Controlled 
Correspondence 
Related to Generic 
Drug Development 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Lisa Bercu 240-402-6902. 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
December 2022 
Generic Drugs 
 
Revision 1 
   
Controlled 
Correspondence 
Related to Generic 
Drug Development 
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) 
           
December 2022 
Generic Drugs 
 
Revision 1   
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  CONTROLLED CORRESPONDENCE ........................................................................ 4 
A.  Guidance on Inquiries Within the Scope of Controlled Correspondence That Cannot Be 
Answered by FDA ................................................................................................................................... 5 
1. Controlled Correspondence Related to a Pending Citizen Petition, Petition for Stay of Action, or 
Petition for Administrative Reconsideration of Action ........................................................................ 5 
2. Requests Related to Matters Still Under Consideration by the Agency ........................................... 5 
B.  Guidance on Inquiries Outside the Scope of Controlled Correspondence ............................... 6 
1. Requests More Appropriately Addressed Through Other Mechanisms ........................................... 6 
2. Exceptions to the Definition of Controlled Correspondence ........................................................... 6 
3. Topics Outside the Scope of Controlled Correspondence ............................................................... 8 
4. Entities Outside the Scope of Controlled Correspondence .............................................................. 9 
IV.  SUBMITTING A CONTROLLED CORRESPONDENCE ....................................... 10 
A.  How To Submit a Controlled Correspondence ......................................................................... 10 
B.  Content of a Controlled Correspondence .................................................................................. 10 
C.  Additional Recommendations on the Content of Specific Types of Controlled 
Correspondence Inquiries .................................................................................................................... 12 
1. Requests Related to Inactive Ingredients ....................................................................................... 12 
2. Requests for Formulation Assessment (e.g., Q1/Q2 Sameness) ..................................................... 14 
3. Requests Related to Product Quality ............................................................................................. 16 
4. Requests Related to the Evaluation of the User Interface of a Drug-Device Combination Product
  17 
5. Requests Requiring Review by More Than One Discipline ........................................................... 17 
6. Considerations for Specific Types of Level 1 Controlled Correspondence ................................... 18 
7. Considerations for Level 2 Controlled Correspondence ............................................................... 19 
D.  Controlled Correspondence Review Disciplines ....................................................................... 21 
1. OGDs Office of Bioequivalence ................................................................................................... 21 
2. OGDs Office of Research and Standards ..................................................................................... 21 
3. OGDs Office of Safety and Clinical Evaluation ........................................................................... 21 
4. OGDs Office of Regulatory Operations, Division of Filing Review............................................. 22 
5. OGDs Office of Regulatory Operations, Division of Labeling Review ........................................ 22 
6. OGDs Office of Generic Drug Policy ........................................................................................... 22 
7. Office of Pharmaceutical Quality .................................................................................................. 22 
V.   FDAS COMMUNICATIONS TO REQUESTORS AND REQUESTS TO 
CLARIFY AMBIGUITIES IN FDAS CONTROLLED CORRESPONDENCE 
RESPONSE ................................................................................................................................. 23 
A.  Communications Related to Initial Submissions ....................................................................... 23 
B.  Clarification of the Controlled Correspondence Response ...................................................... 24 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
 
1  Controlled Correspondence Related to  
2  Generic Drug Development 
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  I.  INTRODUCTION  
15   
16  This guidance provides information regarding the process by which generic drug manufacturers 
17  and related industry or their representatives can submit to FDA controlled correspondence 
18  requesting information related to generic drug development.  This guidance also describes the 
19  Agencys process for providing communications related to such correspondence.   
20   
21  This guidance revises the guidance for industry Controlled Correspondence Related to Generic 
22  Drug Development issued in December 2020.  When final, this guidance will replace the 
23  December 2020 guidance.  The December 2020 guidance was issued as part of FDAs 
24  implementation of the Generic Drug User Fee Amendments of 2017 (GDUFA II).2  This 
25  guidance is being issued to incorporate program enhancements related to the review of controlled 
26  correspondence to which FDA committed, and industry agreed, as part of their negotiations 
27  relating to the reauthorization of the Generic Drug User Fee Amendments (GDUFA) (GDUFA 
28  III),3 as described in GDUFA Reauthorization Performance Goals and Program Enhancements 
29  Fiscal Years 2023-2027 (GDUFA III commitment letter).4  Other significant changes from the 
30  December 2020 version include providing additional recommendations for specific types of 
31  inquiries in controlled correspondence.   
32   
33  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
34  Instead, guidances describe the agencys current thinking on a topic and should be viewed only 
 
 
1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research at 
the Food and Drug Administration.  
2 FDA Reauthorization Act of 2017 (Public Law 115-52). 
3 See Division F, Title III, of the Continuing Appropriations and Ukraine Supplemental Appropriations Act, 2023 
(Public Law 117-180). 
4 The GDUFA III commitment letter is available at https://www.fda.gov/media/153631/download. 
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Draft  Not for Implementation 
 
 
35  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
36  the word should in Agency guidance means that something is suggested or recommended, but 
37  not required.  
38   
39   
40  II.  BACKGROUND 
41   
42  The Generic Drug User Fee Amendments of 2012 (GDUFA I)5 amended the Federal Food, 
43  Drug, and Cosmetic (FD&C) Act to authorize FDA to assess and collect user fees to provide the 
44  Agency with resources6 to help ensure patients have access to quality, affordable, safe, and 
45  effective generic drugs.  GDUFA fee resources bring greater predictability and timeliness to the 
46  review of generic drug applications.  GDUFA has been reauthorized every 5 years to continue 
47  FDA's ability to assess and collect GDUFA fees, and this user fee program has been reauthorized 
48  two times since GDUFA I, most recently in the Continuing Appropriations and Ukraine 
49  Supplemental Appropriations Act, 2023.7  As described in the GDUFA III commitment letter 
50  applicable to this latest reauthorization, FDA has agreed to performance goals and program 
51  enhancements regarding aspects of the generic drug assessment program that build on previous 
52  authorizations of GDUFA.  New enhancements to the program are designed to maximize the 
53  efficiency and utility of each assessment cycle, with the intent of reducing the number of 
54  assessment cycles for abbreviated new drug applications (ANDAs) and facilitating timely access 
55  to generic medicines for American patients.  
56   
57  As further discussed in this guidance, FDA agreed to certain goals and procedures for the review 
58  of controlled correspondence received on or after October 1, 2022.8  Specifically, the Agency 
59  agreed that: 
60   
61    FDA will review and respond to 90 percent of level 1 controlled correspondence9 
62  within 60 calendar days of the date of submission. 
63    
 
 
5 Title III of the Food and Drug Administration Safety and Innovation Act, Public Law 112-144. 
6 User fees are available for obligation in accordance with appropriations acts. 
7 See Division F, Title III, of the Continuing Appropriations and Ukraine Supplemental Appropriations Act, 2023 
(Public Law 117-180). 
8 Starting October 1, 2022, FDA will respond to all controlled correspondence submitted before ANDA submission, 
during an ANDA assessment cycle to seek further feedback from FDA after a product-specific guidance 
teleconference or to seek a Covered Product Authorization, after tentative approval, and after ANDA approval.  
FDA also intends to respond to controlled correspondence submitted after issuance of a complete response letter as 
long as the complete response letter was issued on or after October 1, 2022.   
9 Level 1 controlled correspondence was called standard controlled correspondence in the GDUFA II commitment 
letter.   
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64    FDA will review and respond to 90 percent of level 2 controlled correspondence10 
65  within 120 calendar days of the date of submission.  
66    
67    FDA will review and respond to 90 percent of submitter requests to clarify 
68  ambiguities in the controlled correspondence response within 21 calendar days of 
69  FDAs receipt of the request.11    
70   
71  Consistent with FDAs other user fee programs, FDA will calculate the goal date from the day 
72  after a submission.12 
73   
74  The GDUFA III commitment letter defines level 1 controlled correspondence as correspondence 
75  submitted to the Agency, by or on behalf of a generic drug manufacturer or related industry: 
76   
77  1.  Requesting information on a specific element of generic drug product development: 
78   
79  a.  Before ANDA submission; 
80   
81  b.  After a Product-Specific Guidance (PSG) Teleconference if a prospective 
82  applicant or applicant seeks further feedback from FDA; 
83   
84  c.  After issuance of a complete response letter (CRL) or tentative approval; 
85   
86  d.  After ANDA approval; or 
87   
88  2.  Concerning postapproval submission requirements that are not covered by Center for 
89  Drug Evaluation and Research (CDER) postapproval changes guidance and are not 
90  specific to an ANDA.13  
91   
92  The GDUFA III commitment letter defines level 2 controlled correspondence as correspondence 
93  that meets the definition of level 1 controlled correspondence and: 
 
