Avoid­ing Cell Ther­a­py Man­u­fac­tur­ing Grid­locks — a Do’s and Don’ts Guide

How can de­vel­op­ers pre­pare for the most vul­ner­a­ble as­pects of the cell ther­a­py process? What steps are need­ed to demon­strate prod­uct com­pa­ra­bil­i­ty, with a rapid scale-up to man­u­fac­tur­ing? When does it make sense to part­ner with a cus­tom man­u­fac­tur­er and how can they help through­out the reg­u­la­to­ry process? De­vel­op­ers must or­ches­trate a com­plex set of steps to move pre­clin­i­cal mol­e­cules through the clin­ic and man­u­fac­ture ther­a­pies at scale – all while meet­ing reg­u­la­to­ry guide­lines and pro­tect­ing pa­tient safe­ty. In this re­port, we will of­fer a guide to these is­sues and more, with com­men­tary from con­sul­tants and man­u­fac­tur­ers who have suc­cess­ful­ly nav­i­gat­ed these wa­ters. If you are work­ing to bring a cell ther­a­py to clin­ic, this guide is for you.

DON’T … for­get that tim­ing is every­thing

While small mol­e­cule and bi­o­log­ics man­u­fac­tur­ing read­i­ly make drug prod­ucts to stock, al­lo­gene­ic cell ther­a­pies de­mand man­u­fac­tur­ing fa­cil­i­ties that can han­dle every­thing from in­tri­cate prod­uct de­vel­op­ment to the lo­gis­tics re­quired in pro­duc­ing these ‘off-the-shelf’ ther­a­pies. Au­tol­o­gous cell ther­a­pies man­u­al­ly process and de­liv­er per­son­al­ized, made-to-or­der prod­ucts for each pa­tient. Au­tol­o­gous ther­a­pies have a short shelf life, so de­vel­op­ers al­so face unique de­liv­ery chal­lenges — such as min­i­miz­ing vein-to-vein time to safe­guard the fresh prod­uct.

When strate­giz­ing treat­ment for au­tol­o­gous cell ther­a­py pa­tients — many of whom are bat­tling ter­mi­nal dis­eases — tim­ing is every­thing. “Pa­tients who are pre­scribed cell ther­a­pies of­ten aren’t can­di­dates for oth­er drug prod­ucts that are high­er in the queue,” says An­tho­ny Davies, Ph.D., founder and CEO of Dark Horse Con­sult­ing. “Right now, any length of man­u­fac­tur­ing turn­around for these per­son­al­ized med­i­cines can mean life or death in some cas­es.” Plan­ning a tri­al with au­tol­o­gous cell ther­a­py re­quires map­ping out a se­ries of cru­cial and rapid steps with your man­u­fac­tur­er to op­ti­mize treat­ment goals for the pa­tient, as well as over­all clin­i­cal goals for the tri­al.

What are the main chal­lenges with al­lo­genic cell pro­duc­tion? Amongst oth­ers are fill­ing, freez­ing and stor­ing hun­dreds of prod­uct vials. Al­lo­gene Ther­a­peu­tics Chief Tech­nol­o­gy Of­fi­cer Al­i­son Moore, Ph.D. rec­om­mends de­vel­op­ers plan for ei­ther a cen­tral stor­age lo­ca­tion or strate­gi­cal­ly po­si­tioned sites in or­der to to op­ti­mize trans­porta­tion routes. Do­ing so will help en­sure a well-char­ac­ter­ized, con­sis­tent re­lease of prod­uct at scale for pa­tients in need.

In­no­va­tors should al­so be mind­ful of GMP-com­pli­ant prac­tices in their ear­ly phase stud­ies. A lit­tle bit of fore­sight can go a long way be­cause it’s eas­i­er to im­ple­ment – rather than to lat­er adapt – cost-sav­ing mea­sures like au­toma­tion and an­a­lyt­i­cal strate­gies in the front end ver­sus up­end­ing the en­tire process down­stream. Pre­emp­tive plan­ning can al­so re­duce com­pa­ra­bil­i­ty and bridg­ing is­sues in the clin­ic.

