Benefit-Risk 
Considerations for 
Product Quality 
Assessments 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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 60 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Natalia Comella at 301-796-6226.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2022 
Pharmaceutical Quality/CMC 
25462615dft_benefit-risk.doc 
04/13/22   
Benefit-Risk 
Considerations for 
Product Quality 
Assessments  
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD  20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2022 
Pharmaceutical Quality/CMC 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  Product Quality-Related Statutory and Regulatory Requirements .......................................... 2 
B.  Evidence Supporting Product Quality-Related Requirements .................................................. 3 
C.  The Product Quality Assessment and How It Contributes to FDAs Overall Premarketing 
Benefit-Risk Assessment ................................................................................................................ 4 
III.  APPLIED PRINCIPLES FOR PRODUCT QUALITY ASSESSMENTS .................. 6 
A.  The Interrelationship Among Therapeutic Context, Potential Benefits, and Product 
Quality-Related Risk Considerations ........................................................................................... 6 
B.  Assessment of Risks Posed by a Product Quality Issue or Set of Issues ................................... 7 
IV.  PRODUCT QUALITY ASSESSMENT CONCLUSIONS AND HANDLING OF 
UNRESOLVED QUALITY ISSUES ............................................................................ 10 
A.  Quality Determination ................................................................................................................. 10 
B.  Unresolved Quality Issues ........................................................................................................... 10 
C.  ANDAs .......................................................................................................................................... 11 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Benefit-Risk Considerations for Product Quality Assessments 
2  Guidance for Industry1 
3   
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page.   
12   
13   
14   
15   
16  I.  INTRODUCTION  
17   
18  This guidance describes the benefit-risk principles applied by FDA when conducting product 
19  quality-related assessments of chemistry, manufacturing, and controls (CMC)2 information 
20  submitted for FDA assessment as part of original new drug applications (NDAs) under section 
21  505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), original biologics license 
22  applications (BLAs) under section 351 of the Public Health Service Act (PHS Act), or 
23  supplements to such applications, in addition to other information (e.g., inspectional findings) 
24  available to FDA during its assessment.   
25   
26  This guidance discusses how FDA assesses risks, sources of uncertainty, and possible mitigation 
27  strategies for a product quality-related issue and how those considerations inform FDAs 
28  understanding of the potential effect on a product.3  The product quality assessment determines 
29  whether an applicants product development studies, manufacturing process, and control strategy 
30  will consistently result in a finished product of acceptable quality when manufactured at the 
31  facilities named in the application.  When a regulatory decision regarding the approval of an 
32  NDA or BLA is made, FDA considers the overall benefit(s) and risk(s) identified for the product, 
33  including any residual risk related to unresolved product quality issues.  This guidance also 
34  discusses how unresolved product quality issues may be addressed in the context of regulatory 
35  decision-making. 
36   
 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research at the Food and Drug Administration.  
 
2 FDA regulations refer to chemistry, manufacturing, and controls.  The term product quality is used in this guidance 
to encompass chemistry, manufacturing, and controls as used in FDA implementing regulations.  As used in this 
guidance, product quality applies to both drug substances and drug products. 
 
3 For the purposes of this guidance, all references to drug, drug product, and product refer to both human drugs and 
biological products unless otherwise specified.   
  1  Contains Nonbinding Recommendations 
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37  This guidance is not intended to address the review by other disciplines or sections of a 
38  marketing application (e.g., clinical, nonclinical, biostatistics, pharmacology).  
39   
40  Sections II and III of this guidance focus on product quality assessment in the context of FDAs 
41  review of an NDA or BLA.  Although not specifically addressed in sections II and III, product 
42  quality assessments are also done for abbreviated new drug applications (ANDAs).4  However, 
43  the product quality assessment of an ANDA can be different to the extent that the ANDA relies 
44  on FDAs finding that the reference listed drug (RLD)5 identified is safe and effective.  As with 
45  NDAs and BLAs, an ANDA will not be approved if the applicants product development studies, 
46  manufacturing process, and control strategy will not consistently result in a finished product of 
47  acceptable quality when manufactured at the facilities named in the application.6  Section IV of 
48  this guidance, which discusses how unresolved product quality issues may be handled in the 
49  context of regulatory decision-making, specifically addresses how FDA may handle such issues 
50  as part of its review of an ANDA. 
51   
52  The contents of this document do not have the force and effect of law and are not meant to bind 
53  the public in any way, unless specifically incorporated into a contract.  This document is 
54  intended only to provide clarity to the public regarding existing requirements under the law.  
55  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
56  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
57  Agency guidance means that something is suggested or recommended, but not required. 
58   
59   
60  II.  BACKGROUND 
61   
62  A.  Product Quality-Related Statutory and Regulatory Requirements  
63   
64  Before approving an application, FDA must determine whether the drug product is both safe and 
65  effective for use under the conditions prescribed, according to the product labeling and the 
66  instructions it contains.7  Section 505(b) and (d) of the FD&C Act identify the key components 
67  required for approval of a new drug under an NDA.  Among them are product quality-related 
68  requirements to demonstrate the applicant has developed a drug product and drug substance, 
69  manufacturing process, and control strategy that will consistently result in a drug product of 
 
