Office of Biotechnology Products

Dover, MD, United States

Office of Biotechnology Products

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These different specialty physician organizations joined together to discuss this draft guidance and outlined essential considerations prepared in comment from for FDA to consider when finalizing interchangeability guidance.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following to promote transparency and patient safety: We appreciate the FDA's careful consideration in developing the draft guidance and information that should be considered to demonstrate interchangeability.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 RE: Comment on Food and Drug Administration Draft Guidance "Considerations in Demonstrating Interchangeability with a Reference Product" [Docket ID FDA-2017-D-0154] As members of the Biologics Prescribers Collaborative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 We thank the U.S. Food and Drug Administration (FDA) for its thoughtful draft guidance "Considerations in Demonstrating Interchangeability with a Reference Product."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:http://www.prnewswire.com/news-releases/physician-groups-applaud-fda-for-thoughtful-draft-guidance-on-interchangeability-urge-for-robust-data-to-demonstrate-biosimilarity-300460974.html


Blumel J.,Paul Ehrlich Institute | Brorson K.,Office of Biotechnology Products
PDA Journal of Pharmaceutical Science and Technology | Year: 2016

Guideline ICH Q5A (1) recommends to consider virus clearance capacity during the reuse of a column. It is currently wide practice to perform product-specific virus clearance studies using new chromatographic resin as well as recycled resin for marketing/licensing applications. There is a perception that such studies alone can address this issue and are expected by regulators. However, the guideline has never been worded in such a strict sense and in ICH Q5A it is sated: "Over time and after repeated use, the ability of chromatography columns and other devices used in the purification scheme to clear virus may vary. Some estimate of the stability of the viral clearance after several uses may provide support for repeated use of such columns." It is not required to perform studies with reused resin in each case. In this session an impressive amount of data, accumulated from many viral clearance studies with used and reused resin, was presented. The majority of data (with very few exceptions) showed consistent virus reduction over the resin lifetime. In cases where different LRVs are obtained, nuanced interpretation with caution is warranted if the studies are not directly performed side by side, as variation in the complex experimental setup might introduce some variation. However, the significance of such variation, if observed, has to be assessed in the context of the overall viral safety goals and specific viral clearance strategies. The aim of the cycled resins studies described above was to assure that there is no or only minimal detrimental impact of cycling and resin reuse on viral clearance, not to measure precise "before and after" LRVs. Subsequent to the original publication of ICH Q5A in 1998, specific virus clearance steps such as detergent treatment or virus filtration have been increasingly introduced for many products. Considering the overall clearance capacity in the context of a multistep manufacturing scheme, a certain variability of chromatographic purification steps over the lifespan of the resin could be considered acceptable, while it might be more critical if a chromatography was a key step in a more abbreviated process. Performing studies with used and reused resin with multiple (three to four) model viruses for each marketing/ licensing application can require a significant workload, process materials, and resources. Thus, the possibility to reduce the workload and material used for such studies was intensively discussed at the Cambridge meeting. Although, recycled resin for these studies is usually produced at small scale in a model of routine manufacturing, a significant amount of material and time is needed to cycle the small-scale model and volume of process fluid as feedstock (as well as buffer) to produce a sufficient amount of resin with 50 to 300 cycles of reuse for qualification studies. For example, if a single cycle in a typical large-scale process takes 5 h from equilibration to cleaning/regeneration, then 300 cycles run at small scale just to prepare the resin would take 1500 h (about two months) if the lab scale chromatography system was programmed to run nonstop. If 1.5 L of harvest feedstock per cycle was required to prepare resin for a small-scale protein A model unit operation, then 450 L of harvest (a medium-sized bioreactor) would be needed to get to that stage (assuming no wastage). Aside from buffer and feedstock consumption, bioburden control in a lab chromatography system running for two months nonstop is a challenge. The time taken for completion of studies will be longer if a large panel of viruses is used. These scenarios can be mitigated somewhat if the same aliquot of recycled resin is used for a single virus clearance study, where three to four viruses are added as a "multi-spike". This can be an appropriate way of reducing the amount of resin needed for such studies, provided that the virus detection systems do not interfere with each other. Another alternative, acceptable strategy would be to perform such studies with the same aliquot of resins in sequence, for example reduction of X-MuLV is studied with resin cycled 50 times, reduction of SV40 is studied with resin cycled 51 times, and reduction with parvovirus using resin cycled 52 times. At the Cambridge meeting, it was further suggested to generally limit the number of model viruses in cycling studies to two (i.e., X-MuLV and a parvovirus). It is not possible to conclude which of the viruses represent the worst case and this will be dependent upon the specific process. For example, reduction of BVDV by nonbinding AEX chromatography was less than that of animal parvoviruses (see contribution from R. Chen above). Nevertheless, these two model viruses have been generally accepted as sufficient for clinical-trial applications using well-characterised cell substrates such as CHO cells. A further approach to save material needed for producing recycled resin was presented by R. Chen. He compared the viral clearance of product-aged resin and CIP-aged resin where an AEX resin was exposed to the sanitization agents and buffers only. No significant difference in virus reduction was observed with X-MuLV while the other model viruses were investigated with CIP-aged resin only. This strategy was successfully applied for licensing in the US, EU, Japan, and other countries. CIP and buffer costs are lower than process fluids such as bioreactor harvests, thus this approach affords considerable process economic advantages. For protein A chromatography, the experience presented in this session indicated a trend toward slightly higher LRVs with reused protein A resin. Such a trend has also been observed before (4), and has been suggested to be associated with a phenomenon of "conditioning". Interaction of X-MuLV particles and mAbs and/or the resin has been suggested to explain the co-elution of some virus with antibody during Protein A chromatography (13). Therefore, decreasing antibody- binding capacity of cycled resin or blocking of nonspecific binding sites for virus might explain the trend for slightly increasing LRVs. The Center for Drug Evaluation and Research (CDER) considers virus reduction by Protein A chromatography robust with respect to resin age and has developed internal guides for reviewers to this effect. At the European level, studies with cycled resin are currently expected and usually provided at marketing authorization, although there have been few specific cases where studies with used resin were performed postapproval after completion of full-scale production runs in order to confirm the expected virus clearance. Most studies on AEX chromatography presented at this meeting showed comparable virus reduction with new and reused resin. In the case of nonbinding mode, where virus and other impurities such as negatively charged proteins or host cell DNA are bound to the resin while the product itself flows through, the viral clearance was robust provided that the integrity and binding capacity of the resin was not affected. It remains challenging to identify a single suitable surrogate (e.g., break-through of impurities, pressure rise, or loss of product yield) that is applicable for all the various brands of resin and applications that reliably can predict sufficient viral clearance. AEX resins are often sanitized by NaOH. It would be useful as a followup to the meeting to conduct experiments where virus is spiked to various concentrations of NaOH to find the virus inactivation failure point for stable viruses such as parvoviruses. Studies using high concentrations were presented at this session and are in line with earlier observations. NaOH reliably inactivates all viruses tested so far, but the minimum concentration for universal virus inactivation has not yet been determined. Only at low concentrations (≤0.3M) do the inactivation kinetics become biphasic and some residual infectivity of non-enveloped viruses such as animal parvoviruses or reovirus could be detected after treatment of virus with NaOH. Such a resistant fraction could represent aggregated virus particles, and this could be an issue if a column is cleaned using a low-concentration sanitization buffer. Thus, while it seems difficult to speculate about the aggregation status of a virus contaminant in a given specific intermediate it would be desirable to elaborate a minimum NaOH concentration that reliably inactivates resistant model viruses such as parvoviruses. Given reliable inactivation this could justify not performing resin carryover studies and is a reasonable follow-up action item from the Cambridge meeting. © PDA, Inc. 2016.


