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CDMO strategies for disrupting the biomanufacturing scale-up paradigm

According to data from S&P Global, the global biopharma market was estimated at $1.4 trillion in revenue in 2023. Of this total, markets outside the United States had approximate 56% share, up from 52% in 2020, indicating their growing importance. The market is being propelled by the increase in chronic diseases, advancements in biopharmaceuticals,personalized medicine,targeted therapies, an increase in biosimilars, and the increasing use of artificial intelligence and machine learning.

Biopharmaceutical advancements are pivotal in the evolution and growth of its market. These advancements include genetic engineering, high-throughput scree-ning technologies, and next-generation sequencing. These technologies enhance the ability of researchers to understand diseases at a molecular level and to develop drugs that can target these diseases more effectively and safely. Monoclonal antibodies dominate the biopharmaceutical market as the largest segment in market breakdown by class due to their highly targeted therapeutic capabilities and broad applicability across various diseases. Autoimmune diseases represent the largest segment in the biopharma sector by indication due to the high prevalence and chronic nature of these conditions, coupled with a significant unmet need for effective and sustainable treatments.

New biopharma discoveries have the potential to become new therapeutic modalities for the treatment of diseases with unmet needs like orphan and rare indications. “The translation of these discoveries into commercial products requires scalable manufacturing processes,” says Dr. Parviz Shamlou, senior vice president of Science & Technology at Abzena, an end-to-end, fully integrated

CDMO and CRO for complex biologics and bioconjugates. “Success often depends on speed-to-market, and the ability to establish scalable manufacturing processes that are cost-effective, efficient and robust.”

Scale-up and tech transfer in biomanufacturing are distinctively challengingcompared to traditional pharmaceutical manufacturing due to the inherent complexity of biological drugs. Unlike small molecule drugs, biological drug substances are produced using live cells, requiring a specialized manufacturing platform. “Engineering these cells to achieve high titer and quality is a major development challenge,” says Subodh Deshmukh, CEO of Aragen Bioscience, Inc., a contract research, development and manufacturing organization (CRDMO). “Biological systems introduce significant variability, making process control and consistency difficult. Transitioning from small-scale production to large-scale commercial operations can impact cell growth and product stability. In contrast, traditional pharma deals with chemical synthesis is more predictable and easier to control during scale-up.”

In addition, the impurities generated from the biological processes are poten- tially immunogenic in nature and need to be removed in downstream processes to obtain a product of high quality. Alex Del Priore, senior vice president, manu- facturing at Syngene Intl., a CDMO, explains: “Scaling up of a biomanufacturing processes needs detailed understanding of each of the process parameters and their impact on the process while scaling up, which in turn impacts the quality of the product. Depending on the impact, the first prin- ciples of scale-up have been set and the understanding of the cell behavior and specific product characteristics leads to fine tuning.”

Biological systems introduce significant variability,making process control and consistency difficult. Transitioning
from small-scale production to large-scale commercial operations can impact cell growth and product stability.
– Subodh Deshmukh, CEO of Aragen Bioscience, Inc., a contract research, development and manufacturing organization (CRDMO)

One area where industry made strides in  fine tuning is in scaling up monoclonal  antibodies (mAbs), saving time and money.  With rising costs and smaller budgets, especially for smaller biotechs, all companies are looking to increase titers and  yields and reduce the cost  of  production  of these  biologics,  says Russell  Miller,  vice president, Global Sales & Marketing,  Enzene Biosciences, a CDMO with integrated sites in India and the US. Enzene’s  patented EnzeneX™  technology  is the  first fully-connected continuous manufacturing (FCCM) platform validated for  use in commercial biologics supply, he  claims, and offers up to 10 times higher  productivity, 40-45% reduction in costs,  and a 70% smaller operational footprint compared  to traditional  methods.  Enzene partners with innovators and  biosimilar developers to expedite time to  market while simultaneously increasing  production yields and reducing costs  across a wide array of modalities. “At  Enzene, we have successfully scaled up  our FCCM process to a 320L bioreactor  with a 1.5 RV perfusion rate,” he says.  “Given the high demand for mAbs, especially those requiring higher dosing and  cost-effective  production,  we  anticipate  a growing need for larger-scale to continious processes. We are also introducing  this proven technology to our New Jersey  site, which will feature 500L and  2,000L bioreactors.  Our FCCM platform  is already  lowering  costs, and we expect  to lower mAb production  to  $40 per  gram by 2025.”

