Ful­ly Char­ac­ter­iz­ing a Man­u­fac­tur­ing Process is Crit­i­cal for Ad­vanc­ing Gene Ther­a­pies and Pri­or­i­tiz­ing Pa­tient Safe­ty

Gene ther­a­pies have pos­i­tive­ly im­pact­ed the lives of many pa­tients and fam­i­lies around the world, and they con­tin­ue to hold promise for those suf­fer­ing from dev­as­tat­ing ge­net­ic dis­eases. I am proud to have led the chem­istry, man­u­fac­tur­ing and con­trol (CMC) ef­forts for a glob­al­ly ap­proved gene ther­a­py for spinal mus­cu­lar at­ro­phy (SMA) that has now suc­cess­ful­ly treat­ed more than 3,000 pa­tients world­wide.ⁱ In the case of SMA Type 1, chil­dren with this most dev­as­tat­ing form of the rare ge­net­ic dis­ease are not like­ly to live to age two.ⁱⁱ Thanks to gene ther­a­py, those chil­dren are now cel­e­brat­ing birth­days and mile­stones that were pre­vi­ous­ly im­pos­si­ble. I share this as an ex­am­ple of the tru­ly in­cred­i­ble po­ten­tial gene ther­a­pies and oth­er ad­vanced med­i­cines have for pa­tients and fam­i­lies.

Cur­rent­ly, there are ap­prox­i­mate­ly 16 gene ther­a­pies (in­clud­ing ge­net­i­cal­ly mod­i­fied cell ther­a­pies) ap­proved by the Unit­ed States Food and Drug Ad­min­is­tra­tion (FDA).ⁱⁱⁱ In­no­va­tors, reg­u­la­tors and pa­tients all want to see that num­ber in­crease ex­po­nen­tial­ly in the near term, and a cru­cial part of achiev­ing that goal is en­sur­ing op­ti­mal safe­ty pro­files for gene ther­a­pies. It is well un­der­stood that man­u­fac­tur­ing a ther­a­peu­tic prod­uct with an ex­cel­lent im­pu­ri­ty pro­file con­tributes to im­proved safe­ty and pa­tient out­comes. Com­mon­ly, man­u­fac­tur­ers con­cen­trate on op­ti­miz­ing full ver­sus emp­ty cap­sid ra­tios in a fi­nal drug prod­uct. How­ev­er, pay­ing at­ten­tion to cap­sids alone will not whol­ly ad­dress this is­sue. What’s miss­ing from that cal­cu­la­tion is a fo­cus on the com­pre­hen­sive im­pu­ri­ty pro­file, in­clud­ing a pri­or­i­ty around func­tion­al full cap­sids. Ful­ly char­ac­ter­iz­ing a man­u­fac­tur­ing process to un­der­stand what’s dri­ving rel­a­tive lev­els of im­pu­ri­ties is crit­i­cal. Ul­ti­mate­ly, de­sign­ing a process that max­i­mizes the safe­ty and qual­i­ty at­trib­ut­es of a med­i­cine could sup­port an in­crease in the num­ber of gene ther­a­pies reach­ing the mar­ket.

What are func­tion­al full cap­sids and why are they im­por­tant?

When think­ing about the pu­ri­ty of a gene ther­a­py drug prod­uct, man­u­fac­tur­ers and reg­u­la­tors gen­er­al­ly con­sid­er a cou­ple dif­fer­ent in­di­ca­tors – per­cent­age of full cap­sids and pres­ence of oth­er im­pu­ri­ties. A full cap­sid con­tains a full genome se­quence to en­sure the prod­uct is ther­a­peu­ti­cal­ly ac­tive. An emp­ty cap­sid does not car­ry ge­net­ic ma­te­r­i­al, and a par­tial­ly filled cap­sid may con­tain frag­ments of DNA that are not ther­a­peu­ti­cal­ly rel­e­vant and in some cas­es, may be detri­men­tal to pa­tients. A func­tion­al full cap­sid, how­ev­er,  pro­vides the in­tend­ed ther­a­peu­tic ben­e­fit and con­tains min­i­mal in­ef­fec­tive or sub­op­ti­mal ge­net­ic con­tent that could con­tribute to safe­ty con­cerns. The dis­tinc­tion may seem mi­nor but the ca­pa­bil­i­ty to de­fin­i­tive­ly sep­a­rate full, par­tial and emp­ty cap­sids helps to max­i­mize prod­uct pu­ri­ty and po­ten­cy, pri­or­i­tize pa­tient safe­ty, and sup­port a ro­bust CMC pack­age for reg­u­la­tors.

There’s no sub­sti­tute for deep an­a­lyt­i­cal ex­pe­ri­ence

Tra­di­tion­al­ly, CMC ef­forts fo­cus on iden­ti­fy­ing im­pu­ri­ties, in­clud­ing cap­sid im­pu­ri­ties, us­ing one or two an­a­lyt­i­cal tests. It is vi­tal­ly im­por­tant, how­ev­er, to com­pre­hen­sive­ly as­sess the end prod­uct and con­sid­er ex­act­ly what is con­tained with­in the cap­sid. The Ad­vanced Med­i­cine Part­ners team is re­spon­si­ble for de­vel­op­ing and qual­i­fy­ing an­a­lyt­i­cal meth­ods to sup­port mul­ti­ple com­mer­cial ad­vanced med­i­cine prod­ucts. We lever­age this deep ex­pe­ri­ence to se­lect an ex­ten­sive set of or­thog­o­nal an­a­lyt­i­cal meth­ods and ful­ly char­ac­ter­ize the man­u­fac­tur­ing process to en­sure ro­bust and re­pro­ducible unit op­er­a­tions. At Ad­vanced Med­i­cine Part­ners, we pri­or­i­tize the full char­ac­ter­i­za­tion ear­ly on in the prod­uct life­cy­cle and en­rich for func­tion­al full cap­sids and re­duced lev­els of im­pu­ri­ties to en­sure pa­tients are re­ceiv­ing prod­uct that max­i­mizes po­ten­cy and min­i­mizes safe­ty con­cerns. See Fig­ure 1.

