungsreaktion,”Fachbericht,Nr.80,2006.

32. Henkel,G.,andHenkel,B.,“DerougingvonaustenitischenEdelstahloberflächenmittelspH-neutralerHochleistungschemikalien,”TechnoPharm,1Nr.1,2011.

33. Henkel,G.,andHenkel,B.,“Derouging–ornotDerouging–EinFaktenabgleich,”Pharmind,73Nr.9,2011.

34. Zeiff,A.andHomburg,D.,etal.,“UmweltschonendesDerougenvonEdelstahloberflächen,”Process,2008.

35. Vernier,M.,“WennEdelstahlerrötet,”CITplus,Nr.5,2007.36. Czech,A.,“Rouging–ErfahrungenausderPraxisamBeispieleinerWFI-

Anlage,”Pharmind,73Nr.1;2011.

SE Secondary ElectronsSEM Scanning Electron MicroscopeSIP Sanitization/SterilizationinPlaceSpecific surface load Definedastheamountofrougeformedinacertaintimeunit perunitsurfaceareaThespecificsurfaceloadisexpressedin units of kg/(a*m²) (kilograms per year * square meter)Swab Polyester fabric clothTOC Total Organic CarbonVE-Wasser GermanabbreviationforDemineralizedwater (VollentsalztesWasser)WFI Water For Injection

References1. Deutsches Institut für Normung: DIN EN 10 088 Nichtrostende Stähle –Teil 1:

VerzeichnisdernichtrostendenStähle;2011.2. VereinDeutscherIngenieure:VDI-Berichte;Ausgaben235-238;1975.3. A.v.Bennekom,F.Wilke:Delta-Ferrit-GehaltbeiWerkstoff1.4435undder

BaslerNormII;2001.4. ISPE Baseline® Guide, Volume 4 – Water and Steam Systems,International

SocietyforPharmaceuticalEngineering(ISPE),SecondEdition,December2011,www.ispe.org.

5. Gasgnier,M.,andNévot,L.,“AnalysisandCrystallographicStructuresofChromiumThinFilms,”Physica status solidi,Vol.66,No,2,1981.

6. Hauser,G.,HygienischeProduktionstechnologie,2008.7. Hauser,G.,HygienegerechteApparateundAnlagen,2008.8. Tverberg,J.C.,Tube,T.,etal.,Rouging of Stainless Steel in WFI and High

Purity Water Systems,2000.9. Renner,M.,“Rouging–WerkstoffwissenschaftlicheBetrachtungzueinem

anspruchsvollenPhänomen,”2008.10. Tverberg,J.C.,ASM Handbook,Volume13C,2006.11. AmericanSocietyofMechanicalEngineers,ASMEBPE2009,Bioprocessing

Equipment,2009.12. EuropeanMedicinesAgency,EMEA Guideline on the Specification Limits for

Residues of Metal Catalysts or Metal Reagents,2008.13. International Conference on Harmonisation: ICH Q9 – Quality Risk

ManagementandlocalimplementationintheregulatorysystemsofUS,EU,Japan,2005,www.ich.org.

14. DeutschesInstitutfürNormung:DIN50905Teil1-5DurchführungvonKorrosionsuntersuchungen.

15. Bee,JaredS.,Chiu,David,etal.,“MonoclonalAntibodyInteractionswithMicro-andNanoparticles:Adsorption,Aggregation,andAcceleratedStressStudies,”Journal of Pharmaceutical Sciences,Vol.98,No.9,2009.

16. Corbett,R.A.,“Rouging–ADiscolorationofStainlessSteelSurfaces,”Materials Performance,Vol.40,No.2,Feb.2001,p.64-66.

17. Kane,R.D.,“Rouging:ThePhenomenonandItsControlinHigh-PurityWaterSystems,”Ultrapure Water,23(2006),pp.39-43.



A STRUCTURED TOOL FOR SUT IMPLEMENTATION

Carl Carlson

This article presents a tool for proactive single-use technology (SUT) design review and implementation. The tool utilizes a failure mode and effects analysis and a single-use design template for systematic review and risk assessment of SUT biotechnology facilities.

