Given the knowledge gap under which biosimilars are developed, data to establish biosimilarity should go beyond a simple comparability exercise.

The manufacture of secreted proteins is complicated by the need for both high levels of expression and appropriate processing of the nascent polypeptide. For glycoproteins, such as erythropoietin (EPO), posttranslational processing involves the addition of oligosaccharide chains. We initially noted that a subset of the amino acids present in the cell culture media had become depleted by cellular metabolism during the last harvest cycle in our batch fed system and hypothesized that by supplementing these nutrients we would improve EPO yields. By increasing the concentration of these amino acids we increased recombinant human erythropoietin (rHuEPO) biosynthesis in the last harvest cycle as expected but, surprisingly, we also observed a large increase in the amount of rHuEPO with a relatively low sialic acid content. To understand the nature of this process we isolated and characterized the lower sialylated rHuEPO pool. Decreased sialylation correlated with an increase in N-linked carbohydrates missing terminal galactose moieties, suggesting that beta-1,4-galactosyltransferase may be rate limiting in our system. To test this hypothesis we supplemented our cultures with varying concentrations of manganese (Mn(2+)), a cofactor for beta-1,4-galactosyltransferase. Consistent with our hypothesis we found that Mn(2+) addition improved galactosylation and greatly reduced the amount of rHuEPO in the lower sialylated fraction. Additionally, we found that Mn(2+) addition increased carbohydrate site occupancy and narrowed carbohydrate branching to bi-antennary structures in these lower sialylated pools. Surprisingly Mn(2+) only had this effect late in the culture process. These data indicate that the addition of Mn(2+) has complex effects on stressed batch fed cultures.

Biological medicines (biologics) are produced in living cells and purified in complex, multi-step processes. Compared with chemically synthesized small-molecule drugs, biologics are more sensitive to changes in manufacturing conditions. Process and product consistency should be founded on rigorous design and control of manufacturing processes, but consistency is ultimately ensured through robust quality systems. Even a minor change in any component of a quality system could lead to product drift, evolution, and divergence, which may impact the quality, safety, efficacy, and/or interchangeability of biologics. Unintended or unexplained deviations in manufacturing processes can lead to excursions in product attributes (i.e., drift). Well-managed quality systems can help detect and mitigate drift. Occasionally, quality attributes could shift outside of established acceptable ranges as the result of a known manufacturing change (defined here as evolution). Such changes should be studied extensively for effects on product safety and efficacy. With the advent of biosimilars, similar biologics will be produced by multiple manufacturers with different quality systems. Different patterns of product drift and evolution could contribute, over time, to clinically meaningful differences among biologics, including among originator products across regions and among originator products and biosimilar products, a process defined here as divergence. Manufacturers and policymakers can minimize the potential impact of divergence by establishing robust pharmacovigilance systems; requiring distinguishable names for all biologics, including both originator products and biosimilars; adhering to high standards for designations of interchangeability; and ensuring that patient medical records accurately reflect the specific biologic dispensed, especially if the biologic could be sourced from multiple manufacturers.

IntroductionThe under-reporting of adverse drug events (ADEs) is an international health concern. A number of studies have assessed the root causes but, to our knowledge, little information exists relating under-reporting to practices and systems used for the recording and tracking of drug‐related adverse event observations in ambulatory settings, institutional settings, and retail pharmacies.ObjectivesOur objective was to explore the process for reporting ADEs in US hospitals, ambulatory settings, and retail pharmacies; to explore gaps and inconsistencies in the reporting process; and to identify the causes of under-reporting ADEs in these settings.MethodsThe Tufts Center for the Study of Drug Development (Tufts CSDD) interviewed 11 thought leaders and conducted a survey between May and August 2014 among US-based healthcare providers (HCPs) in diverse settings to assess their experiences with, and processes for, reporting ADEs.ResultsA total of 123 individuals completed the survey (42 % were pharmacists; 27 % were nurses; 15 % were physicians; and 16 % were classified as ‘other’). HCPs indicated that the main reasons for under-reporting were difficulty in determining the cause of the ADE, given that most patients receive multiple therapies simultaneously (66 % of respondents); that HCPs lack sufficient time to report ADEs (63 % of respondents); poor integration of ADE-reporting systems (53 % of respondents); and uncertainty about reporting procedures (52 % of respondents).DiscussionThe results of this pilot study identify that key factors contributing to the under-reporting of ADEs relate to a lack of standardized process, a lack of training and education, and a lack of integrated health information technologies.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-016-0455-4) contains supplementary material, which is available to authorized users.

Platelet formation, occurring from bone marrow or lung megakaryocytes, has been difficult to study mechanistically. Recombinant human megakaryocyte growth and development factor (rHuMGDF), a recently described cytokine, has now been used to establish an in vitro system in which this important and little understood process occurs. CD34+ cells cultured with rHuMGDF develop into megakaryocytes which form long cytoplasmic extensions (proplatelets) that fragment into platelet-sized particles (in vitro platelets). Morphologically, in vitro and human plasma-derived platelets (control platelets) are virtually identical with respect to size, dense granule distribution and ultrastructural features. Functionally, in vitro and control platelets have similar aggregation and activation responses, and similarly incorporate mepacrine into dense granules. These findings suggest that rHuMGDF is sufficient to generate platelet-synthesizing megakaryocytes from CD34+ cells and provide an experimental setting in which the study of human platelet formation can be adequately performed.