Titanic, Men in Black, and Good Will Hunting were box office sensations. Spice Girls, Backstreet Boys, and Elton John dominated Billboard’s Top 100, and President Clinton signed the FDA Modernization Act of 1997 into law.
As the new century's dawn approached, 1997 was a gateway, opening doors to the next major leap in therapeutic innovation.
Although the biotherapeutics sector was in its commercial infancy in 1997, many biologics were moving their way through the development pipeline, and it was clear that the regulatory framework for biologics review and approval needed to mature. Additionally, the act contained provisions designed to speed the timelines for new drug review and approval, provide pharmaceutical manufacturers with more efficient and affordable ways to adjust and improve manufacturing processes, and increase patient access to experimental drugs and medical devices.
While day-to-day progress often seems slow, it is mind-boggling to reflect on the pharmaceutical industry's progress over the past 28 years. Today, the industry sits at a new threshold for industry-transforming progress — advancements that will revolutionize how the medicines of the future are made. Advanced manufacturing innovations are manifesting and being adopted at an accelerating pace, the required regulatory framework continues to be established, and the business case for executing advanced manufacturing approaches is becoming increasingly apparent.
The Promise of Advanced Manufacturing in Pharma
Supply chain disruptions, an overall lack of supply chain resiliency, rising production costs, escalating demand for personalized medicines, and pervasive drug shortages often caused by quality control issues have pushed traditional pharmaceutical manufacturing processes to their limits. An evolved construct was needed for the pharmaceutical industry to take the next steps.
Given the highly regulated nature of the pharmaceutical industry, the practical execution and commercialization of new technologies or approaches require a revised regulatory framework. Fortunately, the FDA and leading regulators worldwide have made tremendous progress on this front.
“Advanced manufacturing is a general term for an innovative pharmaceutical manufacturing approach or technology that has the potential to improve the reliability and robustness of the manufacturing process and supply chain and increase timely access to quality medicines.”1
In short, the FDA considers advanced manufacturing to be novel technologies or existing approaches applied in new ways that improve manufacturing processes in manners that strengthen drug supply dependability and quality and usher valuable therapeutics to patients in need faster and more dependably.
Strengthen Drug Supply Dependability
Develop new tools and technologies to address medical product shortages often caused by obsolete manufacturing and control technologies and insufficient quality management systems. For example, advanced manufacturing favors processes that require less, or in some cases, no human intervention are at much less risk of contamination and errors.
Speed Therapeutic Availability
Facilitate the rapid scaling of therapeutic production to respond to public health emergencies more effectively. Advanced manufacturing approaches will help the industry and governments act in concert for the rapid development of vaccines or treatments as public health emergencies arise.
Improve Supply Chain Resiliency
Advanced manufacturing is also needed to create an agile network of cost-efficient manufacturing sites that can pivot quickly to provide reserve capacity. The COVID-19 pandemic unveiled the lack of supply chain resiliency for many drugs and medical supplies. While reshoring and other near-market production initiatives are gaining momentum, the supply chain must be considered holistically, as local production of essential drug products is not resilient if vital components of the therapeutic (like the active pharmaceutical ingredient (API)) are disrupted. Additionally, when production processes are reshored, processes often need to be retooled to reduce labor requirements and comply with local-market environmental regulations.
Increase Accessibility of Medical Innovations
Enabled by artificial intelligence and other technologies, advanced manufacturing seeks to lower the costs of developing and producing emerging therapeutics. These efficiencies are designed to lower prices making life-enhancing therapeutics affordable to patients and the health care systems that serve them.
Advanced Manufacturing Poses Nearly Endless Possibilities for Progress
The term advanced manufacturing is nebulous and often confused with smart manufacturing, a subset of advanced manufacturing focusing on data and information technology utilization to automate and streamline processes. Advanced manufacturing is a more holistic concept. While far from comprehensive, the list below explores some of the priorities of the advanced manufacturing movement.
Continuous Manufacturing
While continuous manufacturing technology has existed for some time, most pharmaceutical manufacturers have been too reluctant to forego the benefits of batch manufacturing, which include flexible unit operations, discrete process optimization, and straightforward lot traceability.
However, the benefits of continuous or more continuous manufacturing are increasingly overshadowing the benefits and comfort of batch processing. Specifically, continuous manufacturing typically decreases production time, improves product quality, often lowers costs due to high levels of automation, and tends to reduce environmental impact. Current research estimates that continuous manufacturing can reduce product variation by 50%, the time needed for quality control assessments by 50–70% and energy consumption by 40%.2
Additive Manufacturing
Additive manufacturing, or 3D printing, is transforming the production of medical devices and drug formulations by layering materials based on digital blueprints. This technology is ideal for producing patient-specific medical devices and customized drug dosages.
