RNA-based therapeutics are becoming the third milestone in human drug development history, following chemical drugs and protein-based drugs. Platform development for preparing mRNA by in vitro transcription further speeds up this process. Improving the critical quality attributes of mRNA molecules could impact their expression and therapeutic efficiency. These CQAs for mRNA include: the integrity of mRNA; the yield of IVT reactions; polyA tail length and distribution; impurity dsRNA; impurity plasmid DNA; and free cap analogue residue levels. To improve mRNA integrity, in addition to optimizing IVT conditions, linear plasmid quality is also important. I will discuss how these factors affect mRNA quality and our progress in controlling these parameters in the mRNA manufacturing process for early-stage mRNA therapeutic development.

Key factors affecting mRNA quality

1. Linearized plasmid
2. Optimization of IVT conditions

Speaker:

Dr. Fengmei Pi
Head of RNA Biology Department
GenScript USA

Of all the chemical modifications in oligonucleotide therapeutics drug designs to enhance the delivery, phosphorodiamidate morpholino oligomers (PMO) is one successful design in which the five-membered ribose is replaced by a heterocyclic morpholino ring. Further conjugation of peptide-PPMO has been successfully developed and utilized in the treatment of various diseases. However, large-scale manufacturing of PPMO has been challenging because such production requires competency in both peptide and oligo chemistry and related manufacturing capacity. In this talk, we will demonstrate how our unique integrated capability in both peptide and oligonucleotide has enabled our clients to quickly advance important PPMO drugs into clinical studies.

Speaker:

William Fang
Vice President, Head of Oligo/Peptide Business
WuXi STA, a WuXi AppTec Company

Biogen has employed a classification method for identifying phosphoramidite starting materials using online FT-IR to support GMP manufacturing of antisense oligonucleotide drug substance. This plays an integral part of a real-time control strategy of sequence confirmation. With a growing ASO pipeline the number of phosphoramidites has increased from 8 to 26 to position our manufacturing capabilities for future products. Adjusting to a wider manufacturing scope impacts the online model and lifecycle management. Method development followed a risk-based approach to model design for a rugged implementation in a manufacturing setting. Various approaches to hierarchical modeling were explored to minimize lifecycle management. An automated optimization strategy was employed to maximize utility and support the added complexity required for 26 amidites.

Speaker:

Lanfang Zou, Ph.D.
Scientist II
Biogen

DNA G-Quadruplexes, as one type of aptamers, result from the self-assembly of guanine-rich oligonucleotides by Hoogsteen base pairing, which can be produced using classical phosphonamidite chemistry on Oligoprocess at kilo-grams scale. G-Quadruplexes have strong interaction with heavy metal, which increases more difficulty to generate final API with acceptable heavy metal content. Considering that situation, an efficient method was developed to purge the heavy metal and control the residue at low level in final G-Quadruplexes oligonucleotide. 

Speaker:

Chenchen Hu
Director, Oligonucleotide Process R&D
WuXi STA, a WuXi AppTec Company 

Learn the most common challenges of oligonucleotide manufacturing and considerations for selecting/maintaining equipment for your upstream and downstream processes – as well as the implications of Pharma 4.0 and how automation software will play a critical role in its evolution.

Speakers:

Scott Merz
Business Development Manager
AKBA

Stefan Hyde
Automation Manager
AKBA

Wahab Mahmood
Senior Field Service Engineer
AKBA

Immunostimulatory oligonucleotides can be designed to selectively stimulate a variety of endosomal and cytoplasmic innate immune receptors, with diverse immune effects. The oligonucleotide sequence, modifications, backbone, and delivery profoundly modulate the immune effects in predictable ways. Two immunostimulatory oligonucleotides have been approved as vaccine adjuvants, and others are in development for the immunotherapy of cancer and other diseases.

Speaker:

Arthur Krieg, M.D.
Chief Scientific Officer
Checkmate Pharmaceuticals

As a Contract Development & Manufacturing Organization (CDMO) of GMP-grade peptides, a central activity at PolyPeptide Laboratories is the development of robust and scaleable manufacturing processes. Here, we present a case study describing the process development and the first GMP production of a 25-mer linear peptide which had only ever been previously manufactured in non-GMP batches up to 10 grams. We provide insight into a typical process development cycle and underline the key criteria which allowed for the definition of synthesis and purification conditions. Informed by results of our process development, we show how small adjustments applied to the GMP production campaign significantly improved both the yield and purity, enabling the isolation of several hundred grams of peptide API.

This session will provide an introduction into industrial peptide process development. Attendees will learn about key factors that impact the robustness, scalability and process yield in peptide manufacturing. Additionally, PolyPeptide innovations will be discussed, highlighting strategies which enable first time right GMP production campaigns where the number of development iterations are minimized while securing the purity and optimizing the process yield.

Speaker:

Niall McLoughlin, PhD
Development Project Chemist
PolyPeptide Group

Oligonucleotide therapeutics have rapidly grown and the need for analytical tools to identify, characterize, and quantify them has become of equal importance. Analysis of Oligonucleotides found in complex matrices such as Serum or blood need to be purified for LCMS downstream analysis. In this presentation, we show an optimized workflow for oligo sample cleanup in a micro format for limited amount of sample material as well as its comparison with larger SPE cleanup formats. This presentation will also cover the characterization of mRNA sequences such as PolyA tail and Capping by high resolution LCMS. Both LCMS analysis models used bioZen Oligo columns for the proper separation of different oligonucleotide chemistries.

Speaker:

Roxana Eggleston-Rangel
Sr. Applications Scientist
Phenomenex

Rusfertide is a novel injectable synthetic mimetic of the natural hormone hepcidin which is a key regulator of iron absorption, storage, and distribution in the body. Rusfertide under the auspices of a Fast Track Designation is currently completing two Phase 2 clinical studies while initiating a Phase 3 study all for the treatment of polycythemia vera, a myeloproliferative neoplasm characterized by a high risk of thrombosis associated with excessive erythrocyte production.

Speaker:

Ashok Bhandari
Chief Drug Discovery and Preclinical Development Officer
Protagonist