The current trend toward green living and utilizing “earth-friendly goods” continues to rise. Green manufacturing has become so popular that there is even Green Manufacturing Expo. A recent report listed the top “greenest companies in biopharma.” All of the companies listed rank in the top 20 of pharmaceutical companies with regard to sales revenue and include such names as Merck, Novartis, and Pfizer. So where does single-use technology fit in the “Green” manufacturing process? Single-use: Is it just another term for disposable? Proponents of earth-friendly products would certainly say yes and shun those companies who choose to implement these technologies in their manufacturing processes. However, this would be very short-sighted. When I reviewed the top green biopharma companies, many made the list from initiatives to reduce energy consumption and decrease water utilization. Single-use technologies have a positive impact on the environment in this regard. Reusable manufacturing technologies require washing, with detergents. Washing increases water and energy consumption and results in a bio-product which may be hazardous to the environment.
Prior to putting this roundtable article together, I had the opportunity to attend the “Single-Use Applications for Biopharmaceutical Manufacturing” conference in Boston. Economic comparisons were discussed between stainless steel and single-use systems, and other pros and cons to its utilization and implementation. To gain a better understanding of the impact single-use technologies is having on the biopharmaceutical manufacturing industry, as well as the earth, Life Science Leader conducted a roundtable discussion with a panel of single-use experts. The discussion also includes opinions on single-use industry trends, competitive advantage of utilizing, common mistakes in implementation, and challenges to adoption of these technologies.
The panel included Cory Card, associate director, BioProcess Market Development, Thermo Fisher Scientific; Kenneth Clapp, senior director of global marketing and product development, Xcellerex; Jeff Craig, director of global marketing and business development, ATMI Life Sciences; Rich Ferraro, senior product manager, GE Healthcare; Maik Jornitz, senior VP of marketing, Sartorius Stedim; Jerold Martin, senior VP, global scientific affairs, biopharmaceuticals, Pall Life Sciences; Wolfgang Noe, senior consultant, BioProcess Consultants; Barbara Paldus, CEO, Finesse, LLC; Joe Petrosky, VP of global sales and marketing, Charter Medical Ltd; and Tony Pidgeon, head of technical affairs (Europe) pharmaceutical development services, Patheon.
Life Science Leader (LSL): What types of single-use equipment are most accepted by industry, and what is still lacking in these technologies?
Cory Card, Thermo Fisher Scientific: Single-use packaging of raw materials is the most accepted form of single-use equipment in the bioprocessing industry today. These include bags most commonly varying in size from 10 liters to 200 liters containing cell culture media, buffers, or other raw materials. They have served the industry well for over one-and-a-half decades. Other common and well-accepted single-use products include capsule filters and tubing manifolds. An area that needs further development to make these common products more accessible is in connectology. Single-use connectors with the ability to make a connection from one single-use component to another in an aseptic or sterile format have become fairly popular. There are many designs of these connectors, which are incompatible with each other. This requires careful planning and proper connector selection. These connectors have been limited in size, often to ½” or less, which limits the flow of fluids in some applications. Larger sizes are now becoming available. Tubing welders are another good option, but can also be limiting in the size of tubing supported, usually to less than 1”.
Maik Jornitz, Sartorius Stedim: Probably the most-used equipment and highly accepted are filter and bag assemblies, due to the length of time of market introduction and experiences one has with this equipment. Though, the use of single-use bioreactors would be a close second.
Wolfgang Noe, BioProcess Consultants: The Thermo Fisher’ Single-Use Bioreactors are widely accepted. However, standardization around the connectors’ technology is still “weak.”
Barbara Paldus, Finesse: Single-use media and storage bags are most routinely used in bioprocessing today. Single-use bioreactors up to 1,000 L volumes have also gained significant ground. However, robust single-use sensors are now available, but not integrated into these bioreactor platforms. The mainstream adoption of pH and dissolved oxygen optical sensors is hopefully imminent.
What new trends do you see in single-use technologies?
Jeff Craig, ATMI Life Sciences: I consistently see three trends: 1) the advancement and importance of integrity testing on storage bags and mixing vessels; 2) the integration of application-specific single-use mixing systems into process skids or skid-like configurations; and 3) the need and desire from end users for standardized and clearly documented leachable and extractable profiles.
Jerold Martin, Pall Life Sciences: Application of single-use systems comprising filter capsules, tubing, and biocontainers (in some cases just tubing or tubing with biocontainers) applied to final product formulation and filling, where requirements for leachables, particles, and endotoxins are more stringent. Also application for single-use mixers and larger-scale disposable bioreactors, implementation of sensors applying PAT (process analytical technology) to single-use technologies.
Noe: While “upstream disposable technology” is widely accepted, the downstream part is still a little foggy. I mean, who wants to discard an expensive Protein A Column after just one run?