Shamlou of Abzena agrees one of the  major challenges with first-generation  platforms for monoclonal antibodies  (mAbs) was the relatively low product  titers, typically 2-3g/L. Low titers require  large production bioreactors, typically  stainless-steel, which translates directly  into higher production costs. Stainless  steel bioreactors require steam-in-place  (SIP) and clean-in-place (CIP) technologies after each batch, adding to bioreactor down-time, costs and resources in  comparison to more flexible single-use  bioreactors.

Shamlou of Abzena agrees one of the  major challenges with first-generation  platforms for monoclonal antibodies  (mAbs) was the relatively low product  titers, typically 2-3g/L. Low titers require  large production bioreactors, typically  stainless-steel, which translates directly  into higher production costs. Stainless  steel bioreactors require steam-in-place  (SIP) and clean-in-place (CIP) technologies after each batch, adding to bioreactor down-time, costs and resources in  comparison to more flexible single-use  bioreactors. 

“Abzena’s new cell line development  (CLD) platform, AbZelectPRO™, improves the process by rapidly providing high-producing cell lines with consistent  quality, helping to ease scale-up and  manufacturing efforts ” says Shamlou. The  CLD platform has been developed with a  focus on optimizing three key areas: the vector, the host cell line and the process.  These optimizations enable the rapid  generation of stable CHO cell lines for  antibodies and more difficult-to-express  proteins, such as fusion proteins, bispecifics and other novel modalities, with high  titers over 8g/L, in just 10 weeks. 

“This allows us to use smaller upstream  production bioreactors in an accelerated  timeline. Abzena has combined the high-producing cell lines with single-use  bioreactors, achieving significant gains for  our customers. This includes lower overall production costs and faster speed to  market, as well as a lower environmental  impact “.

AbZelectPRO™  utilizes ProteoNic’s  2G UNic® premium vector technology  to boost expression levels and gene-  rate higher-producing, stable cell lines.  Shamlou says: “The flexibility of the  AbZelectPRO™ platform allows for  the efficient and parallel generation of  multiple fast stable pools, allowing the in-depth characterization of multiple candidates. Material from stable pools allows an in-depth assessment of developability  and enables manufacturability risks to  be mitigated as early in the process as  possible.”

The industry-standard three-column  AbZelectPro™ platform process includes  dedicated viral clearance strategy, buffer  exchange and a concentration step, as  well as bulk drug substance presentation  and storage. Abzena can adjust the platform process to meet the specific needs  of the molecule under investigation, full  analytical support and stability studies  are provided throughout the process at  each intermediate step and with the final  drug substance. 

“AbZelectPRO™ provides a solution to  rapidly progress new molecules to IND  by streamlining the CLD process and de-risking upstream and downstream pro-  cesses for improved efficiency,” Shamlou  explains.

Easing scale-up  to mitigate risk

Mitigating risk during scale-up is critical. Syngene Intl. uses a mix of several  approaches to ease scale-up, establishing  equivalence between process development  and manufacturing scales. For instance,  Syngene is setting up computational fluid  dynamics-based scale-up that can help in  predictive modelling of the processes that  can help identify and mitigate risks prior to scale-up. Scaling out of the unit operations is another strategy as an alternative  to scale-up beyond reasonably larger  scales. “We are investing in procuring and  working with different cell lines, media  and bioreactor platforms to develop a  knowledge base across a multitude of  platforms and use the data for successful scale ups and transfers in a platform agnostic way,” says Del Priore.  These varied approaches have proven  beneficial for Syngene’s small biotech and Big Pharma clients when scaling up high productivity and complex cell lines.  “The  learnings from each of these has  been used to anticipate and mitigate the  risks that could potentially arise due to  any variations in client provided cell lines/  processes,” he says. 

Syngene’s manufacturing science and  technology team (MSAT) works closely  with a client’s R&D team from the begin-  ning of the project so that manufacturability is addressed by design and appropriate data is generated prior to scale up to ensure success. This includes following  quick and efficient timelines for delivering a GMP batch to conduct clinical  trials, starting from cell line development.  One example included the involvement of  the MSAT team early in process development to ensure that the process developed  fit into the facility without challenges.  Other strategies included changes in  single-use bioreactor design to support  high cell count, the addition of a depth  filtration scheme in case of early drop of  viability in upstream and a change and elution strategy and pooling for capture  chromatography. 

Del Priore says: “Identifying these risks  and mitigating them during development  enabled the right first delivery of the  clinical-stage batch to the client within  the targeted timelines. From early-stage research and target identification to advancing drug candidates through clinical trials  and ensuring commercial-scale production  of small and large molecules, Syngene ‘s integrated approach ensures safety, efficacy  and scalability.” 

