FDA leads global work on continuous manufacturing approaches to up quality, supply chain resilience

Long-awaited ICH Q13 draft guidelines on CM of drug products released

Under FDA's leadership, the International Council for Harmonisation (ICH) recently published Q13 draft guidelines on continuous manufacturing (CM) to advance the brand and generic drug industries ability to obtain approvals for products manufactured using CM processes in multiple regions. The ICH Q13 guideline is an important milestone in clarifying the regulatory paradigm for more flexibility and reliability in manufacturing processes. The ICH guideline describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of CM in small and large molecule drug products. The guidelines also offer clarification on CM concepts, describe scientific approaches, and present regulatory considerations specific to CM of drug substances/products. While FDA has not yet adopted the ICH’s guideline to apply to biological products, it is expected that both CDER and CBER will continue to prioritize the agency’s efforts to promote CM to improve quality and increase supply chain resilience.

Potential advantages of continuous manufacturing

Quality is the critical element for assuring access to safe and effective drugs. The COVID-19 pandemic has made us acutely aware of the vulnerabilities of inefficient manufacturing and unprecedented global supply chain challenges. Recent events have intensified interest in advanced manufacturing approaches that can improve drug quality, address shortages of essential medicines, and accelerate time-to-market. Key among the approaches is process intensification such as continuous manufacturing (CM): a dynamic process transforming the decades-old batch manufacturing approach into a single system moving pharmaceuticals nonstop through the manufacturing facility. The technology exists, the long-term benefits are undisputed, and FDA has received millions of dollars in recent years to support advanced manufacturing, leading to programs such as CDER’s Emerging Technology Program and CBER’s Advanced Technologies Team, as well as partnerships and research to expand knowledge surrounding advanced manufacturing. The primary reasons for industry’s slower uptake of CM platforms relates to financial incentives and lack of harmonized guidance in inform the regulatory and scientific architecture for a global manufacturing system.

One of most profound lessons from the COVID-19 pandemic is the potential public health value of advanced manufacturing to avoid global supply strains and accelerate the production of medical countermeasures. CBER Director Peter Marks MD recently called for heightened focus on manufacturing capacity and flexibility through advanced manufacturing techniques beyond public health emergencies. “We also need to think about how we can make manufacturing in the inter-pandemic time, between pandemics, more effective,” he said on enabling quicker ramp-up of vaccines, which means “we’re going to need to be focusing on improving agility, flexibility, reliability of manufacturing processes” by continuous or semi-continuous production.

Using a CM approach, input materials are continuously added through a feeder system (e.g., loss-in-weight feeders for solid powders or pumps for liquids) over the duration of a production run. Different batches of input materials can be introduced to the system at different process time points, and variability in input material attributes could affect feeding, introduce process variability into the system and potentially affect finished product quality.

Continuous manufacturing can improve pharmaceutical manufacturing quality by:

  • using an integrated process with fewer steps and shorter processing times;
  • requiring a smaller equipment footprint;
  • supporting an enhanced development approach (e.g., quality by design (QbD);
  • use of process analytical technology (PAT) and models);
  • enabling real-time product quality monitoring; and,
  • providing flexible operation to allow scale-up, scale-down, and scale-out to accommodate changing supply demands.

Advantages for industry may include a reduction in drug product quality issues, lower manufacturing costs, and improved availability of quality medicines to patients based on scalability according to market demand.

FDA issued 2019 draft guidance on quality considerations for CM for new and generic drugs, but industry has been waiting on harmonized guidance to ensure international congruence around regulatory approach and scientific methods.

FDA’s role in advancing manufacturing

FDA’s support for wider use of advanced manufacturing techniques is not new. The agency has been encouraging its adoption to improve product quality, minimize product defects, and reduce drug shortages. Most drug shortages results from quality manufacturing issues. In August 2002, FDA launched an initiative titled, "Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach,” one of the goals of which was to encourage manufacturers to use the latest scientific advances in pharmaceutical manufacturing and technology.

