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PRESENTATIONS
The Use of Disposable Technology for Downstream Processing
With the rapid advance of single-use and disposable-format bioreactors and other technologies enabling rapid and efficient production of vaccines, the demand for disposable-format downstream process technologies is increasing. While single-use capsule filters have been used in biomanufacturing for decades, other downstream unit operations, such as chromatography and tangential flow filtration, have been slower to evolve scalable disposable-format technologies. This presentation will provide a review of the driving forces for adoption of single-use technologies as well as an overview of recent advances in disposable-format technologies for downstream processing.
A World of Biomanufacturing: Shortages or Global Glut?
A short time ago, biopharmaceutical companies bemoaned the manufacturing bottlenecks that slowed drug development and delayed commercialization expressing fear that there would be insufficient capacity to meet the demand for all biopharmaceutical products in development. However, our detailed analysis of the worldwide supply and demand of mammalian cell culture manufacturing capacity confirms that the industry actually has a glut of capacity today with almost 2.5 million liters of installed mammalian cell culture capacity and total facility utilization of approximately 40%. While this is expected to grow to almost 4 million liters of installed capacity by 2015, increases in demand for this capacity will increase facility utilization to just over 65% by 2015. This increased facility utilization still leaves plenty of “breathing room” for unanticipated demand, ensuring that there will be more than adequate supply of manufacturing capacity to meet demand for the foreseeable future. This visionary address will discuss the impact of the current oversupply of manufacturing capacity, current trends in manufacturing technologies and product development, and the implications for the biomanufacturing “factory of the future.”
Disruptive Technologies for the Future of Biomanufacturing
In the 30 years since the harnessing of genetic engineering for making human proteins, production methods for therapeutic proteins have evolved dramatically. The accelerating growth of marketed protein therapies and the need for new vaccines worldwide to prepare for emerging pandemics has spotlighted manufacturing as either a potential bottleneck or a powerful enabler of next-generation drugs. New biotechs such as transgenic animals and plants, single-use and flexible expression systems, designer antibodies and non-native proteins, as well as new vaccine platforms, such as insect cell culture and recombinant baculovirus, may not only transform the development timelines and commercial economics of the biologicals and vaccine industries but also enable the development of previously impossible products.
The session highlighted recent and ongoing potentially disruptive changes in biomanufacturing technology that may transform the global biologics and vaccines industries, explain the surprising range of emerging biomanufacturing technologies that may revolutionize the industry by disrupting the current cell-based paradigm or through paradigm-shifting breakthroughs, and show how revolutionary the evolution of biomanufacturing has been and continues to be in enabling the development of new therapeutics and vaccines.
The Challenges of Demonstrating
Comparability
of Biosimilar Products
With the recent enactment of the Biologics Price Competition and Innovation Act (BPCIA) as part of the Patient Protection and Affordable Care Act, the US now has a regulatory pathway forward for approval of biosimilar products, also known as follow-on biologics. This represents a tremendous opportunity for global growth of the biosimilars industry. The challenge will be for companies to develop appropriate global strategies to enable them to sell their product in all of the major markets, not just niche markets. A key component of any biosimilar development strategy must include the demonstration of comparability to the innovator reference product. A detailed review of the important CMC issues of cell line development, process development, analytical methods development, and manufacturing that must be addressed in developing a biosimilar product and demonstrating its comparability with the innovator reference are addressed.
Disposable Technologies for Purification of Biopharmaceuticals
With the rapid advance of single-use and disposable-format bioreactors and other technologies enabling large-scale production of biopharmaceuticals using disposable technologies, the demand for disposable-format downstream process technologies is increasing. While single-use capsule filters have been used in biomaufacturing for decades, other downstream unit operations, such as chromatography and tangential flow filtration have been slower to evolve scalable disposable-format technologies. This presentation provides a review of the driving forces for adoption of single-use technologies as well as an overview of recent advances in disposable-format technologies specifically applicable to the purification and downstream processing sections of the biopharmaceutical flowpath.
If You Build It, Will They Come? The Promise and Perils of Investing in Biomanufacturing Capacity
With the increasing likelihood that health-care reform in the US will include a biosimilars regulatory pathway, there is increasing interest from a wide range of companies in the biosimilars market. Any new entrant into the biosimilars market will need to develop a biopharmaceutical manufacturing strategy to support their intended pipeline. The complexities of manufacturing biologic products make this requirement daunting for those with no experience in biopharma manufacturing. This presentation provides an overview of the industry-wide landscape for biomanufacturing capacity and the trends in this area, including rising productivity of biopharma processes leading to lower capacity utilization, and increasing use of disposable-format (or single use) technologies. The impact of these trends on biosimlars manufacturers is also reviewed.
