Closed-Loop Solutions to Improve Efficiencies and Yields Using Automated Online Sampling Systems for Bioreactors

Improving production quality, efficiency, and yield is the objective of every commercial biotechnology process. Automation of assay tasks now routinely performed manually directly improves production bioprocesses. The US FDA supports and encourages this activity through the process analytical technology (PAT) initiative within its regulatory structure. The features and benefits of the online series of Automated Reactor Sampling (ARS-M™) systems supplied by Groton Biosystems are detailed here.

Online Automatic Assays

Today the most vital late-stage and production assay measurements — with the exception of basic temperature, dissolved gasses, and pH — continue to be performed using off-line, manually operated laboratory instruments. For example, amino acid analysis, cell viability, and nutrient monitoring are typically performed using traditional off-line instruments. This leads to inevitable delays and creates the potential for errors in sample handling. The historical nature of these data would be difficult to incorporate in a real-time control loop for the associated system.

Real-time sampling and monitoring of the state of a bioreactor for all vital parameters of the culture process is necessary to practically achieve the goal of improved production efficiency. The ARS-M series of automatic online sample systems for bioreactors and cell culture/fermentation fills the need for a programmable, universal sampling interface between process vessels and all analytical instruments and assay systems associated with and required for control of traditional bioprocesses.

“Universal Interface”

The ARS-M system is designed to permit programmed, sterile sampling of a bioreactor or fermentor with direct, automatic sample delivery to associated analytical instruments or assay devices. These instruments are connected to and controlled by the ARS-M. This permits a facility’s process monitoring to be performed through continued use of familiar, robust, and validated laboratory instruments while enjoying the productivity benefits of a completely automated sample interface and instrument control structure.

The ARS-M has been used successfully to monitor both cell culture and fermentation processes. In addition, the system comes in models that scale up from development to production reactors and fermentors. The ARS-M series is compatible with standard sample ports found on such vessels. It has been successfully coupled to HPLC systems (Agilent and Shimadzu), standard nutrient monitors (YSI and Nova), cell viability counters (Beckman and Cedex), and the Groton fraction collector. Interfaces for other analytical instruments are in development. Multiplexed input reactor ports and output instrument ports permit the ARS-M to connect a suite of laboratory analytical instruments to a number of reactors so users can enjoy the advantages of sampling automation throughout their entire installation. Groton supplies complete fluidic, mechanical, and software interfaces for all supported instruments.

Sterile

The benefits, features, and advantages of the ARS would be of little value if reactor/fermentor sterility was not protected during operation. The system design incorporates clean-in-place (CIP) and steam-in-place (SIP) modules depending on the size of the supported reactor and the type of connected analytical instrument(s). The ARS automatically performs a CIP process on all components in contact with the sample after each sample acquisition.

In addition, the mechanical design of the ARS incorporates a unique reactor isolation module (“iRIM”) comprising a series of automatic, sanitary diaphragm valves to isolate the reactor from its external environment when idle. The iRIM is cleaned and sanitized as part of the intersample CIP process of the ARS-M. Results recorded from mammalian and microbial installations using development to pilot-plant-scale reactors and fermentors at customer sites confirm that the ARS-M with iRIM reactor isolation systems maintain reactor/fermentor sterility while simultaneously permitting completely automatic sample collection and unattended assay instrument operation.

The ARS-M is an efficient, user friendly, and reliable system to automate bioprocess assay instruments. Reactor sterility is maintained by the ARS CIP and/or SIP system.