The Challenges of Oligonucleotide Synthesis: Addressing Key Hurdles in Biotechnology

Oligonucleotide synthesis plays a vital role in modern biotechnology, enabling advancements in genetic research, diagnostics, and drug development. As demand for these molecules increases, so too do the challenges in ensuring their quality, scalability, and cost-effectiveness. In this blog, we will explore the main hurdles in oligonucleotide synthesis and highlight the innovations that are helping to overcome them.

 

1. Sequence Complexity and Synthesis Accuracy

One of the most significant challenges in oligonucleotide synthesis is dealing with sequence complexity. The longer and more intricate the sequence, the more prone it is to errors. For example, repetitive sequences, palindromic motifs, or sequences that contain high GC content are notoriously difficult to synthesise. These complexities can lead to inaccuracies during the synthesis process, resulting in incomplete or incorrect sequences that require additional purification steps to achieve the desired product.

Innovation Solutions: Advances like Exactmer’s Nanostar Sieving and liquid-phase synthesis have made significant strides in improving synthesis accuracy by minimising errors in the synthesis process, ensuring more reliable outputs.

 

2. Purity and Yield

Achieving the desired purity and yield is crucial for the effectiveness of oligonucleotides, especially in therapeutic applications. The synthesis of high-quality oligonucleotides often involves side reactions and incomplete sequences, leading to impurities that can affect the performance of the final product. This is particularly problematic when scaling up synthesis for commercial production, where the consistency and reliability of each batch are critical.

Tackling the Issue: Innovations in purification processes and the use of solid-phase synthesis have helped increase the purity of oligonucleotides. Technologies such as Nanostar Sieving aid in better separation and purification, while liquid-phase synthesis offers a streamlined approach to reduce waste and minimise side reactions, ultimately improving yield.

 

3. Scalability of Production

While small-scale oligonucleotide synthesis is relatively straightforward, scaling up production to meet the needs of commercial demand presents unique challenges. To produce large quantities efficiently, manufacturers must ensure that the quality and consistency of each batch remain intact. This often requires the development of advanced equipment and methods that can handle larger volumes without compromising quality.

Innovative Solutions: To meet this demand, companies like Exactmer have focused on optimising the manufacturing process using techniques that improve scalability. By incorporating automated synthesisers and advanced monitoring techniques, production can be scaled up while maintaining high standards of quality and reducing costs.

 

4. Process Mass Intensity (PMI)

Process Mass Intensity (PMI) is a critical metric in the oligonucleotide synthesis process. It measures the amount of raw materials used to produce a unit of product. In other words, PMI helps manufacturers assess the environmental and cost impact of their production processes. A lower PMI indicates a more efficient and sustainable production process, reducing material waste and improving cost-effectiveness.

Why PMI Matters: PMI is essential for optimising the overall efficiency of oligonucleotide production, especially as demand for these molecules grows. Manufacturers must focus on reducing PMI without sacrificing product quality or performance. Innovations such as Nanostar Sieving and liquid-phase synthesis can significantly reduce PMI by streamlining processes and reducing the number of reagents required for production.

 

5. Regulatory and Quality Control Challenges

Given the critical role of oligonucleotides in therapeutic applications, stringent regulatory standards are required to ensure that the final products meet safety and efficacy requirements. Achieving compliance with these regulations while maintaining consistent production quality is an ongoing challenge for manufacturers. Regular quality control checks must be performed at every stage of the synthesis process to ensure that impurities are minimised and that the product is safe for use.

Meeting Regulatory Requirements: Continuous innovation in process monitoring and improvement technologies, along with automated quality control systems, has helped manufacturers comply with regulatory standards while maintaining high production quality. By continuously tracking key synthesis parameters such as temperature, reagent quality, and reaction time, companies can identify potential issues early, minimising the risk of non-compliance.

 

Overcoming the Challenges of Oligonucleotide Synthesis

Oligonucleotide synthesis faces several challenges, from sequence complexity and purification issues to scalability and regulatory requirements. However, ongoing innovations in synthesis technology, such as Exactmer’s Nanostar Sieving and liquid-phase synthesis, are addressing these hurdles head-on. By focusing on optimising production processes, reducing waste, and ensuring high-quality outcomes, the biotechnology industry is poised to meet the growing demand for oligonucleotides in both research and therapeutic applications.

At Exactmer, we are committed to providing cutting-edge solutions that enhance oligonucleotide synthesis, helping our clients navigate the complexities of this critical field. To learn more about how our innovations can assist you in your oligonucleotide synthesis needs, contact us today.