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June 2012 Supplement
The biopharmaceutical industry is emerging from four years of economic challenge in a very healthy state. Process improvements over the past decade have played a major role in keeping the industry healthy. Earlier this decade, most companies were more concerned about quickly getting their drug products to market than about strategically controlling costs of operations. But according to my group’s recent study, this has changed in most areas of manufacturing.
In fact, although this year companies reported overall increases in every budget area surveyed, the largest increases continue to be in areas that affect process improvement and productivity.
The
9
th
Annual Report and Survey of Biopharmaceutical Manufacturers
from BioPlan Associates reflects major advances in bioprocess improvements over the past decade
.
Responses came from 302 bioprocessing professionals in 29 countries and 185 suppliers to the industry (see the “Survey Methodology” box) (
1
).
Capacity Concerns:
To get an idea of how far the i...
A high-quality product begins with efficient upstream process equipment. Ten years ago, manufacturers were still warming up to single-use bioreactors, which were mainly rocking-bag–based solutions. The benefits relating to cleaning and validation were clear, but their use as bioreactor vessels was still new, and stainless steel systems up to 20,000 L in scale were still needed. Today’s facilities are a hybrid of sophisticated single-use components and stainless steel equipment, the mechanisms of both having undergone improvement during the past decade.
Thanks to increasing cell culture titers, vessels can be smaller, and the large tanks of the past are more of an exception. Add that factor to a healthcare industry that is leaning toward paying for only treatments that “work” (fueling efforts toward “personalized” medicine). Biotech facilities of the future appear poised to have smaller footprints with flexibility and “just-in-time” manufacturing in mind.
Advanced Stainless Steel Designs
Don’t expect stai...
Microorganisms play a vital role in modern life — with applications ranging from wine fermentation to biofuel production to solutions for complex mathematical problems (
1
). During the past decade, microbial fermentation for protein production reached a higher level of sophistication and wider adoption. When BPI was first published in 2003, the physical and biological characteristics of many microbial cells and the attributes of their fermentation processes were well known. Nonetheless, the economic environment at that time created immense pressure on the biopharmaceutical industry to drive innovation and emphasize manufacturing efficiency (
2
).
BPI’s
Protein Expressions
supplement in 2004 reviewed microbial fermentation, its advantages over mammalian cell expression (e.g., lower generation time, growth time, media costs, robustness), and its shortfalls (e.g., for most systems, glycosylation and posttranslational modifications) (
3
). Our 2008 coverage of microbial expressions confirmed that companies...
Single-use technology has arguably been the biggest “story” of the past 10 years in bioprocessing. And for many people, implementation of disposable elements began soon after the turn of the century with a bioreactor (
1
,
2
), first developed by Wave Biotech in 1996, now a mainstay of many upstream process development laboratories and sold by GE Healthcare. BPI identified the significance of such technologies early on, making them the subject of a supplement in its second year.
By the fourth installment of what became an annual tradition, there were even more disposable bioreactor options available than I could pack into an overview article (
3
), as I heard from a few readers after it was published. A 2009 update by two Swiss academics narrowed the field to two main categories: static and dynamic bioreactors (
4
). Among the latter, mechanically driven (rotating, shaken, stirred, and wave-mixed) options outnumbered the pneumatically or hydraulically mixed options, and hybrid systems were already being ...
Over the past 10 years, the biopharmaceutical industry has placed increasing pressure on analytical laboratories, whose work is more important to the success of biotherapeutic products than ever before. Nearly concomitant with the appearance of BPI on the scene, the US Food and Drug Administration put forth its final report on the 21st century good manufacturing practice initiative, which in changing how regulators would review product applications, changed how companies must approach them (
1
). The guiding principles — risk management, science-based policies and standards, integrated quality systems, and international cooperation for strong public health protection — particularly emphasize the value of analysis in characterizing products and processes, identifying critical quality and process attributes (CQAs, CPAs) and critical process parameters (CPPs), setting specifications, and defining a design space within which unit operations can function with full confidence in their results. As a result, BPI ...
Allen Roses, former worldwide vice president for genetics research and pharmacogenetics at GlaxoSmithKline, raised eyebrows in 2003 when the newspaper
The Independent
quoted him as saying that the vast majority of drugs — more than 90% — work in only 30 or 50% of the people. “I wouldn’t say that most drugs don’t work,” he said. “I would say that most drugs work in 30 to 50 percent of people.”
