Across the biopharmaceutical industry, companies are striving to be more continuous, more modular, and more flexible during both development and manufacturing to increase throughput and maximize resource use to reduce the time and cost required. This desire is reflected in the new often closed and increasingly automated single-use solutions being adopted for clinical and commercial production.
Effective process optimization can have a tremendous impact on the manufacturing requirements in terms of number of batches, plant footprint, process time, and many other factors. For instance, high-yielding processes that generate purer products require less downstream purification and can reduce the number of batches that must be produced. There is also reduced risk of batch failure, which can have a significant impact on both scheduling and the costs associated with drug development and production. Equipment, raw materials, personnel, and time must be secured to enable completion of an additional production run. If that is not possible — in the worst-case scenario — a drug shortage could result, leading to negative impacts for the manufacturer in terms of both loss of revenue and brand credibility and, even more importantly, potentially serious consequences for patients relying on supply of their lifesaving medications.
One key to successful implementation of continuous, modular, flexible development and manufacturing solutions is access to in-line/on-line process analytical technologies (PATs) for the gathering of real-time in-process data and new rapid analytical methods and data analysis technologies that provide accurate and detailed information to developers faster and in many cases earlier in the development cycle.
Advances in analytics have come at a slower pace, however. There are definitely more in-line sensors and integrated analytics today that provide basic information and can be used to support limited real-time decision-making, but for many modalities the technologies available today remain insufficient for monitoring complex process parameters, preventing developers from gaining a full understanding of their processes by only relying on limited information, despite the benefits of it being real-time data.
One of the challenges to greater development and use of in-line/on-line analytics is the conservative nature of the biopharmaceutical industry, which tends to rely on technologies that have been previously validated and used. That is changing, however, with the U.S. FDA and other regulatory authorities encouraging drug makers to pursue more modern manufacturing practices and leverage innovative technologies that can increase efficiency, productivity, and quality while reducing cost.
However, new solutions must be easy to use and implement. PAT solutions in particular must be designed for use by operators and other personnel without the need for any extensive analytical training. They must be easy to put in place, not create additional burdens for users, and provide readily interpretable results in a rapid fashion.
There are both obvious and less obvious benefits of having access to real-time process data that can readily inform decision-making. First, getting answers more quickly helps to accelerate development, reducing the time it takes to bring molecules to market. Gaining a richer understanding of complex processes early on in development using high-throughput lab-scale multi-parallel mini-bioreactor systems combined with advanced PAT solutions helps reduce the number of larger-scale runs required, saving time and money. Better process understanding also derisks later development and commercial-scale manufacturing operations and leads to the development of safer drug products.
Implementation of on-line versions of more complex analytical techniques, such as mass spectrometry and liquid chromatography, has not been fully achieved at this point. PAT solutions must be practical for use in the production environment, which means easy integration with bioreactors in the upstream and with tangential-flow filtration, chromatography, and other purification systems in the downstream. In addition, rapid processing of the data generated by these systems, with results linked back to the processes to provide process control, is essential.
Ultimately, the goal will be to link process parameters to critical quality attributes. Ideally, integrating analytics from sample collection to analysis and then feeding them back into the process will also be possible in the form of validated plug-and-play solutions. Such an approach would eliminate the need for operators and process engineers to understand the analytical techniques involved.
The first steps in this direction are being taken by analytical instrument companies. The BioAccord™ LC-MS System offering and easy-to-use workflows from Waters Corporation represent a significant move in the right direction. The BioAccord System is the first biopharma solution supported by SmartMSTM, a comprehensive and intuitive set of features that makes high-quality, sophisticated MS techniques accessible to a broader base of scientists and technicians, enhancing uptime and productivity and accelerating decision-making while reducing training needs. Further improvements in integration and ease of use will continue, and Waters is working closely with customers, particularly those involved in early-phase development work, to customize solutions that meet their needs. Eventually, we expect that they will be transitioned from process development to process monitoring for GMP manufacturing as validated analytical technologies.
Further focused collaborations among solutions providers will also accelerate progress toward the goal of achieving fully on-line implementation of complex analytical techniques. Waters recently announced a new collaboration with Sartorius to develop integrated analytical solutions for downstream biomanufacturing, building on a previous joint agreement focused on upstream analytics. Establishing comprehensive software and hardware integrations between Waters’ PATROLTM UltraPerformance Liquid Chromatography (UPLCTM) Process Analysis System and Sartorius’ Resolute® BioSMBTM multi-column chromatography platform grants bioprocess engineers access to detailed downstream manufacturing data, which can improve yields while reducing waste and costs.
Mass spectrometry is an attractive analytical technique for process monitoring because it can be used to measure a wide range of product quality attributes (PQAs) and critical process parameters (CPPs). The ability to monitor both types of data makes it possible to understand the product outputs and the process inputs and outputs simultaneously.
Currently, in-line/on-line analytical systems measure only specific aspects of a process, such as dissolved oxygen content or amino acid or glucose concentration. Some of these solutions are well designed and work effectively. The Rebel Analyzer from 908 Devices is a good example: a simple-to-use kit that quickly provides data about amino acid content. Wyatt’s (now Waters) multi-angle light scattering (MALS) solution for downstream aggregate analysis is another. Raman probes and affinity probes have also demonstrated real value in a range of applications, providing specific information quickly and accurately.
Liquid chromatography–mass spectrometry (LC-MS), however, is far more comprehensive. While LC-MS technology can be complex, current commercially available PAT systems, like the BioAccord System, are easy to deploy in bioprocess environments, simpler, and much cheaper. As a result, they enable faster decision-making than can be achieved today using off-line LC-MS methods and represent a far more accessible and useable solution.
