[Ama-Raw material]
I-Peptide Engineering Centre yase-Shenzhen JYMed Technology Co., Ltd. inamakhono aqinile ekuthuthukisweni kwempahla eluhlaza. Siholwa ithimba labacwaningi lososayensi abayi-130, okuhlanganisa nama-PhD angu-12, lesi sikhungo sinolwazi olunzulu ekuhlanganiseni ama-peptide kanye nokwenza ngcono inqubo. Sisebenzisa ubuchwepheshe be-solid-phase peptide synthesis (SPPS) kanye ne-liquid-phase peptide synthesis (LPPS) technologies, kuhlanganiswe nemishini yokukhiqiza ezenzakalelayo ngokuphelele, siqinisekisa imikhiqizo ye-peptide ehlanzekile futhi esebenza kakhulu. Ithimba lethu le-R&D lihlinzeka ngezinsizakalo ezibanzi kusukela ekwakhiweni kwamangqamuzana kuya ekuthuthukisweni, linikeza izixazululo eziklanyelwe ukuhlangabezana nezidingo zamakhasimende ezihlukahlukene.
Yonke imisebenzi yenziwa ngaphansi kwamazinga aqinile e-cGMP, asekelwa amathuluzi okuhlaziya asezingeni eliphezulu njenge-HPLC kanye ne-mass spectrometry (MS), ukuqinisekisa ukuthi ikhwalithi yomkhiqizo ihambisana nezidingo ze-pharmacopeial zomhlaba. Kwa-JYMed, sizibophezele ekunikezeni amandla amakhasimende ekuthuthukisweni okuyimpumelelo nasekuhwebeni kwemithi yokwelapha emisha ngokwenza kahle kwezobuchwepheshe kanye nenkonzo.
Ukuthuthukiswa Kwenqubo
Ithimba lokuthuthukiswa kwenqubo le-JYMed ligxile kakhulu ekuthuthukiseni nasekukhuliseni ukukhiqizwa kwe-peptide API, linikeza izixazululo eziphumelelayo nezithembekile ezenziwe ngokwezifiso eziqhutshwa ukuqanjwa kabusha kwezobuchwepheshe. Ngobuchwepheshe obujulile ku-SPPS, i-LPPS, kanye nokuhlanganiswa kokugeleza okuqhubekayo, sihlinzeka ngezinsizakalo zokuthuthukiswa kokuphela ukuya ekupheleni ukusuka ekuhlolweni kwesikali se-milligram kuya ekukhiqizweni kwesikali sekhulu lamakhilogremu.
Ngenkundla yethu yokuphathelene yamakhemikhali aluhlaza yama-peptides, sizinqobile izinselele ekuhlanganiseni ukulandelana okuyinkimbinkimbi, okuthuthukisa kakhulu kokubili ubumsulwa kanye nesivuno. Lokhu kusenza sikwazi ukuhlangabezana nezidingo eziqinile zama-peptides aphezulu asetshenziswa ku-oncology, izifo ze-metabolic, nezinye izindlela zokwelapha ezithuthukisiwe.
Uhlelo lwethu lokukhiqiza lunamathela ngokuqinile eziqondisweni ze-cGMP futhi lufakwe ngokugcwele amayunithi okwenziwa azenzakalela kanye namathuluzi okuhlaziya athuthukile njenge-UPLC kanye ne-MS yokulungiswa okuphezulu. Ngokuhambisana namamodeli okuthuthukisa enqubo athuthukiswe ngaphakathi, siqinisekisa ukuqina kwenqubo kanye nokuvumelana kwe-batch-to-batch. I-JYMed iqede ngempumelelo amaphrojekthi amaningi wokuthuthukiswa kwe-peptide API kuwo wonke ama-preclinical kuya ezigabeni zezentengiso, iletha izixazululo ezisheshayo, eziqhutshwa yidatha ukusheshisa ukusungulwa kwemithi emhlabeni jikelele.