4 An ANDA is an application submitted and approved under section 505(j) of the FD&C Act for a drug product that 
is a duplicate of a previously approved drug product.  An ANDA may not be submitted if clinical investigations are 
necessary to establish the safety or effectiveness of the proposed drug product.  See the guidance for industry 
Determining Whether to Submit an ANDA or a 505(b)(2) Application (May 2019).  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. 
 
5 The RLD is the listed drug identified by FDA as the drug product upon which an applicant relies in seeking 
approval of its ANDA (21 CFR 341.3(b)). 
 
6 See 21 U.S.C. 355(b)(1)(B)-(F), (j)(2)(A)(vi). 
 
7 See section 505(b)(1) and (d) of the FD&C Act (21 U.S.C. 355(b)(1) and (d)). 
 
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70  acceptable quality to ensure it is both safe and effective for use.8  Specifically, section 
71  505(b)(1)(C) and (D) of the FD&C Act requires a new drug applicant to submit a full statement 
72  of the composition of such drug as well as a full description of the methods used in, and the 
73  facilities and controls used for, the manufacture, processing, and packaging of such drug; this 
74  information informs the Agencys assessment of whether the applicant can ensure the identity, 
75  strength, quality, and purity of the drug substance and drug product.  Regulations further 
76  describe these requirements.9 
77   
78  Likewise, BLAs have similar considerations with respect to product quality-related requirements.  
79  Under section 351(a)(2)(C) of the PHS Act,10 FDA will approve a BLA based on a 
80  demonstration that the biological product is safe, pure, and potent and that the facility in which 
81  the biological product is manufactured, processed, packed, or held meets standards designed to 
82  ensure the biological product continues to be safe, pure, and potent.   
83   
84  B.  Evidence Supporting Product Quality-Related Requirements 
85   
86  Applicants must submit data and supporting information to demonstrate that they can ensure and 
87  preserve a drug products identity, strength, quality, and purity for NDAs11 or a biological 
88  products safety, purity, and potency for BLAs.12  The information available to FDA at the time 
89  of the assessment, namely the relevant sections of the marketing application and other 
90  information (e.g., an inspection report) about the facilities named in the application, are assessed 
91  during the product quality assessment of the application. 
92   
93  FDA will approve an NDA, BLA, or supplement to an NDA or BLA after it determines that the 
94  product meets the statutory standards for safety and effectiveness, manufacturing and controls, 
95  and labeling.13  Although the statutory standards apply to all drugs, the diversity of drugs and the 
96  wide range of processes used to manufacture those drugs demand flexibility in applying the 
97  standards.  Thus, FDA exercises its scientific judgment to determine the type and quantity of 
 
8 See section 505(d) of the FD&C Act (21 U.S.C. 355(d)); 21 CFR 314.50(d)(1). 
 
9 For example, 21 CFR parts 210 and 211, 21 CFR 314.50(d)(1). 
 
10 See 42 U.S.C. 262(a)(2)(C); see also 21 CFR 601.2. 
 
11 Section 505(b)(1)(D) of the FD&C Act (21 U.S.C. 355(b)(1)(D)) requires an applicant to submit a full description 
of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such 
drug.  See also 21 CFR 314.50(d)(1).  FDA must refuse to approve an NDA if the methods used in, and the 
facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its 
identity, strength, quality, and purity (section 505(d)(3) of the FD&C Act (21 U.S.C. 355(d)(3))).  See also 21 CFR 
314.125(b)(1).   
 
