How to safe­ly and suc­cess­ful­ly speed your in­jectable in­to the clin­ic

With house­hold names like Botox and can­cer treat­ment Keytru­da, it’s no sur­prise that the glob­al in­jectable drugs mar­ket is ex­pect­ed to top $1.2 tril­lion be­tween 2022 and 2030. With a pro­ject­ed 9% com­pound an­nu­al growth rate (CA­GR) in that same pe­ri­od, the mar­ket is quick­ly ex­pand­ing to pro­vide des­per­ate­ly need­ed treat­ments in ar­eas like on­col­o­gy and or­phan dis­ease to psy­chi­atric dis­or­ders and im­mun­od­e­fi­cien­cies.

For all their promise and in­creas­ing pop­u­lar­i­ty – fu­eled large­ly by the de­mand for bi­o­log­ics – in­jecta­bles com­mon­ly face a stub­born chal­lenge: so­lu­tion sta­bil­i­ty. Many mol­e­cules are less chem­i­cal­ly sta­ble in liq­uid so­lu­tion than in sol­id form. Bio­phar­ma com­pa­nies are in­creas­ing­ly pur­su­ing a process called lyophiliza­tion – or freeze-dry­ing – that re­moves liq­uid to cre­ate a shelf-sta­ble sol­id for­mu­la­tion that can be more eas­i­ly stored, dis­trib­uted and safe­ly re­con­sti­tut­ed for pa­tient de­liv­ery.

Lyophilized in­jecta­bles are speed­ing new drugs’ path to clin­ic and ex­tend­ing shelf life – and grow­ing rapid­ly. Lyophilized drugs ac­count for about 16 per­cent of the top 100 phar­ma­ceu­ti­cal drugs and 35 per­cent of bi­o­log­ics, ac­cord­ing to BCC Re­search. The ma­jor­i­ty of in­jectable drugs may soon re­quire lyophiliza­tion. This bur­geon­ing seg­ment re­quires spe­cial­ized ex­per­tise and equip­ment to per­form ef­fec­tive­ly, ef­fi­cient­ly and in full com­pli­ance. In­deed, the lyophiliza­tion equip­ment mar­ket alone is pro­ject­ed to more than dou­ble in the next ten years to $2.3 bil­lion by 2032, with 8.8% CA­GR be­tween 2022-2032.

In this guide, we look at how de­vel­op­ers can har­ness the pow­er of lyophiliza­tion to get their small mol­e­cule and bi­o­log­ic in­jectable prod­ucts in­to the clin­ic to help pa­tients even faster.

Get­ting lyophiliza­tion right

A lyophiliza­tion cy­cle con­sists of three core process­es that can span sev­er­al days. First, a prod­uct’s wa­ter or sol­vent is frozen to cre­ate ice crys­tals. Next, pri­ma­ry dry­ing or sub­li­ma­tion oc­curs, and ice crys­tals are re­moved via vac­u­um. Fi­nal­ly, a sec­ondary dry­ing or des­orp­tion step re­moves resid­ual mois­ture.

Each step must be per­formed with ex­act­ing pre­ci­sion to avoid com­pro­mis­ing the fi­nal prod­uct. Even the sub­tlest vari­a­tions in freez­ing rate, dry­ing rate, tem­per­a­ture con­trol and lev­els of vac­u­um or mois­ture, for ex­am­ple, can ru­in a batch. It takes re­peat­ed ex­per­i­men­ta­tion to cal­i­brate the right pa­ra­me­ters for each unique prod­uct, dosage and con­tain­er used. If the lyophiliza­tion cy­cle is suc­cess­ful, it re­sults in a sta­ble sol­id or “cake” that may lat­er be eas­i­ly re­con­sti­tut­ed just be­fore pa­tient de­liv­ery through in­jec­tion, in­fu­sion or im­plan­ta­tion.

Plan­ning for suc­cess: Is­sues to con­sid­er

The in­her­ent pres­sures of drug prod­uct de­vel­op­ment and man­u­fac­tur­ing are height­ened by pa­tient, provider and reg­u­la­tor ex­pec­ta­tions for the qual­i­ty, pu­ri­ty and steril­i­ty of in­jecta­bles and oth­er drugs. The tech­ni­cal rig­ors of the lyophiliza­tion process add an­oth­er lay­er of com­plex­i­ty. Craft­ing an ide­al lyophiliza­tion cy­cle for a par­tic­u­lar prod­uct is both art and sci­ence. Ex­ten­sive test­ing and val­i­da­tion are re­quired to de­ter­mine how for­mu­la­tion com­po­nents re­spond to the freez­ing and dry­ing process­es.

To move through the jour­ney ef­fi­cient­ly, de­vel­op­ers must un­der­take thor­ough plan­ning and dili­gent im­ple­men­ta­tion for qual­i­ty con­trol and steril­i­ty as­sur­ance. “In our in­dus­try, peo­ple get caught up in ‘What’s the sci­ence? What’s the equip­ment? What are the cool tech­nolo­gies?’ But re­al­ly, suc­cess comes down to do­ing the right things every day,” not­ed Richard Sid­well, vice pres­i­dent and chief sci­en­tif­ic of­fi­cer at So­ci­etal CD­MO, a leader in lyophiliza­tion that serves glob­al clients seek­ing for­mu­la­tion de­vel­op­ment, clin­i­cal and com­mer­cial man­u­fac­tur­ing, pack­ag­ing, lo­gis­tics and reg­u­la­to­ry sup­port.