Ukukhiqiza
Indawo yethu yokukhiqiza ihlanganisa ama-mu angu-300 (cishe ama-square metres angu-200,000) nendawo eyakhiwe cishe engu-54,000 square metres. Lesi sikhungo sihlanganisa izindawo zokusebenzela zokukhiqiza ama-peptide, izakhiwo ze-QC ne-R&D, izindawo zokugcina izimpahla ze-Class A kanye ne-B, isikhungo sokubuyisela izinto ezincibilikayo, izikhungo zezinsiza, indawo yokuqoqwa kukadoti oqinile, kanye nesiteshi sokuhlanza amanzi angcolile.
I-Hubei Jianxiang Biopharmaceutical Co., Ltd. isebenzisa imigqa yokukhiqiza ye-peptide API engu-10 (okuhlanganisa nemigqa yesikali somshayeli) ethobela amazinga e-cGMP ase-US, EU, nase-China. Lezi zifakwe inqwaba yama-solid-isigaba esiqinile kanye nesigaba se-liquid-peptide synthesis synthesis reactors, enengqikithi yamalitha angaphezu kuka-30,000 ngevolumu ye-reactor.
Ngohlelo olusungulwe kahle lokuphathwa kwekhwalithi yezemithi kanye nohlelo lokuthobela i-EHS, u-Hubei Jianxiang uphumelele ukuhlolwa okusemthethweni kwe-NMPA GMP, ukucwaningwa kwamabhuku okuningi okuvela eceleni, kanye nokuhlolwa kwe-EHS okuvela kumakhasimende ahamba phambili emhlabeni jikelele. Umthamo wayo wonyaka wokukhiqiza i-peptide usufinyelele esikalini samathani amaningi. Ngokuphawulekayo, ukukhiqizwa kwama-analogue e-GLP-1 kubalwa phakathi kwamakhulu kakhulu e-China ngevolumu yeqoqo elilodwa, futhi amanye ama-peptide wezimonyo adlula i-100 kg iqoqo ngalinye, okubeka inkampani njengomkhiqizi we-peptide API wokuncintisana wamakhemikhali kuzo zombili izimakethe zasekhaya nezamazwe ngamazwe.
I-High-Potency Peptide APIs
Imigqa yokukhiqiza ye-Jianxiang's high-potency peptide API imelela inzuzo eyinhloko yokuncintisana, enikeza izixazululo eziphephile nezisebenzayo kumakhasimende omhlaba. Lesi sikhungo sihlanganisa amayunithi amabili ezinga eliphezulu le-OEB4 kanye nezinga eliphezulu le-OEB5 aklanyelwe ukuhlangabezana nezidingo zokukhiqiza ezidingekayo zezinhlanganisela ezinamandla kakhulu njenge-anti-tumor kanye nama-cytotoxic peptides, okuqinisekisa ukuphepha kwabasebenzi kanye nemvelo.
Imigqa yokukhiqiza isebenzisa ubuchwepheshe be-SPPS obuhamba phambili embonini kanye ne-LPPS enezinhlelo zokulawula ezizenzakalelayo ngokuphelele, okuvumela ukukhiqizwa okuyingozi kakhulu kwama-peptide ahlanzekile futhi anamandla aphezulu ukusuka esikalini segram kuye kwekhilogremu. Ukungaguquguquki kweqoqo kanye nekhwalithi yomkhiqizo kuhambisana ngokugcwele namazinga omhlaba jikelele we-pharmacopeial.
Yakhelwe ohlelweni lokuphatha ikhwalithi oluhambisana ne-cGMP, yonke inqubo yokukhiqiza—kusukela ekukhetheni izinto ezingavuthiwe, ukuhlanganiswa, ukuhlanzwa kuya ekuhlolweni kokugcina—kulandeleka ngokugcwele. Amathuluzi okuhlaziya athuthukile njenge-HPLC ne-MS aqinisekisa ubumsulwa bomkhiqizo ≥99% ngamaphrofayela okungcola okulawulwayo. Ukuze kubhekwane nezidingo eziyingqayizivele zokuphepha zama-API anamandla amakhulu, amayunithi eleveli ye-OEB5 asebenzisa amasistimu okuzihlukanisa avaliwe, izindawo ezizimele zokucindezela okungemuhle, nezinhlelo ezihlakaniphile zokuqapha ukuvuza, kanye nezimiso eziqinile ze-PPE zokuqinisekisa ukuphepha okuphelele.
