Readers of our February 2008 article “Construction and Start-Up Costs for Biomanufacturing Plants: Canadian Case Studies in the Cost of Regulatory Compliance” may have noticed something missing (
1
). Two somethings, in fact: First, biographical information for coauthor Agnès Coquet was not listed at the end of the article. She is manager of analytical development for Debiovision Inc. of Montreal, Quebec, in Canada; 1-514-842-9976, ext. 104; acoquet@debiopharm. ca. Second, “Table 1” was called out on the fourth page of the article (p. 20 of the February issue), but that table was not included in the layout. We apologize for any inconvenience or confusion that may have resulted. The online archival version of the article is now correct (
www.bioprocessintl.com/default.asp?page=articles&issue=2%2F1%2F2008
).
Table 1: Multiplying factors used by three consulting firms (cost/ft
2
of each area)
To make up for the “snafu,” I wanted to offer in this space all the tables the authors included with their original ...
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 (O
2
) transfer. Traditional methods for mixing use an impellor, and the classical O
2
transfer method features a sparging stone that expels air bubbles to increase the O
2
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 O
2
atmospheres. A classical steel deep-tank bioreactor usually has a sophisticated control tower to control O
2
and impellor mixing speed (
2
). Reasonably, the use of ambient air is ideal for bioreactors because it is nontoxic to mammalian cells. But because of the inefficiency of sparging-stone O
2
transfer, an enriched or pure O
2
supply is usually necessary. We might try to increase the flow rate of O
2
(thus increasing O
2
transfer), but that causes cell death when bubbles burst at the ...
+10Come join the staff of
BioProcess International
at the Biotechnology Industry Organization’s 2008 International Convention in San Diego, 17–20 June. As organizers of the
BioProcess Product Focus Zone
in the BIO Exhibition Hall, we will look forward to seeing you at our
Booth #2438.
Not only will you have a chance to visit with our exhibitors, but attendance is free at the zone’s Process Theater. There, for the second year in a row, a number of industry experts and exhibitors will present the latest information about developing processes and products — offering vital information on the changing landscape(s) of this dynamic industry. Below is the schedule information available at press time. Updates and more detailed abstracts are available online at
www.bio2008.org
and at
www.bioprocessintl.com
Tuesday, 17 June 2008
3:45
–
4:10
Howard L. Levine, president and principal consultant, BioProcess Technology Consultants, Inc.:
“Efficient Project Management of Biopharmaceutical Development: Ensuring ...
Pilot-Scale Fermentation
Product:
19.5-L and 40-L sterilizable-in-place fermentors
Application:
Bacterial, yeast, or fungal cultures
Features:
BioFlo 510 is an intermediate-sized CGMP-compliant modular fermentor design for easy addition or removal of components as requirements change. The compact system offers control of =32 process loops from a touchscreen interface, with multiple analog inputs and outputs provided for connection of =14 external devices. The controller enables trend-graphing of eight process parameters simultaneously, stores multiple batch recipes, and can be used with optional SCADA software. A built-in load cell measures vessel volume; 24 vessel penetrations provide flexibility to position sensors, sprayballs and more, as convenient. Numerous options and validation packages are offered.
Contact
New Brunswick Scientific
www.nbsc.com/bih.htm
Technical Assistance
Services:
Scale-up and technology transfer
Applications:
Aseptic processing using single-use technologies
Features:
Sar...
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, glycosyltransferase and glycosidase location and availability, and so on can lead to products with different carbohydrate structures. Such parameters are different for different cell lines, and they can change with cell age and density of a culture as well as with the CO
2
, pressure, and the concentration of critical nutrients such as ammonium or metabolites such as butyrate. Changes in glycan structures can cause differences ...
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 biopharmaceutical development times and costs, different analytical techniques and experimental protocols are applied for rapid screening of formulations toward finding appropriate stability
PRODUCT FOCUS
: MONOCLONAL ANTIBODIES (MABS)
PROCESS FOCUS
: PREFORMULATION AND FORMULATIONS ANALYSIS, DOWNSTREAM PROCESS OPTIMIZATION
WHO SHOULD READ
: QA/QC, PROCESS DEVELOPMENT, FORMULATORS
KEYWORDS
: STABILITY, DENATURATION, FLUOROP...
