More Science. Less Paper®.
Digital transformation has impacted so many aspects of our personal and professional lives – from how we communicate to how we live and how we work. One might think that industries as groundbreaking and innovative as pharma and biotech would also be leaders in digitization and automation. But the fact is, many pharma and biotech companies are only starting their digital transformation journeys and are still reliant on manual, paper-based workflows.
It's this surprising reality that Lonza is working to change with the MODA® platform. The first step in automating any workflow is to remove the paper from the process and the leap to automation and digitization starts with the simple idea "More Science. Less Paper®." The benefits of removing paper from the workflow are clear; the reliance on a paper-based system is inefficient, time-consuming, and error-prone.
Implementing a solution like the MODA® platform will have a significant impact on enforcing the workflow and improving compliance with regulatory guidelines. It removes the non-value-added steps that are necessary when using paper to make the overall workflow more efficient. It also provides the ability to integrate data from multiple sources and gain access to it in real-time to facilitate on-demand decision-making.
If the benefits of removing paper are clear, why has the adoption of digital solutions been so slow? The implementation of a Manufacturing Execution System (MES) solution traditionally has been viewed as a complex and lengthy project that requires a significant investment of time and resources. Over 39% of decision makers have told Lonza in a recent poll that traditional MES systems are not flexible/configurable enough; 13% said they are too expensive; and 10% say that implementation and validation take too much time, and the cost to maintain and support is too high.
The MODA® platform, which is developed with Lonza Informatics know-how and Lonza's manufacturing experience, aims to overcome all of those barriers. It is cost-effective to adopt, maintain and deploy for medium and small biotech organizations. It has a lower total cost of ownership than other solutions with an optimized implementation approach. And, it provides a solution that is flexible and easy to configure at a price that allows the entire manufacturing industry to go paperless.
The three modules that make up the MODA® platform combine to digitize both QC and manufacturing by automating the data capture of electronic batch records and lab execution software. This solution combines data capture and error prevention with the flexibility to gather and trend key quality and performance metrics. This integrated solution gives organizations the ability to capture and react to data in both in the laboratory and on the production floor. Together and individually, these modules make “More Science. Less Paper®” in both manufacturing and QC, a reality.
MODA-EM® encompasses automation of the full spectrum of QC activities, including environmental monitoring (EM), utility testing, and product testing. As an out-of-the-box solution, already used by many of the top global pharma companies, implementation and ramp-up time is only 6-8 months, and the system can be easily integrated into commonly used instrumentation and media in manufacturing, production and laboratory areas. The MODA-EM® Solution is compatible with Lonza's PyroTec® PRO Automated Robotic Solution and WinKQCL® Endotoxin Detection Software.
MODA-ES® is a comprehensive MES solution that bridges the gap between manufacturing and QC to provide a single batch record with an intuitive review and approval interface. MODA-ES® has been designed -- by the end user for the end user -- to provide a solution that has the flexibility to meet business requirements and is easier and more cost-effective to implement. As a next-generation MES solution, it also provides Cell and Gene Therapy manufacturers with a comprehensive solution to meet those businesses’ digitalization needs.
MODA® Elogs is the final module of the platform that facilitates the removal of all the paper logbooks that are used to track equipment usage, cleaning processes, and room entries among other processes. These paper logs can be related to a manufacturing batch but often are for supporting functions surrounding a batch process. This data has a major impact on the release of quality products and investigations when something goes wrong. The MODA® Elog module automates the capture of this information and make it available in real-time. For some customers, this is the first step to removing paper and automating their processes and has a tangible and immediate ROI.
The MODA® platform, with its modular and full platform approach, is a prime example of Lonza’s wide expertise in technology, manufacturing and quality control that enables organizations to be more efficient, compliant and to expedite their product release. By removing manual, error-prone workflows, Lonza is moving the pharma and biotech industries closer to widespread automation and integration. More Science. Less Paper® will help organizations make more informed, timely decisions and to better track key metrics across their manufacturing and QC processes.
