A view on

Episode 3: A View On Manufacturing Cell and Gene Therapies

Scaling Up Cell and Gene Therapies: Automation Is the Next Step  

In this episode, we take a deep dive into manufacturing cell and gene therapies with Lonza expert Behnam Ahmadian Baghbaderani, executive director of Cell and Gene Therapy Process Development.  

Cell and gene therapies have the potential to revolutionize the treatment of rare genetic diseases, cancer, and neurodegenerative disorders. These therapies involve extracting cells or genetic material from a patient or donor, altering them and then re-injecting them back into the patient to provide a highly personalized treatment. However, the manufacturing process for these therapies is complex and expensive. To increase the availability of these therapies, the industry is making strides in scaling up the manufacturing process to reduce costs.  

According to Behnam Ahmadian Baghbaderani, executive director of Cell and Gene Therapy Process Development at Lonza, “It is important to incorporate innovative technologies and reduce the cost of goods and production in order to make these therapies widely accessible for a large number of patients.” 

One essential way to achieve this is through automation: automated cell culture systems, including bioreactors, can be used to grow and expand cells in a controlled environment, which reduces the need for manual labor while increasing consistency and reproducibility. Simply put, scaling up the manufacturing process using automation makes these therapies more widely accessible to the large number of patients who need them. 

Curious to Know More? 

Listen to this episode of A View On Cell and Gene Therapies to explore how cell and gene therapies are manufactured. Get an inside look into the next steps for the industry from Lonza expert Behnam Ahmadian Baghbaderani.  

Episode 2: A View On Manufacturing Inhaled Drug Products

What If the Jab Were a Puff? A Look at Drug Delivery to the Lungs

In this episode we explore the advantages of using inhalers for drug delivery with Lonza experts Kim Shepard and Matt Ferguson.

In late 2022, China introduced the world’s first Covid-19 vaccine to be inhaled into the lungs. The Chinese scientists who developed the vaccine tout its ability to directly stimulate the immune system’s first line of defense – the lungs’ mucous membrane. However, vaccines are just the tip of the inhaler iceberg. While we all are familiar with metered-dose inhalers, as well as nebulizers, for asthma, a whole range of therapeutic options for many diseases are becoming available through the technology known as dry-powder inhalers, or DPI.

While the first commercially available DPIs appeared in the seventies, recent advances have opened the door to treatments for diabetes and even cancer. As with the Covid-19 vaccine, direct delivery to the lungs can be more efficient, but it also has the advantage of lowering toxicity by bypassing the liver altogether. Still, getting the correct amount of the molecule to the right part of the lung without unwanted immune responses is tricky business. Recently developed manufacturing techniques and new types of molecules make drug inhalers a continually evolving field full of potential advantages for patients.

Curious to Know More?

Listen to this episode of A View On Manufacturing Inhaled Drug Products to learn more about what it takes to develop effective treatments with insights from Lonza’s Associate Director, R&D, Kim Shepard and Matt Ferguson, Lonza’s Head of Respiratory Drug Delivery.

*REPOST* Horseshoe crabs and recombinant factor C

Safe Jabs Thanks to Horseshoe Crabs: Making Sure Your Injection is Free of Endotoxins

Allen Burgenson, Lonza’s expert for all things testing, speaks to us about the dangers of endotoxin contamination and the future of non-animal testing for it.

“Before testing for endotoxins in the 1940s, a physician literally had to gauge the risk to your life because of something called injection fever,” explains Allen Burgenson. Luckily, we’ve come a long way since then. Thanks to advanced testing methods, one can rest assured today that any sort of injection or implant is completely free of dangerous endotoxins. Currently, the predominant mode is Limulus Amebocyte Lysate (LAL) testing, in which scientists harvest the bright blue blood of American Horseshoe Crabs and use the animal’s primitive immune system to look for clotting reactions that would indicate the presence of any endotoxins. The horseshoe crabs, Burgenson explains, survive the extraction unscathed and are safely returned to the waters in less than 24 hours. However, in a continual attempt to remove animals from the testing pipeline, Lonza’s recombinant factor C assay known as PyroGene could eventually replace LAL testing.

