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Monoclonal Antibody Manufacturing Strategies for the 21st Century
Reprinted with permission of Pharmaceutical Outsourcing, July|August 2010
One of the greatest challenges facing biopharmaceutical companies is ensuring adequate manufacturing capacity for products that are under development and potentially years away from commercialization. Companies without existing manufacturing capacity must decide among several alternatives, including building internal manufacturing capability, acquiring existing manufacturing facilities, outsourcing production to a contract manufacturing organization (CMO), or combinations of these. We present the strategic and tactical implications of various "make versus buy" strategies and discuss such critical aspects of developing appropriate manufacturing strategies for biopharmaceutical products as capital investment and risk, CMO selection, and the timing and cost of building manufacturing capacity.
Technology Transfer of CMC Activities for the Manufacture
of Monoclonal Antibodies
Reprinted with permission of BioProcess International, June 2010
With combined 2009 revenues estimated to be over $40 billion, monoclonal antibody products have become the dominant component of the biopharmaceutical market. To aid companies in the development of monoclonal antibody products, BioProcess Technology Consultants recently published The Development of Therapeutic Monoclonal Antibody Products, a comprehensive report outlining the complex technical, regulatory, and strategic Chemistry, Manufacturing, and Control (CMC) activities necessary to successfully advance new monoclonal antibody products from discovery to First-in-Human clinical trials and the market as quickly and economically as possible. There are numerous interconnected tasks that must be completed in a timely and cost effective manner to enable human clinical testing of a new monoclonal antibody candidate. All technology developed prior to the first cGMP manufacturing run will need to be transferred to the manufacturing and product testing site(s). Later in product development, manufacturing processes and analytical methods are often transferred from the initial manufacturing site to facilities that can produce larger batches of product. Whether these transfers occur within a company or between different organizations such as from a company to a service provider, careful planning and management is essential to ensure the knowledge and experience gained during development and/or early clinical manufacturing is effectively transferred so that the receiving organization or party can perform the critical elements of transferred methods or process. The sending and receiving parties must be well aligned in expectations and plans. This is facilitated by early and detailed planning and communications. The better the process and product are understood in terms of CQAs and CPPs the greater the likelihood of a successful transfer and demonstration of comparability. Risks should be identified and controlled as best as possible. This article discusses each of these technology transfer considerations to enable a smooth and successful technology transfer process.
CMC Activities for Development of MAbs: Critical steps to reach IND with a therapeutic antibody
by Susan Dana Jones, Ph.D.,
Patricia Seymour,
and Howard Levine, Ph.D.
Reprinted with permission of Contract Pharma, April 2010
The current economic crisis combined with increasing competition and the need to make healthcare more affordable present formidable challenges to today’s biopharmaceutical industry. By 2015, spending on prescription medicines in the United States alone is forecast to be approximately $450 billion or greater than 10% of all US healthcare expenditures. Biologic products already account for almost 15% of the total market for pharmaceutical products. Spending on these products is expected to continue to grow in the coming years, with monoclonal antibody products being the fastest growing segment of biologic products.
BioProcess Technology Consultants recently published The Development of Therapeutic Monoclonal Antibody Products report which is an indispensable guide to the complex technical, regulatory, and strategic Chemistry, Manufacturing, and Control (CMC) activities necessary to successfully advance new monoclonal antibody products to clinical trials and the market as quickly and economically as possible. This article is a summary of Chapter 3, "Overview of CMC Activities for Monoclonal Antibody Development," which provides a synopsis of the key CMC development functions:
Is Ignorance of Regulations Delaying Your New Product Launch?
Life Science Leader,
Sometimes drug development can feel like a Sisyphean challenge in the progress from laboratory bench to the clinic and, for a small percentage of companies, to the market. Global regulatory requirements, embodied in regulations governing Good Laboratory Practice (GLP), Good Clinical Practice (GCP) and Good Manufacturing Practice (GMP), collectively referred to as GxP, can intensify this frustration. These requirements exist, however, for very valid reasons, and when followed properly can actually decrease the risk and frustration that frequently goes hand-in-hand with drug development by providing a clear compliance roadmap.
