The quality attributes of siRNA drug substances are affected by used raw materials including customized starting materials such as linkers and conjugates, as well as by the manufacturing process, process parameters, and potential degradation products of the compounds. It is important to increase the understanding of processes and products to allow for improvements of processes and product quality. One of the prerequisites for this is to have good analytics in place. Outsourcing these processes allows the use of different equipment settings and parameters and learning from the experience of the different CMOs.

Driving manufacturing process improvement is one of the most effective ways to increase quality, operational efficiency, and ROI (return on investment). Improving the processes that contribute to the final product is an easy way to create scalable and sustainable change. The right improvements can reduce defects, decrease production time, and boost client satisfaction. Organizations experiencing rapid growth, finding new and innovative approaches will ensure that the enterprise operates at full capacity during busy periods. Those that simply want to improve their approach will benefit from adopting modern lean and innovative thinking methods. Every business could take advantage of new ideas, technologies, and best in practice/class in a way that fits with their existing model. Methodologies that can drive manufacturing process improvement, boosting the productivity of the operation, and insuring business outlooks.

Current regulatory intelligence for early development and late-phase filings will be discussed, including common health authority requests and recent regulatory guidance, and approaches for their phase-appropriate implementation. The impact of recent regulations on development activities will be discussed and examples provided.

Currently, there are no standards available for Phosphoramidites, which augments the necessity of developing Phosphoramidite standards.USP have explored new opportunities for development of standards for Phosphoramidites raw materials, including both DNA amidites RS and RNA amidites RS. This talk will focus on the development of DNA amidites RS, which will be available to customers soon. Each of the DNA amidites RS has been evaluated through collaborative studies with multiple international labs involved. The reference standard materials were analyzed for identification and purity using HPLC, MS and NMR techniques. Water content and residual solvent level were also determined for quality control. All the DNA amidites RS have shown NLT 98% purity within the specification limits. The results collected during collaborative study support the suitability of use as reference standards for DNA amidites, the raw materials of oligonucleotide-related products.

Sharing novel methods developed to characterise challenging impurities and method simplification for QC methods.

• Do we need an ICH guideline for the development of oligonucleotides? 
• How should we address diastereogmer control in phosphorothioated oligonucleotides? 
•  Avoiding lyophilisation and providing drug substance in solution, a better approach to compounding? 
• A single industry specification and methods for amadite impurities​

There are a number of challenges in developing a control strategy for therapeutic oligonucleotides. In this presentation we will discuss these challenges. Ensuring identity is confirmed with the correct sequence, that reproducible quantitation of impurities is maintained across batches, providing reliable batch purity for drug product compounding and demonstrating consistent diastereomeric ratios across batches of phosphorothiolated oligonucleotides will be discussed as some of the current hot topics.

Avidity Biosciences is a clinical phase company developing a new type of modality, Antibody Oligonucleotide Conjugates (AOCs). This therapeutic consists of a monoclonal antibody, as well as an oligonucleotide and, is therefore a hybrid of a biologic and a small molecule. In this talk, we will discuss the challenges and pathways associated with the Chemistry, Manufacture, and Control of these novel hybrid therapeutics. 

CMC (Chemistry, Manufacturing, and Control) for oligonucleotides synthesized by solid phase synthesis and purified by chromatography is an unusual regulatory situation compared to small molecules or synthetic peptides due to that situation and the various types of oligonucleotides. The presentation will describe solutions for a smooth development and control strategy.

New oligonucleotide therapeutics under investigation offer unique challenges relative to other pharmaceuticals. During preparation and submission of an investigational new drug (IND) application there are a number of regulatory gray areas due to the large heterogeneity in the type of oligonucleotide therapeutics and our knowledge of any particular subclass. Based on lessons learned, this talk will describe selected general considerations to a successful non-clinical IND submission.