Regulatory compliance is the means by which biopharmaceutical companies bring new medicines to market. But as we embark on developing and bringing to market more complex, more personalized medicines in the 21st century, we are about to find that our most experienced sources of compliance know-how and intelligence are getting ready to leave for the comforts of retirement. Demographics are working against the biopharmaceutical industry.
Survey Results
A 2006–2007 survey by the University of Southern California (USC) found that two-thirds of experienced regulatory compliance professionals in the United States — those with over 10 years of experience — are preparing to retire within the next five to nine years (
1
). Some of these people will stay engaged in the field through speaking and advisory roles. But how interested will those semiretirees be in accumulating new skills for navigating regulatory expectations, reimbursement strategies, and globally harmonized regulations governing personalized medicine?
Smart management and maintainance of multiple production sites is essential for global manufacturers and suppliers to reach both existing and emerging markets. Optimal performance of these networks requires keen efficiency, due diligence, and cost reduction. Biomanufacturers are taking a close look at their facilities when developing strategies for reducing time to clinic and decreasing the cost of operations, including labor, energy, raw materials and supplies, and other resources. The Managing Manufacturing Networks track of the BioProcess International Conference and Exhibition will include sessions (see box below) highlighting the technology, innovation, and strategic business approaches to optimize performance of current operations and prepare new facilities to meet future technological challenges.
Modernizing Facilities with New Process Technologies
How much and when to invest in novel technology certainly depends on the unique needs of each company. Biomanufacturers should determine how the new tec...
Many modern medicines are highly potent, with only tiny doses required to achieve a therapeutic effect. But a nanomolar medicine poses extra hazards during manufacturing, whether the product is a biologic or a small molecule. These issues have to be evaluated and addressed in the design of a manufacturing facility for such products. Not only is it vital that the product not become contaminated, but employees and the general public must be protected from the product. Exposure to just a small quantity of a highly potent compound can pose significant health risks.
Highly potent products have their individual manufacturing requirements. But the issues pertaining to safe handling are often common and not product specific. Potency is often a function of structural class, but it cannot be predicted for new molecules or new biological products without sufficient testing. A dramatic increase in development of new drugs, particularly in oncology, is more likely to require engineering controls for containment. My co...
Downstream processing can be complex, expensive, and time-consuming part of biotherapeutics production. Biomanufacturers are seeking technologies to clear bottlenecks and incorporate rapid in-or at-line analytics. Data obtained from using these methods under a well established design space can then help companies better characterize, monitor, and control their processes. The BioProcess International Conference and Exhibition features a Recovery and Purification track over three days, 22–24 September 2010, that will cover these issues and provide attendees with the information needed to manage downstream challenges.
Analytical Tools for Process Monitoring and Control
Unlike the semiconductor or chemical processing industries, the bioprocessing industry is relatively new to adopting process analytical technology (PAT)-based methods for monitoring and controlling unit operations. Nonetheless, some analytical methods familiar to the industry are gaining popularity as elements for improving process understandi...
For many young companies, choosing a contract manufacturing organization (CMO) for their lead pharmaceutical candidate is critical. Choose the wrong contractor, and you could be faced with delays and cost overruns — and little sympathy from investors or patients. With so much on the line, how should you make this important decision? It doesn’t need to be based on instinct alone or on overanalysis. With the right set of tools, selecting a CMO doesn’t require endless investigation, and the process can be well documented. Although there is no guarantee that companies will always make the right decisions, some tools can help you make a thoughtful, meaningful, and objective choice through an organized procedure.
Much has been written about the selection of contract manufacturers, including case studies (
1
), assorted tips (
2
), management issues during the selection process (
3
), regulatory implications of outsourcing (
4
), FDA guidance (
5
), and survey results (
6
) highlighting the importance of outsour...
Time to market, cost of goods, and reduction of financial risk are major challenges in protein manufacturing. Process intensification can help biotech companies achieve their goals. Already underway in several other industries, implementing this concept shrinks production facility sizes by 10–1,000 times using novel processes and products (e.g., single-use and isolator technologies in biotechnology) to reduce capital and operating costs. The results can be safer, more energy-efficient, and environmentally sustainable manufacturing processes. For example, Gerben Zijlstra (senior scientist in R&D at DSM Biologics) will report at the BPI Conference this year on his company’s XD process culture strategy, with viable cell densities >150 million cells/mL achieved by Chinese hamster ovary (CHO) and other cell lines in a combination fed-batch/perfusion process, yielding up to 27 g/L of high-quality product.
To compete in an increasingly cost-conscious world, the biopharmaceutical industry is reinventing itself. P...