The Challenges of Demonstrating
Comparability
of Biosimilar Products
Despite the current economic woes in the Western world, the economies of China, India, Russia, and Brazil are forecasted to grow substantially compared to the rest of the developed world. With this growth will come an increasing demand for better healthcare, including biologic drugs. These market opportunities along with the soon to open US market for biosimilars, also known as follow-on biologics, represent a tremendous opportunity for global growth of the biosimilars industry. The challenge will be for companies to develop appropriate global strategies to enable them to sell their product in all of the major markets, not just niche markets. A key component of any biosimilar development strategy must include the demonstration of comparability to the innovator reference product. This presentation begins with an overview of such key drivers as potential market size, the number of biologic products coming off patent in the next 5-10 years, and evolving regulations which are compelling pharmaceutical companies to enter the biosimilar market. This is followed by a detailed review of the important CMC issues of cell line development, process development, analytical methods development, and manufacturing that must be addressed in developing a biosimilar product and demonstrating its comparability with the innovator reference. The presentation concludes with a discussion of different CMC strategies that companies are taking to enter and succeed in the biosimilar market.
The Pros and Cons of Using Platform Approaches for Early Development of Monoclonal Antibodies: When Do We Deviate from the Platform?
Platform technologies are used by most organizations today in conjunction with product development. Deviating from the use of an organization’s standard platform requires consideration of the alternative’s rewards versus risks, the pros and cons of the alternative versus the standard approach, and the company’s strategic goals. Risks sometimes carry ample rewards and newer technologies most likely to challenge prevailing platforms are reviewed.
Developing a Biotherapeutic: From Clone to Clinic®
Developing a biologic is very different from developing a small molecule drug and the data needed to support regulatory filing of an IND reflects these differences. This presentation describes the development process for a biotherapeutic and compare it to development of a NCE. It also includes discussions of the regulatory expectations for filings, with particular focus on IND filings.
For QbD, What Should a Small Company Do and Why?
QbD (Quality by Design) is seen by some as a "large company" driven initiative. It can, however, benefit small companies in both technical and business arenas (e.g., aid partnering). QbD can speed time to market, keep program focus, and help manage risks and knowledge appropriately. For QbD implementation, small companies need to keep it simple and systems should be product lifecycle appropriate.
Strategic Decisions and Risk Assessment in Production Cell Line Development
Many different approaches are available to develop high expressing mammalian cell lines for production of therapeutic proteins or antibodies. Decisions on which approach to use will be made based on whether productivity, speed to clinic, suitability for a platform process, or other criteria are the most important. This presentation includes a strategic analysis of different expression technologies, host cell lines, and screening and selection methods for development of high expressing production cell lines. An assessment of risks and benefits of different approaches are also discussed.
Negotiating the Regulatory Minefield of Process Change
This paper aims to provide the key to successful change control. It covers the design of comparability studies and their application to change control, in the context of the national and international regulations. It also examines how to determine the relationship between the magnitude of the change and the required scope of the comparability studies and the way in which the change is to be reported and approved by the regulatory agencies. Actual case histories illustrate these topics.
Validation for the 21st Century
The presentation explains and discusses the differences between the original FDA Guidance on Process Validation of 1978 and the new Draft Guidance issued in November 2008. The old approach to validation, including the preparation of, usually, three conformance batches at full scale, is contrasted with the new, life-cycle approach.
There will be three stages in the new procedure, process design, process qualification and continued process verification. Each of these stages is discussed in detail, along with the need for additional monitoring, sampling and testing in Stages 3. Extensive statistical analysis of the process data will be required, which may place a strain on QC capability.
The presentation includes a summary of the responses so far received by the FDA from
firms and industrial associations, including the suggestion that the guidance should now be handed over to an ICH working party for harmonization with other ICH guidelines.
A World of Biomanufacturing: Shortages or Global Glut?
A short time ago, biopharmaceutical companies bemoaned the manufacturing bottlenecks that slowed drug development and delayed commercialization. Now, between corporate mergers, recent construction of several new or expanded facilities, technological improvements, and the rise of Asian biomanufacturing, the biopharmaceutical world is finding itself facing an excess capacity. However, geographic and development-stage mismatches between supply and demand may prevent this growing glut from shrinking the costs of biological drugs to world markets and may result in some smaller companies still having difficulties accessing manufacturing capacity. This session brings together representatives from companies large and small around the world to illuminate the issue and explain how they are tackling the challenges of global biomanufacturing.