Read E.K.,Office of Biotechnology Products | Lute S.,Office of Biotechnology Products | Brorson K.A.,Office of Biotechnology Products
International Journal of Pharmaceutics | Year: 2013

An efficient and potentially scalable technology was evaluated to control the ice nucleation step of the freezing process for a model monoclonal antibody formulation and the effect on process performance and quality attributes of the final lyophilized product was compared with the conventional shelf ramping method of freezing. Controlled ice nucleation resulted in uniform nucleation at temperatures between -2.3 and -3.2 C while uncontrolled nucleation resulted in random nucleation at temperatures between -10 and -16.4 C. The sublimation rate (dm/dt) during primary drying was higher in the controlled nucleation cycle (0.13 g/h/vial) than in the uncontrolled nucleation cycle (0.11 g/h/vial). This was due to the formation of larger ice crystals, leading to lower product resistance (Rp) and 19% reduction in the primary drying for the controlled nucleation cycle. Controlled ice nucleation resulted in lyophilized cakes with more acceptable appearance, no visible collapse or shrinkage and decreased reconstitution times compared with uncontrolled nucleation. There were no observed differences in the particle size, concentration (A 280 nm) and presence of aggregates (A410 nm) between the two nucleation cycles when the lyophilized cakes were reconstituted. These were confirmed by SEC and protein A-HPLC analyses which showed similar peak shapes and retention times between the two cycles. However, uncontrolled nucleation resulted in cakes with larger specific surface area (0.90 m2/g) than controlled nucleation (0.46 m2/g). SEM images of the lyophilized cakes from uncontrolled nucleation revealed a sponge-like morphology with smaller pores while cakes from controlled nucleation cycle revealed plate-like structures with more open and larger pores. While controlled nucleation resulted in a final product with a higher residual moisture content (2.1 ± 0.08%) than uncontrolled nucleation (1.62 ± 0.11%), this was resolved by increasing the secondary drying temperature. © 2013 Elsevier B.V. All rights reserved.


Bhatia H.,University of Massachusetts Lowell | Read E.,Office of Biotechnology Products | Agarabi C.,Office of Biotechnology Products | Brorson K.,Office of Biotechnology Products | And 2 more authors.
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 R2, Q2, 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. © 2016


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 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.

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