As part of The Automation Partnership’s “20 Years of Automated Cell Culture” series, science writer Sue Pearson interviewed Dr. John Birch, the chief scientific officer of biopharmaceuticals for Lonza Custom Manufacturing APIS based in Slough, UK. Birch has been with that company since 1996, Before that, he held senior technical positions at Tate and Lyle, GD Searle, and Celltech. Birch has a PhD in microbiology from London University, where he also spent a period lecturing before moving into the industry. Internationally recognized as an expert in the production of therapeutic proteins (particularly from mammalian cells) Birch has published extensively in the field. He has been involved in bioprocess research for >30 years, and in this interview he explains both how bioprocessing has developed over the past 20 years and what it might look like in years to come.
Pearson:
Can you give a brief idea of what
bioprocessing
means to you and what it looked like in 1989?
Birch:
A wide range of products are ma...
Biopharmaceutical manufacturers have often explored the idea of real-time process control and monitoring — but until relatively recently, few case studies were available to help put all the information together in a coherent plan for true product lifecycle management. Shifting from previous BPI Conference programs that included a “scale-up” track, this year’s lifecycle track will reflect how companies are being encouraged to view development, design, and manufacturing as a continuum rather than (more “traditionally”) as a set of discrete phases. And continuous improvement throughout a product’s lifecycle, including postlaunch activities, is an important goal of these new approaches.
Upstream and downstream processes still exist as separate operating units, but much development and design work is performed in parallel these days. Different functional departments within biopharmaceutical companies are communicating with one another in ways not encouraged (or facilitated) before. Software to operate and trac...
As we have discussed, cost has not always featured highly during bioprocess development, in which traditionally the focus was on product quality, regulatory compliance, and speed to generate material for the clinic (
1
). As the industry matures in commercializing successful products, increasing competition (both from competing products and biosimilars) leads to issues of cost and manufacturability coming to the fore. Solutions adopted will depend on each organization: At one extreme are small biotech companies developing novel therapeutic proteins; at the other end are large multinationals with full product portfolios. In all cases, choices made during process development will affect the final cost outcomes. A key early issue is why attention should be paid to cost early in development given the high attrition rates seen during clinical trials. Isn’t the top priority simply to initiate and complete phase 1–2 clinical trials? We consider the rationale for looking at cost early on as follows:
Trends are oc...
With infusions of public and private venture capital as well as technological advances, vaccine development is entering a new golden age as one of the fastest growing sectors in the biotechnology industry. In the 19th and 20th centuries, immunization programs eliminated or controlled infectious diseases including smallpox, polio, measles, mumps, and rubella. The biotech era has made significant changes both in the number of companies involved in vaccine manufacture and the production systems they use.
BPI CONFERENCE SESSIONS
Wednesday, 22 September 2010
Keynote Presentation: Global Vaccine Production Challenges — Emerging Immunotherapeutics, Manufacturing Flexibility, and Reducing COGS
Lessons Learned from the 2009 Flu Season to Guide Rapid Vaccine Development and Manufacturing Scale-Up
Process Development for Novel Vaccines and Immunotherapeutics
Defending Biosimilar Competition: Bioprocess IP Protections for Next-Generation Vaccines and Immunotherapeutics
Process Development and Analytical Characterizat...
In BPI’s June issue, we presented a supplement on geographical trends in biomanufacturing. We looked at the influence of a growing demand for biotherapeutics in emerging countries and the influence of new technologies that are driving interest in smaller, perhaps more geographically distributed production. We wanted to explore what a global bioeconomy would look like and where its primary capacity would be concentrated. Authors provided examples of how to balance cost with control issues. They talked about working in different legal and regulatory environments and addressed differences in intellectual property (IP) regulations and supply chain monitoring. Unavoidably, the issue of biosecurity was addressed: the need for pandemic preparation, mitigating supply chain contamination risks, guarding against bioterrorism — and so on.
A large part of our preparation for that supplement was a panel discussion at the 21 April 2010 Interphex conference in New York City. As we examined geographical opportunities and...
Product Lifecycle Management
Jayne Hesley,
applications scientist in marketing for Molecular Devices, Inc. (Sunnyvale, CA)
Homogeneous Antibody Binding Assay: Comparing Imaging Systems and Optimizing Acquisition Parameters for High-Throughput Screening
Hybridoma cell lines are cultured to produce monoclonal antibodies for use in diagnostics, vaccine development, or therapeutics. One well-accepted assay for screening the antibody-containing supernatant of hybridomas is to capture the antibody on the surface of beads (<10-μm diameter microspheres) and then measure the captured amount by tagging with a fluorescently labeled secondary antibody and imaging the beads' fluorescence. A similar assay can be done to measure ligand-binding on cell surfaces. Robust homogeneous assays are straightforward to develop and these assays can be automated and scaled up to 1,536-well plates because no washing away of excess antibody or label is required. These studies show that the IsoCyte DL scanning cytometer achieves sen...
Monoclonal antibodies are usually expressed in mammalian cell lines and are produced in several variants known as
isoforms
(
1
,–
2
).
