Driving Innovation in Nucleic Acid Therapeutics

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In the rapidly evolving landscape of healthcare, nucleic acid therapeutics have emerged as a promising frontier. These innovative treatments, which include modalities such as antisense oligonucleotides, messenger RNAs (mRNAs), small interfering RNAs (siRNAs), microRNAs (miRNAs), aptamers, and gene therapies, have the potential to address a wide range of diseases, from rare and infectious diseases to cancers (1), and offer hope for many patients worldwide.

Each modality presents unique mechanisms of action and therapeutic potential, broadening the scope of diseases that can be targeted. However, the journey from concept to clinic is fraught with challenges, particularly in the areas of manufacturing, regulatory compliance, and technological innovation.

GMP compliance and regulatory adherence

Ensuring GMP compliance and regulatory adherence are paramount in the manufacture of any medicine. When considering a nucleic acid therapeutic, the intricate nature of manufacturing processes and the high standards required to produce safe and effective therapies only emphasize this importance. GMP guidelines provide a framework for maintaining consistency, quality, and safety throughout the manufacturing process, mitigating risks of contamination, variability, and product failure. Regulatory requirements further ensure that nucleic acid therapeutics meet these stringent standards before they can be brought to market.

Navigating the intricate landscape of nucleic acid manufacturing regulations, guidelines, and best practices requires specialist knowledge and expertise. Partnering with a knowledgeable contract development and manufacturing organization (CDMO) specializing in nucleic acid therapeutics becomes imperative. An experienced CDMO partner brings a thorough understanding of GMP compliance and regulatory affairs with which to offer guidance and support throughout the manufacturing process. A CDMO’s expertise ensures that all regulatory requirements are met, which minimizes the risk of delays, rejections, or compliance issues that could hinder the progress of nucleic acid therapeutic development.

Key principles of GMP

The core of GMP lies in ensuring accountability, documentation, and traceability throughout the manufacturing process. This involves meticulously documenting who performs each task and tracking all materials and manipulation steps involved. For example, when producing mRNA therapeutics, adherence to GMP principles remains critical, mirroring the requirements for any drug product.

However, certain aspects of GMP, particularly regarding DNA starting material, may require interpretation due to the lack of clear guidance in both the United States and Europe. The industry currently relies on a risk-based approach outlined in a question and answer series provided by the European Medicines Agency (EMA) (2). While this resource provides a starting point, further clarification is needed.

The principles of GMP revolve around the philosophy of work execution, while regulatory guidance provides the framework for compliance. Within this framework, quality systems follow the attributable, legible, contemporaneous, original, and accurate principles, emphasizing the importance of knowing who does what, when, and with what, and ensuring comprehensive documentation.

Regulatory requirements dictate the systems necessary to meet these principles, including the design of risk-based approaches and the identification and control of risks throughout the manufacturing process. This extends to demonstrating process control for the manufacturing process itself, identifying critical process parameters and quality attributes, and defining parameters to maintain during drug manufacturing.

In essence, GMP principles serve as the philosophy guiding work execution. At the same time, regulatory requirements define the systems and approaches necessary for compliance—essential to ensuring the quality, safety, and efficacy of nucleic acid therapeutics.

Challenges and strategies to maintain compliance

The nucleic acid therapeutic manufacturing landscape presents specific challenges in maintaining GMP compliance and meeting broader regulatory expectations. One of the primary challenges lies in the manual processes traditionally used for mRNA and encapsulated RNA production, leading to human error and potential contamination. To address this, leveraging automated robotic equipment, minimizes human intervention, reduces errors, and mitigates contamination risks.

A significant industry-wide challenge in the mRNA space pertains to analytics, particularly regarding double-stranded RNA. Understanding the immunogenicity and tolerance levels of double-stranded RNA for different indications remains a hurdle. The current variability in analytical tests, ranging from characterized antibodies to rudimentary dot plot assays, further complicates the situation. To overcome these challenges, industry efforts are focused on enhancing analytics for double-stranded RNA.

