Reducing Cross-Contamination Risks in Process Chromatography
When first introduced, single-use technologies were cautiously used in R&D laboratories for upstream processing. Today, single-use bioreactors are widely used for biologic drug manufacturing, and downstream disposable technologies for commercial-scale production operations are being introduced and increasingly adopted. Single-use solutions for process chromatography are no exception and offer distinct advantages over permanent, stainless-steel systems in many circumstances.
Manufacturers are increasingly looking for single-use technologies, according to Andrew Bulpin, head of process solutions for MilliporeSigma. “When it comes to new facilities, the small footprint and easy-to-use format of the products reduces investment needs with respect to facility, equipment, and labor, enabling cost savings and faster time to market,” he says. All of the attributes of single-use technologies--reduced process time, faster equipment turnaround, greater manufacturing flexibility, and reduced risk of cross contamination--apply to chromatography, according to Michele Morelli, global product manager for single-use automated technologies at Pall Life Sciences.
“With typical bioprocessing tools, a lot of effort and care goes into cleaning and cleaning validation of contact surfaces since any contamination in the purification process can be detrimental to the manufactured drug,” adds Fredrik Lundström, product manager for bioprocess hardware with GE Healthcare Life Sciences. “The obvious advantage with single-use technology is that it provides a replaceable fluid path that eliminates the risk of cross-contamination between different molecules,” he notes.
In addition, disposable flow-paths on single-use downstream processing equipment typically come gamma irradiated, leading to better bioburden control, according to Lundström. Preparatory and post-processing steps such as column packing, validation of packed-bed efficiency, verification of endotoxin clearance, unpacking, cleaning of unpacked columns, etc., can also be eliminated with the use of single-use processing tools, leading to increased efficiency and productivity due to a reduction in the change-over times between batches. Elimination of cleaning and cleaning validation activities also leads to smaller and simpler (open ballroom) facilities for biopharmaceutical manufacturing.
Market risks can be minimized as well. “Facilities incorporating single-use technologies provide flexibility not only with respect to the number and types of products they produce, but also market demand, because production capacities can be readily adapted in response to changes in market needs,” observes Bulpin. “It is quite straightforward to add an additional disposable processing line to increase capacity. Furthermore, the manufacturing facility can be utilized for another product after the target yearly supply of the initial product has been achieved,” he explains.
With its inherent benefit of avoiding cross-contamination, single-use chromatography is most suitable for application to campaigned manufacturing of drugs, according to Lundström. “Single-use chromatography is an increasingly attractive option for multi-drug facilities, such as [contract manufacturing organizations] CMOs and [contract research organizations] CROs, because single-use products allow quick facility changeovers and require less resources and facility time for setting up processes and performing manufacturing operations, and are more economical from a capital expenditure viewpoint,” Bulpin comments.
The main drivers for using single-use chromatography systems are batch size and frequencies, according to Morelli. “It becomes a balance between the total cost of operation and manufacturing agility, particularly for multiproduct facilities,” he says. When performing cost analyses, he adds, it is important to consider the cost of additional equipment such as steam generators that are required with stainless-steel equipment.
The flexibility afforded by single-use chromatography can also be beneficial for the production of therapies in smaller volumes, which is important when considering the advancement of personalized medicines and niche products for rare diseases, according to Bulpin. Lundström notes that single-use chromatography processing tools lend themselves to preclinical- and clinical-scale production of drugs where time-to-market is more of a critical consideration than other aspects, such as process economics.
High-potency drug manufacturing and other processes requiring closed processing and/or minimization of potent/toxic material in wastewater also benefit from adoption of single-use technologies for process chromatography unit operations, according to Lundström. Bulpin adds that from a supply perspective, single-use products can be adapted to new facilities for at-location processing including nationalized supply or even point-of-care processing, and can support mobile processing paradigms when needed.
Preferred target molecules
A variety of biologics benefit from the use of disposable technology in their production, from monoclonal antibodies (mAbs) and recombinant medicines to vaccines and novel therapies, according to Bulpin. Typically, adds Lundström, the decision to use single-use or traditional process tools for process chromatography unit operations stems from requirements such as scale of manufacturing and single-product vs. multi-product manufacturing, as opposed to the drug that’s being produced.
Because manufacturing equipment that offers a truly single-use flow path minimizes operator exposure, however, single-use chromatography systems are used in particular for the production of biologic drug substances with high cytotoxic potency, such as antibody-drug conjugates (ADCs), according to Morelli. In Lundström’s experience, in addition to highly potent compounds, single-use technologies tend to be used more often for vaccine and cell/gene therapy manufacturing due to the natures of these target molecules.
When single-use is not viable
After issues of safety and process economics are considered, technical feasibility determines whether single-use chromatography will be used in a given manufacturing process. In general, disposable systems are not a viable option for facilities that produce significant volumes per year or those that use large stainless-steel tanks for production, according to Bulpin. “Facilities with dedicated production lines for processing a single drug molecule with clear projections of demand requirements will benefit economically from using traditional process chromatography tools as opposed to single-use processing tools,” Lundström observes.