Microheterogeneity can result from posttranslational and enzymatic modifications as well as those caused by processing, alteration, storage, and incorrect translation of the target protein (
1
,
3
). Common sources of heterogeneity include Fc glycosylation, partial carboxypeptidase processing of heavy-chain (HC) C-terminal lysine residues (
4
), deamidation or isomerization (
5
), Fc methionine oxidation, hinge-region fragmentation (
6
), aggregation, and sequence variants. Sequence variants are protein isoforms containing unexpected amino acid sequences. They are classified as “product-related impurities.” The presence of unexpected amino acids may pose concerns regarding bioactivity, stability, and immunogenicity (
1
,
3
).
PRODUCT FOCUS: RECOMBINANT MONOCLONAL ANTIBODIES AND OTHER THERAPEUTIC PROTEINS
PROCESS FOCUS: PRODUCTION
WHO SHOULD READ: PROCESS AND PRODUCT DEVE...
+4Biomanufacturers must take active measures to minimize their environmental footprints and promote environmental sustainability. The collateral benefit of reducing environmental footprint often is viewed as only a secondary consideration after cost of goods and product quality. Biopharmaceutical processes are 80% defined by the time of proof-of-concept studies (clinical trial stage 2b). This milestone is before the official technical transfer to commercialization or manufacturing organizations and almost always before the environmental evaluation of a production process. This step is considerably earlier in the development lifecycle than it is for the development of pharmaceutical products. Consequently, an urgent need exists to rebalance current process evaluation criteria and advance evaluation timing to raise emphasis on environmental footprint reductions early in biopharmaceutical product development.
Because the number of biopharmaceutical products is increasing and bioprocess productivity is rising, ...
Increased adoption of disposable storage vessels and mixing systems for biopharmaceutical manufacturing operations has provided economic and efficiency benefits to a number of life-science companies. Single-use technologies have reduced validation requirements, shortened turnaround times, eliminated cleaning regimes, increased the speed of set-up procedures, and facilitated the development of flexible manufacturing platforms. Many biomanufacturers have sought to extend those benefits into the field of cell culture by using disposable bioreactors. Here we describe work undertaken to develop and demonstrate the advantages of the scalable Nucleo bioreactor. Its design is significantly different from that of stainless steel and other single-use bioreactors.
Porous or nonporous microcarriers suspended in a stirred tank or airlift bioreactor are desirable for increasing the available growth area for anchorage-dependent cell lines. Suspending these microcarriers with low sheer stress is an important aspect of th...
+1 IBC’s Well Characterized Biologicals conference is the top forum for hearing industry case studies and unpublished new data on the challenges, strategies, and technologies involved in protein characterization. Register now for exclusive access to meet FDA reviewers and industry experts who will share their insights to help you implement new approaches and avoid common pitfalls in your own characterization projects.
Hear first-hand from FDA reviewers about their “pet peeves” and suggestions to help you improve your IND packages and characterization efforts. Find new strategies to help you characterize complex protein products, including enzymes, conjugates, vaccines, and fusion proteins. Gain insights into the development of new biological assays for product characterization that you can benchmark against your own analytical testing efforts. Discover new testing and characterization methods for host cell impurities and posttranslational modifications that you can apply in your own laboratory. Learn new tec...
Single-Use Bioreactors
Product:
Modular, integrated bioreactors
Applications:
Single-use cell culture
Features:
PBS Biotech has introduced its “next-generation” single-use bioreactors. The first three models support maximum working volumes of 3 L, 15 L, and 80 L to support expansion and process scale-up from R&D to pilot plants. The modular, preconfigured bioreactors feature an integrated controller with a graphical user interface, proprietary low–shear-stress Air-Wheel agitation, automated sampling, and an on-board database. Each unit is built to order, with options for customization.
Contact PBS Biotech
www.pbsbiotech.com
Tangential-Flow Filtration
Product:
Cadence TFF systems
Applications:
Concentration of biomolecules in volume capacities from several to thousands of liters
Features:
Cadence single-pass TFF systems eliminate the recirculation loop and streamline operations to optimize downstream processing in single-use or reuse modes of operation. The new Cadence module TFF format incorporates ...
Many regenerative medicine products represent a convergence of pharmaceutical, biologic, and medical device technologies. Although such products could have a great impact on medicine, they often pose significant challenges for their developers, requiring companies to incorporate competencies from several technology sectors. By addressing commercial regulatory and manufacturing challenges at an early stage in product development, these companies are more likely to succeed in reaching their commercial goals.
Exact regulations governing the manufacture of a convergent technology — or “combination product” — such as a biologic and delivery device depend on the primary designation applied to that product by regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Different regulatory agencies have different requirements, so companies must establish manufacturing processes that comply with the strictest regulations for which they intend to seek approval.
A ...