Though the newspaper characterized this as an “open secret within the drug industry,” it said that the declaration was the first time a senior executive within the industry had stated so publicly. Given individual genetic variance and the differing molecular mechanisms underlying diseases, as much as US$350 billion a year (by some estimates) are wasted on ineffective medications. In simple terms, many classes of drugs are ineffective on a large percentage of the patients for whom they are prescribed.
In the past 10 years we’ve experienced radical changes in the pharmaceutical and biotechnology industries in how dru...
Chromatographic separations are vital both to the analysis of biological macromolecules and to their manufacturing. When properly applied, chromatography provides exquisite specificity in separating different molecules from solution based on their size, electrical charge, or other physicochemical properties. Large liquid chromatographic (LC) columns remove host-cell nucleic acids, endotoxins, viruses, and process intermediates from harvest material. Combine high-pressure liquid chromatography (HPLC) with mass spectrometric (MS) or ultraviolet–visible (UV–vis) spectroscopic detection, and you can qualify and quantify macromolecules in such complex biological mixtures. Apply Fourier-transform infrared (FTIR) detection to gas chromatographic analysis, and you convert data into wave form, making it easy to compare spectra for confirming the identity of raw materials or determining leachable/extractable components in single-use equipment.
This column appeared on the cover of BPI in February 2004. ()
Speaking o...
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 first...
Eukaryotic cells are fragile and finicky, requiring very specific culture conditions and nutrients to survive, grow, and be productive in an ex vivo environment. Even so, they have become vital to the biopharmaceutical industry’s ability to make complex biological products — overtaking yeast as a production system around 1990 and surpassing bacteria in the number of associated product approvals five years later (
1
).
Since then, they have become even more useful, expanding their reach into the vaccine world. Mammalian cell lines — especially Chinese hamster ovary (CHO), NS0, and Sp2/0 myelomas and hybridomas, baby hamster and human embryonic kidney cells (BHK, HEK), and newer proprietary lines such as Crucell’s PER.C6 cells — can express correctly formed proteins with complicated posttranslational modifications that are essential to their biological function. And the baculovirus expression vector system (BEVS) for transient protein expression by insect cells — well established in laboratory settings but ...
Outsourcing has been such an integral part of the bioprocessing industry that BPI made it the focus of its first supplement (September 2003). Since then, manufacturers continue to reach beyond local and national borders to extend their networks of partnerships to emerging markets. Global economics during the past decade have not always made outsourcing easy. Ten years ago, manufacturers faced tough decisions over whether it was more cost effective to outsource or keep process activities in-house (possibly expand or build) while facing the seemingly inevitable “capacity crunch” that many industry experts had projected.
Crunch Averted
A 2004 survey revealed that manufacturers were not exactly warming up to the idea of increasing capacity, but rather seemed to favor process improvement and opportunities in emerging markets (
1
). By some projections, outsourcing (for mammalian cell culture processes especially) would nearly double over the next five years (thanks in part to the “capacity crunch”), even thoug...
In 2004, the United States Food and Drug Administration (FDA) transferred regulation of many highly purified, “well-characterized” biopharmaceutical proteins from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER), which until then had primarily regulated only synthetic, small-molecule drugs and chemical substances. The most novel/complex and the less-characterized biologics remained within CBER’s jurisdiction. This change complicated BPI’s mission somewhat. When the magazine was founded, we responded to questions from advertisers and public relations professionals about our coverage by pointing them to the CBER website. But suddenly, the answer wasn’t so easy.
This photo appeared on the cover of BPI in February 2008. ()
Therapeutic products that transferred to CDER included monoclonal antibodies (MAbs); cytokines, growth factors, enzymes, immunomodulators, and thrombolytics; immunotherapeutics; and proteins (except clotting factors) extracted fro...
The preliminary separation of a protein of interest from a reactor “soup” of process impurities (e.g., cell debris, colloids, lipids) is the first step in a downstream process. It is also a primary step that introduces a significant risk of product degradation, bioburden concerns, or process errors, especially if a harvest method is not a good “fit” with a newly designed bioreactor (e.g., single-use) or fermentation vessel.
