Dover, MD, United States
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These different specialty physician organizations joined together to discuss this draft guidance and outlined essential considerations prepared in comment from for FDA to consider when finalizing interchangeability guidance. "BPC believes data required to demonstrate biosimilarity should be robust and risk-based to build prescriber confidence in this new class of medicine," stated BPC co-convener Dr. Dennis Cryer. He continued, our Collaborative of biologics prescribers believe "such confidence is particularly important for interchangeable biosimilars as these products may be substituted for the reference product without intervention from the prescribing healthcare provider." In determining its final guidance on interchangeability, BPC's comment urges FDA to consider the following to promote transparency and patient safety: We appreciate the FDA's careful consideration in developing the draft guidance and information that should be considered to demonstrate interchangeability. Biosimilars hold tremendous promise to increase access to life-saving and life-enhancing biologic medicines for the millions of patients who rely on them. As FDA evaluates additional biosimilars, and as further official agency guidances are issued, the BPC will continue to weigh in and to provide the critical perspective of biologics prescribers to help ensure patient safety. The Biologics Prescribers Collaborative is an organization of groups representing physicians who regularly prescribe biologics that aims to ensure that sound policies are in place to promote the safest possible use of all biologics, including biosimilars, for all patients. The comment can be found below. RE: Comment on Food and Drug Administration Draft Guidance "Considerations in Demonstrating Interchangeability with a Reference Product" [Docket ID FDA-2017-D-0154] As members of the Biologics Prescribers Collaborative (BPC) and professional organizations with members who are biologics prescribers, we welcome the availability of biosimilars in the United States. Biosimilars will provide greater access to more therapeutic options for the millions of patients who rely on biologic medicines. We thank the U.S. Food and Drug Administration (FDA) for its thoughtful draft guidance "Considerations in Demonstrating Interchangeability with a Reference Product." When final, the guidance will provide important scientific information for manufacturers to consider when seeking licensure for proposed interchangeable products. Once available, it is critical that we, as prescribers, have all of the information we need to make informed decisions with our patients. BPC believes data required to demonstrate biosimilarity should be robust and risk-based to build prescriber confidence in this new class of medicine. Such confidence is particularly important for interchangeable biosimilars as these products may be substituted for the reference product without intervention from the prescribing healthcare provider. In determining its final guidance on interchangeability, BPC poses the following considerations to promote transparency and patient safety: We commend FDA for its careful consideration in developing the draft guidance and information that should be considered to demonstrate interchangeability. CC: Dr. Janet Woodcock, Director, Center for Drug Evaluation and Research Dr. Leah Christl, Associate Director, Therapeutic Biologics, Center for Drug Evaluation and Research Dr. Steven Kozlowski, Director, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research Sandra Benton, Senior Policy Coordinator, Office of Medical Policy, Center for Drug Evaluation and Research Steven Ripley, Center for Biologics Evaluation and Research To view the original version on PR Newswire, visit:

PubMed | Office of Biotechnology Products and Office of Testing and Research
Type: | Journal: BioMed research international | Year: 2016

Formulating appropriate storage conditions for biopharmaceutical proteins is essential for ensuring their stability and thereby their purity, potency, and safety over their shelf-life. Using a model murine IgG3 produced in a bioreactor system, multiple formulation compositions were systematically explored in a DoE design to optimize the stability of a challenging antibody formulation worst case. The stability of the antibody in each buffer formulation was assessed by UV/VIS absorbance at 280nm and 410nm and size exclusion high performance liquid chromatography (SEC) to determine overall solubility, opalescence, and aggregate formation, respectively. Upon preliminary testing, acetate was eliminated as a potential storage buffer due to significant visible precipitate formation. An additional 2(4) full factorial DoE was performed that combined the stabilizing effect of arginine with the buffering capacity of histidine. From this final DoE, an optimized formulation of 200mM arginine, 50mM histidine, and 100mM NaCl at a pH of 6.5 was identified to substantially improve stability under long-term storage conditions and after multiple freeze/thaw cycles. Thus, our data highlights the power of DoE based formulation screening approaches even for challenging monoclonal antibody molecules.

