Guest Column | January 9, 2024

Oligonucleotides Outsourcing In 2024


By Louis Garguilo, Chief Editor, Outsourced Pharma


Two thousand twenty three, among other potential designations, was the year of oligonucleotides – now ubiquitously and tidily referred to as “oligos.”

Accordingly, here’s a question I raised with professionals throughout the year:

How do you successfully outsource development and manufacturing of an oligo program?

The replies might best be generalized as:

  • Stick closely to the all-time basics of outsourcing – with a powerful focus on CDMO selection
  • Beware of, shall we say, elevated challenges due to the nature of this rising therapeutics class

More specifically, if you are a biotech looking for a CDMO partnership to assist in developing and manufacturing a proprietary oligonucleotide, here are essential characteristics and capabilities to look for.

CDMO Must Haves

1. Expertise in Oligonucleotide Chemistry

Yes, paint this as obvious, but there’s a coloring problem.

Although the CDMO should have a proven expertise in oligo chemistry, the out-of-the-gate challenge, I have been told, is there are more CDMOs who claim expertise than actually can exhibit it. Beware the sell, and seek out the heart of their current capabilities and expertise, and confirm the CDMO’s plans for the near and longer term regarding oligos specifically.

Of course, the build out of a new facility or section of an existing facility, the introduction of new equipment, the hiring of professionals who have gained oligo-related experience elsewhere, are bright signs of the committed.

Nonetheless, because you'll be selecting a CDMO just entering this service category, due diligence on a number of particular and strategic levels is critical. Look to enter a real partnership of learning as you go.

2. Formulation and Delivery Technology

When starting out to develop an oligo project, perhaps not well known are the often unique challenges formulating oligonucleotides can present. Here are a few.

Chemical And Biological Stability – Oligonucleotides are susceptible to chemical degradation in biological environments, such as hydrolysis and oxidation. Formulating the drug to protect it from enzymatic degradation until it reaches the target site is essential for maintaining its therapeutic activity.

Cellular Uptake and Intracellular Delivery – Oligos need to be efficiently taken up by target cells to exert their therapeutic effects, but their large size and other aspects hinder cellular uptake. Developing effective delivery systems that can facilitate cellular entry and intracellular delivery is a significant challenge.

Pharmacokinetics Oligos can exhibit a short plasma half-life due to rapid renal clearance and enzymatic degradation. Formulating the drug to improve its pharmacokinetic profile, such as prolonging circulation time and reducing clearance, is crucial for optimal therapeutic outcomes.

Immunogenicity and Safety Oligos can stimulate the immune system, leading to unwanted immune responses and potential safety concerns. Formulation approaches that minimize immunogenicity while maintaining therapeutic efficacy are sought after.

Combination Therapies Oligonucleotides may need to be co-formulated with other drugs or agents for combination therapy, bringing in further complexity in formulation considerations and development.

Lyophilization And Nano Oligos often need to be lyophilized; CDMOs need this capability and capacity. Oligos face other challenges because they are packaged in lipid nanoparticles (LNPs), which again can add to formulation (and other) challenges.

3. Analytical Capabilities

I’ll refrain here from going on and on regarding the analytical challenges presented by oligos, but to say:

Most of the professionals I’ve spoken to start here when discussing the specific challenges with developing oligos. I’m told they can challenge anyone’s analytical prowess.

It is suggested that as much as possible you build up and maintain this capability internally. Or else outsource to specific analytical service providers outside of your selected CDMO.

But if you choose to hire the analytical services that come with your CDMO relationship, at the very least ensure:

(a) the CDMO has the most advanced analytical capabilities to assess purity, identity, and potency of the oligonucleotide throughout the development and manufacturing process;

(b) there are trained and experienced analytical/quality personnel who will be devoted to your program; and

(c) do as much as possible to understand the workload these professionals are under, and the timing to run assays and other testing, and return those results to clients.

4. Regulatory Experience

The FDA appears to be getting a handle on how the agency wants the above analytics and the quality/safety assessed in oligos approached. Some professionals suggest a subset of oligos will end up being viewed by the FDA (and other regulatory bodies) much similarly to small-molecule drugs.

But for the more complex oligo programs – and as technology and science advance, there’s every reason to believe larger oligos will grow even larger and more complex – the agencies will continue to define and redefine guidelines, regulations, and approval pathways.

Look, then, to rigorously access your CDMOs track record with regulatory bodies. Have they communicated well with global agencies, for example?

One thing you can be sure of: CDMOs will need to be communicative, and flexible in culture and applicability, and have the quality/analytical systems in place to adopt to regulatory changes and scrutiny.

5. Process Development Expertise

Here, too, we’ll keep what could be a deep analysis, simple.

Look for CDMOs with strong process development capabilities, with an eye to improving yields and efficiency, and optimizing the manufacturing process. These process development professionals should be well-assisted by analytical and quality help (see above), and able to communicate clearly to their clients. Decisions at this stage may end up being the most important of all decisions.

And with that we’ll move to manufacturing.

6. Large-Scale Manufacturing

Let’s throw in here another should-be obvious observation: Large Scale Manufacturing of oligonucleotide drugs can be complex and costly, especially when considering the need for high purity and consistent quality.

CDMOs need the requisite cGMP labs/facilities, and that can mean for varying volumes and amounts of material, from quite small batches to much larger ones.

GMP trained and experienced personnel should be available throughout much (and in many cases all) of your development, scale-up and final formulation and commercial manufacture.

Confirm, and continue to confirm, your CDMO's capacity. Many have reported elongated – as much as 18-month lead times – for oligo development batches and manufacturing.

7. Project Management and Communication

Effective project management and clear communication are crucial for a successful collaboration in any sponsor-provider relationship, but at this point in our busy industry, and considering the rapid advancement of oligo science and technology, these attributes have never been more important.

Important, that is, internally as well as with external partners. Both sides of the oligo-outsourcing equation need to be in full collaboration and communication mode, and stay on top of progress, and setbacks.

If 2024 is to be another year of the advancement of oligonucleotides, much will rely on these eternal outsourcing fundamentals.