Associate Director, Informatics Marketing & Strategy, Lonza
Uncovering the Potential of Exosomes
Lonza Takes Innovative Steps in the Development and Manufacture of Exosomes
Exosomes are emerging as a promising new drug/drug carrier modality and there is widespread excitement around their potential. With the increasing understanding of exosome biology and function, the pharma/biotech industry is getting closer to harnessing their therapeutic properties to fight or deliver drugs that will fight diseases and viruses. At this stage, exosomes are showing potential in a wide variety of research, diagnostic and therapeutic applications. Several pre-clinical studies are indicating potent effects and early clinical data is emerging with encouraging safety and efficacy results.
Exosomes’ natural functions in the body make them a potentially powerful drug and drug carrier. An exosome is an extracellular vesicle (EV) that is widely distributed in cellular systems that are secreted to exert specific biological functions. They play a significant role in many physiological and pathological processes. Exosomes often function as “communication vehicles,” transferring bioactive proteins and genetic material between cells.1 That ability to “communicate” to other cells throughout the body can produce positive or negative outcomes. As every cell in the body produces unique exosomes with their own unique characteristics and contents, those unique and distinct signals can be distributed throughout the body. For example, exosomes produced from cancer cells may support cancer spread and development. On the other hand, exosomes produced from stem cells may promote anti-inflammatory and regenerative activity, like their originating cell.
Exosomes’ ability to convey information and stimulate cellular activity has given rise to the concept that they can serve as a delivery system for therapeutic compounds to target specific diseases, injuries or viruses -- especially because exosomes are able to pass the blood–brain barrier. There is potential to use exosomes as a vector for delivery of proteins or nucleic acid payloads in therapeutic applications that fight diseases, modulate immune responses and repair tissues. If this can be achieved, the potential for exosomes is quite extensive.
However, there is not a full understanding of the relationship between exosome’s characteristics and function, and that lack of understanding is impacting the industry’s ability to develop scalable solutions to separate specific exosomes from others. Isolation and purification of exosomes from the cell debris is complex, and it is even more difficult to isolate a particular subpopulation of exosomes. As exosomes are products of cells, their manufacture depends on the ability to produce large quantities of cells in ways that do not alter certain cell behaviors and characteristics.2 The potential for changes in cellular phenotype during technical transfer (e.g., scale-up and equipment change) is a key consideration. Alteration in any number of characteristics of the cell culture platform might alter the production, composition, attributes or function of the exosomes.3 Large-scale production of exosomes is also influenced by the specific therapeutic application, so it will be important to produce a therapeutic exosome composition that reflects the expression pattern of the parent cells.
Lonza has taken the initiative to be the first company to build out CDMO capability for supporting exosome-based therapeutics in order to be ready to develop commercial products when the time is right. To date, there are no commercial exosome-based products, but Lonza is currently working with three Research and Development clients on exosome therapies and are eager to advance to clinical trials to demonstrate benefits.
The path to commercialization for exosome therapy products has two distinct challenges. The first challenge is answering the question, “Do exosomes actually prove a therapeutic benefit compared to other modalities (e.g., LNPs)?”. The second challenge comes in addressing the question, “How do we scale-up?” as we are not yet able to provide enough drug substance for commercial use.
Lonza is undertaking substantial buildout for the development of exosome therapies to answer both of these questions. The company currently has functional exosome development at Walkersville-Shady Grove and has undertaken technology transfer to its Houston facilities. In addition, Lonza recently acquired Codiak Biosciences, an exosome manufacturing facility. With that acquisition, Lonza added a 500L perfusion bioreactor and downstream process for the production of exosome drug substance and product to its current 3L STR Bioreactor and downstream process with fully scalable unit operations.
Additionally, Lonza’s expertise in upstream and downstream unit operations of viral vectors will be used as a starting point for building out an exosome manufacturing process. Since exosomes are extremely complex, advanced analytics will be required. Therefore, Lonza has developed state of the art characterization toolbox, including single exosome analysis with nanoflow cytometer, to analyze exosome products
Lonza’s goal is to become the pre-eminent, end-to-end solution for exosome-based therapies. The company has recently, and will continue to, put in place multiple development and manufacturing solutions to serve clients that are looking to develop engineered exosomes with tissue-specific properties for targeted delivery of therapies that harnesses exosomes' potential regenerative, viral fighting and disease-fighting potential.