Best practices for ensuring GMP compliance revolve around automation to minimize human interaction with the product. By removing or reducing human intervention, the risk of errors and contamination is significantly reduced. Additionally, traditional mRNA production involves scaling up in volume, which poses complexities due to non-linear scaling of parameters such as shear and thermodynamics.

An ideal approach streamlines this process by maintaining a set volume and process. An effective strategy for this is scaling out using robotic parallel reactions to maintain consistency in production regardless of batch size. This simplified approach streamlines production and simplifies the chemistry, manufacturing, and controls process by keeping process parameters consistent across different material volumes.

Role of innovative technologies

Investment in novel and innovative technologies is pivotal in enhancing the efficiency, scalability, and quality of nucleic acid therapeutics manufacturing. By leveraging these technologies, such as continuous, optimized, and high-yield manufacturing platforms, significant improvements are observed across various aspects of the manufacturing process.

Firstly, these innovative technologies enable more concentrated reactions with higher yields, leading to a decrease in costs of goods by efficiently converting raw ingredients into final products. Additionally, the reduction in manipulation time and faster reaction rates further contribute to cost savings, as time is a critical factor in manufacturing operations.

The integration of continuous manufacturing platforms allows for decentralized manufacturing, as the set process and equipment can be deployed at any global location to achieve consistent results. This flexibility not only enhances efficiency but also opens doors to global collaboration and market access.

Although cost reduction is a significant benefit of these technologies, their impact extends beyond financial metrics. Consistency of the product is also enhanced, as the process remains standardized and repeatable. This not only ensures product quality but also minimizes the need for expensive rework or adjustments.

In addition to these tangible benefits, there is a theoretical potential to reduce raw material costs for the actual in-vitro transcription process. The efficiency of the manufacturing process means that less starting material is required, leading to potential savings in raw material expenses. As time goes by and continuous manufacturing programs are more widely adopted, there is potential to collect a greater amount of real-world data to add support to this hypothesis, presenting a promising avenue for further exploration and optimization.

Furthermore, it is crucial to highlight other pertinent technologies in the field of nucleic acid manufacturing. Several groups and companies are actively working on similar aspects of RNA manufacturing, utilizing innovative approaches and automation. For instance, similar continuous manufacturing platforms are being developed, with pioneering microfluidics-based approaches for RNA production representing one of these exciting technologies. Additionally, academic groups worldwide are also exploring automated equipment to streamline nucleic acid manufacturing processes, showcasing the collaborative efforts driving innovation in the industry.

Navigating the regulatory landscape

Navigating the complex regulatory landscape to ensure compliance with diverse global, regional, and industry-specific regulations is essential. Companies with dedicated expertise in these areas play a pivotal role in guiding regulatory compliance across markets such as the US, Europe, Japan, and others. A CDMO that extends this expertise as a service to clients can be critical to project success, assisting companies in meeting regulatory requirements and facilitating regulatory filings.

This service is particularly crucial for drug developers who may lack extensive quality teams or experience in navigating regulatory complexities. By offering regulatory assistance, clients are free and empowered to focus on bringing their therapeutics to patients efficiently. Whether it’s providing documentation support for regulatory filings or representing clients at regulatory meetings, streamlining the regulatory process and accelerating the path to market are vital facets to remaining competitive in a modern market.

Part of an industry-wide effort to ease the pathway of medicines to approval is seen in international harmonization. The role of international harmonization efforts in shaping GMP standards and regulatory frameworks holds immense significance in nucleic acid therapeutic development and commercialization. Diseases and conditions, including cancer and infectious diseases such as coronaviruses, transcend borders, thus necessitating a streamlined regulatory approach. Harmonizing regulations allows for a more straightforward path to bringing therapeutics to market, ensuring consistency in defining indications and manufacturing techniques across different regions.

In recent discussions at mRNA meetings convened by both FDA and EMA, there has been a concerted effort to integrate and align regulatory approaches globally (3). The goal is to establish a unified set of rules that can be applied on a global scale, fostering a conducive environment for the development and commercialization of nucleic acid therapeutics.