Ithimba lethu le-R&D futhi linikezela ngezinsizakalo zokuthuthukiswa kwenqubo eyenziwe ngokwezifiso kanye nezinsizakalo zokuthuthukisa ezihlanganisa lonke uchungechunge lwenani ukusuka ekwakhiweni kwamangqamuzana nokukhushulwa kuye ezifundweni zekhwalithi, okusekela ukuthuthuka okusheshayo kwezindlela zokwelapha ezisekelwe ku-peptide.
[Ukwakha]
Ithimba lethu eliyinhloko lezobuchwepheshe lakhiwe abacwaningi abanolwazi abangochwepheshe bezokwakha nesayensi yokuhlaziya. Ngobuchwepheshe obuningi kulo lonke uchungechunge lwenani lokuthuthukiswa kokubunjwa, sinikezela ngezinsizakalo zokuphela konyaka kusukela ocwaningweni lwangaphambi komtholampilo kuya ekukhiqizeni ezentengiso. Sesisungule amandla ayingqayizivele ezobuchwepheshe emikhakheni engasemngceleni njengezidakamizwa ze-GLP-1, ama-peptides nama-peptide formulations, ukwakheka kwe-peptide ekhishwa isikhathi eside, kanye nokuthuthukiswa kwe-radiopharmaceutical (RDC).
Ngokusebenzisa i-R&D yethu esatshalaliswa emhlabeni wonke kanye nezindawo zokukhiqiza, sakhe uhlelo olubanzi lokuthuthukisa ukwakheka. Emkhakheni wokwenziwa kwe-peptide, sinikeza izixazululo ezihlukahlukene ezihlanganisa izixazululo zekhatriji zethamo eziningi/zomthamo owodwa, impushana e-lyophilized yokujova, nezixazululo zokuhogela. Ekuthuthukisweni kwe-RDC, ithimba lethu selikwazi kahle izindlela zokuhlanganisa ezithuthukisiwe zama-radionuclides kanye nama-vector aqondisayo, ahlinzeka ngobuchwepheshe obusha bokusekela ukuxilonga nokwelashwa kwe-oncology ngokunembayo. Kusukela ekupheleni kuka-2024, ithimba lethu selisekele amaphrojekthi amasha angaphezu kwe-100 okuthuthukiswa kwezidakamizwa (okuhlanganisa izigaba ze-preclinical to Phase III), ngokuyinhloko egxile kuma-analogue e-GLP-1, eminye imithi ye-peptide, nama-RDC. Siphinde futhi saphothula ngempumelelo amaphrojekthi angu-5 wokuhlola ukungaguquguquki kwemithi ejwayelekile ehlanganisa imijovo nokunye.
Njengethimba eliqhutshwa ubuchwepheshe, sihlala sizibophezele ekusunguleni nasekuhumusheni okuqhubekayo kocwaningo ezisombululweni zomhlaba wangempela. Imizamo yethu ayihlinzeki nje kuphela ngezixazululo eziphephile nezisebenzayo zokulungisa imakethe yomhlaba wonke yezemithi, ukukhuthaza ukusetshenziswa komtholampilo kanye nezimboni zemithi ye-peptide ne-RDC, kodwa futhi isungula umkhawulo oqinile wokuncintisana emkhakheni wokuhlola ukungaguquguquki kwemithi ejwayelekile.
Ucwaningo Lokwakhiwa Kwangaphambili
Njengesinyathelo sokuqala esibalulekile ekuthuthukisweni kwezidakamizwa, ucwaningo lokwakhiwa kwangaphambili lusebenza njengesixhumanisi esibalulekile phakathi kokutholakala kwezidakamizwa kanye nokwakhiwa kwezidakamizwa. Ikhwalithi yayo yobuchwepheshe ithinta ngokuqondile ukuthuthukiswa kwefomu lomthamo kanye nokuba nokwenzeka kwenqubo.
