Synthetic oligonucleotides differ from traditional small molecules in a number of respects.

• They are not covered by key ICH guidelines
• They are synthesised by solid-state synthesis which has different dynamics than solution chemistry. There are around 80 reaction steps which cannot be monitored by traditional in process analysis.
• The drug substance is often less pure with multiple impurities which are hard to separate using HLPC/UPLC methods.
• Assaying the drug substance is often difficult

Therefore, applying the principles of a modern control strategy is not straightforward and challenging.

The course will focus on the specific requirements for control that are common to all therapeutic oligonucleotides. For example, common impurities from solid-state synthesis especially those which come from the starting materials, the synthetic process and degradation products. The issues of determining water in hygroscopic products. Issues with assays for both single and double stranded oligonucleotides.

In addition, we will discuss how establishing an ongoing control strategy is important to determine and monitor critical quality attributes that affect the drug product and the key aspects of specification setting across the phases of development. The course will also touch on risk assessment in late phase quality by design approaches and the role of analysis in determining critical process parameters and their relationship to critical quality attributes.

• How to determine a Quality Target Product Profile (QTPP) from the preclinical phase through clinical development
• How to identify Critical Quality Attributes (CQA’s) and set specifications from early development through clinical development.
• How to design analytical methods to support the QPP, CQA’s and specifications.
• Overview of regulatory expectations for therapeutic oligonucleotide drug substances in terms of specifications and impurity control
• How to approach risk assessment and the identification of Quality Critical Attributes during late development