Feliza Mirasol is the science editor for 

Feliza Mirasol

Lonza’s Joe Garrity and Jerry Jiang discuss the importance of not only automating CGT manufacturing, but also standardizing across processes.

The Need for Automated and Standardized CGT Manufacturing (BIO 2024)

While cell and gene therapy (CGT) manufacturing must remain flexible out of necessity, it is also important to standardize processes at an industry level while establishing aseptic-friendly automated operations. Standardization, in particular, is important from a scaling perspective, says Joe Garrity, senior director and head of Autologous Cell Therapy, Lonza.

During BIO 2024, Garrity pointed out the many challenges incurred on the cell therapy side. “It stems from supply chain to operations to clinical sites. There's just so much that needs to go into, specifically, autologous cell therapies, with the batch quantities going into the hundreds and thousands that we're seeing from some of [the] large drug developers.” Thus, he says, standardizing the manufacturing process allows for robustness and process control across the board.

Garrity also notes, however, that even with standardization, “it's not a one size fits all”. Instead, he says, “[much of the time,] it's a little bit of a one size fits most, and you're going to have to be relatively variable, but in the end, the overall standardization of the manufacturing process and the intent of that remains the same because it's better control at scale. Once you find something that really funnels that process robustness and that scalability, you … stick with it so it's reproducible time and time again.”

In discussing whether it’s possible to have manufacturing processes that are both standardized and flexible, Jerry Jiang, clinical application specialist, Personalized Medicine, Cell and Gene Therapy, Lonza, says, “Definitely. One of the things that we really have to start standardizing is the release criteria and the quality of the cells that are being put into the patients. [The] material that comes in is going to be different, but standardizing what we expect the cells to do and behave and what they look like is going to be a huge part of what the standardization process needs to overcome right now.” However, flexibility remains in the details. “[T]he standardization is the same, but the flexibility of the process allows these different companies to optimize the process with their ‘secret sauce’ that will really differentiate their treatment from all the other treatments out there,” says Jiang.

“We definitely need to standardize the way we are inspecting and checking the cells before it goes into a patient, but the flexibility allows each company to … show off their technology and allow for them to shine with the advancements that they've made,” Jiang adds.

Click above to view the full interview. BIO 2024 occurred on June 3–6 in San Diego, Calif.

Articles

Lonza’s Joe Garrity and Jerry Jiang discuss the latest trends and challenges in commercializing new CGTs. 

Trends and Obstacles in the CGT Field (BIO 2024)

Cell and gene therapies (CGTs) remain an important focus in the biopharma industry. During BIO 2024, Joe Garrity, senior director and head of Autologous Cell Therapy, and Jerry Jiang, clinical application specialist, Personalized Medicine, Cell and Gene Therapy, both at Lonza, discuss the latest trends and hurdles in the CGT space.

“Moving from the 2017 timeframe into 2020, we saw a heavy focus on a [significant amount of] money floating around focusing on autologous cell therapies and how we can better provide these life changing therapies to patients,” Garrity says. From the autologous cell therapy perspective, efficacy has been achieved, but the challenge remains that an autologous cell therapy is one manufacturing batch, or one dose, per patient. “The scaling is a little bit of a challenge,” Garrity says, noting, “This is where the allogeneic approach has taken over, and in the cell therapy space, we've really seen that shift … seen [focus] go from two-thirds autologous to one-third allogeneic to almost a 50/50 split.”

Garrity expects this trend to continue to where the industry may see a rise in allogeneic cell therapies, from a molecule number standpoint. “We're seeing a [bigger] influx of allogeneic cell therapies trying to provide a secondary option to commercially viable CAR-T [chimeric antigen receptor T cell]/CAR-NK [chimeric antigen receptor natural killer cell] drug products,” he states.

“At the end of the day it’s really about providing access and availability of cell therapies to those who really need it,” Jiang adds. “The cell therapy production process can be complex, and current solutions are not sufficient to be able to scale to the patient demand. So, as a result, new technologies are being developed to help reduce timelines and cost and improve scalability.”

Another issue Jiang points out is the difficulty in finding technicians who are able to work with and produce these therapies. “We've seen [many] different manufacturers try to figure out different ways of scaling down … either making the process faster or taking out other aspects of their manufacturing process to really streamline this process, as well as just reducing the costs [of these] therapies.”