In 2003, BPI’s first year, industry concerns revolved around potential capacity shortages, leading manufacturers to seek solutions through enhancing their process operations. One author suggested improving harvesting methods as a solution. “The goal is to recover product cost effectively, regardless of batch-to-batch variability. For maximum transmission of the product, all cells and cell debris must be retained” (
1
). Today, the concern is not so much about dealing with capacity issues as it is about handling high cell densities from both microbial and cell cultures.
The selected har...
At about this time of the year, 10 years ago, the four founders of
BioProcess International
were in arguably the most creative period of their lives. By the middle of 2002, we began designing our collaborative production and operating processes with our new Informa colleagues (then Eaton Publishing). We were assembling author and advertising contacts pretty much from scratch, trading opinions about page designs, building a manuscript pipeline, choosing fonts (something those outside of publishing might not realize can provoke a great amount of discussion!) — all in anticipation of our first issue, planned for January of the coming year. That first-issue’s masthead shows publisher, Brian Caine; associate publisher, Stephanie Shaffer; editor in chief, S. Anne Montgomery; and senior technical editor, Cheryl Scott.
We have since then tried a few things that haven’t worked, but (thankfully) many other things that have. We have held true to our original desire to drive rather than simply report on innovations...
About halfway through our first decade in publication, we became well acquainted with a new buzzword phrase in the biopharmaceutical industry:
downstream bottleneck
(
1
). This followed on the heels of a manufacturing capacity crunch that had been forecast shortly before BPI made its debut. Thanks to herculean efforts by upstream process and cell-line engineers, that crunch didn’t pan out. In its place, however, high-titer production moved the pressure downstream. Now separation and purification engineers were tasked with handling concentrated feed streams, hard-to-purify proteins, and new contaminant profiles as culture media transitioned from serum-based to chemically defined ingredients.
Meanwhile, a few high-profile incidents of adverse events in patients were focusing regulatory, public, and industry attention on the subject of viral safety. BPI acknowledged its importance in a dedicated supplement late in 2005. Editorial advisor Hazel Aranha urged a risk-based approach (
2
), following an FDA qual...
Although no biopharmaceutical pills are yet on the horizon, formulation and delivery have advanced over the past 10 years. Formulators have new biophysical technologies and new product types (such as protein–drug conjugates) to work with. The most important issues haven’t changed much, though — from aggregation to stability, freezing to freeze-drying — although the FDA’s quality by design (QbD) initiative changes the strategies used to address them.
Fragile proteins and other biologically sourced macromolecules need protection to achieve product stability in final formulations. The larger a molecule is, the more difficult it will be to make, ship/store, and administer to patients. Biotech drug formulators have many concerns to juggle in their work, beginning with the physicochemical characteristics of an active molecule and including the reliability, cost, and availability of analytical methods used in formulation work; the array of excipients and adjuvants on the market (and their chemistries); evolving ...
In 2003, BPI’s first year of publication, the Food and Drug Administration released a draft of its updated guidelines on aseptic processing. In it, the agency included the statement, “A well-designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and control offers tangible advantages over classical aseptic processing, including fewer opportunities for microbial contamination during processing” (
1
).That kind of statement, seemingly approving one technology over another, was unprecedented in an FDA guidance and perhaps an indication of the industry’s future emphasis in aseptic processing. Today, maintaining the sterility and quality of biologic products through aseptic fill and finish operations, whether conducted in isolators or cleanrooms, remains a vital part of the bioprocessing industry.
Advances in barrier isolation, single-use technologies, automation, and packaging moved fill and finish operations in line with the FDA’s quality by design principles a...
Filtration is just as vital to bioprocessing as chromatography — and arguably even more so. Filters are not only used as downstream unit operations in themselves, but also in support of nearly every other step in bioprocessing. Gas or liquid filters ensure the quality of incoming air and feeds for cell culture operations, clean the circulating media in perfusion processes, aid in harvest clarification, and remove buffers from chromatographic eluate after chromatography columns. They are used in formulation work and fill–finish, as well as in environmental monitoring and process waters. And in the 21st century, filters have expanded their utility even more with the advent of chromatographic membranes.
This photo of a technician setting up a filtration operation graced the cover of BPI’s November 2006 issue. ()
Disposability
Filter cartridges were among the first disposable items available for use in bioprocessing. In fact, filter manufacturers have led the charge toward single use — in many cases merging w...
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