CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of PCT/EP2017/084483 filed on Dec. 22, 2017 which claims priority benefit of Indian Application No. 201611044875 filed on Dec. 29, 2016. The entire contents of which are hereby incorporated by reference herein.

TECHNICAL FIELD

The present invention relates to failure recovery methodology in cell culture bioreactor systems.

BACKGROUND

Cell culture bioreactor systems are known which comprise hardware including a bioreactor which provides a generally closed volume, and further hardware and software to measure and control certain environmental parameters so they are maintained within a predetermined range, to provide a consistent environment for the successful multiplication of cells within the volume. To reduce operating costs, it is known to provide a disposable bioreactor, for example in the form of a flexible bag (often called a cell bag) including fluid connectors, and to have the remainder of the hardware as reusable components. In this way, little sterilisation is required between cell culture batches. Whilst such bioreactor systems are robust, failure, is not impossible. For example, the bringing together of, mechanical, electrical power, electronic, software, liquid, and gas functions can lead to numerous potential failure modes.

In addition, for some cell culture procedures, small batches of cells are cultured for specific therapies, for example autologous immunotherapy, where a patient's cells are isolated, manipulated if necessary, expanded and reintroduced into the patient. These batches are usually expanded in process liquid quantities up to 5 liters and more usually in liquids up to 2.5 liters. In those cases, the cell culture regime also includes initiation of the cells into a bioreactor, followed by equilibration, inoculation and then expansion. These initial phases add to the complexity of cell expansion, and require careful process control. The process control is even more important with small cell batch culture because small batches are affected by even very small deviations in the maintained parameters, and, because the cells start the culture process in liquid quantities of around 500 mLiters or less, then deviation in the parameters can quickly take place during a hardware or software failure.

Larger scale process control systems, like those used in a large scale (e.g. 1000 liter) bioreactor control systems, typically include one or more process control devices in communication with one or more process controllers via analog, digital or combined analog/digital buses. The process controller is, in turn in communication with at least one host or operator workstation via suitable input/output (I/O) devices. The process control devices, which may be, for example, pumps, agitators, mass flow controllers, and transmitters, as well as parameter measurement devices such as temperature, pressure and flow rate sensors, perform functions within the process such as increasing or decreasing fluid flow and measuring process parameters. The process controllers receive signals indicative of process measurements made by the process control measurement devices and/or other information pertaining to the process control devices, use this information to implement a control routine, and then generate control signals that are sent over the buses or other communication lines to the process control devices to control the operation of the process. In this manner, the process controllers may execute and coordinate control routines using the process control devices via the buses and/or other communication links communicatively coupling the process control devices. Large scale process control systems are often configured to perform processes in accordance with batch recipes to produce products. Product designers or engineers prepare recipes during a development phase and store the recipes to be subsequently used a plurality of times by a process control system. A recipe typically includes a combination of unit procedures, operations, and phases, all of which include instructions to control process control devices (e.g., mixers, pumps, transmitters, valves, etc.) to transfer, mix, etc. ingredients in a process control system to generate a product.

Stock cell lines, used in large scale commercial cell culture behave in a predictable manner, and so predefined culture recipes and routines can be used to good effect. That large scale methodology where a predetermined routine is followed is only partially of use in small scale culture, because unique batches of cells derived from different patients rarely behave in the same way so control of their environmental parameters needs to be conducted based on measurement feedback and an iterative approach, rather than wholly or mostly driven by predetermined routines as in large scale culturing. Ideally smaller scale culture is also predictively based i.e. processing measurement data derived from previous parameter measurements, to predict the degree to which certain parameters will change with a step change in inputs, to thereby bring the culture back into an acceptable measured parameter range. That methodology is not problematic until a system failure occurs, then the parameters which are needed for present and future parameter control are lost and the reset or replaced system needs to re-learn what adjustments are needed to maintain the environmental parameters for that, often unique, batch. The default position of a predetermined routine is rarely suited to the unique batch characteristics.

BRIEF SUMMARY

The inventors have realised that there is a need to provide a back-up function in the event of system failure which back-up can accommodate system failure where the failed system was controlling parameters of a cell culture batch. In addition, the inventors have realised that there is need to provide a back-up function where cell batches respond differently to changes in environmental parameters compared to the same changes made to a different batch.

Aspects of the invention are set out in the claims, and thereby, embodiments of the invention provide that where a bioreactor system fails and cannot be restarted, a disposable cell bag which is being used as a culture bioreactor volume can be physically moved to a back-up system and the culture process can be carried on without undue delay, and without having reprogram the back-up system. Various ways to put this procedure into practice are described in more detail below.

Furthermore, advantages and benefits of the present invention will become clearer to the person skilled in the art in view of the detailed description below.

