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 of designing or optimizing a production process is obtaining a maximum yield while maintaining high product purity through minimization of degradation forms and product heterogeneity. However, changes in a production process may create the need for comparability assessment to ensure that a consistent pattern of critical quality parameters is obtained — and thus safety, purity, and efficacy of the product are uncompromised. Such an assessment entails a comprehensive se...
+3Over the past 25 years, the biopharmaceutical industry has transformed itself from a largely R&D enterprise to a global product economy with rapidly growing sales and regulatory approvals worldwide. Some 125 new biologics are expected to hit the market in the next 10 years. This transition from R&D to manufacturing has placed an enormous strain on existing biomanufacturing expertise and production capacity.
India presents a huge opportunity for biopharm companies trying to meet this challenge with its competitive labor cost, skilled talent, and existing capabilities and capacities in manufacturing. IBC’s third BioProcess International Asia Pacific is strategically located in Mumbai to allow companies to come together to explore growth and partnership opportunities, ramp up their learning curve on processing techniques, and increase production capacity quickly and cost-effectively. Held for the first time in India, this international event will bring together bioprocess scientists, analytical engineers, he...
Production and Economics
Friedrich Nachtmann,
head of biotech cooperations in biopharmaceuticals at Sandoz GmbH
NAFT: Npro Autoprotease Fusion Technology
Microbial expression systems play an important role in the biopharmaceutical industry. A robust, scalable, and well-understood process, reduced development times, and competitive costs are requirements for successful manufacturing. In cooperation with the Austrian Center of Biopharmaceutical Technology, Sandoz has developed a platform
Escherichia coli
expression technology that provides high expression levels and rapid process development for a broad range of peptides and proteins. The Npro fusion technology is highly suitable for difficult-to-express molecules (e.g., toxic peptides and proteins). Quantitative autoproteolytic cleavage at the desired and authentic N-terminus is simply induced by changing buffer conditions without costly additives or additional process enzymes. Furthermore, the fusion partner may be used for integrated bioprocessing (b...
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 weeks).
The annual study from BioPlan Associates, Inc., provides an ongoing analysis of worldwide biomanufacturing, with data from 434 biopharmaceutical developers and contract manufacturing organizations in 32 countries. In addition, 126 industry suppliers provided supporting data, and eight subject matter experts provided in-depth analysis. This year’s survey also covers issues such as current capacity, future capacity constraints, expansions, use of disposables (with trends and budgets), trends in...
It’s been a quarter-century since the Orphan Drug Act became law in 1983. An
orphan drug
is any therapeutic, vaccine, or blood product that treats a rare disease or condition (one with fewer than 200,000 US patients). Such drugs may be new products or those already approved for other diseases but discovered to treat a rare disease. Drug sponsors must apply for orphan drug designation through the US FDA (
1
). Similiar status may be obtained in Europe through the EMEA’s Committee on Orphan Medical Products.
25 Years of Success
Originally introduced by Republican senator Nancy Kassebaum (KS) and Democratic representative Henry Waxman (CA), the Orphan Drug Act of 1982 was cosponsored by several members of both parties in Congress. But it really came about as a result of hard work by founders of the National Organization for Rare Disorders (NORD,
www.rarediseases.org
). Since the drug was signed into law in 1983 by then-president Ronald Reagan, about 1,700 drugs and biologics have been designated as orphan...
Downstream processing is a sequence of unit process operations that purify biopharmaceuticals and prepare them primarily for bulk formulation (Figure 1). Typically, a large volume (hundreds to thousands of liters containing kilograms of therapeutic protein) is delivered from an upstream fermentation or cell culture process — and this ends up as a small volume (a few liters) of purified concentrate product after processing.
For many years, biopharmaceutical manufacturers have been working to increase capacity, address upstream production issues, and improve yields. Notable successes have been achieved recently in upstream technology, significantly increasing expression rates and therefore upstream production capacities. Successes in generating higher titers combined with increasingly stringent quality and regulatory requirements creates a number of challenges in aligning the efficiency of downstream process with those upstream titers.
PRODUCT FOCUS:
Recombinant proteins (monoclonal antibodies)
PROCESS FOC...
+1 Automated Welding
Product:
M200 orbital welding system
Application:
Welding power supply
Features:
The orbital welding system M200 power supply offers ease of use, portability, and 200 amp capability, all at a weight of less than 50 lbs (23 kg). A high-resolution, 12.1-in. (307-mm) color industrial touch screen gives users a simple, intuitive pathway to enter weld programs. Users can choose from one of three forms to enter weld programs, including automatic weld schedule programming.
Contact: Swagelok Company
www.swagelok.com
RNA Purification
Product:
PureLink RNA Mini kit
Application:
Phosphorylation detection
Features:
The kit enables purification of total RNA from a number of cell and tissue types under 20 minutes. The protocol requires no phenol/chloroform extraction or ethanol precipitation and allows purification of up to 1,000 µg of total RNA. The resulting RNA is appropriate for all downstream applications including quantitative PCR (polymerase chain reaction), RNA amplification for microa...
Several cellular therapies are currently progressing through clinical development with the potential to address unmet medical needs affecting millions of patients. As cell-based therapeutics receive regulatory approval and reach the market, the primary challenge will quickly become manufacturing such products in sufficient volume to meet demand.
Aastrom Biosciences has developed tissue-repair cell (TRC) technology for use in autologous, patient-specific cellular therapy (PSCT) and is conducting late-stage clinical trials both in the United States and Europe. TRCs are derived from a patient’s own bone marrow and processed through a short two-week culture under media perfusion conditions that lend potent functional properties to the final product. Development and clinical use of a PSCT product has raised unique manufacturing challenges that we have addressed through a series of innovative solutions, many of which could have broad application in the field of commercial-scale cell manufacturing.
