Generics account for a significant percentage of the global small-molecule drug market today, and biosimilars are poised to make strong gains in the biopharmaceutical sector. Aggressive generics/biosimilar companies develop their products parallel to the innovator company and increasingly are introducing them before patent protections on branded counterparts have expired.
Consequently, pharmaceutical product life cycle management (LCM) strategies can no longer focus solely on the period from launch to patent expiry. Successful drug manufacturers now include the entire lifecycle from discovery through end of life. Contract development and manufacturing organizations (CDMOs) with expertise in both the development and commercialization of new drug products and life cycle management strategies play a key role in supporting these much more extensive and complex LCM activities.

Stiff Competition
In Europe and the U.S., generics account for approximately 80% of small-molecule drugs sales. Generics are also preferred in emerging market countries where increasing incomes are allowing more people to seek medical treatment, but at a minimal cost. Healthy growth over the last two decades attracted a number of new entrants to the market, resulting in fierce competition. Recent acquisitions (e.g. Endo’s $8.1 billion acquisition of Par Pharmaceutical and Teva’s recently announced $40.5 billion purchase of Allergan) reflect this situation. So does the increasing aggressiveness of the most successful generics firms, who now often launch their products at the earliest possible time, including in advance of patent expirations in some cases.

Rethinking LCM Strategies
Conventional product life cycle management strategies focus on new drug products from the time they are launched to the expiration of patent protection, with the assumption that any revenues in the post-exclusivity period are minimal. The more rapid introduction of generics makes this traditional LCM approach insufficient today. In addition, it is now recognized that drugs sales after patent protection runs out can account for as much as 30% of lifetime sales for small-molecule drugs.

To better fight aggressive generic competition and retain a greater percentage of the sales generated in the post-patent-expiry period, many pharmaceutical manufacturers are taking a much more holistic approach to product life cycle management that covers the entire life cycle of a drug product from discovery through development and commercialization and on into post-market exclusivity. These strategies often include planning for generics competition early in the development phase, rather than after a product is launched. Many companies file multiple patents based on different compositions of matter, methods, formulations, etc. to create multiple expiration dates in different geographic markets. New delivery methods and secondary packaging solutions, modification of manufacturing processes, the formation of partnerships, and logistics and marketing activities are also employed today as part of modern LCM strategies. 

The Challenge of Changing Value Perceptions
While many of these tactics can be quite effective for extending the life of branded small-molecule drugs, it is becoming more challenging to rely on simple modifications of existing technology. Governments, payers, physicians and patients all demand demonstrated value (evidence-based medicine) and expect new therapies (including modified versions of existing drugs) to either provide significantly improved benefits or meet previously unmet medical needs. Fortunately, demonstrating value can involve not only improved efficacy; reduced side effects, improved dosing regimens, greater ease of use and increased compliance are also important benefits.

To develop more comprehensive life cycle management strategies under these complex conditions, many pharmaceutical companies have found that input from many different business groups must be considered. A cross-functional LCM team that includes representatives from marketing, R&D, manufacturing, process engineering, regulatory and other groups across all therapeutic areas can establish an overall company-wide strategy as well as product-focused strategies that leverage past experience across the entire product portfolio. Such a holistic or integrated approach can result in the identification of new markets and new technologies for extending the lifetime of small-molecule drug products.

The Value-Add of CDMOs
Branded drug manufacturers that adopt this new approach to life cycle management often rely on contract manufacturing and development organizations with experience in the development and implementation of life cycle management solutions.
CDMOs cannot only help increase the efficiency of production processes; they can help reduce the risks associated with product development and commercialization. Sponsor companies that work with CDMOs experienced in LCM from the earliest discovery stage through the end of a product’s life typically are confronted with fewer problems and benefit from lower costs and higher yields. These CDMOs can help accelerate the initial drug development and commercialization processes as well as develop and implement ongoing process improvements and novel delivery and packaging solutions. To be most effective, it should be noted that close collaboration and communication between the CDMO and the branded drug manufacturer, including all members of its cross-functional LCM team, are crucial.

Focused on Life Cycle Management
As a CDMO that is a business unit of a global pharmaceutical manufacturer (Orion Corporation) and a producer of generic active pharmaceutical ingredients (APIs), Fermion recognizes the critical need for effective product life cycle management. Throughout the lifetime of each project, we are constantly evaluating how to improve process cost-efficiencies, environmental, health and safety aspects and product quality. In addition, a dedicated team of lifecycle management engineers works closely with our customers to develop and implement solutions that support their LCM strategies.

The potential impact of our LCM efforts can be seen pictorially in Figure 1. The first case shows the relationship between the R&D investment and cost-of-goods sold (COGS) for a product that currently is in clinical development. Initial, R&D efforts increased significantly as the product was transferred from the medicinal chemistry group to Fermion’s R&D, bench scale and pilot lab. A second increase in R&D investment occurred during production scale-up. Overall, however, the COGS consistently decreased as the process was optimized and economies of scale were realized.

The second graph in Figure 2 (Case 2) shows the impact of LCM efforts at Fermion on the COGS of an API that had been commercially available for two years. Significant R&D efforts were expended to optimize each step of the production process at that point, resulting in a decrease in the COGS. During year seven of the product’s lifetime, additional R&D investment was made to allow outsourcing of certain intermediates, resulting in a further COGS decrease in subsequent years. The slight increase in COGS in year seven was due to increases in raw material costs.

It is also important to note that in addition to specific life cycle management, developing initial processes for advanced intermediates and APIs is essential, including highly potent compounds, that are well-engineered with cost and quality considerations built into each step of the synthesis. Using a highly systematic and effective strategy in order to design optimal synthetic sequences that take into consideration yield, quality and processability, is also essential. 

Carefully planned, efficient testing and evaluation combined with the use of design of experiment and Quality by Design (QbD) approaches help ensure the development of effective processes. Production facilities with advanced on-line and conventional analytical techniques, along with automated systems to ensure high productivity and quality, should be employed.

Furthermore, expertise in particle engineering, polymorph control and impurity control and capability for GMP micronization complement continuous improvement efforts with respect to process engineering. A comprehensive set of skills and capabilities for all phase of drug development and commercialization, are essential to help pharmaceutical companies implement their holistic product life cycle management strategies. 

Conclusion
The fundamental goal of the pharmaceutical industry is to develop new therapies that improve patient lives. However, drug manufacturers must be profitable in order to be able to continue investing the large sums required to discover new drugs, develop cost-effective synthetic routes, prove their safety and efficacy and bring them to market. In the highly competitive and constantly changing pharmaceutical market of today, branded drug owners are increasingly committed to the development of integrated life cycle management strategies in order to realize the maximum revenues from each product in their portfolio and ensure their continued ability to find new treatments that will bring real benefits to more patients. CDMOs with the appropriate expertise, capabilities and facilities can help these sponsor companies successfully implement their increasingly important LCM strategies. 

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Marko Salo is vice president of sales and marketing at Fermion Oy. He has over 10 years of experience in the pharmaceutical industry in various positions at the Orion Corporation and its subsidiary Fermion Oy, including finance controlling, business development, project management and marketing. From 1997 to 2000 Marko worked at a predecessor of one of the largest forest industry companies globally, Metsä Group, as a researcher. Since 2010 he has headed the marketing of contract manufacturing organization (CMO) and generic API sales of Fermion.