高级治疗药物产品(ATMP)是基于基因的新药,细胞或组织发展来治疗许多不同的疾病。需要对每种新型ATMP进行稳定性研究,以确定其保质期,并保证输注后的有效性和安全性。这些目前是基于最初为标准药物起草的指南,它们具有特性并储存在与细胞产品完全不同的条件下。本报告的目的是为ATMP的稳定性研究提供基于证据的信息,以促进该领域实践的实验室间协调。
我们收集并分析了19种不同的基于细胞的实验性ATMP的稳定性研究结果,由五个授权的细胞工厂生产,组成伦巴第“Plagencell网络”,用于36个批准的I/II期临床试验;大多数被冷冻保存并储存在液氮蒸气中1至13年。
在稳定性研究中收集的细胞属性包括细胞活力,免疫表型和效力测定,特别是免疫抑制,细胞毒性,细胞因子释放和增殖/分化能力。微生物属性,包括不育,内毒素水平和支原体污染也进行了分析。所有药品(DP),冷冻保存在含有10%DMSO的各种赋形剂和不同的主要容器中,在<-150°C下长期非常稳定,并且在长达13.5年的时间内没有显示出任何降低活力或功效的趋势。
我们的数据表明,稳定性研究的新指南,特定于ATMP,并基于风险分析,应该起草来协调做法,显著降低稳定性研究的成本而不降低安全性。讨论中提出了一些具体的建议。
Advanced therapy medicinal products (ATMPs) are novel drugs based on genes, cells or tissues developed to treat many different diseases. Stability studies of each new ATMP need to be performed to define its shelf life and guarantee efficacy and safety upon infusion, and these are presently based on
guidelines originally drafted for standard pharmaceutical drugs, which have properties and are stored in conditions quite different from cell products. The aim of this report is to provide evidence-based information for stability studies on ATMPs that will facilitate the interlaboratory harmonization of practices in this area.
We have collected and analyzed the results of stability studies on 19 different cell-based experimental ATMPs, produced by five authorized cell factories forming the Lombardy \"Plagencell network\" for use in 36 approved phase I/II clinical trials; most were cryopreserved and stored in liquid nitrogen vapors for 1 to 13 years.
The cell attributes collected in stability studies included cell viability, immunophenotype and potency assays, in particular immunosuppression, cytotoxicity, cytokine release and proliferation/differentiation capacity. Microbiological attributes including sterility, endotoxin levels and mycoplasma contamination were also analyzed. All drug products (DPs), cryopreserved in various excipients containing 10% DMSO and in different primary containers, were very stable long term at <-150°C and did not show any tendency for diminished viability or efficacy for up to 13.5 years.
Our data indicate that new
guidelines for stability studies, specific for ATMPs and based on risk analyses, should be drafted to harmonize practices, significantly reduce the costs of stability studies without diminishing safety. Some specific suggestions are presented in the discussion.