Challenges in Vaccine Production and Rapid Scale up to Meet Emerging Pandemic
Threats
,
Over 95 percent of US flu vaccine is manufactured in eggs. This provides ~50 million vaccine
doses annually but requires 8-10 months. In a pandemic, more doses must be produced
quickly and therefore rapid, scalable methods must be used. Cell-based production and
disposable bioreactors can accelerate production by several months and enable
manufacture of larger quantities. This presentation reviews alternative production methods for
influenza vaccines.
The New Draft FDA Guidance on Process Validation—What Does it Mean for You?
The FDA issued new draft guidance to industry on process validation for comment in November of 2008. While not finalized, this guidance along with other "21st Century" initiatives, such as QbD, provide a road map that organizations can use now to approach their development efforts, whether in-house or outsourced. Here is a comprehensive review of these initiatives and impact to key industry players along with with practical insights that can be used for the entire product development lifecycle.
The presentation examines the qualification of a contractor and the responsibilities of contract givers and contractors of all types in compliance with quality standards and GxP practices. Emphasis is placed upon adequate definition of these in the contract, especially the use of the Quality Agreement. Following the creation of the agreement, the operations should be monitored by the sponsor’s staff or a suitably qualified consultant. Exhaustive documentation is essential to the success of the contract.
Process Validation for the
21st Century
This presentation explains and discusses the differences between the original FDA Guidance on Process Validation of 1978 and the new Draft Guidance issued in November 2008.
Challenges and Solutions for Biopharmaceutical Manufacturing
The biopharmaceutical industry is a dynamic one with many risks and uncertainties associated with product development and commercialization. The ability of a company to manufacture sufficient quantities of their product when they need it, whether for early stage clinical trials or to meet commercial market demands, present significant challenges throughout the lifecycle of a biologic product. Worry over “capacity crunches” resulting from notable capacity shortages for individual products in the past spurred dramatic improvements in manufacturing processes, the emergence of standardized processes and facilities for the production of biopharmaceutical products, and the massive expansion of manufacturing capacity industry-wide. This presentation reviews strategies for ensuring access to adequate capacity and reviews future trends in biopharmaceutical manufacturing.
Technologies to Improve Cell Line Development and Engineering
One of the critical activities for decreasing the time for moving a biologic product from candidate selection to first in human clinical trials is the rapid generation of a stable high expressing production cell line. Technologies that can enable this rapid development include expression vectors with elements that increase transcription or translation of the linked recombinant gene, pre-adapted host cell lines, and high throughput screening methods for optimizing media composition to improve bioreactor performance and increase volumetric productivity. Strategies for achieving rapid cell line development and reducing overall development costs are addressed along with an assessment of the risks and strategic impact of short cuts taken early in development on later stage production, partnering opportunities, product valuation, and regulatory acceptance.
Considerations in Rapid Scale-Up of Vaccine Manufacturing Processes
Vaccine manufacturing processes must be developed and scaled up quickly to meet market demand in case of emerging disease or pandemic. To insure efficient scale up, suitable process and analytical methods need to be in place. Product manufactured at the new scale and location should be rigorously evaluated to demonstrate biochemical and immunological comparability. Scalable influenza manufacturing approaches and methods for implementing rapid changes in manufacturing process scale are described.
Quality by Design in biopharmaceutical manufacturing processes includes the identification of critical process steps and parameters and the use of rational design to reduce risk and increase product quality. Using previous knowledge of process performance, product quality, and comparable process issues can help identify materials or operations that may impact product quality and safety in similar products or production systems. It can help in developing reliable, robust processes to address each potential risk area. Overall product quality may be improved through the use of Quality by Design not only to improve overall product quality but also reduce costs and speed candidate products through clinical development.
Companies must insure that the selected CMO has sufficient resources to develop a robust manufacturing process and to meet requirements of global regulatory authorities. The project should be closely managed through frequent meetings with the CMO, weekly data review, and communication of program goals and activities to insure a unified and efficient approach to product development. Concurrence on timelines and quality issues is essential.
Efficient Project Management of Outsourced Biopharmaceutical Development and Manufacturing Programs
Efficient and cost effective biopharmaceutical development requires coordination of numerous activities, including cell line generation, process development, preparation of reference standard, analytical method development and qualification, stability testing, and aseptic fill/finish activities. In many cases some or all of the activities are outsourced to external service providers to ensure timely completion of all tasks. Effective project management tools can be utilized by companies managing these development programs to enable seamless coordination of all activities, identify and manage critical path items, and ensure on-time and successful regulatory submissions.