Ekuthuthukisweni kwezidakamizwa ezintsha, senza izifundo ngokuhlelekile ezimpahleni ezibalulekile zama-API - okuhlanganisa ukuhlolwa kokuncibilika, ukuhlolwa kwe-polymorph, ukuhlaziya ukuwohloka okuphoqelekile, nokuhlola kokuqala kokuzinza - ukuhlonza ngokunembile izici ze-physicochemical nezindlela zokuwohloka okungenzeka. Le mininingwane isebenza njengesisekelo sokuklama ukuklama, ukuthuthukiswa kwenqubo, nokuthuthukiswa okujwayelekile kwekhwalithi, ekugcineni kunciphisa ubungozi be-R&D futhi kuthuthukiswe ukutholakala kwezidakamizwa kusukela ekuqaleni.
Ekuthuthukisweni kwezidakamizwa ezijwayelekile, ukuhlaziya okujulile komuthi osohlwini lwereferensi (RLD) kuwukugxila okumaphakathi kocwaningo lokwakhiwa kwangaphambili. Ngobunjiniyela obuhlehlayo, sinquma ukwakheka, inqubo yokukhiqiza, kanye nezimfanelo ezibalulekile zekhwalithi (ama-CQA) zomuthi womsunguli. Lokhu kuvumela isiqondiso esihlosiwe sokumatanisa ukwakheka kanye nokukhiqizwa kabusha kwenqubo, futhi, ngokuhambisana nendlela ye-Quality by Design (QbD), kuqinisekisa ukuthi umkhiqizo ojwayelekile uzuza ukulingana ekuphepheni, ekusebenzeni kahle, nasekulawuleni ikhwalithi—ukubeka isisekelo esiqinile sobuchwepheshe sokuhlola ngempumelelo ukungaguquguquki.
Ukuthuthukiswa Kokwakha
Njengebhuloho elibalulekile phakathi kokuthuthukiswa kwezidakamizwa nokwakhiwa kwezimboni, ukuthuthukiswa kokwakhiwa kudlala indima ebalulekile ekuhumusheni imiphumela yelebhu ibe yizinhlelo zokusebenza zomtholampilo. Ithimba lethu ligxile kubuchwepheshe bokusungula obusha kanye nezidingo zezimboni ezingaka, ukwakha isistimu yokuthuthukiswa kwenqubo ephelele ehlanganisa ukuklama kokuklama, ukuthuthukiswa kwenqubo, ucwaningo lwekhwalithi, nokukhiqizwa kwesikali sokuhlola. Sinikeza izixazululo ezenziwe ngokwezifiso ezifanelana nezinhlobo zezidakamizwa ezihlukene (ama-molecule amancane, ama-peptide, ama-radiopharmaceuticals) namafomu omthamo (imijovo, imikhiqizo yokuhogela, ukwakheka kokukhishwa okuqhubekayo).
Ekuthuthukisweni kokwakhiwa kwezidakamizwa ezintsha, sisekela umsebenzi wethu kudatha yokwakhiwa kwangaphambili futhi sicabangele inkomba ehlosiwe kanye nomzila wokuphatha wefomu lomthamo kanye nomklamo wenqubo. Ngezinselelo zokuzinza kwezidakamizwa ze-peptide, senze izisombululo ezijovwayo zekhatriji yedosi eminingi/yedosi eyodwa kanye nemijovo yempushana e-lyophilized. Ngokulungiselela amasistimu we-buffer nezinqubo ze-lyophilization, sithuthukisa kakhulu ukuqina komkhiqizo. Kuma-RDC, sisungule izinqubo ezinembile zokuhlanganisa phakathi kwama-vector aqondisayo nama-radionuclide kanye nezinhlelo zokulawula ikhwalithi ukuze kuqinisekiswe ukufakwa kwe-radiolabeling okuphumelelayo nokuphephile. Sisebenzisa i-computer-aid formulation design (CADD) kanye nezimiso ze-QbD, silungiselela kahle ukwakheka nokucubungula amapharamitha ukuze silawule ngokunembile izinkomba zokusebenza ezibalulekile ezifana nokuqedwa, ukukhipha amaphrofayela, nokuziphatha okuqondiwe.
