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the Agency) released a draft guidance document titled,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Draft Guidance)2. The Draft Guidance explains FDA's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the Draft Guidance recommends a scientific and risk-based approach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 production9. 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.
Footnotes
1 21 C.F.R. § 211.110.
2 FDA, Draft Guidance for Industry, Consideration for Complying with 21 CFR 211.110 (Jan. 2025).
3 Id. at 3.
4 Id.
5 Id. (emphasis added).
6 Id. at 4.
7 Id.
8 Id. at 5.
9 Id. at 6.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.
