Advanced manufacturing: Industry tells FDA process modeling is sufficient for batch uniformity

The US pharmaceutical industry has told the US Food and Drug Administration (FDA) that using process models alone is sufficient for assessing batch uniformity in advanced manufacturing. They believe that it is not necessary to combine this approach with in-process material testing to demonstrate uniformity.

Groups argued that excluding the modeling approach as a sole tool could impede the development of advanced manufacturing.

In January, FDA issued a draft guidance to assist manufacturers in complying with its good manufacturing practice (GMP) regulations under 21 CFR 211.110 governing batch uniformity for products made through advanced manufacturing techniques, such as continuous manufacturing and 3D printing. (RELATED: Batch uniformity: FDA details testing approaches for continuous manufacturing, 3D printing, Regulatory Focus 6 January 2025)

At issue is FDA’s insistence in the guidance that pairing process models with in-process testing is the best way to measure batch uniformity for advanced manufacturing techniques.

The guidance states that “process models, when paired with in-process material testing or process monitoring (including process inputs and outputs), can be powerful tools for maintaining a state of control and ensuring drug product quality.”

Such in-process material testing can be conducted through laboratory testing of a physical sample taken from the process or by utilizing innovative technologies or methods that are at-line, on-line, or in-line.

The FDA acknowledged industry’s interest in using in-process control strategies that depend solely on process models to meet the batch uniformity requirements under Section 211.110.

Yet the agency notes that “to date, FDA has not been made aware of process models that demonstrate that: (1) the underlying assumptions of the process model will remain valid during routine manufacturing; and (2) the manufacturer can detect if an underlying assumption is no longer valid (e.g., a continuous mixing model that assumes uniform mixing would be unable to detect that uniform mixing is no longer occurring due to material agglomeration on the walls of the mixer).”

In its comments, three major industry groups, including the Pharmaceutical Research and Manufacturers of America (PhRMA), the Biotechnology Innovation Organization (BIO), and the International Society for Pharmaceutical Engineering (ISPE) argued that process models alone are sufficient for predicting batch uniformity.

PhRMA said the guidance “appears to rule out the use of process models alone to satisfy cGMP requirements.” The group said this thinking “contradicts” the International Council for Harmonisation’s Q8, Q9, and Q10 guidances which say process models provide “superior assurance of product quality.”

PhRMA states that “the exclusion of process models as the main or only means of control could hold back advanced manufacturing generally, beyond just continuous manufacturing or as relates to § 211.110.”

BIO states that “the core message of the current guidance appears to be in lines 199-215, which categorically rules out the use of process models solely to comply with requirements of 21 CFR 211.110. We recommend that FDA update this discussion to be consistent with the scientific and risk-based approach.”

ISPE said that “such a strict exclusion of process models as the primary or sole means of control could significantly hinder the advancement of innovative manufacturing control strategies, extending beyond continuous manufacturing and the specific applicability of 21 CFR 211.110. ISPE recommends removing or substantially revising lines 199–215 to mitigate this potential impact.”

In other areas, PhRMA also requested a more detailed definition of process models. “For example, this term could include novel statistical methods as applied to manufacturing or it could comprise digital twins; listing examples in the definition would be helpful.”

BIO also suggested that the scope of the guidance be expanded to include advanced therapy drugs as well as new or currently marketed large or small molecule drugs.

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Advanced manufacturing: Industry tells FDA process modeling is sufficient for batch uniformity

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