Capacity Counts
Reprinted with permission of Inside Outsourcing, Pharm Exec
BioProcess Technology Consultants and PharmSource Information Services recently published a detailed report analyzing the complex and dynamic balance of supply and demand for mammalian cell culture manufacturing capacity for production of therapeutic recombinant proteins and monoclonal antibodies. This article summarizes the key findings and results from this report and provides commentary on several trends in biopharmaceutical manufacturing, including advances in technology which may lead to significantly lower utilization of existing capacity, globalization of the biopharmaceutical industry, and the emergence of biosimilar products.
New Validation Guidance Causes a Stir
BioProcess International
In November 2008, the US FDA finally issued a new draft guidance on process validation. The new guidance is intended to reflect some goals of the FDA’s Pharmaceutical GMPs for the 21st Century, an initiative that was finalized in 2004. The new draft is to be applied to manufacturing human and veterinary drugs, biological and biotechnology products, finished products and APIs. Its key principle is alignment of process validation activities with the product development life-cycle and the use of quality by design (QbD).
A Method for Forecasting Industry-wide Biopharmaceutical Manufacturing Capacity Requirements
Advances in Large Scale Biopharmaceutical Manufacturing and Scale-Up Production,
The ability of biopharmaceutical companies to manufacture sufficient quantities of their products to meet market demand is a critical risk factor. Concern over capacity forecasting has been a driving force, leading to a number of analyses on the topic of supply and demand for manufacturing capacity. Because of the enormous uncertainties associated with development of a biopharmaceutical product, the estimates for future supply and demand for manufacturing capacity is continually changing as new data from clinical trials, market penetration rates for new products, and progress on construction projects emerge. Any analysis of manufacturing capacity must be updated on a regular basis in order to provide a current and accurate picture of industry-wide utilization rates with a historical perspective. Finally, recognizing that the biopharmaceutical industry is a global one, ongoing analysis of manufacturing supply and demand enables tracking of geographical trends in manufacturing capacity.
The Rise of Biopharmaceutical Contract Manufacturing
BioPharm International,
Biopharmaceutical products are complex macromolecules that must be manufactured to meet high purity and quality standards. Due to the complexity of biopharmaceutical manufacturing processes and the technically challenging analytical test methods used to characterize these products, biomanufacturing facilities are expensive to build and operate. Added to this complexity is the need to begin construction of a commercial manufacturing facility early in the clinical development of a new biologic product when it is extremely difficult to accurately predict manufacturing capacity requirements. Even against a backdrop of increasing use of outsourcing in the pharmaceutical and other industries, regulatory and technical challenges have created additional obstacles for the outsourcing of biopharmaceutical products. This article reviews the growth in biopharmaceutical contract manufacturing over the last two decades and discusses current industry trends and dynamics resulting from the increasing use of biopharmaceutical contract manufacturing for both clinical and commercial manufacturing.
Advances in the Development of Therapeutic Monoclonal Antibodies
Reprinted with permission of BioPharm International, October 2007
Since the commercialization of the first therapeutic monoclonal antibody products in the early 1990’s, these products have become a dominant component of the biopharmaceutical market with combined revenues of several billion dollars. The early monoclonal antibody products were generally chimeric antibodies containing murine variable regions and human constant regions. As a result, these products posed a moderate risk of immunogenicity to patients from the residual murine components. With the development of new technologies for humanization and for generation of fully human antibody products, the industry standard has changed and most future antibody products will be humanized or fully human antibodies. One challenging feature of most therapeutic antibody products is that the doses required these products are much higher than other biologic products resulting in significant annual production requirements. To meet these needs, companies have made substantial progress in developing more efficient and cost effective methods for manufacturing antibody products, especially in the critical areas of cell line generation and antibody productivity from a production cell line. Advances in cell culture technology over the past decade include new expression vectors and transfection technology, novel parental cell lines that have been selected or designed to grow to maximum density and productivity under bioreactor conditions, and high throughput, robust screening technologies that in combination can enable rapid generation of production cell lines expressing multi-gram quantities of antibody per liter of culture media. In the future, the competing demands of growing production requirements and reduced cost to the patient will present challenges to the industry to make manufacturing processes even more efficient, including making downstream processing more robust and capable of processing the increased product quantities produced with increased bioreactor titers, advances in product formulations for greater stability of high concentration antibody products and alternative delivery systems, and the implementation of Quality by Design to reduce the cost and development timelines for monoclonal antibody products without adversely impacting the quality of these products.