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The field con­tin­ues to grow at a rapid pace, so de­vel­op­ers can ex­pect in­creas­ing de­mand for com­mer­cial man­u­fac­tur­ing sup­port to bring these ther­a­pies to mar­ket. Whether it is a tech­ni­cal trans­fer or a man­u­fac­tur­ing restart, Kim Raineri, Chief Man­u­fac­tur­ing and Tech­nol­o­gy Of­fi­cer at AVRO­BIO, ad­vis­es de­vel­op­ers to plan for ca­pac­i­ty as far out as pos­si­ble. “Peo­ple are of­ten op­ti­mistic with an ex­pec­ta­tion that you can re­boot in a short pe­ri­od of time, but it al­ways takes longer than ex­pect­ed,” says Raineri. “Think with a long-term ap­proach, even for clin­i­cal ma­te­r­i­al.”

DO … plan for sup­ply chain is­sues

Af­ter the pan­dem­ic wreaked hav­oc on cell ther­a­py sup­ply chains, it is vi­tal to have back up ven­dors in place for all crit­i­cal ma­te­ri­als used in the process. “We do have lim­i­ta­tions on that end where cer­tain ma­te­r­i­al is avail­able on­ly from a sin­gle source,” says Mad­havi Anu­mu­la, Di­rec­tor of Process De­vel­op­ment at Catal­ent. “But wher­ev­er pos­si­ble, ex­plore back­up op­tions to test and qual­i­fy reagents.” She adds that sup­ply lim­i­ta­tions are par­tic­u­lar­ly cum­ber­some with vi­ral vec­tor man­u­fac­tur­ing, not­ing pro­duc­tion snags faced by sev­er­al ma­jor com­pa­nies whose CAR-T drugs strug­gled to keep pace with de­mand.

De­vel­op­ers con­duct­ing man­u­fac­tur­ing or clin­i­cal tri­als in mul­ti­ple lo­ca­tions must be mind­ful that sup­ply chains vary across coun­tries. A com­po­nent that is avail­able in the U.S., for in­stance, may not be read­i­ly avail­able in Eu­rope or Asia. Se­lect­ing a ma­te­r­i­al that is avail­able across the world, or part­ner­ing with a glob­al man­u­fac­tur­ing part­ner, can avoid com­pa­ra­bil­i­ty chal­lenges lat­er.

Us­ing dif­fer­ent equip­ment across mul­ti­ple man­u­fac­tur­ing sites can al­so el­e­vate the risk pro­file dur­ing reg­u­la­to­ry ap­provals. Much like a bak­er will dis­cern changes us­ing dif­fer­ent tools for the same recipe, Davies notes that de­vel­op­ers can ex­pect us­ing a 10-liter stor­age tank at one fa­cil­i­ty and a 100-liter tank at an­oth­er will al­ter prod­uct com­pa­ra­bil­i­ty. By think­ing about the end of the process and work­ing back­ward, de­vel­op­ers can ac­cel­er­ate time­lines to clin­ic and com­mer­cial scale as pro­grams progress across the drug de­vel­op­ment spec­trum.

For com­pa­nies in pre­clin­i­cal and phase 1, late-stage chal­lenges can be mit­i­gat­ed by cre­at­ing a sol­id da­ta in­fra­struc­ture and a cul­ture that em­pha­sizes prod­uct and process learn­ing from the very start. Moore rec­om­mends build­ing col­lab­o­ra­tive re­la­tion­ships with man­u­fac­tur­ers, vec­tor sup­pli­ers, and con­tract test­ing labs in­volved with lat­er-stage pro­duc­tion and re­lease. “En­abling the learn­ing from ex­ter­nal par­ties to be in­cor­po­rat­ed in­to the grow­ing body of knowl­edge around the prod­uct and process is im­por­tant,” she says. “It’s nev­er too ear­ly to ini­ti­ate these ac­tiv­i­ties.”