Point-of-Care Manufacturing
Point-of-care, or near point-of-care, manufacturing is essential to grow the efficiency and feasibility of patient-specific autologous cell therapy products. A centralized process where patient cells are harvested and shipped to a distant manufacturing site, processed, and then returned can take weeks, is not widely available, and is hugely resource-intensive.
Another highly promising application is combining 3D printing and point-of-care manufacturing. API 'ink' is produced at a centralized manufacturing site under cGMP conditions. The API ink is then distributed to point-of-care sites like hospitals and pharmacies for personalized dose deposition and delivery. Dose deposition can include a range of formats, from tablets, capsules, transdermal patches, and orodispersible films to liquid vials.
Distributed Manufacturing
Decentralized therapeutic production calls for smaller manufacturing facilities, likely in greater numbers, that are distributed closer to the patient populations being served. As alluded above, distributed manufacturing is essential for the feasibility of personalized medicines, such as cell and gene therapies. Distributed facilities are also highly valuable in managing crises like pandemics and natural disasters better.
Digital Stockpiles
The concept of a Digital Stockpile and Manufacturing Response Network took shape after the COVID-19 pandemic exposed the weaknesses of the global pharmaceutical and medical products supply chain. Digital stockpiles will complement traditional, physical stockpiles by “storing comprehensive electronic plans, instructions, and methods for the production and testing of medical products, ensuring that critical resources can be produced on demand.”3 A network of manufacturers with capabilities to make the needed products would be activated in times of emergency.
Robotics
Sophisticated robotics, in coordination with advanced sensors and detection systems, data analytics, vision systems, augmented reality, virtual reality, and artificial intelligence (AI), are essential for increased automation and the operator-free facilities many pharmaceutical facility designers envision. While completely operator-free facilities are unlikely, replacing human operators with robotics decreases opportunities for error and contamination.
Augmented Reality (AR)
AR improves various processes by providing real-time instructions, reducing errors, and accelerating training. It also assists with maintenance tasks by guiding technicians through complex repairs.
Digital Twins
Digital twins are digital replicas of physical production assets, including a specific production line, processing suite, or entire facility. Aiding in manufacturing process improvements, digital twins simulate the production environment in question and predict issues, allowing companies to identify areas for optimization. Digital twins enable operators to virtually test process designs or proposed changes, saving time and money by minimizing real-world testing.
Addressing Advanced Manufacturing Adoption Challenges
Like virtually all advancements in the pharmaceutical industry, adopting advanced manufacturing is taking time. Manufacturers require confidence in the regulatory framework, enabling technologies must be available and affordable, and there needs to be a business case for change. Until quite recently, these conditions were not met.
However, the FDA has released a series of programs, guidances, and discussion papers that provide much of the needed regulatory structure and have made progress in establishing and clarifying target performance indicators for the Emerging Technology Program (ETP). Additionally, commercially practical AI, a key enabler for many advanced manufacturing technologies and approaches, has progressed considerably in four to five years. Finally, pharmaceutical pricing control policies by governments worldwide, including the United States, are mandating the need to find efficiencies across the entire pharmaceutical value chain, including manufacturing.
Maturing Regulatory Framework
In 2021, CDER announced the development of a regulatory framework called FRAME — Framework for Regulatory Advanced Manufacturing Evaluation — to support the innovation expected to accelerate over the next five to 10 years. The framework was created to direct the creation of needed guidances and other structures with a priority focus on four technologies: continuous manufacturing, distributed manufacturing, point-of-care manufacturing, and AI. In the pursuit of achieving FRAME’s objectives, numerous papers and guidances have been published, including:
Advanced Manufacturing Technologies Designation Program guidance finalized in December 2024. While it is too early to draw definitive conclusions, this guidance could have some of the most meaningful impacts in accelerating the adoption of advanced manufacturing. This program offers early access to regulators, submission advice as resources permit, and priority review. In short, this initiative presents the possibility for accelerated review and approval.
Considerations for the Use of Artificial Intelligence to Support Regulatory Decision-Making for Drug and Biological Products draft guidance released in January 2025. The guidance advises those seeking to produce information or data intended to support regulatory decision-making regarding drug safety, effectiveness, or quality. Notably, the guidance offers a risk-based credibility framework for establishing the credibility of an AI model.
