June 2012

BIOLOGICS ENABLING TOOLS PART 2

B I O L O G I C STHIS DECADE

by Simin Zaidi

BIOSIMILAR

NPT | The Community of Big Thinkers

Being in the Biologics industry and interacting with many different product development teams, I often have the pleasure

of learning about potential biological miracle products. From Biologic drugs that can turn back time on a DNA level to self-administrable agents that allow soldiers to protect themselves from bio/chemical-warfare agents in the field, the potential is awesome. However working in applied science, my job involves taking these technologies and making them into a reality. To be of practical consequence, brilliant ideas have to get past the inventor’s self-gratifying “pie in the sky” stage of “could” solve-blank, to one not as sexy. Economics and Regulations are obvious driving forces at this next stage; however the correct methodology for execution of a successful biopharmaceutical product development process is still largely nebulous. It must be, as the rate of success is so low.

The three main areas of Biologics Product Development covered in this article are Discovery, Manufacturing and Clinical phases. The tools used to accomplish them define these areas. These tools can be ‘hard’ or ‘soft’. Soft tools include project and operations management, scientific method, engineering problem solving, analytical ability, risk management, and business strategy. Hard tools include software, measurement and analysis tools, raw materials, process equipment, and communication and information management tools.

DiscoveryThe majority of Biologics Discovery still takes place primarily in North America and Europe. This decade will see growth of successful discovery efforts in countries such as Singapore, India, China, Russia, South Korea and South America. This effort, supported by wealth and often government policy, also relies on the hiring of experienced personnel from

the nations currently leading in Biologics development. In other words there is a need for soft tools in the latter group of countries. Massive layoffs in North America and Europe do help supply competing economies with this key ingredient of expertise and experience. On the flip side, often the political and cultural differences are still likely to be a deterrent to individuals considering relocation.

Despite the risk of Intellectual Property protection issues, many small to mid-size companies are outsourcing parts of their more labor intensive discovery efforts to countries such as China.

Contract research organizations (CRO) and even offshore departments specializing in scouting, affinity maturation of large molecules and early animal studies, are a financially attractive and possibly competent enough alternative making sense to Western companies looking to stretch their finances. I don’t doubt that colleagues in discovery would shake their heads at the experimental design and methods used at these CROs however if these CROs can afford to perform many more experiments, in the same amount of time it would take an elegantly designed study here, actual success rates among experiments becomes less important. The key is that a successful outcome is reached, in the same amount of time and at a significantly lower cost. Whether such CROs are able to achieve an acceptable balance of expertise at a lower

cost as a long term business model is to be seen in the coming years.

In the meantime, in North America and Europe the innovative flames do remain stoked. Increasingly sophisticated modeling and predictive discovery techniques developed out of the experience of scientists and engineers and fueled by entrepreneurs are coming to fruition. Expensive machines that some of us would have only dreamed of a few years ago can perform highly complex development tasks, precisely and rapidly. Similarly in terms of tool innovation; animal testing concerns, non-embryonic stem cell culture techniques and biomarker discovery are leading to the rise in the number of companies offering non-animal models for aiding and complementing discovery, analytical and clinical efforts. It may be foreseeable later this decade that we see reduced Clinical Study costs as reliable models begin to replace the need for as many studies in animals and humans.

BIOLOGICS THIS DECADE PART II - BIOSIMILAR

“Biologics development is an intricate, multifaceted exercise with many potential areas for waste and opportunities for failure...”

