Key Considerations For Peptide And Oligonucleotide CDMO Selection

By Life Science Connect Editorial Staff

A new era of peptide and oligonucleotide therapeutics is upon us. Amid ongoing demand for glucagon-like peptide-1 (GLP-1) therapeutics, a growing number of drug developers are exploring the possibilities of customized peptide and oligonucleotide therapies to treat prevalent diseases such as cancer, cardiovascular disorders, and genetic diseases. In response, CDMOs are striving to build out their in-house capacity, increase their analytical capabilities, and reduce overhead for peptide and oligonucleotide drug developers. As sponsors navigate this shifting and competitive climate, it is essential to identify trustworthy and knowledgeable partners that can manufacture a high-quality peptide or oligonucleotide therapeutic to meet timeline goals.  

Understand The Unique Aspects Of The Market

The primary considerations for manufacturing these complex molecules are the inherent technical and analytical challenges, increasing competition for CDMO manufacturing slots due to growing demand, and the need to ensure continuous compliance across a therapeutic life cycle. For peptide manufacturing regulation, FDA guidance is relatively straightforward due to their small molecule designation. One distinction is that peptides require more robust non-clinical data because of their potential for toxicity.

From an oligonucleotide perspective, there is not yet draft guidance from the FDA on oligonucleotide quality and chemistry, manufacturing, and controls (CMC), but in 2024, the EMA issued draft guidance for oligonucleotide impurity levels, setting them at ~10x higher than those for typical small molecules. This reflects the intrinsic complexities of their chemical synthesis, the analytical challenges in fully separating and characterizing related substances, and a risk-based regulatory approach that considers the actual safety and efficacy implications of these impurities.

As you embark on your outsourcing journey, first determine whether your team is ready to make the transition. For smaller companies, the jump from research to clinical development is significant and it is vital to establish your CMC staff prior. In a recent Outsourced Pharma live event on peptide and oligonucleotide manufacturing, Tony Sampognaro of Stoke Therapeutics noted the following: “There are a lot of differences when moving from an unregulated space into GMP manufacturing, which is one of the most heavily regulated markets in the world. Having the right personnel with the right expertise in-house will help guide your selection process.”

Identify A CDMO Who Checks Your Boxes

Once you start to vet your partnering options, consider what type of CDMO aligns best with your budget and project stage. These manufacturing partners typically fall into one of three buckets:

• Small: These partners are typically linked to academic institutions; they tend to be low cost and may require more hands-on collaboration from your team, but this size of CDMO tends to offer strong value, making them a great option for companies with limited budgets.
• Medium: Most of these partners offer a fair amount of capacity and capability; they tend to move quickly and be cost-effective.
• Large: These CDMOs are less common, in higher demand, and the most expensive; companies typically work with them on Phase 3 and commercial products. If you start — and stay — with a large CDMO, it will mitigate the number of tech transfers on your project which will speed up your timeline.

For those with limited budgets, one option is to start with a small CDMO and then pivot to a larger one as your project moves through the pipeline. However, a tech transfer can take anywhere from six to nine months, so factor this into your timeline if you plan to transfer to a larger CDMO for late-stage trials and/or commercial production.

Beyond size, it is also critical to assess a partner’s previous knowledge and experience. If your company has limited resources, you may rely heavily on your partner to provide guidance, so it is important to find a team that has worked on a similar product. Most peptides necessitate a level of sophisticated conjugation, while oligonucleotide therapies leverage chemical modifications and require robust impurity control; both of which require a knowledgeable team.

When it comes to cost, peptide scaleup is relatively linear. With oligonucleotides, which are significantly more expensive, the primary cost driver is the starting materials, i.e., phosphoramidites. Another consideration is solvent and product waste, which is especially challenging for oligonucleotides that require numerous steps and materials to produce. CDMOs are exploring options to modify solid phase synthesis to be more efficient or pivoting to liquid phase synthesis to escape costs and scale restraints. The key is knowing what makes sense for your project and finding a CDMO that can accommodate it.

To finalize your decision, conduct CDMO site visits to assess facilities, equipment, and operations, as well as to meet with the technical teams that will be working on your project. Request examples of their previous work, especially if you have unique chemistry, unusual conjugates, high toxicity levels, or distinct raw materials. If they lack experience in your specific area of focus, weigh that heavily into your decision. For CDMOs located in a different country, consider the exchange rate, tax laws, shipping costs, and geopolitical environment to determine whether they make sense with your budget and risk tolerance.

Secure And Maintain A Strong CDMO Partnership

Once you find a CDMO well-suited for your peptide or oligonucleotide manufacturing, confirm their manufacturing slot availability. If you have the financial resources and risk tolerance but aren't yet ready for development, one option is to book a future manufacturing slot. This allows time to complete research and declare a development candidate, though you will need to be prepared for a significant upfront payment and closely monitor your progress toward a candidate. Before making a final decision on a candidate, you will need to gather in vivo models, pharmacology, drug metabolism and pharmacokinetics (DMPK), and basic toxicology data. The goal is to avoid bringing a molecule to a CDMO that would be unsuitable for IND purposes.

A CDMO should also provide you with a designated project manager — ideally one with technical expertise across drug substance, drug product, and supply chain — that will keep your project on track. A strong project manager maintains open lines of communication among the quality, technical, and regulatory teams. However, should issues arise, confirm that the CDMO offers a clear path for escalations. Per Sampognaro, “One of the best CDMOs I ever worked with assigned an executive sponsor from day one. There was a built-in channel for escalation, which made a big difference.”

Commit To Collaboration

The rapid technical innovation in peptide and oligonucleotide therapeutics has made the space relatively accessible for new entrants compared to other industry sectors. Even so, it's crucial to partner with organizations that are knowledgeable, experienced, and dedicated to quality. As more of these therapies become available for larger patient populations, manufacturing costs will likely decrease. Regulators, sponsors, and CDMOs must continue to prioritize transparency and robust understanding to quickly meet demand without sacrificing safety.