Investment in biotech R&D is reportedly now outpacing that of big pharma (http://www.burrillandco.com/content/news/PR-BIO-2013-4-16-13-final.pdf ) and is driving rapid developments across the biopharmaceuticals sector. The race to identify candidates and to produce effective biological therapeutics is intense and brings unprecedented challenges. Even with traditional small molecule drugs, the route from candidate selection through formulation and into manufacturing is often difficult to negotiate. When it comes to biologics, it may well be a journey into the unknown where, for example, traditional analytical methodologies don’t apply and where many of the rules are still being written by the regulators. Dr E Neil Lewis, chief technology officer at Malvern Instruments, leads the company’s Bioscience Development Initiative, established to work in tandem with the biotechnology and biopharmaceutical industries to rapidly identify, evaluate and deliver the new analytical technologies they need, when they need them.
What is driving the demand for new analytical techniques in biopharmaceutical development?
“Unlike chemical entities, large biological molecules cannot be delivered as powders or tablets and instead, are delivered in suspension via injection. Large biological molecules are heterogeneous in nature, and the therapeutic molecule itself may become misfolded, aggregated or denaturated. Consequently, biological materials bring a level of complexity to the development process that is simply not present for small molecule drugs. Safety and efficacy of the final product are paramount, and have been driving analytical requirements to this point. However, as the industry grows, the analytical expectations throughout the development cycle will mature. Potentially, a suite of analyses will be applied at all stages of development, evolving into the biopharmaceutical analogue to Quality by Design. This includes pre-formulation and formulation stages, where critical decisions must be made as to the likely downstream suitability of a molecule.
In this fast-moving environment, some of the biggest challenges lie in understanding not only what can be measured but what will provide meaningful predictive information as to quality, and finally anticipating what measurements you will be required to make in the future. Such dynamism is pretty exciting and is stimulating some significant scientific advances, but means that we have to keep defining and redefining the metrics, and as analytical instrument providers we have to deliver the necessary tools.”
How is Malvern addressing these challenges?
“We at Malvern believe that the traditional model of getting an analytical instrument into the hands of the people who need it, where it can take a number of years to perfect a market acceptable product, needs to be bypassed. In the rapidly changing environment of biopharmaceutical development there is a high risk that by the time an instrument developed the ‘old’ way gets to market, analytical requirements will have advanced beyond the original capabilities. The Bioscience Development Initiative has been established to encourage industry players to partner and share with us their challenges, to provide a vehicle for us to identify and target emerging technologies and to provide fast-moving, agile technology development. Our team engages on both sides of the market. We work with the end customers, those biopharmaceutical companies who have the analytical needs, as well as the leaders on the sharp edge of technology development who have a strong in-house team of scientists and engineers, and with those in small companies and academia.
We gain a real-time understanding of the biopharmaceutical industry’s needs and have the ability to access emerging technologies from a variety of sources, through in-house development, partnership, licensing and/or acquisition. We can quickly test concepts, build prototypes and take the most promising designs forward. As a result, our biopharmaceutical partners get their hands on new technologies at a much earlier stage than compared to traditional product development cycles. Their iterative feedback then shapes further development, or alternatively, will accelerate the decision to cease work on a concept that fails to deliver on its potential. Such high-level partnering allows Malvern and its affiliates to take the risks needed, to explore technologies that traditionally would appear at too early a stage for consideration, and to know quickly if these instruments will deliver the information to justify further investment. Malvern is really in the business of accelerating technology evaluation and development, quickly eliminating dead ends, and driving through those products that will provide real value to the biopharmaceutical industry as and when they need it.”
Where is your technology focus at present and can you give examples of successful product development that has come through the Bioscience Development Initiative (BDI)?
“The biopharmaceutical industry has cited analytical testing as one of the bottlenecks in screening new candidate molecules. Selecting suitable biological entities post-discovery involves various physicochemical testing processes that are designed to rule out those that will be ‘problem children’ in downstream processing. So the question to be answered is ‘how will these entities behave in formulation?’
Typically there are only microliter quantities of extremely high-value material available, yet many parameters to be tested. Concerns include stability, propensity to aggregate, structural integrity of the molecule, and viscosity of the formulation. All of these critical to quality attributes should influence whether or not a candidate entity is advanced, but sometimes it is not possible to characterize all of them with the small quantities of material available.
For example, protein aggregation is a ubiquitous problem, as aggregates have the potential to trigger an immune response in the recipient. Malvern has established solutions for measuring protein aggregation, including Size Exclusion Chromatography and Dynamic Light Scattering techniques. However, to provide complementary and additional characterization capability, the company has negotiated an exclusive distribution agreement with Affinity Biosensors to employ their Resonant Mass Measurement technology to detect, in some cases speciate, and more importantly, count particles in the size range 50 nm - 5 µm. It is especially useful for characterizing protein aggregates in a formulation or buffer.
The viscosity of protein and formulations is another area that can critically impact manufacturability and how a drug is delivered, either intravenously or subcutaneously. As a result Malvern also has an ongoing partnership and development program with another company to develop microviscosity measurement technology, with the aim of providing automated screening of extremely small volume samples and formulations. The results of this joint development project will be marketed as a full Malvern product later in 2013.”
Can you provide some thoughts as to what’s on the horizon at Malvern?
“One key goal will be to satisfy the industry’s need for automation. This is important for analytical techniques that are applied early to determine a molecule’s ‘developability.’ Many pharmaceutical candidates are likely to be under consideration and the process of applying numerous physicochemical measurements to identify lead candidates can be labor intensive, expensive and perhaps less reproducible than an automated workflow. Therefore the automation and integration of these new technologies with existing workflows and established industry practices will likely be one of the keys driving the molecule’s success.”
What about regulatory acceptance?
“Regulatory acceptance is certainly an important aspect to consider. Typically, new technology and instrumentation undergoes a process of validation by the scientific community via peer-reviewed publication before it ultimately garners the attention of industry, and ultimately, the regulator. This process can take a significantly long period of time when it happens ‘sequentially.’ A program such as BDI aims to compress that time schedule as much as possible so that everybody benefits.
Finally, Malvern will be keeping track of industry trends. The biopharmaceutical industry is changing rapidly and the next generation of biopharmaceutical products is quickly evolving beyond a standard monoclonal antibody. Antibody-drug conjugates, for instance, are a unique combination of a small molecule drug attached to an antibody. A variety of other molecules and delivery technologies are entering the market space as well: bispecific antibodies, antibody fragments, peptides, liposomes, etc., All of these are likely to quickly drive new analytical requirements. The need for an agile analytical instrument development process to support it is clear.
Dr E. Neil Lewis
Chief Technology Officer, Malvern Instruments
Dr. E. Neil Lewis: Received his Ph.D. in chemistry from the Polytechnic of Wales in the UK and did his postdoctoral fellowship at the National Institutes of Health (NIH) in the USA. He was tenured by the NIH in 1992 holding the position of Senior Biophysical Researcher. He is the founder of several high technology companies, including Spectral Dimensions, Inc., a company that developed hyperspectral imaging systems, and he has been at the forefront of the development of these technologies. He has authored more than 70 papers, book chapters and patents and has received numerous awards for his contributions. After the sale of Spectral Dimensions Inc. to Malvern Instruments Ltd., he was appointed to Malvern’s Board of Directors and holds the position of Chief Technology Officer.