AbstractEvaluation for the implementation of single-use technology (SUT) can be accomplished by utilizing a structured analysis by linking a single-use design (SUD) template with a failure mode and effects analysis (FMEA) template. The SUD template, coupledwith FMEA, has been developed as atool to document process steps and parameters. This enables the correlation of process steps and parameters with a risk assessment for the useof single-use systems (SUS) andSUT.Themany facets of SUT implementationwill be reviewed, andthe use of the structured tool will be applied. Fixed stainless steel systems have the benefit of a fully scrutinized InstallationQualification/Operational Qualification (IQ/OQ) prior to usein manufacturing. SUT performing operations would benefitfrom having an abbreviated IQ/OQ applied every time a SUS/SUT is used. Process documentation via the SUD template iscoupled with a risk-based evaluation of design approach via an FMEA template that could help to document process risks. This numerical evaluation also allows for sensitivity analysis to be performed so that key risk assumptions can be evaluated in a proactive way to support decision making.

IntroductionThisarticlepresentsastructuredapproach forevaluatingSUS/SUTthatcanbeusedtopartiallyorcompletelyreplacetraditionalstainless steel systems. Regardless of what the motivation is to implementSUT(suchasreducecost,increasespeedtomarket,and reducenon-recoverable investment), thediscussionsof itsmerits have been well documented.1-3 Successful implementation requires a complete understanding of the process design space and the quality structure that will be applied to maintain control. A life-cycle approach for product process design and production shall be assumed.

Ingeneral,thetoolforSUTimplementationevaluationfollowsthissequence: 1. Establish the quality system.2.Definethedesignspace(DS).3.DocumenttheDSwiththeSUDtemplate.

4.Performrisk-basedanalysiswiththeFMEAtemplate.5. Perform sensitivity analysis on the risk data.6.Conclusion:finalizethedesignapproach.

Establish the Quality SystemThere are many quality systems that can be employed to implementanddocumentamanufacturingprocess.Inaddition,standardsforequipmentdesign,suchasASMEBPEandASTME25006, have been developed to aid in designing productionfacilities with lessons learned for stainless steel systems that requirecleaningandsteamsterilization.GuidelinesforSUThavenot yet been well established; however, a Quality by Design(QbD) life-cycle approachcanbeutilized as thequality systemframework4forSUTimplementation.

One such quality system can be found in the International Conference on Harmonisation (ICH). ICH has guidelines that are broken down into four categories

Q–QualityGuidelinesS–SafetyGuidelinesE–EfficacyGuidelinesM–MultidisciplineGuidelines

OfparticularinterestareICHQ8(R2)QbD,Q9RiskManagement,andQ10QualitySystem.ICHQ11,“DevelopmentandManufactureof Drug Substances (Chemical Entities and Biotechnological/BiologicalEntities),” illustrates the life-cycleapproachdescribedinICHQ8(R2),Q9,andQ10.

The ISPE Product Quality Lifecycle Implementation (PQLI®) Guides,parts3and4,hasdetailsonhowtoutilize thisqualitysystem.5

Define the Design SpaceAkeyaspectoftheICHQ8(R2)QbDsystemisthedefinitionofthedesign space and the life-cycle approach to design. The use and effectofstainlesssteelsystemsonprocessdesignspacehasbeenwell established over the years for food, dairy, pharmaceutical,and biological processes. Many aspects that have an impact on productqualityandefficacycanmostlybeconfinedtowithinthefacility,withafewexceptionsbeingoutsourcedmaterials(media,filtermembranes,andchromatographyresin,forexample).

With SUT, biopharmaceutical manufacturers are outsourcinga great deal more of the process design space. Not only does a quality attribute have to be met within the facility but the manufacture of the SUT has a dynamic process of its own.Leachables, modified leachables, leachable by-products, andmechanical stability are slowly being identified and the effectscharacterizedbybothvendorsandmanufacturingorganizations.With SUT being used more throughout the process, therewill be some process development testing required within the



Once the RPN values have been linked to the SUD template,thedesigncanbeinvestigatedbyusingthesortingandfilteringfunction within the FMEA template.

1. Investigate high RPN with the goal of reducing the value through PAT or operational factors. The results will indicate those items where there is too much risk to perform the operation as planned and a decision to go with a system or

equipment with acceptable risk is required.2. Investigate the middle region to move items in the acceptable risk range as agreed upon in a corporate directive (selected acceptable risk) or consider this a member of the high RPN.3. Accept low RPN results for design as these items evalua-ted are within risk tolerance.

Results Tabulation and EvaluationGroup the failure modes andestablish the reproducibility around the FMEA results.

Evaluation tables can be deve-loped by filtering the failuremodes and tabulating the indi-vidual FMEA results. By usingMicrosoft Excel functions, onecan then investigate RPNs with wide deviation. For example (Figure 8), with 10 individualsrankingtherisks,Step10.3.0.7has only seven matching RPN values.Lookingback,theSUDtemplate will provide all process datarelatedtothatspecificstepand that particular failure mode. The other RPN values matching this step can quickly be found by sorting on the specific stepand including all RPN values in thefilter.

