Considerations for

Complying With
21 CFR 211.110
Guidance for Industry

DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 90 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document, contact (CDER) Brittany Avaritt at 240-402-5982
or brittany.avaritt@fda.hhs.gov; (CBER) Office of Communication, Outreach and Development
at 800-835-4709 or 240-402-8010; or (CVM) at AskCVM@fda.hhs.gov.

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Veterinary Medicine (CVM)

January 2025
Pharmaceutical Quality/Manufacturing Standards (CGMP)
 Considerations for
Complying With
21 CFR 211.110
Guidance for Industry
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and/or
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Center for Veterinary Medicine
Food and Drug Administration
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https://www.fda.gov/animal-veterinary/guidance-regulations/guidance-industry

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Veterinary Medicine (CVM)

January 2025
Pharmaceutical Quality/Manufacturing Standards (CGMP)
 Contains Nonbinding Recommendations
Draft — Not for Implementation
TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 1
III. GENERAL CONSIDERATIONS FOR IN-PROCESS SAMPLING AND
TESTING ........................................................................................................................... 3
IV. ADDITIONAL CONSIDERATIONS FOR ADVANCED MANUFACTURING
AND PROCESS MODELS .............................................................................................. 5
REFERENCES.............................................................................................................................. 7
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1 Considerations for Complying With

2 21 CFR 211.110
3 Guidance for Industry1
4
5
6 This draft guidance, when finalized, will represent the current thinking of the Food and Drug
7 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not
8 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
9 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
10 for this guidance as listed on the title page.
11
12
13
14
15 I. INTRODUCTION
16
17 This guidance, when finalized, will describe considerations for complying with the requirements
18 in 21 CFR 211.110 to ensure batch uniformity and drug product integrity. In addition, this
19 guidance discusses related quality considerations for drug products that are manufactured using
20 advanced manufacturing. It also discusses how manufacturers can incorporate process models
21 into commercial manufacturing control strategies. 2,3
22
23 This guidance applies to the manufacture of human drug products, including biological products,
24 and animal drug products; these will be collectively referred to as drug products in this guidance.
25 This guidance does not apply to the manufacture of active ingredients.
26
27 In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
28 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
29 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
30 the word should in Agency guidances means that something is suggested or recommended, but
31 not required.
32
33 II. BACKGROUND
34

1
This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and
Research in cooperation with the Center for Biologics Evaluation and Research, the Center for Veterinary Medicine,
and the Office of Regulatory Affairs at the Food and Drug Administration.
2
Process models can be used at any stage of a drug product’s life cycle, from development to commercial
manufacturing. However, this guidance applies to process models that are used as part of a control strategy during
commercial manufacturing. This guidance does not apply to process models used in other phases of the drug product
life cycle, such as drug development or technology transfer.
3
See ICH guidances for industry Q8(R2) Pharmaceutical Development (November 2009), Q9(R1) Quality Risk
Management (May 2023), and Q10 Pharmaceutical Quality Systems (April 2009). We update guidances
periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

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35 To ensure batch uniformity and drug product integrity, the current good manufacturing practice
36 (CGMP) regulations 4 require, among other things, that manufacturing processes are designed
37 and controlled to ensure that in-process materials consistently and reliably meet predetermined
38 quality requirements. 5 This guidance explains the requirements for drug product manufacturing
39 in § 211.110. This guidance also describes considerations for the use of advanced manufacturing
40 (e.g., 3D printing, continuous manufacturing) 6 and the use of process models as a part of
41 commercial manufacturing control strategies. FDA supports the adoption of advanced
42 manufacturing as a foundation for improving the overall quality and availability of drug products
43 for patients.
44
45 Advanced manufacturing is a term for an innovative pharmaceutical manufacturing technology
46 or approach that has the potential to improve the reliability and robustness of the manufacturing
47 process and supply chain and increase timely access to quality medicines for the American
48 public. Advanced manufacturing can integrate novel technological approaches, use established
49 techniques in an innovative way, or apply production methods in a new domain where there may
50 be limited experience or no defined best practices. Advanced manufacturing can potentially be
51 used for new or currently marketed large or small molecule drugs. 7
52
53 All manufacturers, regardless of whether they are using advanced manufacturing, should apply a
54 scientific- and risk-based approach to controlling processes and ensuring drug product quality.
55 This approach should be based on robust product and process understanding. Manufacturers
56 must maintain the process in a state of control over the life of the process to ensure drug product
57 quality, even as materials, equipment, production environment, personnel, and manufacturing
58 procedures change. 8 Planning and executing a system that monitors process performance and
59 drug product quality helps ensure that a state of control is maintained. An effective monitoring
60 system helps maintain a state of control in multiple ways, which include helping manufacturers:
61 (1) ensure that processes and controls are continuously capable of producing a drug product of
62 desired quality; and (2) identify areas for continual improvement. 9 In addition, § 211.110(a)
63 requires that manufacturers establish and follow written procedures “that describe the in-process
64 controls, and tests, or examinations to be conducted on appropriate samples of in-process
65 materials of each batch.” Section 211.110(c) also requires that in-process materials are “tested
66 for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality

4
See 21 CFR parts 210 and 211.
5
See § 211.110.
6
Continuous manufacturing can be applied to some or all unit operations in a manufacturing process. This includes
the approach in which active ingredient and drug product unit operations are integrated to form a single continuous
manufacturing process. Manufacturers who use continuous manufacturing processes must still define batches to be
tested for release under 21 CFR 211.165 and for other CGMP requirements, including the requirements in § 211.110
that ensure batch uniformity and drug product integrity. See also 21 CFR 210.3(b)(2) and the ICH guidance for
industry Q13 Continuous Manufacturing of Drug Substances and Drug Products (March 2023).
7
CDER established the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) initiative to
prepare a regulatory framework to support the adoption of advanced manufacturing technologies that could bring
benefits to patients. This guidance is being issued as part of the FRAME initiative. For more information on
CDER’s FRAME initiative, see https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/cders-
framework-regulatory-advanced-manufacturing-evaluation-frame-initiative.
8
See, e.g., section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)) and 21 CFR 211.100.
9
See ICH Q10.

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67 control unit, during the production process, e.g., at commencement or completion of significant
68 phases or after storage for long periods.”
69
70 III. GENERAL CONSIDERATIONS FOR IN-PROCESS SAMPLING AND TESTING
71
72 Under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act, a drug is deemed to be
73 adulterated if it is not produced in accordance with CGMP. The CGMP regulations for drug
74 products are in 21 CFR parts 210 and 211, and FDA monitors drug product manufacturers'
75 compliance with these regulations. 10 The CGMP regulations contain minimum requirements for
76 the methods, facilities, and controls used in manufacturing, processing, packing, and holding of
77 drug products. The CGMP regulations also provide flexibility for manufacturers to use better,
78 more efficient methods to meet CGMP requirements because these innovative methods benefit
79 patients. 11 The determination of whether in-process controls, and tests, or examinations meet the
80 regulatory requirements in § 211.110 primarily depends on the nature of the drug product (e.g.,
81 dosage form) and the type of process used by the manufacturer. Knowledge and understanding
82 that manufacturers gain from robust product and process development are an important basis for
83 establishing and maintaining control strategies throughout the lifecycle of a drug product. This
84 helps ensure that drug products have the required quality attributes. 12
85
86 To ensure conformance to drug product quality requirements, the manufacturer should identify
87 which critical quality attributes 13 and in-process material attributes to monitor and control.
88 Section 211.110 allows flexibility in the in-process controls, and testing, or examinations that are
89 employed to ensure that processes deliver in-process materials and drug products with the
90 appropriate quality attributes. To ensure that drug products have the properties that they are
91 represented to possess, the in-process materials used throughout the manufacturing process
92 should be of consistent quality.
93
94 In addition to identifying which critical quality attributes and in-process material attributes to
95 monitor, the manufacturer should define and justify where and when the proposed in-process
96 controls, and testing, or examinations that are used to monitor those attributes should occur. The
97 definition and justification should be based on the manufacturer’s understanding of the product
98 and the process. Under § 211.110(c), “[i]n-process materials shall be tested for identity, strength,
99 quality, and purity as appropriate, and approved or rejected by the quality control unit, during the
100 production process, e.g., at commencement or completion of significant phases or after storage
101 for long periods.” As noted in the preamble of the final rule, “Current Good Manufacturing
102 Practice in Manufacture, Processing, Packing, or Holding,” FDA declined to define the term
103 significant phase. 14 Instead, FDA stated that “significant phases in the processing of drug
104 products can vary greatly depending on the methods used and nature of the individual

