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In mammalian cell culture, especially in pharmaceutical manufacturing and research, biomass and metabolic monitoring are mandatory for various cell culture process steps to develop and, finally, control bioprocesses. As a common measure for biomass, the viable cell density (VCD) or the viable cell volume (VCV) is widely used. This study highlights, for the first time, the advantages of using VCV instead of VCD as a biomass depiction in combination with an oxygen-uptake- rate (OUR)-based soft sensor for real-time biomass estimation and process control in single-use bioreactor (SUBs) continuous processes with Chinese hamster ovary (CHO) cell lines. We investigated a series of 14 technically similar continuous SUB processes, where the same process conditions but different expressing CHO cell lines were used, with respect to biomass growth and oxygen demand to calibrate our model. In addition, we analyzed the key metabolism of the CHO cells in SUB perfusion processes by exometabolomic approaches, highlighting the importance of cell-specific substrate and metabolite consumption and production rate qS analysis to identify distinct metabolic phases. Cell-specific rates for classical mammalian cell culture key substrates and metabolites in CHO perfusion processes showed a good correlation to qOUR, yet, unexpectedly, not for qGluc. Here, we present the soft-sensoring methodology we developed for qPyr to allow for the real-time approximation of cellular metabolism and usage for subsequent, in-depth process monitoring, characterization and optimization.

細(xì)胞轉(zhuǎn)瓶2L

在哺乳動(dòng)物細(xì)胞培養(yǎng)中，尤其是在藥物制造和研究中，生物量和代謝監(jiān)測(cè)對(duì)于開發(fā)和最終控制生物過程的各種細(xì)胞培養(yǎng)過程步驟是必不可少的。作為生物量的常用度量，活細(xì)胞密度 (VCD) 或活細(xì)胞體積 (VCV) 被廣泛使用。本研究首次強(qiáng)調(diào)了使用 VCV 代替 VCD 作為生物量描述的優(yōu)勢(shì)，結(jié)合基于吸氧率 (OUR) 的軟傳感器，用于實(shí)時(shí)生物量估算和一次性過程控制中國(guó)倉(cāng)鼠卵巢 (CHO) 細(xì)胞系的生物反應(yīng)器 (SUB) 連續(xù)過程。我們研究了一系列 14 個(gè)技術(shù)上相似的連續(xù) SUB 工藝，其中使用了相同的工藝條件但使用了不同的表達(dá) CHO 細(xì)胞系，關(guān)于生物量增長(zhǎng)和需氧量來校準(zhǔn)我們的模型。此外，我們通過外代謝組學(xué)方法分析了 SUB 灌注過程中 CHO 細(xì)胞的關(guān)鍵代謝，強(qiáng)調(diào)了細(xì)胞特異性底物和代謝物消耗以及生產(chǎn)率 qS 分析對(duì)識(shí)別不同代謝階段的重要性。CHO 灌注過程中經(jīng)典哺乳動(dòng)物細(xì)胞培養(yǎng)關(guān)鍵底物和代謝物的細(xì)胞特異性速率顯示出與 qOUR 的良好相關(guān)性，但出人意料的是，與 qGluc 無關(guān)。在這里，我們介紹了我們?yōu)?qPyr 開發(fā)的軟傳感方法，以允許實(shí)時(shí)近似細(xì)胞代謝和使用情況，以便進(jìn)行后續(xù)深入的過程監(jiān)測(cè)、表征和優(yōu)化。我們通過外代謝組學(xué)方法分析了 SUB 灌注過程中 CHO 細(xì)胞的關(guān)鍵代謝，強(qiáng)調(diào)了細(xì)胞特異性底物和代謝物消耗以及生產(chǎn)率 qS 分析對(duì)識(shí)別不同代謝階段的重要性。CHO 灌注過程中經(jīng)典哺乳動(dòng)物細(xì)胞培養(yǎng)關(guān)鍵底物和代謝物的細(xì)胞特異性速率顯示出與 qOUR 的良好相關(guān)性，但出人意料的是，與 qGluc 無關(guān)。在這里，我們介紹了我們?yōu)?qPyr 開發(fā)的軟傳感方法，以允許實(shí)時(shí)近似細(xì)胞代謝和使用情況，以便進(jìn)行后續(xù)深入的過程監(jiān)測(cè)、表征和優(yōu)化。我們通過外代謝組學(xué)方法分析了 SUB 灌注過程中 CHO 細(xì)胞的關(guān)鍵代謝，強(qiáng)調(diào)了細(xì)胞特異性底物和代謝物消耗以及生產(chǎn)率 qS 分析對(duì)識(shí)別不同代謝階段的重要性。CHO 灌注過程中經(jīng)典哺乳動(dòng)物細(xì)胞培養(yǎng)關(guān)鍵底物和代謝物的細(xì)胞特異性速率顯示出與 qOUR 的良好相關(guān)性，但出人意料的是，與 qGluc 無關(guān)。在這里，我們介紹了我們?yōu)?qPyr 開發(fā)的軟傳感方法，以允許實(shí)時(shí)近似細(xì)胞代謝和使用情況，以便進(jìn)行后續(xù)深入的過程監(jiān)測(cè)、表征和優(yōu)化。強(qiáng)調(diào)細(xì)胞特異性底物和代謝物消耗和生產(chǎn)率 qS 分析的重要性，以確定不同的代謝階段。CHO 灌注過程中經(jīng)典哺乳動(dòng)物細(xì)胞培養(yǎng)關(guān)鍵底物和代謝物的細(xì)胞特異性速率顯示出與 qOUR 的良好相關(guān)性，但出人意料的是，與 qGluc 無關(guān)。在這里，我們介紹了我們?yōu)?qPyr 開發(fā)的軟傳感方法，以允許實(shí)時(shí)近似細(xì)胞代謝和使用情況，以便進(jìn)行后續(xù)深入的過程監(jiān)測(cè)、表征和優(yōu)化。強(qiáng)調(diào)細(xì)胞特異性底物和代謝物消耗和生產(chǎn)率 qS 分析的重要性，以確定不同的代謝階段。CHO 灌注過程中經(jīng)典哺乳動(dòng)物細(xì)胞培養(yǎng)關(guān)鍵底物和代謝物的細(xì)胞特異性速率顯示出與 qOUR 的良好相關(guān)性，但出人意料的是，與 qGluc 無關(guān)。在這里，我們介紹了我們?yōu)?qPyr 開發(fā)的軟傳感方法，以允許實(shí)時(shí)近似細(xì)胞代謝和使用情況，以便進(jìn)行后續(xù)深入的過程監(jiān)測(cè)、表征和優(yōu)化。

