While physicians stay informed about the medications they prescribe to ensure that patients receive the best possible treatment, one question rarely asked is, “How was this medicine manufactured?” Doctors and patients alike tend to take it for granted that drug manufacturers have the right processes and controls in place to fully and consistently comply with regulatory requirements. With few exceptions, this assumption has been justified.

However, these exceptions can have serious consequences. In recent months, there have been more than 500 cases of fungal meningitis and 36 deaths linked to contamination at a facility that formulated injectable corticosteroids. An even more severe incident occurred five years ago, when the U.S. Food and Drug Administration (FDA) linked 150 deaths to heparin manufactured with an adulterated ingredient designed to evade quality-control testing. Colossal failures like these represent the worst cases in a spectrum of problems, which can also include drug shortages and recalls linked to manufacturing issues. Since 2004, the FDA reports that there have been more than 160 biologic recalls related to issues with product quality, labeling, packaging, and distribution.

Today, most of the biological medicines sold in the United States are manufactured by a small number of companies that not only developed these drugs, but also, in many cases, discovered them and fine-tuned the process for making them. Recently, the FDA established an abbreviated approval pathway for “biosimilars,” which are similar versions of an existing biological medicine made by a different manufacturer. This is expected to result in an increase in the number of biological medicines available, and in the number of companies making these complex therapies.

On the whole, this is a very welcome development for patients. The safe and regulated introduction of biosimilars to the market is forecast to increase access to much needed therapies and reduce costs. Many physicians view the promise of these new medicines based on their long experience with traditional pharmaceuticals and the generics that follow. Biosimilars are not, however, directly comparable to generic drugs. Biological medicines are more difficult to characterize, produce, and reproduce than most traditional pharmaceuticals.

While traditional pharmaceutical medicines are manufactured from chemical ingredients, biological medicines are derived from or made in living cells grown in vitro in a highly controlled environment. The therapeutic proteins produced by those cells are influenced by a number of factors, including individual cell characteristics, the system in which the cells are grown, and the nutrients that feed them. A small change in the quality of the raw materials, in the temperature, or the pH may modify the purity or potency in an unexpected manner. This can in turn affect the medicine’s quality, safety, or efficacy and ultimately, impact the reliability of supply.

Even organizations with significant expertise and manufacturing experience can face hurdles in dealing with the inherent complexity of biological medicines. Maintaining a consistent supply of safe and effective biological medicines requires expert staff, advanced science, and sophisticated technology throughout the manufacturing process and supply chain. It also requires high standards for compliance with regulatory requirements and an organizational culture of quality.

In the United States, the FDA sets manufacturing requirements, licenses only those companies that can meet these requirements, and maintains a broad inspection program to safeguard the drug supply. Compliance with regulations is among the most important steps that manufacturers can take to help ensure the quality of their biological medicines. Physicians should consider asking about companies’ regulatory compliance history when deciding which medicine to prescribe. 

Healthcare professionals have a responsibility to know what medicines they are prescribing and—especially in the case of biological medicines—need to better understand that manufacturing matters. If manufacturers of biological medicines see that prescribers and payers are demanding excellence in manufacturing, they will realize that their track record and reputation in this arena are more important than ever. This push could help ensure that potential problems remain very rare, even as biological agents become more common and accessible as treatment options. Ultimately, it is the interest of patients, doctors, and the biopharmaceutical industry—including those companies that will produce biosimilars—to follow regulatory guidance and best practices. Doing so minimizes the chances for problems, and helps to ensure that these new medicines will be available without interruption.

A new educational initiative, Manufacturing Matters with Biological Medicines, is aimed at providing information about the manufacturing process for biological medicines and how the process can impact product quality and supply.

About the author
Dr. Petricciani is president of the International Alliance for Biological Standardization and a paid consultant to Amgen Inc, sponsor of the Manufacturing Matters initiative. He was formerly the head of the FDA Office of Biologics and received his doctorate in medicine from Stanford University.

The content in this article does not represent the official views of the International Alliance for Biological Standardization. The article was developed with support from Amgen.