Episode 1: A View On Cell Culture Media

Developing Cell Culture Media For Growing Cells

We are back! And in the first episode of our new season, we explore growing cells for therapeutic purposes with Lonza specialists Alexis Bossie, Director of Media R&D, and Tariq Haq, Senior Director of Global Media Marketing.       

Lab-grown meat is having a moment—the FDA just declared one company’s cultivated chicken safe to eat, and another type of lab poultry was just served for dinner to delegates at this year’s COP27 climate conference in Egypt. Whether this piques your pallet’s curiosity or turns your stomach, one thing is clear: growing meat in a lab for human consumption will take massive amounts of cell media.

What is cell culture media? It is the medium in which cells grow in a lab, serving as both the cell’s food and its shelter. The medium can take various forms, depending on which cell type is being grown and for what specific purpose. It is a careful recipe that balances the complex needs of cells in nutrients, energy, pH balance and saline percentage. Like our bodies, cell culture media is mostly water. However, crafting the right media is no simple matter: choosing the correct formula can make all the difference for the cell growth outcome, whether trying to stimulate virus production or make the tastiest animal-free cultivated cordon bleu on the planet.

Curious to Know More?

Listen to this episode of A View On to learn more about what it takes to grow cells in a lab. As a bonus for our listeners, at the end of the discussion, Alexis Bossie shares insights into the possibilities and obstacles of growing meat in the lab.

 

KEY TERMS IN CONTEXT:

Cell culture media is the medium in which cells grow. It must meet all environmental conditions to keep a cell alive and flourishing. Either as a liquid or gel, synthetic or organic, the cell culture media’s most important function is to deliver nutrients to cells and to wash away waste products.

The osmotic balance in cell media is the salt and water balance needed to maintain proper cell functioning. An imbalance creates uneven flows of water between a cell and its media, resulting in a cell burst or cell shrinkage.

A protein factory is a name given to batches of cells cultivated in a laboratory to produce high quantities of one or several types of proteins, often for therapeutic purposes. It must not be confused with the cell’s own protein factory, aka the ribosome.  

The metabolomics and the proteomics are the biological disciplines describing the metabolites and proteins in a cell. As these fields advance, so does the understanding of cultivating cells and developing the correct media for each type of desired growth and outcome.

Episode 11: Season 2 Highlights

Join us in celebrating the finale of our second season of A View On, the Lonza podcast.

Over the past few months, we have brought you a series of insider conversations with our experts at Lonza, our partners, and leaders in the industry exploring the new pharma and biotechnology trends. We explored exciting topics, such as oncolytic viruses, the human microbiome, antibody-drug conjugates, nuances of early drug development, capsule manufacturing, and the use of artificial intelligence in the pharma industry.

In the latest episode, the podcast host, Lonza’s Martina Ribar Hestericová, recaps the highlights from this season and looks forward to later this year for what is coming up in the next season.

 

Interested to learn more? Visit our dedicated podcast site on www.lonza.com/a-view-on and don't forget to subscribe.

Episode 10: AI in the Pharma Industry

Artificial Intelligence and Life Sciences: The Dawning of a Digital Revolution in Pharma Manufacturing

Dr. Loubna Bouarfa, CEO of OKRA.ai, and Stephan Rosenberger, Lonza's Head of Digital Transformation, discuss how AI is currently transforming the pharma industry.

Machine learning is an essential subset of the vast field of Artificial Intelligence, in which computer programs aim to mimic human intelligence. Machine learning is at work in many of the algorithms that impact our daily lives, from suggesting new songs we might like to targeting ads. These algorithms learn from large data sets similarly to how a child learns during the early stages of development. As the algorithm matures from child to teenager to adult, it refines its own functioning by learning from its errors and through help from humans, much like we do.

This powerful way of programming is making tsunamis across nearly all industries. It notably transforms the pharmaceutical world from drug discovery to production and even sales. Whether it is creating AI brains for companies to build digital workers to help their human employees or streamlining the factory with ultra-reliable predictive maintenance, the machine learning and artificial intelligence revolution is well underway.

