Industrial-scale bioprocessing underpins much of the production of pharmaceuticals, nutraceuticals, food, and beverage processing industries of the modern world. The profitability of these processes increasingly leverages the economies of scale and scope that are critically dependent on the product yields, titers, and productivity. Most of the processes are controlled using classical control approaches and represent over 90% of the industrial controls used in bioprocessing industries. However, with the advances in the production processes, especially in the biopharmaceutical and nutraceutical industries, monitoring and control of bioprocesses such as fermentations with GMO organisms, and downstream processing has become increasingly complex and the inadequacies of the classical and some of the modern control systems techniques is becoming apparent. Therefore, with increasing research complexity, nonlinearity, and digitization in process, there has been a critical need for advanced process control that is more effective, and easier process intensification and product yield (both by quality and quantity) can be achieved. In this review, industrial aspects of a process and automation along with various commercial control strategies have been extensively discussed to give an insight into the future prospects of industrial development and possible new strategies for process control and automation with a special focus on the biopharmaceutical industry.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s43393-021-00048-6.

Culture pH is a critical process parameter during CHO cell bioreactor operations that is key for proper cell growth, protein production, and maintaining the critical quality attributes of a monoclonal antibody drug substance. The traditional means of measuring pH in bioreactors is with an electrochemical probe that can withstand and maintain accuracy through repeated sterilization cycles. An alternative technique for measuring pH is an optical sensor composed of a fluorescent dye that is sensitive to the hydrogen ion concentration. In this work we explore single-use electrochemical and single-use optical pH sensors in stirred-tank and rocking bioreactors, respectively, to understand how their overall performance compares to traditional electrochemical probes in benchtop glass stirred tank bioreactors. We found that the single-use optical pH sensors were generally less accurate than the electrochemical probes, especially in detecting large pH drifts from the setpoint. The single-use electrochemical probes were increasingly accurate as pH was increased from <7.0 to 7.5 but tended to decrease in accuracy as the batch age increased. In conclusion, single-use pH sensors offer a convenient means to measure pH during an upstream bioprocess, but the limitations of these sensors should be built into process control such that deviations in process pH, and consequently potential fluctuations in product quality, can be avoided.

In the current transition to intensified upstream processing, the risks of adopting traditional single-use systems for high-titer, long-duration perfusion cultures, have thus far not been considered. This case study uses the Failure Modes and Effects Analysis (FMEA) method to evaluate the risks associated with implementing upstream single-use technology. The simulated model process was used to compare the risk level of single-use technology for a traditional fed-batch cell culture with that for perfusion culture, under the same annual protein production conditions. To provide a reasonable source of potential risk for FMEA, all single-use upstream operations for both fed-batch and perfusion processes were investigated using an analytical method developed to quantify the impact of process parameters and operating conditions on single-use system specifications and to ensure objectivity. Many of the risks and their levels, were similar in long-duration perfusion cultures and fed-batch cultures. However, differences were observed for high-risk components such as daily sampling and installation. The result of this analysis indicates that the reasons for risk are different for fed-batch cultures and perfusion cultures such as larger bioreactors in fed-batch and longer runs in perfusion, respectively. This risk assessment method could identify additional control measures and be part of a holistic contamination control strategy and help visualize their effectiveness.

Single-use (SU) devices and assemblies used as manufacturing equipment in the biopharmaceutical industry require comprehensive qualifications. These qualifications include the assessment of compounds released from SU devices in contact with the process fluids, and how these leachable compounds potentially influence process performance, drug product quality, and patient safety. SU suppliers need to provide comprehensive qualification data for several parameters, for both new products and product changes, such as changes in the sterilization process applied to the SU device. The introduction of X-ray irradiation as an alternative to the currently used and established gamma irradiation of SU devices represents a situation where robust data is required to demonstrate equivalency between these two radiation technologies. Here, we present the results of a comprehensive extractables study for three SU components, bags, tubing, and sterilizing grade filters, evaluated after X-ray and gamma-ray irradiation. The selected study conditions were set up to allow a direct comparison of the results from the two sterilization methods, and to allow conclusions to be made on the impact of irradiation type on the polymers and their additives. Orthogonal analytical methods are applied to identify and quantify all organic compounds present. The data package provided here supports risk assessments for application of irradiated SU equipment in biopharmaceutical manufacturing. The formation of reaction products and the fundamental chemical pathways are discussed and found to be independent of the irradiation type. The results demonstrate the equivalency of both irradiation methods for extractables from plastic components used in pharmaceutical and biopharmaceutical manufacturing.

Single-use technologies have transformed conventional biopharmaceutical manufacturing, and their adoption is increasing rapidly for emerging applications like antibody-drug conjugates and cell and gene therapy products. These disruptive technologies have also had a significant impact during the coronavirus disease 2019 pandemic, helping to advance process development to enable the manufacturing of new monoclonal antibody therapies and vaccines. Single-use systems provide closed plug-and-play solutions and enable process intensification and continuous processing. Several challenges remain, providing opportunities to advance single-use sensors and their integration with single-use systems, to develop novel plastic materials, and to standardize design for interchangeability. Because the industry is changing rapidly, a holistic analysis of the current single-use technologies is required, with a summary of the latest advancements in materials science and the implementation of these technologies in end-to-end bioprocesses.