Recent Trends in the Development and Manufacturing of Fusion Proteins as Therapeutics
This webinar discusses the development and manufacturing of fusion proteins. Fusion genes are created by joining two or more genes each coding for separate proteins. Recombinant "antibody fusion proteins" are created artificially by recombinant DNA technology by fusing the constant region (Fc) of an antibody with another biologically active protein such as a cytokine, enzyme, or toxin. These fusion proteins combine the targeting ability of the non-antibody partner with the long serum half-live and stability of a monoclonal antibody. Trends and challenges in producing fusion proteins are discussed including a case study describing the development and cGMP manufacturing of a fusion protein.
Advances in Disposable-Format Downstream Processing Technologies
With the rapid advance of single-use and disposable-format bioreactors and other technologies enabling large-scale disposable bioprocessing, the demand for disposable-format downstream process technologies is increasing. While disposable capsule filters have been used in biomaufacturing for decades, other downstream unit operations, such as chromatography and tangential flow filtration have been slower to evolve scalable disposable-format technologies. This presentation will provide an overview of the driving forces for adoption of single-use and disposable-format technologies as well as an overview of recent advances specifically applicable to the purification and downstream processing sections of the biopharmaceutical flowpath.
Challenges in Scaling Up Newly Developed Microbial Manufacturing Processes
This presentation describes an approach that can save time and money for companies developing unique products expressed in microbial systems. The approach streamlines development and scale up of a microbial manufacturing process. Usually, biopharmaceutical manufacturing processes that utilize microbial production cell lines are developed individually for each product. Due to the unique structure and behavior of the target protein, platform processes are usually not applicable to microbial systems and therefore the development timeline can be longer. The streamlined process utilized an E. coli production host and was developed at the 5-10 L scale. The parameters for the scaled up production were fixed based on multiple process demonstration runs at the smaller scale. Fermentation scale up to the 1000 L scale was seamless in most parameters due to the wealth of information obtained at the small scale. Some unit operations in recovery and downstream process did not transfer perfectly and these are described and reviewed to identify small scale activities and approaches that would increase the success rate of scaling up these steps. The overall program and GMP manufacturing were very successful, demonstrating that there is not a need for intermediate scales but that with rigorous development and testing at small scale, transfer directly to the large scale manufacturing plant can be performed.
The efficient and cost effective development and commercialization of biopharmaceutical products requires close coordination of numerous activities, including cell line generation, upstream and downstream process development, development of analytical methods for product characterization and release, identification of suitable formulations to ensure product stability, and manufacture of clinical trial supplies. In many cases some or all of these activities are outsourced to external service providers to insure timely completion of all tasks. In order to provide the proper management of all internal and external CMC activities and to ensure seamless coordination of these technical activities with regulatory filings, effective project management tools must be used. Project management tools that can help identify critical path items, ensure proper allocation of resources, and orchestrate the interplay and dependencies of wide ranging CMC activities with pre-clinical and clinical activities to maximize the probability of successful product development are presented.
The Outsourcing Decision: Which Assays and Methodologies are Best to be Outsourced and Which Should be Developed Internally?
The importance of analytical testing to biopharmaceutical manufacturing cannot be overemphasized. At all stages of development and production, analytical results impact processing decisions and the ultimate quality of your product. Decisions about outsourcing analytics are critical, and selection of a testing facility is as important as selection of a manufacturing facility. This presentation discusses the general approach to decisions on outsourcing of testing as well as concerns on outsourcing specific methods and the potential impact on your product.
Panel members: Jorg Thommes, Biogen Idec;
Tim Tressel, Amgen;
Marc Bisschops, Tarpon Biosystems; and
Pete Gagnon, Validated Biosystems. Topics:
The Use of Critical Process Analysis to Reduce Risk and Increase Biologics Product Quality
Quality by Design in biopharmaceutical manufacturing processes includes the identification of critical process steps and parameters and the use of rational design to reduce risk and increase product quality. Unlike traditional pharmaceutical products, the manufacture of biopharmaceuticals involves production of the desired product in a living host organism followed by recovery and purification of the product from contaminating host and culture components. Using previous knowledge of process performance, product quality, comparable process issues when similar products or production systems are used, and overall system performance, those materials or operations that may impact product quality and safety can be properly identified and reliable, robust processes can be developed to address each potential risk area. In the case of monoclonal antibodies, critical process analysis of the manufacturing processes, process parameters, and outcomes from previous antibody products allows one to fully optimize the new production process in less time and with lower risk. Examples such as the optimization of Protein A affinity chromatography or the removal of specific process contaminants such as nucleic acids or viruses will be presented to demonstrate how the use of Quality by Design can not only improve overall product quality but also reduce costs and speed candidate products through clinical development more efficiently.