Ekuthuthukisweni kwezidakamizwa ezijwayelekile, sihlanganisa ubunjiniyela obuhlehlayo be-RLD nokuthuthukiswa kwenqubo eya phambili ukuze kuzuzwe ukubunjwa kanye nenqubo yokulingana. Kumafomu emithamo ayinkimbinkimbi afana nemijovo kanye nezixazululo zokuhogela, sifanisa ngokunembile ama-CQA afana nokusatshalaliswa kosayizi wezinhlayiyana, ubumsulwa, namaphrofayili wokungcola. Ngokukhulisa inqubo nokuqinisekisa isikali sokuhlola, siqinisekisa ukuthi amajenerikhi afana nomuthi oyinkomba ngokuphepha, ukusebenza kahle, kanye nokulawulwa kokukhiqiza—okuvumela ukugunyazwa kokulawula okuphumelelayo.
Kuze kube manje, siye sasekela ngempumelelo amaphrojekthi okwakhiwa kokwakhiwa kwezidakamizwa emisha nejwayelekile, okuhlanganisa nezidakamizwa ze-GLP-1, ukwakheka kokukhishwa okuqhubekayo kwe-peptide, kanye nama-RDC. Sizinqobile izingqinamba zobuchwepheshe ezifana nokuwohloka kwe-peptide, ukusebenza kahle kwe-radiolabeling ephansi, nezinselele zokukhuphula kumafomu emithamo ayinkimbinkimbi. Kusukela ekuhlolweni kwesilinganiso selebhu kuya ekukhiqizeni kokuhlola okuthobela i-GMP, sinikwa amandla izinjini ezimbaxambili "zokushintsha kwezobuchwepheshe + ukuhumusha kwemboni," okuhlinzeka ngosekelo oluphelele lokuthuthukiswa kwezidakamizwa emisha kusukela kumqondo kuye emtholampilo, futhi kuvumela ukukhiqizwa kwenqwaba yezinto ezijwayelekile nezingabizi kakhulu eziqhuba uguquko olusebenzayo ukusuka kumiphumela ye-R&D ukuya enanini lomtholampilo.
Ukukhiqiza Ukwakhiwa
Njengesinyathelo sokugcina ekuhumusheni i-R&D yomuthi ekusetshenzisweni komtholampilo, ukwakhiwa kokwakhiwa kuyisixhumanisi esibalulekile esixhumanisa ukuqanjwa kabusha kwelabhorethri nemikhiqizo yohwebo. Ngokuthembela ezikhungweni zethu zokukhiqiza ezididiyelwe emhlabeni wonke kanye nemigqa yokukhiqiza ehlakaniphile, sisungule uhlelo lokukhiqiza olugcwele uchungechunge oluhlanganisa ukulinganisa ukulinganisa, ukuqinisekiswa kwenqubo, kanye nokukhiqizwa kwezinga lezentengiso. Ngamandla aqinile kuwo wonke amafomu emithamo eminingi, imikhiqizo, kanye nokucaciswa, sihlangabezana nezidingo zamandla emithi emisha kusukela ekuthuthukisweni komtholampilo kuya ekwenziweni kwezentengiso, kuyilapho sisekela ukukhiqizwa kwemithi ejwayelekile yekhwalithi ephezulu, ngezinga elikhulu.
1. Amakhono Ezobuchwepheshe Nengqalasizinda Yokukhiqiza
Amakhono efomu lemithamo ehlukahlukene: Emithini eyinkimbinkimbi efana nama-peptides nama-RDC, sisungule amasistimu okukhiqiza ayisipesheli athobela i-GMP ezixazululo ezijovwayo ze-cartridge enedosi eminingi/yedosi eyodwa kanye nemijovo yempushana e-lyophilized. Sihlomeke ngokugcwalisa okuzenzakalelayo, i-lyophilization, kanye nobuchwepheshe bokuhlunga obuyinyumba, siqinisekisa ukulawula okuzenzakalelayo kokuphela ukuya ekupheleni kusuka kokokufaka kwempahla eluhlaza kuya ekupakishweni komkhiqizo ophelile.
