Stakeholders React to FDA's Push for Quality, Integrity, and Uniformity

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In its April 2025 issue, Pharmaceutical Technology®’s “Ask the Expert” column explored the implications of FDA’s January 2025 draft guidance Considerations for Complying With 21 CFR 211.110 and how it impacts the approach that has been taken, up to now, in complying with 21 Code of Federal Regulations (CFR) 211.110 (1–3).

“Allowing flexibility to use new technological advances to determine drug product integrity and batch uniformity during manufacturing could reduce product reject rates because in-process results could be reported sooner (perhaps in real time) and manufacturing corrections could be made to ensure the batch integrity,” column authors Susan J. Schniepp and Rona LeBlanc-Rivera, PhD, wrote at the time (1). “Drug products manufactured using advanced in-process techniques may have non-traditional quality considerations to determine the suitability of the product, and this guidance allows for flexibility and latitude on how to implement these controls effectively.”

Between the issuing of the draft guidance and the closing of the comment period on April 7, 2025, which came after our “Ask the Expert” feature was published, numerous industry stakeholders weighed in on their perceived effectiveness of the guidance in its final version, suggesting certain changes to verbiage or focus. Here, we present a summation of those comments, as an update on the progress of this document.

Individuals raise their concerns

Two comments were directed to FDA by experts on their own behalf. Rodolfo Romanach, professor of Chemistry at the University of Puerto Rico at Mayagüez, said he was happy with FDA’s efforts to define the term “advanced manufacturing,” but he was concerned with the proposed definition as worded in this and other documents (4,5).

“I believe that the current definition is confusing pharmaceutical manufacturing research with advanced manufacturing,” Romanach wrote, contending that the definition restricts advanced manufacturing only to that which “has the potential to improve the reliability and robustness of the manufacturing process and supply chain and increase timely access to quality medicines for the American public” (4).

He added that “many companies in the [United States] export products (4). Medicines could contribute to good relations between countries. The timely access should be to all patients, not just the American public.”

Jitendra Pund, Quality Management System head at Shilpa Medicare, suggested alterations to the section “General Considerations for In-Process Sampling and Testing,” including ensuring that in-process parameters are selected based on drug product quality attributes and that critical process parameters be controlled and monitored in process validation studies (6,7).

“When continuous process verification is used, the continuous manufacturing system performance and output material quality [should be] continuously monitored, such that the real-time data collected demonstrate the maintenance of a state of control and production of output material with the desired quality for the runtime duration,” Pund wrote in the comment to FDA (6).

Manufacturers, other companies respond

While Pund submitted an individual comment, Bristol Myers Squibb, as a whole, submitted a response to FDA that sought to address the risk of using in-process control strategies that rely solely on process models (8).

“We think that there could be a challenge in demonstrating continued model validity via process monitoring or testing via alternate tool (PAT) during routine manufacture,” reads the Bristol Myers Squibb comment (8). “It will be beneficial to acknowledge in the guidance that this can be alternatively achieved through a model maintenance [or] model assumption verification plan [or] protocol.”

To achieve this, Bristol Myers Squibb suggested the use of a tablet PAT method to support model maintenance and the continued validity of assumptions (8).

The asset optimization software company Aspen Technology also submitted a comment touching upon several topics in the draft guidance, including statistical validation in multivariate models, mitigating unplanned disturbances, and the role of engineering principles (9).

“When used effectively, statistical metrics help ensure that the process model’s underlying assumptions remain valid during routine manufacturing,” Nithiya Parameswaran, Aspen Technology vice-president of Product Management, wrote in the company’s statement (9). “They also provide a means for detecting when an assumption is no longer valid, triggering the need for physical retesting as confirmation. Simulated data derived from rigorous models... ensures that multivariate process models maintain control over manufacturing operations using the aforementioned statistical methods.”

Professional organizations share their views

The International Society for Pharmaceutical Engineering (ISPE) raised concerns about a 17-line passage within the document which, as they wrote, “categorically excludes the use of process models solely for compliance with the requirements of 21 CFR 211.110” (10).