Successful CMO Selection: CMC Strategies for Outsourcing Biopharmaceutical Product Manufacturing
BioProcess International
The outsourcing of biopharmaceutical product manufacturing has grown significantly over the past several years, and the trend is predicted to continue. There are several reasons behind this growth. First, the sheer number of biopharmaceutical products being developed and commercialized has increased. Second, there are more highly qualified Contract Manufacturing Organizations (CMOs). Third, companies are choosing to outsource their biopharmaceutical product manufacturing because: (1) tactically, they do not have the capacity, capability or expertise in-house to manufacture such products and do not want to invest in facilities; or (2) outsourcing is part of a larger overall strategic plan. A CMC (chemistry, manufacturing and control) strategic plan must take into consideration several issues including intellectual property; stage gated investment; risk tolerance levels; and finally, access to specialized biopharmaceutical manufacturing capacity, both in-house and in the outsourcing marketplace. Many companies, after completing the strategic planning process specifically for CMC, include outsourcing as a key element. In this article, we discuss certain CMC strategic planning considerations which lead to an outsourcing decision and then how to successfully manage the CMO selection process in an outsourcing scenario.
Biopharmaceutical Characterization Techniques for Early Phase Development of Proteins
BioPharm International,
Characterization of biopharmaceuticals (proteins) during early development is done for several reasons. The most important reason is the need to have supporting data that demonstrates the comparability of material used throughout development. This is particularly important as the production process is optimized and small changes in the process may affect the structure of the product. Demonstration of comparability of proteins produced throughout product development is more complicated, due to the inherently heterogeneous nature of many biologicals. This may be the result of many possible causes, such as micro-heterogeneity of glycosylation, differential proteolytic processing during cellular production, or variations in post-translational modifications. The methods used in the early phase development of these proteins must provide a meaningful way to characterize the proteins produced. This article focuses on the many analytical methods available to characterize biotherapeutics, and discusses the nature and use of the information obtained. While no single article can fully discuss all the analytical methods available, this one covers the most commonly used spectrophotometric, chromatographic, and electrophoretic methods. Mass spectroscopy is discussed separately, even though it is frequently used as a hyphenated method, i.e., liquid chromatography -mass spectroscopy (LC-MS or LC-MS/MS).
Managing Biopharmaceutical Manufacturing Vendor Identification and Selection Through Use of a Request for
Proposal
Reprinted with permission of American Pharmaceutical Outsourcing, July/August 2005
Selection of the appropriate CMO is a critical activity in biopharmaceutical development. 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 are described using case studies.
Biotech Emerges in India:
A Changing Business and Legal Environment Drives the Expansion
BioExecutive International,
India has long had a strong reputation for the quality of its synthetic and medicinal chemists, but it used to lag behind other countries in developing expertise in biology and biopharmaceuticals. Now India sees development of biotechnology as an emerging opportunity to become a significant player in the world, as with its success in high technology. The highly publicized, successful IPO of India’s first and largest independent biotechnology company, Biocon, has fueled a strong interest in the Indian investment community to support this industry. This article discusses the many partnership opportunities for companies in search of new markets who are willing to overlook India’s past reputation for copying patented medicines, a practice that will not continue because India has finally joined the worldwide patent treaty.
You Can Outsource Manufacturing But You Can’t Outsource Responsibility
Reprinted with permission of BioExecutive International, March 2005
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, manufacturing, product-specific assay 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 the sponsor company requires a dedicated program manager, either internal or a consultant specializing in this field, who can efficiently manage the entire development program through managing the vendors and the flow of information, SOPs, and material in order to keep the product development within the intended budget and timeline.
Forecasting Industrywide Biopharmaceutical Manufacturing Capacity Requirements
Advances in Large Scale BioManufacturing and Scale-Up Production,
Among the many risks biopharmaceutical companies face is whether or not they will be able to manufacture sufficient quantities of their products to meet market demand. Recent concerns over a potential biomanufacturing "capacity crunch," especially for monoclonal antibodies, were sparked by high-profile capacity shortages including those by Immunex and Berlex. Such shortages have led to serious consequences including loss of market share and acquisition by other companies.