PRODUCT FOCUS...
Development of robust inoculum expansion procedures from cell banks is crucial to successful upstream manufacturing processes. Typically, vial thaw and cell culture expansion processes follow well-established procedures. Certain recombinant cell lines, however, need extra attention and development efforts to optimize conditions for robust and reproducible vial thaw and further subculturing. Difficulties in thawing frozen cells might be clone specific or could originate from suboptimal conditions during freezing. Such conditions might not be known initially and could need further optimization at a later stage. Growing and freezing cells under serum-free conditions in animal-component–free (ACF) or chemically defined (CD) media is desirable to meet regulatory requirements for therapeutic product development (
1
). However, certain cell lines might be more fragile to freezing techniques in ACF or CD freezing media. That could potentially lead to challenges in thawing and cell recovery as well as during initi...
+2 Q&A with the Scientific Advisors
THOMAS C. RANSOHOFF
vice president and senior consultant at BioProcess Technology Consultants, Inc
.
How long have you worked for your current employer, and where did you work before that?
I’ve worked for BioProcess Technology Consultants for six years (since 2002). Before joining BPTC as a senior consultant, I held senior positions in manufacturing, development, and operations for several biotechnology companies including Repligen, Dyax, and TranXenoGen.
What degrees do you hold, and from where?
I hold BS and MS degrees, both in chemical engineering, from MIT and UC-Berkeley, respectively.
When and why did you get involved in the biotechnology industry?
I had become interested in biochemical engineering at MIT and had an opportunity to join a start-up biotech company called Xoma in California after graduating from UC-Berkeley.
What interested you the most about it?
I enjoy the intersection of the incredible science on which modern biopharmaceutical products are based ...
It wasn’t so long ago that people in the biotherapeutics industry talked about a “capacity bottleneck” to describe the difficulty faced by bioprocessors as their many products moved forth through development to require production at larger and larger scales (
1
). Expression technologies at the time were making proteins at levels suggesting that huge amounts of manufacturing capacity would be needed soon. Just after the turn of the century, product titers (in terms of protein present per liter of culture broth/supernatant) of 0.5 g/L were common, and 1 g/L was considered impressive. Downstream processes that took those production titers and ultimately yielded around half of the original protein content in purified form were once considered good enough — but everyone could see that technological limitations were presenting an increasingly daunting obstacle to manufacturers of biological drugs. There were over a thousand products in the development pipeline, many of which would ultimately be needed in large...
Q&A with the Scientific Advisors
HOWARD L. LEVINE
president of BioProcess Technology Consultants, Inc
.
How long have you worked for your current employer, and where did you work before that?
I’ve worked for my current employer since 1994. Before BioProcess Technology Consultants, I worked as vice president of manufacturing operations for Repligen.
What degrees do you hold, and from where?
PhD in chemistry from the University of Chicago (1978); BS in chemistry from the University of Southern California (1975)
Who will be most interested in the subject matter of your discussion session (Biosimilars: Where Are We Now?), and what do you expect them to “take away” with them? Anyone interested in the topic of biosimilars will be interested in this session. We will cover the technical, regulatory, and economic challenges faced by companies attempting to seamlessly transition biosimilar replacement products into the marketplace. The “take-away” messages from this workshop will be ideas and approaches to biosim...
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 with rapid technological advances and evolving regulatory expectations, limits the ability of biotechnology companies to progress rapidly with their pipeline candidates. Also, the biopharmaceutical industry is heavily regulated, but most regulations are targeted at commercial products, with a significant gap in available guidance for earlier stages of product development.
This two-part article discusses the ana...
Q&A with Scientific Advisor Dennis Kraichely
How long have you worked for your current employer, and where did you work before that? When and why did you get involved in the biotechnology industry? What interested you the most about it?
Since 2001, I have worked for Centocor R&D, Inc. (a Johnson & Johnson Company) located in the greater Philadelphia, PA area. Prior to that I worked in cardiovascular discovery research at Procter & Gamble Pharmaceuticals in Cincinnati, OH. Being trained as a molecular biologist, I have always been intrigued by the use of recombinant proteins as therapeutics. I think what has interested me most is the exquisite precision that a monoclonal antibody has for a target antigen and how researchers can take advantage of that feature to develop specific and effective therapeutic agents to treat life-threatening diseases.
Which biologics does your company have currently on the market
—
or in later stages of clinical development? What kinds of production/economicsrelated tools and...
Q&A with the Scientific Advisors
CHARLES SCHMELZER
senior scientist in late-stage purification at Genentech, Inc
.
How long have you worked for your current employer, and where did you work before that? What degrees do you hold, and from where?
I have been working at Genentech since September 1987. I have a BS degree (chemistry) from Rutgers University (Cook College) and a PhD degree (biochemistry) from North Carolina State University.
UWE GOTTSCHALK
vice president of purification technology at Sartorius Stedim Biotech in Germany
How long have you worked for your current employer, and where did you work before that?
1991–2004 Bayer Health Care, head of GMP purification; 2004–today Sartorius Stedim Biotech, VP purification technologies
What degrees do you hold, and from where?
PhD in immunochemistry
When and why did you get involved in the biotechnology industry? What interested you most about it?
main interest in downstream processing of monoclonal antibodies
What kinds of titers (e.g., 0.5 g/L, 1 g/L...
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 greater opportunity to introduce innovative, enhanced technologies that can improve contamination control to satisfy regulatory requirements not only today but in the foreseeable future.
Introducing a new technology into a process may, however, bring concern over possibly time-consuming, demanding process qualification and validation studies and ultimate regulatory approval. We address these issues by using as an example new techno...
