Optimising Bioreactor Yields with Smart Sensors

用于生物反应器精确状态控制的智能传感器为医疗保健和制药行业创造了新的机遇。通过集成连接系统，制药仪器制造商可以以合理的成本提供更高的产量，以及关键的附加功能。
Bioreactors are used, among other things, to grow organisms such as enzymes, plant and animal cells, and microorganisms. Such active ingredients are used for medical drug research, treatment development, clinical trials and the production of high-value pharmaceuticals. Besides the latest example of mRNA vaccines, monoclonal antibodies for treating cancer, rheumatoid arthritis and other diseases are produced in these vessels. Life science innovators assume they will likely be able to grow organ and other muscle tissue in the future.

无论是在制药研发、大规模生产还是医疗领域，生物反应器都必须提供一个完美的环境，使敏感微生物在该环境下相互作用并受仪器环境条件的影响而发生变化和生长。为了理想的细胞生长在质量和产量方面，生物种群的环境需要精确控制。从根本上说，这意味着维持pH值和温度，确保空气、氮气和其他气体以及营养物质的供应。

This is not new, but today’s increased requirements can make the growing of organic materials so complex that the physiochemical dependencies of the individual parameters have to be carefully synchronised with each other. In addition, the more and more versatile deployment of bioreactors, the aim to reduce contamination risks for operators and avoid disrupting ongoing processes by conventional “measuring by sampling” are complicating the matter, too.

Versatility, repeatability and efficiency

生物反应器必须能够容纳不同类型的细胞。如果我们看一下流感疫苗，它的生产过程每年都不同，因为不同的病毒在每个寒冷的季节都有略微不同的特征。此外，正如疫情向我们表明的那样，每天都需要大量培养细胞，对最高产量的需求很高。大量生产mRNA疫苗不仅需要高效的反应器，而且需要高工艺可靠性和可重复性。这些要求也适用于生物反应器的任何其他应用，这些应用被部署在各种大规模药物生产中。
随着生物技术的崛起和最近的经验，制药制造和医疗保健需求也要求更高的稳健性，以提高产量。满足新需求的关键不仅在于开发新型生物反应器设计，还在于使用生物兼容、快速、稳定、准确和易于清洁(如果它们不是一次性的)的智能传感器的新过程控制概念。

Parameters for optimum cell growth

Creating physiochemical conditions and enabling fast adjustments for specific cell cultures require the measurement of the following parameters inside a bioreactor:
• pH-value
• Temperature
• Humidity
• Gas and liquid concentration
• Gas and liquid flow
• Headspace pressure
In most cases the temperature is kept at 37°C and the CO2 concentration at 5% during cell growth. However, in some cases these parameters must be finely adjusted to reach the target pH range, to which priority is given.
Often, the pH value must be kept in between 7.0 and 7.4. Keeping it stable in this narrow range can be challenging, insofar as there are several other parameters that have to be balanced in parallel, such as temperature, cell growth, lactic acid and the CO2 level. This can be done by so-called buffers, which neutralise any additional acid (H+ ions) or base (OH ions) to keep the pH value stable.
此外，氧气浓度需要精确控制。对于大多数细胞培养物，它必须保持在20%;有时，一些文化在不同的条件下生长得更好。因此，在细胞培养液中氧气有效地从气态转化为液态，使细胞代谢尽快发挥作用是至关重要的。氧传递效率受温度、pH值和产气速率的影响。
最后，湿度应稳定并实时监测，以检测蒸发系统故障。这同样适用于顶空压力，特别是在一次性生物反应器中，因为它们的柔性塑料袋不能长期承受几百毫巴的超压。

Condition monitoring, failure detection and data logging

在控制条件方面，连接传感器在生物反应器中发挥着关键作用。多智能传感器系统用于高精度的物理化学过程控制和精确监测，可以将这种设备的性能提高到一个新的水平。
Due to the already addressed mutual dependencies of the different parameters, successful cell growth can turn out to be a complex undertaking. The easiest and most cost-efficient way to optimise the growth of organic materials is to consistently monitor and control the cultivation condition with a closed-loop system. Stable environments are particularly relevant for any high-volume drugs or during the R&D phase of drug design. In such cases, only small deviations occurring for a short time can affect the desired output of organic material.
最先进的传感器可以实现实时反馈回路，不仅可以让生物反应器立即和高精度地改变条件，而且还可以检测故障。在设置点偏离的情况下，系统会自动触发警报，并在任何损坏发生和昂贵的材料被浪费之前阻塞桶(如在一次性设备的超压情况下)。
因此，可以使用不同类型的传感器来检测不同的故障模式。例如，还可以部署用于监测液体浓度的传感器，以验证是否将正确的液体注入设备。这同样适用于液体流量传感器，它可以用于测量总分配体积(特别是昂贵的液体)，以及精确地给多种液体剂量，以获得正确的浓度。这也适用于气体流量传感器。简而言之，反馈回路有助于优化流程的安全性和可靠性。
Furthermore, in some bioreactors it can be helpful to implement multiple sensors of the same type – for example, one at the inlet and one at the outlet of the bioreactor. Obtaining spatial information of different locations allows for a better understanding of the physiochemical processes in the cell culture.
智能控制系统的另一个好处是能够记录传感器数据并将其存储在数据库中。如果增长结果不令人满意，一个容易获得的所有测量参数的日志提供澄清。特别是出于安全考虑和研究目的，获取培育过程的数据历史是非常有价值的。由于有了跟踪系统，操作人员可以快速确定故障的根本原因，从而修改流程。

The solution: reliable, fast and robust sensors

Recent advances in MEMS-based sensors have led to compact, low-power and high-performance solutions that are also suitable for single-use bioreactors (which, compared to conventional bioreactors, require lower volumes of water and detergents and no cleaning or maintenance procedures). Besides environmental reasons, such applications also stand out due to reduced costs and better turnover rates.
Sensirion offers a wide portfolio of compact, high-performance sensors - including single-use sensors - for precise process control and accurate process monitoring in various types of bioreactors, from pilot to commercial manufacturing. Sensirion’s biocompatible new-generation sensors can easily be integrated in existing bioreactors, allowing users to upgrade their apparatus instead of acquiring a new one. The digital sensors of the Swiss manufacturer cover wide measurement ranges without losing their high accuracy, even down to the lowest limits. No wonder that they have become an in-demand component for next-level bioreactors in various pharmaceutical fields.

Sensirion’s bioreactor portfolio

Liquid flow sensors
Liquid flow concentration sensors
Mass flow controllers
Mass flow sensors
Differential pressure sensors
Humidity and temperature sensors
CO2 sensors
Gas analysers/gas chromatography