When a drug candidate is deemed suitable for clinical trials, its production needs to be upscaled. This step is crucial in determining the success of the end-product. Biotech and pharma companies need to choose appropriate analysis techniques and production processes to avoid late-stage failure of their biologics. Partnering with an experienced contract development and manufacturing organization (CDMO) can help companies take the best steps to ensure a safe and fast delivery of their product to patients in need.
Once a drug is identified in the research and development stage, the early preclinical drug development cycle begins. This stage often involves screening of different drug formulation combinations to provide the best stability and least toxicity.
For biological drugs, extracted from living organisms, the preclinical stage is often complicated. It involves identifying the right organisms for the production of the biologic, providing ideal growth conditions for these organisms, optimizing protein expression and purification, and conducting a host of analytical development and stability studies.
In parallel, the shortlisted biologic formulations are also designed to cater to the choice of administration route – oral, topical, nasal, ophthalmic, intramuscular or intravenous – selected for the drug.
After being declared safe in animal models, the drug gets cleared to move on to in-human clinical trials, where the safety, dosage, and efficacy of the drug get tested further.
The biologic needs to be efficacious and its production cost-effective, even when produced at large scales. To ensure this, whenever the expression, extraction, purification, or manufacturing processes are scaled up, they are continuously validated.
Once the different clinical phases find the biologic to be safe and effective for humans, the drug goes through regulatory evaluation before it can be approved for use. Early in the commercialization stage, another round of validation is required to certify that the biomanufacturing processes are fit for upscaling for commercial production and abide by industry standards.
“Pharma companies are traditionally very good in identifying new compounds and they invest heavily in initial proof of concept and characterization assays.”
“However, whilst a particular series of steps from formulation to production may work in an academic environment or a small laboratory setup, it may not necessarily translate to a large-scale manufacturing setting,” said Jo Vercammen, Vice President of Technical Business Management at Eurofins CDMO.
How to get large-scale biologics manufacturing right
According to Vercammen, the success of the biologic is very much related to doing things right from the beginning and this makes it highly worthwhile to invest in good process as well as formulation development. In fact, running pre-formulation studies along with process development has proven to be beneficial in fine tuning the production process.
“Optimizing the formulation during the initial purification stages, provides an in-depth understanding of the materials required, the resulting degradation products, as well as the environment best suited to the end-product, at a small scale itself. It is imperative to work under conditions where all of these are stable when upscaling the process,” Vercammen added.
When a production process is being upscaled, multiple factors need to be considered. These include availability and quality of raw materials, desired drug quantities (influenced by the dosage and number of suitable patients) and process costs.
Moreover, processing times as well as product concentrations can turn out to be different in large-scale, when compared to small-scale settings. Knowing which appropriate expression conditions (including cultivation parameters, choice of cell culture medium, etc.) and purification strategies (along with suitable resins, buffers and filters) to choose for optimal large-scale performance can help avert downstream physical or chemical modifications.
Moreover, by applying this knowledge correctly, any additional clinical or stability studies that may be required by the regulatory authorities can also be avoided.
Apart from having knowledge and expertise over a broad suite of analytical methods, knowing how and when to leverage the latest trends is also key to successful process development.
“The landscape is continuously evolving; more companies are developing non-conventional biologics. Even methodologies are shifting, such as the recent move from large, stainless-steel bioreactors to smaller single-use bioreactors for production.”
“Only with the right skill sets and tools, can one be assured that the product has optimally obtained its defined specifications,” asserted Fons Bosman, Principal Scientist at Eurofins CDMO.
Lastly, as the scales magnify, drug production also needs to comply with good manufacturing practices and regulatory requirements. “Not only do the parameters that control your product quality and process have to be consistent, they also need to meet industry regulations,” cautioned Geraldine Buysschaert, Downstream Processing Manager at Eurofins CDMO.
Seeking the required expertise – Accepting support from CDMOs
With the many crucial decisions that need to be made, biotech and pharma companies often turn to CDMOs for guidance, especially for technically challenging projects with non-standard processes.
“As an experienced CDMO, we have covered a large diversity of projects working on a variety of molecules in the past,” explained Vercammen. “This experience limits both the time and the effort we take to identify beneficial process parameters across projects. This also puts us in a better position to help with new formulation types that companies may not be experienced with.”
Time to completion is crucial in most projects, explained Buysschaert: “Clients usually come to us in the preclinical to phase I stages, when the speed to get to a later clinical stage is very important. To address this, we have broadened our offering to be a flexible CDMO with a high synergy between different departments.”
The Eurofins CDMO team provides support across the full product development cycle, from process development and formulation activities to manufacturing, as well as regulatory support. Clients can also “choose to plug-in CDMO services at different stages of development”, added Vercammen.
An optimized future for drug development and manufacturing
“The continuous goal of drug development is to achieve a higher yield with better quality by employing a more efficient, safer, and quicker process than before,” said Buysschaert.
Therefore, Eurofins CDMO has adopted steps like introducing single-use consumables and new approaches like membrane chromatography for drug purification. Such measures, along with an increased adoption of continuous processing and automation, fall under the realm of process intensification. This involves identifying critical process parameters, improving them and reducing risk.
“The future of drug development is in bringing out the best results from the biomanufacturing process,” explained Bosman. “Towards this, the know-how of each unit in the process is becoming increasingly important, as is higher inter-unit interaction. This is the real strength of a CDMO environment: we can help realize this future by leveraging technology to contribute to a scalable and robust production process for our clients.”
With a track record of successfully running biologics development projects, the experts at Eurofins CDMO can draw on their breadth of experience to shorten timelines and obtain better quality end-products. Learn how Eurofins CDMO can help you in your path to optimizing drug development and manufacturing here.
Images via Eurofins CDMO