In light of this initiative, in September 2004, FDA published the guidance “A framework for Innovative Pharmaceutical Development Manufacturing and Quality Assurance,” which discusses using the approach of building quality into products and the necessity for process understanding and opportunities for improving manufacturing efficiencies through innovation in embracing manufacturing technologies and enhanced scientific communication between manufacturers and the agency.

FDA issued 2019 draft guidance on “Quality Considerations for Continuous Manufacturing” to support the proactive identification and resolution of potential barriers for the transition to advanced manufacturing. This guidance discusses the advantages of embracing the concept of CM, control strategies and approaches to process validation as well as scale-up, stability and bridging existing batch manufacturing process to a CM process.

FDA leadership has long pressed industry to invest in advanced manufacturing technologies. In addition to better quality, the agency has supported advanced manufacturing to “enable U.S.-based pharmaceutical manufacturing to regain its competitiveness with China and other foreign countries, and potentially ensure a stable supply of drugs critical to the health of U.S. patients,” said Acting FDA Commissioner Janet Woodcock MD in 2019 in her remarks to the House Committee on Energy and Commerce, Subcommittee on Health. Most recently, in an August 2020 FDA Voices post, then-FDA Commissioner Stephen Hahn MD, promoted CM to “improve America’s capacity to rapidly manufacture medical countermeasures during emergency situations,” like the COVID-19 pandemic. Examples include CDER’s multi-year partnership with BARDA to explore CM techniques to improve domestic manufacturing capacity to rapidly manufacture medical countermeasure.

FDA plays an important role in clarifying the regulatory frameworks for innovative manufacturing techniques. The agency adopted certain recommendations from the FDA COVID-19 Pandemic Recovery and Preparedness Plan (PREPP) Initiative report issued in January, including reviewing its inspectional approaches (which we summarized here) and identifying supply chain gaps and challenges to improve resilience. Notably, the PREPP initiative’s summary report recommended that FDA continue to facilitate adoption and scaling of “new manufacturing technologies” including CM techniques and the use of digital and advanced analytics to improve supply chain resilience.

Practical challenges and slow progress

While there is sustained great interest — harnessing the potential from advanced manufacturing techniques is a challenge — requiring the FDA’s investment time and resources in developing scientific standards and program implementation. Progress has been slow but steady from an industry uptake perspective. There are 10 approved continuous manufacturing applications in the United States. The first approval using CM was in 2015 for Vertex’s Orkambi (lumacaftor/ivacaftor) to treat cystic fibrosis. Janssen’s Prezista (darunavir) to treat HIV was the first drug that FDA allowed to be switched from batch manufacturing to CM. By early 2019, FDA approved 6 products using CM, treating diseases like leukemia, cystic fibrosis, HIV-1 infections, and breast cancer. According to CDER’s 2020 annual quality report, the agency approved 3 applications using CM processes, including the first regulatory application using CM for API and the first continuous biomanufacturing process was approved in 2020.

ICH Q13 provides harmonized guidance

The ICH Q13 guidelines provide long-awaited guidance to inform industry’s development and lifecycle management decisions. However, constructing an ICH Q13 guidelines that are acceptable to all members of the ICH Expert Working Group (EWG) is not an easy task. The EWG is comprised of representatives for 11 regulatory authorities and industry organizations, including representatives from the Pharmaceutical Inspection Cooperation Scheme (PIC/S).

FDA’s draft CM-related guidance is narrower than the ICH guidelines, addressing quality considerations for brand and generic small molecule drugs, while ICH Q13 more broadly addressed both large and small molecule products. Until FDA makes a decision with respect to the 2019 draft guidance, the policy document represents its current thinking with respect to small molecule drugs only. The guidance discusses the importance of understanding how product and process dynamics of the input material attributes (e.g., potency, material flow properties), process conditions (e.g., mass flow rates), and equipment design elements (e.g., blade types for a continuous blender) enable material traceability (the ability to preserve and access the identity and attribute of a material throughout the system), both during and after production. Understanding and monitoring how these inputs influence the quality of the finished product is crucial in forming the foundation for effective risk management for CM process.