1 Manufacturing Exosomes: A Promising Therapeutic Platform -Trends in Molecular Medicine
2 Exosome manufacturing status - Future Science
3 Exosome manufacturing status - Future Science
Associate Director of R&D, Cell and Gene Technologies, Lonza
Pulmonary Delivery of Spray Dried Monoclonal Antibodies to Treat Lung Cancer
If oncologists and patients who are fighting non-small cell lung cancer could create an optimal cancer fighting therapy, what would be on their list of optimal attributes? That list might include:
- A drug that would shrink and impede tumors’ growth and reoccurrence.
- A targeted therapy that avoids needlessly exposing healthy tissue to powerful cancer fighting drugs.
- Therapies that minimize adverse effects that arise from the systemic delivery of potent drugs.
- A delivery system that is easy, convenient and fast.
- Lower dosages that save time, money and minimize the physical toll of fighting cancer.
At Lonza, we recently set out to see if each of these enhancements to fighting non-small cell lung cancer are possible.
One of the earliest questions to address was – are monoclonal antibodies the right treatment to begin with? There are more than a dozen monoclonal antibodies approved for lung indications such as lung cancer with VEGF or EGFR targets, asthma and infections. But all current therapies are systemically delivered. They are often invasive, expensive and inconvenient for patients as they are delivered in the clinic, put increased time burdens on travel and length of administration. In their current form, monoclonal antibodies don’t meet the optimal attributes desired. But could we develop a monoclonal antibody that is self-administered and locally delivered while maintaining efficacy?
If monoclonal antibodies were a possible answer and the desired attributes were localized delivery and self-administration, could nebulizers be a possible remedy? The answer was no, as nebulizers presented stability concerns. However, direct delivery to the lungs is a positive attribute – if it was possible to solve for the respiratory system’s success at preventing the introduction of particles into the lungs. The challenge would be to create a therapy that features molecules with an aerodynamic diameter of between 1-5 microns. Particles larger than 5 microns are trapped in the mouth and throat, while particles smaller than about 1 micron are exhaled.
We began work with bevacizumab, a monoclonal antibody that inhibits VEGF angiogenesis. It is generally used in combination with chemotherapy and can be a maintenance treatment after chemotherapy is no longer tolerated. But Bevacizumab can cause severe bleeding as a direct result of being systemically delivered, which results in exclusion of a substantial number of potential patients who are at increased risk of bleeding.
An inhaled bevacizumab drug product could resolve the systemic delivery challenge. Yet, biotherapeutics are very delicate and do not react well to heat or shear exposure (which are often associated with developing inhaled therapies). To develop an inhalable formulation for this program, we suspected that we might need heat and shear to produce droplets and then dry them into a powder.
We employed a spray drying method to enable particle engineering for the inhalation of bevacizumab. It did not damage the biologic, minimized biologic degradation, and used excipients like trehalose to stabilize the formulation. In addition, it allowed for shear exposure to be controlled, heat exposure was limited by evaporative cooling, and the particles were engineered in the critical 1-5 micron range of size. The final product exhibited good aerosol properties; was stable at acceptable ambient temperature for 6 months; and it maintained its anti-VEGF activity. At this stage, all positive outcomes.
Before going to the clinic, an in vivo efficacy study would give the team the confirmation they needed to continue moving forward. Inhaled bevacizumab was compared to the injected version in combination with the chemotherapy cisplatin in an in vivo study. The inhaled monoclonal antibodies plus injected chemotherapy did an equivalent job at reducing tumor burden and was, therefore, considered efficacious in vivo. And the inhaled version only needed 10% of the injected dose.