Curious to Know More?

Listen to the conversation between A View On host Martina Hestericová and two world specialists about the present and future applications of AI and Machine Learning in the pharmaceutical industry.

 

KEY TERMS IN CONTEXT:

Artificial Intelligence is a field of computer science where simulations of human intelligence by computer processes are used to improve the performance of machines.

Machine Learning is a subset within the field of AI that is inspired by the way humans learn. Computational programs in the form of algorithms continually evolve by "learning" or processing information through trial and error, often with the help of human intervention. The goal of machine learning is to create machines that are independent learners capable of solving problems without human involvement.

An AI brain, or digital brain, is the term used by OKRA CEO Dr. Lubna Bouarfa to describe a form of AI that learns from several data sets to create a company-specific intelligence to aid decision-making and predictions. For Bouarfa, the company's product can be employed to solve many of the current bottlenecks and problems in Life Sciences and pharma.

Synthetic route optimization is used to map out the best way that a scientist can synthesize a compound. With the help of machine learning and AI, this route can be even further optimized by harnessing vast data sets and predicting outcomes. It is only one of many avenues where AI can greatly improve the efficiency of existing technologies in pharma manufacturing.

In edge computing the computational work happens outside of the cloud and closer to the actual data event, which allows for real-time processing. With bigger data sets needed to feed in-house AI systems, edge computing architecture holds many advantages for companies looking to harness the power of AI for functions such as automation and safety.

Episode 9: De-risking Drug Development

Where There’s A Risk, There’s A Way: De-risking Drug Development at the Earliest Stages

Lonza’s wide array of analytical tools and professional experience create a go-to solution for small biotechs looking to decrease risk in their drug development process.

An evolving toolbox of technology and advanced scientific knowledge is fueling the growth of a wide range of next-generation drugs in today’s pipelines. These novel but complex products, while offering the ability to treat previously unmet medical needs across the globe, also present many challenges. This is often due to their unique profiles that require bespoke development and manufacturing processes as opposed to using well-known platform approaches, adding even more risk to a space fraught with uncertainty. This increasingly competitive market leaves little room for error or delay. Therefore, selecting and optimizing the right lead candidate becomes critical, as this allows you to de-risk your drug development process and maximize your chances of success.

The largest cause of failure during drug development is most often related to safety and efficacy, so it is important to have processes in place that can identify potential issues as early as possible. Simple, cost-effective in silico and in vitro assessments can help look at potential developability challenges  in the earliest stages and allow for modifications to the drug candidate and its process development to mitigate potential efficacy, safety or manufacturability risks.

Many of the drugs currently in early development around the world are initially developed by small biotechs, companies that often require the support of service providers to assist and to accelerate the de-risking of their candidates This is where Lonza’s Early Development experts step in. Today’s guest is Raymond Donninger, Senir Director of Commercial Development for Lonza’s Early Development Services in Cambridge.

To start the de-risking process, the team can predict development issues very early, based on the candidate’s sequence and structure. This knowledge allows for modifications to the drug candidate and its process development to mitigate risk early and increase the likelihood of a successful first-in-human study. The experts then also apply in vitro tools to look at developability challenges  and to mitigate potential efficacy, safety or manufacturability risks.

Curious to Know More?

We previously addressed the importance of immunogenicity in decreasing risk in drug production in Episode 5. To take an even deeper dive into the whole process, listen to the conversation between Martina Hestericová and Raymond Donninger, the Senior Director of Commercial Development for Lonza’s Early Development Services.

 

KEY TERMS in Context:

In silico immunogenicity and human cell in vitro assays are two essential ways to de-risk a molecule’s development pathway . In silico tests run computer models to predict a molecule’s interaction with the human immune system; in vitro testing assesses the molecule’s interaction with human immune cells.

The attrition of a drug candidate occurs when it reaches clinical trials but fails for one reason or another. According to Donninger, an attrition rate of nine out of ten candidates has remained stubbornly high over the years.

Attrition happens when a molecule has therapeutic potential but safety, target engagement or developability (for example complex, uneconomic manufacturing processes)  issues prevent the product from reaching the market. The de-risking process aims to reduce attrition to improve the chances for viable and safe therapies to make it to market.