This guidance document further states that in developing an effective control strategy for CM, manufacturers should consider unexpected and expected variations and transient disturbances in input material attributes, process conditions, or environmental factors over time during normal operation. Further, an effective control strategy for this continuous mode of operation should place special emphasis on mitigating the risk of these potential disturbances to product quality.

The ICH Q13 guidelines closely align with FDA’s draft guidance, and also provides and also provides specific examples on perspectives and approaches to managing transient disturbances and their effect on product quality variation. It also offers a decision tree for material diversion as a result of these disturbances, as depicted below.

The ICH guidelines describe three different CM models that can be applied to some or all operations in a manufacturing process:

  • A combination of approaches in which some unit operations operate in a batch mode while others operate in a continuous mode
  • All unit operations of a drug substance or drug product manufacturing processes are integrated and operate in a continuous mode
  • An approach in which the drug substance and drug product unit operations are integrated across the boundary between drug substance and drug product to form a single CM process.

The guidelines incorporate the ICH Q7 definition of a “batch” to continuous manufacturing. The size of a batch produced by CM can be defined by either the quantity of the output materials, the quantity of the input materials, or the run time at a defined mass flow rate. Other approaches will also be considered for defining a batch if scientifically justified.

Congressional interest and next steps

The release of the ICH Q13 guidelines provide helpful insight into FDA and comparable regulatory authorities’ current thinking on acceptable scientific and regulatory standards to inform regulatory decisions, while promoting innovation to improve quality and reliability of complex supply chains. The ICH EWG plans to meet in November 2021 to discuss the comments received on the draft, and final sign-off is expected in November 2022.

FDA’s leadership in developing the ICH guidelines, and the establishment of CBER’s Advanced Technologies Team, to work with prospective developers on technical considerations for advanced manufacturing technologies in gene therapy, suggests that the agency may adopt ICH’s broader guidance for using CM techniques for small molecule drugs as well as certain biological products. We see the ICH guidelines as important progress in clarifying the regulatory paradigm for using CM techniques in drug development, which may also include rulemaking to update FDA’s regulations for current good manufacturing practices (cGMP) to address both batch and advanced manufacturing approaches.

In recent years, FDA has received significant funding to promote advanced manufacturing. For example, for FY19, Congress approved $35 million in appropriations to advance drug and biological product technologies. FDA requested $25 million in its FY20 budget. U.S. Rep. Frank Pallone (D-NJ) and Chairman of the House Energy & Commerce Committee has been a key leader in advancing investments in advanced manufacturing. Beginning in October 2019, Chairman Pallone has advocated for legislation to create a “National Centers of Excellence in Continuous Pharmaceutical Manufacturing.” (H.R. 4866 introduced in Oct 2019; H.R. 4369 introduced July 2021).

In FY20 and FY21, Congress enacted a series of COVID-19-related supplemental appropriations to respond to the pandemic including, among other things, promoting advanced manufacturing technologies. FDA has stated that these additional resources will help to support an advanced manufacturing center of excellence. Additionally, the proposed Cures 2.0 discussion draft includes implementation of a national strategy to prevent and respond to pandemics that addresses “modernizing and expanding domestic drug manufacturing, including through continuous manufacturing.”

While the spotlight has focused on enhancements to FDA’s public health infrastructure, noticeably less attention has been paid to the need for stronger market-driven industry incentives. Investment time and resources to adopt advanced manufacturing may be prohibitive to some companies. Legislators and industry stakeholders have advocated for legislation to provide incentives to sponsors and manufacturers that are similar to the approach to promote developing medicines for rare diseases, such as user fee waivers, market exclusivity, and tax credits for domestic investments in advanced manufacturing platforms to manufacture essential medicines.

We will continue to monitor the legislation and keep you apprised of developments in this evolving space. If you may wish to comment on the ICH Q13 draft guidelines, or have questions on continuous manufacturing more generally, please do not hesitate to contact any of the authors of this alert or the Hogan Lovells attorney with whom you generally work.

 

Authored by Lowell Zeta, Jim Johnson, Daniel Roberts, and Stephanie Slater

 

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