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While the debate between stainless steel and single-use systems (SUS) will continue to rage for the foreseeable future, most would agree that there is a time and place for either approach. Naturally, however, this raises the question: when is it ideal to utilize an SUS approach? What advantages does it confer? How are they being used in the current manufacturing environment?

Pharmaceutical Technology spoke with SUS experts Nick Johnson, director of Product Management, Biopharma, CPC, Wolfgang Walcher, chief commercial officer, Single Use Support; and Helene Pora, vice-president, Technical Communication & Regulatory Strategy, Pall, to get their perspective on the current benefits of single-use systems.

Merits of the technology

PharmTech: Can you share your thoughts, broadly speaking, on the merits of single-use systems, consumables, etc., in manufacturing? Is there any aspect that you feel is under or over-emphasized in this discussion?

Johnson (CPC): Think about the flexibility single-use systems allowed during the pandemic. Manufacturers urgently reallocated new therapy and other capacities to commercial vaccine production. The capability to quickly switch from one kind of production to another is a huge benefit that SUS affords in everyday practice. Single-use technologies (SUT) definitely contribute to speed and efficiency by allowing multiple products to be produced in one manufacturing suite with relative ease.

SUT’s flexibility and sterility also has made it simpler to ‘fail fast’ in clinical trials, too, compared to traditional stainless steel. The impact on bioprocessing from early-stage development through commercial manufacture has been an industry game changer.

Pora (Pall): SUS offer a level of flexibility, scalability, and cleanliness that is near impossible to achieve with glass and stainless-steel counterparts. Lines can be repurposed more easily, and there is no need for cleaning and cleaning validation. This saves a great deal of time and money while making the process safer for operators. SUS can also reduce the time to build a plant and lower overall capital expenses. And from an environmental perspective, there is a lower carbon footprint, less water, and less chemicals despite higher solid plastic waste.

Unfortunately, the amount of solid waste is frequently overstated compared to the benefits. In 2020, ISPE released a review showing that SUS is responsible for .01% of all global plastic waste, which is largely driven by consumers. This does not mean that the industry does not see the use of plastic as a problem—we are actively investing in recyclability and overall process impacts—however, it does not deserve the level of criticism it gets.

Walcher (Single Use Support): Single-use systems are trending for a reason:

• They help to improve safety, cost-efficiency, and sustainability in comparison with the use of durable stainless-steel manufacturing facilities.
• With single-use assemblies, bioprocess containers, and other sterile consumables operators can transfer liquids in closed systems and as customized options.
• They are adaptable to changing requirements of system setups.
• Usually, the systems are designed to minimize manual interventions, thus preventing human errors which can result in quarantined or even rejected batches.

The most under-emphasized aspect is probably sustainability. Different life-cycle assessment studies have proven that single-use systems can be more sustainable than stainless-steel solutions (1). However, there is still room for improvement, and we’ll drive innovation to further improve sustainability in the pharmaceutical industry.

The costs of single-use

PharmTech: What are the costs of using single-use systems, consumables, etc.? What factors should be considered when deciding whether or not to employ them?

Walcher (Single Use Support): There are different factors that come into play to influence costs of single-use systems because of the wide range of consumables on the market, which offers a wide span of prices.

The answer is strongly dependent on the application/use of single use systems. For example, in API primary packaging the alternative to single use systems is shipping hundreds of kilograms of cryo-vessels worth millions of dollars and causing tons of CO2 [carbon dioxide] emissions; alternatively, SUS, like bags, are low at cost, easy to store, and safe to ship.

For other applications, [such as] sampling or bioprocess containers, it is a question of flexibility, and people forget that stainless-steel multi-use vessels require a high amount of resources—producing, repairing and maintenance, cooling, etc.

Johnson (CPC): Ease of use, flexibility, reliable sterility, production efficiency—these are all factors to be considered. Thanks to SUT, it’s economically feasible to manufacture therapies for diseases that affect small patient populations that have the kinds of numbers that might not justify an investment in a traditional stainless-steel operation.

Modular, purpose-built SUS can be optimized for specific processes so they’re ready when needed. The production suite can be changed over quickly to accommodate the next process. There’s no downtime between production runs because SUS don’t require cleaning or equipment requalification in between batches. The ability of SUS to eliminate the risk of cross-contamination between processes is significant. All of this contributes to more streamlined operations.

