The biopharmaceutical development community has successfullydeveloped a broad range of highly effective therapies for a wide variety ofserious and debilitating diseases. However, developing biopharmaceuticals isinherently an extremely challenging and commercially risky undertaking, oftenworking to tight timelines and typically resource-constrained. For many, thismeans adopting a pragmatic approach to development, where the goal is to getthe product to a point where its clinical performance and analyticalcharacterization are "good enough" to satisfy the regulatory authorities andget to market.
Very often, we do not have the time, resources, or indeed, the motivation, towork toward an optimum "best-it-can-possibly-be" position. Typically, the"good-enough" approach may be adopted during selection of candidates,development of formulations and manufacturing processes and in the degree ofanalytical characterization performed. Although this approach has successfullydelivered safe and efficacious drugs to the market, we are now moving into anew era for biopharmaceuticals, characterized by increased competition in themarketplace. Good enough to satisfy the regulators may no longer be good enoughto compete effectively in the marketplace.
There are a number of drivers simultaneously working to movethe biopharmaceutical industry into this increasingly competitive era,including: the availability of multiple innovator products to treat the sameindications; the emergence of biosimilar products and development of aframework by which they can get approval; arguably, an increasingly demandingregulatory environment; evolving scientific understanding that also highlightsareas of ignorance; and emerging markets such as those in Asia.
As a result, healthcare refunders, practitioners andpatients will have an ever-increasing choice about which drug to buy and canincreasingly be expected to base their purchasing decisions on factors such asrelative price, convenience and cost of administration, effectiveness anddegrees of adverse reactions. Both innovator and biosimilar developers willneed to adapt in order to compete effectively in this new environment. A numberof aspects of the development process, although already very important, willbecome increasingly critical to the commercial success of the resultingproducts.
It would seem that both originators and biosimilardevelopers will need to do more—and do it better, faster and more cheaply—ifthey are to succeed in the new marketplace. However, for many, the economicreality in the current climate may be that there will be little, if any,additional resources available to achieve these ambitious goals. New strategiesand ways of working will be required; developers will need to be more open to newideas and approaches, and to embrace new and emerging technologies thatconservative attitudes may previously have prevented. Working harder isprobably not enough, or in many cases, possible. Developers will need to worksmarter.
Every stage of the development and manufacturing process haspotential for optimization, and a wide range of innovative technologies andstrategies are already available. Embracing new technology, however, bringswith it some risk and fear of the unknown. If current practices are consideredgood enough, why risk something new? As a result, many innovations havestruggled to gain acceptance; this may be the time to reconsider some of these,in the drive to move beyond "good enough" and toward "the best things can be."As these innovations, both relatively developed and just emerging, are toonumerous to detail here, a few areas where the development process might beadvanced to improve product competitiveness have been selected fordiscussion.
Speeding development:Start right, move faster
A key potential cause of slow and expensive development canbe early selection of a candidate molecule that, while efficacious andspecific, is fundamentally unstable and consequently difficult to develop,manufacture and achieve adequate storage stability in a convenient dosage form.Picking the right candidate is, however, easier said than done. Early indevelopment, both time and protein material are typically in short supply,limiting the number of candidates that can be investigated and the extent ofanalytical characterization that is possible for each.
To overcome these issues, analytical screening technologiesare needed which are rapid and automated (high-throughput), consume very littlematerial and also make analytical measurements that are in some way predictiveof how the protein will behave during manufacture and subsequent storage. Suchtechnologies allow candidate protein molecules to be screened for"developability"—or, in the context of this article, "competitiveness"—in additionto basic therapeutic function. If the measurements made have some predictivepower, the risk of progressing too far with a molecule which is ultimatelyincompatible with modern, cost-effective platform manufacturing processes, orwhich can't be made suitably stable for long-term storage in a convenientdosage form, is reduced. The same small-volume, high-throughput approach alsooffers the potential to rapidly and cost-effectively test the efficacy ofprotein engineering efforts to improve stability earlier in development, and toidentify optimum solution conditions for processing and storage.