Further ConsiderationsLeachables/ExtractablesThe SUT is evaluated on itsstand-alone merits. The issues of leachables can become very subjective. This tool provides a means to document the issue and to identify potential courses

of action to minimize the risk to the product. The BioPhorumOperationsGroup (BPOG) isdevelopingaprotocol forworkingwith SUT vendors to determine what Leachable/Extractablesmay exist and how to detect them. The goal is to open dialog withvendorsto improveourunderstandingof theSUTmaterialprocessing and to provide a proactive way to anticipate the effectsonprocessingbasedon theseknown leachables.40-43This author believes it is no longer acceptable to just look at Class

Table B Failure mode ranking

Potential Effect or Severity (SEV)

Effect Severity of Effect Ranking

Hazardous without Warning Affects safe system operation with no warning 5

Hazardous with Warning Affects safe system operation with some warning 4

Moderate System inoperable with minor damage 3

Minor System is operable with some degradation of performance 2

None No Effect 1

Potential Cause or Probability of Failure (PROB)

Probability of Failure Failure Probability Ranking

Very High, Failure is inevitable > 1 in 2 5

Repeated Failures 4

Occasional Failure > 1 in 100 3

Few Failures 2

Failure is Unlikely > 1 in 1,000,000 1

Current Design Controls and Likelihood of Detection (DET)

Detection Likelihood of Detection by Design Controls Ranking

Uncertain Design Control cannot detect potential mechanism and resulting failure

5

Remote Remote chance that design control will detect potential failure 4

Moderate Even change of detection by design control 3

Minor Good chance that design control will detect potential failure 2

Almost Certain Design Control will detect potential failure 1

Table C Standard testing examples

Test Units References

Tensile Property N (kg·m/s2) ASTM D412, ASTM D638, ASTM D882, ISO 37, ISO527.5

Toughness kN·m/m−3 ASTM 2794, ASTM D1709, BS2782 Part 3 Method 352E

Elastic Modulus at 2% elon-gation

psi ASTM E111, ISO 17025

Puncture Resistance N (kg·m/s2) ASTM F1306, ASTM D3787, ASTM D4833

Tear Resistance kN/m ASTM D1004, ASTM D1922, ISO 6383-2, BS2782:3

Flex Durability WVTR – g/m2·24hr ASTM D392, BS 3177AEA

1.00 N·m/m−3 ≃ 0.000145 in·lbF·in−3 and 1.00 in·lbF·in−3 ≃ 6.89 kN·m/m−3



ValueoftheSUDandFMEATool:

1.Evaluatethehigh-riskstepsfortheSUTdesign.MicrosoftExcel-basedfilteringandsortingcapabilitiesforevaluationreviews

2. Proactive evaluation of design and potential failures in an FMEAreviewlinkedtoSUDsummaryoftheprocess

3. Team alignment through group involvement4.Thoughtfulwalk-throughofprocess(es)andevaluationof

failure and risk impacts5. Evaluation and documentation of process design space

By linking theSUD templatewith theFMEA template,high-riskactivities can be identified and evaluated as per operationalactivities. This proactive review provides a platform for facility designandriskmitigation.Ongoinguseofthetool (SUD/FMEAtemplates) can document process improvements and risk mitigation for the life cycle of the facility processes. |

References1. Barnoon,BarakI.,andBobBader,“LifecycleCostAnalysisforSingle-Use

Systems,”BioPharm International,2November2008, www.biopharminternational.com.

2. Peuker,Thorsten,andJean-MarcCappia,“SingleUseComponentsforFlexibleBiomanufacturingProcesses,”Pharmaceutical Engineering,March/April2011,www.pharmaceuticalengineering.org.

3. Eibl,D.,Eibl,R.,Köhler,P.,eds.ReportoftheTemporaryWorkingGroup“SingleUseTechnologyinBiopharmaceuticalProduction,”Dechema Biotechnologie,2ndEdition,March2012.

4. Dolgin,David,“CommissioningandQualification(Verification)inthePharmaceuticalProductProcessLifecycle,”Pharmaceutical Engineering,May/June2013,www.pharmaceuticalengineering.org.

5. ISPE Guide Series: Product Quality Lifecycle Implementation (PQLI®) from Concept to Continual Improvement,InternationalSocietyforPharmaceuticalEngineering(ISPE),www.ispe.org.• Part3–ChangeManagementSystemasaKeyElementofa

PharmaceuticalQualitySystem,FirstEdition,June2012.• Part4–ProcessPerformanceandProductQualityMonitoringSystem

(PP&PQMS),FirstEdition,June2013.6. ASTME2500-07,Standard Guide for Specification, Design, and Verification

of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment,ASTMInternational,www.astm.org.

