Operational and Regulatory Considerations

Three areas to consider when developing an operational plan:

1. Manufacturing: Keep the process simple, perform characterization early, and control amidites and key raw materials.
2. Quality Control: Develop specifications in compliance with ICH from the beginning, identify impurities early, and build a comprehensive control strategy. Perform experiments with appropriate controls for filing as supportive data.
3. Stability: Design stability studies strategically for regulatory submission and conduct forced degradation studies early.

Oligonucleotides are considered “big small molecules” and must meet ICH guidelines for New Chemical Entities. Collaborate closely with vendors and stakeholders to establish agreements on:

• Raw material and excipient sourcing, testing, and specifications
• In-process controls and associated specifications
• API and DP specifications and tests
• Stability requirements for raw materials, intermediates, and API/DP

Documenting the details help focus efforts and accelerate development while assuring product quality.

Specifications: How Are They Set and Who’s Responsible?

Specifications comprise product information, test attributes, testing method, and acceptance criteria. While Sponsors may delegate some specification establishment to CMOs, Sponsors must drive these conversations as they have the most product knowledge.

Since specifications are based on multiple sources (safety/tox studies, process capability, stability, and analytical method limitations), regulatory agencies rarely define specification limits except for patient safety concerns.

Setting specifications requires input from multiple functions:

• Pharmacology: Ensures specifications maintain drug activity
• Toxicology: Confirms drug batches in safety studies include potential impurities while maintaining study integrity
• Process Development/Manufacturing: Ensures proposed specifications can be consistently met
• Analytical Development/Quality Control: Confirms methods can test to proposed specifications
• Quality Assurance/Regulatory: Ensures specifications meet regulatory expectations

The Sponsor should document supporting rationale in a Justification of Specification (JOS) document. When developing specifications, start broad and narrow as data accumulates. Justify limits on safety arguments, not process capability, and use preclinical/clinical exposures to establish safety thresholds for impurities.

Changes to specifications must be carefully managed and justified. Tightening limits may be done at any time with supporting data, while widening limits requires safety data.

Release Versus Stability Specifications

Release specifications must be met at batch release, while stability specifications must be met over the entire shelf-life. If product attributes don’t change over shelf-life, these specifications may be the same. If attributes change, release specifications are more restrictive than stability specifications to account for degradation. Shelf-life specifications must guarantee Safety, Identity, Strength, Purity, and Quality at end of shelf-life.

Analytical Test Methods

Both generic/compendial and custom/oligonucleotide-specific methods are necessary. Generic methods require verification, while custom methods require validation. To ensure methods are scientifically sound:

1. Document the method’s intended use
2. Classify the method using ICH Q2 categories
3. Determine required validation characteristics
4. Demonstrate performance through qualification experiments
5. Develop system suitability criteria

For method validation timing, qualify non-safety methods for early clinical development and validate safety methods before human administration, critical methods before routine testing, methods during lab transfers, when conditions change, and before pivotal trials.

Stability

Early stability studies can accelerate development and inform decisions. Three types provide different information:

• Storage stability studies: Establish acceptable storage timeframes for drug product (shelf-life) and substance (retest period)
• In-use stability studies: Establish acceptable timeframes between preparation and administration
• Stress stability studies: Establish method’s stability-indicating capability and degradation pathways

Additional studies may include freeze/thaw and multi-use container studies.

Assuring Quality and Compliance

As oligonucleotide therapeutics development accelerates, maintaining quality throughout the process is vital. Keep up with evolving regulatory expectations and understand the development process.

Plan activities with long-term view, select qualified vendors and consultants, and ensure the right internal people to manage relationships and drive programs. Make quality a priority by creating a company culture where people feel safe to share concerns.