CMC North America Summer 2022

Monoclonal antibody-like molecules, including bi- and tri-specifics, Fc-fusion proteins and antibody-drug conjugates, have become prominent as the next generation therapies in development. These designs can generally take advantage of the manufacturing processes established for mAbs albeit each still has its own nuances around control strategies, as will be examined further in this forum. What else is out there besides these mAb-like constructs, and what does their manufacturability look like? And what about their CQAs and control strategies?

In this session, we will explore new innovations in molecular designs and scaffolds outside of the realm of traditional mAbs. In addition to recombinantly derived biologics, possibilities may also include a combination of chemical and biological approaches, such as protein conjugates and even synthetically derived molecules. A variety of new modalities ranging from novel (fusion) proteins to antisense oligonucleotides will be discussed.

While development is ongoing and success may be somewhat unknown at this time, each example will shed light on the benefits of their design, CMC issues, immunogenicity risks and regulatory landscape. The topics covered will give us a glimpse into the endless possibilities of future molecular constructs that may be entering clinical development.




Session Speakers:

09:05 - 09:30
Process Development in the Age of Multispecifics and Novel Modalities
Jennitte Stevens, Amgen Inc.
09:30 - 09:55
Novel Modalities May Warrant Novel Product Quality Controls
Deborah Schmiel, CDER, FDA
09:55 - 10:20
Analytical Challenges and Solutions For an Orally Delivered Single-Domain Antibody (VHH/Nanobody)
Bingchuan Wei, Genentech, a Member of the Roche Group
10:20 - 10:45
Analytical Control Strategy for Antisense Oligonucleotide
William Zhang, Biogen

Safe, stable, and effective biopharmaceuticals require an in-depth understanding of biophysical, biochemical, and bio-functional attributes as well as the correlation between these properties.  To advance products through phases of development, from candidate selection to commercial manufacturing, product characterization must evolve to inform refined process development that facilitates the manufacturing of products with sufficient control over safety, efficacy, purity, quality, and strength.

There is an ever-growing diversity of new modalities in biopharmaceuticals such as multi-specifics, ADCs, mRNA, and nanoparticle modalities. Along with this expansion of therapeutic modalities and novel mechanisms of action, the characterization of such products accordingly requires unique strategies – new techniques or new approaches using existing techniques. This session aims to discuss product understanding of novel modalities along with the challenges in establishing the appropriate and biologically-relevant critical quality attributes that is the foundation of the control strategy for these new products. 




Session Speakers:

13:50 - 14:15
Characterization of Novel Biological Product Modalities: A Regulatory Perspective
Leslie Rivera Rosado, CDER, FDA
14:15 - 14:40
Characterization of mRNA Fragments to Evaluate Risk of Truncated or Off-Target Antigen Expression
Thomas Lerch, Pfizer, Inc.
14:40 - 15:05
Process Development Challenges for Bi-specific/Multi-specific Drug Development
Twinkle Christian, Amgen Inc.

In recent years there has been a significant effort to expand the types of modalities used to target various disease pathways or for use as a vaccine. Examples of these modalities include fusion proteins, bi- and tri-specifics, multivalent scaffold proteins, peptide mAb fusions, mAb mimetics, as well as mRNA and anti-sense oligonucleotides. In addition to differences in the manufacturing process, compared to traditional mAbs, many of these modalities also rely on complex formulations creating various challenges for routine manufacturing. Even though this requires exploring new approaches for development, manufacturing, and scale-up, the industry can build on the vast amount of experience gathered with the manufacturing of traditional biologics. The purpose of this session is to discuss approaches which have been used by companies to accommodate new modalities as well as the challenges encountered compared to traditional biologics. Specifically, the session will cover:

-    Efficient approaches to screening and assessing manufacturability

-    How to overcome productivity and scale-up challenges to ensure materials meet high-quality standards and demand while controlling cost of goods 

-    Comparability strategies to assess the impact of changes of quality attributes to safety, efficacy, PK, or immunogenicity 

-    Flexible process and facility designs to accommodate the larger diversity of modalities




Session Speakers:

09:05 - 09:30
Manufacturing Challenges for Bi-specific Antibodies from an FDA Standpoint
Wen Jin Wu, CDER, FDA
09:30 - 09:55
Leveraging a Novel Flexible Facility Concept to Provide Solutions to Current and Future Manufacturing Challenges
Charles Christy, Lonza
09:55 - 10:20 
Development and Manufacturing of an Engineered IL-2, Reprogrammed for Anti-Tumor Therapy, Using a Semi-Synthetic Organism
Christopher Means, Synthorx, a Sanofi Company

Potency assays are an integral part of the overall control strategy and should be designed for each product to measure its specific ability or capacity to effect a given result.  The activity measured should represent the intended clinical mechanism of action (MOA) of the product, which can present with unique development challenges for products with multiple active modalities, or for novel product platforms intended for multiple individual or combined targets.  These types of products generally function by binding to two or more soluble (e.g., cytokines) or surface-associated target antigens found on different cells (e.g., bridging of two different cells to mediate a response) or on the same cell type. The complexity of MOA(s) create unique development considerations, such as limited ability to leverage prior knowledge, greater reliance on product characterization studies to build product understanding over time (e.g., structure-function studies), and development of new analytical tools capable of predicting whether biologically relevant responses are elicited.  This can be a challenge for implementing potency assays that not only reflect the MOA(s), but that are also capable of supporting the control strategy (e.g., detecting changes in relevant CQAs), and are suitable for routine testing in the QC laboratory environment.  Challenges in assay development can include, understanding the binding affinity of each modality and overall avidity, the need for multiple targets to be engaged simultaneously to have the intended biological outcome, the possibility for additive or synergistic effects and need for one or more assays to provide a meaningful assessment of the intended clinical response.  Therefore, the potency assays for these types of products are more likely to evolve during clinical development as additional product understanding is gained.  These unique considerations for development and implementation of potency assays for these novel products will be covered in this session from both the industry and regulator perspectives.




Session Speakers:
13:30 - 13:55
Expectations on Potency Assays for Antibody-based Novel Modalities – A Regulatory Perspective
Nailing Zhang, CDER. FDA
13:55 - 14:20
Cell-based Potency Assay: Design and Considerations
Janani Kumar, Molecular Templates
14:20 - 14:45
A Potent Solution to a Low Affinity Problem: Potency Release Methods for an NK Cell Targeted Cytokine
Morgan Wilson, InhibRx, Inc.
14:45 - 15:10
A High-Throughput Cell-Based Assay for Measuring mRNA-LNP Vaccine Product Potency
Nicole Smiddy, Merck & Co., Inc.