Without question, biopharmaceutical manufacturing has changed dramatically since 1977, when it was in its infancy. The ball really began rolling 20 years ago and has picked up speed in the past five years. Without question, single-use (i.e., disposable) technology has been one of the most significant changes. Advantages of single-use technology include greater flexibility, reduced resources for cleaning and cleaning validation, and faster turnaround between products and batches, resulting in reduced capital costs and increased speed to market. Single-use technology has also precipitated changes in upstream and downstream processing.
Pharmaceutical Technology spoke with Eric Langer, managing partner at BioPlan Associates; John Boehm, chairman of the Bio-Process Systems Alliance (BPSA) and Colder Products Company Bioprocessing Business Unit manager; Eric Isberg, director of Life Sciences, Entegris and BPSA Board Member; Parrish M. Galliher, chief technology officer, Upstream, GE Healthcare Life Sciences; Sabrina Restrepo, associate director in the Sterile & Validation Center of Excellence, Global Technical Operations at Merck; Helene Pora, PhD, vice-president, Single-Use Technologies, Pall Life Sciences; Peter Levison, senior marketing director, Downstream Processing, Pall Life Sciences; Fritjof Linz, vice-president, Purification Technologies, Sartorius Stedim Biotech; and Eva Heintz, global market manager, Healthcare, at Solvay Specialty Polymers about advances the industry has made and the challenges that remain.
PharmTech: What have been the most significant advances in single-use systems for biopharmaceutical manufacturing in the past 40 years?
Langer (BioPlan Associates): Over the past 40 years, single-use systems have moved from simple blood and intravenous bags to simple media and serum containers, and to highly engineered, complex devices that are now mainstream technologies in bioproduction. Over the past five years, these devices have steadily made progress in bioprocess operations as their scalability has increased.
Galliher (GE): In the past five years, new advances include an increase in closed systems and in larger-scale, higher-throughput, high-duty applications, such as microbial fermentation and centrifugation. Single-use sensors have been developed for a variety of process parameters for downstream steps such as chromatography, tangential flow filtration, direct filtration, and fill/finish, as well as for smart mixers for measuring parameters such as temperature, PH, and conductivity.
Linz (Sartorius): In the past couple of years, we have seen just about every bioprocessing technology become available in a fully single-use format. Companies are implementing end-to-end single-use platforms for monoclonal antibody, antibody drug conjugate, and vaccine production. Flexible facilities are likely to become an important part of large biopharma’s production network and allow much needed agility in operations.
Isberg (Entegris): I think the biggest advance in single-use technology in the past 20 years was the development of three-dimensional bags, which opened the door for large-scale mixing and cell-culture manufacturing. The industry was able to scale up volume while also creating systems equivalent in shape and volume to stainless-steel vessels. Equivalency is important because much of the engineering in areas like mass transfer was performed in stainless steel.
Pora (Pall): In the past 20 years, the sentiment has gone from, ‘why use/trust these systems’ to ‘how do we best optimize/leverage these systems.’ Overall, the ability of single-use technologies to offer sterile connections and operate a closed system, while still maintaining flexibility, has been a game-changer. In the past five years, we have seen the technology go past acceptance to start maturing, with a range of market options and sizes to accommodate various needs.
Boehm (BPSA): First used for media and buffer prep, single-use manufacturing now applies from inoculum to final formulation and filling. An initial focus on small-batch clinical trials has expanded to full-scale cGMP commercial production. More recently, drug manufacturers are using fully closed systems to make multiple drugs in large ballroom suites.
Heintz (Solvay): The evolution of single-use containers from several decades ago to today’s gamma irradiation-stable bioreactors has been one of the most significant transformations; it was the impetus to move all other components to single use to close the loop. In the past five years, we have seen many advancements in sterile connectors and sensors that are gamma irradiation-stable and non-ion migrating.
PharmTech: What are the most significant challenges that remain for fully optimizing single-use systems?
Heintz (Solvay): There are still challenges to single use in the final fill/finish and storage. From upstream to downstream, single-use components are gaining traction in development and use. Fill and finish technology still has room to grow, including the delivery systems of biopharmaceuticals.
Isberg (Entegris): I continue to hear that one of the biggest challenges is consistency and optimization of the materials used to manufacture single-use systems. Materials of construction have changed little in the past 20 years, with polyethylene and silicone dominating. I see the industry moving towards advanced materials like fluoropolymers, which solve most if not all of the challenges posed by other materials.
Galliher (GE): High-pressure resistant, high-temperature resistant, solvent resistant, better, and more extensive sensors and smart films are needed, along with systems that enable high-G centrifugation, elimination of seams for bags, and larger connectors for higher flow rates.
Restrepo (Merck): Single-use systems need to prove themselves to be a well-understood and robust technology. That might imply driving toward standardization from different perspectives: designs, interconnectivity, technical qualification packages, certificates, manufacturing practices, and product lifecycle management aspects (from user requirement specifications to management of supplier change notifications post-implementation). The establishment of industry standards such as ASTM E3051-16 or the ongoing joint efforts between the BioPhorum Operations Group (BPOG) and BPSA definitely contributes to move toward standardization. Being able to provide consistent information from drug manufacturers to health authorities around the globe will ultimately favor the prompt launch of more medicines to meet the needs of many patients.
Two other aspects to be considered are a broader spectra of integrated process analytical technology tools that can interface with many of the control systems available in the market and ergonomic designs or solutions for safe use by operators.