In addition, single-use process chromatography tools are limited to low-pressure applications, and these tools typically cannot withstand the harsh chemicals used in reversed-phase chromatographic separations.
While scale has been a limiting factor with single-use chromatography, Lundström points to the development of tools that can process reasonably high-titer batches coming from 2000-L bioreactors. On the other hand, he notes that established processes with strict limits on process control parameters may need to use traditional processing tools because the analytical and functional performance of single-use components may not match up to those of traditional components such as pumps or sensors.
With single-use systems providing advantages for some, but not all, process chromatography applications, often biopharmaceutical manufacturers use hybrid solutions that incorporate both disposable and traditional stainless-steel technologies.
“There seems to be wide variation in the use of these tools, depending on facility provenance, number of molecules manufactured, regionalization requirements, drive towards standardization, productivity, and process economic considerations, etc.,” states Lundström. The goal, he adds, is to “extract the maximum benefit while managing existing and future constraints, leading naturally to a hybrid approach to processing either within a unit operation or across unit operations used in the bioprocessing workflow.” As examples, Lundström notes that single-use chromatography systems are often used with traditional columns, and clean-and-reuse systems can be used with pre-packed disposable columns.
Single-use system suppliers have developed products that are designed to work in conjunction with stainless-steel equipment, according to Bulpin. MilliporeSigma, for instance, offers single-use chromatography membranes designed for high mAb throughput that allow the high loadings often obtained in stainless-steel facilities.
Morelli observes that many biologics manufacturing facilities use a combination of smaller pre-packed columns and re-packable columns at the 1-L size and above because pre-packed columns are not economically viable at larger scales. Often disposable buffer and collection bags are used across all scales. “Chromatography is a case study for the combined application of single-use and reusable components,” he says.
A continuous dynamic
Continuous processing has the overall advantage of maximizing production efficiency while minimizing capital expenditures and equipment downtime, according to Morelli, which are advantages shared by single-use technologies. Advances in single-use technology are, in fact, facilitating process intensification and continuous processing.
Continuous chromatography is a technique that many facilities are currently evaluating or plan to evaluate in the immediate future. “When applied to chromatography, such as in the form of simulated moving bed technology, continuous processing allows purification in a continuous mode using smaller columns and exploiting the full resin capacity, with no safety factors to prevent product loss,” Morelli comments.
The complexity of a continuous chromatography system paired with the need for high bioburden control could make gamma irradiated single-use flow paths attractive, but reliable and robust technology is essential too, because the operation is often carried out for a very long time, according to Lundström. During early development phases, consumable savings can be a big factor, whereas at late stages, reductions in capital expenditures are more important. Of course, process economics and cost of goods when using single-use flow-paths or consumables in a continuous mode must be considered. Changes in extractable and leachable profiles for contact materials when exposed to process buffers for several days, weeks, or even months in a fully continuous process workflow must also be addressed.
Bulpin notes that single-use chromatography affinity solutions will enable rapid cycling chromatography and continuous capture at high speed. To address the industry need for continuous processing, MilliporeSigma acquired Natrix Separations, a provider of hydrogel membrane products for single-use chromatography. The company has also implemented a multi-year, dedicated program focused on developing both innovative applications and approaches using existing, widely known used and new products, technologies, and expertise that facilitate continuous processing.
Advanced manufacturing techniques like 3-D printing (i.e., additive manufacturing) can bring significant benefits to manufacturing processes. For example, a 3-D printed part can combine 20 parts into a single part and improve performance. “Reducing parts in a manufacturing process benefits industries like the biomanufacturing industry, where the processes and manufacturing equipment can be complex and made up of hundreds of different parts,” says Lundström.
In October 2017, GE Healthcare opened its first 3-D printing lab (the Innovative Design and Advanced Manufacturing Technology Center for Europe) in Uppsala, Sweden. The center combines advanced manufacturing technology such as metal and polymer printers and collaborative robots, or “cobots”, with traditional machining equipment. The company is working with Amgen to test the performance of a custom-designed, 3D-printed chromatography column to determine if it can be used in Amgen’s R&D efforts to develop improved processes for the purification of biopharmaceuticals.
The role of suppliers
One important aspect to consider when choosing to use single-use technologies for any part of a commercial production process is the role of the supplier. With single-use tools, more of the typical responsibilities become shared with suppliers, because they not only take responsibility for timely delivery of the equipment and associated consumables, but also of other aspects such as gamma sterilization, validation, documentation, integrity, batch-to-batch consistency, and change control notifications, according to Lundström.
“Users of disposable technologies should ensure that their suppliers have adequate expertise and controls in place to ensure quality, timely supply, and documentation support of the systems they provide. If done right, and if the supplier has implemented robust security of supply protocols, it is possible to optimize ongoing order-receipt and inventory management of single-use consumables. If it is not done right, the savings in footprint and resources resulting from traditional to single-use transition can easily be lost due to expansion of facility space needed to keep consumables in stock for use at the right time,” Lundström observes.