Txoj kev tshawb nrhiav tus kab mob tshem tawm: Kev sib raug zoo rau NMPA / FDA / EMA triple tshaj tawm

NMPA Regulatory System

Tom qab ntau tshaj 20 xyoo ntawm txoj kev loj hlob, NMPA tus kab mob kev nyab xeeb kev tswj hwm txoj cai tau tsim ib qho kev cai ua tiav. Cov ntaub ntawv tseem ceeb suav nrog: 2002 "Technical Methods and Validation Guidelines for Removal/Inactivation of Viruses from Blood Products" (Sinopharm [2002] Tsis yog. 160) raws li cov ntaub ntawv qhia tshwj xeeb tshaj plaws; 2005 "Cov Ntsiab Cai ntawm Kev Tshawb Fawb Txog Kev Nyab Xeeb Kev Nyab Xeeb ntawm Cov Khoom Siv Hluav Taws Xob Cov Khoom Siv Hluav Taws Xob thiab Eukaryotic Cell Expression Products" raws li lub hauv paus ntsiab lus rau kev tshuaj xyuas; 2024 "Cov Lus Qhia Txog Kev Siv Hluav Taws Xob rau Kev Ua Haujlwm ntawm Viral Clearance Process Platforms rau Kev Tshawb Fawb Kev Kho Mob ntawm Cov Khoom Siv Kho Mob Recombinant Protein (Tsim Ua Haujlwm)" raws li cov ntaub ntawv tshiab, qhia lub platform validation tswvyim thawj zaug; thiab General Kev Cai 0238 "Kev Tswj Xyuas Kev Nyab Xeeb ntawm Cov Khoom Siv Hluav Taws Xob" hauv 2025 tsab ntawm Suav Pharmacopoeia. Nws yog ib qho tsim nyog sau cia tias NMPA tau hais meej meej tias nws yuav maj mam ua raws li ICH Q5A (R2), thiab cov lus qhia kev txheeb xyuas lub platform rau 2024 yog qhov kev xav ntawm qhov sib txawv no.

FDA Regulatory System

FDA's viral clearance verification requirements rely primarily on the following documents: ICH Q5A (R2) Guidelines, which FDA adopted as the Guidance for Industry in January 2024; USP Section < 1050.1 >, uas muab kev qhia dav dav - theem kev qhia txog kev tsim, kev tshuaj xyuas, thiab kev ua tus yam ntxwv ntawm cov txheej txheem tshem tawm kab mob; thiab FDA's biennial Viral Clearance Symposium (feem ntau tsis ntev los no hauv 2023), uas muab lub platform rau kev lag luam los cuam tshuam lub ntsej muag -rau -feeb nrog cov tswj hwm. Ib qho tseem ceeb ntawm FDA txoj hauv kev rau kev siv tshuaj tua kab mob yog tias nws cov ntsiab lus xav txog cov ntaub ntawv thiab cov txiaj ntsig ntawm PDA kev cob qhia muaj kev cuam tshuam loj heev rau kev lag luam xyaum.

EMA Regulatory System

EMA cov txheej txheem tswj hwm kev nyab xeeb ntawm tus kab mob suav nrog CPMP/BWP/268/95 Cov Lus Qhia rau Kev Tsim Kev Tshawb Fawb Viral Validation (1996), uas tau sib haum xeeb thiab hloov kho nrog ich Q5A; EMEA/CHMP/BWP/398498/2005 Cov Lus Qhia rau Kev Ntsuam Xyuas Viral Safety Evaluation of Biotechnological Drugs for Clinical Trials, uas qhia meej txog cov ntaub ntawv kev nyab xeeb ntawm tus kab mob rau ntau theem kev sim tshuaj; thiab European Pharmacopoeia (Ph. Eur.) (Tshooj 5.1.7 "Viral Safety"). Ib qho tseem ceeb ntawm EMA yog nws cov ncauj lus kom ntxaws txog kev kho mob ntawm cov kab mob validation cov kev tshawb fawb, thiab cov ntaub ntawv ntsuam xyuas ntawm tus kab mob titer thiab kev suav ntawm cov ntsiab lus txo tau hais tshwj xeeb hauv cov ntawv ntxiv rau CPMP / BWP / 268/95.