Critical Factors to Consider when Implementing Quality by Design for Biopharmaceuticals
The concept of Quality by Design is that the quality of a drug product cannot be created by testing, but must be designed into the product during the development stages. The methods used to produce synthetic drugs involve defined chemical processes whose outcome can be accurately projected. By contrast, a biological or biopharmaceutical is manufactured by a living system. While the desired function of the target molecule (usually a protein) can be written down, the actual three-dimensional structure of the molecule (and thus its performance in the human subject) depends strongly on the living system used to manufacture it. This performance can only be determined by testing, often in living systems. These test systems have their own variability. Therefore, the critical factors which influence our ability to design and produce quality biologicals are those which determine how nature’s intrinsic variability can be controlled and measured. These include:
From Target to Clinic: Reduce the Time to Your First Important Milestone
This presentation includes an overall timeline and budget for biopharmaceutical development and a "best in industry" accelerated timeline. It also covers early steps in product development based on clone generation and transient expression using PER.C6® cells.
The Ever-Changing Landscape of Biopharmaceutical API Outsourcing
Manufacturing biopharmaceutical APIs present a range of technical and commercial challenges. The contract manufacturing segment of the biopharmaceutical industry has changed dramatically over the brief history of the biopharmaceutical industry and is still a dynamic, growing segment of the industry. Twenty years ago, it was accepted that firms developing biopharmaceuticals would need to build their own development and API manufacturing capacity to commercialize their products. Today, virtually every aspect of development, manufacturing and testing of biopharmaceutical APIs can be outsourced to experienced and reliable firms. During this period, contract manufacturing has grown from a niche segment to a truly significant industry with revenues in excess of $1.5B per year. Industry’s attitudes and perceptions related to outsourcing have also changed significantly during this period and continue to change. This presentation will review the key aspects and challenges of biopharmaceutical API outsourcing in this dynamic industry environment. A brief analysis of the current supply of biopharmaceutical manufacturing capacity will also be presented.
Recent Advances in Antibody Development
Monoclonal antibodies have become a dominant component of the biopharmaceutical market in the past decade. The required doses are much higher than those of enzyme products and therefore the annual production demands for each product are significant. Against this backdrop, companies have invested heavily in developing the most efficient and cost effective methods for manufacturing antibody products. This talk will review recent advances in expression vectors, cell line development and selection, and high throughput screening technology that in combination can enable expression of grams of antibody product from each liter of culture media.
Strategies for CMC Excellence: Playbooks for Product Development from First in Human through Commercialization
To streamline product commercialization and enable rapid product development, PDL and BioProcess Technology Consultants assembled Playbooks describing CMC activities from First in Human clinical trials through Late Stage development, supply chain, and commercial manufacturing. The Playbooks describe key tactics for improving and accelerating development. The creation and implementation of these Playbooks and their value in product development will be presented.
The Future of Viral Validation
Viral safety of biologic products continues to be a major concern of regulatory agencies worldwide. New trends in the conduct of viral clearance studies and the assessment of viral safety will be presented.
Evaluating Strategic Options for Biomanufacturing:
Build vs. Buy vs. Acquire
This presentation reviews the many factors that must be considered in developing a comprehensive manufacturing strategy against the backdrop of the current industry-wide supply and demand situation for biomanufacturing capacity. In addition to suitability and availability of contract manufacturing capacity, biopharmaceutical firms must consider the strategic importance of establishing internal manufacturing capacity, the risks associated with both internal and external manufacturing options, and of course financial considerations.
Finding the Right Partner to Fit Your Outsourcing Needs
Whether you are outsourcing out of need or to supplement internal capacity, selecting the right partner, managing the risk, and monitoring performance are critical components of the process. Topics include:
Successfully Managing Biopharmaceutical Manufacturing Outsourcing
Much has been written about the advantages of outsourcing biopharmaceutical development activities that are either not accessible internally or are not a core competency of the organization, such as manufacturing. While enlisting qualified CMOs to perform tasks including process development, formulation development, stability testing and fill/finish, appears to reduce the time a company needs to spend on these activities, it is essential that companies plan for enough resources to oversee each vendor and each activity that is outsourced. This oversight by sponsor company requires a dedicated project manager, either an internal professional or a consultant who specializes in this field, who can:
This workshop addresses these critical issues and suggests best practices and proven strategies that attendees can implement when they return the office.