“It is curious why this interpretation is issued at this point [versus] continuing to rely on the scientific and risk-based approach outlined, for example, in lines 86, 121, and especially line 130 about the spirit of flexibility that regulations provide,” Carol Winfield, senior director, Regulatory Operations, wrote on behalf of ISPE (10). “The somewhat categorical exclusion of the use of process models as the main or only means of control could have a significantly detrimental effect on the development of advanced manufacturing control strategies for process models in general.”

While the Parenteral Drug Association (PDA) provided proposed changes to the background information provided in the draft guidance, as well as additional suggested references, like Pund, the group devoted much of its attention to the “General Considerations for In-Process Sampling and Testing” section (11). Similarly to Romanach, PDA raised concerns related to the term “advanced manufacturing,” saying that a sentence “highlighting ‘innovative methods’ is not consistent with the recently issued guidance on advanced manufacturing technologies ... [and] moves away from the idea that innovative methods are superior” (11).

The Biotechnology Innovation Organization (BIO) registered some of the most pointed concerns about considerations for batch uniformity (12).

“Overall, it is not more difficult to perform in-process evaluation in a CM [continuous manufacturing] process; it just requires different approaches,” E’Lissa Flores, director, Science & Regulatory Affairs, commented on behalf of BIO (12). “The draft guidance as written implies that you have more opportunity to evaluate the quality of a batch product.”

Final thoughts

Comments submitted by the Pharmaceutical Research and Manufacturers of America (PhRMA) drilled down on manufacturing controls and the use of process models but also provided recommendations on the scope of the guidance in general (13).

“PhRMA would appreciate more discussion of the balancing necessary to increase the use [of] innovative approaches and the need to meet regulatory expectations,” the group wrote (13). “Specifically, we would appreciate additional guidance on how a sponsor can ensure a suitable redundancy in testing without an excessive burden on the control strategy.”

In a best-case scenario, as Schniepp and LeBlanc-Rivera wrote in April, expansion of the guidance that clarifies the flexibility that sponsors may be afforded will be a welcome step in the finalized document. “This new guidance offers flexibility to manufacturers, including contract manufacturing organizations, to introduce new, more efficient methodologies to measure batch uniformity and product integrity required to determine product suitability to ensure continued access to necessary pharmaceutical products,” they wrote (1). “It is up to [the] pharmaceutical industry to work with FDA and determine the best implementation strategy for realizing the benefits of modernizing manufacturing processes.”

References

1. FDA, Draft Guidance for Industry, Considerations for Complying With 21 CFR 211.110 (CDER/CBER/CVM, January 2025).
2. CFR Title 21, 211.110 (Government Printing Office, Washington, DC) 169–170.
3. Schniepp, S. J. and LeBlanc-Rivera, R. Drug Shortages and Complying with FDA’s 21 CFR 211.110 Guidance. Pharmaceutical Technology 2025, 49 (3) 34.
4. FDA. Comment from Rodolfo Romanach. Regulations.gov, Jan. 22, 2025 (accessed Sept. 23, 2025).
5. LinkedIn. Rodolfo Romanach. LinkedIn.com, accessed Sept. 23, 2025.
6. FDA. Comment from Jitendra Pund. Regulations.gov, Apr. 8, 2025 (accessed Sept. 23, 2025).
7. LinkedIn. Jitendra Pund. LinkedIn.com, accessed Sept. 23, 2025.
8. FDA. Comment from Bristol Myers Squibb. Regulations.gov, March 18, 2025 (accessed Sept. 23, 2025).
9. FDA. Comment from Aspen Technology. Regulations.gov, April 7, 2025 (accessed Sept. 23, 2025).
10. FDA. Comment from International Society for Pharmaceutical Engineering (ISPE). Regulations.gov, March 24, 2025 (accessed Sept. 23, 2025).
11. FDA. Comment from Parenteral Drug Association (PDA). Regulations.gov, April 2, 2025 (accessed Sept. 23, 2025).
12. FDA. Comment from Biotechnology Innovation Organization (BIO). Regulations.gov, April 4, 2025 (accessed Sept. 23, 2025).
13. FDA. Comment from Pharmaceutical Research and Manufacturers of America (PhRMA). Regulations.gov, April 4, 2025 (accessed Sept. 23, 2025).