Careful thought must be invested in establishing a strategy for incorporating on-line/at-line analytics and advanced off-line techniques, such as LC-MS, into overall workflows to ensure both efficiency and access to all the data necessary for making informed decisions during process development, scale-up, and GMP manufacturing.
Early in development, rapid, high-throughput screening of large numbers of samples is needed. During late-stage development and GMP manufacture, robust, reliable validated methods are crucial. The earlier in development, the more opportunities there are to make changes and adjustments to analytical techniques. Once processes are locked down and analytics have been validated, making changes becomes very difficult.
There is generally a trade-off between the amount of information desired and speed. At the research stage, the goal is to collect as much data as possible, and time is therefore more available for this activity. Analytical techniques used in a GMP production environment must be compliant, robust, easy to use, and as rapid as possible yet provide the data necessary to assess CPPs and PQAs and prevent batch failures. Ideally, they also help increase the sustainability and reduce the cost of bioprocesses.
There are also different needs for upstream and downstream analytics. Upstream, complex mixtures must be analyzed, typically without any cleanup. With MS, these mixtures can lead to ion suppression and interference from the sample matrix. The key, therefore, is to determine what quality of data is needed to allow operators to make informed decisions, rather than looking for the best data quality that is possible.
It is also worth noting that LC-MS solutions may entail higher upfront investment but can replace large numbers of different sensors and in the long-term lead to an overall reduction in cost. Furthermore, rapid analytics today are not sufficiently robust to be used for batch release. On the other hand, the robustness, precision, and accuracy of MS instruments designed for use in bioprocess environments are continuously increasing. And unlike ELISA assays, which provide indirect measurements, MS directly measures the target molecule of interest, which affords both considerably higher accuracy and a higher degree of trust in the results.
As ever more complex analytical techniques are successfully designed for use in the bioprocess environment, they are creating the next challenge to truly leveraging rapid methods: data management. The quantity of data generated today is massive, and each instrument maker and end user manages data in slightly different ways. Key decisions must be made regarding which data are valuable and who will process those data.
For instance, approximately 200 different components in cell media can be monitored in a bioreactor. In any one bioprocess run, 80–100 of those components are typically tracked, with many samples collected daily over multiple weeks. Fully analyzing those data alone could take six months. It is essential to determine what data is needed versus what is merely nice to have — and focus on the data that pertain to CQAs and CPPs.
This issue is further complicated by the bottleneck associated with the difficulty today of finding skilled R&D and manufacturing personnel. There is a shortage of skilled and trained personnel across the biopharmaceutical industry. Increased automation will help address this problem to some degree, but even for highly automated manufacturing plants, skilled operators and engineers with a deep understanding of the processes involved, including analytical experts, are essential to oversee those operations. Thus, the drive is to develop automated analytical LC-MS tools that can be used in a “walk-up” fashion, where the operator does not need to be an expert in mass spectrometry but can still collect advanced and comprehensive MS data rapidly and in a standardized manner.
Waters Corporation recognizes that, for the company to be successful, our customers must be successful. Consequently, the main focus is on providing customer support. That begins with innovating in the analytical space to develop instruments, data processing and management software, and workflows that address their unmet needs, which we determine in close collaboration with our customers, and continues with installation, education, and training assistance to ensure that they maximize the benefits of Waters technologies.
Our bioprocess collaborative program is a prime example. In such collaborations, scientists can gain access to Waters technologies before they buy them to determine if they fit their needs. After a customer purchases a Waters instrument, such as a mass spectrometer or chromatography system, we provide ongoing support to ensure that they are positioned to use those solutions to their full potential. We help them get started using the instrument and are available to provide assistance down the road if needs change. Overall, Waters’ customer success programs add real value beyond the performance of the technologies themselves.
Other collaborative partnerships are focused on identifying new ways in which customers can use Waters technologies to resolve issues they are facing — for instance, looking to see if there is value in using mass spectrometry to solve a specific analytical problem. If there is, then we work closely with the experts dealing with the issue to understand how we can best provide a solution for that challenge.
This approach also helps to address the hesitancy in the biopharmaceutical industry to adopt new technologies, as education is key to increasing awareness and understanding. Closely collaborating with customers facilitates knowledge transfer and helps lead to more user-friendly interfaces that are not intimidating, which reduces the fear and wariness that many engineers and operators not trained in advanced analytical technologies have about using mass spectrometry and other techniques that can, if properly deployed, dramatically improve process performance.
Mass spectrometry is becoming ever more important in the biopharmaceutical industry as the number of cell, gene, mRNA, and other next-generation therapies in the clinic continues to rapidly climb. While there is a lot of knowledge and experience surrounding analytics for recombinant proteins and monoclonal antibodies, those solutions do not necessarily transfer readily to these new modalities. Characterizing large viral vectors and differentiating between full and empty capsids for gene therapies or analyzing very small sample volumes for personalized treatments all require new analytical technologies.
Waters Corporation and other analytical instrument companies are evolving promising new technologies to meet this need. At the same time, Waters continues to focus on making existing technologies, particularly mass spectrometry given the invaluable data it can offer, easier to use for non-experts so that they have more relevance in the GMP production environment and not just in R&D labs. That includes automated sampling systems that maintain an aseptic environment, more user-friendly software, simpler sample preparation protocols, and overall smoother workflows. The goal is to offer comprehensive, effective, single-vendor bioprocess analytics solutions that solve customer problems while also increasing convenience and ease of use.
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