 
10 Level 2 controlled correspondence was called complex controlled correspondence in the GDUFA II 
commitment letter. 
11 GDUFA III commitment letter at 11.  See also the definition of days, which unless otherwise specified, means 
calendar days (id. at 47). 
12 GDUFA III commitment letter at 4.  Also, refer to FDAs guidance for industry Providing Regulatory 
Submissions in Electronic Format  Receipt Dates (Feb. 2014) for information on how FDA calculates receipt 
dates for regulatory submissions in electronic format, including controlled correspondence.  As described in that 
guidance, controlled correspondence will be received by the Agency Monday through Friday from 12:00 a.m. to 
11:59 p.m. Eastern Standard Time/Eastern Daylight Time, excluding Federal holidays and days when the FDA 
office that will review the correspondence is closed.  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 GDUFA III commitment letter at 46.  
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94   
95  1.  Involves evaluation of clinical content; 
96   
97  2.  Requests a Covered Product Authorization14 and review of bioequivalence (BE) 
98  protocols for development and testing that involves human clinical trials for an 
99  ANDA where the reference listed drug (RLD) is subject to a Risk Evaluation and 
100  Mitigation Strategy (REMS) with Elements to Assure Safe Use (ETASU);  
101  3.  Requests a Covered Product Authorization to obtain sufficient quantities of an 
102  individual covered product subject to a REMS with ETASU when development and 
103  testing does not involve clinical trials;  
104  4.  Requests evaluations of alternative BE approaches (e.g., pharmacokinetic, in vitro, 
105  clinical); or 
106  5.  Requires input from another office or center.15 
107   
108  This guidance provides additional detail and recommendations concerning:  
109   
110    What inquiries FDA considers to be controlled correspondence for the purposes of 
111  meeting the Agencys agreements under the GDUFA III commitment letter 
112   
113    What information requestors should include in a controlled correspondence to 
114  facilitate FDAs consideration of and response to a controlled correspondence 
115   
116    What information FDA will provide in its communications to requestors that have 
117  submitted controlled correspondence 
118   
119    How requestors can submit requests to clarify ambiguities in FDAs controlled 
120  correspondence responses and the Agencys process for responding to those requests 
121   
122   
123  III.  CONTROLLED CORRESPONDENCE 
124   
 
 
14 A Covered Product Authorization is a letter from FDA authorizing an eligible product developer to obtain 
sufficient quantities of an individual covered product subject to a Risk Evaluation and Mitigation Strategy with 
Elements to Assure Safe Use for product development and testing purposes, as described in section 610 of Division 
N of the Further Consolidated Appropriations Act, 2020 (21 U.S.C. 355-2), commonly referred to as the 
CREATES Act (GDUFA III commitment letter at 47).  For further information on how to obtain a Covered 
Product Authorization, see FDAs draft guidance for industry, How To Obtain a Covered Product Authorization 
(Sep. 2022).  When final, this guidance will represent FDAs current thinking on this topic. 
15 GDUFA III commitment letter at 46. 
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  Contains Nonbinding Recommendations 
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125  A controlled correspondence can be submitted by or on behalf of a generic drug manufacturer or 
126  related industry before ANDA submission.  Under the GDUFA II commitment letter framework, 
127  correspondence seeking regulatory and/or scientific advice after issuance of a CRL or tentative 
128  approval, or after ANDA approval, was considered general correspondence.  Under the GDUFA 
129  III commitment letter, these types of correspondence can be submitted as controlled 
130  correspondence.  Also, under the GDUFA III commitment letter, a controlled correspondence 
131  can be submitted during an ANDA assessment cycle if an applicant seeks further feedback from 
132  FDA after a PSG Teleconference or seeks a Covered Product Authorization.  During an ANDA 
133  assessment cycle, all other correspondence will be considered general correspondence and 
134  should be submitted to the ANDA so that it becomes part of the full administrative record for 
135  that application.  
136   
137  A.  Guidance on Inquiries Within the Scope of Controlled Correspondence That 
138  Cannot Be Answered by FDA 
139   
140  1.  Controlled Correspondence Related to a Pending Citizen Petition, Petition for Stay of 
141  Action, or Petition for Administrative Reconsideration of Action 
142   
143  If a controlled correspondence is submitted about an issue that relates to one or more pending 
144  citizen petitions, petitions for stay of action, or petitions for administrative reconsideration of 
145  action, FDA intends that the response to the controlled correspondence will explain that we 
146  cannot answer the question posed because the request is about an issue related to a petition and 
147  we will close the controlled correspondence.16  Once FDA responds to the pending citizen 
148  petition, petition for stay of action, or petition for administrative reconsideration of action, the 
149  requestor can resubmit the controlled correspondence.  Requestors can monitor the current status 
150  of the petition at https://www.regulations.gov. 
151   
152  2.  Requests Related to Matters Still Under Consideration by the Agency 
153   
154  FDA occasionally receives requests for information about issues that the Agency is considering, 
155  but for which no scientific or regulatory decision has been made or for which there is no clear 
156  scientific consensus.  For a request for which controlled correspondence is the appropriate 
157  pathway but the subject is still under consideration at the time of the goal date, FDA will notify 
158  the requestor that the goal date has been missed because the request raises issues about which 
159  FDA has not made a decision.  In such instances, the request will remain open until FDA issues a 
160  response.  
161   
 
 
16 Under the GDUFA I and GDUFA II commitment letters, if a controlled correspondence was submitted about an 
issue that related to one or more pending citizen petitions, petitions for stay of action, or petitions for administrative 
reconsideration of action, the time period for responding started on the date FDA responded to the petition (if there 
was only one petition) or the last pending petition. 
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162  B.  Guidance on Inquiries Outside the Scope of Controlled Correspondence 
163   
164  1.  Requests More Appropriately Addressed Through Other Mechanisms 
165   
166  In certain circumstances, controlled correspondence may not be the optimal mechanism to gain 
167  FDAs feedback on a topic.  For example, topics that are general in nature would be more 
168  appropriately considered as part of the Regulatory Science Initiative, such as the proposed use of 
169  in vitro data to support demonstration of bioequivalence for a class of RLDs for which no 
170  ANDAs have been submitted.   
171   
172  As another example, for certain questions, it may be more appropriate to submit a meeting 
173  request in lieu of submitting a controlled correspondence.  The purpose of the controlled 
174  correspondence process is to provide a mechanism for a direct inquiry about FDAs position with 
175  respect to a particular element of generic drug development and for the Agencys direct, brief, 
176  and timely response. A controlled correspondence may also be appropriate if the requestor has 
177  clarifying questions or questions that are outside of the scope of a meeting request.  In contrast, 
178  one of the meetings described in the GDUFA III commitment letter may be a better forum in 
179  which to seek a dialogue with the Agency about a particular matter for which the controlled 
180  correspondence process is not suitable (e.g., methods of characterization for complex products or 
181  clinically critical BE considerations).  FDA recommends that prospective applicants and 
182  applicants refer to the GDUFA III commitment letter and FDAs guidances for industry for 
183  additional information on GDUFA III meetings.17  For such questions that are more 
184  appropriately addressed in a meeting, the Agency will notify the requestor of the recommended 
185  alternative pathway and close the controlled correspondence.   
186   
187  2.  Exceptions to the Definition of Controlled Correspondence 
188   
189  Historically, FDA has excluded three types of inquiries about generic drug development from 
190  controlled correspondence: (1) requests for recommendations on the appropriate design of BE 
191  studies for a specific drug product; (2) requests for review of BE study protocols; and (3) 
192  requests for meetings to discuss generic drug development.  Additional information on these 
193  types of inquiries is provided below. 
194   
195  First, FDA will continue to address PSG requests consistent with the public process described in 
196  the Agencys guidance for industry Bioequivalence Recommendations for Specific Products 
197  (June 2010) and FDAs good guidance practices regulation.18  Under this approach, FDA 
198  publishes BE recommendations in PSGs. The availability of a PSG is announced in the Federal 
199  Register, and public comments are requested for a designated period to ensure they are received 
 
