Assuring quality of oligonucleotide APIs and DPs

This article discusses necessary steps to execute and assure quality of oligonucleotide Active Pharmaceutical Ingredients (APIs) and Drug Products (DPs), as well as compliance and expectations from regulatory agencies.

The basis of this work begins with “good science” and a grounded understanding of the drug development process.

Most start-up or mid-size life sciences organizations face the challenge of bridging the gap between research and regulated drug development to accelerate the time to market without sacrificing quality. Many of these organizations outsource most, if not all, of the drug development activities. As such, the first step towards accelerating time to market and building quality into the product is knowing that as the Sponsor, you must be the expert about your products, so you can collaborate with vendors appropriately in order to ensure clear communication of responsibilities (see Figure 1).

Sponsors need to share important information with vendors to inform drug and process development. And while information (e.g., journal articles, other company or therapeutic drug product labels, API or DP specifications, and stability data) can inform the process, it must not be the sole basis for how to manufacture and/or test/release a therapeutic.

The operational challenges involved with developing oligonucleotide therapeutics can include having smaller and fewer batches that offer limited batch history and stability data; managing novel chemistries, conjugates, and delivery systems; dealing with longer and more complex development timelines; and understanding regulatory expectations. Once we recognize these challenges, we can begin to proactively devise the plans necessary to accelerate drug development while building quality into the product.

To accelerate drug development and ensure that the drug sold to the public is safe and meets appropriate quality standards, consider front-loading your CMC plan. This approach offers the opportunity to make informed decisions sooner related to candidate selection and design. It also can help you select candidates to promote through the development process faster based on criteria associated with accelerated development such as ease of manufacture, available regulatory guidance, and similar approved products or special designations.

Three areas to consider when developing an operational plan to accelerate development and ensure quality are (see Figure 2):

When considering regulatory plans, remember oligonucleotides are considered “big small molecules” and are expected to meet the ICH guidelines for New Chemical Entities (small molecules) (1).

When characterizing your oligonucleotides, the expectations for testing are not that clear, especially when it comes to related substances. Related substances in oligonucleotides can arise from a variety of sources and are typically divided into process-related and product-related type of impurities. Process-related substances of oligonucleotide therapeutics are covered adequately by the current ICH small molecule guidelines; however,  potential product-related substances are not addressed by the ICH guidelines. ICH Q3A (2) and ICH Q6A specifically exclude oligonucleotides from the scope of those documents. Therefore, no regulatory guidance is available on what reporting, identifying, and qualifying thresholds should be used for oligonucleotide product-related substances. In 2017, the Oligonucleotide Safety Working Group (OSWG) published on impurities in oligonucleotide Drug Substances and Products (3) and categorized impurities as detailed in Table A.

A number of organizations have taken this approach using the OSWG proposal; however, it is recommended that you collaborate closely with your vendor or internal stakeholders to build understanding and agreement on (see Figure 4):

Capturing these details in a documented plan helps solidify and focus efforts, yielding efficiencies that can accelerate development and assure quality of the product.

Four elements comprise specifications: product detail information, test attributes, testing method, and acceptance criteria. In many instances, the Sponsor delegates establishment of specifications to the CMO. This may be fine for raw materials, like commonly used amidites, that most CMOs have familiarity with, but not for specialty raw materials or the product itself.

Since the Sponsor has the most knowledge of the product, it is critical they drive these conversations and work collaboratively with the CMO, internal stakeholders, and other parties (preclinical/tox CROs). Given regulatory agencies rarely define specification limits except for patient safety (e.g., residual solvents, heavy metals, sterility, particulate matter, endotoxin levels of parenteral dosage forms), setting specifications needs to be well thought out and based on data.

As all parties have contributions to make; setting specifications takes a village.

The Sponsor captures the supporting rationale and data for specifications in a Justification of Specification (JOS) document. The JOS is revised and updated as development progresses and more data informs specification adjustments. Use preclinical and clinical exposures to establish “threshold of safety” to “qualify” key known/specified process related impurities. Managed well, these “threshold limits” should be higher than what the manufacturing process can effectively deliver, even upon scale up.

The justification of limits can then be argued on “process control” grounds rather than patient safety. Such an approach will pay off during late-stage development through product launch when the process needs to be scaled up and potentially moved to multiple manufacturing sites. Setting specifications for impurities requires careful consideration to meet reporting requirements as discussed above.

Using formal change controls for modifications to specifications and acceptance criteria will ensure adequate scientific justification for changes, alignment with all regulatory filings, as well as CMO specifications.

Analytical Test Methods Validation vs. Verification vs. Qualification

Both generic/compendial and custom/oligonucleotide specific analytical test methods will be necessary to characterize the drug, release batches, and test stability samples.

Generic/Compendial test methods (see Figure 4) only require verification. Custom/Oligonucleotide specific test methods require validation. Verification and validation can be time-consuming activities, if not approached correctly. To ensure methods are scientifically sound and appropriate, approach method development with validation in mind.

Once the method’s intended use is defined, use the table in ICH Q2 (4) to classify the method into one of four categories shown (Identification, Testing for Impurities—Quantitative, Testing for Impurities—Limit, or Assay). Based on the classification, determine the required validation characteristics for each method type. Demonstrate that the method performs as intended through implementing controlled qualification experiments, which use authentically prepared standards and markers or crude samples. Develop appropriate system suitability criteria to assure method performance. Use this data to inform decisions for specification limits.

To conduct stability studies, analytical methods that have been shown to be scientifically sound and appropriate and stability-indicating are required. To meet these requirements, methods need to be qualified and used to analyze samples that have been part of a forced degradation study. Regulations state that these activities don’t need to occur until Phase 3; however, if building quality into your product and accelerating development is your goal, these activities must happen sooner.

Typical method validation timing that usually meets regulatory expectations includes qualifying non-safety methods for early clinical development, as well as validating:

If conducted early, stability studies can accelerate development and inform drug design, formulation, manufacturing, and clinical study design decisions.

Three types of stability studies provide different information:

Given the pace of change in development of oligonucleotide therapeutics, keeping up with evolving regulatory expectations is paramount, as is understanding the development process or bringing on the people or vendors who do—and listening to them. Should you have challenges in complying with ICH guidelines for an oligonucleotide-based product, it is incumbent on the Sponsor to engage with regulators and gain alignment.

Plan all activities with a view to the long term. Remember that making quality a priority is a vital element of the final product. It begins with a company culture where people feel safe and empowered to share concerns and voice them when appropriate.

Figure 1.

Table A. Proposed Oligonucleotide Impurity Classification by the OSWG Impurity Class.

Figure 3.

Figure 4.