June 2012

ManufacturingYet another way of looking at Biologic Product Development is as an exercise with two main facets; Proof of Concept (in terms of product safety, efficacy and manufacturability) and production of an actual product for proof of concept activities. It is not unheard of that a Biologic fails as manufacturing it is not possible or is too costly to make economic sense. Once the Biologic is found to be producible the next step is producing material for Pre-Clinical followed by Clinical Proof of Concept work. This need has led to the growing establishment of Contract Manufacturing Organizations (CMO) and CRO companies in the West and now the East. However as we can see with the number of United States Food and Drug Administration 483s being issued, Biologics production is not as straight forward as manufacturing, say, iPads. This is due to both production complexity and the gravity of intended use. In biopharmaceutical manufacturing, my own area of focus, many aspects are still approximated (e.g. biologic processes) and manual, even in a current Good Manufacturing Process environment. It is imperative that design space characterization, statistical design and data analysis be added as tools to increase processing reliability. In addition to such tools the personnel designing processes need to understand the science, biological systems, scale up complexities and regulatory requirements to ensure proper control and repeatability. The same applies to the operators and quality assurance personnel involved in manufacturing biologics. Data trending is a quality control function as well. Such expertise, which should be both broad and deep, comes with relevant education, training and years of experience with multiple projects. So it follows that having in-house expertise in all the necessary product development areas for a Sponsor company makes little sense unless they intend to offer the services to others as part of their business model. We are seeing more Biologic companies retain a smaller number employees consisting of

experts in technical and business product development who orchestrate activities performed by expert service companies.

ClinicalComplementary clinical studies are carried out in countries such as India, Mexico and Eastern Europe. The goal in such cases may be to supplement ongoing efforts in the intended filing country or to provide proof of concept data to attract investors (more so the former as governments clamp down on the idea of offering up their citizens as “guinea pigs”). The advantage has been cost savings and larger populations with the required clinical status. This strategy is not unique to the Biologics industry however general understanding of product handling (biologic molecules and tissues are extremely sensitive to storage conditions) and complicated administration protocols, in addition to “lost in translation” scenarios may add a risky variable to the mix of developing a Biologic. It will be key that information exchange platforms continue to be developed and optimized while being available at affordable rates for this to be successful. Many software design companies are beginning to answer the call for universal solutions.

Cost ControlThe ultimate goal of Biologic Enabling Tools is to control costs (by increasing success rates and efficiencies). As a Global Biopharmaceutical Market Report from 2010 (IMARC) points out that the high costs of Biologics is expected to be closely scrutinized by payers in coming years. Coincidently a recent interview with Fareed Zakaria on Your Money CNN, about his upcoming special on Fixing US Healthcare, points out analysis showing 20 countries that do Healthcare better and less expensively than the US. Nobel Prize Winning economist Kenneth

Arrow’s 1963 paper “Uncertainty and the Welfare Economics of Medical Care” points out how Healthcare does not work as a regular market economy. This is because one can’t predict the need to purchase it thus leading to the argument for an insurance system of a sort. In addition, a universal insurance system’s costs must be controlled. With Healthcare being an issue that cannot be ignored, paired with large numbers of unemployed Biologic experts looking for work and a growing middle class in Eastern economies, we seem to be approaching an inevitable truth. Biologics represent human innovation for human good. There are emerging markets and there are Biologic products to be developed and sold affordably. In other words, the opportunity for Biologics Product Development is ripe.

FinallyBy all indications, in the coming decade, we will see even greater international product development efforts. In the Biologic leader countries we should continue to see an improvement of product development philosophy and methodology (that increases success rates while decreasing costs). Materializing shifts already apparent include a move to smaller Biologic company workforces consisting of technical and business project orchestrators, the use of more sophisticated technical tools and a focus of working with contract service companies specializing in various key areas. Due to tightening in investment capital, it is already a business model norm to develop a product to a stage and then sell it to Big Pharma. However as tools improve and costs decrease, will we see an increase in Biologic product success rates and move away from this model? It is an option worthy of consideration.

Simin Zaidi is a Bioprocess Professional in Southern California, USA, experienced in taking multiple biopharmaceutical products through Clinical and Commercial Production. She can be reached at Stamford Bioprocess Technologies on contact@stamfordbio.com.

BIOLOGICS THIS DECADE PART II - BIOSIMILAR

“From Biologic drugs that can turn back time on a DNA level to self-administrable agents that allow soldiers to

protect themselves from bio/chemical-warfare agents in the field, the potential is awesome. ..”