Click the video above for the full interview. BIO 2024 occurred on June 3–6 in San Diego, Calif.

industry experts discuss the current outsourcing landscape in the post-COVID world 

Changes and Trends in the Outsourcing Landscape

The outsourcing landscape has seen many changes in recent years coming out of the COVID pandemic. Driven by a burgeoning pipeline of clinical-phase therapeutic candidates and the practical need for more advanced analytics, the contract services industry is hustling to meet the expected growth of new, more complex therapeutics to hit the market over the next decade. In this episode of 

 Video series, industry experts discuss the current outsourcing landscape in the post-COVID world and the changes the pandemic has enforced in the demand for outsourced bioprocessing services.

Eric S. Langer, president and managing partner, BioPlan Associates

Eric S. Langer has over 25 years experience in life sciences market assessment, valuation, marketing, management, and publishing. He been senior manager at biopharmaceutical supply companies and is an experienced biotechnology strategist. His team has advised hundreds of companies on marketing strategy development, valuation, pricing, and message strategy. Langer has also developed strategic plans based on quantitative analysis of market trends and buyer needs in valuation services, pricing, and analysis. He teaches graduate biotechnology marketing at Johns Hopkins University and biomedical valuation to the National Institutes of Health Graduate School

Jordi Robinson, chief commercial officer, Navin Molecular

Jordi Robinson has nearly 30 years of experience in the pharma and specialty chemicals industries, and is currently chief commercial officer at Navin Molecular, with responsibilities for all customer-facing activities, including business development and project management. Prior to joining Navin Molecular, he worked for six and a half years leading the European business development team for global contract development and manufacturing organization, Asymchem Laboratories, and has also held commercial and technical roles at Robinson Brothers and Endeavour Speciality Chemicals. He has a bachelor’s degree in chemistry from the University of Central Lancashire, UK.

Drug Digest is a tech talk video series with the 

® editors, who interview industry experts to discuss the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

Biopharma Drug Development and Manufacturing

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In this episode of Drug Digest, industry experts discuss the current outsourcing landscape in the post-COVID world and the changes the pandemic has enforced in the demand for outsourced bioprocessing services. 

Drug Digest: Changes and Trends in the Outsourcing Landscape

Lars Petersen, CEO, FUJIFILM Diosynth Biotechnologies discusses the company’s strategic goals and meeting market demand for mammalian cell culture capacity.

Demand Remains Strong for Mammalian Cell Culture Capacity (BIO 2024)

Demand for mammalian cell culture capacity remains strong and is growing, notes Lars Petersen, CEO of FUJIFILM Diosynth Biotechnologies, during BIO 2024. The company’s main strategic goals for this year centers around meeting this demand. “We are starting up a facility right now in Denmark (1), which is maybe the highest priority,” Petersen says, who also emphasizes that the company has “multiple CAPEX [capital expenditures] projects that we need to finish up.”

“In general, we are we shifting the business after COVID, after some of the financial challenges, to [focus on] what demand is most important … and we see a lot of new interest coming in. Being ready for that [demand] … is the most significant goal of the year,” Petersen says.

As for the company’s expansion of its Holly Springs, N.C., mammalian cell culture facility (2), Petersen explains that this expansion “has really been driven by demand … Demand is high.”

The market for mammalian cell culture needs more capacity, according to Petersen. “There's so much volatility shift and demand from new products coming in, shifting the market from innovators to CDMOs [contract development and manufacturing organizations] [for] new modalities [in treating diseases] like Alzheimer's. The pressure is on [for] other modalities that all end up with higher demand,” he says.

In terms of the future of therapeutic modalities, Petersen sees antibody drug conjugates making a comeback after about a decade and, conversely, a bit of slowdown in messenger RNA. “All these modalities, they really are difficult to foresee,” he observes. However, he expects that monoclonal antibodies will remain a major therapeutic modality for potentially the next 10–15 years, at least.

Click the video above for the full interview. BIO 2024 is being held in San Diego, Calif., on June 3–6.

1. FUJIFILM Diosynth Biotechnologies. FUJIFILM Diosynth Biotechnologies Breaks Ground For Major Expansion of Its Large Scale Biologics Production Facility in Denmark. Press Release, March 3, 2021.
2. FUJIFILM. FUJIFILM to Invest Additional $1.2 Billion to Expand its Large-Scale Cell Culture CDMO Business in North Carolina. Press Release, April 11, 2024.

Lars Petersen, CEO, FUJIFILM Diosynth Biotechnologies discusses the company’s strategic goals and meeting market demand for mammalian cell culture capacity. 

