Harmonizing Compendial 

Standards With Drug Application 

Approval Using the USP Pending 

Monograph Process 

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DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 (CDER) Lana Bruney 240-402-3462 or 
(CVM) Mai Huynh 240-402-0669. 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
Center for Veterinary Medicine (CVM) 

 
July 2019 

Pharmaceutical Quality/CMC 

 
2266833dft.docx  
06/26/19    
Harmonizing Compendial 

Standards With Drug Application 

Approval Using the USP Pending 

Monograph Process 

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  

 
and/or 
 
 
Policy and Regulations  Staff, HFV-6 

Center for Veterinary Medicine 
 
Food and  Drug Administration 
 
7500  Standish  Place, Rockville, MD   20855 

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 Veterinary Medicine (CVM) 

 
July 2019 

Pharmaceutical Quality/CMC 

 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
TABLE OF CONTENTS  
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 1
  
III.   THE USP PENDING MONOGRAPH PROCESS ........................................................ 3 
 
IV.   INITIATING THE USP-PMP ......................................................................................... 4
  
V.   RECOMMENDATIONS FOR APPLICANTS.............................................................. 4 
 
APPENDIX: QUESTIONS AND ANSWERS ............................................................................ 6 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Harmonizing Compendial Standards With Drug Application 
1 
Approval Using the USP Pending Monograph Process 
2 
Guidance for Industry1  
3 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations. To  discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page.   
13   
14   
15   
16   
17  I.  INTRODUCTION  
18   
19  This guidance assists applicants and drug master file (MF) holders in the initiation of either  
20  revisions to an existing monograph(s) or development of a new monograph(s) under the United 
21  States Pharmacopeial Convention Pending Monograph Process (USP-PMP) during FDAs 
22  evaluation of a drug master file or drug product application.2 This guidance describes the process 
23  that allows for the revision of compendial standards that are harmonized with the approved 
24  quality and labeling requirements for a drug product application.  
25    
26  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
27  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
28  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
29  the word should in Agency guidances means that something is suggested or recommended, but 
30  not required. 
31   
32   
33  II.  BACKGROUND 
34   
35  Under sections 501 and 502 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), a drug 
36  with a name recognized in an official compendium must comply with compendial identity 
37  standards or be deemed adulterated, misbranded, or both.3 To avoid being deemed adulterated, 
                                                 
1 This  guidance has been  prepared by the Center for Drug Evaluation and Research in cooperation with the Center 
for Veterinary Medicine  at the Food and Drug Administration.   
2 In this guidance, the term  application may refer to a new drug application (NDA), an abbreviated new drug  
application (ANDA), a new animal drug application (NADA), or an abbreviated new animal drug application 
(ANADA), as well as supplements to all these applications. For investigational new animal drugs, an applicants 
proposed  revision to an existing monograph or  development of a new monograph may also be reviewed  under the 
investigational new animal drug file. The abbreviation MF  may refer to  drug master files or veterinary  master files. 
3 See sections  501(b) and  502(e)(3)(B) and  (g)  of the FD&C  Act; also  21 CFR 299.5.  
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38  such drugs must also comply with compendial standards for strength, quality, and purity, unless 
39  labeled to show all respects in which the drug differs from compendial standards.4 The term  
40  official compendium means the official United States Pharmacopeia (USP), official Homeopathic 
41  Pharmacopeia of the United States, official National Formulary (NF), or any supplement to any 
42  of these.5    
43   
44  The official USP-NF compendium is published by the United States Pharmacopeial Convention 
45  (USP), a private, non-governmental organization. USP revises (or develops) compendial 
46  standards from draft standards and supporting data that it receives from the pharmaceutical 
47  industry and/or the public, and reflects those standards in the USP-NF through, among other 
48  things, individual drug product and drug substance monographs.  
49   
50  It is the responsibility of both the applicant and MF holder to ensure that a drug product or drug 
51  substance complies with applicable standards in the USP-NF. When official USP-NF 
52  monograph(s) are available for the drug substance and/or drug product named in the application, 
53  FDA compares the quality standards found within the official USP-NF monograph with the 
54  quality attributes found in the application as part of the evaluation process. If the submitted 
55  information is not in compliance with official compendial standards, applicants and/or MF 
56  holders provide justification to FDA and should work with USP to revise the monograph. 
57  (Approval of the proposed changes is contingent upon FDA science and risk-based assessments.) 
58  Though the USP-NF is legally recognized in the FD&C Act, and USP works closely with FDA, 
59  FDA typically cannot share the application-specific information contained in submitted 
60  regulatory filings with USP because this information is considered proprietary and confidential.6  
61  An applicant or an MF holder therefore should provide any information needed to revise or 
62  develop an official monograph directly to USP. 
63   
64  Applicants and MF holders can petition USP to revise standards in official monographs.7  
65  However, the USP standards development processes do not accept proposals requesting changes 
66  to compendial standards (or proposing a new monograph) from applicants with drug products 
67  that are not currently approved by FDA.8 Historically, if during the evaluation of an application 
68  it was clear that the proposed specifications would not comply with the current monograph, 
69  approval of the application (and patient access to the drug) was delayed in some cases pending 
70  the applicant making revisions to enable the product to meet the monograph. The USP-PMP was 
71  developed to address these issues. 
72   
73   
                                                 