Lonza now has opened the door to the possibility of better outcomes for patients with non-small cell lung cancer using a spray-dried bevacizumab for inhalation. The monoclonal antibody is delivered through a dry-powder inhaler to patients in lower dosages with fewer side effects. Moreover, the costs are potentially lower, it is a self-administered system that can be used at home, potentially resulting in better compliance and improved outcomes. Additionally, the probable success of this spray dried inhalation formulation has the potential for positive impacts with other diseases such as asthma, COPD, lung infections and other lung cancers
The spray-dried bevacizumab project illustrates how Lonza brings a unique combination of science, technology, creativity and commitment to its projects. Drawing on 25 years of experience in particle engineering formulation design and encapsulation technologies, the company’s premier particle engineering technology services are tailored to our customers’ molecule target product profiles and delivery devices. Our formulation, analytical and manufacturing teams ensure that development timelines are met and that program risk and complexity is minimized.
In this on-demand talk, Kim Shepard presented Lonza’s approach to formulation and manufacturing of local lung cancer treatments by dry powder inhaler. The presentation discussed two case studies: bevacizumab (a monoclonal antibody) and 5-azacytidine (a small molecule).”
Principal Engineer R&D, Small Molecules Division
Head of Respiratory Delivery, Small Molecules Division
Lonza Expands the Boundaries of Sub-Cutaneous Injections
Innovations in formulations and injection devices improve compliance and quality of life for patients using new antibody formats.
The field of biologics is undergoing a significant change as it increases its focus on identifying new diseases to target, novel constructs to treat those diseases and innovative administration devices that include self-administration technologies to improve compliance and patient quality of life.
Patients who have diseases that demand regular administration of these new antibody treatments, on a monthly or bi-monthly basis, will see the significant benefits from these self-administration innovations, as their lives will not be highly impacted from constant travel to the doctor or the hospital. These formulation and device innovations will also have a positive impact on how well patients are able, or willing, to comply with the administration schedule as it becomes less disruptive to their lives.
The goal at Lonza is to support our customers who are breaking new ground in biologics by supporting them in the development and manufacturing of their target drug product profile, ensuring that their patients are receiving the right dose of a stable drug product using an easy-to-use device. To achieve these goals, there are important aspects to consider.
- High-concentration formulations are typically required for these treatments, which come with a range of technical challenges.
- The drug and the formulation must be compatible with special container closure systems.
- The functionality of the drug/device combination product must be ensured so that the dose can be delivered safely and effectively.
As noted earlier, producing high-concentration formulations presents some important technical challenges. These formulations have a tendency towards association and aggregation due to macromolecules crowding, which can result in aggregation and the formation of subvisible and visible particles. So, the stability of the formulation is very important.
In addition, high-concentration formulations tend to have a high viscosity due to reversible self-association leading to the formation of large networks/meshes that resist flow and increase viscosity. As these high-concentration formulations often need to be self-administered, they must have the right viscosity (a viscosity which will allow for reasonable “syringability” and injection time). It’s important to manage this balance during the formulation development, in order to find the sweet spot of concentration, volume and formulation design space that will ensure both adequate viscosity and stability of the formulation.
Our experience in balancing concentration, volume and formulation design has led us to begin recommending to our customers that they consider these important variables early on when selecting molecule candidates. Molecule candidates can not only be screened for their pharmacological activities, but also with regards to their physico-chemical properties or their developability, including the tendency to self-associate that can lead to aggregation and/or increased viscosity.
While developing a safe and effective formulation, it is also important to evaluate the compatibility of the drug product formulation with the container closure system. For self-administration (usually prefilled syringes or cartridges) these devices come with a special material for contact with the drug product. For instance, the inner wall is usually coated with silicone oil to facilitate “syringeability.” Interaction of the protein with silicon oil can produce protein aggregates or rub-off silicone oil from the syringe wall, leading to an unreliable injection. Moreover, there can be traces of heavy metals from the manufacturing process (e.g., Tungsten oxides) that can induce drug product degradation. These risks should be carefully investigated, and mitigated for, during formulation development.
We have done a great deal of research and testing for products that allow for self-administration and home use. In order to have a safe and reliable self-administration package, it’s necessary to develop a device that can reliably deliver the protein solution. For prefilled syringes, Lonza has worked to set up the respective technologies for measuring the integrity of the plunger, the needle tip, and the functionality of the device.
