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Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.
The advantages of single-use systems become clear as they become more broadly implemented.
As part of Pharmaceutical Technology’s 40th Anniversary issue, the editors interviewed biopharmaceutical industry experts about the biggest changes the industry has seen in the past 40 years and the challenges still to be addressed (see “The New World of Biopharmaceutical Manufacturing” in the July issue). Here, these experts share their perspectives on the advantages of single-use (i.e., disposable) technology and on some of the changes the industry is seeing in biopharmaceutical facility design.
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; 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; Eva Heintz, global market manager, Healthcare, at Solvay Specialty Polymers; and, for facility design, Par Almhem, at ModWave.
PharmTech: What has been the biggest advantage of single-use systems for biopharmaceutical manufacturing to date?
Boehm (BPSA): Single-use technology saves lives, saves money, and saves the environment. The flexibility and reliability of single-use technology enable drug manufacturers to develop new therapies more quickly. Single-use technology lowers capital expenditures for facility construction and improves operational costs by increasing process flexibility, delivering faster campaign turnover and higher product yield. Single-use technology consumes less water, utilities, and chemicals with a smaller carbon footprint than traditional stainless-steel processing, creating a greener manufacturing platform. All these advantages demonstrate the potential of single-use technology in maintaining or improving sterility assurance and the quality of final drug product.
Restrepo (Merck): In my opinion, the biggest advantage single-use systems have brought to biopharmaceutical manufacturing is flexibility. Now, it is possible to create sterile, closed systems with ready-to-use or steam-sterilized components that can fit into a diversity of facilities and allow for faster implementation and manufacturing times.
Heintz (Solvay): In many cases, the biggest advantage is the increased speed to market for products manufactured using single-use systems. Single-use systems allow for more flexibility in development; less time and resources are spent in cleaning and validating activities, which therefore increases speed to market.
Pora (Pall): The biggest advantage of single-use technology remains the absence of cleaning and cleaning validation-critical to the operation of traditional stainless-steel systems-which saves time and money. And because you are replacing the product contact layer every time the equipment is used, you remove the risk of contamination from previous batches. Additionally, single-use systems provide greater flexibility in footprint, at all scales-users can arrange and rearrange equipment as needed.
Galliher (GE): The benefits of single use continue to expand and unfold as the industry applies it more extensively. The benefits compared to stainless-steel facilities include reduced capital cost, reduced facility footprint, and no steam-in-place (SIP) or clean-in-place (CIP) facilities. Reduced time to build allows delaying the decision to build. Faster turnaround between batches, faster turnaround between different products, and reduced chance of cross contamination between different batches are benefits that also enable multi-product manufacturing.
Langer (BioPlan Associates): BioPlan Associates’ 14th Annual Report of Biopharmaceutical Manufacturing continues to show consistent trends in single-use device adoption. The top three critical reasons given in the 2017 survey, which are driving the implementation of single-use devices are:
Other factors include: ‘reduced time to get facility up and running,’ ‘decreased risk of product cross-contamination,’ and the ‘flexibility of a modular approach.’ Essentially, single-use devices are being increasingly seen as strategic tools to reduce costs and speed up both operations and facility construction.
PharmTech: What have been the most significant changes in facility design for biopharmaceutical manufacturing in the past 40 years? Past five years?
Galliher (GE): Since the early 1980’s, biomanufacturing facility design has historically been dependent upon the level of segregation and separation across processes. These designs take into account flow patterns for the product, materials, operators, and waste; they are designed to ensure protection of the product, and they have been complicated by open (i.e., exposed to the environment) processing operations. To achieve this protection, the process is spread across multiple cleanroom suites with multiple heating, ventilation, and air conditioning (HVAC) zones.
