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Downstream Processing in the Age of Precision Medicine: Trends and Challenges

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Drug development and manufacturing have undergone a seismic shift in the last two decades,1 from blockbuster small molecules to highly personalized biologics2 and cell and gene therapies. Because these therapies are designed for specific populations, they don’t require the kinds of large-scale manufacturing operations that many companies and contract development and manufacturing organizations (CDMOs) have optimized.


While the drugs may offer significant value for patients, smaller batch medicines may not be financially feasible for a larger company to manufacture – especially if they have a broader pipeline. Companies are now working to address this disconnect, optimizing their processes for smaller batch biologics.


This article discusses one of the key areas where innovation is needed: downstream processing. Surveys show downstream processing remains a serious bottleneck – one that significantly impacts overall production.3 Surging demand for treatments and vaccines fueled by the COVID-19 pandemic has only exacerbated these bottlenecks.4,5 Many have been exploring alternative processes and products, such as new chromatography columns that better reflect modern manufacturing needs. Biopharmaceutical leaders urgently need these kinds of solutions to improve the productivity, efficiency and flexibility of downstream processing.


Trends in Drug Development

New drug modalities

As the name suggests, precision medicine is about targeting medical care to each person to improve outcomes and reduce side effects. This field has advanced rapidly over the last two decades, with highly selective biologics and new modalities including bispecifics, trispecifics, antibody-drug conjugates (ADCs), cytokines, and bespoke cell and gene therapies (CGT). Each of these modalities introduces new manufacturing challenges, many related to the potency of the drugs.


ADCs are a validated modality and one that oncology players are increasingly recognizing as important to their discovery and development efforts. We are truly in an ADC renaissance with 11 approved ADCs and more than 100 in development,” said Engin Ayturk, PhD, senior director for process engineering and bioconjugation for Mersana Therapeutics. Mersana Therapeutics is advancing a pipeline of novel ADCs, including its lead candidate UpRi (upifitamab rilsodotin), which is being studied in ovarian cancer.


Medicines with greater potency generate increasingly complex regulatory requirements. As a result, the processing of these high-potency molecules – including ADCs – requires specialized equipment and expertise. Developers must find manufacturing partners that can safely handle high-potency molecules while meeting regulatory requirements.


The shift toward precision medicines

Technologies such as next-generation sequencing (NGS) provide key insights into the drivers of disease,6,7 and how individuals respond to medications. Over the last two decades, this information has helped usher in a new era in precision medicine, targeting unique mutations in cancer or specific pathways in rare or autoimmune diseases (Figure 1). Since these are medications that treat diseases in a target population, these “orphan” drugs tend to be produced in small batches.

Graph showing number of FDA orphan drug/precision medicine designations and approvals by year.

Figure 1: Count of FDA orphan drug/precision medicine designations and approvals by year (1983-2019).8

Single-use technologies

The rise in “disposable” single-use technologies has also impacted downstream manufacturing processes and efficiencies. Single-use reactors, membranes and chromatography systems cut down on laborious cleaning processes, giving companies and CDMOs greater flexibility to handle a variety of projects. For smaller-scale manufacturing, they can more readily change out the single-use products and switch to a new therapy. This changeover capability reduces cross-contamination,9 provides better bioburden control and ensures companies manufacture high-purity products. Overall, single-use technologies decrease the time and resources spent on clean-up and set-up between different drugs, improving operational efficiency.


“You can no longer build a facility that handles just one drug. Your facility must be able to handle more than one drug efficiently, and more and more, we’re seeing single-use technologies enable that,” explained Kasper Møller, PhD, chief technology officer of AGC Biologics. AGC Biologics is a global CDMO offering microbial and mammalian capabilities as well as CGT, fulfilling early-phase through late-phase projects at both small and large scales.


Møller further stated, “Disposable single-use technology is rapidly fueling the innovations we see in manufacturing today. As an example, in upstream processing, we developed and implemented the 6-PackTM scale-out concept, which allows us to inoculate and harvest several main bioreactors from one seed train to establish flexible process scaling.”


He says this capability is important because manufacturing volume after launch is uncertain for some molecules, even if clinical trial and launch manufacturing is built at a standard 2000L scale. The 6-PackTM scale-out technology allows manufacturers to adjust scale very quickly after launch.


The biopharma experts we interviewed agreed that disposables are now used in every step of the manufacturing process, from buffer preparation, buffer storage and eluate collection all the way to the medication dispensing and weighing rooms. However, some technologies, such as single-use chromatography columns and membranes, have yet to see widespread adoption despite eliminating time consuming packing of columns, qualification, storage and re-validation of oversized columns, and increased throughput. These are expected to become more common in the near future.


“A while ago, it became clear that membranes are a great alternative to columns and were becoming more widely used. We’ve especially seen great success with flowthrough membranes,” Møller explained. “Overall, I think we’re approaching a future in manufacturing where we implement fully disposable processes including all the chromatography steps that support the flexibility that is needed in rare disease and small volume manufacturing.”