Qhia txog kev sib raug zoo ntawm kev xaiv tus kab mob

Table 1 Kev sib piv ntawm cov kev cai xaiv tus kab mob qhia los ntawm peb qhov chaw

Raws li tuaj yeem pom los ntawm Table 1, peb qhov chaw muaj qhov zoo sib xws hauv cov ntsiab lus tseem ceeb uas qhia txog kev xaiv tus kab mob, thiab txhua yam yuav tsum muaj kev pheej hmoo -raws li kev ntsuam xyuas los npog cov kab mob nrog cov yam ntxwv ntawm lub cev thiab tshuaj sib txawv xws li lipid/non- lipid hnab ntawv, DNA / RNA, thiab loj / me. Qhov kev sib raug zoo siab no muab lub hauv paus ruaj khov rau kev tsim ib qho kev qhia qhia tus kab mob sib koom ua ke uas ua tau raws li qhov xav tau ntawm peb qhov chaw.

Narrowing qhov sib xws ntawm cov qauv validation xav tau

Tag nrho peb qhov chaw xav kom tus qauv txo qis tuaj yeem sawv cev rau kev tshem tawm tus kab mob ntawm cov txheej txheem tsim khoom thiab ua raws li cov txheej txheem tseem ceeb. Qhov no tau piav qhia hauv ICH Q5A (R2) Tshooj 6.2.2. Muaj qhov sib txawv me me hauv qab no nyob rau hauv cov kev cai tshwj xeeb ntawm peb txoj cai tswj hwm: FDA thiab EMA muab qhov tseem ceeb tshaj plaws ntawm kev ua qauv qhia kev tshawb fawb ntawm linear / nonlinear amplification ntawm tus qauv txo; NMPA tso rau pem hauv ntej kom meej meej cov khoom sawv cev rau kev soj ntsuam cov cai rau kev txheeb xyuas cov qauv txo nyob rau hauv cov txheej txheem pov thawj platform; thiab EMA CPMP/BWP/268/95 muab cov kev ntsuam xyuas tshwj xeeb hauv cov ntawv ntxiv.

Kev sib raug zoo ntawm Inactivation Mechanics nrog rau qhov yuav tsum tau ua phem tshaj plaws

Tag nrho peb qhov chaw xav tau tias kev tshawb nrhiav kev tshawb fawb txog kev tsis ua haujlwm yuav tsum suav nrog kev tshawb fawb txog kev siv tshuab. NMPA "Technical Methods and Validation Guidelines for Removal/Inactivation of Viruses from Blood Products" kom meej meej hais tias "lub zog ntawm tus kab mob inactivation, nrog rau tus nqi ntawm tus kab mob inactivation thiab inactivation nkhaus, yuav tsum tau kawm". FDA kuj tseem hais txog qhov tseem ceeb ntawm kev tsis ua haujlwm kinetic nkhaus hauv kev ntsuas qhov ua tau zoo ntawm cov txheej txheem inactivation ntawm 2023 Viral Clearance Symposium. Tag nrho peb qhov chaw yuav tsum tau muaj pov thawj nyob rau hauv qhov phem tshaj - rooj plaub, tab sis NMPA teev qhov phem tshaj - cov ntaub ntawv tsis zoo nyob rau hauv kom meej ntxiv nyob rau hauv lub platform pov thawj cov lus qhia.

Kev sib raug zoo ntawm LRV statistical calculation method

Table 2 Kev sib piv ntawm LRV cov txheej txheem suav nrog hauv peb qhov chaw

Peb qhov chaw ua tau zoo ib yam hauv LRV txoj kev suav, thiab txhua tus siv cov qauv log10 (N0/N). Qhov sib txawv tseem ceeb yog tias EMA muaj cov kev cai nruj dua rau kev ntsuam xyuas kev ntseeg siab (Appendices I thiab II muab cov ncauj lus kom ntxaws txog cov txheej txheem), thaum NMPA, thaum pom zoo rau kev siv cov kev ntseeg siab ib ntus, tsis txwv lawv.

