March 2012

Our “manufacturing” theme could be considered a sort of catch-all, encompassing much of what BioProcess International covers. You could argue that “the whole development process” is all about manufacturing biotherapeutics. But we instead consider this “pillar” of bioprocessing to include everything that isn’t strictly “upstream” (production) or “downstream” (processing) of biomolecules. Facility and supply-chain isssues come into play here, as do formulation and fill–finish (and of course, outsourcing). We discuss quality systems and their associated analytics in this context, as well, and product testing too. And increasingly over the past decade, the topic of cost control has entered and then begun to dominate our vernacular. Facilities: In BPI’s 10 years, the image of a typical bioprocess facility has been transformed. What once was dominated by gleaming stainless steel and hard piping is now a vision of smooth plastics and self-contained processes. We’ve gone from “the disposables option” (our firs...

The weakest link in the chain is also the strongest. It can break the chain. — Stanislaw Jerzy Lec, Polish writer, poet and satirist (1906–1966) Biologicals ushered in a new era for treating debilitating and life-threatening illnesses. According to a Pharmaceutical Research and Manufacturers of America (PhRMA) 2011 report, more than 900 biotech medicines and vaccines are in development that are targeting more than 100 diseases ( 1 ). Market researchers expect annual sales of biologics (now at about US$100 billion) to grow two to three times faster than conventional small molecule drugs during the next five years ( 2 ). Advances in cell line development, bioreactor design, and purification techniques have led to a sevenfold increase in global protein output from mammalian cell cultures alone from 2000 to 2005 (500 kg versus 3,600 kg) ( 3 ). From a virological safety standpoint, biopharmaceuticals have had an excellent safety record during the past quarter of a century ( 4 ). This excellent safety profile h...

Almost every aspect of the biopharmaceutical and medical device industries raises regulatory compliance concerns. Heightened scrutiny is required across product lifecycles — from clinical trials to manufacturing, pricing, formulary placement, and promotional practices. Those areas (as well as patient privacy and adverse event reporting) require close attention to and compliance with healthcare laws, regulations, and guidelines. Part 1 of this two-part article describes statutes, regulations, and guidances applicable to the biopharmaceutical and medical device industries. Anti-Kickback and False Claim Laws Under the US federal anti-kickback law ( 1 ), it is illegal for any individual to offer to pay to induce a person to Illegal payments include — directly or indirectly — kickbacks, bribes, rebates, cash, or “in kind remuneration. A person need not have actual knowledge of the anti-kickback statute or a specific intent to violate that statute. Violations of the anti-kickback statute are deemed “federal hea...

Not long ago, I was playing the popular board game Snakes and Ladders (also known as Chutes and Ladders ) with my son. Based on an ancient Indian board game, it has over the years become a worldwide classic. The game is rather simple to play: Two or more players place their tokens on a game board that has numbered, gridded squares. They take turns rolling a single die to move their tokens by the number indicated by the die, following a fixed route marked on the game board. A number of ladders and snakes (or chutes) are pictured on the board, each connecting two specific board squares. The object of the game is to navigate your game piece from start to finish, helped or hindered by ladders and snakes, respectively. If, on completion of a move, you land on the lower-numbered square with a ladder, you can move their token up to the higher-numbered square. If you land on the higher-numbered square with a snake (or chute), you must move your token down to the lower-numbered square. The winner is the player ...

The US FDA’s quality by design (QbD) initiative and associated ICH Q8, Q9, and Q10 guidance documents are increasingly embraced by the biopharmaceutical manufacturing industry for ensuring consistent product quality and lower costs of development and manufacturing. One critical problem the industry faces involves understanding how to implement QbD and determine the benefit of such projects — which require the work of many groups across quality, manufacturing sciences, and engineering departments. Here we present the results from a survey of biopharmaceutical manufacturing professionals undertaken to determine current QbD understanding in the industry. We outline key gaps and show how QbD has been implemented in practice. We focus on simple, practical implementation of QbD principles and show the perceived value of such investment by industry. QbD and ICH: A Primer Extensive definitions of QbD and the associated ICH Q8–Q10 framework can be found in the references ( 1 , 2 ). PRODUCT FOCUS: ALLBIOLOGICS PRO...

Due to the molecular complexity of monoclonal antibodies (MAbs) and potential impurities in cell culture media before purification (host-cell proteins, DNA, media components) ( 1 ), subsequent downstream operations must consistently and reproducibly purify products to ensure safety and efficacy. The latest member of GE Healthcare’s MabSelect family is called MabSelect SuRe LX ( 2 ). As Table 1 shows, it has been developed using the same highly cross-linked agarose base matrix and protein A ligand as for other MAb affinity resins (Table 1). Here, we provide an overview of a novel system for MAb capture from a user’s perspective. Table 1: Comparing the specifications for MabSelect SuRe and MabSelect SuRe LX protein A adsorbents; a higher dynamic binding capacity is observed (using a longer residence time) with MabSelect SuRe LX (MabSelect media, technical information, GE Healthcare). Characteristics Interaction involves fragment B of protein A, which establishes a highly selective interaction with IgG and i...

Most biopharmaceutical production platforms are based on fed-batch cell culture protocols, which can support high volumetric productivity while maintaining low operational complexity ( 1 ). The industry is interested in developing or refining high-titer cell culture processes to meet increasing market demands and reduce manufacturing costs ( 2 ). Although advancements in cell engineering have enabled development of high-performing recombinant cell lines ( 3 , 4 , 5 , 6 ), improvements in cell culture media and process parameter settings are required to realize the maximum production potentials of those cells ( 7 ,– 8 ). In a fed-batch process, a basal medium supports initial growth and production, and a feed medium prevents depletion of nutrients and sustains the production phase ( 9 ). Those media can contain different assortments of nutrients to accommodate the distinct metabolic requirements during different production phases. Process parameter settings — including feeding strategy and control paramete...

Knowledge of k L a (the volumetric mass-transfer coefficient that describes the efficiency with which oxygen can be delivered to a bioreactor for a given set of operating conditions) is not new. Here I provide information for those who are unfamiliar with the measurement method and/or issues that must be considered when making these measurements. Advances in this area now make it advisable to run k L a measurements routinely in many bioprocesses. The Importance of Measuring k L a Before examining the process theory and tactical specifics of k L a determinations, it is essential to understand why k L a measurements are relevant and how they add value to bioprocesses. Dissolved oxygen (DO) is often the limiting substrate in fermentation and cell-culture systems. For bacteria and yeast cultures, the critical oxygen concentration is usually 10–50% of air saturation. Above that critical level, the oxygen concentration no longer limits growth. For optimum growth, it is therefore important to maintain D...