Biosimilars Development and Supply: How Complex Can the Process Be?

Countries around the world face a growing, aging population and an increase in chronic disease. With expanding demand for good-quality healthcare comes the challenge of controlling healthcare expenditures (1). The goals behind the safe and regulated introduction of biosimilars into the market include increasing access to much-needed biologic medicines and reducing costs (2).

A recent report (3) from the European Commission looking at Europe’s strong regulatory and commercial foundation for biosimilars found that biosimilars are improving competition in Europe and increasing patient access to biologic medicines. As this new class of biologic medicines is introduced into healthcare systems worldwide, there must be an uncompromising commitment to patient safety, which starts with high regulatory approval standards and ongoing manufacturer accountability. High-quality, reliably supplied biosimilars offer additional therapeutic choices to patients and other key stakeholders; however, development and supply of these complex medicines are scientifically challenging and capital intensive. Manufacturers will need to have significant expertise, infrastructure, and investment capital to successfully develop these molecules.

Gauging the Outlook of the Biologics Market

Quality, first-in-class biological therapies have revolutionized treatments in many disease categories. Bringing these crucial medicines to market, however, is a challenging process because of the complex nature of biologics. For approximately every 5000 to 10,000 pharmaceutical and biologic discoveries in preclinical testing, only one is eventually commercialized (4). An even smaller number of these medicines are biologics.

A typical biologic development route includes: preclinical discovery and validation of target; clinical development; drug approval, launch, and commercialization. During preclinical and early clinical testing, investigators must determine how much of the biologic is required to be effective. The key challenges during this stage are addressing the unique and complex nature of each biologic, including immunogenicity and the pharmacokinetic profile. Unlike the development of small molecules, several bioanalytical assays are necessary in the early development of biologics, which are typically produced within engineered cells from pharmacologically relevant species. The standard preclinical testing as used for small molecules is, therefore, not appropriate. The process is extremely complex, with the research, clinical testing, and approval process taking approximately 10 years. Developing a high-quality biologic medicine that is safe and effective also requires a commitment to manufacturing excellence. Innovator companies often need to invest up to $1.2 billion to bring a biologic to launch (5).

The manufacturing process
The manufacturing process is important for all drugs, but it is particularly so for biological medicines. The key challenge in biologics manufacture is that these compounds are far more complex structurally and more difficult to characterize, produce, and reproduce than most small-molecule pharmaceutical compounds (6). Precision is so crucial that even small variations in the manufacturing process can potentially alter the medicine’s safety and efficacy (7). It takes significant expertise and experience to ensure a consistent level of precision in the manufacturing process for a biological product and the key to such precision involves investing in quality processes to consistently achieve high levels of product purity and manufacturing success through robust manufacturing processes.

The complexity of the manufacturing process can have an impact on the reliability of supply (8). Shortages of prescription medicines are a growing problem around the world. FDA defines “drug shortages” as “a situation in which the total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand at the patient level.” Biologics manufacturers can avoid drug shortages of their biologic therapies by investing in good manufacturing practices to help eliminate the potential of unexpected supply shortfalls of crucial drugs.

As the complex requirements of manufacturing biologics are manifold, it is important that biomanufacturing companies adopt quality-by-design principles, which integrate quality control into the manufacturing process. This approach requires a thorough understanding of a product and its process of manufacture, necessitating an investment in time and resources up front in the discovery and development of a product. Although current technologies, if correctly utilized, are sufficient to address the complex processes involved, manufacturers must look to the future and continue to invest in quality processes and pioneering technologies to keep evolving and improving. Between 2005 and 2016, Amgen expects to invest approximately $1.5 billion in numerous strategies, including the geographic diversification of our capacity, to help ensure high-quality biologics get to the patients that need them. We are also leading the way forward to the next generation of biotech manufacturing, which includes a $200-million investment in a new, world-class manufacturing facility in Singapore as part of our “Manufacturing of the Future” initiative.

References
1. D. Bloom et al., “Population Aging: Facts, Challenges, and Responses” (Harvard University’s Program on the Global Demography of Aging, Cambridge, MA, May 2011).
2. H. Mellstedt et al., Annals of Oncology 19 (3) 411-419 (2008).
3. EC, “Platform on Access to Medicines in Europe,” ec.europa.eu/enterprise/sectors/healthcare/competitiveness/process_on_corporate_responsibility/platform_access/, accessed Aug. 5, 2013.
4. J.E. Klees and R. Joines, Occup. Med. 12 (1) 5-27 (1997).
5. J. Di Masi and H.G. Grabowski, Manage Decis. Econ. 28 (4-5) 469-479 (2007).
6. M. Kuhlmann and A. Covic, Nephrol. Dial. Transpl. 21 (S5) v4-v8 (2006).
7. FDA, “Frequently Asked Questions About Therapeutic Biological products,” www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/, accessed Aug. 5, 2013.
8. FDA, “Biologic product shortages,” www.fda.gov/Biologics
BloodVaccines/SafetyAvailability/Shortages/default.htm, accessed Aug. 5, 2013.

About the Author
Martin Van Trieste, senior vice-president of quality at Amgen