Current Trends in Bioprocessing
This is an overview of major industry trends, including in the areas of biotherapeutics, production technologies, scale-up and plant design, and supply and demand of manufacturing capacity. Therapeutic antibody markets are growing at about 20% and products are increasingly antagonistic towards their therapeutic targets; these types of products typically require relatively more capacity than agonists due to higher dosing requirements. Trends in newer antibody-related therapeutics are also discussed. Production technology trends include disposables, microbioreactors, platform technologies, and controlled glycosylation in yeast. Regulatory views of scale-up, development timelines, and overviews of bioreactor and chromatography scale-up are given. Examples of scale-up issues are presented for cell culture and chromatography. Scale-up issues include nutrient effects and changes to media; glycosylation and deamidation product changes; and large-scale chromatography effects. Advantages of modular construction of biopharmaceutical facilities are presented. Modular construction will often increase upfront capital costs, but can lower overall project and organizational risk by delaying the build decision based on clinical or other strategic information. The BioProcess Technology Consultant approach to estimating future supply (bioreactor capacity) and demand (from biotherapeutics) is given along with projections of market dynamics. In general, industry capacity supply is expected to match industry demand out to 2010, but market variables, as shown in a Monte Carlo analysis, can result in large swings in capacity demand, particularly from biotherapeutics commanding the most capacity.
The Impact of the EU Clinical Trials Directive
and Other Recent Regulatory Changes on PD
and the Manufacture of Biopharmaceuticals
This presentation contrasts the 2006 FDA GMP regulations in support of Phase 1 clinical trials with the effect of the European Union’s Clinical Trial Directive (EU CTD) on biopharmaceutical manufacturing strategies and costs. For Europe, the costly compliance issues now face companies wishing to conduct clinical trials in Europe, and these higher costs of compliance are likely to slow the growth of the biopharmaceutical industry in Europe and reduce the probability of discovering valuable new biologic compounds. The impact of the directive will depend on its interpretation by regulatory agencies; the most conservative interpretation may result in increased costs of entering early clinical development in Europe, forcing these development activities to other countries outside the EU. Further, the EU CTD may significantly affect manufacturing capacity for early stage clinical trial material, since facilities that have served this market may not be equipped to meet the more stringent requirements. The FDA is moving in the opposite direction to the EU in this area.
Mycoplasma — Recent Developments in Detecting and
in Preventing Bioreactor Contamination
In this presentation, the implications of mycoplasma contamination on cell culture companies are discussed along with two primary means used to reduce risk of contamination in large scale operations — heat treatment and media filtration. The biology and detection methods, including recent developments, are discussed, along with common contamination sources and the principles of filtration governing mycoplasma removal. Experimental data on mycoplasma filtration efficiency for different filter makes during filter challenge studies is presented.
The State of Biomanufacturing Capacity – Do We Finally Have Enough?
As development commercialization of new biopharmaceutical products continues, BioProcess Technology Consultants has updated its in-depth analysis of the supply and demand for biomanufacturing capacity. This analysis indicates demand for cell culture manufacturing capacity will continue to increase with supply roughly matching this demand as several companies bring new and/or renovated facilities online. Access to capacity and availability of capacity for companies seeking to outsource production may result in short-term constraints.
The successful adoption of buffer and media bag systems and disposable bioreactor technologies by many biopharmaceutical firms in pilot and commercial manufacturing operations has increased interest and awareness in these technologies. However, the full benefits of adopting disposable processing systems come from implementing the technologies across the entire biopharmaceutical process flow diagram. This presentation will cover the few fully-developed disposable technologies currently available for downstream processing unit operations as well as trends that promise more future options for biopharmaceutical manufacturers.
This presentation focuses on the effect of the European Union’s Clinical Trial Directive (EU CTD) on biopharmaceutical manufacturing strategies and costs. New and costly compliance issues now face companies wishing to conduct clinical trials in Europe, and these higher costs of compliance are likely to slow the growth of the biopharmaceutical industry in Europe and reduce the probability of discovering valuable new biologic compounds. The impact of the directive will depend on its interpretation by regulatory agencies; the most conservative interpretation may result in increased costs of entering early clinical development in Europe, forcing these development activities to other countries outside the EU. Further, the EU CTD may significantly affect manufacturing capacity for early stage clinical trial material, since facilities that have served this market may not be equipped to meet the more stringent requirements.
Ensuring Complete and Efficient Process Validation Within a CMO-Sponsor Relationship
When companies outsource process development and manufacturing, ensuring that process validation does not fall through the cracks becomes important. Some process validation studies must be performed by the CMO while others can be performed by either the CMO or Sponsor. A process validation master plan that outlines who is responsible for what studies is an important tool for managing studies at different sites. This presentation covers strategies for coordinating and conducting process validation studies in a CMO-Sponsor relationship.