Lyophilized drug de­vel­op­ers must con­sid­er:

  • For­mu­la­tion de­vel­op­ment – Var­i­ous con­cen­tra­tions of the ac­tive phar­ma­ceu­ti­cal in­gre­di­ent (API) and ex­cip­i­ents should be test­ed. The right com­bi­na­tion will op­ti­mize prod­uct ap­pear­ance, sta­bil­i­ty and ef­fi­ca­cy – in both sol­id and re­con­sti­tut­ed forms – and re­sult in long-term cost sav­ings as pro­duc­tion scales. Bio­com­pat­i­ble ex­cip­i­ents such as sta­bi­liz­ers and bulk­ing agents must be se­lect­ed with at­ten­tion to their spe­cif­ic prop­er­ties re­gard­ing phys­i­cal state, sol­u­bil­i­ty and phys­i­cal and chem­i­cal sta­bil­i­ty.
  • Equip­ment com­pat­i­bil­i­ty and safe­ty stud­ies – Stud­ies must as­sess the com­pat­i­bil­i­ty of the drug prod­uct and the ma­te­r­i­al with which it comes in­to con­tact dur­ing pro­duc­tion and stor­age. Fin­ished prod­ucts must be as­sessed for steril­i­ty, en­do­tox­in con­tent and physic­o­chem­i­cal sta­bil­i­ty of lyophilized and re­con­sti­tut­ed ma­te­r­i­al.
  • Scal­ing, man­u­fac­tur­ing, and lo­gis­tics – Fu­ture phas­es of the process should be con­sid­ered from the be­gin­ning to avoid de­vel­op­ing a small-scale process that can­not work at a larg­er scale due to in­suf­fi­cient lyophiliza­tion cham­ber and/or con­denser ca­pac­i­ty, in­ad­e­quate heat trans­duc­tion in the lyophiliza­tion cham­ber, and/or non-uni­form nu­cle­ation in the sam­ples, ster­il­iza­tion (steam-in-place and clean-in-place) ca­pac­i­ty or oth­er tech­ni­cal is­sues. De­vel­op­ers must demon­strate that their pro­duc­tion and fa­cil­i­ty man­age­ment pro­to­cols can sup­port asep­tic man­u­fac­tur­ing at scale, in­clud­ing main­tain­ing steril­i­ty through rig­or­ous en­vi­ron­men­tal con­trols and mon­i­tor­ing. Lo­gis­ti­cal plans must al­so as­sure that spe­cial con­di­tions, such as low-tem­per­a­ture stor­age, can be met through­out the sup­ply chain.
  • Sup­ply chain is­sues – Long lead times are fre­quent in to­day’s sup­ply chain en­vi­ron­ment, re­quir­ing pur­chase de­ci­sions to be made quick­ly to keep projects on track. So­ci­etal helps clients by main­tain­ing a stock of com­mon ex­cip­i­ents and com­po­nents and by lever­ag­ing ven­dor re­la­tion­ships for time­ly ful­fill­ment. The com­pa­ny’s new sec­ond-source ser­vice mod­el en­hances clients’ pre­pared­ness for and re­spon­sive­ness to sup­ply chain vul­ner­a­bil­i­ties by ex­e­cut­ing the nec­es­sary sourc­ing and plan­ning phase ac­tiv­i­ties of a stan­dard tech­ni­cal trans­fer process in ad­vance of the phys­i­cal tech­ni­cal trans­fer ac­tiv­i­ties, well be­fore prod­uct sup­ply is need­ed. Clients not on­ly save time and mon­ey but al­so safe­guard the con­ti­nu­ity of vi­tal drug sup­ply.
  • Doc­u­men­ta­tion – Ac­cu­rate doc­u­men­ta­tion for all steps of the process is es­sen­tial to sup­port fil­ing and ap­proval.

A qual­i­fied con­tract de­vel­op­ment and man­u­fac­tur­ing or­ga­ni­za­tion (CD­MO) work­ing as your part­ner can help as­sess these fac­tors to mit­i­gate risk and tai­lor prac­tices to your prod­uct pro­file.

Find­ing the right part­ner to ad­vance your drug can­di­date

Many de­vel­op­ers are seek­ing ex­ter­nal sup­port for lyophiliza­tion ac­tiv­i­ty giv­en its com­plex­i­ty and the sig­nif­i­cant cost to ac­quire and main­tain the nec­es­sary equip­ment. You must eval­u­ate both a po­ten­tial part­ner’s tech­ni­cal ca­pac­i­ty and cul­tur­al fit.

