Expert sees shift to ‘ecosystem-centric assurance’ under FDA’s distributed manufacturing rule
A proposed amendment to 21 CFR Part 207 that eases registration rules for distributed manufacturers by allowing them to register as a single establishment could lead to a new paradigm where manufacturers shift their focus from product development to ensuring a product remains the same across multiple manufacturing sites.
Under the proposed rule, distributed manufacturers with multiple sites could create a single drug establishment under a “hub-and-spoke” model that manages distributed manufacturing units (DMUs), rather than registering each individual site. The rule change would also close a loophole that allows active pharmaceutical ingredient (API) manufacturers that ship products only to foreign sites to avoid registering with the agency by applying changes made by the PREVENT Pandemics Act that specify these manufacturers must register with FDA (RELATED: FDA proposes rule to ease registration for distributed manufacturers, require foreign API sites to register, Regulatory Focus 10 July 2026).
“For the clinical pharmacology community, this rule should be read as part of a larger shift: the science of therapeutics is moving from product-centric development toward ecosystem-centric assurance,” Amalia M. Issa, editor-in-chief of Clinical Pharmacology in Drug Development, wrote in a recent editorial in the journal.
Issa noted that the proposed rule does not state DMUs need to be identical across sites, only “equivalent in design and operation,” which is open to interpretation based on context. This allows for DMUs in areas with demand for products that are at risk of shortages, such as sterile injectables, starting products for cell and gene therapies, and emergency countermeasures.
Clinical pharmacology as a field is familiar with products that need to be pharmacokinetically indistinguishable as how they are made changes, she said. A distributed manufacturing environment “pushes that question into a more dynamic setting,” that considers factors like climate, utilities, and local conditions in whether a product is equivalent, she explained. These issues would also need to be identified and confirmed before manufacturing at a new site occurs.
Clinical pharmacologists will need to answer questions about “not whether a post-approval site changed, but whether a unit that relocated last month still behaves, in vivo, like the sibling unit that never moved,” she said.
Changes for API manufacturers
API manufacturers that exclusively supply foreign sites “had, in practice, remained invisible to the Agency even when its material eventually reached the United States as finished product,” Issa said.
Sourcing an API for a clinical pharmacologist is critically important because it “underlies every impurity qualification and every claim in a first-in-human protocol about what is actually being dosed,” and insight into these drug establishments will improve our knowledge surrounding dose-escalation and safety margin decisions, she noted.
“For clinical pharmacologists, this is not merely an administrative adjustment; it is an acknowledgement that modern development and supply chains are networked, modular, and often geographically dispersed,” Issa added. “That matters because the scientific risk profile of a drug is inseparable from where and how it is made.”
Challenges in distributed manufacturing
However, distributed manufacturing also raises issues around comparability, process control, batch genealogy, and change management. This will require supporting FDA’s existing tools around registration and listing infrastructure, including inspections, recalls, postmarket surveillance, counterterrorism, and supply chain resiliency.
“For clinical pharmacology, the practical implication is improved traceability across the product lifecycle. When registration and listing data are current, regulators and sponsors can more readily connect a marketed product to its manufacturing history, site network, and labeling state, which in turn helps interpret unexpected safety signals, performance drift, or geographic differences in product behavior,” Issa explained.
Changes in registration and listing also lead to questions about product credibility for sponsors. “If a product intended for first-in-human or dose-range studies is, or may later be, manufactured under a decentralized strategy, comparability assessments belong in the development plan from the outset, not retrofitted once a DMU relocates,” she said.
Issa said that clinical pharmacologists could help FDA determine when evidence in a DMU relocation can serve as a substitute for a bridging study. “Equivalence in design is not the same as equivalence in performance, and that gap is precisely where clinical pharmacology earns its keep,” she said.
Ultimately, the rule change will shift to “ecosystem-centric assurance” where manufacturing visibility and traceability in the supply chain aid dose selection strategies.
“[R]egistration and listing are not peripheral compliance requirements; they are part of the scaffolding that allows clinical pharmacology to translate into dependable patient care,” Issa concluded.
The public comment period for the proposed rule closes on 11 September 2026.