PubMed | Office of Biotechnology Products, U.S. National Institute of Standards and Technology and Office of Testing and Research
Type: Journal Article | Journal: Journal of pharmaceutical sciences | Year: 2015

Consistent high-quality antibody yield is a key goal for cell culture bioprocessing. This endpoint is typically achieved in commercial settings through product and process engineering of bioreactor parameters during development. When the process is complex and not optimized, small changes in composition and control may yield a finished product of less desirable quality. Therefore, changes proposed to currently validated processes usually require justification and are reported to the US FDA for approval. Recently, design-of-experiments-based approaches have been explored to rapidly and efficiently achieve this goal of optimized yield with a better understanding of product and process variables that affect a products critical quality attributes. Here, we present a laboratory-scale model culture where we apply a Plackett-Burman screening design to parallel cultures to study the main effects of 11 process variables. This exercise allowed us to determine the relative importance of these variables and identify the most important factors to be further optimized in order to control both desirable and undesirable glycan profiles. We found engineering changes relating to culture temperature and nonessential amino acid supplementation significantly impacted glycan profiles associated with fucosylation, -galactosylation, and sialylation. All of these are important for monoclonal antibody product quality.

PubMed | Office of Biotechnology Products
Type: Journal Article | Journal: International journal of pharmaceutics | Year: 2015

The objective of the study was to analyze the effect of controlled and uncontrolled freezing step of a lyophilization process on the extent of non-enzymatic glycation and aggregation of an IgG1 formulation at two concentrations (1mg/ml and 20mg/ml). The degree of glycation (%) was determined through boronate affinity chromatography and its effect on the formation of soluble aggregates and higher molecular weight species was studied using dynamic light scattering (DLS) and size exclusion chromatography with multi-angle light scattering (SEC-MALS). The effect of non-enzymatic glycation on the secondary structure of the formulations was also studied using circular dichroism (CD) spectroscopy and Fourier transform infrared (FT-IR) spectroscopy. Results indicated that controlled nucleation yielded higher residual moisture contents and significantly lower specific surface areas for the two monoclonal antibody concentrations compared with uncontrolled nucleation cycle (p<0.05). For the two concentrations, uncontrolled nucleation resulted in significantly higher levels of glycation compared with controlled nucleation samples (p<0.05). Further, it was observed that higher storage temperatures (25C/60% RH) versus 5C resulted in higher glycation. Even though SEC-MALS analyses of the low concentrated formulations did not reveal the formation of higher molecular weight species, DLS analyses at two storage conditions revealed increases in the hydrodynamic radii and polydispersity index of the reconstituted formulations, suggesting the onset of formation of smaller species in the formulations. CD spectroscopy did not reveal any differences in the secondary structure of the mAb for the two concentrations after lyophilization. In conclusion, the freezing step method impacted the extent of glycation in lyophilized samples and the hydrolyzed component of sucrose was critical for increasing glycation. Even though some level of glycation was observed in lyophilized samples, the native structure of the protein was not affected. Further, it was demonstrated that storage of both lyophilized cakes and reconstituted formulations at higher temperatures could increase the extent of glycation in monoclonal antibody formulations.

PubMed | Office of Biotechnology Products and University of Massachusetts Lowell
Type: Journal Article | Journal: International journal of pharmaceutics | Year: 2016

A unique design space (DSp) exploration strategy, defined as a function of four key scenarios, was successfully integrated and validated to enhance the DSp building exercise, by increasing the accuracy of analyses and interpretation of processed data. The four key scenarios, defining the strategy, were based on cumulative analyses of individual models developed for the Critical Quality Attributes (23 Glycan Profiles) considered for the study. The analyses of the CQA estimates and model performances were interpreted as (1) Inside Specification/Significant Model (2) Inside Specification/Non-significant Model (3) Outside Specification/Significant Model (4) Outside Specification/Non-significant Model. Each scenario was defined and illustrated through individual models of CQA aligning the description. The R(2), Q(2), Model Validity and Model Reproducibility estimates of G2, G2FaGbGN, G0 and G2FaG2, respectively, signified the four scenarios stated above. Through further optimizations, including the estimation of Edge of Failure and Set Point Analysis, wider and accurate DSps were created for each scenario, establishing critical functional relationship between Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs). A DSp provides the optimal region for systematic evaluation, mechanistic understanding and refining of a QbD approach. DSp exploration strategy will aid the critical process of consistently and reproducibly achieving predefined quality of a product throughout its lifecycle.