 
17 See footnote 4.  See, e.g., FDAs guidances for industry Formal Meetings Between FDA and ANDA Applicants of 
Complex Products Under GDUFA (Oct. 2022) and Post Complete Response Letter Clarification Teleconferences 
Between FDA and ANDA Applicants Under GDUFA (Oct. 2022).  
18 21 CFR 10.115.      
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200  before the Agency begins work on the final version of the guidance.  However, comments can be 
201  submitted on draft or final guidance documents at any time under our good guidance practices.  
202  The PSG process enhances transparency, provides a mechanism for public comment about 
203  recommended BE studies, provides for more efficient use of Agency resources, and follows 
204  FDAs good guidance practices regulation.   
205   
206  With this public process, FDA can be proactive in developing and publishing guidance for new 
207  drug products without waiting for inquiries about BE methodologies from individual 
208  requestors.19  FDA anticipates that this process will continue to expedite the availability of BE 
209  methodologies to generic drug manufacturers.  However, this process involves time frames that 
210  differ from the goal dates for controlled correspondence, and the Agency has determined that it 
211  would not be appropriate to circumvent this public process by responding to individual 
212  requestors to meet the GDUFA III commitment letter goal dates for controlled correspondence 
213  because we believe public input is important to the development of BE methodologies.  The 
214  Agency will continue to consider BE guidance requests in prioritizing PSG development.20   
215   
216  Second, FDA will continue to generally exclude requests for BE study protocol review from 
217  controlled correspondence and the related goal dates.21  These include requests for review of 
218  protocols for in vivo BE studies with pharmacokinetic, pharmacodynamic, or comparative 
219  clinical endpoints conducted to support demonstration of bioequivalence for a proposed generic 
220  drug.  Historically, FDA has not considered such requests as controlled correspondence because 
 
 
19 FDA has committed to continuing to issue PSGs identifying the methodology for generating evidence to support 
ANDA approval.  For complex products approved in new drug applications (NDAs) on or after October 1, 2022, a 
PSG will be issued for 50 percent of such NDA products within 2 years after the date of approval, and for 75 percent 
of such NDA products, within 3 years after the date of approval.  FDA will continue to develop PSGs for complex 
products approved before October 1, 2022, for which no PSG has been published.  For non-complex drug products 
approved in NDAs on or after October 1, 2022, that contain a new chemical entity (as described in section 
505(j)(5)(F)(ii) of the FD&C Act (21 U.S.C. 355(j)(5)(F)(ii))), a PSG will be issued within 2 years after the date of 
approval for 90 percent of such products.  GDUFA III commitment letter at 23. 
A complex product generally includes: (1) products with complex active ingredients (e.g., peptides, polymeric 
compounds, complex mixtures of active pharmaceutical ingredients, naturally sourced ingredients); complex 
formulations (e.g., liposomes, colloids); complex routes of delivery (e.g., locally acting drugs such as dermatological 
products, complex ophthalmological products, and otic dosage forms that are formulated as suspensions, emulsions, 
or gels); or complex dosage forms (e.g., transdermal systems, metered dose inhalers, extended release injectables); 
(2) complex drug-device combination products (e.g., prefilled auto-injector products, metered dose inhalers); and (3) 
other products where complexity or uncertainty concerning the approval pathway or possible alternative approach 
would benefit from early scientific engagement (GDUFA III commitment letter at 45-46). 
20 Interested parties can submit requests for a PSG to be developed through the CDER Direct NextGen Collaboration 
Portal, which can be accessed at https://edm.fda.gov/.  In addition, interested parties, including those that fall outside 
the scope of entities that can submit controlled correspondence, can submit requests for consideration of alternative 
BE approaches to the public docket for PSGs (FDA-2007-D-0369).   
21 FDA intends to accept requests for BE study protocol review as controlled correspondence in two circumstances: 
(1) as part of a request for a Covered Product Authorization and (2) after issuance of a CRL that identified 
deficiencies related to establishing equivalence. 
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221  these requests are more time- and resource-intensive than other requests and often call for 
222  consultation with multiple disciplines within the Office of Generic Drugs (OGD), as well as with 
223  other offices or centers (e.g., the Center for Devices and Radiological Health).  Below are 
224  recommended alternatives to submitting a request for BE study protocol review:22 
225   
226    If the request is intended to address a specific question not covered by a PSG, FDA 
227  recommends submitting a controlled correspondence requesting FDA to comment on 
228  the specific question in lieu of submitting a request for BE study protocol review.  
229    
230    If the request involves the evaluation of a BE study design that deviates from the BE 
231  study recommended in the PSG, FDA recommends submitting a controlled 
232  correspondence requesting that FDA evaluate the alternative approach in lieu of 
233  submitting a request for BE study protocol review.   
234   
235    If the request involves multiple questions or complex issues, FDA recommends 
236  submitting a pre-ANDA meeting23 request or a controlled correspondence in lieu of 
237  submitting a request for BE study protocol review. 
238   
239  Third, FDA will not treat requests for meetings as controlled correspondence, because, as 
240  described in section III.B.1 of this guidance, such requests serve a different purpose than 
241  controlled correspondence.  In addition, meeting requests include different information from the 
242  requestor; materials and information submitted with a controlled correspondence should provide 
243  the Agency with the relevant information on which to base its considerations, while the materials 
244  submitted in support of a meeting request should help the Agency determine whether a meeting 
245  is appropriate.  Accordingly, we will treat meeting requests separately.   
246    
247  3.  Topics Outside the Scope of Controlled Correspondence 
248   
249  This section provides additional guidance on the types of inquiries that do not fall within the 
250  definition of controlled correspondence.  First, during an ANDA assessment cycle, a controlled 
251  correspondence can only be submitted if an applicant seeks further feedback from FDA after a 
252  PSG Teleconference or to seek a Covered Product Authorization.24  All other correspondence 
 
 
22 Requestors that would like to submit a BE study protocol to FDA for review outside the controlled 
correspondence process should submit the protocol through the CDER Direct NextGen Collaboration Portal, which 
can be accessed at https://edm.fda.gov/.  
23 See FDAs guidance for industry Formal Meetings Between FDA and ANDA Applicants of Complex Products 
Under GDUFA (Oct. 2022).  We recommend applicants review the guidance and the GDUFA III commitment letter 
when evaluating whether the product under development could qualify for a pre-ANDA meeting.   
24 Consistent with FDAs historic practices, the Agency has identified limited situations, beyond those described in 
the GDUFA III commitment letter, in which we will consider a request for information in a controlled 
correspondence related to a specific pending ANDA.  For example, the Agency will consider a request for 
 
 
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253  submitted during an ANDA assessment cycle will be considered general correspondence and 
254  should be submitted to the ANDA. 
255   
256  Second, inquiries submitted to FDA that are not directly related to generic drug development will 
257  not be considered controlled correspondence for the purposes of GDUFA III.  For example, 
258  inquiries requesting information about the administrative practices of OGD, or about 
259  development of a generic drug for which there has never been a U.S.-approved RLD identified in 
260  FDAs Approved Drug Products with Therapeutic Evaluations (the Orange Book), will not be 
261  considered controlled correspondence.25   
262   
263  Third, as reflected in the definition of controlled correspondence, a controlled correspondence 
264  should not contain general questions related to product development.  Consistent with FDAs 
265  past and current practices, general or insufficiently detailed questions related to product 
266  development are not appropriate subjects of controlled correspondence.26  For example, an 
267  inquiry seeking information about general approval standards for a particular product is not an 
268  appropriate subject of a controlled correspondence.  Likewise, an inquiry about the acceptability 
269  of an inactive ingredient without providing the proposed level of the inactive ingredient and 
270  information about the RLD, including a specific product strength for the RLD, provides 
271  insufficient detail for the Agency to respond.  FDA provides information to stakeholders about 
272  its approval standards and general submission recommendations through FDA regulations and 
273  guidances, and the Agency encourages generic drug manufacturers and related industry to review 
274  this information before submitting controlled correspondence to OGD.  The controlled 
275  correspondence process is intended to facilitate, not supplant, the generic drug development 
276  endeavor and the full scientific assessment of an ANDA. 
277   
278  4.  Entities Outside the Scope of Controlled Correspondence 
279   
280  The controlled correspondence process is available to generic drug manufacturers and related 
281  industry, or their authorized representatives, that have a question related to a potential or actual 
282  ANDA submission to OGD, because this mechanism exists to facilitate generic drug 
283  development.  Other parties (e.g., private citizens, financial firms, or public advocacy groups that 
 