12 Section 351(a)(2)(C) of the PHS Act (42 U.S.C. 262(a)(2)(C)) states that FDA will approve a BLA based on a 
demonstration that the biological product is safe, pure, and potent and that the facility in which the biological 
product is manufactured, processed, packed, or held meets standards designed to ensure that the biological product 
continues to be safe, pure, and potent.   
 
13 See 21 CFR 314.105(c) and 21 CFR 601.20.  
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
98  data and information an applicant is required to provide to enable FDA to make a determination 
99  whether a product meets the statutory standards for approval.14 
100   
101  Product quality assessments consider every aspect of a drugs components and formulation, 
102  manufacturing, and control strategy to determine the drugs overall quality.  For example, the 
103  assessment for a small molecule drug product examines the method of synthesis and isolation of 
104  the drug substance to ensure purity and control over levels of any impurities and degradation 
105  products including mutagenic impurities; the stringency of validation and suitability of the 
106  analytical procedures; and the processing and related process controls to ensure that they are 
107  designed and controlled to ensure consistent product quality, including, when appropriate, 
108  ensuring product sterility.  For biological products, a product quality assessment may examine 
109  the expression system used, the quality of the production cell banks, the manufacturing process, 
110  control of any microbial contaminants, and potential process-related impurities as well as 
111  product-related variants.  The appropriateness of end product or release testing is evaluated; 
112  microbial control (for drug substance) and, as applicable, sterility assurance (for a drug product) 
113  are also assessed.   
114   
115  C.  The Product Quality Assessment and How It Contributes to FDAs Overall 
116  Premarketing Benefit-Risk Assessment 
117   
118  Using the information available to the Agency, a product quality assessment identifies any 
119  product quality issues and evaluates the risk of harm posed by the issues, along with the 
120  uncertainties associated with those issues and risks.  Typical sources of product quality-related 
121  uncertainty may include, but are not limited to, gaps in current knowledge, such as projecting 
122  performance at the end of shelf life based on extrapolation given the limited stability data 
123  provided for small molecule drug products.  Other illustrative examples for potential sources of 
124  uncertainty for small molecule drug products include new technologies or dosage forms, 
125  potential frequency of an observed issue, and limited commercial manufacturing experience 
126  when the manufacturing process might behave differently on scale up.  Additionally, uncertainty 
127  could come from gaps in process understanding, sources of variability, and the probability of 
128  detection of problems.15  Many of the principles and concepts noted in the International Council 
129  for Harmonisation (ICH) guidance for industry Q9 Quality Risk Management (June 2006) are 
130  generally applicable during FDAs product quality assessment and may help determine whether 
131  the product meets the requirements for the identity, strength, quality, and purity for a drug, or 
132  safety, purity, and potency for a biological product.  
133   
134  When conducting a product quality assessment, the Agency identifies potential risks to product 
135  quality associated with the formulation, manufacturing process, and packaging components.  The 
136  Agency analyzes the potential effect of the risk on safety and/or effectiveness and assesses the 
137  proposed control strategy for mitigating those risks.  The regulations allow for the assessment to 
138  be iterative, with the Agency engaging applicants to better understand the issues or areas of 
139  uncertainty, while at the same time, exploring possible options to mitigate the issue or 
 
14 See 21 CFR 314.105(c). 
 
15 See the International Council for Harmonisation (ICH) guidance for industry Q9 Quality Risk Management (June 
2006).   
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140  uncertainty.16  How FDA views the identified product quality issues depends on whether the 
141  control strategy can adequately address the risk.  When there remains an unresolved product 
142  quality issue, the Agency will factor into its decision-making process any residual risk posed by 
143  the product quality issue.  How FDA addresses the outstanding issue(s) is informed by relevant 
144  published guidance documents but may also depend on certain application-specific parameters 
145  (see section IV., Product Quality Assessment Conclusions and Handling of Unresolved Quality 
146  Issues). 
147   
148  Product quality assessors may also use the interdisciplinary teams understanding of the 
149  therapeutic context and the assessment of benefit during the product quality assessment.  A 
150  greater understanding of the patient population and disease or condition helps to frame the 
151  importance of a product within the overall therapeutic armamentarium that is available to 
152  patients and health care providers and may facilitate an evaluation of the potential significance of 
153  risks identified during the assessment to inform FDAs recommendation regarding the risk 
154  mitigation or reduction.  
155   
156  When determining whether a drug or biological product meets the standard for approval, FDA 
157  conducts an overall benefit-risk assessment that takes into account the extensive evidence of 
158  safety and effectiveness submitted by a sponsor . . . as well as many other factors affecting the 
159  benefit-risk assessment.17  Benefit-risk assessments are the foundation for FDAs regulatory 
160  evaluation of human drugs and biological products.  Benefit-risk assessment in the FDA 
161  regulatory context involves making a judgment regarding whether the benefits (with their 
162  uncertainties) of the product outweigh the potential risks (with their uncertainties and approaches 
163  to managing risks) under the conditions of use defined in labeling.   
164   
 