For best re­sults and to stay ahead of the curve, plan your scale-up ear­ly on with an ex­pe­ri­enced man­u­fac­tur­ing part­ner. Many com­pa­ra­bil­i­ty is­sues are the re­sult of poor tim­ing, which is why com­pa­nies that plan to scale-up in lat­er stages would be wise to in­stead start ear­ly. Do­ing so will help pre­lim­i­nary clin­i­cal da­ta align with lat­er stage da­ta. From Davies’ per­spec­tive, this fail­ure to plan is one of the rea­sons cell ther­a­pies can ex­cel dur­ing phase 2 tri­als with ex­cep­tion­al­ly promis­ing da­ta, but stall dur­ing phase 3 with de­fi­cient CMC screen­ings.

DON’T … put off think­ing about ‘build vs. buy’

When it comes to build ver­sus buy, con­struct­ing re­al­is­tic sce­nar­ios are es­sen­tial for long term plan­ning.

Com­pa­nies that opt for in-house man­u­fac­tur­ing re­quire sig­nif­i­cant up­front cap­i­tal to build, staff and qual­i­fy the fa­cil­i­ties. Down the line, in-house man­u­fac­tur­ing can re­duce long-term costs, pro­vide more flex­i­bil­i­ty and yields bet­ter con­trol of in­tel­lec­tu­al prop­er­ty. While the de­ci­sion to build af­fords com­plete pro­duc­tion con­trol and a de­tailed un­der­stand­ing of the process and prod­uct un­der de­vel­op­ment, com­pa­nies must be ful­ly com­mit­ted to a com­mer­cial­ly ca­pa­ble com­pli­ance en­vi­ron­ment.  “Should a com­pa­ny choose to build, they ul­ti­mate­ly need to fore­see a fu­ture in which the com­pa­ny-owned plant is well uti­lized in or­der to de­liv­er ef­fi­cient cost of goods man­u­fac­tured,” says Moore.

Anu­mu­la rec­om­mends that com­pa­nies with ear­ly phase tri­als part­ner with a cus­tom man­u­fac­tur­ing or­ga­ni­za­tion. “If a drug fails in clin­i­cal tri­als, an in-house man­u­fac­tur­ing in­fra­struc­ture would be dif­fi­cult to re­pur­pose,” she says. “This al­so gives them an op­por­tu­ni­ty to fo­cus on their R&D pipeline rather than sink­ing funds in­to a man­u­fac­tur­ing fa­cil­i­ty.”

Some com­pa­nies are find­ing new ways to stream­line the cell ther­a­py man­u­fac­tur­ing process by try­ing new so­lu­tions. “There’s a new­er mod­el emerg­ing where some com­pa­nies will rent a clean­room fa­cil­i­ty to have their own peo­ple and process­es in place but avoid brick and mor­tar ex­pens­es,” says Raineri.

De­ci­sions made in the ear­ly stages of dis­cov­ery are key to avoid­ing risk, low­er­ing costs and pro­tect­ing the over­all qual­i­ty of the prod­uct. Care­ful, in­formed se­lec­tion of raw ma­te­ri­als, strate­gic au­toma­tion and con­trolled Crit­i­cal Process Pa­ra­me­ters (CPPs) and Crit­i­cal Qual­i­ty At­trib­ut­es (CQAs) can en­sure a con­sis­tent, scal­able prod­uct at the end of the process.

DO … con­sid­er how to sus­tain­ably scale

“When your prod­uct sees a spike in man­u­fac­tur­ing de­mand, many start­up com­pa­nies sim­ply aren’t pre­pared to start build­ing right away.” says Davies. “CD­MOs cer­tain­ly have a unique role to play.”

