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CMC IMP considerations for Oligonucleotides

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The challenge of oligonucleotide delivery

The only effective way to administer an oligonucleotide is by injection into the target organ. Oligonucleotides are typically large hydrophilic polyanions, meaning they do not easily pass through plasma membranes. Several factors prevent these molecules from reaching their correct intracellular site of action. As a result, almost all approved oligonucleotide drugs must be administered locally. At the moment the liver is the only exception due to its high tissue perfusion and abundance of receptors that facilitate oligonucleotide uptake.

Strategies for enhancing oligonucleotide delivery

There are numerous strategies being developed to enhance the delivery of oligonucleotides, potentially changing the formulation and mode of drug delivery. However for now, we have to manufacture a sterile injection formulation. For this reason, the current guidance for sterile manufacturing is applicable for oligonucleotide manufacturing, and as mentioned in a previous blog "Minimising impurity formation in oligonucleotide synthesis", ICH Q6A should be considered for oligonucleotide drug products as most tests as described in 3.3.2.3 are applicable for this type of formulation with the exception of some non-compendial tests.

Oligonucleotide drug product manufacturing process

The general process flow for drug product manufacturing of oligonucleotides is relatively simple. Lyophilization of synthetic oligonucleotides is considered common practice and for that reason it can be assumed that the API used in drug product manufacturing is a lyophilized powder.

These APIs generally dissolve well in an aqueous solution. Water as its only excipient may be sufficient in many cases but stability or tonicity limitations may require the addition of other excipients. Oligonucleotide DP concentrations may vary significantly depending on the method of delivery. Intravenous products generally utilise lower DP concentrations compared with products delivered subcutaneously.

In-process controls to determine the concentration of the drug product solution can be considered but in-process controls to assess the microbiological burden of the product or filter integrity should be in place.

Considerations for drug product concentration and Sterility

Oligonucleotide drug product (DP) concentrations vary depending on the delivery method. 

A primary function of the parenteral drug product manufacturing process is to ensure sterility of the final product. Generally, oligonucleotides are sterilised by membrane filtration followed by aseptic filling and finish. Currently, the only sterilisation technique used for marketed oligonucleotide drug products, for which public information is available, is exclusively by membrane filtration. In most cases, the justification for using sterile filtration and aseptic processing over terminal sterilisation (TS) was due to an observed negative impact of TS to product quality. However, TS provides greater sterility assurance than membrane sterilisation and it is a regulatory expectation that TS is the preferred method for sterilising parenteral products.

Oligonucleotides may have fundamental differences in physical and chemical properties between subclasses and therefore feasibility assessment for TS should be performed on a case-by-case basis and follow a scientific and risk-based approach. 

Platform knowledge is important and may be sufficient to rule out TS for a given chemical entity, provided there is deep understanding of the impacts of the sterilisation process on the product. For more thermally stable oligonucleotides and instances where deep product and process knowledge does not exist, feasibility must be assessed by well-designed and controlled laboratory studies.

Solid vs. liquid oligonucleotide APIs

As mentioned oligonucleotide APIs are typically provided as a lyophilized powder, but there is a growing interest in having the API as a solution, although this is not in line with current guidance, for example: EMA guidance. Here is a list of pros and cons for a solid or liquid API. The most important factors to have Oligonucleotides as a solution are stability and microbiology.

In general, oligonucleotides are very stable in solution at 2C–8C around neutral pH and with common excipients such as sodium chloride. Additional steps in the drug substance manufacturing process to obtain a solid may have a negative influence on physical or chemical stability. 

As we are manufacturing a sterile product microbiology is an important factor. Although the microbiological stability of a solid is typically better than a liquid an additional compounding step in the drug product manufacturing process may eliminate this benefit. Compounding of a solid to a solution occurs typically in a GMP grade C area before transferring the GMP grade B and A for Aseptic Fill-Finish, while API in solution may be used directly in GMP grade B and A.

Advantages of a solution API

This method, commonly used in biologics, eliminates dissolution and compounding steps required for powder APIs. It also allows for process flexibility, enabling dilution adjustments for different drug product concentrations.

A solution API offers greater robustness and efficiency in drug product manufacturing. The ready-to-fill solution API is common for biologics. This scenario is the least complex and this approach eliminates the initial dissolution and compounding steps in the DP manufacturing process that are required with a powder API. Additional dilution steps may be added to the same process if the final product requires different drug product concentrations. 

Regulatory considerations for solution APIs

Currently, the EMA considers formulated oligonucleotide APIs, (solution APIs) as drug product intermediates rather than drug substances. This is in contrast with formulated biologic APIs. The current regulatory framework is more restrictive for oligonucleotides and the use of formulated APIs should be justified extensively with improved stability over solid APIs. The manufacturing process should be substantially more sustainable, incorporating less resource-intensive steps in both drug substance and drug product production.

However, the current draft of the EMA Guideline on the Development and Manufacture of Oligonucleotides includes the option of solution APIs, provided some requirements are met. The composition of the formulation should be clearly defined, components used in the manufacture of the formulated API should be controlled as critical raw materials, and the downstream process must be adequately characterised and controlled to consistently produce API meeting its quality targets. 

Ensuring quality and microbial control

Microbial controls incorporated into the process should assure consistent delivery of low bioburden, low endotoxin-formulated API appropriate for further aseptic processing yielding a sterile drug product. The microbial control strategy should include elements of facility design, process controls, personnel requirements, environmental and utility monitoring systems, and procedural responses to contamination.

Stay tuned for part three of our series, where we’ll explore oligonucleotide progression into early phase studies.

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