16 The regulations under 21 CFR 314.102 describe communications between FDA and applicants.  The regulation 
states, FDA shall communicate with applicants about scientific, medical, and procedural issues that arise during the 
review process (21 CFR 314.102(a)).  FDAs regulation at 21 CFR 314.102(b) further states:  
 
FDA reviewers shall make every reasonable effort to communicate promptly to applicants easily 
correctable deficiencies found in an application or abbreviated application when those deficiencies are 
discovered, particularly deficiencies concerning chemistry, manufacturing, and controls issues.  The agency 
will also inform applicants promptly of its need for more data or information or for technical changes in the 
application or abbreviated application needed to facilitate the agencys review.  This early communication 
is intended to permit applicants to correct such readily identified deficiencies relatively early in the review 
process and to submit an amendment before the review period has elapsed. 
 
17 See Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making, Draft PDUFA V 
Implementation Plan - February 2013, Fiscal Years 2013-2017, p. 1 and pp. 57, available at 
https://www.fda.gov/media/84831/download.  See also Benefit-Risk Assessment in Drug Regulatory Decision-
Making, Draft PDUFA VI Implementation Plan (FY 2018-2022), pp. 34, available at 
https://www.fda.gov/media/112570/download.  
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165  FDAs vehicle for conducting these assessments is the Benefit-Risk Framework.18  To inform the 
166  process, FDA conducts an interdisciplinary assessment in which each included discipline (such 
167  as clinical, product quality, nonclinical, pharmacology, biostatistics) assesses the relevant 
168  sections of the marketing application and provides key inputs into the overall Benefit-Risk 
169  Framework for Human Drug Review; the conclusions of the product quality assessment are 
170  considered in the Benefit-Risk Framework if there are product quality issues that pose risks.  
171  When a regulatory decision regarding approval or licensure is made, FDA considers the overall 
172  risks, including those related to unresolved product quality issues, in the context of the overall 
173  benefits to determine whether the statutory requirements have been met.   
174   
175   
176  III.  APPLIED PRINCIPLES FOR PRODUCT QUALITY ASSESSMENTS 
177   
178  FDA considers the following guiding principles during product quality assessments of marketing 
179  applications.   
180   
181  A.  The Interrelationship Among Therapeutic Context, Potential Benefits, and 
182  Product Quality-Related Risk Considerations 
183   
184  The determination of a drugs overall clinical benefit(s) is outside the scope of the product 
185  quality assessment and is not addressed in this guidance.19  However, as previously mentioned, 
186  an understanding of the therapeutic context and the clinical benefit may inform the product 
187  quality assessment and its conclusions.  
188   
189  During the product quality assessment, assessors may use the interdisciplinary teams 
190  understanding of the therapeutic context and the assessment of benefit to:   
191   
192    Gain a greater understanding of the patient population and disease for which the product 
193  will be used 
194   
195    Identify whether the drug addresses an unmet medical need   
196   
197    Identify potential sources of product quality risk that, if unmitigated, could result in a risk 
198  to the patient 
199   
200  A greater understanding of the patient population, disease or condition, and whether there is 
201  unmet medical need helps to frame for the product quality assessor and team the importance of 
202  the product within the overall therapeutic armamentarium that is available to patients and health 
 
18 For more information regarding the Benefit-Risk Framework, see the draft guidance for industry Benefit-Risk 
Assessment for New Drug and Biological Products (September 2021) (when final, this guidance will represent the 
FDAs current thinking on this topic).  This draft guidance was developed in accordance with the PDUFA VI 
commitment goals letter titled PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2018 
Through 2022, section I.J.2., available at https://www.fda.gov/industry/prescription-drug-user-fee-
amendments/pdufa-vi-fiscal-years-2018-2022. 
 
