Abstract
Cytokine-induced killer (CIK) cells are advanced therapy medicinal products, so their production and freezing process has to be validated before their clinical use, to verify their stability as a drug formulation according to the good manufacturing practice (GMP) guidelines. We designed a stability program for our GMP-manufactured CIK cells, evaluating the viability, identity and potency of cryopreserved CIK cells at varying time periods from freezing, and compared them with fresh CIK cells. We evaluated the effects of the cryopreservation method, transportation, and the length of time of different process phases (pre-freezing, freezing and post-thawing) on the stability of CIK cells. This included a worst case for each stage. The expanded CIK cells were viable for up to 30 min from the addition of the freezing solution, when transported on dry ice within 48 h once frozen, within 60 min from thawing and from 12 months of freezing while preserving their cytotoxic effects. The reference samples, cryopreserved simultaneously in tubes and following the same method, were considered representative of the batch and useful in the case of further analysis. Data obtained from this drug stability program can inform the accurate use of CIK cells in clinical settings.
Highlights
In recent times, the research and development of drug formulations in which the main biological action is carried out by cells or tissue has led to the definition of a new category of medicines: advanced therapy medicinal products (ATMP)
Cytokine-induced killer (CIK) cells are advanced therapy medicinal products, so their production and freezing process has to be validated before their clinical use, to verify their stability as a drug formulation according to the good manufacturing practice (GMP) guidelines
The CIK cells were harvested after 21–23 days of culture, and data regarding their cellular growth and viability during expansion is illustrated in the Supplementary Materials in Figures S1 and S2, respectively
Summary
The research and development of drug formulations in which the main biological action is carried out by cells or tissue has led to the definition of a new category of medicines: advanced therapy medicinal products (ATMP). The use of living cells in the final product formulation imposes some limitations on their use because of their rapid loss of viability and, their function after cryopreservation. Their short shelf-life in the final product formulation means it is necessary to validate a suitable cryopreservation method to maintain the functional characteristics of thoPhsaermcaecelultsicaolsv2e02r0,t1i3m, xeF.ORFPoElElRowREiVnIgEWa good manufacturing practice (GMP) production 2porf o14cess, cryopfruenscetrivoantiaofnteralclorywosprfoesretrhveatpiorens.eTrhveaitriosnhoorfttshheeclfe-lllisfeininquthaerafnintainl epurondtuilcatllfotrhme ustleatriiolintymteesatnssreitqiusired to ensnuerceestshaeriyr tsoafveatlyidaartee acosmuiptalbelteedcr.yMoporreesoervveart,iionntmheetchaosdetoofmmauinlttiapinlethdeofsuenicntfiounsiaolnch, athraisctaelrliostwicss foofr all the scthheodseulceedllds oosveesroftiamde.ruFgolfloorwminuglataiogno. Od manufacturing practice (GMP) production process, Icnryroecpernestedrveactaidonesa, lsleovwesraflopr rtohteocporlesseorfvcaetliolunlaorfththeeracpelylsuisninqgucayratonktiinnee-uindtiul caelldtkhiellsetre(rCiliItKy)tceestlsls [1]. The sample wpraescitshcwereaytnsiompptThrreheooenptgeceprcrretryiisoovosgdepirv,raeeetgshslseyeiunvrcstvesoalpytotorilcooeaonldvoopolnueirgdndoitcdnuielagnsimsttiitclarsoiegtneaersxcetihpoasteciterhdhadeettdoihcofetenhfllrtesdeeetcmaeaztmuiepn.spegeHredtarhoatbuetwyurceertehevloleoesffrfao,nntrfiirvmtterreoaeorgtzygiieoelnnonngwvov/tafathpiepcamoeowrrpcssirenayrangsandttcaduywlrswce.alsTseabhsssyetcsosaotroadeumrddledipfdnolagerfffoercat cell staabpirleictyiseantidmleepaderitoodl,otwhuesr pcerollluolnagrinvgiaibtsileitxyp, irreactioovnedryatae.nHdofwunevcteiro,nfr[e1e1z,i1n2g]/.thawing cycles could
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