Gathering information about batch failure rates in the biopharmaceutical industry is about as easy as getting politicians to talk about their most embarrassing gaffes and indiscretions. Although it comes as no surprise that batches do fail, some readers may be surprised at how relatively well many organizations appear to be performing. Based on the results of our recently released annual report and survey (1), facilities are experiencing batch failures at an average rate of about one every nine months (40.6…
Analytical
Managing the Analytical Lifecycle for Biotechnology Products
Biotechnology pipelines have demonstrated significant growth over the past decade, with many therapeutic candidates evolving in a single class of protein molecules: the monoclonal antibodies (MAbs). To develop such therapeutic candidates, a scalable drug development process must leverage in-house and industry-wide knowledge so biotechnology companies can address the economic and medical needs of 21st-century medicine. Biotherapeutics development is complex, resource intensive, and time consuming, taking some 10 years of effort to go from target validation to commercialization. This reality, coupled…
Higher-Order Structure Comparison of Proteins Derived from Different Clones or Processes
Biological product manufacture is a complex process that constantly evolves throughout the lifecycle of each product even after its approval. A number of constraints (such as increased yield, scale-up, or a need for greater purity) can necessitate the redesign or optimization of a given process. Heterogeneity of a biopharmaceutical product at the beginning of its shelf life comes from inherent variations in its production process that lead to various forms of posttranslational modifications and degradation products. Clearly, the foremost aim…
Reducing Microbial Contamination Risk in Biotherapeutic Manufacturing
The risk of contamination (especially microbiological) is always an area for special attention in biopharmaceutical processes. No matter the process stage, whether upstream of a bioreactor or in the final filling of a sterile product, effective contamination control continues to be a critical requirement, so any opportunities for improvement may justify further investigation. Even with established validated processes, demands for higher purity and increased sterility assurance may require manufacturers to reassess their procedures and technologies. New processes present an even…
Vendor Voice: A New Paradigm for Bacterial Strain Engineering
From rapidly obtaining sufficient amounts of active protein in early stage development to cost effectively producing kilogram and even metric ton quantities for commercial supply, protein expression is critical at every stage of biopharmaceutical drug development. Having a high-performance protein expression platform across all stages is invaluable for the speed and success of protein and vaccine development. Historically, biopharmaceutical researchers and process development scientists have used Escherichia coli in their laboratories to generate small quantities of protein. If target expression…
Carbohydrates and Their Analysis, Part Three
A large proportion of the therapeutic biotechnology products already in the market or under development are glycoproteins. Therapeutic glycoproteins are produced as recombinant products in cell culture systems, which raises the importance of understanding the biosynthetic events described in the previous installments of this three-part article. Lack of control in a bioprocess could easily change glycosylation patterns by distorting the activities taking place in the Golgi apparatus. Disruption of the delicate balance among substrate availability, optimum pH for specific activities,…
Determining the Effect of Raw Materials on Manufacturing-Scale Cell-Culture Performance
Large-scale cell culture production processes routinely involve multicomponent cell culture media formulations including both chemically defined raw materials and complex raw materials such as hydrolysates (1). Even minor variations in the compositions of either can lead to variability in protein productivity or product quality. That often persists despite the use of a raw material lot-blending strategy at large scales to “average out” raw material trends. And a raw material lot-blending strategy can makes it more difficult to identify which single…
Probing Thermal Stability of MAbs By Intrinsic Tryptophan Fluorescence
In the arsenal of biophysical techniques available for rapidly monitoring the stability of protein formulations, spectroscopic techniques have some convincing advantages over others (1, 2). The main advantages to using methods such as circular dichroism (CD), infrared spectroscopy (IR) and fluorescence spectroscopy are their extremely high sensitivity (favorable signal-to-noise ratios), freedom from sample interactions with column resins or extrinsic probes (noninvasive techniques), and coverage of an extremely broad protein concentration range — from pM to mM (3, 4). To reduce…
A Bioreactor System Based on a Novel Oxygen Transfer Method
Bioreactor technologies for mammalian cell culture may seem quite sophisticated (1). In fact, efficient mammalian cell culture is simple and requires just two major elements: mixing and oxygen (O2) transfer. Traditional methods for mixing use an impellor, and the classical O2 transfer method features a sparging stone that expels air bubbles to increase the O2 transfer surface area in contact with a culture medium. Mammalian cells are sensitive to shear forces and also to the toxicity of pure or enriched…
A Review of Therapeutic Protein Expression By Mammalian Cells
During the past five years, many biopharmaceuticals have found their way into clinical trials and commercial production (1–4). So far, about 60 million patients worldwide have benefited from these new drugs. The market for biopharmaceuticals was estimated at US$33 billion in 2004 and projected to reach US$70 billion by the end of the decade. During the period 2003–2006, regulators in Europe and the United States approved 32 biopharmaceuticals for human use, including hormones and growth factors, therapeutic enzymes, vaccines, and…