19 See the draft guidance for industry Benefit-Risk Assessment for New Drug and Biological Products.   
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Draft  Not for Implementation 
203  care providers and may provide context used to evaluate the potential significance of risks 
204  identified during the assessment to inform FDAs recommendation regarding the risk mitigation 
205  or reduction.  Some sources of product quality risk will be independent of the therapeutic context 
206  (e.g., sterility failure).  However, there are instances where the sources of product quality risk 
207  relate directly to the therapeutic context (e.g., Size 00 capsules used for a therapy intended to 
208  treat young pediatric patients).  Assessment teams use the therapeutic context to identify 
209  additional potential sources of product quality risk that arise from who would use the product or 
210  how it is intended to be used. 
211   
212  Although adverse events typically result from the pharmacological activity of a product, failure 
213  of a product to perform as intended due to product quality defects may also pose a risk to 
214  patients.  One example of a risk caused by potential product quality defects is failure of the 
215  drugs release mechanism (e.g., dose dumping from modified-release products).  Another 
216  example is a solid oral dosage form that is too large in size for the intended use population, 
217  resulting in a choking hazard.  As the efficacy and safety profile becomes better understood by 
218  FDA, identified benefits (i.e., new drug without a known side effect or a new drug for a medical 
219  condition without any treatment options) may inform how a product quality issue is evaluated 
220  and addressed during the product quality assessment.   
221   
222  Section IV.A., Quality Determination, discusses how the benefits provided by the product and 
223  information relating to currently available treatment options could inform the product quality 
224  assessment.   
225   
226  B.  Assessment of Risks Posed by a Product Quality Issue or Set of Issues 
227   
228  Although each application will contain unique information on CMC strategies, FDA routinely 
229  applies the following principles when evaluating quality issues during its assessment.20    
230   
231    Risk-based considerations related to therapeutic context.  As noted in section III.A., 
232  The Interrelationship Among Therapeutic Context, Potential Benefits, and Product 
233  Quality-Related Risk Considerations, understanding the therapeutic context and benefit 
234  can inform how an identified issue is evaluated and addressed during the product quality 
235  assessment.  The assessment considers relevant characteristics of the target population 
236  and whether certain product quality attributes are intended to address specific unmet 
237  needs such as alternative dosage forms and/or delivery systems that may ease 
238  administration of the drug, provide a targeted drug delivery (e.g., a drug product with 
239  antibody drug conjugates technology relative to a drug without it), or provide continuous 
240  delivery over the course of treatment.  Other clinical issues, such as use in healthy 
241  individuals (e.g., birth control), the duration of use, and use in vulnerable populations 
242  (e.g., pediatric population and geriatric patients), are considered as well.  
243   
244  The evaluation of risk is informed by the combination of these considerations.  For 
245  example, if the same impurity is found in multiple drugs at similar levels, but the 
246  therapeutic context differs for each application (e.g., chronic use for pediatric population 
 
20 The list of principles is not intended to be exhaustive given the diverse and unique product quality attributes 
associated with each drug or biological product. 
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247  versus acute use in adults), the Agency may come to different conclusions with respect to 
248  whether the application should be approved, depending on the vulnerability of the patient 
249  population, condition treated, and dosing regimen (e.g., length and frequency of 
250  exposure).  To give another example, the risk associated with imprecise dosing can 
251  depend on whether the drug has a narrow therapeutic index, which would mean potential 
252  over or under dosing a patient, or if the dose of the drug is saturating its intended target, 
253  which would mean that a certain level of variation could occur without affecting the 
254  drugs safety or effectiveness.  The level of risk associated with the product quality issue 
255  is directly linked to the potential effect on the target patient population.  
256   
257    Extent of impact on safety and/or effectiveness.  In all cases, drug products should be 
258  designed to meet the needs of the intended patient population and to deliver consistently 
259  the intended product performance.21  The quality target product profile forms the basis of 
260  design for the development of the product.  It is a prospective summary of the quality 
261  characteristics of a drug product that ideally will be achieved to ensure the desired 
262  quality, taking into account safety and efficacy of the drug product.  Although all product 
263  quality issues are evaluated for their potential likelihood of harm, not all product quality 
264  issues pose the same level of risk to the intended product performance and patient safety.  
265  Being unable to ensure a drug products intended product performance would raise 
266  concerns about the safety and/or effectiveness of a drug product for the patient 
267  population.  For example, a manufacturing process and/or container closure system that 
268  cannot ensure the sterility of a parenteral product will raise a concern about the safety of 
269  the drug product.  In other instances, an identified issue, such as inconsistent dosing of 
270  the product, may raise concerns relating to the effectiveness or safety, or both, of the 
271  product.   
272   
273    Totality of product quality information.  When evaluating product quality, the Agency 
274  considers the totality of information available and relevant to the product during the 
275  assessment.  Most of the information is provided in an applicants marketing application.  
276  However, the Agency may examine other sources of information associated with the drug 
277  development program, such as information from the products investigational new drug 
278  application that is not contained in the marketing application or any relevant 
279  communications with the sponsor before submission of the marketing application.  Other 
280  relevant information includes, but is not limited to, the effectiveness of the 
281  pharmaceutical quality system to ensure consistent product quality through robust 
282  monitoring and control systems,22 clinical experience during pivotal trials, scientific 
283  literature, and/or the Agencys knowledge of a given issue or class of drugs. 
284   
285    Inspectional findings.  FDA uses a risk-based approach to determine whether a 
286  preapproval or prelicensure inspection is needed using information provided in the 
287  application and information FDA may have regarding the facilities named in the 
 
