Batch uniformity: FDA details testing approaches for continuous manufacturing, 3D printing
The US Food and Drug Administration (FDA) has issued draft guidance to assist manufacturers in complying with its good manufacturing practice (GMP) regulations under 21 CFR 211.110 governing batch uniformity for drug and biological products. The guidance specifically addresses methods for ensuring blend uniformity for products made through advanced manufacturing techniques, such as continuous manufacturing and 3D printing.The guidance recommends the use of process models combined with in-process material testing to ensure the blend uniformity of drug products produced on a continuous manufacturing line.
Until this point, there has been limited FDA guidance on how manufacturers can assess blend uniformity for products that are made on a continuous manufacturing line or 3D printed.
In its guidance, the FDA acknowledges that continuous manufacturing and batch manufacturing utilize different methods to ensure batch uniformity and the integrity of drug products. It states that “typically, with a batch manufacturing process, in-process materials can be easily isolated between each manufacturing step. This allows greater access for sampling and testing of in-process materials before or after each step. However, given the process design for continuous manufacturing, isolating in-process materials may not be feasible.”
An FDA announcement further stated that advanced manufacturing, including continuous manufacturing, generally enables a better understanding and control of the manufacturing process.
FDA acknowledges that in continuous manufacturing, industry is interested in using control strategies that depend entirely on process models to meet the requirements of 211.110 without further testing.
Yet this approach fails to take into account any “unplanned disturbance that is not accounted for by the model’s underlying assumptions.” This includes the occurrence of nonconforming in-process materials such as “nonhomogeneous” powder blends entering the production process.
The guidance states that “control strategies that rely solely on current process models would be insufficient to satisfy the requirements of § 211.110.”
Instead, process models that are paired with in-process material testing or process monitoring "can be powerful tools for maintaining a state of control and ensuring drug product quality." Such in-process material testing can be achieved through laboratory testing of physical samples that are removed from the manufacturing process or implementing innovative technologies such as in-line testing.
The guidance states that in addition to identifying the critical quality attributes and in-process material attributes to monitor, manufacturers should define and justify when and where the proposed in-process controls, testing, or examinations used to monitor those attributes should take place. This definition and justification should be based on the manufacturer’s understanding of both the product and the process.
The guidance was prepared by FDA’s Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Veterinary Medicine (CVM), and the Office of Regulatory Affairs (ORA).
The deadline for submitting comments is 7 April 2025. Stakeholders can comment on www.regulations.gov under docket FDA-2024-D-5374.
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