Process Plat­forms vs. Cus­tom Process De­vel­op­ment for AAVs and Gene Ther­a­pies

Gene ther­a­pies hold huge promise for pa­tients with a range of mono­genic dis­eases and un­met med­ical needs. How­ev­er, they’ve had their fair share of safe­ty con­cerns – dos­ing and de­liv­ery have been the sources of re­cent set­backs. Ef­fi­cient, scal­able, and cost-ef­fec­tive man­u­fac­tur­ing is an­oth­er hur­dle the in­dus­try needs to over­come be­fore com­mer­cial­ly vi­able ther­a­pies can be li­censed. AAV tech­nol­o­gy ad­vances are al­so need­ed to ad­dress yield, ma­te­r­i­al costs, and cy­cle times in a bid to bring down COGS and ul­ti­mate­ly in­crease fi­nan­cial ac­ces­si­bil­i­ty by glob­al pa­tient pop­u­la­tions.

There is al­so a cash crunch echo­ing through the gene ther­a­py in­dus­try with lay­offs and com­pa­ny clo­sures af­fect­ing many promis­ing late-stage ad­vanced ther­a­pies from com­mer­cial­iz­ing. This ap­pears to be the sharp end of a wider in­dus­try trend; the hype bub­ble has burst, and the promise of steady, high-val­u­a­tion cash in­flux­es has gone.

To ad­dress is­sues of cost, time to mar­ket and man­u­fac­tur­ing com­plex­i­ty, many de­vel­op­ers have turned to turnkey man­u­fac­tur­ing plat­forms. The ques­tion is whether these plat­forms pro­vide the right so­lu­tion for suc­cess­ful CMC de­vel­op­ment. Use of plat­forms has come full cir­cle – 5-10 years ago many de­vel­op­ers were man­u­fac­tur­ing their vi­ral vec­tors at aca­d­e­m­ic vec­tor core cen­ters. This led to aca­d­e­m­ic process­es that were not scal­able or suit­able for com­mer­cial GMP man­u­fac­tur­ing, re­sult­ing in a big shift for biotech to de­vel­op process­es that they own and con­trol.

Process Plat­form vs. Cus­tom De­vel­op­ment

There is a cur­rent resur­gence in process plat­forms that of­fer a plug-and-play ap­proach to man­u­fac­tur­ing AAVs. They are in­creas­ing­ly avail­able and not just from aca­d­e­m­ic cen­ters; larg­er com­mer­cial en­ti­ties are now of­fer­ing turnkey plat­forms as part of their suite of man­u­fac­tur­ing and de­vel­op­ment ser­vices. These plat­forms do present an at­trac­tive so­lu­tion for ear­ly-stage as­sets, es­pe­cial­ly when striv­ing to be first-in-clin­ic; they can short­en process de­vel­op­ment time­lines and re­duce costs at a time where in­vest­ment in ear­ly as­sets needs to be tight­ly con­trolled.

How­ev­er, there is a bal­ance of risk at play in the de­ci­sion to im­ple­ment a process plat­form vs. de­vel­op­ing a cus­tom one. While process plat­forms promise speed to clin­ic up front, there re­mains risk in process per­for­mance and ro­bust­ness, and, fur­ther down the line, with clin­i­cal de­vel­op­ment and com­mer­cial­iza­tion. There is a re­duced abil­i­ty to cus­tomize with a turnkey plat­form and it might not re­sult in the best process for your prod­uct. For those de­vel­op­ers who have long-term plans to com­mer­cial­ize and achieve reg­u­la­to­ry ap­proval, it is dis­ad­van­ta­geous to step away from own­ing and un­der­stand­ing their process. It is al­so im­por­tant to note that the val­ue of a com­pa­ny is al­so in­trin­si­cal­ly linked to its process as well as its prod­uct as­sets.

While a cus­tom process may re­quire time up­front for de­vel­op­ment, it will like­ly mit­i­gate many risks down­stream. Process plat­forms present chal­lenges for late-stage man­u­fac­tur­ing and their use may re­quire process changes lat­er down the line with se­ri­ous im­pli­ca­tions for the time, cost, and suc­cess­ful demon­stra­tion of com­pa­ra­bil­i­ty to the sat­is­fac­tion of reg­u­la­to­ry au­thor­i­ties.