Continuous downstream processing


While not unique to the biopharma industry, the gradual shift from traditional batch processing to continuous processing has also impacted therapeutic manufacturing. Instead of starting and stopping each batch, continuous processing operates as a non-stop cycle. This approach can reduce the cost of manufacturing precision medicines without requiring an increase in scale.10,11


In continuous bioprocessing, continuous chromatography processes are crucial for achieving high purity products. A continuous chromatography process uses several chromatography columns in a concurrent manner: as loading is carried out in the first column, all the other steps – washing, elution, regeneration and re-equilibration – are carried out in the other columns.12 A study that performed a cost analysis of traditional batch processing versus continuous processing for 200 kg of monoclonal antibody (mAb) production found that the latter reduced downstream processing cost of goods by approximately $9/kg.13,14

Facility fit challenges

For smaller biopharmaceutical companies working to produce high-value precision medicines, the new wave of approvals is both exciting and overwhelming. One of those challenges is finding the right facility to handle the manufacturing of each medication.


“Facility fit is a big challenge and forward thinking is essential,” said Ayturk. “Most manufacturing partners are optimized for standard or generic processes that are significantly larger in capacity. There are gaps in finding partners that offer variety in scales of operation and, provide services for drugs that require high-potent handling and/or integrated processes, analytical development and release activities. Finding a manufacturing partner that can handle IND-enabling activities and production needs against aggressive timelines can be challenging.”


Supply chain concerns


The COVID-19 pandemic has put pressure on supply chains15 and staffing, with many CDMOs and CMOs solidly booked for a year or more. Smaller biotech and biopharma companies without manufacturing abilities that depend on CDMOs can end up deprioritized or paying a premium as they compete for manufacturing capacity alongside larger-scale drugs.


As one engineer at an emerging cancer immunotherapy company puts it: “If you have a GMP run that needs to be completed in seven months, but the lead time on the resins and products you need is two years, that is a challenge.”


The new wave in precision medicine manufacturing coupled with the COVID-19 pandemic is driving a shortage in new resins and buffers needed for downstream processing. Some market players are quoting lead times of several months to over a year.


To help mitigate these risks, many groups are proactively identifying a second supplier for crucial goods. For example, manufacturers that require a specific resin for removal of a known impurity should find backup products that have a similar resin or membrane. This extra layer of security can help companies meet the deadlines required for clinical trials or for patients who need those therapies the most.


Other backup plans can prove more laborious. “In some cases, when we’ve realized that our columns dedicated to at-scale GMP clinical resupply batches were not going to be delivered on time, we’ve had to revisit conventional ways of doing work and rebuilt the bridges between single-use and re-use manufacturing approaches,” said Ayturk. “We’ve re-established cycling and resin life-time studies and re-introduced cleaning and storage regimens into our processes to ensure uninterrupted supply to clinic because patients waiting.”


Downstream processing solutions


The goal for both biopharma companies and CDMOs is to be efficient with drug production in order to ensure their medications reach the populations that need them the most. However, as noted above, this goal can be disrupted by supply chain shortages and a lack of available manufacturing capacity.


Drug developers beginning their manufacturing journey or looking to adapt can learn from these disruptions and plan accordingly. One important step in this direction is evaluating alternative technologies for cleaning up impurities.


“Membrane technologies have matured noticeably over the years and have become an essential part of bioprocessing. Despite existing membrane technologies, GORE’s introduction of membranes with affinity capture capability is novel and fills a technology gap that could be an alternative to the existing gold standard, Protein A chromatography. GORE’s Protein A membranes create the possibility for developing a membrane-based DSP processing train that is flexible, single-use, fully integrated and enables scale-agnostic processing. This technology could be a game-changer for new modalities, as well modular and continuous bioprocessing applications.” – Engin Ayturk.

Historically, the biopharmaceutical industry has been slow to adopt new technologies – for good reason. Regulatory agencies and other stakeholders value proven products and consistency. However, at a certain point, the latest technology must become the status quo to keep up with the evolution in drug modalities and manufacturing processes.

CDMOs sometimes struggle to convince clients that these new technologies will work for their products. “Naturally, nobody wants to be the first when it comes to implementing new technology. They want to know how many approved INDs have used that technology,” explained Møller. “However, we have also seen more development and a strong push for implementing new technology and innovation by the FDA over the last ten years. And so clients do expect that new technologies may be incorporated into their workflows. We routinely make agreements with clients to implement specific technology that solves a unique problem for their product.”

There are now both technical and supply chain motivations for adopting new chromatography technologies. As one bioprocessing engineer shared, “This is what intrigued us about GORE’s membrane technology—the need to have backup or replacement resins that offer speed, efficiency, and long-term cost savings. Ultimately, it is about being able to get the medicines onto the market in order to save lives. GORE had excellent lead times.”

GORE® Protein Capture Devices with Immobilized Protein A are intended for the affinity purification of precision medicines containing an Fc region in process development to initial GMP clinical applications. The Protein Capture Devices leverage a unique expanded polytetrafluoroethylene (ePTFE) membrane solution that helps to bridge the gap that has long existed between innovations in upstream and downstream processing.

Pre-packed GORE Protein Capture Devices significantly boost productivity with high binding capacity and fast flow rate, enabling a faster path to clinical trials.

As biopharma manufacturers continue to seek alternate solutions in streamlining downstream processes and embrace those with the most viability and efficiency, bottlenecks will be reduced, and productivity will increase. This will have a positive impact as manufacturers shift their focus to precision medicine innovations where ultimately, patients will have access to wider range of therapeutics for a various disease conditions.


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