Qual­i­ty Con­trol in Cell and Gene Ther­a­py – What’s Re­al­ly at Stake?

In ear­ly 2021, Blue­bird Bio was forced to sus­pend clin­i­cal tri­als of its gene ther­a­py for sick­le cell dis­ease af­ter two pa­tients in the tri­al de­vel­oped can­cer. As com­pa­ny sci­en­tists rushed to as­sess whether there was any causal link be­tween the ther­a­py and the can­cer cas­es, Blue­bird’s stock val­ue plum­met­ed – as did those of mul­ti­ple oth­er bio­phar­ma com­pa­nies de­vel­op­ing sim­i­lar ther­a­pies.

While in­ves­ti­ga­tions con­clud­ed that the gene ther­a­py was un­like­ly to have caused can­cer, in­vestors and the pub­lic may be more skit­tish re­gard­ing the safe­ty of gene and cell ther­a­pies af­ter this episode. This re­cent ex­am­ple high­lights how del­i­cate the fields of cell and gene ther­a­py re­main to­day, even as they show great promise.

Ro­bust qual­i­ty con­trol is the key to es­tab­lish­ing trust and max­i­miz­ing these ther­a­pies’ suc­cess. Sen­si­tive tools are need­ed to test batch­es for con­t­a­m­i­nants such as mi­croor­gan­isms and en­do­tox­ins and mea­sure the suc­cess and safe­ty of vi­ral re­pro­gram­ming met­rics such as vec­tor pro­duc­tiv­i­ty, pu­ri­ty, and bi­o­log­i­cal ac­tiv­i­ty.

Droplet Dig­i­tal PCR (ddPCR) tech­nol­o­gy is one of the most sen­si­tive qual­i­ty con­trol tools avail­able to­day, of­fer­ing ab­solute quan­tifi­ca­tion of nu­cle­ic acids and oth­er mol­e­cules. Be­cause of these ad­van­tages, this tool will like­ly be­come even more com­mon as the in­dus­try pro­gress­es.

There are three key ar­eas where com­pa­nies have a lot to lose if qual­i­ty con­trol fails, but much to gain if it is ex­e­cut­ed well: cost, time, and pa­tient safe­ty. Let’s ex­plore how man­u­fac­tur­ers can achieve peace of mind and gain ad­van­tages in all three ar­eas.

Bio-Rad’s QX ONE Droplet Dig­i­tal PCR (ddPCR) in­stru­ment

Click on the im­age to see the full-sized ver­sion

Mil­lions of Dol­lars On the Line

At the high­est lev­el, mod­el­ing stud­ies have shown that low­er­ing the over­all batch fail­ure rate of a prod­uct can re­duce the cost of goods by mil­lions of dol­lars per batch. If qual­i­ty con­trol is­sues or ques­tions come to light in lat­er clin­i­cal tri­al phas­es, cor­rect­ing these can re­quire sig­nif­i­cant in­vest­ment. En­tire plants may need to be stripped of equip­ment to elim­i­nate a con­t­a­m­i­na­tion source, re­sult­ing in lost pro­duc­tiv­i­ty and mas­sive loss of cap­i­tal. In worst-case sce­nar­ios, a prod­uct may fail and cause sig­nif­i­cant loss­es.

In head-to-head tests, ddPCR sys­tems have de­tect­ed con­t­a­m­i­nants at lev­els where oth­er meth­ods such as qPCR yield­ed neg­a­tive re­sults. This en­ables qual­i­ty con­trol spe­cial­ists to iden­ti­fy any is­sues as soon as they arise, pre­vent­ing con­t­a­m­i­nant spread or pro­duc­tion-line domi­no ef­fects that can lead to the cat­a­stroph­ic fail­ures de­scribed above.

On a day-to-day ba­sis, one of the costli­est el­e­ments of qual­i­ty con­trol is the skilled la­bor re­quired to con­duct many stan­dard tests, such as flow cy­tom­e­try as­says. Sci­en­tists who can per­form these tasks are in short sup­ply, so hir­ing large teams can be ex­pen­sive.