Tony Pidgeon, Patheon: Some suppliers are starting to offer small- and large-scale equipment constructed of the same product contact materials. This helps to simplify the scale-up process and reduces the compatibility testing required.
LSL: To what degree is perceived or actual environmental impact of single-use technologies an issue?
Kenneth Clapp, Xcellerex: Environmental impact is a concern. It may grow in importance over time with more and more elements of bioprocessing converting to single-use. Three key areas: (1) materials/plastics and their disposal; (2) resource consumption; and (3) space utilization. With (1), as consumers, we are quite used to plastics and recyclability. Due to the nature of bioprocesses, reusing or recycling plastic material defeats the intention of the application. So, (1) is weighed against (2) — resource consumption. The consumption of water, for sterilization and cleaning, the associated utility costs, and the detergents demonstrate there is a clear advantage to single-use implementation. Another, often overlooked aspect is space utilization. Single-use facilities of equivalent conventional facility capacity, in either a greenfield or within a renovation site, can substantially reduce environmental impact — smaller size in the former and better utilization of existing assets in the latter. Single-use implementation gets products to patients faster, with lower cost and with better product quality.
Rich Ferraro, GE Healthcare: GEHC has conducted a peer-reviewed ISO standard life cycle analysis comparing traditional stainless steel and WAVE single-use bioreactor at the 500 L scale. The conclusion was that the WAVE platform would save 66,000 L of water per year that would otherwise be used for cleaning and steam. Additionally, a 43% energy consumption reduction was realized by eliminating the need for steam used for clean/sterilize in place operations.
Martin: It’s a good topic for discussion to demonstrate one’s concern for the environment, but if you talk to waste management people, it is not a significant issue because the mass is small relative to total plastic disposed, it is a preferred clean fuel for waste-to-energy cogeneration, and it is widely recognized that single-use, while increasing solid waste marginally, provides a significant reduction in carbon footprint due to the reduced energy demand from eliminating production of steam and WFI (water for injection) and from better utilization of smaller facilities.
Joe Petrosky, Charter Medical: There is plenty of evidence to support single-use technologies being comparable or better for the environment than traditional stainless steel technology when evaluating the total picture. However, environmental concerns seem to have little to no impact on adoption of the technology.
LSL: How accepted are single-use processes with the regulators?
Clapp: There is general acceptance in geographies that have experience with them. In geographies that have experience, the limits are being pushed to broaden the application of single-use technology. In geographic locations, or regions, where single-use technology is not as well-established, there is a predicable level of uncertainty driven by the lack of familiarity. However, in these less-familiar regions — the emerging biomanufacturing markets — companies there recognize single-use’s value and often don’t have the burden of legacy infrastructure. Companies there are eager to learn. They are driving regulators to join them as they close the familiarity gap to gain competitive advantage. Regulators have recognized the need to adapt and have shown a willingness to do so.
Ferraro: In general, single-use technologies are accepted by regulators for a number of reasons. First, they have been used in bioprocess for nearly 30 years. Second, as biomanufacturing has evolved, single-use technologies have been proven to streamline operations and allow for flexible manufacturing. This is particularly important today where the economics of launching a drug candidate are so challenging and where in the case of vaccines there is an urgent need for rapid response. That said, as disposables take over more of the typical process train, there is a heightened interest in the impact of any extractables or leachables that may result from single-use products.
Jornitz: I think there is probably still some hesitancy, but regulators start proactively enquiring about the technology, its potential, validation requirements, robustness, supplies, etc. More single-use technology conferences, recent training seminars, and informal discussions will help the adoption of single-use technologies, not only by regulators, but also by skeptic end users. In addition, one has to understand that the known reusable equipment and technologies will not disappear, but single-use technologies will be a beneficial addition.
Paldus: Single-use technologies appear to be gaining not only widespread acceptance but support with regulators. While existing cGMP processes are likely to continue using stainless steel infrastructure, many new products are going directly into single-use production equipment.
LSL: What are the main current requests by single-use technology end users?
Craig: I spend a lot of time with customers, and the requests I receive most often are for documentation of our leachable and extractable profile, detailed explanations of our pressure decay and helium integrity testing procedures, and the fastest possible delivery time for custom bags or hardware systems. Also in high demand is information regarding supply chain security. For ATMI, we address these requests directly through full documentation of our in-house film extrusion in one of the two global manufacturing sites.
Noe: I would say “standardization” as end users usually don’t like to be dependent on “single-sourcing.”
Paldus: On the upstream side of single-use, integrated single-use sensors and intelligent automation are the two most significant requests. Price has also become a touch point with customers. On the downstream side, there is increasing demand for single-use solutions and sensors as well.
Petrosky: End users are looking for custom designs that are durable and robust in the end users’ application conditions. They are also focused on ensuring continuity of supply. End users are increasingly committed to qualifying second sources to avoid supply chain interruptions.
