Our methods included a classification of biologic excipients, identification of their complexity to identify their relevance, and a broad literature search to identify the extent of specifically documented excipient adverse effects. We argue that excipients play a critical role in the safety profile of a biologic and their potential adverse effects warrant serious clinical consideration to ensure safe medicine for each patient. We aim to propose an excipient assessment framework to quantify the complexity of biological products by excipient use frequency and their concentrations, and to identify the most commonly occurring excipients found in large molecule medicines with reported adverse events based on published case reports. Our objective is to assess the potential safety risk of biological formulations by correlating with the type and variability of excipients used in the product development. These ingredients can exert adverse effects on individuals with known sensitivities and intolerances, especially on vulnerable pediatric and elderly populations with serious and life-threatening diseases that might require treatment with unstable biological medicines. Similarly, inactive ingredients in parenterally administered medicines have been associated with increased sensation of pain at the injection site, and a review of factors impacting immunogenicity of biologics has identified a number of inactive ingredients as potential causes. Recent research in oral medications has shown that the “inactive” ingredients are not as inert as the name suggests. A large part of ensuring safety and quality of medicines involves appropriate excipient selection considering for instance that 92.8% of oral medicines contain at least one potential allergen in its formulation. Part of this plan focused on development of scientific tools and resources that would enhance understanding of appropriate analytical methods to demonstrate biosimilarity and thus efficacy of the medicine relative to the reference product. FDA issued the Biosimilars Action Plan (BAP) to stimulate development of biosimilars thereby increasing competition in the biologics marketplace. Īs more biologics are developed and adoption of biosimilars spreads, ensuring efficacy, safety and quality of these medicines is an increasing priority. FDA defines a biosimilar as a “biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and that has no clinically meaningful differences in terms of safety, purity or potency from an existing FDA-approved reference product”. This includes the development of biosimilar formulations, which are expanding rapidly due to the anticipated patent expirations of many biologics. They represented 70 percent of the growth in drug spending from 2010 to 2015 and are forecasted to be the fastest growing sector of the pharmaceutical industry. In the United States, biologics comprise 40 percent of total spending on prescription drugs. Lastly, most of these medicines must be developed in a liquid form for compatibility with subcutaneous, intramuscular, or intravenous administration.ĭespite the challenges in formulation development, biologics are the fastest growing therapeutic class of medications. In addition, protein-based therapeutics have a potential to cause an immunogenic response leading to adverse events that are often not discovered until after the medicine is on the market. First, stability and preservation present a significant challenge as the API of a biologic is more unstable than in small molecule drugs. Due to the complexity and fragility of these active compounds, several challenges exist in formulation development of a biologic. These large molecule compounds can range anywhere from 600 to 150,000 Daltons and most require parenteral administration due to their high molecular weight and low stability properties leading to the risk of denaturalization and proteolytic enzymatic degradation in the gastrointestinal tract.Įxcipients are added to the API to increase their stability and preservation, maintain tonicity, and facilitate drug delivery, ensuring the development of the most efficacious medicine that avoids immunogenic or other side effects. The API of a biologic is most commonly a growth factor, hormone, interferon, monoclonal antibody, or other peptide or protein. Food and Drug Administration (FDA) broadly defines as “any component of a drug product other than an active ingredient”. Pharmaceutical formulation of a drug product consists of the active pharmaceutical ingredient (API) and excipients-the inactive ingredients that the U.S.
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