4 See section  501(b) of the FD&C Act and  21 CFR 299.5(c).  

5 See section 201(j) of the FD&C Act. 

6 See 21 CFR 314.430. 

7 Note: FDA cannot  provide the information needed to  revise USP-NF monographs to  USP. Information contained 

in regulatory filings submitted to FDA is considered  proprietary and confidential. The applicant or the applicants 

referenced MF holder must provide such information to  USP. (See the previous paragraph.) 
 
8 Similarly, MF holders must be referenced by a currently approved  drug  product to  propose changes to  compendial 

standards. 

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74  III.   THE USP PENDING MONOGRAPH PROCESS9   
75   
76  The USP-PMP enables revisions to and/or development of official monographs to begin before 
77  FDAs approval process is complete. The purpose of the USP-PMP is to ensure availability of a 
78  revised official USP-NF monograph that is consistent with FDA-approved specifications 
79  immediately following FDA approval of the application. This results in an official USP-NF 
80  monograph much faster than would be possible if monograph development or revision started 
81  only after final FDA approval of the drug product. 
82   
83  The following is excerpted from the USP Pending Monograph Guideline:10  
84   
85  The USP Pending Monograph process allows for development of monographs or 
86  monograph revisions for articles awaiting approval by FDA, and permits publication of 
87  these proposals in Pharmacopeial Forum (PF) for notice and comment where required in 
88  accordance with USPs typical Request for Revision processes. Following publication in 
89  PF, these proposals remain in an unofficial status until FDA approval of the market 
90  application held by the donor. The Pending Monograph process is available where USP 
91  does not yet have a monograph for a drug, or where there is an existing monograph with 
92  requirements that are not met by a potential product under review by FDA, and allows the 
93  new or revised monograph to become official more rapidly than would be possible if 
94  development began only after final FDA approval. In cases where there is an existing 
95  monograph, it is common for the application holder to propose reconciliation between 
96  their product and the existing monograph requirement by donating  analytical 
97  methodology and reference standard bulk material as necessary to revise the monograph. 
98  The USP Pending Monograph process allows for development of these proposals in a 
99  number of different ways, depending on the type of change that is needed and the amount 
100  of time available before the anticipated approval. In any case, these proposals remain in 
101  an unofficial status until FDA approval of the market application held by the donor. 
102   
103   
                                                 