Also, SUT is the most cost-effective way for manufacturers to make a wide range of drugs from vaccines, to mAbs [monoclonal antibodies], to cell and gene therapies.

Pora (Pall): SUS are priced more affordably than traditional equipment. However, SUS require bags and connectors that will generate consumable costs over the life of each process. The cost of consumables and security of supply is very important to consider. Working with trusted suppliers that have taken steps to secure sourcing is paramount in today’s market.

It is, of course, important to consider batch size and the number of batches that will be needed per year. With size constraints usually hovering around 2000 L, any high-volume drug would require a parallel processing approach. And whether the plant will be multi-product or single product is also critical.

Though it can be argued that the ability to changeover is only valuable if it is needed, it is always a smart investment. Having the flexibility, even in a single product environment, is a good backup if anything were to go wrong (e.g., clinical failure) along the way to commercialization.

Industry trends

PharmTech: What trends have you seen occurring as it pertains to single-use manufacturing? Do you anticipate them continuing for the foreseeable future, or is the end in sight?

Pora (Pall): If you looked back a decade ago, the discussion was still, ‘will this work?’ We are so far past that now, and SUS have helped to enable an era of innovation in this industry that is unmatched. We see a diverse range of modalities, which continues to grow, and a move towards more efficacious or even curative products.

The technologies needed to support the continuous high growth projections in the industry will rely on SUS in many cases. As we’ve seen through the pandemic, SUS not only enable innovation, but they allow for the type of rapid response needed for vaccines. Undoubtedly, the COVID-19 vaccines would not have been introduced and produced so quickly without SUS.

The growth may not be as high as we have seen throughout the last two years of the pandemic, but it will continue. A new product mix with an emphasis on biologicals and smaller indications will keep that demand growing over time. We also cannot ignore that SUS will be the backbone of existing processes (pending the patient population), creating sustainable demand in those areas.

Additionally, the scope of SUS use is continuing to expand, with more critical applications than ever before like formulation and final filling.

Walcher (Single Use Support): SUS will play a vital role in pharmaceutical and biopharmaceutical manufacturing and supply chain in future. The more personal medicines and low volume high potency medication (e.g., gene therapeutics, mRNA [messenger RNA], small interfering RNA, etc.) is progressing, the more important single use system will be. Challenges [such as] recycling of single-use systems will be solved in the near future and [will], therefore, significantly improve the environmental sustainability and CO2 footprints of systems used.

Johnson (CPC): Most new and upgraded contract development and manufacturing organizations, contract manufacturing organizations, and biopharma companies are incorporating single-use bioprocessing equipment. That’s the way the industry has been moving and will continue to go.

From a big-picture standpoint, it might take five to seven years from groundbreaking to a qualified facility using stainless steel. In contrast, a SUS-based facility might require two to three years. Then, after a facility is operational, SUS allow biomanufacturers to process multiple drugs simultaneously in one space or make rapid equipment changeovers between production runs without compromising sterility. That push for efficiency and modularity within and across sites is a driver.

There’s strong interest in standardizing SUT, which begins with components purchased from SUS equipment suppliers. The same equipment, standard operating procedures, and a shared supply chain create efficiency. SUS components also will need to work in automated equipment as the industry moves away from reliance on operators toward automatic processes.

Unique use cases

PharmTech: Are there any unique use cases for single-use consumables, systems, etc. that you have experienced in the industry?

Johnson (CPC): The SUS component industry is catching up a bit to create solutions specifically for small-bore tubing in small-volume work—applications [such as] sampling, seed train expansion, analytical processing, buffer/media transfers, and early cell-culture processes involving shaker flasks and rocker tables.

A growing number of companies are now engaged in small-volume (< 10 L) aseptic processes, such as early-stage drug development. You’ll also see very small volumes in cell therapy, for example, where cell availability is limited or media is expensive, and in the development of small-batch autologous therapies.

In the past, making reliable sterile connections in these smaller aseptic processes was typically handled using biosafety cabinets or tube welding. But biosafety cabinets can only handle a limited number of processes at one time. Tube welding is labor intensive, and the equipment is expensive—easily $15,000 or more per welder—and takes up valuable cleanroom space. Small companies with limited resources may not have the capital to purchase tube welders.