21 See the ICH guidance for industry Q8(R2) Pharmaceutical Development (2009).  Pharmaceutical development 
should include and define the quality target product profile as it relates to quality, safety, and efficacy, considering, 
for example, the route of administration, dosage form, bioavailability, strength, and stability.   
 
22 See the ICH guidance for industry Q10 Pharmaceutical Quality System (2009).   
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288  application.  The Agency may also use information from a previous surveillance 
289  inspection to inform a decision on the need for a preapproval or a prelicensure inspection 
290  or in lieu of such an inspection.  A credible surveillance inspection may have been 
291  performed by FDA or by a national regulatory authority found capable under section 809 
292  of the FD&C Act (21 U.S.C. 384e). 
293   
294  Preapproval inspections for NDAs verify readiness for commercial manufacturing, 
295  conformance to the application, and data and information provided in the application.  
296  Prelicensure inspections for BLAs are intended to verify that:  (1) the facilities continue 
297  to comply with the standards set and described in the BLA for the product and process; 
298  (2) the facility adheres to current good manufacturing practice requirements; and (3) the 
299  information and data regarding the product and the manufacturing process support what 
300  is described in the application.  The inspectional findings will determine if the proposed 
301  manufacturing facilities listed in the application meet those criteria or if there are 
302  outstanding manufacturing risks needing to be addressed to support approval.   
303   
304  When manufacturing or quality issues requiring adjustments to the control strategy are 
305  identified during an inspection, the nature and magnitude of the observed issues, and the 
306  mitigation strategies available to address those issues, inform the level of risk posed by 
307  the drug.   
308   
309    Other considerations that could affect the product quality assessment.  Each 
310  marketing application undergoes the same type of assessment during the decision-making 
311  process regardless of the product, using the principles noted above.  There may be 
312  additional considerations regarding unique aspects of a drugs development or 
313  advancements in pharmaceutical science.  FDA may need additional or new information 
314  (such as additional testing for nitrosamine contaminants in drugs23 found at risk for their 
315  presence) to better understand potential risks previously not known or considered.  These 
316  considerations may raise additional or new product quality issues and concerns.  For 
317  example, a novel combination of a drug or biological product with another medical 
318  product, such as a medical device, or the introduction of a novel technology in the 
319  manufacturing process or analytical testing methodology could introduce additional 
320  complexity to the decision-making process by adding new risks and uncertainties relating 
321  to product quality.  Other circumstances, such as development of or revisions to 
322  applicable compendial standards, also could affect the product quality assessment. 
323   
324    Possible mitigation strategies.  A key consideration in assessing any observed or 
325  potential risks associated with product quality issues identified is an applicants ability to 
326  mitigate or reduce the risk associated with an identified product quality issue.  Some 
327  product quality issues may be easier to address (e.g., confirmation of water vapor 
328  transmission rate for a new blister lidding material or whether a tablet can be split easily 
329  and consistently as directed in labeling).  Identification of a possible mitigation 
330  strategy(ies) and the applicants ability to implement that strategy(ies) to address the 
331  product quality issue are evaluated during the assessment for acceptability.  Any 
 