 
information in a controlled correspondence regarding development of a new strength for a product for which the 
submitter is an applicant of a pending ANDA for other strengths.  In addition, the Agency will consider a request for 
information in a controlled correspondence regarding development of a different package configuration for a 
product for which the submitter is an applicant of a pending ANDA for other package configurations.  For example, 
if an inquiry pertaining to a gel in a metered-dose pump is submitted and there is a pending ANDA for gel in a unit-
dose package, the controlled correspondence could still be accepted for review.   
25 Requestors can submit a controlled correspondence asking a question about an approved suitability petition and 
should provide the docket number for the approved suitability petition because that information is used to confirm 
that FDA can accept the controlled correspondence for review.   
26 Controlled correspondence should not be used to ask FDA to develop a new regulatory policy or to change an 
existing policy.  However, FDA intends to monitor subjects of controlled correspondence to consider future topics 
for developing guidance documents.   
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284  are not directly involved in developing generic drugs) should submit their inquiries related to 
285  generic drugs to the Division of Drug Information.27   
286   
287   
288  IV.  SUBMITTING A CONTROLLED CORRESPONDENCE 
289   
290  A.  How To Submit a Controlled Correspondence 
291   
292  Requestors seeking FDAs response to a controlled correspondence should submit the 
293  correspondence electronically through the CDER Direct NextGen Collaboration Portal (the 
294  portal), which can be accessed at https://edm.fda.gov.28   This process will facilitate prompt 
295  consideration of and response to the controlled correspondence by the appropriate discipline 
296  based on assessment timelines identified in the GDUFA III commitment letter.  Requestors 
297  should register a corporate email address with the portal.29  We do not intend to consider portal 
298  submissions that are generated from general, personal accounts as controlled correspondence.  If 
299  a requestor would like to obtain a secure email account, the requestor (or its U.S. agent) can 
300  apply for a secure email pathway by contacting secureemail@fda.hhs.gov.     
301   
302  FDA strongly discourages submitting controlled correspondence to individual FDA 
303  employees and submitting additional copies of a controlled correspondence in paper form, 
304  by courier, or by facsimile.  As described in section V.A of this guidance, FDA intends to 
305  provide requestors notification via the portal on the status of a request soon after it is submitted, 
306  which should provide a requestor adequate assurance that the Agency has received the 
307  communication.  The Agencys response will either state that FDA is considering the request as a 
308  controlled correspondence or provide the basis for not responding to it as a controlled 
309  correspondence, as described in this guidance.   
310   
311  B.  Content of a Controlled Correspondence  
312   
 
 
27 See contact information for the Division of Drug Information on the second title page of this guidance. 
28 Requestors that are unable to submit a controlled correspondence through the portal can send their controlled 
correspondence, as an attachment to an email, to GenericDrugs@fda.hhs.gov.  In this situation, requestors should 
include the information specified in section IV.B of this guidance.  GenericDrugs@fda.hhs.gov is a general OGD 
address to which certain submissions related to generic drugs can be submitted.  If requestors submit their controlled 
correspondence to GenericDrugs@fda.hhs.gov instead of the portal, all communications regarding that controlled 
correspondence will be through email and will not be captured in the portal. 
29 Requestors can register with the portal at https://edm.fda.gov.  
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313  FDA recommends the cover letter30 to a controlled correspondence be submitted on corporate 
314  letterhead, be dated within 7 calendar days of submission of the controlled correspondence, and 
315  include the following information: 
316   
317    Name, title, address, email, phone number, and entity (e.g., corporate affiliation) of the 
318  person submitting the controlled correspondence.  If the controlled correspondence is not 
319  submitted by the generic drug manufacturer or related industrys authorized 
320  representative, the generic drug manufacturer or related industrys authorized agent, or 
321  the agents authorized representative, located in the United States, then FDA will not 
322  treat the submission as controlled correspondence under the GDUFA III commitment 
323  letter.31   
324   
325    If an authorized agent is submitting the controlled correspondence, identify the 
326  company for which you are the authorized agent and include a copy of a letter of 
327  authorization with each controlled correspondence.32  The letter of authorization 
328  should be on corporate letterhead and dated within 1 year of the date the 
329  controlled correspondence is submitted.  FDA intends to provide a response to the 
330  companys U.S. authorized agent or the agents authorized representative, similar 
331  to FDAs practice when an ANDA is submitted.  
332   
333    FDA-assigned controlled correspondence number and submission date of any previous, 
334  related controlled correspondence that was accepted for substantive review and response, 
335  if any, as well as a single copy of that previous controlled correspondence and FDAs 
336  response, if any.  
337   
338    For controlled correspondence regarding a CRL, FDA recommends submitting a 
339  copy of the CRL and identifying any other controlled correspondence or meeting 
340  requests related to that CRL. 
341   
342    Relevant RLD(s) and/or reference standard(s),33 as applicable, including application 
343  number, proprietary (brand) name, manufacturer, active ingredient, dosage form, route of 
344  administration, and strength(s).  
345   
 
 
30 For more information on preparing cover letters to controlled correspondence, see FDAs draft guidance for 
industry Cover Letter Attachments for Controlled Correspondences and ANDA Submissions (Dec. 2021).  When 
final, this guidance will represent FDAs current thinking on this topic. 
31 See the definition of controlled correspondence (correspondence submitted to the Agency, by or on behalf of a 
generic drug manufacturer or related industry) (GDUFA III commitment letter at 46). 
32 A letter of authorization should be provided by all authorized agents, regardless of whether the prospective 
applicant or applicant is located in the United States.   
33 21 CFR 314.3(b) (Reference standard is the drug product selected by FDA that an applicant seeking approval of 
an ANDA must use in conducting an in vivo bioequivalence study required for approval). 
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346    Statement that the controlled correspondence is related to either a potential ANDA 
347  submission to OGD, an ANDA that is pending with FDA, an ANDA that received a CRL 
348  and is pending with the applicant, an ANDA that received a tentative approval letter, or 
349  an approved ANDA.  
350   
351    Provide the ANDA number, including whether the controlled correspondence is 
352  related to a potential ANDA submission to OGD that has already received a pre-
353  assigned ANDA number. 
354   
355    Concise statement describing the controlled correspondence inquiry, including specific 
356  questions to be answered. 
357   
358    If the controlled correspondence is related to a deficiency identified in a CRL, 
359  include a reference to that specific deficiency. 
360   
361    Recommendation for the appropriate FDA review discipline to assess the controlled 
362  correspondence.  General information regarding review disciplines is provided in section 
363  IV.D of this guidance.   
364   
365  Requestors should also include, either in the cover letter or as an attachment to the cover letter, 
366  relevant prior research and supporting materials on the specific element of generic drug 
367  development about which the requestor seeks information.  In addition, FDA recommends that 
368  all documents be dated. 
369   
370  If FDA determines that the inquiry does not contain the information specified in section IV.B of 
371  this guidance, then FDA will not consider the inquiry to be submitted as controlled 
372  correspondence for purposes of the GDUFA III commitment letter.   
373   
374  C.  Additional Recommendations on the Content of Specific Types of Controlled 
375  Correspondence Inquiries 
376   
377  This section provides additional recommendations for the content of specific types of inquiries 
378  submitted as controlled correspondence. 
379   
380  1.  Requests Related to Inactive Ingredients 
381   
382  The Agency often receives requests for information pertaining to whether particular inactive 
383  ingredients present at higher levels than the maximums listed in the Agencys Inactive Ingredient 
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384  Database (IID) are permissible in a generic drug.34  FDA recommends that a requestor submit for 
385  evaluation no more than three inactive ingredients and no more than three proposed levels for a 
386  drug product in any given controlled correspondence.  For example, in any given controlled 
387  correspondence: 
388   
389    A requestor can submit (1) a request that proposes three inactive ingredients with one 
390  level each, or (2) a request that proposes one inactive ingredient with three levels. 
391     
392    If the drug product is indicated for the adult and pediatric populations, a requestor can 
393  submit (1) a request that proposes one inactive ingredient with one level for three 
394  different dosing ranges (based on body weight or age range specified in the RLD 
395  labeling), or (2) a request that proposes three inactive ingredients with one level for one 
396  dosage range.  
397   
398  If the drug product is indicated for more than one route of administration, requests regarding 
399  inactive ingredients for each route of administration should be submitted in a separate controlled 
400  correspondence.   
401   
402  If a requestor submits a range of levels for an inactive ingredient, the Agency only intends to 
403  review the highest proposed level in that range for that inactive ingredient.  In addition, 
404  requestors should only submit the inactive ingredients they wish to be evaluated and their 
405  proposed levels and not the whole formulation. 
406   
407  FDA notes that certain inactive ingredients are composed of multiple subcomponents (e.g., 
408  flavors).  If levels of individual subcomponents are found within limits by the Agency when 
409  reviewed through a controlled correspondence, applicants should be aware that this does not 
410  necessarily mean the whole inactive ingredient will be found to be within acceptable limits 
411  during ANDA assessment.  This is because the whole inactive ingredients safety profile is 
412  evaluated in the context of the entire drug product formulation during ANDA assessment (and, 
413  as applicable, during assessment of the acceptability of the pertinent drug master file).   
414   
415  Furthermore, when a flavor and/or the subcomponents of a flavor are expressed as  0.1 percent 
416  (weight/weight) of the total weight of the drug product in a controlled correspondence, the 
417  Agency uses this 0.1 percent (weight/weight) limit as a threshold determination that the flavor 
418  and/or the subcomponents of a flavor are acceptable at the filing stage only.  This is because the 
419  amount of a flavor and/or subcomponents of a flavor is reviewed by FDA during ANDA 
 