Kev daws teeb meem tsim raws li ICH Q5A (R2)

Muab hais tias ICH Q5A (R2) tau txais kev pom zoo los ntawm cov cai tswj hwm ntawm peb qhov chaw, tsim kom muaj kev txheeb xyuas kev sib koom ua ke raws li qhov tseem ceeb ntawm Q5A (R2) yog txoj hauv kev zoo tshaj plaws kom ua tiav kev sib koom tes ntawm peb qhov chaw. Nov yog qee cov lus qhia:

Ua ntej, ib qho kev sib xyaw ua ke ntawm cov kab mob qhia tau siv. Nws raug nquahu kom muaj yam tsawg kawg ntawm cov kab mob hauv qab no: MVM lossis PPV (tsis yog-lipid enveloped tus kab mob me), PRV lossis HSV (lipid enveloped tus kab mob loj), X-MuLV (tus qauv retroviral), BVDV lossis VSV (lipid enveloped nruab nrab kab mob), thiab Reo-3 (cov kab mob uas tsis yog-lipid nruab nrab). Qhov kev sib xyaw ua ke no tuaj yeem npog tag nrho ICH Q5A (R2) thiab cov lus qhia tus kab mob cov cai ntawm peb txoj cai tswj hwm.

Thib ob, siv ib qho kev sib koom ua ke tsim qauv tsim qauv. Xyuas kom meej tias tus qauv txo qis sawv cev rau cov txheej txheem tsim khoom lag luam ntawm cov txheej txheem tseem ceeb thiab tau lees paub tag nrho raws li qhov xav tau los ntawm Q5A (R2). Nws raug nquahu kom suav nrog kev sib piv ntawm cov khoom lag luam zoo, cov txheej txheem tseem ceeb, thiab cov txheej txheem sib txawv hauv qhov kev siv tau ntawm cov qauv miniaturized.

Thib peb, txais yuav ib qho kev txheeb xyuas kev txheeb xyuas kev sib koom ua ke. Nws raug pom zoo tias 95% kev ntseeg siab lub sijhawm rau LRV suav nrog hauv txhua qhov kev tshawb fawb pom zoo kom ua tau raws li qhov yuav tsum tau ua ntawm EMA thiab cov lus pom zoo ntawm NMPA / FDA. Nyob rau tib lub sijhawm, kev ntsuas kev ntsuas dav siv hauv kev ntsuas kev ua tau zoo, tsis yog kev cia siab rau ib qho pib.

Modular Document Design Strategy

In order to achieve the goal of adapting a report to three regional declarations, it is recommended to adopt a modular document design strategy: core modules (common parts) - including risk assessment reports, narrowed model description and validation data, virus removal verification results for each process step, statistical analysis reports, and overall virus safety evaluation. NMPA Supplemental Module - Includes a declaration form that meets the specific format requirements of the NMPA, a description of the comparison with the requirements of the Chinese Pharmacopoeia, and a description of the response to the NMPA-specific guidelines. FDA Supplemental Module - Includes FDA Guidance Statement of Suitability, Controlled Analysis of USP < 1050.1 >. EMA Supplemental Module - suav nrog cov ntaub ntawv ntxiv rau kev txheeb xyuas kev txheeb xyuas raws li qhov xav tau hauv CPMP/BWP/268/95 Cov Lus Qhia Ntxiv, cov lus qhia rau kauj ruam - los ntawm - cov lus tshaj tawm thaum lub sij hawm kev sim tshuaj.

Qhov tsim nyog ntawm peb qhov chaw tau txheeb xyuas los ntawm lub platform

Cov "Cov Lus Qhia rau Kev Pom Zoo ntawm Viral Clearance Process Platforms rau Kev Tshawb Fawb Kev Kho Mob ntawm Cov Khoom Siv Kho Mob Recombinant Protein (Siv)" muab los ntawm NMPA hauv 2024 yog qhov tseem ceeb hauv kev sib koom tes ntawm peb qhov chaw. Cov lus qhia kom meej meej hais tias lub platform validation yog muaj feem xyuam rau kev soj ntsuam daim ntawv thov rau kho recombinant protein cov khoom uas tsim los ntawm mammalian hlwb, thiab cov Scope ntawm daim ntawv thov muaj xws li peb txheej txheem: S / D inactivation, tsis muaj pH inactivation, thiab kab mob cuam tshuam thiab pom. Txawm hais tias cov lus qhia tam sim no tsuas yog siv rau NMPA txoj cai lij choj, nws cov kev cai yuav tsum tau ua raws li ICH Q5A (R2), yog li cov qauv kev sib haum xeeb tuaj yeem txiav txim siab thaum tsim cov txheej txheem pov thawj platform.