The pharmaceutical industry has been confronted with new and complex challenges, particularly with regard to the aseptic filling of parenterals, including monoclonal antibodies and ophthalmologic drugs designed for intravitreal injections, which often require fill volumes <200 µL. In addition to intravitreal administration, microliter doses may be required for applications using highly concentrated formulations and cell and gene therapies. Many of these therapies have either a narrow or unknown therapeutic window, requiring a high degree of accuracy and precision for the filling system. This study aimed to investigate the applicability of a linear peristaltic pump as a novel and innovative filling system for the low-volume filling of parenterals, compared with the state-of-the-art filling systems that are currently used during pharmaceutical production. We characterized the working principle of the pump and evaluated its accuracy for a target fill volume of 50 µL. Our results demonstrated that the linear peristaltic pump can be used for fill volumes ranging from 12 to 420 µL. A deeper investigation was performed with the fill volume of 50 µL, because it represents a typical clinical dose of an intravitreal application. The filling accuracy was stable over an 8 h operation time, with a standard deviation of +/-4.4%. We conclude that this technology may allow the pharmaceutical industry to overcome challenges associated with the reliable filling of volumes <1 mL during aseptic filling. This technology has the potential to change aseptic filling methods by broadening the range of potential fill volumes while maintaining accuracy and precision, even when performing microliter fills.

Tobacco BY-2 cells are an attractive platform for the manufacture of a variety of biopharmaceutical proteins, including antibodies. Here, we describe the scaled-up cultivation of human IgG-secreting BY-2 cells in a 200 L orbitally shaken disposable bioreactor, resulting in cell growth and recombinant protein yields that are proportionately comparable with those obtained from cultivations in 500 mL shake flasks. Furthermore, we present an efficient downstream process for antibody recovery from the viscous spent culture medium using expanded bed adsorption (EBA) chromatography.

Aging facilities have become a concern in the pharmaceutical and biopharmaceutical manufacturing industry, so much that task forces are formed by trade organizations to address the topic. Too often, examples of aging or obsolete equipment, unit operations, processes, or entire facilities have been encountered. Major contributors to this outcome are the failure to invest in new equipment, disregarding appropriate maintenance activities, and neglecting the implementation of modern technologies. In some cases, a production process is insufficiently modified to manufacture a new product in an existing process that was used to produce a phased-out product. In other instances, manufacturers expanded the facility or processes to fulfill increasing demand and the scaling occurred in a non-uniform manner, which led to non-optimal results. Regulatory hurdles of post-approval changes in the process may thwart companies\' efforts to implement new technologies. As an example, some changes have required 4 years to gain global approval. This paper will address cases of aging processes and facilities aside from modernizing options.

Tobacco BY-2 cells have emerged as a promising platform for the manufacture of biopharmaceutical proteins, offering efficient protein secretion, favourable growth characteristics and cultivation in containment under a controlled environment. The cultivation of BY-2 cells in disposable bioreactors is a useful alternative to conventional stainless steel stirred-tank reactors, and orbitally-shaken bioreactors could provide further advantages such as simple bag geometry, scalability and predictable process settings. We carried out a scale-up study, using a 200-L orbitally-shaken bioreactor holding disposable bags, and BY-2 cells producing the human monoclonal antibody M12. We found that cell growth and recombinant protein accumulation were comparable to standard shake flask cultivation, despite a 200-fold difference in cultivation volume. Final cell fresh weights of 300-387 g/L and M12 yields of ∼20 mg/L were achieved with both cultivation methods. Furthermore, we established an efficient downstream process for the recovery of M12 from the culture broth. The viscous spent medium prevented clarification using filtration devices, but we used expanded bed adsorption (EBA) chromatography with SP Sepharose as an alternative for the efficient capture of the M12 antibody. EBA was introduced as an initial purification step prior to protein A affinity chromatography, resulting in an overall M12 recovery of 75-85% and a purity of >95%. Our results demonstrate the suitability of orbitally-shaken bioreactors for the scaled-up cultivation of plant cell suspension cultures and provide a strategy for the efficient purification of antibodies from the BY-2 culture medium.

The biopharmaceutical industry continues to face enormous pressure to accelerate time to market, improve productivity and efficiency, and reduce costs. Vaccine manufacturers face additional challenges, including small batch sizes, varied product portfolios, pandemic outbreaks that require rapid responses and highly potent ingredients that place large demands on cleaning processes. Given these pressures, single-use fill-finish assemblies can represent an attractive option for vaccine manufacturing facilities. This article describes the implementation of a single-use fill-finish system at a large vaccine manufacturer. The new assembly enabled flexibility while reducing set-up time, capital investment, cross-contamination risk, and cleaning requirements.
UNASSIGNED: Overall the biopharmaceutical industry is constantly being challenged to bring new products more quickly and efficiently to market while keeping costs as low as possible. One specific segment of this industry is the companies that manufacture vaccines. Vaccines present unique challenges because they tend to be made in smaller amounts for a larger number of individual products. The products can also be very potent, which can require special handling methods. Another challenge is the potential outbreak of a disease that may affect a large area or a large part of the population and would require immediate action. Single-use assemblies for filling the product into its final container are an attractive option for vaccine manufacturing facilities. This article describes the implementation of a single-use filling system at a large vaccine manufacturer. The new assembly was flexible enough to meet the demands of the manufacturer while allowing quick and efficient implementation with low upfront investment.