In fact, when it comes to innovation in the injection devices, Lonza has focused on to how to solve for the increased interest in moving to higher and higher overconcentration. One could use viscosity-reducing agents (depending on the molecule properties and molecular weight) to reduce the protein’s self-association and push the concentration up to 180 to 200 mg/mL. We learned that, when the physical limit of packing hard spheres is reached, there are basically two options: use a device that can handle higher viscosities or deliver volumes of up to 5 or 10 mL. To meet the challenge of delivering higher volumes, Lonza collaborates with Ypsomed on the YpsoDose wearable injector that can deliver up to 10 mL, enhancing the volume (and dose) that can be self-administered by patients.
It’s clear that one of the benefits of working with Lonza is our end-to-end approach to developing formulation and injection technologies that allow companies to develop highly-functional devices that work in concert with their drug product formulations. Our team has extensive expertise and they set up the development correctly, proactively anticipate risks and suggest mitigation measures. We have a well-established formulation platform process that helps move these products into clinics quickly, with defined risks and a good investment of resources. This holistic approach – with a focus on each of the elements necessary to create a successful, self-administered, sub-cutaneous injection – make Lonza the right company to work with for those who are looking to continue to innovate and push the boundaries of successful subcutaneous injections.
Head Formulation Development, Lonza Drug Product Services
By leveraging our own technologies, Lonza now offers more accurate Process Analytical Tools (PAT) at a reduced cost for customers
Imagine if instead of seeing glimpses of data in your process, you could see a continuous data stream?
To provide consistent, safe, and high-quality products for customers and the patients they serve, it is critical to monitor and control bioprocesses.
Current bioprocess monitoring and control schemes still rely on infrequent and time-consuming offline sampling methods. This leads to loopholes in data and major gaps in knowledge, as well as an increased cost.
Having a clear picture of the system, instead of relying on discrete snapshots throughout the day, opens the possibility to see what is really happening with the product profile.
Process Analytical Tools -- better known as PAT, a mechanism to design, analyze, and control pharmaceutical manufacturing processes – provide real time data to improve the process robustness and reduce cost.
A New Method
In order to reduce errors and enhance efficiency, while improving the quality of the product, Lonza formulated a new PAT strategy by leveraging existing technologies and R&D set-up, and bringing PAT into the digital age. This new method not only fills the gaps of previous PATs and improves the quality of the data, but also reduces the cost of the system and the initial upfront investment.
To get rid of the variability in the process during production, which may impact the product quality profile, Raman probes are used to monitor changes of critical bioprocess parameters such as cell counts and metabolite concentrations. Continuous analysis of these components enables operators and data scientists to monitor cellular metabolism and growth while providing mechanisms for continuous process adjustments to maintain nutrient levels at desired targets.Adjusting the bioprocess in this way yields a reproducible process yielding product that meets SISQP standards each and every time
Better Results for Our Customers
The key is that the process itself doesn’t change; the way in which information is obtained about the process does. Lonza is unique in that we are one of the few CDMOs incorporating a platform-based PAT strategy that can work independently, without relying on the customer process.
This results in quick wins with more accurate information. Meaning, there is no disruption to the process. Our customers get access to data from the entire process and a better understanding of how the cultures are growing. For example, when monitoring viable cell count (VCC) in real time, abnormal growth profiles can quickly be identified and flagged.
PAT of the Future
Previously, PAT had only individual data points. Now one can see the entire process, even between data points, and get a better understanding of how the cultures are growing. Better process understanding enables more robust process control resulting in fewer lost batches and higher productivity.
By leveraging existing R&D technologies and the method of customer access, we are eager to see the results of our customers’ products, without requiring the typical large upfront investment associated with traditional PAT.
Senior Manager, PS&T PAT & Automation CoE, Lonza
We help customers develop, manufacture, and innovate their small molecule medicines through our commitment to science, technology and delivery. We provide integrated drug substance and drug product services through our global site network with a strong track record of being present throughout the product lifecycle.
We are here to make a Meaningful Difference. It is the foundation of the way we do business. A career at Lonza is more than a job. We do not just work in the life sciences industries, we are transforming them. What we do today is helping to create a healthier, happier world tomorrow.