9 For further details on the USP-PMP, applicants should reference the USP Pending Monograph Guideline, which  
describes USPs roles and responsibilities in the process. USPs guideline covers the portion  of the process that is 
between the applicant and USP; it does not include FDA application assessment activities. To initiate a USP-PMP 
proposal, applicants should refer to the guideline (found at  http://www.usp.org) and directly contact USP as 
indicated. 
10 Ibid. 
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104  IV.  INITIATING THE USP-PMP 
105   
106  Under the USP-PMP, applicants who have successfully filed an application with FDA may 
107  propose revisions to an existing monograph (or development of a new monograph) while the 
108  application is being assessed by FDA.11,12 Applicants who submit an application for a drug 
109  product (or who reference an MF for a drug substance) that does not meet or differs from the 
110  applicable official compendial standards should contact USP directly to initiate a USP-PMP 
111  proposal. Applicants who do not initiate the USP-PMP may risk delay in the approval of any 
112  application that is not in alignment with the official USP-NF monograph(s). Alternatively, 
113  applicants of drug products that do not meet (or differ from) the official compendial standards 
114  may elect to have all differences, and the extent of each such difference, plainly stated on its 
115  label, thus indicating that the product does not meet applicable compendial standards.13  
116  Therefore, we strongly recommend that applicants initiate a USP-PMP proposal if submitting 
117  applications as described above. In either situation  initiating the USP-PMP or labeling the 
118  product with the difference(s)  FDA will conduct thorough application evaluations using 
119  current established practices to determine the acceptability of the quality standards proposed in 
120  the application. 
121   
122   
123  V.  RECOMMENDATIONS FOR APPLICANTS  
124   
125  To avoid potential delays, USP-PMP proposals should be initiated very early in the application 
126  evaluation process. We recommend that those who intend to initiate the USP-PMP begin 
127  working on a proposal concurrent with an applications submission to FDA. The applicants 
128  intention to initiate the USP-PMP should be stated in the cover letter of the application and 
129  should also be prominently displayed in all applicable section(s) (i.e., the drug substance 
130  specification section (section 3.2.S.4.1) and/or the drug product specification section (3.2.P.5.1), 
131  as applicable). Applicants and MF holders should follow USPs guidelines for USP-PMP 
132  proposals and submit the appropriate information directly to USP. 
133   
                                                 