Managing Vendor Selection through the RFP Process
Many of the activities that encompass biopharmaceutical development can be outsourced to qualified CMOs. Selection of appropriate CMOs for each activity is critical to successful development and meeting timelines. The selection process can be streamlined through generation of a precise set of inclusion/exclusion criteria and use of a formal Request for Proposal (RFP) process. Strategies for efficient management of the RFP process will be described using examples from Drug Substance manufacturing.
Disposable Chromatography: Present Capabilities and Future Possibilities
Interest in disposable chromatography technologies is likely to continue to increase due to:
Technology exists that meets some of the requirements for cost-effective disposable chromatography solutions, including membrane adsorbers and pre-packed columns.
Technologies and alternative operating strategies hold the potential to make disposable chromatography a more broadly viable approach in the future.
Recent Advances in Cell Culture Technology: Improvements in Biopharmaceutical Production and Cost
Mammalian cell culture is used to produce biopharmaceutical products requiring complex post-translational modifications or processing. Early cell culture production systems had low levels of protein expression, typically <100 mg/L. For low volume/high value products such as Erythropoietin, this level of expression still enabled cost-effective production of these products. However, the development of newer biopharmaceutical products, such as monoclonal antibodies, with significantly higher therapeutic doses and patient populations required major improvements in cell culture production systems to meet the market demand and economic requirements of these products. Over the years, several approaches have been used to increase the expression of recombinant proteins and monoclonal antibodies in cell culture and reduce the overall cost of manufacturing these products. Advances in protein expression include the use of enhanced transcriptional control elements, targeted gene insertion to highly active chromosomal regions, selection methods that drive gene amplification of both the selectable marker and the product of interest, changes in the nutrient content and balance of the production media, and improved bioreactor configurations to enable higher cell densities.
These improvements in expression combined with advances in downstream processing that enable more efficient product recovery and higher overall yields have enabled the efficient and economic production of today’s biopharmaceutical products. In this presentation, Dr. Levine will review biopharmaceutical product development and discuss recent advances that have improved production of these products and the economics of producing products for various therapeutic applications at different doses and market demands.
Assessing Strategic Options for Biologics Manufacturing
Click here for Dr. Levine's presentation
or here for Mr. Ransohoff's presentation.
Much has been written over the past couple of years regarding the supply and demand of biopharmaceutical manufacturing capacity. The cost and time required to build this type of capacity make decisions related to manufacturing among the most important ones faced by emerging biopharmaceutical companies. There is an increasing realization that manufacturing decisions are strategic in nature. This presentation reviews the many factors that must be considered in developing a comprehensive manufacturing strategy, including:
Recent changes in the regulatory guidelines for biopharmaceutical production in both the United States and Europe have led to unintended consequences on the cost and efficiency of new product development and manufacturing. In the EU, these changes have resulted in a more unified and more rigorous approach to product and process validation while in the US, new FDA policies and regulations now emphasize product specifications as being an inherent component of product characterization rather than defined by the manufacturing process. These differences in regulatory policy between Europe and the US may influence manufacturing strategies for early stage clinical trial material and in the choice of countries, facilities, or contract manufacturing organizations in which to produce clinical trial material for Phase I and Phase II trials. This presentation includes:
Analysis of Biologics Manufacturing Capacity
As the biopharmaceutical industry matures, access to manufacturing capacity has become an important factor in determining the success of new biologic products. Much has been written over the past couple of years regarding the supply and demand of biopharmaceutical manufacturing capacity making decisions related to manufacturing among the most important ones faced by emerging biopharmaceutical companies. There is an increasing realization that manufacturing decisions are strategic in nature involving such factors as the global supply and demand for manufacturing capacity, the availability and suitability of contract manufacturers, the importance of establishing manufacturing capability to the company, an evaluation of the risks involved, and a review of financial considerations, including risk assessment of over or under building manufacturing capacity.
We have carefully analyzed the pipeline for biotherapeutic products and the current and future manufacturing capacity to produce these products. Our analysis indicates that while the supply of manufacturing capacity is growing rapidly to meet the rapidly increasing demand for capacity, the overall utilization of capacity within the biopharmaceutical industry is rising. This increase in capacity utilization and the potential for several blockbuster products suggests that isolated shortages are possible. Using Monte-Carlo simulations to estimate the range and distribution of outcomes for mammalian cell culture manufacturing capacity supply and demand, we provide a more quantitative estimate of the risk of a capacity shortage in the future. The impact of these conclusions will be discussed in the context of developing overall manufacturing strategies for both small and large biopharmaceutical companies.
