Advance Manufacturing Technology (AMT) : Regulatory Perspective (US-FDA and EU-EMA)

Thursday, August 1, 2024

Recent scientific advances from genomic sequencing to the development of cell and gene therapies, nanotechnologies, end-to-end manufacturing, continuous manufacturing, and regulatory acceptance of these technologies as well as the introduction of IoT, IIoT, AI/ML, and digital twin into the biopharma manufacturing industry have brought the promise of significant improvements to the health of many millions of patients throughout the world. To date, however, we have seen little of this promise in our day-to-day lives because a large and persistent gap separates important scientific advances and the technologies needed to translate those advances into new therapies for patients and new ways to protect public health. The FDA’s Technology Modernization Action Plan (TMAP),6 described in their document, is an important step the US FDA is taking to address and close the gap. The plan describes important near-term actions that the FDA is taking to modernize the use of technology to advance the FDA’s public health mission. TMAP has three elements

  1. Modernization of FDA’s technical infrastructure
  2. Enhancing FDA’s capabilities to develop technology products to support its regulatory mission
  3. Communication and collaboration with stakeholders to drive technological progress that is interoperable across the system and delivers value to consumers and patients

The TMAP provides a sturdy technological foundation for the development of FDA’s ongoing strategy around data itself, a strategy for the stewardship, security, quality control, analysis, and real-time use of data that will accelerate the path to better therapeutic and diagnostic options for patients and clinical care providers, and better tools to enhance and promote public health.

Advanced manufacturing technologies, such as continuous manufacturing, hold great promise for improvements in the reliability, flexibility, and cost-effectiveness of manufacturing biological products. These platforms may be critical to unlocking the full potential of every novel technology like cell and gene therapies APR_JulyAug2024.indd 38 and help encourage the establishment of high-tech manufacturing platforms. The FDA is uniquely positioned to help support these technologies and scientific advances, in part by bridging the gap between the development of enabling technologies that give rise to these platforms and their advancement and implementation by industry partners. As part of these efforts, the agency is committed to supporting advances in regulatory science that can help inform our risk-based guidelines and facilitate faster adoption of innovative technologies, while ensuring the safety and efficacy of biological drug products. FDA awarded grants to five globally-recognized research institutions (Harvard University-Cambridge, MA, $599,910.; Carnegie Mellon University-Pittsburgh, PA, $599,844.; Rutgers University Piscataway, NJ, $600K; Georgia Institute of Technology-Atlanta, GA, $600K; and Massachusetts Institute of Technology-Cambridge, MA, $600K) to study ways in which Advance Manufacturing Technologies (AMT) can be implemented to advance these goals, and enable more innovative, consistent and dependable manufacturing of biological products.

The U.S. Food and Drug Administration awarded five grants, using its authority under the Federal Food, Drug, and Cosmetic Act added by the 21st Century Cures Act, to institutions of higher education and non-profit organizations to study and recommend improvements for continuous manufacturing of biological products, as well as similar innovative monitoring and control techniques.

The FDA recognizes that the implementation of emerging technologies for manufacturing high-quality complex biologics could present a variety of challenges. However, there may be a limited knowledge and experiential base about the technology by the very fact that an approach is new or innovative.

These grants aim to address knowledge and experience gaps identified for emerging manufacturing technology and support the development and adoption of such technology in the biological product sector. The agency will continue to support efforts to develop standards, policies, and policy guidance needed to foster the effective and efficient development and adoption of new manufacturing platforms and modalities.

Modernization of FDA’s Technology Infrastructure

Modernization of the FDA’s technology infrastructure will involve dynamic, enterprise-wide collaboration among agency programs. FDA’s diverse regulatory programs require technology infrastructure that is scalable and flexible. FDA’s enterprise-level technology organization, the Office of Information Management and Technology (OIMT), will have the responsibility for modernizing and maintaining the core technology platform and strategy for the FDA. OIMT will collaborate with FDA’s Centers and regulatory programs to assess business-specific needs and build a technology infrastructure that supports data and computation-intensive regulatory tools.

Technology Modernization Action Plan

The enterprise-wide modernization of FDA technology infrastructure is a multi-year strategic plan developed in collaboration with FDA Centers and external stakeholders.