11 MF holders may also initiate the USP-PMP for revisions of an existing monograph  (or development of a new 
monograph) while the application they support (i.e., the application in which the MF is referenced) is under 
assessment by FDA. MF holders should coordinate USP-PMP initiation  with the applicant. 
12 Applications submitted to FDA undergo an initial filing  assessment. NDAs are filed  once FDA makes a threshold  
determination that the NDA is sufficiently complete to permit a substantive review. (See 21 CFR 314.101(a).)  
ANDAs are received once FDA makes a threshold determination that the ANDA is substantially complete. (See 
21 CFR 314.101(b)(1).) Once the filing assessment is complete, applicants receive communication either 
acknowledging submission of the application or indicating a refusal to file the NDA or refusal to receive the ANDA. 
For more information, see the following:  guidance for industry ANDA Submissions  Refuse-to-Receive Standards  
(December 2016); draft guidance for industry Good ANDA Submission Practices (January  2018); and  draft guidance  
for industry  Refuse to File: NDA and BLA Submissions to  CDER (December 2017). When final, these guidances will 
represent FDAs current thinking on these topics. For animal drug applications, see 21 CFR 514.110  Reasons for 
refusing to file applications, and CVM guidance for industry #119  How the Center for Veterinary Medicine Intends 
to Handle Deficient Submissions Filed  During the Investigation of  a New Animal  Drug. 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. 
13 See section  501(b) of the FD&C Act and  21 CFR 299.5(c).  
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134  Once a USP-PMP is initiated, the applicant should keep USP apprised of the applications status 
135  and work with USP to make any necessary changes to the proposal. For example, if during 
136  FDAs evaluation the applicant is notified that the applications specifications must be modified 
137  before it can be approved (and therefore the applications final specifications will differ from  
138  what was proposed in the USP-PMP proposal), the applicant (or the referenced MF holder, as 
139  applicable) should contact USP to update the proposal. This ensures that the compendial 
140  standards in the proposal reflect the standards in the application at the time of approval. Per the 
141  USP-PMP guideline, pending monographs will not advance to an official status until after an 
142  application has been approved by FDA and FDA has confirmed the compendial specifications in 
143  the USP-PMP proposal. As such, applicants should inform USP of final FDA approval. Once 
144  notified, USP will begin the confirmation process with FDA.  
145   
146  Participation in the USP-PMP does not confer FDA acceptability of the compendial standards 
147  proposed for the product, nor preclude full application evaluation by FDA; all applications will 
148  be subject to complete evaluation using current established practices.  
149   
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150  APPENDIX 
151  QUESTIONS AND ANSWERS  
152   
153  1.  My product is not expected to meet the USP-NF monograph, but I will not use the USP 
154  designation in the established name. Does this exempt my product from complying with the USP-
155  NF monograph (and thus negate the need for a USP-PMP proposal)?  
156   
157  No. As described in current regulations referenced in the guidance, a drug with a name  
158  recognized in an official compendium is subject to the monograph standards found within. The 
159  applicable standards apply to such drugs whether or not the added designation USP is used. If 
160  your product cannot meet the official monograph, you should initiate the USP-PMP regardless of 
161  whether you intend to use USP with the established name. (Note: Use of the USP 
162  designation with the established name is optional for any drug with a name recognized in the 
163  USP.) 
164   
165   
166  2.  My application has been accepted for filing (for an NDA) or received (for an ANDA), but 
167  theres no USP monograph for this drug substance/product. Should I initiate the USP-PMP?  
168   
169  The USP-PMP was developed as a practical way to expedite the monograph revision and 
170  development process based on the new applicants specifications provided in applications 
171  submitted to FDA. Although creation of a public standard can be beneficial to all stakeholders, 
172  FDA typically does not require monograph development when no monograph exists. 
173    
174   
175  3.  Im an MF holder. Theres no monograph for my drug substance, but my client has 
176  submitted an application to FDA. Can I use the USP-PMP to develop a monograph for my drug 
177  substance? 
178   
179  Yes. MF holders cross-referenced by an application currently under evaluation by FDA can 
180  contact USP to initiate a USP-PMP. We recommend that USP-PMP proposals be initiated as 
181  early as possible. However, you should coordinate with the applicant to ensure that the USP-
182  PMP proposal is consistent with the drug substance information in the application submitted to 
183  FDA. It is the applicants responsibility to update the application with specifications consistent 
184  with the USP-PMP. Only the specifications found in the approved application can be confirmed 
185  to USP. 
186   
187   
188  4.  My applications referenced MF has initiated a USP-PMP. What should I do? 
189   
190  In this situation, applicants should work with the MF holder to ensure that the USP-PMP 
191  proposal is consistent with the drug substance information in the application submitted to FDA. 
192  Only the specifications found in the approved drug product application can be confirmed by 
193  FDA to USP.  
194   
195   
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196  5.  Ive initiated a USP-PMP proposal. What happens when FDA recommends that I revise 
