In 2016, Biogen began construction of their first ASO manufacturing facility. After the successful manufacture of several clinical oligonucleotides, Biogen has just completed its first process validation of a commercial oligonucleotide in 2019. This presentation will focus on key learnings from the process validation effort including process characterization, risk assessment, and platform strategies.

For starting material-related product impurities, Ionis supplemented the product impurity data with Monte Carlo simulations of the corresponding starting material impurity.  By building the Monte Carlo simulations from the entire amidite production history, significantly more historical variability was captured than any individual Ionis product experienced.  The methodology for building the starting material impurity and product incorporation models will be discussed along with the Monte Carlo simulation results.

Oligonucleotide drug product (DP) development for (ultra) orphan ophthalmic diseases can be challenging from a formulation, primary packaging and manufacturing point of view. This presentation will elaborate on some of the challenges related to intravitreal (IVT) administered products, such as endotoxin and sub-visible particle specifications of DP, but also dosing accuracy. Also, terminal sterilization as part of DP manufacturing will be discussed.

Development of an accelerated stability assessment program to determine the activation energy required for degradation of antisense oligonucleotides will be presented.  The results from these studies enable calculation of drug product stability at the long-term storage conditions and the rates of formation for individual degradation products. Study design, example data, and potential applications will be discussed.

Determination of specifications and performance prediction of C&G therapy products can be challenging due to small sample size and complex relationships.  Bayesian statistical methods, which can leverage all relevant information, plus allow more flexibility to model complex data relationships, are uniquely suited for these challenges. These methods are used with great success in adaptive clinical trials and can be leveraged in challenging CMC applications to develop more accurate models.

With the commercial success of Antisense oligonucleotides (ASO) drugs, the footprint of this class of new and exciting therapeutics is quickly increasing in the clinical space. It is vitally important to develop a phase appropriate analytical control strategy to ensure the safety and efficacy of the product while keeping the drug accessible to patients. Challenges and considerations in developing such a phase appropriate strategy will be discussed. Examples of development and implementation of new technology and methods will be provided.

In this presentation, we will demonstrate the impact of mobile phase optimization on chromatographic separation and MS sensitivity and spectral quality. Additionally, we will look into how temperature and flow-rate can impact oligo separations as well.

Development of oligonucleotide therapeutics is generally well understood with more than 10 approved molecules. However, it’s not yet a routine. In this presentation, we will address the specificities that need to be understood to avoid issues and delay when receiving questions from authorities. We will also try to explain how to manage tight timelines.

An IND application can be daunting for a small company making such a submission for the first time. This presentation will discuss key activities to consider as you plan for this important FDA interaction, including: Pre-IND dialogue, project plans, use of internal and external resources, creation of your electronic submission and the IND review process.

The complexity of oligonucleotide drug candidates being selected for clinical development has increased in recent years. These oligonucleotides often have significant chemical modifications requiring novel starting materials as well as technical innovations in process development, analytical chemistry, manufacturing and controls. This places extraordinary demands on both sponsor companies and contract manufacturing organizations to meet regulatory expectations under aggressive timelines.