FDA Issues New Guidance on Current Good Manufacturing Practices for Drugs

Introduction

The current good manufacturing practice (cGMP) requirements establish the minimum standards for manufacturing, processing, packing, or holding of human and animal drug products. Specifically, 21 C.F.R. § 211.110 requires, among other things, that manufacturers conduct in-process controls, and tests, or examinations to prevent the contamination and monitor for changes in the quality attributes of in-process materials.¹

On January 6, 2025, the U.S. Food and Drug Administration (FDA or the Agency) released a draft guidance document titled, “Consideration for Complying with 21 C.F.R. 211.110” (the Draft Guidance).² The Draft Guidance explains FDA’s interpretation of the general requirements for drug product manufacturing in § 211.110 and addresses considerations specific to the use of advanced manufacturing. In particular, FDA continues to support the adoption of innovative manufacturing technologies and recommends that process models be paired with in-process testing or examination to ensure compliance with the requirements of § 211.110.

Background

FDA first issued its drug cGMP regulations in 1978. Codified in 21 C.F.R. Parts 210 and 211, the cGMPs applicable to human and animal pharmaceuticals are written in broad strokes and are meant to be adaptable to a variety of drug products. The Agency monitors manufacturers’ compliance with the cGMPs to ensure the safety, quality, and efficacy of human (including biologics) and animal drug products. Failure to comply with the cGMP regulations may render a drug adulterated under Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.

Advanced manufacturing is a term that FDA uses to describe a new or innovative manufacturing technology or approach that has the capacity to enhance drug quality, scale up production, and reduce time-to-market. Production techniques with one or more of the following characteristics qualify as advanced manufacturing technology: (1) integrate novel technological approaches; (2) use established techniques in a new or innovative way; or (3) apply production methods in a new domain where there are no defined best practices or experiences. In FDA’s view, the transition to advanced manufacturing benefits both the pharmaceutical industry and the American public. More information on advanced manufacturing can be found on FDA’s website.

General Considerations for In-Process Sampling and Testing

In order to ensure batch uniformity and drug product integrity, the Draft Guidance recommends a scientific and risk-based approach that outlines what, where, when, and how in-process controls, and tests, or examinations should be conducted on samples of in-process material.

Foremost, FDA states that manufacturers should “identify which critical quality attributes and in-process material attributes to monitor and control.”³ Recognizing that the determination of whether in-process controls, and tests, or examination meet the requirements in § 211.110 varies base on the “nature of the drug product . . . and the type of process used by the manufacturer,” FDA points to the regulation’s flexibility and notes that manufacturers should turn to their knowledge and understanding of product and process development when establishing and maintaining control strategies.

Second, the Draft Guidance indicates that manufacturers should “define and justify where and when the proposed in-process controls, and testing, or examination that are used to monitor those attributes should occur.”⁴ Under § 211.110(c), “[i]n-process materials shall be tested for identity, strength, quality and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g., at commencement or completion of significant phases or after storage for long periods.”⁵ FDA has not defined the term “significant phases.” Although FDA allows manufacturers the flexibility in defining the “significant phases” in their manufacturing process, the Draft Guidance provides that such determination should be justified by a scientific rationale.

In addition, FDA clarifies that “[p]rocess monitoring and control decisions that result in minor equipment and process adjustments do not typically need additional quality unit approval if all of the following conditions are met: (1) the adjustments are within the preestablished and scientifically justified limits; (2) these limits have been approved by the quality unit in the master production and control record and the control strategy; and (3) the production data is reviewed by the quality unit before approval or rejection of a batch.”⁶

Third, in addressing how in-process sampling and testing should be conducted, the Draft Guidance once again emphasizes the flexibility of the cGMP requirements and explains that “sampling does not necessarily require steps for physically removing in-process materials to test their characteristics,”⁷ which is consistent with FDA’s promotion of the use of advanced manufacturing where in-line, at-line, or on-line measurements in lieu of physical sample removal for laboratory testing is feasible.

Considerations Specific to Advanced Manufacturing and Process Models

The Draft Guidance supports the use and the transitioning to advanced manufacturing techniques, such as continuous manufacturing and real-time quality monitoring of in-process materials, including process analytical technology and process models.

Due to the integrated nature of continuous manufacturing, this advanced manufacturing technology causes the physical isolation and removal of samples of in-process materials of each batch to be much less feasible compared to traditional batch manufacturing. However, FDA reiterates that, due to the flexibility of the regulation, “a manufacturer could conduct sampling and testing at an appropriate point in the process (e.g., at the tablet press feed frame or after compression) to evaluate the adequacy of mixing to ensure batch uniformity and homogeneity” and then the quality unit can approve or reject the in-process material before or after such point.⁸

The Draft Guidance also acknowledges the benefits of, and the industry’s interest in, using process models, which can be used to monitor in-process materials affecting the drug’s critical quality attributes and predict the uniformity and homogeneity of in-process material. However, because the predictive accuracy of a process model depends on the validity of the model’s underlying assumptions, FDA is concerned with the use of process models in continuous manufacturing without any in-process testing or examination.

FDA notes that, to date, it has not identified any process models demonstrating that (1) the underlying assumptions remain valid throughout the manufacturing process; (2) the manufacturer can detect an invalid underlying assumption during the manufacturing process; and (3) they can adapt to “unplanned disturbances” and prevent nonconforming in-process materials from continuing through production.⁹ Accordingly, FDA advises against using process models alone and takes the position that process models should be paired with in-process material testing or process monitoring to ensure compliance with the requirements of § 211.110.

Conclusion

The Draft Guidance provides clarity to the industry on how the requirements of § 211.110 can be met and is a reflection of FDA’s continued focus on advanced manufacturing. Comments on the Draft Guidance must be submitted by April 7, 2025. If you have any questions about the content discussed here or would like more information, please reach out to one of the authors of this Advisory or to your existing Arnold & Porter contact.

© Arnold & Porter Kaye Scholer LLP 2025 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.