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Key technical considerations when developing a clinical project in the biotech world.
Imagine a major game designer developing a new video game that is comprised of pitfalls and complexities so numerous and difficult that few players reach the midpoint, let alone complete the game successfully. This situation is analogous to the world of biotechnology, where companies face this scenario regularly and must do everything possible to increase their odds of successfully completing the "development game" and to reduce the risks of elimination. The risks and rewards of playing the game are high but few can afford to fail, even once.
Biotechnology projects are complex and subject to many levels of risk during the early clinical phases. Few products enter Phase III, and fewer still make it through approval and on to commercial manufacture. Furthermore, globalization and other recent developments, such as tighter quality control criteria, evolving technologies, and the increasing stringency of regulatory standards, have imposed enormous pressures on an already difficult task of taking a product to market.
The primary concern in most instances is to maximize the value of the compound in the earliest stages of development to assist in attracting investors, provide outlicensing opportunities or in some cases, allow outright acquisition by a larger company. To such companies, little thought is given to later development or the commercialization efforts that must be applied to the compound or the myriad of interfaces between various partners that might be necessary as they move forward with a project.
In clinical development, finding answers—the right answers—is anything but simple. There are many questions, many unexpected challenges, and many decisions that all need to be carefully and thoughtfully addressed because of their potential impact on the product's success.
Successfully conducting a clinical development project requires a biotech company to:
This article focuses on a few of these steps.
Finding the right solution to specific problem starts with a clear understanding of a compound's underlying technical and scientific requirements. Compounds are becoming more complex and that means greater demands on primary packaging. Highly sensitive drugs, including biopharmaceutical ones, require optimally designed drug-delivery systems. In addition to technical challenges, there are growing cost pressures and increasingly strict rules from regulatory agencies. Therefore, drug manufacturers need a great deal of competence when calibrating packaging with the drug product. On one hand, there is the compound itself and its environmental conditions (e.g., reaction with certain materials, biological specifications). On the other hand, time factors (e.g., time-to-market) and long-term market success (e.g., product life-cycle management) are important criteria to consider.
Among other things, companies must ask—and answer—the following questions:
A well-defined process that helps to frame the key steps to product development and methods that lead to a successful outcome is also important. Complex compounds, such as multivalent vaccines, can present especially challenging issues in the early clinical phase. For example, consider a multivalent vaccine in clinical development at risk of losing biological potency during the filling process.
Multivalent vaccines are comprised of several serotypical polysaccharide protein conjugates. Each serotypical conjugate must be prepared for filling so that the final mix of all serotypes retains its biological potency to elicit the appropriate immune response; having 8–12 different peptide antigens conjugated in the final mix while retaining the required biological potency is a major challenge.
All highly sensitive biologics, including vaccines, monoclonal antibodies, and conjugated peptides, are affected by filtration in the scale-up and filling processes. Many require multiple complex filtration processes that can include ultra, dia and Q-filtration steps in a single run. There are many key variables to control, including fill concentration, viscosity, and pumping pressure.
To ensure biological potency of the final conjugated mix, the process design had several steps, including: constant recirculation during final filling to avoid unwanted volatility in concentration; and specialized pump and filtration technology to optimize bioactivity while preventing protein aggregation. (Designing an optimal pump filtration and process was equally crucial for protecting the bioactivity of the final product).
In this case, a complex, multistep filtration process had to be developed to prevent protein aggregation during pooling, to eliminate leaching of any filter particles or extractable compounds in final drug solution, and to maintain targeted viscosity and concentration during scale-up.
To achieve the goal, specialized teams worked together to develop a novel, customized process design that delivered a high-yield, biologically potent vaccine, which afterwards was planned for smooth scale-up from clinical to full commercial production.
To meet the growing number of challenges facing the biopharmaceutical industry, outsourcing has become a key strategic element. Outsourcing involves fundamental decisions that must be made early in drug development—when there is time to choose the right partner and develop a strong relationship. At the end of the day, the partner that a company chooses to work through its product development plan will strongly influence how the game is played. Choose wisely and everybody wins.
This article is part of a new series on Basic Training for Drug Development and Manufacture, providing business and technical guides for taking drugs from discovery to development. Send ideas and contributions to the editor at firstname.lastname@example.org.
Paul Nelles is vice-president of Vetter Development Service at Vetter Pharma-Fertigung GmbH & Co. KG