Because of the enormous uncertainties associated with developing a biopharmaceutical product, the future supply and
demand for manufacturing capacity continually changes as new data from clinical trials, market penetration rates for new
products, and progress on construction projects emerge. Therefore, any analysis of manufacturing capacity must be updated on a regular basis providing a current picture of industrywide utilization rates with a historical perspective. A detailed analysis of manufacturing supply and demand helps companies identify capacity drivers and long-term trends in biopharmaceutical manufacturing. It can make it possible to track and validate industrywide statistics, such as probability of success at various clinical stages and commercialization. Finally, ongoing analysis of manufacturing supply and demand also enables managers to track geographical trends in manufacturing capacity.
In this chapter, we present types of analysis that improve the ability – on an industrywide or on a company-by-company basis – to forecast potential future shortages or gluts in manufacturing capacity.
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.
Considerations Impacting the Make vs. Buy Decision
American Pharmaceutical Outsourcing
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 article explores 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 Use of Models to Estimate and Control the Cost of Biopharmaceutical Manufacturing
As the biopharmaceutical industry matures and more and more biologic products enter the marketplace, competition, price controls, and dosing have driven product prices down putting increasing pressure on companies to control manufacturing costs. As pressure increases to bring products to market faster and to lower the overall cost of therapeutic products, it has become critical for companies to understand the potential costs of manufacturing a new product, develop economically viable manufacturing processes, develop optimal strategies for manufacturing, and ensure adequate supply of product for the marketplace. These demands have led companies to develop and use a variety of models to analyze and optimize biomanufacturing. In this article, Howard Levine, President of BioProcess Technology Consultants and Peter Latham, President of BioPharm Services, describe some of the most common types of models available for analyzing and evaluating manufacturing processes and operations and discuss when and where each modeling technique should be applied during a product's life cycle.
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Commentary on Capacity Requirements for Biopharmaceuticals - The Shortage That Never Was
Bioprocess News
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. Our analysis suggests that as a result of recent and ongoing facility expansions, the number of companies having very large scale capacity is increasing so that the distribution of capacity within the industry is becoming much broader. This increase in total industry capacity, accompanied by a general increase in bioreactor utilization and overall yields, suggests that supply for manufacturing capacity will be roughly equal to demand and the severe capacity shortages predicted by many are unlikely to materialize.
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Trends in Process Affinity Chromatography
Bioprocess News
Affinity separations have been used for purification of biopharmaceuticals for many years and are attractive due to the strength and specificity of affinity interactions, which can result in a very high degree of purification and concentration in one step. Practitioners have historically capitalized on the use of known ligands for purification of a variety of proteins, and, the broad use of Protein A for production of monoclonal antibody products has validated the viability of process-scale affinity separations. Recently, several groups have been successful at applying broadly-applicable discovery approaches, such as combinatorial chemistry and phage display technology, to the field of affinity separations. As improved expression technologies continue to reduce the "upstream" cost of producing biopharmaceuticals, the development and application of these and other approaches in affinity separations will be an important element in meeting the need for more cost-effective "downstream" purification processes.
Assessing the Benefits and Risks of Internal Manufacturing vs. Outsourcing Production of Biological Clinical Material
American Pharmaceutical Outsourcing
Successful outsourcing requires analysis of and attention to numerous components of a complex interaction between the Sponsor and the Contractor. Both organizations must understand the basis of the interaction and its limits as defined in written and verbal communications, listen closely to the needs of the other organization, and treat each other with honesty and mutual respect. Open and frequent communication is essential for success; this communication falls primarily in four areas: business terms, project management, technology transfer and compliance. Strong lines of communication in each of these areas will ensure rapid exchange of information, problem solving and effective conflict resolution. Methods for ensuring optimal interaction and communication between the client and the contractor, ways to avoid typical outsourcing problems and the best techniques to achieve successful outsourcing are presented.
©Copyright 2010 BioProcess Technology Consultants, Inc.
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