23 See the guidance for industry Control of Nitrosamine Impurities in Human Drugs (February 2021). 
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332  mitigation strategy that introduces a new product quality issue or exacerbates other 
333  already identified product quality issues may further confound the benefit-risk profile 
334  and/or result in an unsatisfactory resolution of the issue.   
335   
336  As noted earlier, this list is not a comprehensive list of considerations given the ever-evolving 
337  advancement of pharmaceutical science and unique considerations that arise during a particular 
338  product quality assessment.  These considerations, when viewed together, inform the product 
339  quality assessment as to whether the applicants development program has adequately addressed 
340  the elements supporting the intended product performance.24  These considerations set up a 
341  framework by which FDA considers product quality issues in light of the benefit(s) and 
342  therapeutic context, thereby informing FDAs assessment of the overall quality of the drug and 
343  the robustness of an applicants product quality system to produce the product with the intended 
344  product performance.   
345   
346   
347  IV.  PRODUCT QUALITY ASSESSMENT CONCLUSIONS AND HANDLING OF 
348  UNRESOLVED QUALITY ISSUES 
349   
350  A.  Quality Determination 
351   
352  A product quality assessment ultimately results in a determination about the quality of the drug 
353  and whether the proposed drug meets the regulatory requirements for identity, strength, quality, 
354  and purity for NDAs or safety, purity, and potency for BLAs.  This determination reflects FDAs 
355  assessment of whether an applicant has developed a product, manufacturing process, and control 
356  strategy that will consistently result in the quality attributes appropriate to meet the intended 
357  product performance throughout the shelf-life of the product.  At the end of the assessment, the 
358  product quality assessment team provides its recommendation to approve or not approve a 
359  marketing application from the product quality perspective.   
360   
361  B.  Unresolved Quality Issues 
362   
363  Under most circumstances, when unresolved quality issues remain, the Agency will not approve 
364  the application.  However, in rare circumstances, an application may meet the standard for 
365  approval despite the presence of certain unresolved quality issues (as determined by the Agency).  
366  In such a case, the residual risk posed by the unresolved quality issue may be outweighed by the 
367  benefits of the product and of having the product on the market more quickly.  In situations like 
368  this, the Agency may allow certain information to be submitted postapproval.  These 
369  circumstances include: 
370   
371    When the Agency determines it is not feasible for the product quality issue to be resolved 
372  before approval AND it can be addressed postapproval without an unacceptable level of 
373  risk.  One example could entail providing postapproval confirmatory photostability data 
374  to address a change in film-coat composition that affects shading of film-coat color. 
375   
 
24 See ICH Q8(R2). 
  10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
376    When the residual risk, in the context of the overall benefit of the drug product, is found 
377  to be acceptable to allow certain confirmatory information to be provided in an agreed-
378  upon postapproval time frame.  This could be the case when there is an unmet medical 
379  need, such as a serious disease or condition for which there is no available therapy.  An 
380  unmet medical need may also exist where there are available therapeutic options but an 
381  additional clinically important benefit (such as superiority over current treatment options 
382  or comparable efficacy with a more favorable safety profile) has been observed.  In these 
383  instances, the overall benefits observed (with the associated uncertainties) would need to 
384  outweigh the overall risks, including the residual risk, and this would be considered on a 
385  case-by-case basis; the more significant the residual risk the greater the benefit would 
386  need to be to outweigh that risk.  
387   
388  In such cases, FDA may use a quality postmarketing agreement (QPA) for a product quality 
389  issue.25,26  A QPA is not a substitute for an applicant satisfying statutory and regulatory 
390  requirements for approval or licensure and should not be part of an applicants planned 
391  development program.  A QPA is an agreement, between FDA and the applicant, specifying the 
392  supporting data or information to be provided within a certain time frame postapproval.  In such 
393  cases, the Agency will determine whether a QPA is appropriate as it concludes the product 
394  quality assessment.  The data or information should be submitted postapproval within an agreed-
395  upon, defined time period.  The applicant should submit this data or information in the agreed-
396  upon reporting mechanism and provide a status update in an annual report until the agreement 
397  has been fulfilled.27    
398   
399  C.  ANDAs 
400   
401  A drug product approved in an ANDA relies on FDAs finding that the RLD identified in the 
402  ANDA is safe and effective, and therefore, relies on FDAs determination that the RLD provides 
403  benefits that outweigh its known and potential risks.  This reliance is premised on the generic 
404  drug product having the same active ingredient(s), conditions of use, route of administration, 
405  dosage form, strength, and (with certain permissible differences) labeling as the RLD, as well as 
 
