BioProcess Development Week 2015

by Maribel Rios

From 30 March to 2 April 2015, more than 750 professionals gathered at the Hyatt Regency Resort in Huntington Beach, CA, to attend the annual Biopharmaceutical Development and Production meeting. Organized by IBC Life Sciences, BDP Week provided attendees with keynote addresses and sessions on the state of the bioprocessing industry and hot technical topics as well as preconference workshops, exhibit hall networking opportunities, poster presentations, and keynote addresses from five bioindustry leaders.

Karol Lacki, PhD (GE Healthcare Biosciences) kicked off the conference by introducing three keynote speakers: Dana C. Anderson (Genentech, a Member of the Roche Group), Uwe Gottschalk (Lonza Pharma/ Biotech), and Anthony Davies (Dark Horse Consulting). The first discussed how breakthrough therapies could be a key factor in making bioprocesses more efficient. Chemistry, manufacturing, and controls (CMC) activities can be a challenge, and companies need to accelerate clinical timelines. Anderson presented scenarios in which breakthrough therapies could “compress” CMC development, including by deferring some activities to postlaunch. He presented other ways to streamline development and improve efficiency, including automation, applying robust and standard platforms, and identifying potential CMC issues early in development.

Gottschalk reviewed present and future issues in biologics manufacturing, emphasizing the growth of the bioindustry. “In 2008, five out of 10 drug products were small molecules,” he said. “Now seven out of 10 are biologics.” He discussed the growth of biosimilars work, facility trends (small, modular, standardized, and decentralized — especially in fermentation), driving technology trends (single-use systems, lean manufacturing, and continuous processing), future downstream changes (faster, leaner, more continuous, and single-use ready), and next-generation expression systems (new scaffolds for antibodies, non-IgG platforms, and commoditization of monoclonal antibody systems). “The best is yet to come,” he said, emphasizing that 74 antibody–drug conjugates (ADCs) are currently in development. Meanwhile, cell therapies need to “move away from two-dimensional models and toward three-dimensional platforms because more material will be needed.”

Davies finished the keynotes by discussing the future of cell and gene therapies. He emphasized the impact that such therapies will have on “significant” diseases, but production timelines and distribution are critical. Davies said that the industry is currently in a “golden age” of biotechnology financing. For example, chimeric antigen receptors T cells (CAR-T) are currently in a “bubble,” with more capital raised in 2014 than for any other cell therapy field. “We are seeing a step change in clinical results,” he added, “which couldn’t have been said even a year ago.” A major challenge for cell and gene therapies is controlling costs of goods sold (CoGs). Cell therapies care rarely compete with small molecules on those terms. Davies concluded his presentation by assessing capacity issues for cell and gene therapy: “Capacity requests are more than there is [available], but not unreasonable.”

Keynote topics were further detailed by speaker presentations during major sessions. Session topics included ADCs (characterization, scale-up, development), upstream processing (cell-line and media development, single-use fermentation, and control processes), single-use applications (implementation and scale-up), analytical methods (quality by design, biosimilars, comparability, and technology transfer), quality and control (process validation, manufacturing methods, and viral safety), downstream processing (harvesting approaches, modeling, and automation), manufacturing efficiencies (control strategies, optimization, and supply chain management), and flexible facilities (design, continuous processing, and single-use systems). Major roundtable discussions were held to discuss extractables and leachables as well as single-use and stainless steel processing.

Big changes are planned for 2016, including a new name and format. The conference will become “BioProcess International West” and will be held 14–17 March 2016 at the Oakland Marriott City Center in Oakland, CA. BPI West will feature preconference symposiums and learning and networking opportunities. And the three-day main conference will include sessions presenting new data and case studies. For more information, visit www.IBCLifeSciences.com/BPIWest.

Niche-Disease: Beta Thalassemia

by Cheryl Scott

Thalassemia syndromes are hereditary blood disorders characterized by a genetic deficiency in the synthesis of hemoglobin chains. Both alpha and beta thalassemias reduce hemoglobin production. Patients thus lack efficient oxygen transport throughout their bodies. Their shortage of red blood cells causes pale skin, weakness, and fatigue, among more serious complications. Patients also can develop abnormal blood clots.