7. ASTME2363-06a,StandardTerminologyRelatingtoProcessAnalyticalTechnologyinthePharmaceuticalIndustry,ASTMInternational,www.astm.org.

8. Rathore,A.S.,R.BhambureandV.Ghare,“ProcessAnalyticalTechnology(PAT)forBiopharmaceuticalProducts,”Received:26February2010/Revised:20April2010/Accepted:23April2010#Springer-Verlag 2010.

9. Yourkin,Jon,“Re-ThinkingPATforCleanabilityPracticalandAchievablePerspectivesforChangingHowYouThinkAboutCleaningValidation,”Pharmaceutical Online,GuestColumn,12March2013, www.pharmaceuticalonline.com.

10. Rudd,Dave,ParaicO’Toole,andIanPepper,“PAT:ExploringtheNewPhilosophyoftheFDA,”Automsoft ®.

11. “PATandTOCAnalysiswithanOnboardAutomatedStandardsIntroductionSystem(Oasis™).StevenSmith,June2008,HachUltraAnalytics,Inc.

12. Ganguly,Joydeep,andGerritVogel,“ProcessAnalyticalTechnology(PAT)andScalableAutomationforBioprocessControlandMonitoring–ACaseStudy,”Pharmaceutical EngineeringJanuary/February2006, www.pharmaceuticalengineering.org.

13. Kline,PhD,Sally,“TheImpactofExtractablesandLeachablesonCellCultures,”IBC Life Sciences Event,Durham,NorthCarolina,3June2013.

14. Kline,Sally,EktaMahajan,DarrellMorrow,BobSteininger,NancySweeney,andRussellWong,“ChangeNotificationsforSingleUseComponents:CriteriafromanEndUserPerspective,”Pharmaceutical Engineering,May/June2014,www.pharmaceuticalengineering.org.

15. Goldstein,Adam,MichaelPohlscheidt,JacquelineLoesch,KellenMazzarella,BorisBeiger,PhilippeLam,andJoeyTeshima,“DisposableFreezeSystemsinthePharmaceuticalIndustry,”American Pharmaceutical Review,10December2012,www.americanpharmaceuticalreview.com.

16. Patient.co.uk/CarpalTunnelSyndrome.Webmd,www.webmd.com/pain-management/carpal-tunnel/carpal-tunnel-syndrome-cause.

17. Shukla,AbhinavA.,SigmaMostafa,MarkWilson,andDirkLange,“VerticalIntegrationofDisposablesinBiopharmaceuticalDrugSubstanceManufacturing,”BioProcess International,June2012, www.bioprocessintl.com.

18. Fox,Sandra,“DisposableBioprocessing:TheImpactofDisposableBioreactorsontheCMOIndustry,”Contract Pharma,June2005, www.contractpharma.com.

19. Elvidge,Suzanne,“Single-UseTechnology:FromBioprocessConveniencetoDrug-DevelopmentDriver,”FierceBiotech,April2013,www.fiercebiotech.com.

20. Stock,PhD,Rick,“WhereIstheRealValueinApplyingSingle-UseTechnologytoClinicalandCommercialManufacturing,”American Pharmaceutical Review,1April2011,www.americanpharmaceuticalreview.com.

21.Sandstrom,Craig,“Single-Use/DisposableTechnologyConsiderationsforBiopharmaceuticalFacilityDesign,”Pharma Focus Asia, www.pharmfocusasia.com.

22.Bodeker,Dr.Berthold,“ImprovingBiologicManufacturingOperationsandPlantDesignThroughSingle-UseTechnologiesApplication,”Pharmaceutical Outsourcing,24May2012,www.pharmoutsourcing.com.

23. Whitford,WilliamG.,“Single-UseSystemsasPrincipalComponentsinBioProduction”BioProcess International,December2010, www.bioprocessintl.com.

24. Kappel,Wilfried,BhimasenVadavi,SanjayLodha,andDanielKarrer,“ApplicationofSingle-UseEquipmentforBufferStorageandDistributioninMediumSizemAbProductionFacility,”Pharmaceutical Engineering, January/February2014,www.pharmaceuticalengineering.org.

25. Laukel,Markus,PeterRogge,andGregorDudziak,“DisposableDownstreamProcessingforClinicalManufacturing,CurrentCapabilitiesandLimitations,”BioProcess International,Supplement,May2011,www.bioprocessintl.com.