FIG­URE 1

It’s Crit­i­cal to Char­ac­ter­ize Prod­uct Us­ing an Or­thog­o­nal Set of Meth­ods

Sev­er­al an­a­lyt­i­cal meth­ods are wide­ly used to iden­ti­fy full, emp­ty and par­tial cap­sids. One is the cal­cu­la­tion of vec­tor genome titer by ddPCR or qPCR ver­sus to­tal cap­sid quan­tifi­ca­tion by serotype-spe­cif­ic ELISA. This is a com­mon­ly used tech­nique, and while it can de­tect full or emp­ty cap­sids, it can­not dif­fer­en­ti­ate func­tion­al full from par­tial­ly full cap­sids. Trans­mis­sion elec­tron mi­croscopy (TEM) and high-per­for­mance liq­uid chro­matog­ra­phy (HPLC) are oth­er tech­niques used for char­ac­ter­iz­ing cap­sids. An ad­vanced and ef­fec­tive method is den­si­ty-based sep­a­ra­tion through an­a­lyt­i­cal ul­tra­cen­trifu­ga­tion (AUC).  In­clud­ing AUC, Ad­vanced Med­i­cine Part­ners em­ploys sev­er­al or­thog­o­nal an­a­lyt­i­cal meth­ods, strate­gi­cal­ly us­ing them at ap­pro­pri­ate stages of the man­u­fac­tur­ing process, to ful­ly char­ac­ter­ize prod­uct and pre­cise­ly iden­ti­fy func­tion­al full, par­tial and emp­ty cap­sids.

By strate­gi­cal­ly us­ing mul­ti­ple an­a­lyt­i­cal meth­ods, Ad­vanced Med­i­cine Part­ners can pro­vide part­nered com­pa­nies with a su­pe­ri­or ther­a­peu­tic prod­uct with max­i­mum pu­ri­ty and po­ten­cy. See Fig­ure 2

FIG­URE 2
To in­crease the ap­provals of gene ther­a­pies with life-chang­ing po­ten­tial, we need to set a new stan­dard for man­u­fac­tur­ing and an­a­lyt­i­cal test­ing. Ful­ly char­ac­ter­iz­ing a man­u­fac­tur­ing process and prod­uct al­lows spon­sors to de­vel­op a fil­ing pack­age that pro­vides reg­u­la­tors with the ro­bust da­ta they ex­pect. In­creased prod­uct pu­ri­ty will sup­port im­proved pa­tient out­comes, and pa­tients de­serve the best of what’s pos­si­ble. Iden­ti­fy­ing and en­rich­ing for func­tion­al full cap­sids is piv­otal for max­i­miz­ing prod­uct pu­ri­ty and in­creas­ing po­ten­cy of gene ther­a­pies. At Ad­vanced Med­i­cine Part­ners, we have mas­tered the ca­pa­bil­i­ty to ful­ly char­ac­ter­ize a prod­uct to en­sure part­nered com­pa­nies re­ceive drug prod­uct that min­i­mizes im­pu­ri­ties. We are ea­ger to use this knowl­edge and deep ex­pe­ri­ence to progress gene ther­a­py man­u­fac­tur­ing and ac­cel­er­ate gene ther­a­py pro­grams to the clin­ic and be­yond.

To learn more about Ad­vanced Med­i­cine Part­ners’ ca­pa­bil­i­ties and ser­vices, vis­it www.ampgtx.com or email us at part­ner­ship@ampgtx.com.

Ref­er­ences:

ⁱNo­var­tis. 2023. Q4 2022 Re­sults In­vestor pre­sen­ta­tion [Pow­er­Point Pre­sen­ta­tion]. Avail­able at: https://www.no­var­tis.com/sites/no­var­tis_com/files/q4-2022-in­vestor-pre­sen­ta­tion.pdf. Ac­cessed De­cem­ber 2023.

ⁱⁱ Kolb SJ, Kissel JT. Spinal Mus­cu­lar At­ro­phy. Neu­rol Clin [In­ter­net]. 2015 Nov [cit­ed 2017 Oct 2];33(4):831–46. Avail­able from: http://www​.ncbi.nlm.nih​.gov/pmc/ar­ti­cles/PMC4628728

ⁱⁱⁱ Amer­i­can So­ci­ety of Gene and Cell Ther­a­py. 2023. Q3 2023 Quar­ter­ly Da­ta Re­port [Pow­er­Point Pre­sen­ta­tion]. Avail­able at: https://as­gct.org/glob­al/doc­u­ments/as­gct-cite­line-q3-2023-re­port.as­px. Ac­cessed De­cem­ber 2023.