10
Positron emission tomography (PET) drug products are subject to CGMP regulations at 21 CFR part 212 and are
not covered by this guidance.
11
See pages 45020-45021 of the final rule, “Current Good Manufacturing Practice in Manufacture, Processing,
Packing, or Holding.” (43 FR 45014 September 29, 1978). The preamble to the final rule refers to benefits for
consumers. For the purposes of this guidance, the term consumer is synonymous with the term patient.
12
See guidance for industry Process Validation: General Principles and Practices (January 2011).
13
For more information about critical quality attributes, see ICH Q8(R2).
14
See 43 FR 45014 at 45052.

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105 products.” 15 Therefore, the regulations generally allow flexibility in the determination of
106 significant phases depending on the manufacturing process and the drug product. Manufacturers
107 should define the significant phases in their manufacturing processes; however, FDA evaluates
108 the adequacy of these determinations and the supporting scientific rationale during application
109 assessment and on inspection. The manufacturer should use a scientific- and risk-based approach
110 to determine what constitutes a significant phase and to justify when and where the appropriate
111 tests or examinations should occur relative to a significant phase. It is important to choose the
112 appropriate in-process controls, and tests, or examinations to ensure the quality of in-process
113 materials as well as the performance of the manufacturing process. Process monitoring and
114 control decisions that result in minor equipment and process adjustments do not typically need
115 additional quality unit 16 approval if all of the following conditions are met: (1) the adjustments
116 are within the preestablished and scientifically justified limits; (2) these limits have been
117 approved by the quality unit in the master production and control record and the control strategy;
118 and (3) the production data is reviewed by the quality unit before approval or rejection of a
119 batch. 17,18
120
121 In-process testing strategies should be dictated by the nature of the drug and the manufacturing
122 processes. Manufacturers should ensure that innovative strategies that streamline in-process
123 testing provide sufficient assurance of product quality. The manufacturer should employ a
124 scientifically sound and appropriate sampling and testing strategy for quality attributes at
125 appropriate points 19 in the process that are adequate to ensure drug product quality. The
126 manufacturer should employ time-based sampling plans for quality attributes, where appropriate
127 (e.g., time-based measurement of the change in dryer outlet temperature during powder drying
128 processes, which can be used as a surrogate measurement for moisture content).
129
130 In addition to appropriate flexibility in where and when in-process sampling and testing should
131 occur, the regulations provide flexibility in how in-process material and drug product testing is
132 conducted. The preamble to the final rule states that a sampling plan “can mean both a plan for
133 collection of physical units for testing, or it can mean a schedule by which an examination of
134 some sort is done.” 20 Although in-process controls, and tests, or examinations of in-process
135 materials are required, 21 sampling does not necessarily require steps for physically removing in-
136 process materials to test their characteristics. Innovative technologies allow in-line, at-line, or
137 on-line measurements in place of physical sample removal for laboratory testing, 22 and these
138 measurements can be used in conjunction with process models.
139

15
Ibid.
16
For the purposes of this guidance, the term quality unit is synonymous with the term quality control unit. For the
definition of quality control unit, see § 210.3(b)(15).
17
Under § 211.100, a manufacturer must have written procedures for production and process control. Such
procedures must be reviewed and approved by the quality unit.
18
See § 211.110(c) and 43 FR 45014 at 45052.
19
An appropriate point can occur during or after a single manufacturing step or a group of manufacturing steps that
the manufacturer has determined to be a significant phase.
20
See 43 FR 45014 at 45033.
21
See § 211.110(a).
22
See guidance for industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and
Quality Assurance (October 2004).