According to Donninger, a T-cell epitope is a sequence within the protein that has the potential to allow the immune system to recognize it as being foreign and then mount an unwanted and potentially dangerous immune response. To learn more about de-risking and immunogenicity, listen to this season’s Episode Five.

Episode 8: Colors of Capsules

Capsule Manufacturing: It’s Not Only What’s Inside That Counts

The recent EU ban on Titanium Dioxide and changing customer habits are shaking up capsule production.

Over the past few years, the coloring and manufacturing of pill capsules have undergone significant changes due to new EU regulations and customer demand for natural ingredients. And while originally invented to mask and protect the contents inside a capsule, research suggests that the color of a tablet or pill can affect how patients feel about their medication.

Until recently, manufacturers have primarily used Titanium Dioxide (TiO₂) to create white capsules due to its efficiency in protecting the active ingredients from UV rays. However, this year an EU-wide ban on TiO₂ has forced the industry to move towards alternatives that work as well, or better, than TiO₂. To add to the colorant shake-up, many people are actively avoiding unnatural ingredients in their food and nutritional supplements, which has created a new demand for plant-based capsule colorants. Anticipating these changes and solving the technological challenges in a timely manner are key to a successful long-term strategy for capsule manufacturing.

Curious to Know More?

Listen to the conversation between A View On host Martina Hestericová and Ljiljana Palangetic, Lonza’s Associate Director of Hard Capsules R&D, about the challenges and solutions in current capsule manufacturing.

 

KEY TERMS IN CONTEXT:

Pharmaceutical capsules can be either hard or soft. Soft-shelled capsules are one unique mold that encapsulates the contents, whereas the more widely-used hard-shelled capsules—such as the ones produced by Lonza—are two molded telescopic pieces of capsule: a smaller one contains the active ingredients, and a larger one encloses the capsule.

Titanium dioxide (TiO₂) is a widely-used pigment in capsule manufacturing, as well as in food, paint and sunscreen. Considered completely inorganic and nontoxic from a chemical point of view, it is labeled as an unnatural ingredient for ingestion, and carries the E number E171. Earlier this year, the European Food Safety Authority (EFSA) announced a six-month phasing-out ban of the colorant over concerns about nano-sized particles of TiO₂ accumulating in the body. The full ban takes effect in August.

The dip molding process is the manufacturing process for capsules. The final shape of the two pieces that make the capsules is defined by specifically designed molds, which are dipped in a bath of liquid formulation to pick up material that will, after the drying process, give the final capsule form, shape and composition.

Episode 7: Antibody-Drug Conjugates

Antibody-drug Conjugates: Next-Generation of Targeted Cancer Treatments

Iwan Bertholjotti and Laurence Bonnafoux from Lonza give an insider look at how these promising treatments make it from development to commercialization.

Chemotherapy is the first-line treatment for most types of cancer. However, one of the major challenges with this approach is that it targets both cancer and healthy cells, with patients suffering severe side effects. A new class of therapies, called antibody-drug conjugates, or ADCs, can target tumors much more precisely by harnessing the power of antibodies. The antibody can bind specific types of tumor cells, delivering a fatal blow to the cancer cells while sparing healthy cells. These promising new drugs have seen a significant uptick in FDA approvals in recent years, pointing towards a trend that could transform the way many diseases are treated.

While numerous companies succeed in developing promising ADCs, manufacturing such complex and highly potent treatments presents unique challenges. The intricacy of scaling up the manufacturing of ADCs leads many companies to outsource their production, and Lonza currently fabricates the majority of ADC therapeutics in the world. For the companies that choose to work with Lonza, the collaboration simplifies the process and streamlines the supply chain. Decades of collective experience in fabricating ADCs means that the drugs make it from discovery to approval in less time, improving patients' lives through more effective, targeted treatments with fewer side effects.

Curious to Know More?

Listen to the conversation between A View On host Martina Hestericová and two of Lonza’s experts on ADC manufacturing—Lonza’s senior director of Commercial Development of bioconjugates, Iwan Betholjotti, and Lawrence Bonnafoux, Lonza’s Head of MSAT BioConjugates.

