A Roadmap to Quality: Performing CMC Activities with an NDA In Mind

Oligonucleotide therapeutics development continues to accelerate with progress in oligonucleotide chemistry and adoption of delivery technologies. This article discusses necessary steps to execute and assure quality of oligonucleotide Active Pharmaceutical Ingredients (APIs) and Drug Products (DPs). It will also discuss compliance and expectations from regulatory agencies.

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

Responsibilities of Sponsor and Vendors

A company has a platform, a therapeutic, or several candidates. They have conducted research, published papers, applied for and obtained grants, and may have other sources of funding. So what now? How do they efficiently bridge the gap between research and regulated drug development to accelerate the time to market without sacrificing quality?

Most start-up or mid-size life sciences organizations are faced with this challenge. And also, 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. 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. (See Figure 1).

The operational challenges involved with developing oligonucleotide therapeutics can include having smaller and fewer batches that off er 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.

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.

This type of approach can also be applied to developing toxicology studies, so they align with process improvements and changes in the formulation. Such types of changes typically require additional toxicology studies and/or changes to bioanalytical methods resulting in revalidation or bridging studies.

Operational and Regulatory Considerations

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

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 fi ling 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

When characterizing your oligonucleotides, the expectations for testing are clear (see Figure 3).

That said, collaborate closely with your vendor or internal stakeholders to build an understanding of and an agreement on (see Figure 4):

• Where raw materials (for APIs) and excipients (for DPs) will be sourced, what testing will be performed, and what the associated specifications will be.
• What in-process controls will be used and the associated specifications.
• What specifications and tests will be required for the API and DP.
• What will be the stability requirements/design for the raw materials, any process intermediates, and API/DP.

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

Specifications: How Are They Set and 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. 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 these are based on multiple sources (data from safety/tox studies, process capability, drug stability and capability/limitations of analytical methods), 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; setting specifications takes a village.

• Pharmacology ensures that specifications allow the drug to maintain its activity. This is particularly important during optimization of drug product formulation and label claim.
• Toxicology makes sure the drug batch tested in safety studies has the widest array and levels of all potential impurities while maintaining integrity of the safety study. This key factor will allow justification of the lower limits of drug purity, as it will directly provide the highest exposures of key process related impurities. When toxicology studies are managed well, the clinical drug quality can be incrementally improved to afford an additional margin of safety while allowing flexibility in manufacturing.
• Process Development/Manufacturing makes certain the proposed quality specifications can be consistently met, particularly when scaling up or moving to contract manufacturing facilities and commercial manufacturing.
• Analytical Development/Quality Control confirms the methods used have the capability to test to the proposed specifications and will continue to operate in the manufacturing Quality Control department of a commercial facility.
• Quality Assurance/Regulatory ensures that proposed Quality specifications will meet expectations of all relevant regulatory agencies.

To reduce churn and maintain access to institutional knowledge, 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. When contemplating the development of specifications, start wide and narrow as you obtain data. Remember to justify limits on safety arguments, not process capability. 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.

Changes to specifications may be made if managed carefully and documented/justified properly. Tightening specification limits may be done at any time, assuming the Sponsor is confident that the process and methods can deliver to tighter limits, and there is data to support them. Conversely, widening specification limits is possible provided sufficient data exists to assure the safety of the new limit. Setting specifications for impurities requires careful consideration to meet the spirit of the reporting requirements as outlined in ICH Q3.²

Considerations for 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 require 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 are different (more restrictive) than stability specifications. Differences, such as potency or impurities, must account for the degradation. Shelf-life specifications must guarantee Safety, Identity, Strength, Purity, and Quality (SISPQ) at the end of shelf-life. Using formal change controls for modifications to specifications and acceptance criteria will ensure adequate scientific justification for changes, alignment with all regulatory fi lings, as well as CMO specifications.

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 (see Figure 5) 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, and provide reliable data with integrity, approach method development with validation in mind. Start early with documenting the method’s intended use (purpose).

Once the method’s intended use is defined, use the table in ICH Q23 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.

The timing for validation of analytical methods has historically been a confusing topic, but if one takes a commonsense approach, it can be simple. What CMC activity takes the longest to conduct, is critical for an IND or NDA submission and requires analytical testing? The answer—stability. Like pregnancy, it takes the time it needs, and no amount of added money or resources will change that.

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 while accelerating development is your goal, these activities must happen much sooner.

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

• All safety methods before any administration to humans and all critical methods (e.g., potency and purity/impurities) before initial use in routine testing (batch release).
• Methods when transferring to another laboratory.
• Whenever conditions or method parameters for which the method has been validated change, and the change is outside the original scope of the method.
• All regulatory methods before production of material for your pivotal efficacy trials (usually Clinical Phase 3).
• Methods earlier at the request of a regulatory agency

Stability

As previously indicated, stability studies are a necessary component of any submission and also 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, with storage stability studies having the longest timeframes:

• Storage stability studies establish acceptable storage timeframes.
  • Drug Product—establishes shelf-life or expiration. This is the period during which a drug product is expected to remain within the approved shelf-life specification, provided that it is stored under the conditions defined on the container label.
  • Drug substance—establishes the retest period. This is the period during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given DP, provided that the drug substance has been stored under the defined conditions.
• In-use stability studies establish the acceptable timeframe between when a drug is prepared and administered; they inform components of the pharmacy manual or DP handling instructions used in the pharmacy.
• Stress (Forced Degradation) stability studies establish a method’s stability indicating capability and the drug’s degradation pathways under various conditions.

Other stability studies that may be performed include freeze/thaw studies that establish impact of multiple freeze/thaw cycles on the drug substance or product, and multi-use studies that provide insight into impact of multi-use containers (e.g., multiple septa pierces).

Assuring Quality and Compliance of Your Oligonucleotide APIs and DPs

As the development of oligonucleotide therapeutics continues to accelerate, it is vital to do good science and keep quality in mind throughout the process. Given the pace of change in this area, 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. Evaluate, select, and qualify the right vendors and consultants. You must also ensure you have the right internal people to effectively manage external relationships and drive programs.

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.

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. ICH Q2 Validation of Analytical Procedures: Text and Methodology

Author Biography

Judy Carmody, PhD is the founder and Principal Consultant of Carmody Quality Solutions, LLC, a quality solutions provider to life science startups and global Fortune 500 organizations who are passionate about keeping patients safe and delivering quality products. Dr. Carmody has 25+ years of expertise driving vision in quality and operations. She is the former founder and president of Avatar Pharmaceutical Services, an FDA-registered contract research organization and manufacturer which was acquired by Vertex Pharmaceuticals in 2010.