Quantifying the Risk of a Shortage of Biomanufacturing Capcity
Tom Ransohoff recently presented BioProcess Technology Consultants 2003 biomanufacturing capacity update at the CHI PepTalk Conference in San Diego, CA. BioProcess Technology Consultants began tracking and analyzing biomanufacturing capacity in 2001 and presented our first industry-wide analysis in 2002 at the Production Economics & Manufacturing Strategies of Biologics conference in Brussels, Belgium.
As the biopharmaceutical industry matures, access to manufacturing capacity has become an important factor in determining the success of new biologic products. Much has been written over the past couple of years regarding the potential lack of manufacturing capacity to meet the growing demand for these biologic products, particularly monoclonal antibodies and antibody-based products. We have carefully analyzed the pipeline for biotherapeutic products and the current and future manufacturing capacity to produce these products. A "base case" analysis indicates that supply of manufacturing capacity is likely to grow rapidly enough to meet the rapidly increasing demand for capacity. While this type of static analysis can estimate industry-wide utilization rates, it does not address the probability of a shortage occurring. To evaluate this, we have performed Monte-Carlo simulations to estimate the range and distribution of outcomes for mammalian cell culture manufacturing capacity supply and demand. This type of analysis allows us to provide a quantitative estimate of the risk of a capacity shortage in the future.
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Process development to insure a reliable and reproducible source of biopharmaceutical material for clinical development and commercialization is a key component of an overall product development plan. Activities that encompass process development must be well integrated with other CMC-related activities, such as formulation, and stability testing, as well as preclinical testing, toxicology, animal efficacy studies. Generating sufficient quantities of biopharmaceutical material of a suitable quality and at appropriate times while developing new production processes can be challenging. This presentation reviews the key steps of process development, including cell line generation, cell banking, cell growth, protein production, purification development, analytical development, and final product formulation. It addresses both technical and strategic issues that arise at each stage of process development.
Considerations Impacting the Make vs. Buy Decision
Decisions related to manufacturing are among the most important ones faced by emerging biopharmaceutical companies. There is an increasing realization that manufacturing decisions are strategic in nature. This presentation reviews the many factors that must be considered in the "make vs. buy" decision, including: a) the availability and suitability of contract manufacturers, b) the importance of establishing manufacturing capability to the company, c) an evaluation of the risks involved (for either path) and d) financial considerations.
The Capacity Crunch -- Reality or Myth?
Much has been written over the past couple of years regarding an apparent lack of manufacturing capacity to meet the growing demand for biologic products, particularly monoclonal antibodies and antibody-based products. To better understand the state of the supply and demand for manufacturing capacity for these products, we have carefully analyzed the pipeline for biotherapeutic products and the current and future manufacturing capacity to produce these products. A supply side analysis of existing and planned manufacturing capacity indicates that the current facility construction will result in more large-scale manufacturing players with a broader distribution of capacity.
To better determine the impact of multiple variables on both the supply and demand for manufacturing capacity, we used a series of Monte Carlo simulations. Using Crystal Ball, commercially available software to run Monte Carlo simulations, we performed over 3,000 iterations of our model and estimated the overall demand for manufacturing capacity and the probability of this demand based on three different variables that will affect total demand. For each iteration, the following inputs were varied for each product:
Approval -- Using a frequency of approval based on industry averages and the stage of development of each product in the database
Overall Yield -- Including expression level and purification yield and a normal distribution around the estimated yield for each product using standard deviations derived
Patient Population -- Using a normal distribution with increasing standard deviation year to year
The results of the Monte Carlo simulations clearly demonstrate that while the currently projected supply of capacity will meet the most probably case in terms of demand for this capacity, the range of possible outcomes is broad enough such that there is a significant probability that the industry will experience a moderate capacity shortage in the coming years.
Monte Carlo simulations allow a wide variety of analyses to be performed on this type of data set. More customized analyses using different variables or specific product data are also possible. Additionally, this type of analysis can be extended to forecast potential supply-demand outcomes for individual company pipelines.
Identifying, Qualifying, and Selecting Outsourcing Partners
Given the complex interactions required between the Sponsor and Contractor, successful outsourcing requires careful planning and analysis of numerous options and potential contractors. Selection of an optimal Contractor involves a comparison of contractor’s strengths and weaknesses, business considerations, and several weighted attributes important to the success of a project, including the best technical fit between Contractor and Sponsor's product, organizational and financial stability of the Contractor, costs, regulatory experience of the Contractor, location of the Contractor, and Contractor's experience with similar products and projects. This presentation covers such topics as:
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