Preventing degredation  during biomanufacturing  scale-up

Biologics are highly sensitive to their  microenvironment, and even minor  deviations can affect the product quality,  efficacy and stability. Biologic products must maintain their efficacy and stability during scale-up. These products are  produced by growing microorganisms  in specialized equipment that must be  carefully controlled environments. A  primary challenge includes maintaining  microorganism viability and growth over  extended periods, optimizing productivity  on a per-cell basis, and managing product  degradation. 

This leads to the buildup of various  degradants, complicating the purification  of the desired product. To address  these challenges, Enzene has employed  advanced technologies, such as the  FCCM, to enhance product stability  and yield. A notable example of Enzene’s approach involves a bi-specific  interleukin molecule, describes Miller. 

Initially, the molecule was produced using  a fed-batch process. However, issues arose  due to degradation during expression and  instability post-purification, likely caused  by residual degradants. Instability in the reactor was likely due to proteolytic  activity.  “To resolve these issues, we implemented  the FCCM technology by transitioning  from the fed-batch process to a fully  connected continuous process,” he says.  “This approach involved integrating a  continuous capture chromatography  step, ensuring a seamless and regulatory-compliant operation. The adoption of  FCCM led to an approximately eight-fold increase in productivity compared to the  fed-batch process and significantly  improved product quality. Through this  successful application, we demonstrated  the potential of FCCM to transform bio-  logic production. Our proof-of-concept  studies have shown that converting fed-  batch processes to FCCM can address  common manufacturing scale-up challenges, offering enhanced stability and efficiency for a range of biologic molecules.  This also proved that FCCM is not limited to the manufacture of monoclonal  antibodies, but also non-mAbs.”

Tech transfer

A conversation about scale-up should  also include tech transfer. The scale-up  and tech transfer processes present a  unique set of challenges compared to  traditional solid-phase pharmaceutical  manufacturing. 

Aragen has created a process and analytical platform that fits its scale-up strategy  and technology transfer approach.  “Upstream processes are scaled up using  Computational Fluid Dynamics (CFD)  technology within the same bioreactor  platform while downstream processes use linear scaling principles,” says  Deshmukh. “To facilitate inbound technology transfer, we follow a meticulous,  step-by-step action plan rooted in our  technology transfer philosophy. This  approach includes conducting a detailed  gap assessment based on risk analysis, to  ensure a smooth and efficient transfer of  technology.”

Similarly, Enzene follows a process for  tech transfer that encourages clients to  establish a proof-of-concept study for  FCCM at laboratory scale. “We assess the  data shared and perform a risk-benefit  analysis over the existing process, if any,”  says Miller. “The  developed process is  then transferred to our manufacturing site for scale-up per client requirements.”

The future requires  adopting PAT

Going forward, developed biomanufacturing processes will require specific technologies. For instance, Abzena’s vision for  scale-up of next generation manufacturing processes for the next five years and  beyond is towards continuous bioprocessing, combining single-use technologies with process analytical technology  (PAT). Currently, fed-batch bioreactors  are the technology of choice in industry  while perfusion bioreactors continue to gain acceptance, explains Shamlou. 

“Combining perfusion bioreactors with single-use technologies provides the next  major step in scale-up,” he says “For this  to happen, the industry needs to adopt  PAT, including on-line, in-line and at-line  measurement and monitoring of all relevant operational parameters and process  control. Abzena sees the development of PAT as an important component of  adoption of perfusion bioreactors and  continuous downstream processing.  While much development work is taking  place in continuous downstream pro-  cessing, additional work is progressing  across multiple unit operations, including chromatography, viral inactivation  and buffer exchange and concentration.  Progress in these areas in the next  decade – and – beyond will make it possible to create the first generation of an end-to-end continuous manufacturing  platform for monoclonal antibodies and  associated products.”

Del Priore agrees: “The use of plat-  form processes and PAT tools will ease  right-first-time scale-up and technology  transfers in a shorter period of time. In addition, the use of next generation technology that involves continuous manufacturing and high-throughput processes  enabled with efficient media, resins and  membranes will increase throughput so  that large-scale manufacturing plant foot-  prints will not be needed.”

He adds that smaller, agile and high-throughput manufacturing will enhance  accessibility and pave the way for personalized biologics. Combined with big-data, artificial intelligence and  machine learning, platforms will be stronger and aid in reducing scale-up timelines  and costs in the biologics space.

Source : https://fr.zone-secure.net/167165/1207456/#page=81%20