In contrast to simpler microbial or yeast-based facilities, mammalian cell-culture facilities require additional considerations for clearance of potential virus and aerosols across the process. Virus reduction by the process steps from cell culture to bulk drug substance (BDS) is so high (10–20 logs) that a minor upstream aerosol or spill could cross-contaminate the BDS. As a result, mammalian cell-culture facility design requires more complex, multiple cleanroom segregation and separate HVAC systems.
In the past 5–10 years, cleanroom facility layout, design, and operation costs have come under new scrutiny as manufacturers continue to hunt down inefficiencies and reduce costs. Cleanrooms are expensive to build and maintain, and they come with high gowning and labor costs. In the past 10 years, better designed closed systems and single-use technology have become more popular. Truly validatable and robust closed systems potentially require less stringent cleanroom environments or isolators and could relieve segregation requirements from upstream to downstream operations.
Because of these trends, open architecture facilities (or ballrooms) are being considered more often to cut capital and operating costs, with an acceptable low risk of adulteration of the product. Implementing single-use is easier in ballrooms as it facilitates the logistics of carrying in the single-use assembles and carrying them out after the batch is complete.
The rebirth of modular facilities is another result of the trend towards single-use manufacturing, because the modules lack the expensive stainless steel piping and infrastructure. As a result, modules are simpler, lighter, and cheaper to build and ship to the facility location.
Almhem (ModWave): A number of significant changes have occurred during the past 15 years. While not an exhaustive list, the following are some of the changes I consider most significant:
A key driver for these changes has been cost. For a long time, the challenge in biopharma manufacturing was capacity to manufacture a growing number of blockbuster products. The key was to supply the market and cost was the secondary priority. The increasing cost pressure on pharmaceutical companies has completely changed this, and cost is now a major factor. While maybe not a dominant driver, regulatory changes are influencing how facilities are being designed and built; the increasing use of isolation technologies is a good example of this influence. Moving forward, regulatory agencies are increasingly supporting continuous manufacturing.
Technology, market, and political trends are also drivers of change. Single-use systems, isolators, and modular systems are all technology improvements that have significantly contributed to this change. Blockbusters are giving way to smaller-volume products, increasing the need for flexibility. And with dramatically increasing yields in biologics drug substance manufacturing, the need for the ‘mega-factories’ has been significantly reduced. In addition, many countries are requiring an increasing share of products to be manufactured locally.
PharmTech: What types of design do you expect will be used for new facilities in the near future?
Almhem (ModWave): I think the trend towards smaller, more flexible, often modular, facilities will continue. Trends towards more potent products, increasingly personalized medicine, and new technologies (e.g., continuous manufacturing) will continue to drive the need for speed and flexibility. Some production systems will likely even be at bench-top scale. At the same time, we will likely see a few (but only a few) large-scale facilities being built.
An interesting question is how the continued consolidation will impact these trends. Will the focus be on retrofitting existing assets (which seems likely) rather than building new facilities? That would mean that innovative ways of refurbishing and repurposing existing facilities could play an important role.
Galliher (GE): Smaller closed system and single-use facilities will be more abundant as in-market, for market distributed manufacturing spreads across the globe. Increases in efficiency to reduce costs and drug prices in emerging territories will further reduce scales as high-productivity technologies and continuous processing are applied more extensively across the process.
PharmTech: How do you expect facilities to increase capacity (e.g., mobile manufacturing pods/trailers, continuous manufacturing, modular facilities)?
Galliher (GE): We see companies considering all of the above when planning their 5–10-year horizon. Scaling out (adding multiple lines of the same scale) is becoming a more popular way to add capacity because it reduces up-front capital risk and avoids scale-up risk. It can be added when the need arises, which allows companies to build the right size at the beginning and grow (or not) as the market grows.
Almhem (ModWave): I think we will see a wide range of alternative solutions. For larger-scale production, continuous manufacturing has significant advantages and will likely be replacing traditional batch systems. For small-volume products (with individual doses as the extreme example), the trend will likely be towards modularity, repeatability, and short cycle times. Operational efficiency will be even more crucial.