Our data also demonstrated that higher model accuracy was established when VCV instead of VCD was used as biomass depiction. This strengthens our strong belief in a paradigm change regarding biomass description in modern bioprocesses. VCD should no longer be the leading, or the only, measurement looked at when it comes to biomass determination. The cell size or volume, its distribution over time and, of course, the VCV should be used by default to accurately describe the biomass and all derived metabolic variables, such as mAB, lactate production rate, or glucose/oxygen consumption rates. Conclusions, based only on cell density measurements, can lead to wrong assumptions, calculations or other unforeseen misinterpretations, generating a fragmented picture of the biomass [38,40]. As modern bioprocesses can be highly complex and dynamic, the biomass and cellular metabolism analysis should be as comprehensive as possible to generate a comparable and reproducible data basis. Furthermore, the utilization of an off-gas-based soft sensor is easy to implement in SUB systems as well as in common stainless steel plants. For this purpose, the installation of any hard-type probes inside the bioreactor is not necessary and does not increase handling or decrease safety and therefore prevents possible contamination risks. The fundamental correlation of biomass growth and increasing oxygen demand can be used, optimized and extended to generate profound real-time knowledge on diverse bioprocess variables such as the shown biomass and metabolic nutrient rate soft sensor. Moreover, off-gas analysis can be used to determine the true bioreactor pH without any sampling or as non-invasive method for online pCO2 monitoring, which underlines the flexibility and outstanding character of having an off-gas analyzer implemented and running.

高效搖瓶5L

我們的數(shù)據(jù)還表明，當(dāng)使用 VCV 代替 VCD 作為生物量描述時(shí)，建立了更高的模型精度。這增強(qiáng)了我們對(duì)現(xiàn)代生物過程中生物質(zhì)描述范式變化的堅(jiān)定信念。在生物量測(cè)定方面，VCD 不應(yīng)再成為主要或唯一的測(cè)量方法。默認(rèn)情況下，應(yīng)使用細(xì)胞大小或體積、其隨時(shí)間的分布以及 VCV 來準(zhǔn)確描述生物量和所有衍生的代謝變量，例如 mAB、乳酸生產(chǎn)率或葡萄糖/氧氣消耗率。僅基于細(xì)胞密度測(cè)量的結(jié)論可能會(huì)導(dǎo)致錯(cuò)誤的假設(shè)、計(jì)算或其他不可預(yù)見的誤解，從而生成生物量的碎片化圖片。由于現(xiàn)代生物過程可能非常復(fù)雜和動(dòng)態(tài)，生物量和細(xì)胞代謝分析應(yīng)盡可能全面，以生成可比較和可重復(fù)的數(shù)據(jù)基礎(chǔ)。此外，基于廢氣的軟傳感器的使用很容易在 SUB 系統(tǒng)以及普通不銹鋼工廠中實(shí)施。為此，不需要在生物反應(yīng)器內(nèi)安裝任何硬型探針，并且不會(huì)增加操作或降低安全性，因此可以防止可能的污染風(fēng)險(xiǎn)?？梢允褂谩?yōu)化和擴(kuò)展生物量增長(zhǎng)和增加的需氧量之間的基本相關(guān)性，以生成有關(guān)各種生物過程變量的深刻實(shí)時(shí)知識(shí)，例如所示的生物量和代謝營(yíng)養(yǎng)率軟傳感器。而且，監(jiān)測(cè)，這強(qiáng)調(diào)了實(shí)施和運(yùn)行廢氣分析儀的靈活性和突出特點(diǎn)。

 
10層細(xì)胞工廠

關(guān)鍵詞：process analytical technologies (PAT),off-gas analytic,real-time monitoring,viable cell biomass, perfusion process,continuous process,single-use bioreactor (SUB),oxygen uptake rate (OUR),soft sensor過程分析技術(shù)（PAT）,廢氣分析,實(shí)時(shí)監(jiān)控,活細(xì)胞生物量,灌注過程,連續(xù)過程,一次性生物反應(yīng)器（SUB）,攝氧率 (OUR),軟傳感器

來源：MDPI https://www.mdpi.com/2227-9717/9/11/2073/htm