+1 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 media component is responsible for a variation. Analysis of cell culture processes to identify their critical raw materials is further complicated by use of multiple raw materials that may interact with each other as well as multiple formulations that are mixed together to create a final basal or feed medium. Identification of a raw material component causing variability in cell culture performance is a critical first step toward establishing better control o...
+1 Mammalian cell expression systems are currently essential for production of glycosylated biopharmaceuticals such as monoclonal antibodies or molecules requiring even more complex glycan structures. Various host cell and vector systems aimed at improving expression levels and quality have been established (
1
,
2
). Development of biopharmaceutical product candidates from genes to clinical trials should be based on technology platforms that will require no major changes in the entire development chain, including manufacturing once a product candidate has successfully progressed through phase 1–2 clinical testing. The intrinsic cost structure thus is widely determined by the category of technology platform chosen very early in development.
Development time is currently considered by modern management to be of utmost importance. Antibody fragments (Fabs) represent an interesting category of potential biopharmaceuticals (
3
,
4
). About 20% of all Fabs have glycosylation sites that putatively might contribu...
+1 O
n 28 March 2008,
BioProcess International
hosted a panel discussion at the annual INTERPHEX conference (26–28 March 2008 in Philadelphia, PA), titled “From Pandemics to Bioterrorism: The Role of Bio-Manufacturing in Global Healthcare.” The discussion format grew out of a series of conversations over several months involving the panel members, INTERPHEX organizers, and BPI’s editor in chief (all participants are listed on the previous page).
The group started with the premise that the biotechnology industry has a vital role to play in response to global threats of pandemic illness or bioterrorism — threats that are all too real today. Such unique challenges require unique collaborations among diverse participants: private organizations such as the Gates Foundation, public agencies including the Defense Advanced Research Projects Agency (DARPA), the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and private industry.
This special report presents highlights fro...
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 monoclonal antibody (MAb)-based products. An additional 1,600 biopharmaceuticals are being evaluated in clinical trials.
MAbs constitute by far the largest product category, with the number of such product candidates rising from 75 to 400 in the period of 2003–2006. The global sale of MAbs in 2006 were US$20.6 billion (
5–8
), and currently 25 are approved for the market. It is expected that many new MAbs will be approved within the coming years. As Figure 1 shows, demand is ra...
+1 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 was low or insoluble, they undertook larger-volume fermentation or performed a refolding step. If a product could not be expressed by
E. coli,
they would investigate alternative hosts (e.g., yeast, insect or mammalian cells). This iterative and linear process is both time consuming and expensive.
Dowpharma’s
Pf
ēnex expression technology platform addresses challenges of speed and cost at every phase of develo...
Since the 1980s launch of the first recombinant-DNA–sourced protein insulin, the 1990s introduction of interferons and interleukins, and the first commercial approval of MAbs around the turn of the century, the therapeutic protein market has shown a very healthy growth of 15–19% (Figure 1). Between 1980 and 2004, about 300 antibodies and 400 other recombinant proteins entered clinical trials, totaling about 750 products (
1
).
A survey of biopharmaceutical production technologies in 2005 shows that Chinese hamster ovary (CHO) cells and a murine myeloma cell line (NS0) among mammalian cells and
Escherichia coli
(
E. coli
) among microbial systems remain the tested and most commonly used workhorses, with known safety and productivity profiles and capabilities (
2
).
More than 66% of approved biopharmaceuticals are glycosylated proteins that require mammalian cell culture. Examples include monoclonal antibodies (MAbs), blood factors, anticoagulants, thrombolytics, EPO, granulocyte-macrophage colony-stimula...
+4 Regulatory compliance is a competitive team activity that creates real value reflected in the bottom-line accounting of company profitability. Champions earn freedom to operate for their companies; losers are enjoined, have products seized, and/or are prosecuted for their (mis)deeds. The players and fans use FDA form 483s and warning letters as metrics for measuring relative standing.
The operational paradigm is that “employees” tend to define competitors in the context of a company’s market. In the regulatory game, competitors are less well-defined and can be anyone or anything that could thwart a company’s freedom to operate. Examples include regulatory authorities, new technologies, other companies (by raising performance bars), intraorganizational conflicts, and misdirected business drivers. So competitors can be people, individually and collectively, organized entities, and even ideas. Adept players recognize the complexity of the playing field: It is not level, and it coexists with a multiplicity of...
