Marching Towards Continuous Manufacturing to the Beat of Regulatory Guidance

A pharmaceutical company’s ultimate responsibility is to produce high-quality, safe, and effective medicines to improve patient and animal health. With the increase of complex drug modalities during the last decade, the FDA has written that “quality cannot be tested into products; it should be built in by design.”¹ The COVID-19 pandemic has exposed the pharmaceutical manufacturing industry’s vulnerabilities and unprecedented global supply chain challenges. The Center for Biologics Evaluation and Research (CBER) Director, Peter Marks, MD, has highlighted the need to make manufacturing more effective and states, “We’re going to need to be focusing on improving agility, flexibility, reliability of manufacturing processes” using continuous or semi-continuous production.²

These recent events have brought to light that traditional manufacturing procedures (typically batch) and end-product testing are not effective in ensuring consistent quality and that advanced manufacturing approaches³, such as continuous manufacturing, can improve drug quality, increase throughput, minimize drug shortages and accelerate time-to-market.

The FDA’s Constant Efforts

Despite the FDA’s 10+ years and countless efforts to promote a risk-based approach to manufacturing, which is aided by the transition to continuous manufacturing, only a handful of pharmaceutical companies have received FDA approvals for continuous manufacturing. Out of the 273 drugs approved by Center for Drug Evaluation and Research (CDER) since 2015,⁴ only 10 included the use of continuous manufacturing, with the first in 2015 for Vertex’s Orkambi (lumacaftor/ivacaftor) to treat cystic fibrosis. Janssen’s Prezista (darunavir), used to treat HIV, was the first instance where the FDA approved the manufacturer to switch from batch to continuous manufacturing after the drug was already commercialized. Janssen changed its manufacturing culture by taking advantage of the 2014 Emerging Technology Application FDA guidance as part of the company’s continuing efforts to innovate. Prezista was a great candidate because of the product’s stability, the team’s deep understanding of its manufacturing processes and the critical patient need. A positive indicator is that CDER approved another three applications in 2020 that have used continuous manufacturing.^4,5

The FDA has received millions of dollars in recent years to support continuous manufacturing, which has bolstered programs such as CDER’s Emerging Technology Program and CBER’s Advanced Technologies Team (2019), as well as partnerships and research to expand knowledge surrounding advanced manufacturing processes. These programs provide the opportunity for pharmaceutical manufacturers to work with the FDA, ask regulatory related questions and get feedback regarding new technology and its adoption and implementation when submitting drugs for approval.

The FDA issued a draft guidance in 2019 on “Quality Considerations for Continuous Manufacturing” to support the proactive identification and resolution of potential barriers for the transition to continuous manufacturing. This guidance discusses the advantages of embracing continuous manufacturing, control strategies and approaches to validate the process, scale-up, and stability that bridge the transition from a batch to a continuous manufacturing process for brand and generic small molecule drugs.

The technology exists, the long-term benefits are undisputed and yet, even with the FDA’s advocacy, the pharmaceutical industry has remained slow to adopt. There is no doubt this lag can be attributed to the lack of harmonized regulatory and scientific guidance for global manufacturing, making regulatory approval and lifecycle management challenging, particularly for products intended to be commercialized internationally.

(draft) ICH Q13: The Potential Catalyst for a Culture Change

To address this challenge and speed the adoption of continuous manufacturing, the International Council of Harmonization (ICH) recently published, under FDA’s guidance, the Q13 draft guideline on continuous manufacturing, with anticipated completion slated for the end of 2022. It describes the scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing for small and large molecule drug products for more flexibility and reliability. The goal of this guideline is to advance the brand and generic drug industries’ abilities to obtain approvals for small and large molecule drugs manufactured via continuous manufacturing across regions.

While the FDA has not yet adapted this ICH guideline for biologics, it is expected that both CDER and CBER will continue to prioritize the agency’s efforts to promote continuous manufacturing to improve quality and increase supply chain resilience for all drug modalities.

The Stage Has Been Set

The forthcoming ICH Q13 guideline coupled with the FDA’s 2019 “Quality Considerations for Continuous Manufacturing” guidance will better inform and in turn, further motivate pharmaceutical manufacturers to deploy technologies that support continuous manufacturing. The lighthouse organizations that have paved the way are showing that continuous manufacturing is viable and scalable, lending to greater throughput and consistency in drug quality and ultimately decreasing time-to-market.

Aspen Technology has over 40 years of experience in innovating and partnering with adjacent industries to advance manufacturing processes and provide solutions that can propel Pharma 4.0 initiatives. Our solutions, such as the award winning, modern Process Analytical Technology (PAT) solution, help facilitate continuous manufacturing, increase quality, yield and throughput and in so doing, build efficiency, resiliency and sustainability into all levels of design, production and quality assurance.

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