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

Drug development plus manufacturing have undergone a seismic shift in the last two decades, 1   from blockbuster small molecules to highly personalized biologics 2   and cell plus gene therapies. Because these therapies are designed for specific populations, they don’t require the kinds associated with large-scale manufacturing operations that many companies and contract development and manufacturing organizations (CDMOs) possess optimized.


While the drugs may offer significant value with regard to patients, smaller batch medicines may not be financially feasible regarding a larger company to manufacture – especially if they have a broader pipeline. Companies are usually now working to address this disconnect, optimizing their processes intended 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 will 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 plus products, such as new chromatography columns that better reflect modern manufacturing needs. Biopharmaceutical leaders urgently need these kinds of solutions to improve the particular 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 brand new modalities including bispecifics, trispecifics, antibody-drug conjugates (ADCs), cytokines, and bespoke cell plus gene treatments (CGT). Each of these types of 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 in order 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 plus bioconjugation to get Mersana Therapeutics . Mersana Therapeutics is advancing the pipeline associated with novel ADCs, including its lead candidate UpRi (upifitamab rilsodotin), which is being studied within ovarian cancer.


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


The shift toward precision medications

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 years, 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 inside 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 plus approvals simply by year (1983-2019). 8

Single-use technologies

The particular rise within “disposable” single-use technologies offers also impacted downstream producing processes and efficiencies. Single-use reactors, membranes and chromatography systems cut down on laborious cleaning processes, giving companies plus CDMOs higher flexibility to handle a variety of projects. For smaller-scale manufacturing, they can more readily change out the single-use products and switch to the new therapy. This changeover capability reduces cross-contamination, 9   provides better bioburden control plus ensures businesses manufacture high-purity products. Overall, single-use technologies decrease the time and resources spent on clean-up and set-up between different medicines, 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 much more, we’re seeing single-use technologies enable that, ” explained Kasper M ø ller, PhD, chief technology officer of AGC Biologics . AGC Biologics is usually a global CDMO offering microbial plus mammalian capabilities as well as CGT, fulfilling early-phase through late-phase projects at both little and large scales.


Møller further stated, “Disposable single-use technology is rapidly fueling the innovations we see in manufacturing today. As a good example, inside upstream digesting, we developed and implemented the 6-Pack TM scale-out concept, which allows us in order 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 elements, even if clinical trial plus launch manufacturing is built in a standard 2000L scale. The 6-Pack TM scale-out technology allows manufacturers to adjust scale very quickly after launch.


The biopharma experts all of us interviewed agreed that disposables are now used in every step associated with the production process, through buffer preparation, buffer storage and eluate collection all the way to the particular medication dispensing and weighing rooms. However, some systems, like single-use chromatography content and walls, have yet to see widespread adoption despite eliminating time consuming packing of articles, qualification, storage space 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 option to columns and were becoming a lot more widely used. We’ve especially seen great success with flowthrough membranes, ” Møller explained. “Overall, I think we are approaching a future in developing where we all implement fully disposable processes including all the chromatography steps that support the versatility that is needed in uncommon disease plus small quantity manufacturing. ”


Continuous downstream processing


While not distinctive to the biopharma industry, the particular gradual change from traditional batch digesting to continuous processing provides also affected therapeutic manufacturing. Instead of starting and stopping each batch, constant processing operates as a non-stop cycle. This approach can reduce the cost of production precision medicines without requiring an increase in level. 10 , 11


In continuous bioprocessing, continuous chromatography processes are usually crucial pertaining to achieving high purity products. A continuous chromatography procedure uses a number of chromatography content in a concurrent manner: while loading is carried out in the first column, all the other steps – washing, elution, regeneration plus re-equilibration – are performed in the other articles. 12   A study that will performed a cost analysis of conventional batch processing versus constant processing meant for 200 kg of monoclonal antibody (mAb) production found that the particular latter reduced downstream running cost of goods by approximately $9/kg. 13 , 14

Facility fit challenges

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


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


Supply chain concerns


The COVID-19 pandemic has put pressure on supply chains 15   and staffing, with many CDMOs and CMOs solidly booked for the year or even more. Smaller biotech plus biopharma businesses without production abilities that will depend upon CDMOs may end up deprioritized or paying a premium like they compete for manufacturing capacity alongside larger-scale drugs.


As 1 engineer from an emerging cancer immunotherapy company puts it: “If you have a GMP run that requirements to end up being completed in seven months, but the lead time on the resins and products you need is two years, that is a challenge. ”


The new influx in precision medicine making coupled along with the COVID-19 pandemic is driving the shortage in new resins and buffers needed for downstream processing. Some market gamers are quoting lead times of many months to over a year.


To help mitigate these risks, many groups are proactively identifying a second supplier designed for crucial products. For example, manufacturers that require a specific resin just for removal of a known impurity should find backup products that will have a similar resin or membrane. This particular extra layer of security can help companies meet the deadlines required for the purpose of 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 in order to at-scale GMP clinical resupply batches had been not going to be delivered on period, we’ve had to revisit conventional ways associated with doing work plus rebuilt the bridges among single-use and re-use production approaches, ” said Ayturk. “We’ve re-established cycling plus resin life-time studies and re-introduced cleansing and storage regimens in to our procedures to ensure uninterrupted supply to clinic due to the fact patients waiting. ”


Downstream control solutions


The goal for each biopharma companies and CDMOs is to be efficient with medication production inside order in order to ensure their own medications reach the populations that need them probably the most. Nevertheless, as noted above, this goal can be disrupted by provide chain shortages and a lack of available processing capacity.