Developing a robust and reliable strategy for analytical studies of a biosimilar in development is crucial for a successful regulatory pathway. The importance of biosimilar products is tied to the push for more affordable, accessible biological treatments. However, bringing a biosimilar to market has strict challenges because the biosimilar developer must have a large set of analytical similarity data compared to the innovator biologic. In addition, the biosimilar developer must also contend with demonstrating interchangeability (1). 

Editor’s note: this article was published in the Pharmaceutical Technology Europe June 2024 issue.

Establishing biosimilar analytical studies

There are several key criteria to consider when establishing analytical studies for a biosimilar drug candidate to ensure its safety, efficacy, and similarity compared to the reference product, says Olaf Stamm, PhD, technical business development director, Biopharmaceutical Testing Solutions, Charles River Laboratories.

Among these criteria are comparability, biological activity, impurity assessment, and stability studies, Stamm notes. He explains that, for comparability, the biosimilar needs to demonstrate similarity to the reference product in terms of structure, function, purity, and potency. Analytical methods should thus be chosen or developed to compare critical quality attributes (CQAs) between the biosimilar and the reference product. “This involves assessing the physicochemical properties of the biosimilar, such as molecular weight, size, charge, and higher-order structure. Techniques [such as] mass spectrometry, chromatography, spectroscopy, and electrophoresis are commonly used for this purpose,” Stamm says.

The biological activity of the biosimilar should also be evaluated in analytical studies to ensure it matches the biological activity of the reference product. Analytical studies for determining biological activity may involve in-vitro assays, cell-based assays, or other relevant biological assays depending on the mechanism of action of the drug, Stamm remarks.

Identifying and quantifying impurities should include process-related impurities, degradation products, and contaminants. This is a crucial aspect of biosimilar development, Stamm notes. “Analytical methods should be sensitive enough to detect impurities at levels that are relevant to safety and efficacy,” he states. Stamm also points out that analytical methods should be established to identify and quantify residual host cell proteins to ensure they are within acceptable limits because their presence could impact safety and efficacy as well. “The evaluation of process-related impurities, such as residual solvents, reagents, and by-products, should be performed using appropriate analytical techniques,” he adds.

Meanwhile, stability studies are essential for assessing the biosimilar product’s shelf-life under various storage conditions. Analytical methods used for stability studies should monitor degradation pathways and stability-indicating parameters over time.

In biosimilars development, it is not enough to establish analytical evidence of the product’s biosimilarity to the reference product, but also its interchangeability. Luckily, establishing analytical studies for testing biosimilarity and interchangeability involves similar principles, Stamm explains. However, there are some key differences in the objectives and scope of these studies.

Stamm points out that the primary objective of analytical studies for demonstrating biosimilarity is to demonstrate that the proposed biosimilar is highly similar to the reference product in terms of quality, safety, and efficacy. “The goal is to show that any differences between the biosimilar and the reference product are not clinically meaningful,” he says.

In comparison, the objective of studies for interchangeability goes beyond demonstrating similarity. “[Interchangeability studies] aim to provide evidence that the biosimilar can be substituted for the reference product without any additional risk in terms of safety or diminished efficacy compared to using the reference product alone,” Stamm states.

Stamm further explains that interchangeability studies may involve additional clinical work. “Clinical studies for interchangeability are specifically designed to assess the impact of switching between the biosimilar and the reference product on safety and efficacy outcomes. These studies may include switching studies, pharmacokinetic (PK) and pharmacodynamic (PD) assessments, and immunogenicity evaluations in both naive and switch populations,” he says.

Both biosimilarity studies and interchangeability studies provide information that is crucial for regulatory authority evaluation. Stamm emphasizes that each type of study yields required data as explained in the following sections.

 According to Stamm, biosimilarity studies generate extensive analytical data comparing the biosimilar product’s CQAs with the CQAs of the reference biologic, including physicochemical characterization, biological activity assays, impurity profiling, and stability data.

 Meanwhile, clinical studies provide evidence of equivalent efficacy, safety, and immunogenicity between the biosimilar and the reference product in sensitive patient populations. These studies typically include PK/PD assessments as well as comparative clinical trials in relevant patient populations.

 Immunogenicity data—including an assessment of the development of anti-drug antibodies—is also a critical component of biosimilarity studies because these data help evaluate the potential risk of immunogenic reactions to the biosimilar.