Effectively integrating novel technologies

As pioneers in nucleic acid therapeutic manufacturing, it is important to lead the charge in effectively integrating novel technologies—all while upholding stringent regulatory standards. Specialized companies dedicated to advancing nucleic acid technologies are pivotal in bringing innovative solutions to the market, with exciting advances such as continuous manufacturing laying the groundwork for faster mRNA generation with high quality.

Although these advancements are impressive, it is essential to recognize that the ultimate goal is to make biologics available and affordable to all patients in need. Therefore, alongside the pursuit of cutting-edge technologies, there is a critical need for services aimed at ensuring the accessibility and affordability of these therapies. By combining innovation with a commitment to equitable access, the industry can revolutionize healthcare and improve patient outcomes on a global scale.

A foundational approach to achieving this integration lies in adopting a quality-by-design (QbD) methodology. By embracing QbD principles, manufacturers can ensure that novel technologies are seamlessly incorporated into the manufacturing process without compromising regulatory standards. This includes rigorous compliance with regulations such as 21 Code of Federal Regulations Part 11, which governs the use of software in manufacturing processes, ensuring robust control and governance over electronic records and data acquisition. Features such as access control, version control, and audit trails are vital components in maintaining the reliability and integrity of electronic records, ensuring they meet or exceed the standards set for traditional paper records.

Moreover, the implementation of a design of experiments (DoE) approach further strengthens the integration of novel technologies. Through DoE, critical factors in the manufacturing process are identified and optimized, ensuring that the benefits of new technologies are maximized while adhering to regulatory requirements. This systematic approach not only facilitates the seamless integration of novel technologies but also ensures that regulatory considerations are embedded into the development process from the outset.

Emerging trends

With the continual approval of new nucleic acid therapeutics globally, regulatory standards are becoming increasingly stringent, necessitating industry-wide adherence. Regulatory agencies emphasize the control of critical process parameters and demand additional robustness data for analytical assays. Notably, a trend toward standardization of quality control assays is evident, particularly in advancements in the double-stranded RNA assay. To address assay variability, companies explore innovative solutions such as manufacturing internal standards and fostering consistency in assay results across different sites.

Proactive preparation for evolving regulatory requirements is crucial for industry stakeholders. Demonstrating unwavering commitment to consistency and adherence to standards through standardized, scalable processes enhances regulatory confidence and streamlines compliance efforts. Moreover, engagement with stakeholders, including regulatory bodies, during the early stages of product development is essential. Open communication and knowledge-sharing about emerging techniques facilitate collaborative efforts to address potential concerns and pave the way for smoother regulatory approval processes.

Fueling future innovation

Looking ahead, the future of nucleic acid therapeutic manufacturing holds great promise, fueled by advancements in GMP compliance, technological innovation, and regulatory success. As the industry continues to navigate the complexities of this evolving landscape, it is clear that collaboration between industry stakeholders, along with expert guidance from specialized CDMOs, will be crucial in driving forward innovation and ensuring the success of nucleic acid therapeutics in improving patient outcomes.

Furthermore, the role of technological innovation in enhancing efficiency, scalability, and quality in nucleic acid manufacturing is essential. Continuous advancements in technology, including optimized and high-yield manufacturing platforms, are driving innovation and setting new standards in the industry.

By remaining committed to GMP compliance principles in achieving regulatory success, and embracing technological innovation, the future of nucleic acid therapeutic manufacturing is bright and poised to revolutionize healthcare.

References

1. ASGCT. Gene, Cell, + RNA Therapy Landscape Report: Q4 2023 Quarterly Data Report. ASGCT, 2023.
2. EMA. EMA/246400/2021, Questions and Answers on the Principles of GMP for the Manufacturing of Starting Materials of Biological Origin Used to Transfer Genetic Material for the Manufacturing of ATMPs (Feb. 24, 2021).
3. EMA. Regulatory and Scientific Virtual Conference on RNA-based Medicines (Feb. 3, 2023).

About the author

Patrick Thiavilleis chief technology officer of Exothera.

Article Details

BioPharm International
Volume 37, No.4
April 2024
Pages: 14–16, 24

Citation

When referring to this article, please cite it as Thiaville, P. Driving Innovation in Nucleic Acid Therapeutics. BioPharm International 2024, 37 (4), 14–16, 24.