A tough, stable molecule, selected from the outset to beinherently compatible with modern platform manufacturing processes and forwhich the successful results of long-term storage stability studies can be(almost) assured, has a better chance of progressing through development morerapidly, costing less to develop and reaching the market sooner. Once atmarket, the selected and/or engineered-in attributes should result in lowermanufacturing costs, longer shelf life and potentially other benefits to thecustomer, increasing the molecule's chances of commercial success.Instrumentation suitable for this type of stability screening is readilyavailable from a wide range of vendors at comparatively modest cost, and anumber of the largest biopharmaceutical developers are already embracing thisapproach.
Analysis as a routeto market … and as a roadblock
Analytical characterization plays a pivotal role inbiopharmaceutical development and manufacture, and takes on a new importancewith the emergence of biosimilar products. Therapeutic proteins are highlycomplex entities, and fully characterizing them is challenging, or indeedarguably not possible, with current technology. This presents a key challengeto biosimilar developers, who need to demonstrate to the regulatory authoritiesthat their product is "highly similar" to the marketed reference product.
U.S. and European regulators have indicated that the scopeand extent of expensive and time-consuming clinical testing they will requirewill depend on the apparent similarity, based on initial physiochemicalcharacterization. The authorities recognize the current limitations of theanalysis of proteins and recommend the use of a wide range of analyticalmeasurements, each of which may have limitations, but which, when combined,build as complete a picture—or "fingerprint"—of the molecule as possible.
This is sometimes described as a "totality-of-the-evidence"approach. It is therefore potentially highly advantageous for biosimilardevelopers to present as comprehensive a physiochemical analytical comparisonof their new proposed product and the reference material, rather than taking amore limited, "play-it-safe, bare-minimum" approach.
A range of both new and established, but traditionallyunderused, analytical techniques are available which can add considerably to aconvincing picture of similarity. Embracing new analytical technologies is notwithout risk, but the potential rewards of a faster, cheaper route to marketcould be significant for biosimilar developers. The corollary, of course, isthat innovative developers may wish to build a more comprehensive analyticalfingerprint of their "reference" product to demonstrate dissimilarity of apotential biosimilar with their material.
New technologies tomeet new challenges
Two related areas where innovation may potentially improvethe competitiveness of a product are the way it is administered to the patient(delivery) and the use of stabilizing additives to improve stability and shelflife (formulation). However, for many time- and cash-pressed developers, the conceptof thoroughly optimizing the protein formulation or adopting new formulationtechnologies for improved long-term storage stability or delivery propertiesmay be seen as a luxury. Additionally, biosimilar developers may consider anydeviation from the originator formulation as a risk that will need explainingto the regulatory authorities.
However, in a newly competitive market, improved formulationmay be a route to achieving a market advantage. This thinking can already beseen with a move away from lyophilized products—which need reconstituting andadministering by healthcare professionals—toward liquid formulations, prefilledsyringes and patient self-administration. The technical challenge of this shiftis sometimes considerable and not free of risk for the developer, but in thisexample, the benefits to the customer are significant, going beyond simpleconvenience and extending to overall cost savings for the healthcare provider.
For innovator and biosimilar developers alike, delivery andformulation provide not only improved product performance, but also thepotential to engineer useful additional intellectual property protection intoproducts where the patent on the basic therapeutic protein has expired. Thereare multiple companies around the world with innovative formulation anddelivery technologies that offer the potential reward of increased productcompetitiveness and improved IP position. Maybe now is their time to shine.
Good enough isn'tgood enough anymore
A host of innovative approaches and technologies exist thathave the potential to improve almost every stage of the process of developingand manufacturing biopharmaceuticals. Embracing them, however, is not withoutrisk to developers, and in an environment where the status quo is consideredgood enough, they struggle to gain acceptance. A change in the market dynamicsfor biopharmaceuticals may, however, mean this attitude will have to change andopportunities for innovation will increase. In the meantime, for all the smallcompanies with the innovative analytical, formulation, delivery andmanufacturing technologies—hang in there!
Simon Webster is chiefscientific officer and co-founder of Avacta Analytical, a specialist contractresearch organization providing biophysical characterization services andinnovative instrumentation to the biopharmaceutical market.