Considerations for Complying with 21 CFR 211.110 draft guidance published in January 2025. When finalized, this guidance will describe considerations for complying with the requirements in 21 CFR 211.110 to ensure batch uniformity and drug product integrity. In addition, this guidance discusses related quality considerations for drug products that are manufactured using advanced manufacturing and describes how manufacturers can incorporate process models into commercial manufacturing control strategies.
Q13 Continuous Manufacturing of Drug Substances and Drug Products, released in March 2023, this guidance describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing (CM). ·
“Distributed Manufacturing and Point-of-Care Manufacturing of Drugs: Discussion Paper,” released in the fall of 2022, discusses considerations for a risk-based regulatory framework addressing issues associated with distributed and point-of-care manufacturing.
CDMOs and Advanced Manufacturing
Contract development and manufacturing organizations (CDMOs) are playing a key role in advanced manufacturing technology and capability curation, allowing their innovator partners to speed up the adoption of these approaches. Capabilities being curated by Enzene, ReciBioPharma, Phlow, and PluriCDMO are merely four examples.
Enzene, an India-based complex biologics and monoclonal antibodies (mAbs) CDMO, recently began U.S. operations at its plant in Pennington, NJ. They support innovation in the space with their patented and validated continuous bioprocess manufacturing platform, EnzeneX™, which significantly reduces the costs of producing these antibody-based therapeutics and improves product quality.
ReciBioPharm, an RNA, recombinant protein, viral vectors, microbiome, and live biotherapeutic products CDMO, partnered with the Massachusetts Institute of Technology (MIT) to accelerate RNA drug product production and increase product purity and yield. Specifically, they leverage continuous and integrated processing, inline process analytics technologies (PAT), and centralized control to offer continuous RNA manufacturing. Their continuous manufacturing platform reduces process development timelines by up to 90% and increases manufacturing speeds by up to 85%.4
Phlow, a U.S.-based API CDMO, utilizes advanced development and manufacturing methods, including continuous manufacturing, to support the reshoring of critical APIs and reduce dependency on foreign supply chains. They have worked extensively with the U.S. government to support the replenishing Strategic National Stockpile (SNS), as well as build domestic infrastructure for advanced manufacturing of essential medicines.
Yet another example is PluriCDMO, a division of Pluri, a specialized CDMO for allogeneic products. PluriCDMO produces cell-based products through automatic reactor harvesting systems and concentration and washing processes suitable for tens of billions of cells. They also offer automatic final formulation processes for large quantities of drug product and fill/finish systems that support the filling, visual inspection, and labeling hundreds of vials.
Outlook for Advanced Manufacturing in Pharma
Given its highly regulated nature, changing the pharmaceutical industry takes time. However, it is pretty breath-taking when one reviews the progress from 1997 — the formal kickoff of the pharmaceutical modernization era — to now. The industry has progressed from being dominated by small molecule therapeutics and painfully slow review and approval processes to incredibly diverse therapeutic modalities, greatly enhanced therapeutic capabilities for patients with conditions formerly classified as untreatable, and AI poised to support and expedite nearly every phase of a therapeutic’s life cycle.
While many fascinating technologies could be included in the pharmaceutical facilities of the future, the industry will not implement advanced technology without business benefits. Fortunately, many advanced technologies are poised to improve product quality and product consistency, increase manufacturing efficiencies and reduce costs, sharply reduce manual work that increases the risk of operator error and contamination, enhance process parameter insights, reduce batch failures, and improve facility flexibility allowing manageable process reconfigurations to accommodate new technologies and modalities. These benefits do not even mention the value of potentially accelerated drug review and approval.
While digital technologies are central to the future of pharmaceutical manufacturing, only the exchange of ideas and collaboration will make opportunities to advance the pharmaceutical industry a reality. “How Will the Medicines of the Future be Made,” will be the central question discussed by attendees, exhibitors, and within the Learning Lab programming at INTERPHEX 2025, April 1–3, 2025 in New York City.
References
Advanced Manufacturing Technologies Designation Program. FDA Guidance for Industry. U.S. Food and Drug Administration. Dec. 2024.
Diego, Malevez and D. Copot. “From batch to continuous tablet manufacturing: a control perspective.” IFAC PapersOnLine. 54-15; 562-567 (2021).
“Digital Stockpile and Manufacturing Response Network.” U.S. Food and Drug Administration.