25 Historically, QPAs have been referred to as CMC postmarketing commitments or CMC postmarketing 
agreements; the ICH guidance for industry Q12 Technical and Regulatory Considerations for Pharmaceutical 
Product Lifecycle Management (May 2021) refers to them as postapproval CMC commitments.  When this Benefit-
Risk Considerations for Product Quality Assessments guidance is finalized and implemented, FDA will refer to 
CMC postmarketing commitments as QPAs.  These QPAs differ from postmarketing requirements (PMRs) imposed 
under section 505(o)(3) of the FD&C Act (21 U.S.C. 355(o)(3)), which are required studies and clinical trials that 
relate to risks of serious adverse drug experiences.  They also differ from postmarketing commitments relating to 
clinical safety, clinical efficacy, clinical pharmacology, and nonclinical toxicology that are subject to the statutory 
reporting requirement of section 506B of the FD&C Act (21 U.S.C. 356b); 21 CFR 314.81(b)(2)(vii).  CMC 
postmarketing commitments are subject to a separate reporting requirement (21 CFR 314.81(b)(2)(viii)).  
 
26 In rare instances, FDA may require a PMR that relates to a product quality issue if the issue poses a risk of a 
serious adverse drug experience.  See sections 505(o)(2)(C) and (3) and 505-1(b) of the FD&C Act.  
 
27 The regulations under 21 CFR 314.81(b)(2)(viii) require submission in an annual report of the status of any 
postmarketing study not included under 21 CFR 314.81(b)(2)(vii) that is being performed by or on behalf of an 
applicant.  This includes any CMC studies that the applicant has entered into an agreement with FDA to conduct as 
well as all product stability studies.  
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Draft  Not for Implementation 
406  demonstrating that the generic drug product is bioequivalent to the RLD.28  FDA will not 
407  approve an ANDA if there is insufficient evidence of the foregoing or if the methods used in, or 
408  the facilities and controls used for, the manufacture, processing, and packing of the drug are 
409  inadequate to ensure and preserve the drugs identity, strength, quality, and purity.29  Drug 
410  products that are approved in ANDAs are generally considered by FDA to be therapeutically 
411  equivalent to their RLD.30  Products classified as therapeutically equivalent can be substituted 
412  with the full expectation that the generic product will produce the same clinical effect and safety 
413  profile as the RLD under the conditions specified in the labeling.   
414   
415  Given the Agencys knowledge and experience with the RLD at the time an ANDA is received, 
416  many of the considerations discussed in this guidance for new drug and biological product 
417  assessments generally are not applicable to the assessment of a generic drug product, including 
418  the use of QPAs.  However, in rare circumstances, FDA may determine that a QPA may be 
419  appropriate in the context of a generic drug that will address an urgent clinical need (e.g., a 
420  public health emergency or pervasive drug shortage).  The decision that a QPA would be 
421  appropriate for a particular ANDA would likely consider the type and extent of information that 
422  will be expected postapproval to resolve the issue and potential effect on similarly situated 
423  ANDAs.  A QPA does not relieve a generic drug applicant from satisfying all the statutory and 
424  regulatory requirements for approval of an ANDA, does not correct a deficient ANDA, and 
425  should not be part of the applicants planned development program.  
426   
 
28 See sections 505(j)(2)(A), 505(j)(2)(A)(iv), 505(j)(4), and 505(j)(4)(F) of the FD&C Act and 21 CFR 314.94, 
21 CFR 314.127, and 21 CFR 320.21(b). 
 
29 See section 505(d)(3) of the FD&C Act and 21 CFR 314.127(a)(1). 
 
30 Therapeutic equivalents are approved drug products that are pharmaceutical equivalents for which bioequivalence 
has been demonstrated, and that can be expected to have the same clinical effect and safety profile when 
administered to patients under the conditions specified in the labeling.  See 21 CFR 314.3; see also FDAs Approved 
Drug Products with Therapeutic Equivalents (the Orange Book), preface to the 41st edition, at page vii. 
  12