LSL: Do you see any existing or emerging companies currently gaining competitive advantages through single-use processes?
Clapp: It may not be possible or appropriate to mention companies by name, but, yes, there are companies out there leveraging single-use for competitive advantage. What business would not benefit from better capital utilization, reduced overall risk, better product quality, and faster time-to-market? A sound approach to business doesn’t go out of style. It is not hard to find some real innovators and rising stars in the CMO space or among biosimilar companies or, to a limited extent, even within big biopharma. There are companies ( and business units within large companies) that have written or rewritten their business models to make single-use technology part of the foundation of their competitive advantage.
Jornitz: The benefits of the single-use technology, especially in new production process designs, are recognized and implemented. These new sites, though, are mainly installed in Asia. These new sites certainly have the competitive advantage single-use technology creates: flexibility and productivity improvements.
Martin: Yes. Single-use processes enable small companies to get into production quickly at reduced cost. This is also advantageous for smaller contract manufacturers.
LSL: What are the hurdles to broader adoption of single-use technologies?
Card: The major hurdle for companies not currently using single-use technologies is typically the perception that single-use technology would increase the process costs significantly. It is a common view that single-use implementation can reduce capital investment and time in trade-off for higher process costs. In order to assess the process cost impact of single-use, it is imperative that all costs of a traditional process are identified and documented. Many factors in the true cost of a process are often overlooked. Once all process costs are understood, a comparison of process costs using single-use technologies can be easily done. Often, although perhaps not immediately apparent, implementation of single-use technologies can reduce process costs as well as capital investment and time.
Ferraro: There are several borders to the implementation of single-use technologies. The most obvious is the existing infrastructure of stainless steel equipment that is still in use. The next is the scalability of single-use products. Until recently there have been limitations on how large single-use products, such as bioreactors and filtration products, could be scaled. However, in recent years, single-use products have developed to be able to handle production capacities up to 2000 L. This will help in the adoption of disposable products.
Pidgeon: The pharmaceutical industry is generally cautious about adopting new technologies. Many in the industry are still unfamiliar with complete single-use systems. Greater knowledge of the acceptance of the use of such systems should abate concerns.
LSL: What are the most common mistakes you see end users making when considering/implementing single-use products?
Card: Perhaps the most common mistake for end users considering or implementing single-use products for the first time is a failure to consult with a single-use technology provider or engineering resource familiar with single-use technologies. Until an understanding of the many applications and benefits of single-use technology is gained, a less than optimal process may be designed, resulting in lower efficiencies and a poor experience with single-use products.
Ferraro: The most common mistakes we see are clients not working closely with their supplier of single-use products to develop a unique solution. There are so many single-use products available off the shelf that end users commonly just buy and put together what is available. This might lead to a process that is close to optimal but not 100%. By working closely with single-use supplier design teams, products can be optimized to fit a particular process. This will cost more in the short term to develop the customized solution, but will pay off in the long term by maximizing productivity and yield.
Martin: The most common mistakes I see end users making are failure to consider design requirements for pre-use integrity testing of sterilizing filters, failure to consider system ergonometrics for operator handling, and failure to conduct appropriate operator training.
Petrosky: End users may underestimate the time involved in qualifying new materials. Better up-front project planning can help avoid delays due to lengthy procedures such as stability testing.
LSL: What advice would you give the end user regarding single-use implementation?
Craig: There is a wealth of information based on the experience available from the providers of single-use technologies. The end user will gain the most from single-use technologies by accessing the multiple layers of design, engineering, supply chain, and quality support available to assure maximum operational efficiency and integration. It is imperative that end users fully explore what these technologies have to offer beyond face value and implement appropriately.
Ferraro: First, look at your most common day-to-day operation that consumes the most value-added time, and explore if there is a single-use technology that can replace it. Then calculate a return on investment considering cost, man-hours, and possible economic impact to determine if single-use is the way to go.
Jornitz: First of all, always check with the vendor for accurate qualification test data and documentation, which can be used by the end user. Having said this, qualification does not replace process validation; therefore, process validation support is needed to implement the technology, and this again can be supported by the vendor. Supply assurance is the next topic on the list, as process-validated equipment needs to be available for years to come. Technical, design, and implementation support is of advantage for the end user. Another factor is the single-use product portfolio offered by the vendor. Undoubtedly the end user would like to have complete assemblies and not bits and pieces of single-use equipment solutions.
Paldus: Request a demo from your vendors, and train your personnel. Ensure that single-use is really fit for your process. Then, spend the time to do due diligence to qualify your vendors so that you obtain the support and service required to be successful.
Pidgeon: Consider how you wish to use the single-use technologies. For example, will it be used for the manufacture of a single product or a multiproduct facility? Consider how the single-use technologies can “futureproof” the facility. Finally, speak to the suppliers. They have a wealth of information about how the technology is used — and how it can be used.