Early Analytical Development of Biotherapeutics
( 早期段階の生物学的製剤に対応する分析法の開発 )
7:30 am Registration and Morning Coffee
8:30 Welcome by Conference Organizer
8:35 Chairperson's Remarks
Krishnan Sampathkumar, PhD, Senior Director, Analytical and Drug Product Sciences, Development, MacroGenics, Inc.
Joint Opening Plenary Session
8:40 Cutting-Edge, Multi-Dimensional Chromatographic, Electrophoretic, and Mass Spectrometry Methods for Biologics
State-of-the-art techniques, such as LC, high-resolution native, and ion mobility mass spectrometry (IM-MS), multi-dimensional (2-4D) LC (RP, HIC, HILIC, CEX, SEC), and capillary electrophoresis hyphenated to MS will be discussed, as well as additional MS fragmentation techniques (CIU, UVPD, TDS). Multiple-level and orthogonal workflows case studies for mAbs, biosimilars, ADCs, BsAbs, and Fc-fusions will be presented.
9:10 The Impact of Excipients and Oxidative Degradation on Product Stability
Excipients in drug products fulfill a range of functions. In parenteral biotherapeutics, excipients provide physical and chemical stability, while contributing to osmolality. Excipients can however display complex behavior and under certain circumstances, may even destabilize the active molecule. Additionally, excipients may not be pharmacologically inert. Excipients must therefore be selected with care, and their control considered during development of the control strategy for the product.
9:40 Current and Emerging Expectations for R&D CMC Data Integrity
- What kind of data integrity operational elements are appropriate for R&D vs. GxP labs?
- How can it be confirmed that everyone in the lab understands the rationale and justification of quality practices for R&D CMC labs?
- How can a regulatory affairs reviewer assure all of the R&D data included in a product dossier are in fact authentic, complete, accurate, etc.?
- What should be done if errors or omissions are discovered in key R&D CMC study reports?
10:10 PANEL DISCUSSION: Challenges in Ensuring Data Integrity in R&D and GxP Labs: Emerging Regulatory Policies and Best Laboratory Practices
10:40 Networking Coffee Break
Analytical Strategies for Early Stage Development
11:10 Chairperson's Remarks
Matthew Traylor, PhD, Principal Scientist, Mosaic Biosciences, Inc.
11:15 Analytical Method Development and Characterization Strategies for Early-Stage Novel Antibody-Based Molecules
Monoclonal antibodies and novel bispecific DART® molecules are being developed for a variety of indications including immune-oncology. Stage-appropriate and risk-based analytical control strategy needs to be developed to ensure product quality as molecules progress from early to late stages of development. This presentation will discuss analytical method development and high throughput characterization approaches during early stage of development using the above molecules as case studies.
11:45 Analytical Strategy for Early Cell Culture Development of Biotherapeutics
Accelerating early development of biotherapeutics to enable a fast timeline to first-in-human trials has been of interest across the industry. This presentation discusses the analytical strategies and opportunities to accelerate program development timelines while maintaining product quality, safety, and efficacy. These include establishing efficient characterization plan via prior knowledge, utilizing high-throughput assays and automation, and developing platform analytical methods and molecule-specific methods to meet product quality requirements.
12:15 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
12:45 Session Break
Developability Assessment and Candidate Selection Strategies
1:30 Chairperson's Remarks
1:35 Candidate Selection from a Pool of Engineered Protease Constructs Using Fit-for-Purpose Analytical Methods
A preclinical candidate was selected from a diverse pool of engineered protease constructs expressed in mammalian and bacterial hosts. Selection from this diverse pool required generic analytical methods and candidate ranking based on developability/QbD principles with an emphasis on production levels and intrinsic stability. Analytical methods were further developed as the program progressed with a fit-for-purpose approach based on performance monitoring and streamlined method verification.
2:05 High-Throughput Developability Platform to Screen Biotherapeutic Candidates for Biophysical and Biochemical (PTM) Liabilities
Biotherapeutic developability assessment (DA) represent a new industry trend. At Denali, we apply a series of state-of-the-art analytical and biophysical technologies to carry out these molecular assessments as early as possible in the preclinical stage of development to select the candidate with the most stable profile. Here we present a case study where we use these techniques to characterize the biophysical stability of therapeutic proteins.