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140 IV. ADDITIONAL CONSIDERATIONS FOR ADVANCED MANUFACTURING
141 AND PROCESS MODELS
142
143 FDA recognizes that advanced manufacturing can enable pharmaceutical modernization and
144 deliver benefits to both industry and patients. The CGMP regulations generally allow flexibility
145 in how manufacturers can demonstrate compliance. Manufacturers can use a variety of
146 approaches including incorporation of certain advanced manufacturing technologies. Both
147 enhanced pharmaceutical development approaches and real-time quality monitoring of in-
148 process materials (e.g., process analytical technology (PAT), 23 process models) can improve
149 drug product quality and support advanced manufacturing. For example, continuous
150 manufacturing that incorporates enhanced process monitoring generally results in increased
151 process understanding.
152
153 Continuous manufacturing and batch manufacturing could have different control strategies to
154 ensure batch uniformity and drug product integrity. Both continuous manufacturing and batch
155 manufacturing generally involve multiple manufacturing steps that physically or chemically
156 transform in-process materials. Typically, with a batch manufacturing process, in-process
157 materials can be easily isolated between each manufacturing step. This allows greater access for
158 sampling and testing of in-process materials before or after each step. However, given the
159 process design for continuous manufacturing, isolating in-process materials may not be feasible.
160
161 As described in Section III, § 211.110 provides flexibility in what in-process sampling and
162 testing should be done in addition to where, when, and how it should be done. Drug product
163 manufacturers must use appropriate in-process control, and testing, or examination strategies to
164 ensure that in-process materials can be meaningfully evaluated at significant phases. 24 This
165 evaluation allows the quality unit to make approval or rejection determinations for in-process
166 materials during the production process. 25 Because of the integrated nature of continuous
167 manufacturing processes, the quality unit can make a scientific determination that two or more
168 unit operations can be considered a single significant phase of manufacturing. This decision
169 should be made before initiating manufacturing, and it should be based on process
170 understanding. For example, in batch manufacturing of a solid oral drug product, blend
171 uniformity should typically be assessed before in-process materials continue to the compression
172 step. However, in continuous manufacturing, a manufacturer could conduct sampling and testing
173 at an appropriate point in the process (e.g., at the tablet press feed frame or after compression) to
174 evaluate the adequacy of mixing to ensure batch uniformity and homogeneity. Then, the quality
175 unit can determine whether to approve or reject the in-process material either before or after the
176 compression stage. Manufacturers should have robust understanding of the process, including
177 system dynamics. This will help manufacturers ensure that the sampling frequency is sufficiently
178 representative to draw a statistically valid conclusion about the quality of the in-process
179 materials and the drug product.
23
PAT is a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e.,
during processing) of critical quality and performance attributes of raw and in-process materials and processes, with
the goal of ensuring drug product quality. See guidance for industry PAT — A Framework for Innovative
Pharmaceutical Development, Manufacturing, and Quality Assurance.
24
See § 211.110.
25
See § 211.110(c) which requires the quality control unit to approve or reject in-process materials during the
production process.