Organizations are setting more aggressive environmental goals, which will drive initiatives to show that single-use systems are environmental-friendly. Since the implementation of single-use systems involves a partnership with suppliers, robust and transparent supply chains to the customers are critical.
Linz (Sartorius): The industry still has more work to do to ensure all technologies are fully compatible with biological systems. Single-use systems must be tested extensively to ensure that their materials of construction do not inhibit cell growth or release chemicals into the product stream during bioprocessing. Biomanufacturers repeatedly cite the robustness of single-use technologies as being a concern, and suppliers need to support their clients by helping improve process integrity. Most significantly, biopharmaceutical companies need vendors to commit to providing a high level of assurance of consistent supply with robust supply chains and highly characterized processes and raw materials.
Boehm (BPSA): The industry’s greatest challenges are driving down drug costs to improve global accessibility and more quickly developing new therapies. Single-use technology plays a vital role in addressing these high-level opportunities. We must drive continuous improvement in education, standardization, and technology. Industry stakeholders (e.g., suppliers, users, regulators) must continue to exchange expertise and knowledge. Collaboration between stakeholders will also be critical to navigating the potentially conflicting goals of advancing standardization and technology innovation.
Langer (BioPlan Associates): Although single-use systems have made great inroads at clinical scale, the advances at larger scale have been slower. Over the past eight years, the reasons biomanufacturers give for not expanding their use of disposables have been relatively consistent. Top concerns are the potential for breakage of bags/loss of production materials and leachables and extractables (L&E) issues. Part of this persistent concern for L&E issues is the increased use of disposables, which, in turn, has increased awareness of the uncertainties regarding related regulatory issues.
Pora (Pall): While single-use systems are starting to mature, automation and process monitoring (sensors) remain pain points. We have yet to see how we can fully take advantage of single-use technologies with automation—even though we now have bioreactors at every size.
PharmTech: What have been the most significant changes in bioreactor technology over the past 40 years?
Pora (Pall): We have come a long way from the first stirred tank bioreactor—even the way single-use bioreactors look has changed—with a broad range of solutions from small to large scale. As single-use systems continue to mature, we are seeing more specialized applications and new innovations. Pall Life Sciences’ square stirred tank bioreactor design has shown clear advantages over traditional round design. And Pall’s iCELLis bioreactor system is an automated fixed-bed bioreactor, designed to simplify adherent cell-culture processes using single-use technology.
Galliher (GE): In the past 40 years, biomanufacturing facilities were primarily built using stainless-steel technology. That technology has grown in sophistication and scale required to produce large scale quantities of biotherapeutics (up to tons/year) and vaccines (hundreds of millions of doses/year). Steam-in-place (SIP) and clean-in-place (CIP) systems, with sophisticated automation, were technological advances in stainless-steel systems to ensure aseptic operation (where needed) and minimization of soil carryover from batch to batch or product to product.
PharmTech: What do you anticipate for the future of bioreactors?
Galliher (GE): Both stainless steel and single-use bioreactors will continue to get smarter (i.e., more sensing of process parameters and product quality) and will continue to get more productive via high cell-density techniques and sub-systems. On average, they will shrink further in scale as productivities further increase and peak. They will also be integrated into recovery/purification and be operated in semi-continuous or continuous mode. The number of drugs that are produced by non-mammalian expression systems, such as yeast and microbes, will continue to climb; these will require more highly engineered microbial bioreactors.
Pora (Pall): Single-use bioreactors present a real solution for today’s drug manufacturer, and there is no doubt that the industry now accepts and understands this fact. Over the past few decades, we have been able to clearly establish the boundaries—for instance, we know that 2000 L is the maximum level that you can leverage the advantages of single-use. Still, users are always looking for innovative ways to optimize the flexibility of single-use technologies, and we see this resonating in approaches like parallel processing, as well as the market drive towards bringing continuous processes to the upstream.
PharmTech: What have been the most significant changes in downstream biopharmaceutical manufacturing in the past 40 years?
Linz (Sartorius): Downstream processing has changed dramatically because of the introduction of single-use technologies. Purification suites were once hard-piped with stainless steel, making them inflexible capital assets requiring utility plants to enable their cleaning and steam sterilization. Today, buffers are held in bioprocess containers and unit operations are connected with tubing. Chromatography columns can be disposable or can be replaced by single-use membrane adsorbers. In the past couple of years, single-use centrifuges have been introduced. These have application as cell retention devices as fully closed systems and can handle very high cell densities. They can also be used in viral vector and vaccine production and for the collection of the cells used in cell therapies.
Levison (Pall): Historically, bioprocesses were carried out with animal or plant products, introducing a great deal of challenges along the way. Today, we can express proteins in cell culture, so the approach to downstream processing is completely different. In the past five years, the biggest advances have been in the introduction, development, and general acceptance/interest in continuous downstream processes for biopharmaceutical production.
PharmTech: What challenges remain for optimizing/debottlenecking downstream separations?
Levison (Pall): The real bottleneck is in the upstream (cell culture), which is why there is so much interest in perfusion technologies for continuous cell culture. Bioprocesses cannot be fully continuous without further advances in upstream processing. Another bottleneck can often come from the cost of goods in implementing newer downstream processing technologies; this bottleneck will likely abate over time as these technologies become fully implemented.
Linz (Sartorius): Integrating downstream processes with continuous upstream steps such as perfusion remains a challenge. There are some options available, but they are at an early stage of development. Although downstream process intensification is possible, we are still quite a long way from having the continuous flow of product through a purification train and into the vial. That is one of the challenge for downstream processing engineers over the next decade.