PubMed | Office of Biotechnology Products and University of Massachusetts Lowell
Type: | Journal: Data in brief | Year: 2016

This is an 11 factor-2 level-12 run Plackett-Burman experimental design dataset. The dataset includes 11 engineering bioreactor parameters as input variables. These 11 factors were varied at 2 levels and 23 response variables that are glycan profile attributes, were measured A Design Space Exploration for Control of Critical Quality Attributes of mAb (H. Bhatia, E.K. Read, C.D. Agarabi, K.A. Brorson, S.C. Lute, S. Yoon S, 2016) [2].

Miesegaes G.R.,Office of Biotechnology Products | Lute S.C.,Office of Biotechnology Products | Read E.K.,Office of Biotechnology Products | Brorson K.A.,Office of Biotechnology Products
Biotechnology Progress | Year: 2014

Anion exchange (AEX) is a common downstream purification operation for biotechnology products manufactured in cell culture such as therapeutic monoclonal antibodies (mAbs) and Fc-fusion proteins. We present a head-to-head comparison of the viral clearance efficiency of AEX adsorbers and column chromatography using the same process fluids and comparable run conditions. We also present overall trends from the CDER viral clearance database. In our comparison of multiple brands of resins and adsorbers, clearance of three model viruses (PPV, X-MuLV, and PR772) was largely comparable, with some exceptions which may reflect run conditions that had not been optimized on a resin/membrane specific basis. © 2013 American Institute of Chemical Engineers.

Brorson K.,Office of Biotechnology Products | Jia A.Y.,Office of Biotechnology Products
Current Opinion in Biotechnology | Year: 2014

Monoclonal antibodies (mAbs) are biological macromolecules with complex post-translational modifications that can be observed when assessing product variants. The N- and C-terminal heterogeneities of commercially produced antibodies have been observed and extensively studied over the past 30 years. This review summarizes the current literature on detectable antibody termini variants from cultured cells. The presence of these heterogeneities can be detected by many different analytical methods, mostly based on sequence, charge and size differences. Examples are presented that highlight terminal heterogeneities, methods of detection, and their impact on the quality of mAbs. Regulatory considerations are also discussed regarding the potential impact on product quality, safety, and efficacy. © 2014 Elsevier Ltd.

Miesegaes G.,Office of Biotechnology Products | Lute S.,Office of Biotechnology Products | Brorson K.,Office of Biotechnology Products
Biotechnology and Bioengineering | Year: 2010

Demonstration of viral clearance is a critical step in assuring the safety of biotechnology products. We generated a viral clearance database that contains product information, unit operation process parameters, and viral clearance data from monoclonal antibody and antibodyrelated regulatory submissions to FDA. Here we present a broad overview of the database and resulting analyses. We report that the diversity of model viruses tested expands as products transition to late-phase. We also present averages and ranges of viral clearance results by Protein A and ion exchange chromatography steps, low pH chemical inactivation, and virus filtration, focusing on retro- and parvoviruses. For most unit operations, an average log reduction value (LRV, a measure of clearance power) for retrovirus of >4 log10 were measured. Cases where clearance data fell outside of the anticipated range (i.e., outliers) were rationally explained. Lastly, a historical analysis did not find evidence of any improvement trend in viral clearance over time. The data collectively suggest that many unit operations in general can reliably clear viruses.

PubMed | Pfizer and Office of Biotechnology Products
Type: Journal Article | Journal: Biotechnology progress | Year: 2015

Anion exchange chromatography (AEX) operated under weak partitioning mode has been proven to be a powerful polishing step as well as a robust viral clearance step in Pfizers monoclonal antibody (mAb) platform purification process. A multivariate design of experiment (DoE) study was conducted to understand the impact of operating parameters and feedstream impurity levels on viral clearance by weak partitioning mode AEX. Bacteriophage was used initially as a surrogate for neutral and acidic isoelectric point mammalian viruses (e.g., retrovirus and parvovirus). Five different mAbs were used in the evaluation of process parameters such as load challenge (both product and impurities), load pH, load conductivity, and contact time (bed height and flow-rate). The operating ranges obtained from phage clearance studies and Pfizers historical data were used to define an appropriate operating range for a subsequent clearance study with model retrovirus and parvovirus. Both phage and virus clearance evaluations included feedstreams containing different levels of impurities such as high molecular mass species (HMMS), host cell proteins (HCPs), and host cell DNA. For all the conditions tested, over 5 log10 of clearance for both retrovirus and parvovirus was achieved. The results demonstrated that weak partitioning mode AEX chromatography is a robust step for viral clearance and has the potential to be included as part of the modular viral clearance approach.

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