Particularly prevalent in areas where malaria has been endemic (as is sickle-cell anemia), thalassemias come from small genetic changes that made some people more resilient to the infection. Those people are now carriers of the genetic disorder, which presents when certain combinations of genes are inherited. For example, the homozygous beta thalassemia major causes severe transfusion-dependent anemia (Cooley’s anemia). The related heterozygous form, beta thalassemia minor, causes mild to moderate microcytic anemia.

Signs and symptoms of beta thalassemia major appear within the first two years of life, when children develop life-threatening anemia, failure to thrive, and even jaundice. Patients may have enlarged organs and misshapen bones. Some adolescents experience delayed puberty. Signs of beta thalassemia minor appear in early childhood or later in life and may include slow growth and bone abnormalities.

Mutations in the HBB gene cause beta thalassemia by altering the structure of beta-globin, one of two hemoglobin subunits. Hemoglobin is a tetramer comprising two molecules each of alpha- and beta-globin. Alpha thalassemia thus involves altered alpha-globin structures. A lack of either subunit leads to a reduced amount of functional hemoglobin. Without sufficient hemoglobin, red blood cells do not develop normally, causing a shortage of mature red blood cells. And that leads to anemia and other associated health problems.

Beta thalassemia is inherited in an autosomal recessive pattern. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene but typically show no signs of the condition. However, some people with only one HBB gene mutation develop thalassemia minor. And in a small number of families, the mutation is inherited in an autosomal dominant manner. So only one copy of the altered gene is enough to cause the disorder.

Epidemiology: Thousands of babies are born each year with beta thalassemia. Cooley’s anemia most commonly occurs in people of Mediterranean heritage, especially Italians and Greeks. It is well represented across northern Africa to southern Europe as well as in Thailand, Indonesia, and southern China. The disorder affects males and females in equal numbers.

According to the Thalassemia International Federation, 7% of people worldwide are carriers for hemoglobin disorders, and those carrying the incorrect pathological Hb gene have no health problems. Globally, 300,000–500,000 children are born every year with a severe hemoglobin disorder, about 80% of them in middle- and low-economic countries. About a third of them have alpha or beta thalassaemia disorders. And in those countries, 50,000– 100,000 children die every year of β-thalassaemia major.

Treatment Options: Chronic blood transfusions can be required by severely affected individuals. Folic acid is often given. Without treatment, thalassemia major can be life threatening. Iron overload can be a consequence of repeated blood transfusions, so patients are given as few transfusions as possible. Daily drug treatment can help prevent severe iron overload, so the small-molecule iron chelator desferasirox (Exjade from Novartis) is used in Europe and North America for treating thalassemia major. However, the FDA reported in May 2007 that renal failure and cytopenias have been reported in some patients taking it. Enlarged spleen may necessitate splenectomy for some patients and reduce the number of blood transfusions they would otherwise require.

Late in 2014, Bluebird bio reported positive ongoing clinical results with its lentiviral-based gene therapy known as LentiGlobin BB305. The product is a regenerative cell therapy: Bluebird samples a patient’s own hematopoietic stem cells, then equips those with a functional beta-globin gene and reinfuses them. One- time infusion is inducing beta-thalassemia major patients to make correct beta-globin on their own. So far well tolerated, LentiGlobin BB305 seemed to induce no serious adverse events. Studies are being expanded this year.

Organizations: Several regional and global organizations devote themselves to beta thalassemia, including the Cooley’s Anemia Foundation, Inc. (www. cooleysanemia.org), the Thalassemia International Federation (www.thalassemia.org.cy) and the Thalassemia Support Foundation (www.helpthals.org).

CORRECTIONS: February and April 2015 The authors of “Affinity Capture of F(ab’)2 Fragments: Using Twin-Column Countercurrent Chromatography” in BPI’s February 2015 issue mistakenly described GE Healthcare’s Capto L chromatography medium as involving camelid antibodies — Ulmer N, et al. BioProcess Int. 13(2) 2015; 22. However, the resin actually binds to the kappa-light chain of Fab fragments on certain IgGs using immobilized recombinant protein L. “It can capture several fragment types,” says Thomas Müller-Späth, Chromacon AG’s chief operating officer, “including the F(ab’)2 fragment used in our study.”

We apologize for any confusion this may have caused. See page 58 of this issue for GE’s elaboration on this resin’s capabilities: “An Industrial Platform Solution for Antibody Fragment Purification,” by Jonathan Royce.

Also, the BioMar facility (below) featured on the cover of BPI’s April 2015 issue was mistakenly identified as located in Lyon, France. It is actually in León, Spain.