26.Whitford,WilliamG.,“Single-UseSystemsasPrincipalComponentsinBioproduction,”BioProcess International,December2010, www.bioprocessintl.com.

27. “Single-UseBioreactorRoundup,”Genetic Engineering & Biotechnology News,15April2013,www.genengnews.com.

28. Strahlendorf,KirstenA.,andKevinHarper,“AReviewofSterileConnectors,”BioPharm International,2November2009,www.biopharminternational.com.

29. Kinney,ShawnD.,ChristianW.Phillips,andKellyJenkinsLin,“ThermoplasticTubingWeldersandSealers,”BioProcess International,Supplement, May2007,www.bioprocessintl.com.

30. Mina,Chuck,“DisposableAutomation,Single-UseTechnologiesforBiopharmaceuticalManufacturing,”Intech,March/April2012, www.intech.com.

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118 | BACK PAGE


THE ORPHAN PARADOXThe increasingly lucrative market for breakthrough therapies

James Hale and Scott Fotheringham, PhD

Johann Kerlow and her family know the life-saving effects that an orphan drug can have. According to a Toronto Star story published 5 November 2015, the Toronto-areawoman was diagnosed with atypical hemolytic uremic syndrome (aHUS),which quickly led to kidney failure that required weekly dialysis. She would no doubt die without Soliris (Alexion Pharmaceuticals),theonlymedicationshown to treat aHUS. But with aprice tag of well over US $500,000annually—Soliris is the most expensive drug on the market—the mother of threecouldnotaffordthetreatment.

Onlyabout1,000peopleinNorthAme-ricasufferwithaHUS,whichmakes itan“orphandisease”asdefined intheUSRareDiseasesActof2002.Toqua-lifyforthisdesignation,adiseasemustaffect fewer than200,000Americans.More than 6,000 of these conditionshavebeenidentified.

Priorto1983,therewaslittlehopeoftreatment for patients suffering froman orphan disease. Drug development and commercialization costs for newtreatments were too high to allow ma-nufacturers to recoup their research and development expenses.

The Orphan Drug Act (ODA) of 1983 changed the landscape. In concert with the Office of Orphan ProductsDevelopment, operated by the USFoodandDrugAdministration (FDA),the act provides incentives for phar-maceutical companies to research,

develop,andcommercializeproductsto treat rare diseases. These include tax incentives (such as clinical-testing credits),waivingprescriptiondruguserfees,reducedcompetition(usuallynogenericcompetition for seven years),and fast-tracked review and approval process during drug development.

Overthepast32years,morethan400orphan disease drugs and biologics havebeendevelopedandmarketed,compared to fewer than 10 in the de-cade preceding passage of the ODA. In 2014 alone there were 440 FDAapplications for orphan drug designa-tion,with48approvals(up53percentfrom 2013).

This has not only improved patient treatment,buthasalsobeenaboonfortheentirepharmaceuticalindustry,which historically depended on drug sales for the treatment of diseases and conditionsthataffectlargenumbersofpeople. Orphan drug treatments have helped boost global pharmaceutical sales, which are expected to growalmost 5 percent annually and reach $1 trillion by 2020.

According to the market research of EvaluatePharma, orphan drug salesalone are forecast to grow 11 percent annually to $176 billion in sales by 2020,when theywill account for 19percentofallprescriptiondrugsales,excluding generics. Importantly, theexpected return for orphan drugs in Phase III clinical trials is nearly double (1.89 times higher) that of other drugs.

What accounts for this phenomenal growth? The incentives provided by the ODAcertainlyhelp,asdoesapatientbase that usually needs lifelong access to these breakthrough therapies. Most topsellersareoncologybiologics,suchasRevlimid(Celgene),Opdivo(Bristol-Myers Squibb), and Rituxan (Genen-tech). Add to this the reduced Phase III development costs (50 percent or lower) and prices that are on average more than six times higher than that of non-orphandrugs,and it is littlewon-der that orphan drugs appear to be the next big thing for the industry.

As big pharmaceutical companies acquire orphan drug developers to gain access to this lucrativemarket, theseailments could need a new name. They maybecalled“orphans,”buttheyarebeing adopted at a record pace.

The bottom-line benefit of orphandrugs is paradoxical: While there were few treatment options for most orphandiseasesufferersbefore1983,now that treatments exist they may be too expensive formany to afford.PatientslikeKerlowmustrelyonthird-party payers—whether insurance companies or publicly fund ed insu-rers—who may be hesitant to pay the hefty bills. |

} Orphan drug treatments have helped boost globalpharmaceuticalsales,whichare

expected to grow almost 5 percent annually and reach $1 trillion by 2020. |

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