Of­fer­ing very spe­cif­ic do­main knowl­edge, cus­tom man­u­fac­tur­ing or­ga­ni­za­tions can pro­vide the right in­fra­struc­ture and ex­per­tise to en­sure cell ther­a­pies have the same char­ac­ter­is­tics through­out the cy­cle. Ma­ture man­u­fac­tur­ing part­ners lever­age knowl­edge from the es­tab­lished bi­o­log­ics space and emerg­ing ther­a­pies realm to po­si­tion cell ther­a­pies for suc­cess through­out each stage of the process. With ful­ly in­te­grat­ed teams in place across the de­vel­op­ment cy­cle, Catal­ent pro­vides prod­uct fil­ing and re­sponse sup­port from pre-IND to prod­uct com­mer­cial­iza­tion — and draws from reg­u­la­to­ry and fil­ing sup­port knowl­edge in the bi­o­log­ics busi­ness along with the fa­cil­i­ties and com­pli­ance ex­per­tise in the cell ther­a­pies space.

“If you are a small biotech com­pa­ny, make sure you choose a part­ner that has the ca­pa­bil­i­ties, re­sources and fi­nanc­ing to grow with you as you move through each clin­i­cal phase and as prod­uct de­mand in­creas­es,” ad­vis­es Raineri. De­vel­op­ers should opt for a man­u­fac­tur­ing part­ner that can sup­port au­tol­o­gous ther­a­pies with a lo­ca­tion in prox­im­i­ty – and al­lo­gene­ic ther­a­pies with cryo­genic fa­cil­i­ties for stor­age and cold chain man­age­ment for ship­ment. Ac­cord­ing to Moore, it is vi­tal that al­lo­gene­ic ther­a­pies are de­liv­ered by trust­ed, ul­tra-cold chain lo­gis­tics providers that use cus­tom-de­signed ship­ping con­tain­ers. “En­sur­ing ro­bust and cost-ef­fi­cient cold chain lo­gis­tics, en­vi­ron­men­tal con­trol and con­tin­u­ous mon­i­tor­ing via ‘con­trol tow­er’ tech­nolo­gies through­out the process are al­so a key con­sid­er­a­tion for the last step of pa­tient de­liv­ery,” she says.

In a dy­nam­ic mar­ket such as cell ther­a­py, cus­tom man­u­fac­tur­ing or­ga­ni­za­tions are evolv­ing from a ca­pac­i­ty and ca­pa­bil­i­ties per­spec­tive to meet the grow­ing de­mand of in­no­va­tors and reg­u­la­tors. As more cell ther­a­pies emerge, man­u­fac­tur­ing part­ners will bridge ex­cess ca­pac­i­ty as they con­tin­ue to make sig­nif­i­cant in­vest­ments and strate­gic ac­qui­si­tions in this area. Catal­ent, for ex­am­ple, has ex­e­cut­ed on a se­ries of ex­pan­sions and ac­qui­si­tions in re­cent years to el­e­vate ca­pac­i­ty and in­te­grate ca­pa­bil­i­ties from plas­mid DNA, vi­ral vec­tor, cell ther­a­py man­u­fac­tur­ing to clin­i­cal sup­ply so­lu­tions. Ad­di­tion­al­ly, the com­pa­ny is com­mit­ted to con­tin­ued man­u­fac­tur­ing in­no­va­tions in next-gen­er­a­tion modal­i­ties like in­duced pluripo­tent stem cells (iP­SCs), ex­o­somes and more.

DON’T … lose sight of the reg­u­la­to­ry end game

While man­u­fac­tur­ing is a chal­lenge, if the prod­uct is to be kept on track through­out the cy­cles then it is im­por­tant for de­vel­op­ers to pri­or­i­tize mea­sures like po­ten­cy as­says from the start to keep the prod­uct on track through­out the cy­cle.

“We are look­ing at a po­ten­cy as­say ma­trix where we es­sen­tial­ly have mul­ti­ple shots on goal,” says Raineri. “That way we can eval­u­ate dif­fer­ent as­pects to prop­er­ly char­ac­ter­ize the prod­uct, and then cor­re­late it to the mech­a­nism of ac­tion and clin­i­cal ef­fi­ca­cy. If you are do­ing that right, that is what reg­u­la­tors want to see.”

