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Monoclonal antibodies (MAbs) are currently the major class of protein bio therapeutic being developed by biotechnology and pharmaceutical companies. Monoclonal Antibodies discusses the challenges and issues revolving around development of a monoclonal antibody produced by recombinant DNA technology into a therapeutic agent.This book covers downstream processing which includes design of processes to manufacture the formulation, formulation design, fill and finish into closure systems and routes of administration. The characterization of the final drug product is covered where the use of biophysical methods combined with genetic engineering is used to understand the solution properties of the formulation. The latter has become very important since many indications such as arthritis and asthma require the development of formulations for subcutaneous delivery (SC). The development of formulations for IV delivery is also important and comes with a different set of challenges. The challenges and strategies that can overcome these limitations are discussed in this book, starting with an introduction to these issues, followed by chapters detailing strategies to deal with them. Subsequent chapters explore the processing and storage of mAbs, development of delivery device technologies and conclude with a chapter on the future of mAbs in therapeutic remedies.
- Discusses the challenges to develop MAbs for intravenous (IV) and subcutaneous delivery (SC)
- Presents strategies to meet the challenges in development of MAbs for SC and IV administration
- Discusses the use of biophysical analytical tools coupled with MAb engineering to understand what governs MAb properties at high concentration
Students in the pharmaceutical sciences as well as industrial pharmaceutical scientists.
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- List of figures
- List of tables
- About the author
- 1. Introduction
- Pharmaceutical development
- Development of the API
- mAbs as protein therapeutics
- Brief review of mAb structure
- 2. Analytical tools used in the formulation and assessment of stability of monoclonal antibodies (mAbs)
- Analytical methods for evaluation of monoclonal antibody stability
- 3. Stability of monoclonal antibodies (mAbs)
- Degradation routes in monoclonal antibodies
- Chemical degradation
- Mechanisms of oxidation
- Nonenzymatic peptide fragmentation
- Nonreducible cross-linking in mAbs
- Physical degradation
- Exposure to air/water interfaces due to agitation
- Use of large-scale pumps in DP unit operations
- Adsorption to surfaces
- 4. Formulation of proteins and monoclonal antibodies (mAbs)
- Formulation of monoclonal antibodies
- Buffers for pH control
- Ionic strength and tonicity modifiers
- Surfactants and surface-active agents
- Protein Stabilizers
- 5. Challenges in the intravenous (IV) administration of monoclonal antibodies (mAbs)
- Extractables and leachables from IV bags and impact on protein/mAb stability
- 6. Challenges in the subcutaneous (SC) administration of monoclonal antibodies (mAbs)
- The challenge of formulating at high concentration
- Impact on delivery due to high viscosity at high mAb concentrations
- Impact on manufacturing of high-concentration SC formulations due to high viscosity
- Bioavailability of a high-concentration mAb formulation for SC delivery
- Development of analytical tools for high-concentration formulation development
- 7. Strategies to deal with challenges of developing high-concentration subcutaneous (SC) formulations for monoclonal antibodies (mAbs)
- Using existing manufacturing technologies through redesign of equipment or modification of process variables to produce high-concentration formulations
- Development of alternative processes/formulations for manufacturing of high-concentration dosage forms
- Using formulation excipients to reduce viscosity
- 8. Development of delivery device technology to deal with the challenges of highly viscous mAb formulations at high concentration
- Using delivery devices to deliver large volume mAb formulations by the subcutaneous route
- Delivery of viscous solutions using a prefilled syringe
- The technical challenges for device and formulation development
- Primary container/closure systems for devices to be used with mAbs
- Silicone oil interactions with proteins and mAbs in prefilled syringes
- Impact of leachables from prefilled syringe components
- Potential interactions with stainless steel needles
- Potential problems with tungsten in prefilled syringes
- Filling of highly concentrated mAbs into prefilled syringes
- 9. The molecular basis of high viscosity of monoclonal antibodies (mAbs) at high concentration
- What is viscosity?
- How is viscosity measured experimentally?
- Other methods for determination of viscosity
- The dependence of viscosity on attractive protein–protein interactions
- Specific interactions in mAb1 that result in increase of viscosity
- Impact of net charge versus localized surface charge distribution on protein–protein interactions and viscosity as a function of mAb concentration
- Linking amino acid sequence to self-association and viscoelastic behavior of mAb1 and mAb2
- Coarse-grained molecular dynamics computations
- 10. The future of monoclonal antibodies (mAbs) as therapeutics and concluding remarks
- No. of pages:
- © Woodhead Publishing 2015
- 23rd April 2015
- Woodhead Publishing
- Hardcover ISBN:
- eBook ISBN:
Steven J. Shire is currently consulting and serving as an adjunct faculty member of the USC School of Pharmacy and University of Connecticut School of Pharmaceutical Sciences. He was at Genentech for 32 years where the majority of his career was in the pharmaceutical development department. He retired in June 2013 as Staff Scientist in the Late Stage Pharmaceutical Development Department. He has been responsible for directing research and development of formulations for a variety of recombinant human proteins including Pulmozyme® and Xolair®. Dr. Shire has served as the chair of the American Association of Pharmaceutical Scientists (AAPS) Biotechnology Section, and was elected as a Fellow of AAPS in 1998 and member at large to the AAPS Executive Council in 2001. He has published over 80 reviews and papers dealing with various aspects of formulation and pharmaceutical development of therapeutic proteins.
Adjunct faculty member, University of Southern California School of Pharmacy and University of Connecticut School of Pharmaceutical Sciences, USA
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