 Interchangeability studies yield data on the safety and efficacy of switching between the biosimilar and the reference product, notes Stamm, who explains that these studies also include assessments of PK/PD, immunogenicity, and clinical outcomes following multiple switches between the two products.

Data from interchangeability studies also provide insights into patient outcomes from the impact of switching medications, including any potential risks associated with switching between the biosimilar and the reference product.

 Immunogenicity of the biosimilar product is also assessed in patients who undergo repeated switching between the biosimilar and the reference product.

 Regulatory authorities require evidence demonstrating that switching between a biosimilar and its reference product neither compromises clinical outcomes nor poses additional risks to patient safety or efficacy compared to using the reference product alone.

“Overall, both biosimilarity and interchangeability studies generate comprehensive data sets that regulatory authorities evaluate to assess the similarity, safety, efficacy, and interchangeability of biosimilar products compared to their reference products. These studies are essential for the regulatory approval of biosimilars and for ensuring their safe and effective use in clinical practice,” Stamm concludes.

1. Mirasol, F. Moving Biosimilars Forward in a Hesitant Market. 

ope®
Vol. 36, No. 6
June 2024
Pages: 32–33

When referring to this article, please cite it as Mirasol, F. Reviewing the Importance of Biosimilarity and Interchangeability. 

Biosimilar analytical assessments focus on demonstrating biosimilarity and interchangeability with the reference biologic.

Reviewing the Importance of Biosimilarity and Interchangeability

Founder and CEO of Atomic AI, Raphael Townshend, explores AI’s usefulness as a tool to characterize molecular structure and advance molecule engineering.

Applying AI to Molecular Structure (BIO 2024)

Raphael Townshend, founder and CEO of Atomic AI, a US-based emerging biotechnology company specializing in applying the fusion of artificial intelligence (AI) and structural biology for RNA-based drug discovery, discusses the use of AI as a tool for characterizing molecular structure and, in doing so, advance molecule engineering.

“At a high level, why we care about molecular structure is because the structures of molecules really determine what they do: structure determines function, so to speak. What we found in the last few years is that AI is a very powerful tool for understanding the structures of these molecules,” Townshend says. He notes that, traditionally, methods for understanding structure have names, such as X-ray crystallography, or nuclear magnetic resonance, or cryo-electron microscopy. “The issue is that they can oftentimes be very expensive to use and slow to use; it's a very bespoke process. Every single structure that is solved can be a very manual and involved undertaking. And what we've seen is that we can take all this work that's been performed in the field of structural biology, of understanding structures, and feed that into these AI algorithms that are now able to predict those structures in minutes or seconds instead. We've seen these orders of magnitude speed up our ability to model these structures and understand what they look like in their native environments,” he explains, emphasizing that AI enables a “rational drug design”.

“We're already starting to see that and bear fruit today. The use of [AI] … speed[s] up the process of … the whole drug discovery space, of doing the whole drug discovery process, so to speak,” he observes. He further explains that, as an additional layer on top of the traditional drug discovery process, AI can enable rapid screening, or a rapid search, through many possible drug candidates. “[T]he idea is that we're using these kinds of approaches to get to better, faster drugs, and getting things faster to the clinic and running those through a better rate.”

“As I like to say, AI is a cool thing of the day. It's a powerful tool, but it's a tool nonetheless,” Townshend adds. “It's not going to be a panacea; it's not going to solve every single problem under the sun. In particular, the areas where AI works well are those where there's [a significant amount of] data associated with it … and, so, in areas where that data [are] more limited … that can be an obstacle to the development of the correct AI applications in this space,” he notes when discussing some of the hurdles in implementing AI in the drug discovery space. Townshend says that, to address these limitations, the industry would need to collect additional datasets to push progress forward.

“Some areas to really think about, for example, are 

 studies where the amount of animal data that we might have might be relatively limited as compared to high throughput screening stages where you have [much] data, comparatively speaking. [T]hese are resolvable obstacles, but, today, the amount of data out there does not allow for the use of AI in its most advanced form across the entire drug discovery landscape. And that's not even speaking about the development cycle, [such as] clinical trials. There's even more complexity and even more limitations interpret the data. So, while there was this dream of one day using AI across the entire process, right now, there are some key areas where it's providing significant leverage, and we're working towards shoring up those additional gaps,” Townshend says.

View the video above for the full interview with Townshend. Townshend spoke at the 

New Tools, New Times: Chemical and Structural AI for Drug Discovery

 panel at BIO 2024 in San Diego, Calif., which is being held June 3–6.