Rau cov khoom kho noob, txawm hais tias nws tseem tsis tau suav nrog hauv qhov kev siv ntawm kev txheeb xyuas lub platform, lub tswv yim ntawm kev txheeb xyuas lub platform "raws li kev paub txaus sab hauv ua ntej, kev ntsuam xyuas tus kab mob tshem tawm kev ua tau zoo ntawm lwm yam khoom zoo sib xws" kuj muaj nqi siv. Nrog rau tag nrho kev saws me nyuam ntawm ICH Q5A (R2) los ntawm NMPA, lub peev xwm ntawm kev siv lub platform yuav tsum tau nthuav dav ntxiv.

Differentiated coping tswv yim

Thaum nrhiav kev sib xws, cov kev xav sib txawv hauv qab no yuav tsum tau saib xyuas tshwj xeeb:

Kev Cia Siab Lub Sijhawm Yuav Tsum Tau: EMA tau txiav txim siab 95% kev ntseeg siab lub sijhawm rau LRV, uas tau pom zoo kom suav nrog lub neej ntawd hauv Txoj Cai Sib Koom Tes kom zam dhau qhov xav tau kev kawm ntxiv. Txawm hais tias NMPA qhov pib ntawm Greater dua los yog sib npaug rau 4 lub cav feem ntau yog rau cov khoom siv ntshav, nws yuav tsum tau tsim los xyuas kom meej tias qhov kev tshem tawm ntawm cov txheej txheem tseem ceeb tsis qis dua qib no.

Kev Kawm Inactivation Mechanics: NMPA qhia meej meej yuav tsum tau kawm txog kev siv tshuab tsis siv neeg kis kab mob, suav nrog tus nqi inactivation thiab inactivation nkhaus. Nws raug pom zoo tias ntau- cov qauv qauv taw qhia suav nrog hauv kev siv tau ntawm txhua kauj ruam tsis ua haujlwm kom ua tau raws li cov cai tshwj xeeb ntawm NMPA. Cov kev cai NMPA rau tiam thib peb ntawm qhov muag tsis pom kev sib kis yuav tsum tau txiav txim siab hauv cov txheej txheem kuaj.

Kev sib txuas lus Forward

Raws li qhov nyuaj ntawm kev txheeb xyuas tus kab mob no thiab qhov sib txawv me ntsis ntawm peb txoj cai hauv zos, nws raug pom zoo kom sib txuas lus nrog ntau lub koom haum tswj hwm ua ntej txoj kev npaj pov thawj tau txiav txim siab: kev sib txuas lus nrog NMPA tuaj yeem ua los ntawm Pre-IND lub rooj sib tham lossis kev sib tham dav dav ntawm CDE, thiab tshwj xeeb tshaj yog pom zoo kom sib txuas lus nrog lub platform pov thawj ua ntej siv. Kev sib txuas lus nrog FDA tuaj yeem yog los ntawm Pre-IND lossis Pre-BLA lub rooj sib tham. Kev sib txuas lus nrog EMA tuaj yeem ua tiav los ntawm Cov Txheej Txheem Qhia Txog Kev Tshawb Fawb. Hauv kev sib txuas lus, nws raug nquahu kom tsom mus rau qhov laj thawj ntawm kev qhia txog kev xaiv tus kab mob, tus neeg sawv cev ntawm kev nqaim ntawm tus qauv tsim, lub hauv paus rau kev teeb tsa cov xwm txheej tsis zoo, thiab kev txiav txim siab tshwj xeeb rau cov khoom tshwj xeeb.