 

KEY TERMS IN CONTEXT:

Bioconjugates are a class of biopharmaceuticals developed by attaching two molecules together, of which at least one is a biomolecule. Examples of bioconjugates include antibody-drug conjugates (ADCs), PEGylated proteins, and vaccine conjugates.

Antibody-drug conjugates consist of three parts: an antibody, a cytotoxic drug and the linker that covalently binds these two together. This approach combines the targeted delivery of the antibody with the cancer-killing power of the cytotoxic drug that would be too potent to be used on its own.

A cytotoxic drug is a drug that contains a molecule toxic to cells, leading to cellular death. Used in traditional chemotherapy, these molecules attack both healthy and cancerous cells. When linked to an ADC antibody, they target only the tumor. 

Targeted delivery of a cytotoxin is when a cell-killing toxin is delivered to a specific type of cell, such as tumor cells. This specificity allows for effective cancer treatment with fewer unwanted side effects for the patient.

Scaling up production for bioconjugates involves moving from manufacturing small batches for clinical trials to large batches up to five kilograms for commercial production. This major challenge for companies is essential for the successful commercialization of ADCs.

Episode 6: Manufacturing of Exosomes

Putting Manufacturing First: Codiak Moves Swiftly into Clinical Trials with Exosome-based Treatments 

Sriram Sathyanarayanan, Codiak’s CSO, and Linda Bain, their CFO, share how the company moved into clinical trials in under 6 years.

 

Exosomes, extremely small vesicles shed by all cell types, promise to become a viable delivery system for treatments of many diseases. But until recently, manufacturing them at a commercially viable scale has been unfeasible. That is why in 2015 the company Codiak took a two-pronged approach to developing exosome-based treatments: prioritizing both the engineering and manufacturing tracks from the outset. A mere six years after the company was launched, this approach has proven effective, with two promising studies in the clinic for tumor treatments, while most other developers are still at the starting blocks.

The exosome field today holds the kind of promise that antibody and protein-based therapeutics did in the 1980s—the potential to improve both treatments and patient well-being is great. With a low risk of immunotoxicity, leveraging their natural abilities and engineering them to deliver targeted therapies could open new therapeutic pathways to previously undruggable targets. Yet as recently as only a couple of years ago, manufacturing exosomes was limited to small batches. Codiak has successfully increased production to thousand-liter batches, permitting clinical studies and greatly improving the prospective of widespread use. In collaboration with Lonza, Codiak is doubling down on their advantage with a recently established Center of Excellence for exosome manufacturing in Massachusetts.

To learn more about Codiak’s pipeline of therapeutic candidates with a potential to transform patients’ lives, visit: https://www.codiakbio.com/pipeline-programs/pipeline

Curious to Know More?

Listen to Martina Hestericová’s conversation with Sriram Sathyanarayanan and Linda Bain as they discuss the advantages of exosome treatments, how they are developed and why the company’s early manufacturing strategy is paying off.

 

KEY TERMS IN CONTEXT:

 

Exosomes are nano-sized delivery vehicles generated by all eukaryotic cells. They are roughly between 30 and 120 nanometers large and originate when endosomes, or intercellular vesicles, are released into the blood, milk or tissue. Exosomes then become messengers and surrogates for the original cell. Their surface markers represent a location code and spread through the extracellular space in the body to communicate with other cells and deliver packages.

Commercial exosome manufacturing is the scaling-up process of moving from small-batch exosome production that uses ultracentrifuges to large-scale production that in many ways resembles the processes already used to manufacture antibody and protein-based therapies.  

The exosome’s lumen is the interior volume of the exosome where, through biological engineering, the therapeutic molecule can be placed. The molecule can also be on the surface of the exosome, allowing for two alternative payload capacities, depending on the target.

Immunosafety and immunotoxicity refer to how potentially safe or toxic the immune system’s reaction to a molecule may be. Since exosomes already have a history of low immunotoxicity – think of blood transfers – their immunosafety is already proven to be very high.