Mit­i­gat­ing process con­trol risks

One of the most cru­cial fac­tors to con­sid­er is whether the plat­form tech­nol­o­gy can be pur­chased, li­censed or sub-li­censed in the event you want to move man­u­fac­tur­ing in house or to an­oth­er CD­MO. In many cas­es, there is no li­cens­ing op­tion, there­fore, if you move away from the CD­MO and their plat­form tech­nol­o­gy, it is not pos­si­ble to con­tin­ue us­ing that process. More­over, there may be no ac­cess to crit­i­cal process in­for­ma­tion and the con­trol strat­e­gy; no pro­duc­tion or pu­rifi­ca­tion pa­ra­me­ters, no for­mu­la­tion in­for­ma­tion etc. so all con­trol may be giv­en up when us­ing process plat­form so­lu­tions.

It is vi­tal to be able to ask the right ques­tions of your CD­MO be­fore en­ter­ing in­to an agree­ment in­volv­ing a process plat­form. For ex­am­ple:

    • – Is the process plat­form avail­able to pur­chase or li­cense?
    • – What is the li­cens­ing or sub li­cens­ing fee struc­ture?
    • – Will you pro­vide in­for­ma­tion on process con­trols, pro­duc­tion and pu­rifi­ca­tion pa­ra­me­ters?
    • – What is the con­trol strat­e­gy?
    • – Will I be able to con­tin­ue to use pro­pri­etary ma­te­ri­als?
    • – Will I have ac­cess to the an­a­lyt­i­cal meth­ods?

Fur­ther­more, it is es­sen­tial for the spon­sor to de­cide how much con­trol they need to un­der­stand the process, ma­te­r­i­al, equip­ment, and an­a­lyt­i­cal re­la­tion­ships that ul­ti­mate­ly in­form the con­trol strat­e­gy and en­sure prod­uct qual­i­ty. With­out this knowl­edge, a high lev­el of risk is as­sumed when en­ter­ing the clin­ic or in­ter­act­ing with reg­u­la­tors.

It all comes down to how much con­trol you are will­ing to give up and how you plan to de­vel­op and man­age the life­cy­cle of your prod­uct.

Off­set­ting time and cost of cus­tom de­vel­op­ment

At the Cen­ter for Break­through Med­i­cines (CBM) we be­lieve that it is pos­si­ble to achieve the same cost and time sav­ing ad­van­tages of a plat­form process with a cus­tom ap­proach by tak­ing es­tab­lished tech­nolo­gies and build­ing a team and part­ner­ships that have the skills to op­ti­mize for suc­cess­ful com­mer­cial­iza­tion.

‘Plat­form process’ is a some­thing of a mis­nomer be­cause there isn’t a true turnkey process, some lev­el of de­vel­op­ment will be need­ed based on your prod­uct, for ex­am­ple, if your cap­sid starts ag­gre­gat­ing, for­mu­la­tion de­vel­op­ment will be need­ed. In com­par­i­son, when build­ing a cus­tom process, the same ar­eas are ad­dressed, but it al­so al­lows for process de­vel­op­ment with built-in flex­i­bil­i­ty.

Con­sid­er­ing the cost and time sav­ing ben­e­fits of a process plat­form, it’s im­por­tant to con­sid­er how much can be saved, as the cost of the cus­tom ap­proach is a frac­tion of the over­all man­u­fac­tur­ing costs. The cost sav­ing is less than 15% of over­all CMC costs and time sav­ing is up to four months. Is this lev­el of cost-sav­ing worth the loss of con­trol and fu­ture risks?

More im­por­tant­ly, there are ways to off­set these in­cre­men­tal cost and time in­creas­es. The aim is to make mean­ing­ful in­vest­ments in process de­vel­op­ment, while still main­tain­ing an ac­cept­able time­line. In some in­stances, de­vel­op­ment is not al­ways the bot­tle­neck to fil­ing an IND (for ex­am­ple pre­clin­i­cal tox­i­col­o­gy stud­ies can of­ten be the lim­it­ing step). So, by im­ple­ment­ing a strate­gic de­vel­op­ment plan up­front you can make the best use of your time and off­set the ad­di­tion­al time need­ed to cus­tomize your process de­vel­op­ment at the out­set.


Avi Nandi

VP, Process Development at Center for Breakthrough Medicines