Ekwakhekeni kwe-peptide, sibhekana nezinselele zokuzinza ngokusebenzisa isistimu ye-buffer optimization, amaphrofayili e-lyophilization enziwe ngendlela efanele, nezixazululo zesitoreji seketango elibandayo. Iplathifomu yethu yokwandisa inqubo ephelele, eyakhelwe kuhlaka lwe-QbD, inika amandla uguquko olushelelayo ukusuka ekuhlolweni kwesilinganiso zelebhu ukuya ekukhiqizeni isikali sokuhlola (10L–100L), siqinisekisa ukukhiqizeka kabusha kwenqubo nokuvumelana kweqoqo-to-batch ngokuhlola okuhlelekile nokuqinisekiswa kwemingcele yenqubo ebalulekile (CPPs).
Ukwesekwa kwezidakamizwa okusha: Uhlelo lwethu lokukhiqiza luhlanganisa ukukhiqizwa kwesampula kweSigaba I-III kanye nokuthunyelwa kweqoqo lokubhalisa, kusheshisa imigqa yesikhathi emisha yokuthuthukiswa kwezidakamizwa.
Ukukhiqizwa kwezidakamizwa ezijwayelekile: Sinikeza izixazululo ezisheshayo zokudluliswa kwenqubo kanye nezinga eliphezulu ukuze kuhlangatshezwane nesidingo somhlaba wonke samajenerikhi angabizi kakhulu, ekhwalithi ephezulu.
2. Ukulawulwa Kwekhwalithi Nokuhambisana
Sisungule uhlelo oluphelele lokuphatha ikhwalithi ye-lifecycle ehlanganisa ukuhlolwa kwezinto ezingavuthiwe, ukuqapha okungaphakathi kwenqubo, nokukhishwa komkhiqizo kokugcina. Izikhungo zethu zifakwe amathuluzi okuhlaziya athuthukile njenge-HPLC, i-LC-MS, nezikena zomsakazo-TLC, okuvumela ukuhlolwa okunembile kwama-CQA kufaka phakathi amaphrofayili okungcola, ukufana kokuqukethwe, ubunyumba, kanye nokusebenza kahle kwe-radiolabeling.
Amasayithi ethu okukhiqiza agunyazwe yi-China NMPA yokuthobela i-GMP futhi anamathela ngokuqinile eziqondisweni ze-ICH, okuqinisekisa ukulandeleka okugcwele kanye nokuhlelwa kwemithetho yamazwe ngamazwe kumakhasimende ethu omhlaba.
3. Inani Lemboni Nezimpumelelo
Kuze kube manje, sesinyuse ngempumelelo futhi sathengisa ngemikhiqizo yokwakheka engaphezu kwe-100, okuhlanganisa imijovo ye-GLP-1, ukwakheka kokukhishwa okuqhubekayo kwe-peptide, kanye nemithi ye-RDC ehlosiwe. Umthamo wethu wokukhiqiza wonyaka ufinyelela emashumini ezigidi zemithamo/izitsha. Sihlinzeka ngamasevisi okukhiqiza “okukodwa” asekela izidakamizwa ezisungulwayo kusukela kumasampula omtholampilo ukuya ekuqalisweni kwemakethe, okufinyeza kakhulu isikhathi sokuya emakethe. Ngokuthuthukiswa kwenqubo nokuthuthukiswa kokuzenzakalela, sisiza amaklayenti ezidakamizwa ezijwayelekile ukuthi afinyelele ukulawulwa kwezindleko kanye nokuthuthukiswa kwekhwalithi, okuthuthukisa ukufinyeleleka komhlaba wonke kwemithi yokwelapha enenani eliphezulu.
Kusukela ekuhunyushweni kobuchwepheshe kuya ekukhiqizweni ngobuningi, sisekela imigomo "yekhwalithi kuqala, eqhutshwa ukusebenza kahle," ukuhlanganisa ngaphandle komthungo i-R&D nokukhiqiza ukuze sibe uzakwethu othembekile ekuguquleni izinto ezintsha zemithi zibe izixazululo zomtholampilo emhlabeni wonke.