197  my specifications (e.g., test, test method, acceptance criteria) during the assessment cycle?  
198   
199  Applicants should contact USP and update their proposals to ensure that the applications final 
200  approved specifications are consistent with their USP-PMP proposal. FDA can only confirm  
201  whether the specifications presented in the proposal match the specifications in the application at 
202  the time of approval; FDA cannot divulge specific inconsistencies. If the USP-PMP proposal is 
203  not consistent with the applications final approved specifications, the draft monograph will not 
204  move forward and the applicant will be required to revise the product labeling to plainly state all 
205  differences from the official USP-NF monograph. 
206   
207   
208  6.  FDA recommended that I initiate the USP-PMP. Is this required for approval?  
209   
210  Initiation of the USP-PMP is not required for approval; however, applicants who do not initiate 
211  the USP-PMP when recommended may risk delay in the approval of any application that is not 
212  in alignment with the relevant official USP-NF monograph(s). Alternatively, applicants of drug 
213  products that do not meet (or differ from) the official compendial standards may elect to have all 
214  differences and the extent of each such difference plainly stated on its label, in accordance with 
215  current regulations. 
216   
217   
218  7.  My application has been tentatively approved. Will my USP-PMP proposal advance to 
219  official status? 
220   
221  Final approval (and FDA confirmation of the approved specifications) is required by USP before 
222  a USP-PMP proposal can be incorporated into the official USP-NF. FDA will not confirm  
223  tentatively approved specifications. 
224   
225   
226  8.  If I choose to label my product with all respects it differs from the official USP-NF 
227  monograph, what sort of statement is necessary?   
228   
229  Industry cooperation is essential to ensure that modern compendial standards are available to the 
230  public. However, for applicants who instead choose to label their products in accordance with 
231  current regulations, we recommend that they work with the applicable division to develop 
232  appropriate labeling statements for their products.  
233   
234   
235  9.  I initiated a USP-PMP proposal. In my ANDA, the proposed labeling included statements 
236  to show all respects in which the drug differs from the current USP-NF monograph. When 
237  should I update my labeling with the USP-NF test number?   
238   
239  We recommend that you update your labeling and document this in the next annual report. An 
240  applicant may also submit an amendment containing revised labeling during review of the 
241  ANDA or in response to a request by FDA (e.g., in response to deficiencies identified in an 
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242  Information Request, a Discipline Review letter, or Complete Response letter). Please note that 
243  as outlined in the guidance for industry ANDA Submissions  Amendments to Abbreviated New 
244  Drug Applications Under GDUFA (July 2018), amendments to ANDAs may impact GDUFA 
245  goal dates.14   
246   
247   
248  10.  A product that does not meet the current USP-NF monograph may risk approval delays if 
249  a USP-PMP is not initiated. My product is not expected to meet the USP-NF monograph. When 
250  should I prepare my USP-PMP proposal? When should I contact USP? 
251   
252  We recommend that you initiate USP-PMP proposals as early as allowed by the USP Pending 
253  Monograph guidelines. It may be beneficial to prepare the proposal and initiate contact with USP 
254  concurrent with the submission to FDA. The USP-PMP proposal is between the applicant/holder 
255  and USP; therefore, it may be helpful to either review the most current version of USPs Pending 
256  Monograph Guideline for any changes to the initiation criteria or contact USP directly to 
257  determine the best approach.  
258   
259   
260  11.  We have submitted our MF to FDA with analytical methods for the drug substance that 
261  are not compliant with the official USP-NF monograph. We have demonstrated, through method 
262  equivalency studies, that our in-house methods are either equivalent or superior to the USP 
263  methods. Do we need to initiate the USP-PMP process to have our methods added to the drug 
264  substance USP-NF monograph? 
265   
266  No. It is not necessary to initiate the USP-PMP for analytical method equivalency. Though a 
267  compendial article must conform to the official monograph specifications/acceptance criteria, the 
268  analytical procedures used to show conformance may differ from official USP methods if the 
269  alternative methods are fully validated, suitable for use, and provide comparable results to the 
270  official USP method, as determined by FDA. In the event of a dispute, the compendial method is 
271  considered legally conclusive. As such, the drug must be able to meet the compendial standards 
272  if tested as described in the applicable official monograph(s). 
273   
                                                 
14 The Generic Drug User Fee Amendments Reauthorization  of 2017 (GDUFA II, FDA Reauthorization  Act of  2017  
(Public Law 115-52 Title III)) was signed into law on August 18, 2017, to facilitate timely access to quality, 
affordable generic medicines. Under the GDUFA Reauthorization Performance Goals and Program Enhancements 
Fiscal Years 2018-2022 (GDUFA II Commitment Letter) that accompanied the legislation, FDA agreed to certain 
review  goals and procedures  for amendments under assessment as of or received on or after the GDUFA II effective  
date (i.e., October 1,  2017).   See the referenced guidance for further information. 
8