2:35 Sponsored Presentation (Opportunity Available)
3:05 Networking Refreshment Break and Breakout Discussions
4:30 Integrated Analytical Strategies in Developability Assessment for Complex Modalities
Since the introduction of the first recombinant DNA-derived insulin in the 1980s and the launch of Interferons and Interleukins in the 1990s, the biotherapeutics market has shown steady growth. Given significant challenges in the treatment of many life-threatening diseases, biotherapeutics are becoming increasingly complex. Integrated analytical strategies are required to address potential issues in developability assessment for such complex molecules. This presentation will discuss recent developments in leveraging protein analytics for elucidating key aspects of molecular developability, including post-translational modifications and higher-order structure using examples encountered in bispecific antibodies and fusion proteins.
5:00 Analytical Challenges with Complex Modalities in Developability Assessments
Determining the development risk of an IgG1 mAb therapeutic is relatively straightforward. However, multi-specific antibodies, Fc-fusion, Fab, or other novel modalities can present many analytical challenges. As more complex modalities enter the biologics drug development landscape, developability assessments must remain flexible to address the challenges that they exhibit. This talk will highlight several case studies where biophysical characterization has been instrumental in determining risk.
5:30 Close of Day One and Dinner Short Course Registration
6:00 Dinner Short Courses
SC1: Particles in Biotherapeutics: Characterization & Impact
SC2: Advanced Analytical Technologies for Developability & Formulation Assessments
8:00 am Morning Coffee
Early Stage Formulation Development
8:30 Chairperson's Remarks
Lisa A. Kueltzo, PhD, Director, Formulation & Stability, Vaccine Production Program Lab, NIH NIAID
8:35 Parallelism and Risk in Early Formulation Development: Strategies and Case Studies
“First in human” biologic programs often rely upon rapid development of GMP suitable process, analytics and formulation, to reach Phase 1 trials as quickly as possible. Complex programs, (co-formulated therapeutics, multi-valent vaccines) can require parallel development of multiple components. This talk discusses potential risks of parallelism in early stage development, specifically formulation, analytical and stability challenges that arise and strategies to overcome them.
9:05 Evaluation and Implementation of Automated Buffer Exchange for Early-Stage Formulation Development
Buffer exchange is a critical step during formulation development, involving exchange of buffers and concentration of protein solutions utilizing a membrane-based system. However, the process is labor-intensive and time-consuming, requiring multiple cycles of manual buffer refills and mixing. In this study, an automated buffer exchange workflow in a 96 well format is implemented using Big Tuna and evaluated using a model protein. The efficiency of the buffer exchange process is evaluated by such parameters as volume, osmolality, and pH of the prepared protein solution. The quality attributes of the exchanged protein solution are examined by multiple biophysical and analytical approaches, e.g., DSC, DSF, SEC-HPLC, and DLS. Moreover, the samples prepared by this process are compared to those made by standard dialysis process in terms of quality, materials requirement, and efficiency. Implementation of automation enables early-stage, high-throughput formulation screening in a timely manner. Application of automation in early formulation development in conjunction with DOE could become a valuable alternative to platform formulations, especially for more challenging protein scaffolds.
9:35 Sponsored Presentation (Opportunity Available)
10:05 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Early Implementation of QbD in Biopharmaceutical Development, and Practical Approaches to Biopharmaceutical Candidate Selection and Formulation Development
Early developability assessment of biopharmaceutical drug candidates, using rational methodologies and computational methods, can assist in reducing stability risks during development in a cost-effective way. In this presentation, the author will discuss one potential algorithm to illustrate how developability strategies can be introduced in practical terms during early protein drug development in order to mitigate risks, and ultimately increase the robustness of the biopharmaceutical.
11:15 Challenges and Mitigation in Early-Stage Formulation Development of Biologics
The presentation will focus on major challenges in formulation development, analytical method development and stability assessment of biologics drug candidates in early phase clinical trials. Mitigation strategies used to stabilize the biologics will be discussed. Close collaboration of formulation scientists and analytical scientists are essential to ensure quality and successful product development within aggressive timelines. Case studies will be included in the presentation.
11:45 Early Prediction of Particle Formation in Protein Formulation during Long-Term Storage
In biologics formulation development, particle formation in protein solutions is often monitored over 2-3 years. During long-term storage under refrigerated conditions, therapeutic proteins in liquid formulations can form particles after a lag-time ranging from days to over a year. This type of particle formation is often of the nature of crystalline aggregation and not predicted by protein structural stability assays. Early assessment of the risk of particle formation during storage is highly desirable for developability evaluation and pre-formulation development. Based on the fundamental relationship between protein crystallization and liquid-liquid phase separation, we have developed a method to predict the thermodynamic condition for crystalline particle formation in monoclonal antibody solutions. This method provides an efficient means to quickly evaluate protein solubility with low sample assumption and is especially useful for the early development of concentrated therapeutic protein formulations.
12:15 pm Close of Early Analytical Development of Biotherapeutics