Until recently, tube welding was the only option for creating sterile closed systems at small volumes. Now there are single-use aseptic micro-connectors designed to sterilely connect small-bore tubing, so that’s new to the industry. Aseptic connections with new micro connectors can be completed in three steps and up to four times faster than an operator using tube welding, which can require a dozen steps or more to get a successful weld.

Also, in our line of work—connection technologies—there’s never been a genderless connector that can both connect and disconnect tubing using one product in bioprocessing until this past spring. Users appreciate genderless products because they’re more convenient. They eliminate mating complexity, reduce inventory requirements, simplify system design and reduce operator error. That genderless convenience factor was taken up a notch by creating a product that connects and disconnects aseptically without the need for ancillary equipment.

Pora (Pall): Initially the use of SUS was focused on providing a solution for media and buffer preparation and handling. Over the last decade, we can now leverage the benefit of SUS throughout the process and even into the final filling applications. The use here is very functional—we only use exactly what we need, which is another part of how we keep the volume of waste minimized.

Walcher (Single Use Support): There is a broad application of SUS established, so you will find all (even exotic) applications of SUS in the industry.

Diving into the supply chain

PharmTech: While the broader effects of the COVID-19 pandemic have lessened in public discourse, the supply chain interruptions it brought on remain a concern. Can you discuss the impact this has had on manufacturing? How would a mass return to the just-in-time (JIT) delivery model shift the current landscape?

Walcher (Single Use Support): The industry wasn’t prepared for such a supply chain challenge. The shortages have jeopardized business continuity of major manufacturing sites apart from COVID-19.

The shortage of SUS has therefore made biopharmaceutical manufacturers reflect on their relationship with suppliers. It has shown that it is crucial to have reliable partners, to plan ahead, and to establish reliable forecasts. Suppliers can react accordingly by building stock and procuring it early. Manufacturers and suppliers need a common understanding and common standards across the industry with respect to equipment and consumable design, as this enhances delivery speed.

A JIT delivery model in the pharmaceutical industry needs suppliers who rethink supplier relationships by offering solutions [such as] supplier agnostic solutions for flexibility or various business continuity measures to allow fast delivery times.

Pora (Pall): From a supplier perspective, it has driven us to significantly increase our manufacturing footprint and take deeper steps internally to secure our supply chain. Just about a year ago, Danaher announced an investment of $1.5 billion into the Cytiva and Pall lines of business (2). Over $300 million of that has been dedicated to strengthening the SUS line of business. Even as we start to realize some of the benefits of these investments, we remain committed to honing an agile approach to business processes standardization in parallel with our daily activities.

There will be a tradeoff for every approach. JIT will be largely dependent on the capability of biomanufacturers to produce accurate forecasts. While this can be achieved to a certain level with commercial products, it will remain very difficult for clinical manufacturing. Therefore, JIT delivery will be a combination of demand and how much some form of standardization is achieved, together with improved forecasting practices. It will still take some time to reach that level after the pandemic. The goal is really to more reliable and reproducible lead times, regardless of the model.

Johnson (CPC): From a supply-chain perspective, there’s no question that COVID-19 has disrupted everything from obtaining raw materials used to create components to the ability to ship sterilized equipment in a timely way. This isn’t exclusive to SUS, but it’s had an impact throughout the supply chain.

Supply-chain considerations are especially important when selecting suppliers of single-use assemblies. That’s because no supplier of single-use assemblies manufactures all of the products used in that assembly. For example, the manufacturer of a single-use mixer bag probably sourced the aseptic connectors, tubing, tubing clamps, T or Y connectors, filter capsules, etc., from other companies. Each of those component suppliers has a supply chain that may comprise sub-component suppliers, external assemblers, raw material suppliers, contract manufacturers, and so on. You can see that the SUS supply chain is multi-tiered and complex; the ability of the SUS manufacturer to supply product is 100% dependent upon the robustness of the entire supply chain.

References

1. Single Use Support, “Enhancing sustainability in the pharma industry,” Press Release, June 10, 2021.
2. Cytiva, “Cytiva and Pall Corporation investing 1.5 billion USD over two years to meet growing demand for biotechnology solutions,” Press Release, July 27, 2021.

About the author

Grant Playter is the Assistant Editor at Pharmaceutical Technology.