If com­pa­nies are lax with their po­ten­cy as­says, they run the risk of reg­u­la­to­ry push­back if the da­ta does not cor­re­late strong­ly with the clin­i­cal ef­fi­ca­cy and mech­a­nism of ac­tion. Af­ter mon­i­tor­ing the reg­u­la­to­ry trends, in­dus­try an­a­lysts are sig­nal­ing more strin­gent as­says will be forth­com­ing to bet­ter con­trol for cel­lu­lar vari­abil­i­ty. In fact, the FDA’s 2011 guid­ance in­di­cates that “…a sin­gle bi­o­log­i­cal or an­a­lyt­i­cal as­say may not pro­vide an ad­e­quate mea­sure of po­ten­cy. If one as­say is not suf­fi­cient to mea­sure the prod­uct at­tribute(s) that in­di­cates po­ten­cy, then an al­ter­na­tive ap­proach could be used, such as de­vel­op­ing mul­ti­ple com­ple­men­tary as­says that mea­sure dif­fer­ent prod­uct at­trib­ut­es as­so­ci­at­ed with qual­i­ty, con­sis­ten­cy and sta­bil­i­ty.”

Cer­tain­ly, com­pa­nies must be pre­pared to demon­strate ex­act­ly how their prod­uct works amid all the vari­ables that can arise. “In en­gi­neer­ing, what you can’t mea­sure, you can’t con­trol,” says Davies. “An­a­lyt­ics char­ac­ter­i­za­tion has typ­i­cal­ly lagged in this field, and es­pe­cial­ly for cell-based ther­a­pies, one test in par­tic­u­lar is throw­ing many for a loop. That is the po­ten­cy as­say. Ig­nore these at your own per­il.”

To avoid los­ing sight of these as­says, Anu­mu­la ad­vis­es de­vel­op­ers to fol­low a phase-ap­pro­pri­ate ap­proach across the prod­uct’s life cy­cle. “Dur­ing the pre­clin­i­cal stage, de­vel­op­ers should fo­cus on the de­vel­op­ment and op­ti­miza­tion of re­lease meth­ods. As the prod­uct moves through phas­es 1 and 2, con­tin­u­ous op­ti­miza­tion is re­quired – along with set­ting ac­cep­tance cri­te­ria and method qual­i­fi­ca­tion,” she says. “Full as­say val­i­da­tion should be im­ple­ment­ed dur­ing phase 3 when process­es are locked, and prod­uct is in its fi­nal ma­trix.”

Test­ing and char­ac­ter­i­za­tion meth­ods are al­so im­por­tant strate­gies in un­der­stand­ing cell ther­a­py prod­ucts. Moore rec­om­mends de­vel­op­ers close­ly part­ner with out­side test­ing lab­o­ra­toies that share, along with their re­sults, method per­for­mance in­for­ma­tion – and al­so cul­ti­vate re­la­tion­ships with com­pa­nies de­vel­op­ing nov­el test­ing and se­quenc­ing tech­nolo­gies. “De­vel­op­ers should al­so pri­or­i­tize tal­ent with­in the At­tribute Sci­ences dis­ci­plines, as the types of meth­ods re­quired to char­ac­ter­ize an al­lo­gene­ic CAR-T prod­uct can be very di­verse and re­quire broad scope and deep ex­per­tise for ap­pro­pri­ate de­vel­op­ment, ex­e­cu­tion and in­ter­pre­ta­tion,” she notes.

DO …  con­nect the dots to reg­u­la­to­ry align­ment at each stage of the process.

In ad­di­tion to COVID-19 man­u­fac­tur­ing con­sid­er­a­tions is­sued in Jan­u­ary 2021, the FDA re­leased six guid­ance doc­u­ments in 2018 and two ad­di­tion­al guid­ance doc­u­ments in 2019 for cell and gene ther­a­py prod­ucts (CGT). Con­sid­er­ing that CGT didn’t have a li­censed prod­uct un­til 2017, reg­u­la­tors are march­ing on­ward to keep up with the evolv­ing mar­ket. Reg­u­la­to­ry agen­cies are con­tin­u­ing to ded­i­cate re­sources to help progress cell ther­a­pies in­to the clin­ic and to com­mer­cial ma­tu­ri­ty.