Areas of focus include:

  • Cloud strategy
  • Streamlined software development capabilities for business-specific needs (“devops*”)
  • Data stewardship, data management, and data exchange including application programming interfaces (APIs), standards, and other exchange mechanisms and tools
  • Data clean-up and migration to cloud environments
  • Continued adoption of “as-a-service” models
  • Ongoing dedication to cybersecurity excellence
  • Integration of scientific computing into enterprise IT planning
  • Organizational alignment within the enterprise-level technical organization OIMT and across FDA
  • Operational excellence and multi-year technical planning
  • Cost containment and elimination of redundancy
  • Enterprise IT governance
  • Retiring legacy systems and software applications where appropriate

*DevOps:  A compound of development (Dev) and operations (Ops), DevOps is the union of people, processes, and technology to continually provide value to customers. What does DevOps mean for teams? DevOps enables formerly siloed roles—development, IT operations, quality engineering, and security—to coordinate and collaborate to produce better, more reliable products. By adopting a DevOps culture along with DevOps practices and tools, teams gain the ability to better respond to customer needs, increase confidence in the applications they build, and achieve business goals faster.

Enabling Technologies Driving Drug Research and Development - EMA

The strategic goals of the European Medicines Agency (EMA) and the European Medicines Regulatory Network are to support the research and uptake of innovative methods and technologies in the development of medicines. To promote this goal, EMA drew up a list of enabling technologies (ETs), which are novel and fast-growing technologies that have the potential to enable innovation and therefore exert considerable impact on drug development. In this work, enabling technologies identified by the EMA are analyzed to measure their impact on drug development by following their journey from publications through early regulatory interactions to clinical trials between 2019 and 2022. The current list of EMA-identified ETs was revealed by scrutinizing previously unseen innovative technologies identified in EMA submissions data. The analysis shows large variations in the appearance of the various innovative technologies in the different studied data sources, which provided valuable insights into the “Journey of Innovation” that innovative technologies undergo. Several emerging technologies were identified and endorsed for inclusion in the enabling technologies list, whereas some others already on the list were proposed to be excluded due to their low appearance in regulatory interactions as well as clinical trials and publications. Overall, this analysis highlights the relevance and value of continuously scanning and monitoring enabling technologies, supporting Europe’s goal to remain a leader in the research and development of innovative technologies, methods, and methodologies relevant to drug development.

One of the strategic goals of the European Medicines Agency (EMA) and the European Medicines Regulatory Network is to foster research and the uptake of innovative methods in the development of medicines, as set out in the “Regulatory Science Strategy to 2025”7 and the “European Medicines Agencies Network Strategy to 2025”.8 Supporting this goal, assistance and guidance are provided across the EU regulatory network through various initiatives and procedures, including Scientific Advice, Innovation Office meetings, Qualification of Novel Methodologies, and specific support for Small and Medium Sized Enterprises (SMEs). The EMA’s Innovation Task Force (ITF),9 offers an early contact point for developers for an informal dialogue on innovative scientific, technical, or legal aspects in medicines development. These early interactions enable the EMA to get an insight into emerging enabling technologies (ETs). This is also supported by Horizon Scanning initiatives at the Agency and other organizations that systematically examine information from various sources to detect early signs of important and potentially disruptive developments in the public health space.10,11

ETs are defined as novel and fast-growing technologies that have the potential to enable innovation and therefore exert considerable impact on drug development.12,13 ETs have a broad range of applications across multiple industries and fields, allowing for the creation of new, more efficient solutions and platforms to tackle societal challenges. ETs are highly adaptable and can often be combined with other technologies to create even more powerful solutions.

An example of ETs is artificial intelligence (AI), which, in the context of health, can be used to analyze large amounts of data and identify relevant patterns efficiently. AI tools can be utilized in many ways in drug research, discovery, and development.14,15 For instance, AI can make the discovery process faster, more efficient and cost-effective, better targeted, and more specific, e.g., by utilizing computational drug screening.16–18 Another example of ETs is genetic modification or genome editing, which has the potential to transform how certain diseases are treated or potentially cured. Therapies based on these ETs (e.g., cell and gene therapies) can stop or slow down the effects of diseases by targeting them, e.g., at the genetic level.19 Additionally, molecular matching of patients to treatments is also possible, given that the genetic driver for the disease is known.16 Another ET, advanced manufacturing, including continuous manufacturing or 3D printing, could be essential in public health emergency preparedness and response. Innovations in manufacturing technologies can lead to integrated processes with fewer steps, consistency, and shorter processing times. They can also support enhanced development methodologies that enable real-time product quality monitoring, e.g., by Quality by Design (QbD) approaches and the use of Process Analytical Technology (PAT) tools and models. Advanced manufacturing technologies also enable flexible processes that allow scale-up, scale-down, and scale-out to accommodate varying demands in supply.20

The European Medicines Agency drew up a list of ETs in 2016, based on knowledge at that time. A cross-agency multidisciplinary team analyzed the previous submissions and stakeholder interactions and agreed to the list of ETs. Since then, ITF and other EMA procedures, including Scientific Advice,21 Orphan applications,22 and Qualification of novel methodologies,23 have been collecting data on ETs.