 
34 The IID Update mailbox (IIDUpdate@fda.hhs.gov) can be used to inform FDA of errors in the IID and to ask 
questions about IID listings. The GSRS mailbox (FDA-GSRS@fda.hhs.gov) can be used for unique ingredient 
identifier requests and for questions about the preferred term for an excipient listed in the IID. These types of 
communications should not be sent to GenericDrugs@fda.hhs.gov.  The IID is available at 
https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.  For more information on the IID, see the draft guidance 
for industry Using the Inactive Ingredient Database (July 2019).  When final, this guidance will represent the 
current thinking of FDA. 
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420  assessment when the complete drug product formulation information is available to assessors.  
421  Thus, the Agencys filing determination does not mean that the proposed amount will ultimately 
422  be found approvable at the ANDA assessment stage.   
423   
424  A requestor should wait for FDAs response to the controlled correspondence before submitting 
425  a different request for consideration.  The Agency believes this is a reasonable limit based on 
426  what can be evaluated for a particular drug product within the GDUFA III commitment letter 
427  goal date time frame.  This process also encourages requestors to provide targeted submissions to 
428  the Agency and allows requestors to refine their subsequent formulation proposals based on 
429  FDAs previous responses.   
430   
431  Such requests should identify the RLD (including the specific drug product strength(s)), the 
432  requestors determination of the maximum daily dose of the drug product, and information 
433  supporting this determination (e.g., information from literature searches, drug information 
434  services, approved labeling, pharmacology review of the Summary Basis of Approval for the 
435  RLD).  Absent that information, there is no means for FDA to evaluate the safe use of that 
436  inactive ingredient, which depends on many factors, including context of use (e.g., dose, route of 
437  administration, duration of use, and patient population) for the RLD.  Although FDA may 
438  provide information regarding an inactive ingredient through a controlled correspondence, FDA 
439  evaluates the ultimate acceptability of an inactive ingredient in the context of a specific proposed 
440  drug products formulation during ANDA assessment, when the Agency has the full complement 
441  of data and information in support of ANDA approval to consider.  
442   
443  2.  Requests for Formulation Assessment (e.g., Q1/Q2 Sameness) 
444   
445  For certain types of products, FDAs regulations generally require that proposed products be 
446  qualitatively (Q1) and quantitatively (Q2) the same as the RLD with respect to certain inactive 
447  ingredients.35  When submitting a controlled correspondence for a Q1/Q2 sameness assessment, 
448  FDA recommends the controlled correspondence include the information about the RLD in the 
449  bulleted list below, which can be found in the Orange Book.  Consistent with the Agencys past 
450  and current practices, FDA does not intend to review proposed formulations for Q1/Q2 sameness 
451  that are not required to be Q1/Q2 the same as the RLD by regulation.  Formulations that are not 
452  Q1/Q2 the same as the RLD are permissible for certain products as long as the differences do not 
453  affect the safety or effectiveness of the product.  The acceptability of such differences would be 
454  considered in the context of ANDA assessment.  It should be noted that Agency policy or 
455  regulation may limit the amount or type of information that FDA can disclose in response to a 
456  request for Q1/Q2 sameness assessment, and that FDA does not intend to provide clarification on 
457  why a formulation is not Q1/Q2 the same as the RLD (see section V.B of this guidance).36   
458   
 
 
35 21 CFR 314.94(a)(9)(iii-iv).   
36 See e.g., 21 CFR 20.61(a) and (b). 
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459  For products where Q1/Q2 sameness is not required by regulation, FDAs guidances (e.g., PSGs) 
460  sometimes recommend specific BE approaches that may be suitable when the formulation 
461  components and composition of the proposed generic drug product meet specified criteria for 
462  sameness or for no significant difference relative to that of the reference standard, which 
463  ordinarily is the RLD.37  In these instances, requestors can submit a controlled correspondence to 
464  ask whether one or more proposed formulation(s) may be suitable for the specific BE approach 
465  recommended in FDAs guidance, and should include the information about the RLD and 
466  reference standard (if the reference standard is not the RLD) in the bulleted list below.  
467  Consistent with the Agencys past and current practices, FDA does not intend to review requests 
468  for formulation assessment that are not recommended as part of a BE approach in a guidance.38  
469  In addition, FDA only intends to opine as to whether it is acceptable for the applicant to use the 
470  requested BE approach based on the proposed formulation and does not intend to comment on 
471  whether the proposed formulation is the same (e.g., Q1/Q2) as the RLD or reference standard. 
472   
473  As described above, the following information should be included in the controlled 
474  correspondence: 
475   
476    Application holder 
477    Application number  
478    Proprietary name  
479    Active ingredient  
480    Strength (if a parenteral drug product, specify both the total quantity of drug substance in 
481  the container closure and the concentration of the drug substance) 
482    If a parenteral drug product, specify the fill volume  
483    Dosage form  
484    Route of administration 
485    Approval date  
486    Marketing status (i.e., whether the product is prescription, over-the-counter, or in the 
487  Discontinued section of the Orange Book (which includes drug products that have been 
488  withdrawn from the market)) 
489     
490  The formulation descriptions should include adequate details, including salt and hydration forms, 
491  purity, grade or type, function, and appropriate units (e.g., amount/milliliter, amount/gram, 
 
 
37 For more information on the terms RLD and reference standard, see the guidance for industry Referencing 
Approved Drug Products in ANDA Submissions (Oct. 2020).  
 
38 If FDA has previously reviewed and responded to a proposed alternative BE approach within the scope of a pre-
ANDA product development meeting, and FDAs response indicated that the proposed formulation is not 
appropriate for the proposed alternative approach, then the requestor can submit a controlled correspondence for 
feedback on the appropriateness of using the proposed alternative approach with an updated formulation.   
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492  percentage weight/weight, percentage weight/volume, percentage volume/volume), as 
493  applicable, of the active ingredients and inactive ingredients in the product.39   
494   
495  FDA recommends that no more than three proposed formulations of a single drug product be 
496  submitted in one controlled correspondence.  Limiting a single controlled correspondence to no 
497  more than three formulation assessment requests allows for FDAs targeted and timely review of 
498  such requests.  In addition, the Agency recommends against submitting a request for formulation 
499  assessment and a separate request for evaluation of a proposed inactive ingredient amount or 
500  concentration at the same time.   
501   
502  If a requestor is seeking formulation assessment for multiple drug products, FDA recommends 
503  that each drug product request be submitted in a separate controlled correspondence.  Thus, a 
504  requestor should not seek formulation assessment for generic drugs with different RLDs in a 
505  single controlled correspondence.  This includes separate formulation assessment requests for 
506  drug products with multiple strengths, such as parenteral drug products with different fill sizes, 
507  because each strength is a separate drug product.40   
508   
509  3.  Requests Related to Product Quality 
510   
511  In addition to product quality questions related to generic drug development, the Agency often 
512  receives requests for information pertaining to chemistry, manufacturing, and controls for Type 
513  II drug master files for drug substances submitted in support of generic drug applications.  FDA 
514  recommends that a requestor include prior research and supporting product quality information 
515  in the controlled correspondence so the Agency can adequately respond to the inquiry. The level 
516  of detail of the supporting product quality information should be appropriate considering the 
517  question(s) being asked.  Typically, a submission related to product quality would include, as 
518  applicable, a brief description of the proposed formulation, manufacturing process, container-
519  closure system, and developmental studies.  For example:  
520    An inquiry on stability bracketing/matrixing design should include whether a common 
521  blend is used to make the drug product, proposed product strengths, storage conditions, 
522  and a description of the container-closure system, including any other information to 
523  justify the reduced stability design. 
 