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


“Membrane technology have matured noticeably over the years and have turn out to be 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 substitute towards the current gold regular, Protein A chromatography. GORE’s Protein The membranes create the possibility regarding developing a membrane-based DSP handling train that will is versatile, single-use, completely integrated plus enables scale-agnostic processing. This technology could be a game-changer for new modalities, as well modular and continuous bioprocessing applications. ” – Websit Ayturk.

Historically, the biopharmaceutical industry has been slow to adopt new systems – for good reason. Regulatory agencies and other stakeholders value proven items and consistency. However, at a certain point, the latest technology should become the status quo to keep up with the particular evolution within 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 technologies, ” described Møller. “However, we have also observed more advancement and a strong push intended for implementing brand new technology plus innovation by the FDA during the last ten many years. And so clients do expect that new technologies might be incorporated into their workflows. We routinely make agreements with clients to implement specific technology that will solves an unique problem for their own product. ”

There are now both technical and supply chain motivations to get adopting brand new chromatography technology. As one bioprocessing engineer shared, “This is what intrigued us about GORE’s membrane technology—the need to have got backup or even replacement resins that provide speed, efficiency, plus long-term price savings. Ultimately, it is definitely about becoming able in order to get the medicines onto the market in order to save lives. GORE experienced excellent guide times. ”

GORE® Protein Capture Devices along with Immobilized Protein A are intended for the affinity purification of accuracy medicines containing an Fc region in process growth to initial GMP medical applications. The particular Protein Catch Devices leverage an special expanded polytetrafluoroethylene (ePTFE) membrane layer solution that helps to bridge the particular gap that has long existed between innovations in upstream and downstream processing.

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

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


1 . Congressional Budget Office. Research and development in the pharmaceutical industry. Published August 4, 2021. Accessed March 25, 2022. .

2. Yamamoto Y, Kanayama N, Nakayama Y, Matsushima N. Current status, issues and long term prospects of personalized medicine for every disease.   J Pers Med . 2022; 12(3): 444. doi: ten. 3390/jpm12030444

3. Bioplan Associates. thirteen th annual report and survey of biopharmaceutical manufacturing capability and creation. 2016.

4. Challener C. Maximum output starts with optimized upstream processing. BioPharm International . 2021; 34(4): 10-17. Published April two, 2021. Accessed August 23, 2022.

five . Barone P, Keumurian F, Wiebe Meters, et al. The effect of SARS-CoV-2 on biomanufacturing operations. BioPharm International . 2020; 33(8): 34-38. Utilized February seven, 2022.

6 . Gu W, Miller S, Chiu CY. Clinical metagenomic next-generation sequencing for pathogen detection. Annu Rev Pathol Mech Dis . 2019; 14(1): 319-338. doi: 10. 1146/annurev-pathmechdis-012418-012751

7 . Adams DR, Eng CM. Next-generation sequencing to diagnose suspected genetic disorders. N Engl J Med . 2018; 379(14): 1353-1362. doi: ten. 1056/NEJMra1711801

8. Miller KL, Fermaglich LJ, Maynard J. Using four decades of FDA orphan drug designations in order to describe trends in rare disease medication development: substantial growth seen in development associated with drugs pertaining to rare oncologic, neurologic, and pediatric-onset diseases. Orphanet M Rare Dis . 2021; 16(1): 265. doi: 10. 1186/s13023-021-01901-6

9. Sandle T, Saghee MR. Some considerations meant for the implementation of disposable technology plus single-use systems in biopharmaceuticals. J Commer Biotechnol . 2011; 17(4): 319-329. doi: 10. 1057/jcb. 2011. 21

ten. Macdonald GJ. Disrupting downstream bottlenecks. GEN – Genetic Engineering and Biotechnology News. Published June 14, 2018. Accessed February 4, 2022.

11. Tripathi NK, Shrivastava A. Recent developments in bioprocessing of recombinant proteins: expression hosts and process development. Front Bioeng Biotechnol . 2019; 7: 420. doi: 10. 3389/fbioe. 2019. 00420

12. De Luca Chemical, Felletti H, Lievore G, et ing. Modern trends in downstream processing associated with biotherapeutics through continuous chromatography: The potential of Multicolumn Countercurrent Solvent Gradient Purification. Trends Analyt Chem . 2020; 132: 116051. doi: 10. 1016/j. trac. 2020. 116051

13. Klutz S, Holtmann L, Lobedann M, Schembecker G. Cost evaluation of antibody production processes in different operation modes. Chem Eng Sci . 2016; 141: 63-74. doi: 10. 1016/j. ces. 2015. 10. 029

14. Somasundaram B, Pleitt K, Shave E, Baker Nited kingdom, Lua LHL. Progression associated with continuous downstream processing of monoclonal antibodies: Current styles and difficulties. Biotechnol Bioeng . 2018; 115(12): 2893-2907. doi: ten. 1002/bit. 26812

fifteen. Singh A, et ‘s. Decision-Making Models for Healthcare Supply Chain Disruptions: Review and Insights for Post-Pandemic Era. JGBC. 2022. Singh A, Parida R. Decision-making models designed for healthcare supply chain interruptions: review plus insights just for post-pandemic era. JGBC . 2022. doi: 10. 1007/s42943-021-00045-5