As oligonucleotide therapeutics development continues to accelerate, there are necessary steps to execute and assure quality of oligonucleotide Active Pharmaceutical Ingredients (APIs) and Drug Products (DPs).
The basis of this work begins with “good science” as well as a substantial understanding of the drug development process. Here are the major areas to consider.
Clearly Delineate Responsibilities of Sponsor and Vendors
After a company has conducted research, published papers, applied for and obtained funding sources, what’s next? How do they efficiently bridge the gap between research and regulated drug development? Most start-up or mid-size life sciences organizations are faced with this challenge, outsourcing most, if not all, drug development activities.
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. This allows you to collaborate with Vendors appropriately. Sponsors must work to build a collaborative approach from the beginning in order to ensure clear communication of responsibilities. Sponsors need to share important information with Vendors to inform drug and process development.
Starting with a strong knowledge base around regulatory requirements is vital to lay the foundation for a successful application review. And while there are accelerated options for clinical development and regulatory review, it is critically important to know there are no meaningful changes to CMC/Quality requirements with any of these options. This means that, if any accelerated options are granted, there is less time to produce the same amount of CMC/Quality work for submission.
Create Strategic Development Plans With the NDA In Mind
Typically, CMC plan development happens with a back-ended approach; however, 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.
Operational and Regulatory Considerations
Three areas to consider when developing an operational plan to accelerate your development and ensure quality integration include:
1.Manufacturing
Strive to keep the process as simple as possible, perform characterization early in development, and get control of amidites and other key raw materials.
2. Quality Control
Work on developing specifications in compliance with ICH from the beginning and identify impurities and degradation products as early as possible. Build a comprehensive control strategy from raw materials, intermediate products, and final API, DP, and finished drug product. Perform all experiments with appropriate controls, so as to make available for filing as supportive data.
3. Stability
Be strategic in designing stability studies to allow for the filing of data in a regulatory submission. Conduct forced degradation studies early to inform and adjust method’s capabilities.
When considering regulatory plans, remember that oligonucleotides are considered “big small molecules” and are expected to meet the ICH guidelines for New Chemical Entities (small molecules).1
Setting Specifications: How Are They Set? Who’s Responsible?
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. 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).
Specifications are based on multiple sources (data from safety/tox studies, process capability, drug stability and capability/limitations of analytical methods), and regulatory agencies rarely define specification limits except for patient safety (e.g., residual solvents, heavy metals, sterility, particulate matter, or endotoxin levels of parenteral dosage forms). Setting specifications needs to be a well-thought-out exercise based on data, rather than conjecture—“throwing darts at a dart board.”
As all parties and functions have contributions to make—from Pharmacology and Toxicology to Process Development/Manufacturing, Analytical Development/Quality Control, and Quality Assurance/Regulatory—it takes a village to set specifications to meet the spirit of the reporting requirements as outlined in ICH Q32 (and Capaldi et al3 for impurities).
Consider Release Versus Stability Specifications
Release specifications involve criteria that must be met at the time of release of a specific batch of drug substance or drug product. Stability specifications involve criteria that must be met over the entire shelf-life of the DP. Each requires scientific justification using results from accelerated and long-term stability studies. If the DP attributes do not change over shelf-life, release specifications are the same as the stability. However, if DP attributes do change over shelf-life, then release specifications will be different (more restrictive) than stability specifications.
Examine Analytical Test Methods Validation Versus 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 only require verification. Custom/Oligonucleotide specific test methods require validation according to ICH Q24. Since verification and validation can be time-consuming activities, ensure that methods are scientifically sound and appropriate, and provide reliable data with integrity, through proper development and qualification. Approach method development with validation in mind. Start early with documenting the method’s intended use (purpose) in an analytical test method profile, conduct forced degradation studies and qualification to determine the method’s capability and obtain the data to support the acceptance criteria for validation.
The timing for validation of analytical methods has historically been a confusing topic, but if one takes a commonsense approach, it can be simple. Typical Method Validation timing that usually meets Regulatory Expectations:
● Qualify non-safety methods for early clinical development
● Validate all safety methods before any administration to humans (including purity/impurity methods)
● For critical methods (e.g., potency) – Before initial use in routine testing (release testing)
● When transferred to another laboratory
● Whenever the conditions or method parameters for which the method has been validated change and the change is outside the original scope of the method
● Validate all Regulatory Methods before production of material for your Pivotal Efficacy Trials (usually Clinical Phase 3)
● Validate earlier at the request of a Regulatory Agency
Be Thoughtful About Stability Studies
Stability studies are necessary for any submission and can have long timelines depending on the study. If conducted early, they can accelerate development and inform drug design, formulation, manufacturing, and clinical study design decisions.
Three types of stability studies provide different information: Storage studies (which have the longest time frames) support retest dates and shelf-life periods; in-use studies, which establish the acceptable time frame between when a drug is prepared and administered; and stress (forced degradation) studies, which establish a method’s stability indicating capability as well as the drug’s degradation pathways under various conditions.
Be thoughtful about your design. For storage studies consider:
● Worse case scenarios (inverted orientation) to ensure contact of your product with the closure will not be an issue
● Container Closure Integrity Testing (CCIT) vs Sterility Testing – note, they both have to be performed at release before CCIT can be used to replace Sterility Testing
● Using a bracketing design to conserve on material and resources
For in-use studies, don’t try to boil the ocean and test every IV kit that exists. If your drug product has sensitivities to particular plastics then find the IV kit that works with your drug product and consider providing that to the clinical sites or providing the budget for them to procure it. If your drug product doesn’t have any sensitivities to the materials of construction of IV kits then consider testing 2-3 of the most commonly used kits.
Assuring Quality and Compliance of Your Oligonucleotide APIs and DPs
Given the pace of change, 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.
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.
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References:
1. ICH Q11 Development and manufacture of drug substances (chemical entities and biotechnological/biological entities).
2. ICH Q3A Impurities in New Drug Substances and ICH Q3B Impurities in New Drug Products.
3. Capaldi D, Teasdale A, Henry S, Akhtar N, den Besten C, Gao-Sheridan S, Kretschmer M, Sharpe N, Andrews B, Burm B, Foy J. Impurities in Oligonucleotide Drug Substances and Drug Products. Nucleic Acid Ther. 2017 Dec;27(6):309-322. doi: 10.1089/nat.2017.0691. Epub 2017 Nov 10. PMID: 29125795.
4. ICH Q2 Validation of Analytical Procedures: Text and Methodology.