 
39 To facilitate consideration of the request, FDA recommends that the inactive ingredient and/or the formulation 
information be presented in the format in which it would be submitted in an ANDA.  In cases in which a drug 
product is supplied as a dose pack, such as a vial containing lyophilized product and a diluent, the requestor should 
submit formulation compositions for both the lyophilized product and the diluent. 
40 For parenteral drug products, strength is generally determined by both the total quantity of drug substance in a 
container closure and the concentration of the drug substance.  Orange Book, 42nd ed. (2022), at xvii; see also 80 
FR 6802 at 6816 (February 6, 2015).  Therefore, a deviation from the total drug content of the RLD parenteral drug 
product or the concentration would constitute a change in strength.  The Orange Book Preface explains, however, 
that the strengths of certain parenteral drug products, including contrast agents, may be expressed as a percentage 
(Orange Book, 42nd ed. (2022), at xvii).   
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524   
525    A question on size, shape, or other physical attributes of a drug product should be 
526  supported by comparative data of the proposed generic drug and RLD with regard to 
527  product dimensions, volume, images, and other relevant properties.   
528  A detailed description, with relevant prior research and supportive information, in a controlled 
529  correspondence will increase the likelihood that FDA will have sufficient information to provide 
530  a specific response to the inquiry.  We also recommend that requestors review FDAs guidance 
531  for industry Questions and Answers on Quality Related Controlled Correspondence (September 
532  2021) before submitting a controlled correspondence. 
533  4.  Requests Related to the Evaluation of the User Interface of a Drug-Device 
534  Combination Product  
535   
536  Requestors can submit controlled correspondence requesting preliminary feedback regarding 
537  differences between the user interface of a proposed generic drug-device combination product as 
538  compared to the user interface of its RLD.  These submissions should include comparative 
539  analyses,41 specific questions about the user interface for the proposed generic combination 
540  product, and three samples each of the proposed generic combination product and the RLD.42  If 
541  the requestor would like FDAs feedback on more than one strength, the requestor should 
542  include three samples of each strength (proposed generic and RLD) unless the device user 
543  interfaces of the different strengths are identical except for color scheme and labeling 
544  information.  In this case, three samples of one strength (proposed generic and RLD) and one 
545  sample of each of the other strengths are sufficient.  If the samples of the generic combination 
546  product are prototypes and do not represent the final, to-be-marketed version, the controlled 
547  correspondence should specify that the samples are prototypes and identify any components 
548  (including device labeling) that have been omitted or are still in development.  Questions related 
549  to device performance and specifications are considered product quality questions and should be 
550  submitted in a separate controlled correspondence (see section IV.C.3 of this guidance).   
551   
552  5.  Requests Requiring Review by More Than One Discipline 
553   
 
 
41 For more information on how to conduct analyses of the proposed user interface for a generic drug-device 
combination product when compared to the user interface of the RLD, see FDAs draft guidance for industry 
Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination 
Product Submitted in an ANDA (Jan. 2017).  When final, this guidance will represent FDAs current thinking on this 
topic. 
42 Product samples should be sent to:  
Office of Research and Standards 
Office of Generic Drugs 
U.S. Food and Drug Administration 
10903 New Hampshire Avenue 
Building 75, Room 4723 
Silver Spring, MD 20993 
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554  If a requestor seeks information related to separate elements of generic drug development or 
555  postapproval submission requirements that require review by more than one discipline, which are 
556  identified in section IV.D of this guidance (e.g., information on a proposed formulation and 
557  proposed product labeling), FDA recommends that the requestor submit separate requests 
558  regarding the product.43  This process will facilitate our timely review and response.   
559   
560  6.  Considerations for Specific Types of Level 1 Controlled Correspondence 
561   
562  Below are additional recommendations regarding specific types of inquiries submitted as level 1 
563  controlled correspondence.   
564   
565  a.  Controlled correspondence submitted after a PSG teleconference 
566   
567  When a new or revised PSG is published and an applicant or prospective applicant has already 
568  commenced an in vivo BE study (i.e., the study protocol has been signed by the study sponsor 
569  and/or the contract research organization), the applicant or prospective applicant can request a 
570  PSG Teleconference to obtain FDAs feedback on the potential impact of the new or revised 
571  PSG on its development program.44 If the applicant or prospective applicant seeks further 
572  feedback from FDA after the PSG Teleconference, they can request a Pre-Submission PSG 
573  Meeting or a Post-Submission PSG meeting, or they can submit a controlled correspondence.45  
574  FDA recommends that requestors do not submit a controlled correspondence and a request for a 
575  Pre-Submission PSG Meeting or a Post-Submission PSG meeting at the same time.46   
576   
577  b.  Controlled correspondence submitted after issuance of a CRL or tentative 
578  approval 
579   
580  FDA intends to respond to controlled correspondence seeking regulatory and/or scientific advice 
581  after the issuance of a CRL for an ANDA and after the issuance of a CRL for a supplement as 
582  long as the CRL for the ANDA or supplement was issued on or after October 1, 2022.  If the 
583  CRL was issued before October 1, 2022, the correspondence should be submitted as general 
584  correspondence.  A controlled correspondence submitted after issuance of a CRL should not be 
585  used to submit proposed responses to deficiencies identified in the CRL to FDA for review.  
 
 
43 Requests requiring review by more than one discipline can be submitted concurrently.  As discussed in section 
IV.B of this guidance, FDA recommends that a controlled correspondence include the submission date of any other, 
related controlled correspondence that was accepted for substantive review and response.   
44 GDUFA III commitment letter at 24.   
45 Id. 
46 FDA may deny a Pre- or Post-Submission PSG Meeting if the inquiry would be more appropriately resolved 
through a controlled correspondence.  FDA may grant a Pre- or Post-Submission PSG meeting after such a 
controlled correspondence if FDA determines that any issues remain unresolved or would be more appropriately 
resolved in a meeting (GDUFA III commitment letter at 25). 
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586  FDA will also respond to controlled correspondence submitted on or after October 1, 2022, after 
587  issuance of a tentative approval. 
588   
589  c.  Requests submitted after ANDA approval and concerning postapproval 
590  submission requirements 
591   
592  FDA will respond to controlled correspondence submitted on or after October 1, 2022, that 
593  contains questions about a specific approved ANDA.47  FDA will also respond to controlled 
594  correspondence submitted on or after October 1, 2022, seeking information on postapproval 
595  submission requirements that are not covered by CDER guidance on postapproval changes and 
596  are not specific to an ANDA (i.e., the requirements impact more than one ANDA owned by the 
597  application holder).48  Such controlled correspondence includes, but is not limited to, specific 
598  questions related to a product site transfer and specific questions related to modernizing a 
599  manufacturing facility (e.g., expanding an existing production line or constructing a new 
600  building within an existing manufacturing facility) that impact more than one ANDA.  FDA 
601  recommends submitting questions concerning postapproval submission requirements in a 
602  separate controlled correspondence from other questions (e.g., a question about post-approval 
603  manufacturing requirements should be submitted in a separate controlled correspondence from a 
604  question about a quality deficiency identified in a CRL). 
605   
606  7.  Considerations for Level 2 Controlled Correspondence 
607   
608  Below are additional recommendations regarding inquiries submitted as level 2 controlled 
609  correspondence.   
610   
611  a.  Requests that involve evaluation of clinical content  
612   
613  Consistent with FDAs past and current practices, FDA will continue to consider controlled 
614  correspondence that requires evaluation of clinical content (and is therefore level 2 controlled 
615  correspondence) to include requests that require input from OGDs Office of Safety and Clinical 
616  Evaluation and OGDs Office of Research and Standards Clinical Safety and Human Subject 
617  Research Team.  As further described in section IV.C.7.d of this guidance, FDA will also 
618  consider controlled correspondence that requires input from other offices and centers outside of 
619  OGD (e.g., the Center for Devices and Radiological Health), including about the evaluation of 
620  clinical content, to be level 2 controlled correspondence.  The evaluation of clinical content 
621  includes, but is not limited to, clear, specific questions related to the planning of a BE study with 
622  comparative clinical endpoints and questions related to adverse events that occur during the 
623  conduct of a BE study. 
624   
625  b.  Requests for a Covered Product Authorization 
 