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180
181 Other approaches can also be used to monitor the characteristics of in-process materials and
182 validate the performance of manufacturing steps that may be responsible for causing variability.
183 These other approaches could provide data that supports the quality unit’s approval or rejection
184 of in-process materials during the production process. For example, a process model can be used
185 to help monitor the attributes of in-process materials that affect the drug product’s critical quality
186 attributes. Process models can be useful for implementing advanced manufacturing, such as
187 continuous manufacturing. Thus, process models can be a component of the overall control
188 strategy. This approach can enhance understanding and control of the manufacturing process.
189
190 The behavior of a process can be mathematically represented by a process model. During routine
191 commercial operation, a process model’s ability to predict quality attributes of in-process
192 materials depends upon the sufficiency and applicability of the model’s underlying assumptions.
193 Therefore, both the adequacy of a process model and its ability to facilitate a maintained state of
194 control are dependent upon the underlying assumptions remaining valid. 26 Advanced
195 manufacturing (such as continuous manufacturing) generally lends itself to more extensive
196 understanding and control of the manufacturing process; thus, it is generally suitable for
197 implementation of process models as part of the control strategy.
198
199 FDA is aware of industry’s interest in using in-process control strategies that rely solely on
200 process models to satisfy the requirements of § 211.110. This includes interest in strategies that
201 use process models in continuous manufacturing to predict in-process material uniformity and
202 homogeneity without any testing or examination of the in-process material (whether direct or
203 indirect). However, to date, FDA has not been made aware of process models that demonstrate
204 that: (1) the underlying assumptions of the process model will remain valid during routine
205 manufacturing; and (2) the manufacturer can detect if an underlying assumption is no longer
206 valid (e.g., a continuous mixing model that assumes uniform mixing would be unable to detect
207 that uniform mixing is no longer occurring due to material agglomeration on the walls of the
208 mixer). In other words, current process models cannot ensure the continued validity of all of the
209 model’s underlying assumptions at all times, particularly during certain unplanned disturbances.
210 In the event of an unplanned disturbance that is not accounted for by the model’s underlying
211 assumptions, such control strategies would be unable to prevent nonconforming in-process
212 materials (e.g., nonhomogeneous powder blend) from continuing through production and being
213 used “in manufacturing or processing operations for which they are unsuitable.” 27,28 Therefore,
214 control strategies that rely solely on current process models would be insufficient to satisfy the
215 requirements of § 211.110.
216
217 Process models, when paired with in-process material testing or process monitoring (including
218 process inputs and outputs), can be powerful tools for maintaining a state of control and ensuring
219 drug product quality. In-process material testing can be achieved either through laboratory
220 testing of a physical sample removed from the process or implementation of other innovative

26
For more information on the design and validation of process models, see ICH guidance for industry Q8, Q9, &
Q10 Questions and Answers — Appendix Q&As from Training Sessions (July 2012).
27
See § 211.110(d).
28
This would be particularly true of an unplanned disturbance that could affect the model’s output without being
detected.

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221 technologies or methods which can be at-line, on-line, or in-line. As an alternative to certain in-
222 process tests, process monitoring (e.g., surrogate measurements), where scientifically
223 appropriate, could be acceptable. Process models should incorporate process monitoring or in-
224 process testing to maintain a state of control, facilitate model maintenance, and ensure drug
225 product quality. FDA encourages the use of a scientifically valid combination of modern control
226 strategies to develop and implement effective and innovative approaches in pharmaceutical
227 development, manufacturing, and quality assurance.
228
229 As part of FDA’s mission to protect and promote the public health, FDA is committed to
230 supporting and enabling pharmaceutical innovation and modernization. As the science
231 supporting innovative in-process control tools and methods continues to develop, FDA
232 anticipates that these scientific advancements can be leveraged to pursue in-process control
233 strategies that increasingly rely on process models. Based on the challenges associated with these
234 approaches, FDA encourages industry representatives and manufacturers to contact FDA if they
235 are interested in using alternative control strategies. Industry representatives and sponsors can
236 contact the Center for Drug Evaluation and Research’s Emerging Technology Team, 29 the
237 Center for Biologics Evaluation and Research’s Advanced Technologies Team, 30 or the Center
238 for Veterinary Medicine, 31 as appropriate. These strategies should be discussed as early in the
239 development process as possible. These discussions will also help inform future policy
240 development to support the adoption of robust alternative control strategies.
241
242 REFERENCES
243
244 Guidances for Industry
245
246 PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality
247 Assurance (October 2004)
248
249 Process Validation: General Principles and Practices (January 2011)
250
251 ICH Guidances for Industry
252
253 Q8, Q9, & Q10 Questions and Answers — Appendix Q&As from Training Sessions (July 2012)
254
255 Q8(R2) Pharmaceutical Development (November 2009)
256
257 Q9(R1) Quality Risk Management (May 2023)
258
259 Q10 Pharmaceutical Quality Systems (April 2009)
260
261 Q13 Continuous Manufacturing of Drug Substances and Drug Products (March 2023)
262

29
https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/emerging-technology-program
30
https://www.fda.gov/vaccines-blood-biologics/industry-biologics/cber-advanced-technologies-program
31
Questions or requests may be sent directly to CVM through email AskCVM@fda.hhs.gov.