CD­MOs must have high­ly spe­cial­ized ex­per­tise and equip­ment to han­dle for­mu­la­tion, asep­tic fill-fin­ish, lyophiliza­tion, pack­ag­ing and lo­gis­tics ser­vices at scale. So­ci­etal’s state-of-the-art fill­ing line, with fill rates up to 2,000 vials per hour, and ex­ten­sive ex­pe­ri­ence in for­mu­la­tion de­vel­op­ment, asep­tic fill-fin­ish and lyophiliza­tion of ster­ile so­lu­tions, poly­mer-based sus­tained-re­lease and/or long-act­ing nanosus­pen­sions or mi­cros­pheres, en­able it to flex­i­bly sup­port cus­tomers through­out drug de­vel­op­ment. A pres­ence on both east and west coasts of the Unit­ed States fa­cil­i­tates the lo­gis­tics of do­mes­tic and glob­al projects.

The com­pa­ny’s nov­el lyophiliza­tion equip­ment, with Con­troLyo® lyophiliza­tion tech­nol­o­gy, uni­form­ly and in­stan­ta­neous­ly in­duces nu­cle­ation with­in the en­tire freeze-dry­er space, per­mit­ting ad­van­ta­geous pro­cess­ing of a va­ri­ety of in­jectable prod­ucts, such as small mol­e­cules, bi­o­log­ics, li­po­somes, ster­ile sus­pen­sions, emul­sions and dilu­ents. Ben­e­fits in­clude re­duced dry­ing times, less­ened freez­ing stress on com­plex prod­ucts, and short­er re­con­sti­tu­tion times – there­by pre­serv­ing func­tion­al­i­ty and in­creas­ing the sta­bil­i­ty of high-val­ue drug prod­ucts and sav­ing valu­able time.

De­vel­op­ers should ver­i­fy that a po­ten­tial CD­MO part­ner has the ex­pe­ri­ence to get the job done. For ex­am­ple:

  • Does the com­pa­ny have a suc­cess­ful track record with in­jectable prod­ucts across key di­men­sions in­clud­ing for­mu­la­tion, process, an­a­lyt­ics, qual­i­ty as­sur­ance, ma­te­ri­als man­age­ment and reg­u­la­to­ry com­pli­ance?
  • If the com­pa­ny has pro­duced a tech­ni­cal­ly sound and well-doc­u­ment­ed for­mu­la­tion sim­i­lar to your prod­uct pro­file, did it sat­is­fy reg­u­la­to­ry re­quire­ments, or were there da­ta gaps and cost­ly de­lays?

“Lyophiliza­tion is the most proven tech­nol­o­gy to im­prove the shelf life and han­dling of com­plex in­jectable prod­ucts, but it is not sim­ple,” not­ed Ig­or Nikoulin, se­nior di­rec­tor of phar­ma­ceu­ti­cal de­vel­op­ment and man­u­fac­tur­ing at So­ci­etal. “Work­ing with a part­ner who has done it suc­cess­ful­ly for mul­ti­ple com­plex prod­ucts will dra­mat­i­cal­ly in­crease the chances of suc­cess.” The com­pa­ny has solved an ar­ray of de­vel­op­ment and man­u­fac­tur­ing hur­dles for its di­verse client base, help­ing clients de­vel­op a va­ri­ety of lyophiliz­able for­mu­la­tions along with prod­uct-tai­lored freeze-dry­ing cy­cles that im­proved prod­uct ap­pear­ance, re­con­sti­tutabil­i­ty and in­creased prod­uct sta­bil­i­ty from months to  years.

En­gag­ing a col­lab­o­ra­tive CD­MO

Equal­ly im­por­tant to the se­lec­tion process is ev­i­dence of a CD­MO’s col­lab­o­ra­tive ap­proach that al­lows more mean­ing­ful, sus­tained en­gage­ment and client sup­port across a part­ner­ship span­ning months or even years. As a mid­size CD­MO, So­ci­etal is well po­si­tioned to serve small­er spe­cial­ty phar­ma com­pa­nies who re­quire re­spon­sive, ex­pert-lev­el sup­port to nav­i­gate the high-stakes lat­er stages of clin­i­cal, scale-up, process qual­i­fi­ca­tion or pre-com­mer­cial and com­mer­cial launch ac­tiv­i­ties – but who don’t get the fo­cus they need from larg­er CD­MOs.

With a mis­sion to “bring sci­ence to so­ci­ety,” So­ci­etal fo­cus­es on re­la­tion­ship-build­ing to form a high-func­tion­ing project team built around open­ness, trans­paren­cy, ac­count­abil­i­ty and reg­u­lar com­mu­ni­ca­tion. This ap­proach helps teams over­come the in­evitable chal­lenges that can sink or de­lay a project.

“It’s our goal to part­ner with bio­phar­ma­ceu­ti­cal com­pa­nies to help turn their great ideas in­to ap­proved, scal­able, safe and ef­fec­tive prod­ucts. Do­ing so ful­fills our mis­sion of help­ing the pa­tients our in­dus­try ul­ti­mate­ly serves live longer, health­i­er lives,” said David En­loe, the com­pa­ny’s chief ex­ec­u­tive of­fi­cer. “We help bring our clients’ drugs to life.”