 
47 GDUFA III commitment letter at 11 and 46. 
48 GDUFA III commitment letter at 46. 
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626   
627  FDA will consider requests for a Covered Product Authorization, including the review of BE 
628  protocols for development and testing that involve human clinical trials for an ANDA if the RLD 
629  is subject to a REMS with ETASU to be level 2 controlled correspondence.49  FDA will also 
630  consider requests for a Covered Product Authorization to obtain sufficient quantities of an 
631  individual covered product subject to a REMS with ETASU to be level 2 controlled 
632  correspondence when development and testing does not involve clinical trials.50   
633   
634  FDA has issued guidance on how to obtain a Covered Product Authorization. This draft guidance  
635  for industry How To Obtain a Covered Product Authorization (Sep. 2022) explains how to 
636  submit a request for a CPA and what to include in the request.51 
637   
638  c.  Requests for evaluation of alternative BE approaches  
639   
640  FDA will consider requests to evaluate alternative BE approaches (e.g., pharmacokinetic, in 
641  vitro, comparative clinical endpoints) for drug products for which a PSG is available to industry 
642  to be level 2 controlled correspondence.  In addition, FDA will consider requests to use an 
643  alternate reference product in a BE study, or otherwise use an alternative BE approach, when 
644  there is no market availability of the reference standard and the RLD, and there are no approved 
645  generic drugs referencing the same listed drug, to be level 2 controlled correspondence.52 
646   
647  d.  Requests that require input from another office or center 
648     
649  FDA will consider requests that require the review discipline to obtain input from another office 
650  or center to be level 2 controlled correspondence.  For example, if OGDs Office of Research 
651  and Standards has to consult OGDs Office of Bioequivalence or OPQs Office of Lifecycle 
652  Drug Products has to consult OPQs Office of Biotechnology Products on a request, that would 
653  constitute a level 2 controlled correspondence.  As another example, if the controlled 
654  correspondence includes questions about the device constituent part of a drug-device 
655  combination product, and those questions require input from another office (e.g., OGDs Office 
656  of Safety and Clinical Evaluation or the Office of Surveillance and Epidemiology) or center, then 
657  that would constitute a level 2 controlled correspondence.  During substantive review of the 
 
 
49 GDUFA commitment letter at 46.   
50 Id. 
51 When final, this guidance will represent FDAs current thinking on this topic. 
52 Section 505(j)(2)(A)(iv) of the FD&C Act requires ANDA applicants to include information showing that their 
proposed new drug is bioequivalent to a previously approved listed drug.  Listed drugs are those that have been 
approved for safety and effectiveness under section 505(c) of the FD&C Act or approved under section 505(j) of the 
FD&C Act (section 505(j)(7) of the FD&C Act; 21 CFR 314.3).  Given the potential for bioequivalence 
inconsistencies that may result from differences between a non-U.S.-approved product and the U.S. RLD, the 
Agency generally does not accept bioequivalence studies based on a non-U.S.-approved product to show that a drug 
is bioequivalent to the U.S. RLD. 
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658  controlled correspondence, FDA might determine that input from another office or center is 
659  required and change the classification of the controlled correspondence from level 1 to level 2.   
660   
661  D.  Controlled Correspondence Review Disciplines 
662   
663  This section provides additional information on the different disciplines that might review and 
664  respond to a controlled correspondence.  In addition, this section provides examples of the types 
665  of inquiries each discipline reviews.  The Agency anticipates that this information will assist 
666  requestors in recommending the appropriate discipline to review a particular controlled 
667  correspondence.  These descriptions are not intended to be exhaustive, and FDA has the 
668  discretion to determine which discipline should review and respond to a controlled 
669  correspondence. 
670   
671  1.  OGDs Office of Bioequivalence 
672   
673  The Office of Bioequivalence reviews correspondence containing inquiries related to the 
674  planning of BE studies.  The Office of Bioequivalence also reviews questions related to the 
675  maximum daily exposure of an inactive ingredient.  In addition, the Office of Bioequivalence 
676  reviews controlled correspondence when applicants want to add an additional strength to their 
677  approved product line and request feedback on whether they need to conduct the studies 
678  recommended in the PSG for the additional strength. 
679   
680  2.  OGDs Office of Research and Standards 
681   
682  The Office of Research and Standards reviews correspondence about alternative BE approaches 
683  to those recommended in a PSG and questions related to the use of modeling and simulation 
684  methods.  The Office of Research and Standards also reviews controlled correspondence 
685  submitted before ANDA submission that contains questions about complex products,53 including 
686  questions on formulation sameness (e.g., Q1/Q2 sameness) for complex products.  In addition, 
687  the Office of Research and Standards reviews questions submitted before ANDA submission 
688  about the user interface of drug-device combination products. 
689   
690  3.  OGDs Office of Safety and Clinical Evaluation 
691   
692  The Office of Safety and Clinical Evaluation reviews correspondence containing questions on 
693  the maximum daily dose, thresholds for extractable and leachable studies, and requests for 
694  Covered Product Authorizations, including those involving review of BE protocols for 
695  development and testing that involves human clinical trials for drug products subject to a REMS 
696  with ETASU.  The Office of Safety and Clinical Evaluation also reviews correspondence sent to 
697  the Agency after issuance of a CRL or after ANDA approval that contains questions on the user 
698  interface of a drug-device combination product.   
 
 
53 See footnote 19 for the definition of complex product. 
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699   
700  4.  OGDs Office of Regulatory Operations, Division of Filing Review 
701   
702  The Division of Filing Review reviews correspondence containing inquiries regarding Q1/Q2 
703  sameness and inquiries that involve the review of the amount per dosage unit or percent 
704  composition of inactive ingredients by reference to the FDAs Inactive Ingredient Database. 
705   
706  5.  OGDs Office of Regulatory Operations, Division of Labeling Review 
707   
708  The Division of Labeling Review reviews correspondence regarding submission requirements 
709  when the ANDA packaging configuration differs from the RLDs and appropriate labeling 
710  differences. 
711     
712  6.  OGDs Office of Generic Drug Policy 
713   
714  The Office of Generic Drug Policy, which includes the Division of Orange Book Publication and 
715  Regulatory Assessment, reviews correspondence regarding RLD designation or certain reference 
716  standard selection questions. 
717   
718  7.  Office of Pharmaceutical Quality 
719   
720  The Office of Pharmaceutical Quality (OPQ) reviews correspondence containing inquiries 
721  regarding chemistry, manufacturing, and controls, including product quality microbiology for 
722  generic drugs.  In addition, OPQ reviews inquiries related to Type II drug master files for drug 
723  substances submitted in support of generic drug applications.  
724   
725  As listed below, OPQ contains subdisciplines that respond to various types of controlled 
726  correspondence:   
727   
728    The Office of Lifecycle Drug Products responds to correspondence containing inquiries 
729  related to formulation, specifications, container-closure, and stability.   
730    The Office of New Drug Products, Division of Lifecycle Active Pharmaceutical 
731  Ingredient, responds to correspondence containing inquiries related to starting materials, 
732  polymorphs, and drug substance manufacturing processes.  
733    The Office of New Drug Products, Division of Biopharmaceutics, responds to 
734  correspondence containing inquiries related to dissolution testing, dissolution methods, 
735  and in vitro-in vivo correlation. 
736    The Office of Pharmaceutical Manufacturing Assessment, Division of Microbiology 
737  Assessment, responds to correspondence containing inquiries related to sterile 
738  processing, bacterial endotoxin limits, and antimicrobial testing.  
739    The Office of Pharmaceutical Manufacturing Assessment, Division of Pharmaceutical 
740  Manufacturing, responds to correspondence containing inquiries such as those related to 
741  blend uniformity, excess fill volumes, facility information submission recommendations, 
742  and current good manufacturing practice requirements. 
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743   
744  Consistent with the recommendation in section IV.C.5 of this guidance, requestors with inquiries 
745  related to generic drug development or postapproval submission requirements for more than one 
746  OPQ subdiscipline should generally submit the inquiries for each specific subdiscipline in 
747  separate controlled correspondence to facilitate a timely and complete response, with the 
748  following exception:  for controlled correspondence related to a CRL, requestors should submit 
749  inquiries for OPQ in a single controlled correspondence. 
750   
751   
752  V.   FDAS COMMUNICATIONS TO REQUESTORS AND REQUESTS TO 
753  CLARIFY AMBIGUITIES IN FDAS CONTROLLED CORRESPONDENCE 
754  RESPONSE  
755   
756  A.  Communications Related to Initial Submissions 
757   
758  For inquiries submitted through the portal, FDA will provide the following information to a 
759  requestor through the portal regarding receipt and consideration of the inquiry.54   
760   
761  Upon receipt of a submission, FDA will evaluate whether the submission will be considered a 
762  controlled correspondence for the purposes of the GDUFA III commitment letter.  FDA will then 
763  send the requestor one of two emails that can be accessed through the portal: (1) an email 
764  confirming acceptance of the submission as a controlled correspondence, which will include an 
765  FDA-assigned controlled correspondence number;55 or (2) an email informing the requestor 
766  either that the Agency does not consider the submission a controlled correspondence and the 
767  basis for that decision or that FDA lacks adequate information to make this determination.  In 
768  most instances, we anticipate confirming acceptance of the submission within 7 calendar days,56 
769  and the communication will contain a receipt date57 that the requestor can use to calculate the 
770  goal date.  If a requestor resubmits a request for information that addresses any problem that 
771  FDA identified with a previous request, the Agency will consider this to be a new controlled 
772  correspondence and process it as such.   
773   
774  If FDA determines, during substantive review of the inquiry, that the inquiry lacks sufficient 
775  information, it can either close the controlled correspondence at that time or contact the requestor 
776  for additional information through the portal.  If the Agency decides to close the controlled 
 
