By Elizabeth Oestreich, Greenleaf Health
The FDA has devoted significant time and attention to creating programs and guidance to assist manufacturers around the world in adopting emerging technologies. The agency has focused particular attention on continuous manufacturing (CM), which uses a more efficient process to manufacture drugs than the traditional multi-step batch process that has been prevalent for over 50 years. The idea of fostering the adoption of new technologies like CM stems from the hope that a more streamlined manufacturing process will improve the quality of drug products, thus eliminating shortages and perhaps even impacting price.
The Office of Pharmaceutical Quality (OPQ), which is located within the Center for Drug Evaluation and Research (CDER), has used its Emerging Technology Program to encourage and assist companies in making this transition. Through this program, manufacturers may seek early engagement with the FDA to work through scientific and policy issues that might arise with use of the emerging technology. Since 2015, four companies have successfully transitioned their manufacturing operations from batch to continuous for five approved products using CM, with the FDA approving two new drug applications (NDAs) in 2018.1 So far, OPQ has completed 27 meetings with companies considering new technologies, and the upward trajectory for applications containing new manufacturing technologies is bound to continue.2
On Feb. 26, 2019, the FDA issued a draft guidance entitled “Quality Considerations for Continuous Manufacturing”3 in an effort to advance greater predictability for companies adopting CM technology. Specifically, the FDA hopes this draft guidance will support the development and adoption of CM for brand, generic, and over-the-counter drugs. While this is challenging to implement, the FDA hopes more companies will switch from batch to CM.
This draft guidance was created to expand upon previous guidance. The FDA defines CM as an integrated process that consists of a series of two or more unit operations where the input materials are continuously fed into and transformed within the process, and the processed output materials are continuously removed from the system.3 Although this definition could be applied to individual unit operations or a manufacturing process consisting of a series of unit operations, as described in the draft guidance, CM is an integrated process that consists of a series of two or more unit operations.3
In this draft guidance, the FDA offers insight on its current thinking on key quality issues in NDAs, abbreviated NDAs (ANDAs), supplemental NDAs, and ANDAs for small molecule, solid oral drug products produced via a CM process.
First, the FDA outlines key concepts of CM by defining process dynamics and batches for CM processes. Next, the FDA defines and discusses control strategies and offers guidance on input material control, process monitoring control, material diversion, real-time release testing, specifications, equipment and systems integration, and data processing and management.
This draft guidance also explores the three stages of process validation: process design, process qualification, and continued process verification. Since CM is a variable system, these three steps are the key to maintaining an effective process. The FDA recognizes that “the ability to evaluate real time data to maintain operations (within established criteria) to produce drug products with a high degree of assurance of meeting all the intended attributes is an integral element of process validation.”3
This draft guidance offers additional pharmaceutical quality system (PQS) considerations for potential adopters. Specifically, for those implementing CM in an existing manufacturing facility, the FDA recommends the site evaluate its PQS and associated elements to determine if the design of and programs within the PQS should be modified. If so, revised or additional procedures may need to be established to support the new continuous process, including:
- handling of planned and unplanned process disturbances which occur in real time, including associated investigations
- raw and in-process material investigations
- in-process material diversion strategy, including criteria for rejection of the entire batch
- change management and maintaining an effective corrective and preventive action system
- process performance qualification protocol and continued process verification approach, including process robustness, actual yield, and multivariate tracking and trending
- equipment qualification and maintenance
- use of formal and informal quality risk management principles throughout manufacturing operations and quality decision making.3
The draft guidance includes information on the different modes and methods of scale-up and the risks associated with each and recommends communication with the agency to determine the complexity of a change and potential impacts on the finished product. The methods discussed for scaling up are: (1) increasing run time with no change to the mass flow rate, (2) increasing the mass flow rate, and (3) increasing both run time and mass flow rate. The FDA includes recommendations for post-approval filing strategies for scale-up in the draft guidance. Submissions should include sufficient details on how the scale-up would be evaluated, including testing and sampling, acceptance criteria, and the number of runs supporting the change. Comparability protocols may also be useful. The draft guidance explains that an increase in batch size by increasing only the run time with no changes to the approved manufacturing process, ranges, and equipment is the most straightforward type of scale-up for CM processes (but still involves risks).3
In the section on stability, the FDA points out that regulatory expectations for demonstrating stability over the finished product’s shelf life do not change between batch and continuous processing. “Data from stability studies should be provided on at least three primary batches of the drug product, and where possible, these should be manufactured by using different batches of the drug substance.”
The FDA also offers guidance on bridging existing batch to CM operations. “A change from batch to continuous manufacturing is a change in the scientific operating principle, and it likely results in changes in many aspects of product and process design, such as equipment, process parameters, and control strategy. Therefore, the most appropriate filing strategy for a postapproval change to a CM process usually would be a prior approval supplement (PAS).”3 The FDA encourages discussing the proposed change and the bridging strategy with the agency for feedback prior to conducting the studies.
Finally, the draft guidance offers specific instructions on where to include information within a submission to the FDA using the Common Technical Document format.
Implementing this type of manufacturing process, or any form of emerging manufacturing technology, is highly technical and expensive. However, given the potential benefits of a system with fewer interventions and the expectation of increased quality, many companies find the switch worthwhile. The latest draft guidance provides relevant insights companies should consider, but for more tailored guidance, companies should pursue early engagement with the FDA through the Emerging Technology Program so they can work together to resolve issues as they try to adopt this new technology.
- FDA, Office of Pharmaceutical Quality 2018 Annual Report, available at https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM632265.pdf; see also Statement from FDA Commissioner Scott Gottlieb, M.D., and Janet Woodcock, M.D., director of the Center for Drug Evaluation and Research on FDA’s modern approach to advanced pharmaceutical manufacturing, Feb. 26, 2019, available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632043.htm.
- FDA, Office of Pharmaceutical Quality 2018 Annual Report, available at https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM632265.pdf.
- FDA, Quality Considerations for Continuous Manufacturing, Draft Guidance, February 2019, available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM632033.pdf.
About The Author:
Elizabeth "Liz" Oestreich is VP of regulatory compliance at Greenleaf Health. In this role, she advises clients on compliance issues in the drug and medical device sectors, explains the impact of compliance-related regulations and guidance, and provides regulatory assistance on agency communication. Prior to joining Greenleaf Health, Oestreich served as director of educational programming for the Food and Drug Law Institute (FDLI) in Washington, DC. She earned a B.A. from the University of Arizona and a J.D from the University of the District of Columbia, David A. Clarke School of Law.