Mech­a­nisms like the Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­py (RMAT) des­ig­na­tion in the U.S. and the Ini­tial Tar­get­ed En­gage­ment for Reg­u­la­to­ry Ad­vice on CBER prod­ucts (IN­TER­ACT) meet­ings can fa­cil­i­tate both prod­uct de­vel­op­ment and reg­u­la­to­ry ap­proval. The FDA has al­so is­sued guid­ance for in­no­v­a­tive tri­al de­signs, such as the Au­gust 2018 guid­ance doc­u­ment “Ex­pan­sion Co­horts: Use in First-In-Hu­man Clin­i­cal Tri­als to Ex­pe­dite De­vel­op­ment of On­col­o­gy Drugs and Bi­o­log­ics Guid­ance for In­dus­try” and sub­se­quent “Mas­ter Pro­to­cols: Ef­fi­cient Clin­i­cal Tri­al De­sign Strate­gies to Ex­pe­dite De­vel­op­ment of On­col­o­gy Drugs and Bi­o­log­ics.”

Com­pa­nies that en­gage with reg­u­la­tors ear­ly and of­ten, and learn the rec­om­men­da­tions for each stage, will be bet­ter pre­pared to meet reg­u­la­to­ry stan­dards. For in­stance, al­lo­gene­ic CAR-T ther­a­pies re­quire the in­clu­sion of raw ma­te­ri­als from a healthy donor source and (source). “These as­pects are rel­a­tive­ly new in­clu­sions in­to pro­duc­tion process­es and so the bi­ol­o­gy around what con­sti­tutes a ‘healthy donor,’ and the safe­ty con­sid­er­a­tions of gene edit­ing, are rel­a­tive­ly fresh ar­eas for both the in­dus­try and our reg­u­la­tors,” says Moore. “Align­ment of ap­proach with reg­u­la­tors is ide­al and can be achieved via IN­TER­ACT meet­ings or dur­ing de­vel­op­ment in the nor­mal course of reg­u­la­to­ry in­ter­ac­tions.”

Rather than pro­cras­ti­nat­ing with CMC time­lines, com­pa­nies that di­al up these ac­tiv­i­ties in ad­vance will save on costs, time and reg­u­la­to­ry grid­lock down the line. “If you are in the cell and gene ther­a­py space, you should al­ways be watch­ing what is hap­pen­ing on the reg­u­la­to­ry front,” says Raineri. “That said, there’s not much mys­ti­cism as to what com­pa­nies need to do to get through the reg­u­la­to­ry pipeline. Above all, its im­por­tant that com­pa­nies fol­low ex­ist­ing guid­ance, un­der­stand their prod­uct, and en­sure CMC is but­toned up be­fore fil­ing a Bi­o­log­ics Li­cense Ap­pli­ca­tion (BLA).”

In an in­ter­view with Cell & Gene, Dr. Ji­wen, Chief Reg­u­la­to­ry Of­fi­cer, Reg­u­la­to­ry Af­fairs and Qual­i­ty As­sur­ance at Ren­o­va­cor, sug­gests that stake­hold­er en­gage­ment can al­so go a long way in sus­tain­ing these ther­a­pies in the reg­u­la­to­ry realm and be­yond. “Al­liance groups, pub­lic-pri­vate part­ner­ships, and con­sor­tia on var­i­ous ini­tia­tives are all mak­ing progress and con­tribut­ing to the sec­tor’s growth. Pa­tient ad­vo­ca­cy groups, in par­tic­u­lar, are in­te­gral to help­ing with ther­a­py de­vel­op­ment, pa­tient care and man­age­ment and ul­ti­mate­ly pa­tient ac­cess to in­no­v­a­tive treat­ment for un­met needs.”

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