The tracking of ETs in regulatory interactions, clinical trials, and publications, and the exploration of the collected data is highly valuable as it supports the continuous future-proofing of the Agency. By analyzing the information on ETs, science and technology trends in innovative drug development can be detected early on, allowing the Agency to focus on relevant, most promising developments.

Given its relevance, the list of ETs must be up-to-date. The field of drug development is rapidly changing, and the emergence of novel ETs is continuously ongoing. Additionally, the development and adoption of novel technologies in the pharmaceutical industry in Europe are progressing at different speeds across the various stakeholders in the field (large pharma, SMEs, academia, etc.) driven by a whole set of changing priorities, challenges, and use cases. For instance, this process has been impacted by the COVID-19 pandemic, resulting in the expedited development and adoption of some innovative technologies, like mRNA-based vaccines and digital technologies.24 These factors justify the investment in an up-to-date list of ETs to incorporate novel and evolving ETs and remove ETs that prove to be less impactful than previously expected.

The aim of this work was two-fold: on the one hand, it was aimed to measure the impact of the identified ETs by following and analyzing their route (i.e., the “Journey of Innovation”) from publications through early interactions with EMA to clinical trials (CTs). On the other hand, this work also aimed to review and suggest an update to the current list of ETs with previously unseen innovative technologies identified during the data analysis to further strengthen the support of EMA for the development of innovative technologies, methods, and methodologies.

Early Interactions on Innovation at EMA

The Innovation Task Force (ITF) is a multidisciplinary platform for preparatory dialogue and orientation on innovative methods, technologies, and medicines.

Innovation Task Force Objectives

  • Assist knowledge exchange on innovative strategies involving regulatory networks.k
  • Support drug development via early informal dialogue on;
    • Scientific, legal, and regulatory issues
    • Products, methodologies, and technologies
  • Address the impact of emerging therapies and technologies on the current regulatory system
  • Preparing for formal procedures

Emerging Technologies

Novel treatment technologies

  • Genome editing
  • 3D printing of viable cells
  • Externally activated products (magnetic / photo)
  • Microbiomics
  • M-health and E-health (Apps)
  • Disease modeling
  • Treatment algorithms (CT, software), CT: computed tomography
  • Epigenetics

Novel manufacturing technologies:

  • Nanotechnology
  • Biomaterials
  • Continuous manufacturing / QbD

Innovative Products in Clinical Development

ATMPs

  • Gene-edited modified cells
  • Stem cell-based (facilitated by novel stem cell sources)

Nanotechnology incorporating products

  • Guidance in four areas: Block Co-Polymer Micelles, Iron-oxide, Liposomal formulations, Coating

Novel “complex” products (Hybrids)

  • Complex synthetic oligonucleotides and peptides (mixtures) (Allergens / “Cancer-Immunotherapy.”)
  • Phages (not novel but revival)
  • Multifunctional recombinant biologicals - including borderline
  • Bi/multi-functional monoclonal antibodies and conjugated monoclonal abs/chemicals,

Biomaterials

  • Novel polymers

Impact of Innovation Task Force

92 ITF Briefing meetings were organized between 2014 – 2016, of which 80% were submitted by academia, SMEs, and consortia (ITF support focus);

  • 30% of applicants consider applying a formal scientific advice request
  • 11% consider Qualification of methodology (e.g. Biomarker qualification)
  • 15% are Advanced Therapies (Gene, Cell, Tissue engineered products)
  • 14% consider seeking EU Orphan Drug designation (rare diseases)
  • 20% consider interaction with the EMA Paediatric Committee (PDCO)
  • 10% consider Marketing Authorization Applications within the foreseeable future

References

  1. https://www.fda.gov/science-research/science-and-research-special-topics/real- world-evidence
  2. Framework for FDA’s Real-World Evidence Program, available at https://www.fda.gov/ media/120060/download.
  3. FDA Guidance for Industry and FDA Staff: Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices, available at, https://www.fda.gov/ regulatory-information/search-fda-guidance-documents/use-real-world-evidence support-regulatory-decision-making-medical-devices  
  4. https://www.fda.gov/science-research/science-and-research-special-topics/real-world evidence
  5. Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance the development of safe and effective cell and gene therapies, available at, https://www.fdaGovov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb md-and-peter-marks-md-phd-director-center-biologics
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Author Details 

Robert Dream- HDR COMPANY LLC

Publication Details 

This article appeared in American Pharmaceutical Review:
 Vol. 27, No. 5
July/Aug 2024
Pages: 38-43


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