Com­pared to many oth­er tech­nolo­gies, ddPCR in­stru­ments are easy to use and al­lows for greater au­toma­tion, free­ing skilled in­di­vid­u­als to per­form com­plex da­ta analy­ses and oth­er im­por­tant work. ddPCR tech­nol­o­gy is al­so ver­sa­tile – it can pre­cise­ly de­tect, iden­ti­fy, and quan­ti­fy mul­ti­ple kinds of mol­e­cules. This al­lows com­pa­nies to de­vel­op stan­dard op­er­at­ing pro­ce­dures across var­i­ous ar­eas of qual­i­ty con­trol, there­by stream­lin­ing pro­duc­tion process­es over­all and al­low­ing for op­ti­miza­tion ben­e­fits that can lead to sig­nif­i­cant cost sav­ings over time.

No Time to Waste

More tra­di­tion­al ther­a­pies, such as small mol­e­cule drugs and even an­ti­body ther­a­peu­tics, can be pro­duced, test­ed, and stored in large batch­es that can then be dis­pensed to pa­tients on an as-need­ed ba­sis. But many cell and gene ther­a­pies are au­tol­o­gous, mean­ing they take the pa­tient’s cells, mod­i­fy them, and then re­turn them to the pa­tient’s body. A stage IV can­cer pa­tient may not be able to wait a month or more to re­ceive their treat­ment. There­fore, time is of the essence when pro­duc­ing and test­ing these prod­ucts.

Gold-stan­dard tests for con­t­a­m­i­nants like my­coplas­ma take up to 4 weeks per batch, caus­ing sig­nif­i­cant bot­tle­necks in man­u­fac­tur­ing process­es. But cut­ting cor­ners on qual­i­ty con­trol can re­sult in even greater de­lays due to the need to re­peat tests or even pro­duce re­place­ment batch­es. Sav­ing time re­quires a so­lu­tion that is both more ef­fi­cient and of­fers equal or greater ac­cu­ra­cy and pre­ci­sion.

In con­trast to tra­di­tion­al meth­ods, sci­en­tists can use ddPCR tools to de­tect con­t­a­m­i­nants and as­sess vi­ral titer met­rics in un­der a day. Fur­ther­more, be­cause the tech­nol­o­gy is less af­fect­ed by am­pli­fi­ca­tion ef­fi­cien­cy vari­ables, there is less need to re­peat tests to con­firm mea­sure­ments.

On longer timescales, lack of scal­a­bil­i­ty for ther­a­pies is an ex­is­ten­tial threat to their fu­ture suc­cess. Since so many cell and gene ther­a­pies are nov­el, first-in-class treat­ments, in­no­va­tor com­pa­nies have of­ten kept scale in­cred­i­bly low and fo­cused on push­ing prod­ucts through to ap­proval. But to make these types of ther­a­pies wide­ly ac­ces­si­ble to pa­tients and tack­le big­ger in­di­ca­tions, the in­dus­try needs scal­able, high-through­put so­lu­tions for qual­i­ty con­trol. Man­u­fac­tur­ers can­not sim­ply keep build­ing big­ger fa­cil­i­ties and hir­ing more peo­ple ad in­fini­tum, and chang­ing qual­i­ty con­trol meth­ods af­ter a prod­uct has been brought to mar­ket can cause reg­u­la­to­ry road­blocks. ddPCR tech­nol­o­gy is scal­able and has op­tions for in­creas­ing through­put, such as cre­at­ing mul­ti­plexed as­says.

Keep­ing Pa­tients Safe

Every­thing is about the pa­tients. ddPCR as­says can de­tect dan­ger­ous con­t­a­m­i­nants and oth­er is­sues – such as in­cor­rect dosages – that might slip through the cracks with oth­er tech­nolo­gies. This en­sures safe­ty and yields da­ta qual­i­ty that pro­tects pa­tients and sat­is­fies reg­u­la­tors.

The most sig­nif­i­cant in­cen­tive for hav­ing the most sen­si­tive, pre­cise qual­i­ty con­trol tools and meth­ods is min­i­miz­ing the pos­si­bil­i­ty that any in­di­vid­u­als will ex­pe­ri­ence un­nec­es­sary or un­fore­seen con­se­quences from your cell or gene ther­a­py. Qual­i­ty con­trol may not seem ex­cit­ing from the out­side, but sci­en­tists in this area take their work in­cred­i­bly se­ri­ous­ly. They know they are the last line of de­fense be­tween pa­tients and any faulty or un­safe prod­uct. Equip­ping these in­di­vid­u­als with the best tools for the job ben­e­fits every­one.

Vis­it Bio-Rad’s web­site to learn about the wide range of ap­pli­ca­tions for ddPCR tech­nol­o­gy for cell and gene ther­a­py qual­i­ty con­trol.

AUTHOR

Mark White