 
54 For inquiries submitted to GenericDrugs@fda.hhs.gov, FDAs communications regarding the controlled 
correspondence will be sent to the email address from which the controlled correspondence originated. 
55 OGD recommends that the requestor refer to the controlled correspondence using the FDA-assigned controlled 
correspondence number in the cover letter of any related ANDA submissions and include a copy of the 
correspondence. 
56 If you do not receive confirmation from FDA within 7 calendar days, please contact GenericDrugs@fda.hhs.gov.   
57 As noted above, FDA will calculate the goal date from the day after a submission (GDUFA III commitment letter 
at 4).   
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777  correspondence, it will notify the requestor through the portal of that decision and the basis for 
778  that decision.  If FDA contacts the requestor for additional information, the goal date for that 
779  controlled correspondence will be extended by the amount of time that the Agencys request for 
780  additional information is outstanding with the requestor.   
781   
782  After substantive review of the request for information in the controlled correspondence, FDA 
783  will respond in written form via an email that can be accessed in the portal.  FDA will only send 
784  a response to the person who originally submitted the controlled correspondence.  The length and 
785  content of FDAs response will depend on the nature of the inquiry submitted.  We intend that 
786  the comments we provide in response to a controlled correspondence will be comprehensive as 
787  of the date of the response.  We note that comments in the response represent our thinking on a 
788  topic at that time and that our thinking may evolve in the future. 
789   
790  FDA will not respond to status requests regarding pending controlled correspondence before the 
791  goal date.  If the Agency does not respond to the controlled correspondence by the goal date, 
792  FDA will send an acknowledgement to the requestor with notification that the request is still 
793  under consideration.     
794   
795  B.  Clarification of the Controlled Correspondence Response 
796   
797  FDA will respond to requests to clarify ambiguities in the Agencys controlled correspondence 
798  response, and such requests might be treated differently than follow-up questions.  As defined in 
799  the GDUFA III commitment letter, ambiguity in the controlled correspondence response means 
800  the controlled correspondence response or a critical portion of it merits further clarification.58  
801  All requests for clarification of a controlled correspondence should be included in a single 
802  submission to FDA.  The request for clarification should be submitted within 7 calendar days of 
803  issuance of FDAs controlled correspondence response.59  Requests for clarification received 
804  after 7 calendar days from issuance of the controlled correspondence response will be considered 
805  a new controlled correspondence.    
806   
807  Requestors seeking clarification of ambiguities in FDAs controlled correspondence response 
808  should submit the request electronically through the portal, which can be accessed at 
809  https://edm.fda.gov.60  The request should be submitted under the same event ID for the original 
 
 
58 GDUFA III commitment letter at 45. 
59 The Agency believes that 7 calendar days provides a requestor sufficient time to review FDAs controlled 
correspondence response and identify any portion of the response the requestor believes is ambiguous.  This process 
also ensures that requestors submit clarification requests for controlled correspondence that have recently been 
reviewed and responded to by the Agency.    
60 Requestors that are unable to submit a request for clarification through the portal can send their request, as an 
attachment to an email, to GenericDrugs@fda.hhs.gov.  In this situation, requestors should include the information 
specified in section V.B of this guidance.  For inquiries submitted to GenericDrugs@fda.hhs.gov, FDAs 
 
 
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810  controlled correspondence submission.  The cover letter for the request to clarify ambiguities in 
811  the controlled correspondence response should include the following information: 
812   
813    Name, title, address, email, phone number, and entity (e.g., corporate affiliation) of the 
814  person submitting the request for clarification.  If the request for clarification is not 
815  submitted by the generic drug manufacturer or related industrys authorized 
816  representative, the generic drug manufacturer or related industrys authorized agent, or 
817  the agents authorized representative, located in the United States, then FDA will not 
818  treat the request for clarification as subject to the GDUFA III commitment letter.   
819   
820    Where possible, the request for clarification should be submitted by the person 
821  who originally submitted the controlled correspondence on which clarification is 
822  sought.  If this is not possible, FDA will accept the request from an alternate, 
823  authorized representative of the generic drug manufacturer or related industry, its 
824  authorized agent, or the agents authorized representative, located in the United 
825  States.   
826   
827    If an authorized agent is submitting the request, identify the company for which 
828  you are the authorized agent and include a copy of a letter of authorization.61  The 
829  letter of authorization should be on corporate letterhead and dated within 1 year of 
830  the date the request for clarification is submitted.  FDA intends to provide a 
831  response to the companys U.S. authorized agent or the agents authorized 
832  representative, similar to FDAs practice when an ANDA is submitted.   
833   
834    FDA-assigned controlled correspondence number, submission date of the controlled 
835  correspondence on which the requestor is seeking clarification, a copy of that controlled 
836  correspondence, and FDAs response to the controlled correspondence. 
837   
838    Clarifying questions and the corresponding section(s) of FDAs controlled 
839  correspondence response on which the requestor is seeking clarification.   
840   
841  The scope of the clarifying questions should be limited to the content of FDAs controlled 
842  correspondence response.  Any requests to review follow-up questions, or new or additional 
843  information, will be considered a new controlled correspondence.  In these instances, we 
844  recommend that the requestor submit a new controlled correspondence through the portal and 
845  include the FDA-assigned controlled correspondence number of the previous inquiry to facilitate 
846  FDAs review and response.  This process ensures that the question is tracked and that all 
847  requestors are treated equitably.     
 
 
communications regarding the request for clarification will be sent to the email address from which the request 
originated. 
61 A letter of authorization should be provided by all authorized agents, regardless of whether the prospective 
applicant or applicant is located in the United States.   
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848    
849  As agreed to in the GDUFA III commitment letter, FDA will review and respond to 90 percent 
850  of requests to clarify ambiguities in the controlled correspondence response within 21 calendar 
851  days of the Agencys receipt of the request.62  If FDA determines that the request does not 
852  contain the information specified in the bulleted list in this section, the request will not be 
853  considered to be received for purposes of the GDUFA III commitment letter.   
854   
855  After reviewing the request for clarification, FDA, at its discretion, will either call the requestor 
856  or respond in written form via an email that can be accessed in the portal.  FDAs response will 
857  either clarify the ambiguity in the controlled correspondence response or state that, in FDAs 
858  judgment, the controlled correspondence response does not merit further clarification.  Any 
859  subsequent inquiries regarding FDAs response to a controlled correspondence or FDAs 
860  response to a request for clarification of ambiguities should be submitted in a new controlled 
861  correspondence.   
 
 
62 GDUFA III commitment letter at 11.  FDA will calculate the goal date from the day after a submission (GDUFA 
III commitment letter at 4).  For the purpose of meeting this commitment, requests to clarify ambiguities in FDAs 
controlled correspondence response will be received by the Agency Monday through Friday from 12:00 a.m. to 
11:59 p.m. Eastern Standard Time/Eastern Daylight Time, excluding Federal holidays and days when the FDA 
office that will review the clarification request is closed.    
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