In this draft guidance, the agency provides insights on its current stance on critical quality issues in NDAs, abbreviated NDAs (ANDAs), supplemental NDAs, and ANDAs for small molecule, solid oral drug products produced using continuous manufacturing methods. However, while some of the recommendations made in the guidance may apply to other types of pharmaceuticals, the FDA states that it does not provide recommendations for biological products.
For several decades, manufacturing industries, from petroleum to food processing, have employed continuous manufacturing processes. In stark contrast, pharmaceutical companies have been much more conservative to adopt new continuous manufacturing approaches and the majority have opted to remain with traditional production methods, moving materials through each step of the manufacturing process in single large batches. Continuous manufacturing processes produce drug ingredients or finished drug products continuously, without having to wait for each batch to finish before commencing a new batch.
The Office of Pharmaceutical Quality (OPQ), which is located within the Centre for Drug Evaluation and Research (CDER), has used its Emerging Technology Program to encourage and support companies in implementing continuous manufacturing. Drugmakers may communicate with the FDA to understand and navigate through scientific and policy issues that might arise with emerging continuous manufacturing technologies. The guidance document released by the FDA provides quality system considerations for companies seeking to adopt continuous manufacturing.
Within the guidance document, the agency advises each manufacturing site to evaluate their quality system design to determine if modifications are required to support continuous manufacturing. Such considerations include equipment qualification and maintenance, in-process material diversion strategy including criteria for rejecting batches, handling of unplanned process disruptions which occur, raw and in-process material investigations, and more.
Dr Janet Woodcock, Director of FDA’s CDER, commented, “Right now, manufacturing experts from the 1950s would easily recognize the pharmaceutical manufacturing processes of today. It is predicted that manufacturing will change in the next 25 years as current manufacturing practices are abandoned in favor of cleaner, flexible, more efficient continuous manufacturing.” The FDA stated that potential benefits of continuous manufacturing may include:
Integrated processing with fewer steps
- Reduced manual handling, increased safety
- Shorter processing times
- Increased efficiency
Smaller equipment and facilities
- More flexible operations
- Reduced inventory
- Lower capital costs, less work-in-progress materials
- Smaller ecological footprint
On-line monitoring and control for increased product quality assurance in real-time
- Amenable to Real Time Release Testing approaches
- Consistent quality
‘Quality Considerations for Continuous Manufacturing’ draft guidance document examines three stages of process validation: process design, process qualification, and continued process verification. Given that continuous manufacturing systems involve many variables, the three stages outlined by the FDA are imperative to focus on if companies are seeking to improve operational and quality efficiency. Adopting continuous manufacturing is highly technical and incurs great costs. However, taking into account the possible benefits and long-term savings of continuous manufacturing, this transition may be worthwhile for many companies due to fewer interventions and the expectation of increased quality. The draft guidance document can be viewed here.
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- 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.
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