Upstream Development

Opportunities and Challenges in Biosimilar Development

A biosimilar biotherapeutic product is similar (but not identical) in terms of quality, safety, and efficacy to an already licensed reference product. Unlike generic small molecules, it is difficult to standardize such inherently complex products based on complicated manufacturing processes. Table 1 describes the main differences between biosimilar and generic drug molecules. The global biosimilar market is growing rapidly as patents on blockbuster biologic drugs expire (Table 2) and other healthcare sectors focus on reduction of costs. Biologics are among…

Implementing Quality By Design in Analytical Development: A Case Study on the Development of an Anion-Exchange HPLC Method

The concept of quality by design (QbD) initially was outlined in ICH Q8 guidance for drug-product development and later in Q11 for drug-substance development (1, 2). Since then, the QbD concept was further expanded to the development of analytical methods. FDA issued a 2015 guidance on analytical procedures and method validation for drugs and biologics (3). Although the agency did not explicitly state the requirement for implementation of QbD in analytical method development, the concept is embedded in its section…

Comparing Culture Methods in Monoclonal Antibody Production: Batch, Fed-Batch, and Perfusion

Recombinant protein manufacturing with Chinese hamster ovary (CHO) cells represents over 70% of the entire biopharmaceutical industry (1). In fact, human monoclonal antibodies (hMAbs) produced by CHO cells have played a major role in both the diagnostic and therapeutic markets for decades. One of the first human–mouse chimeric MAbs to obtain FDA approval was Roche’s rituximab treatment for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. Since that approval in 1997, scores of chimeric, humanized, and human MAbs have gained…

Conditional/Inducible Gene-Expression Mouse Models Using Advanced Gene Editing

Transgenic mouse models have been an essential part of biomedical research for many decades. They have provided valuable insights in developmental biology, gene regulation, and our understanding of the genetic basis of human disease. And they play a critical role in drug discovery and development. Traditional methods to generate these mouse models entailed a milieu of disadvantages: e.g., low efficiency, high incidence of undesirable recombination outcomes, randomly and multiply inserted genes of interest, ectopic expression, gene silencing, and insertional mutations…

Accelerated Development Through Strategic Analytical Partnerships

The analytical field for biologics has evolved greatly over the past 30 years, and the underlying growth has shifted from biopharmaceutical companies to contract research organizations (CROs). The global biopharmaceutical market is growing annually at >15%, making it the largest and consistently fastest growing segment of the healthcare industry with annual sales in excess of US$200 billion. Contract manufacturing organizations (CMOs) are expanding capacity by building new cost-efficient facilities, reflecting market demand. Many product sponsors are outsourcing, some even increasing…

Outsourcing Biosimilar Development

As the debate continues over the high cost of pharmaceutical treatment options, the development of biosimilars continues to play a dominant role in that discussion and will be an important part of the solution. Biosimilar companies are working at a feverish pace to develop the next generation of follow-on products. Outsourcing to a growing group of contract development and manufacturing organizations (CDMOs) is a key strategy for savvy developers to accelerate their products’ launch. Finding the right CDMO isn’t an…

Introduction: Process Issues in Cell, Gene, and Tissue Therapies

It’s hard to believe that just six years ago, BioProcess International published its first cell therapy supplement, which included just one article on “cell therapy bioprocessing” (1). At the time, most such processing was conducted in special clinical laboratories and academic institutions. As BPI continued to cover this relatively new segment of the biopharmaceutical industry, we heard more about “the product is the process” and “scale out instead of scaling up.” After many trials, errors, and milestones, regenerative medicine has…

Platform Solutions for Cell Therapy Manufacturing

Advances in cell therapy have resulted in significant progress toward treating some widespread and difficult diseases, many of which represent unmet medical needs. For example, phase 3 clinical trials are already under way for therapies based on mesenchymal stem cells (MSCs), including therapies for graft-versus-host disease, acute myocardial ischemia, and chronic obstructive pulmonary disease (COPD) (1–3). Successful cell therapy treatments for such afflictions will be not only significant medical breakthroughs, but also in very high demand. However, their commercialization is…

Buffers in Biologics Manufacturing

Biotechnology has enabled commercialization of protein-based drugs including insulin, growth factors, blood factors, and antibodies. Production and purification of such biologic products require different buffers for pH control and stabilization of reactions in different steps during biomanufacture. These processes include cell culture production (the “upstream” phase), purification (the “downstream” phase), and a final phase in which excipients are introduced to the drug substance to create a drug product (“formulation and storage”). In upstream processes, buffers are primarily used for their…

Simplification of Fed-Batch Processes with a Single-Feed Strategy

Chinese hamster ovary (CHO) cells commonly are used to produce recombinant proteins such as monoclonal antibodies (MAbs) for research, diagnostic, and therapeutic purposes. Culture processes typically rely on a fed-batch approach in which a basal medium enables initial cell growth. Concentrated feeds are used to prevent nutrient depletion, thereby extending culture duration and improving cell growth, viability, and protein titer. A neutral pH feed is desirable because culture pH should remain stable after feedings. The extremely low solubility of l-tyrosine…