Fixed-Combinations and 
Single-Entity Versions of 
Previously Approved 
Antiretrovirals for the 
Treatment or Prevention of 
HIV-1 Under PEPFAR  
Guidance for Industry 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 
days of publication in the Federal Register of the notice announcing the availability of 
the draft guidance.  Submit electronic comments to https://www.regulations.gov.  Submit 
written comments to the Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments 
should be identified with the docket number listed in the notice of availability that 
publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Division of Antivirals at 
301-796-1500. 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
Procedural 
August 2023 
 
Revision 1
35868275dft.docx  
7/31/2023   
Fixed-Combinations and 
Single-Entity Versions of 
Previously Approved 
Antiretrovirals for the 
Treatment or Prevention of 
HIV-1 Under PEPFAR  
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) 
 
Procedural 
August 2023 
 
Revision 1
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Table of Contents 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ON HIV TREATMENT, HIV PREVENTION, AND PEPFAR .... 3 
A.  HIV Treatment ............................................................................................................................... 3 
B.  HIV Prevention .............................................................................................................................. 3 
C.  PEPFAR .......................................................................................................................................... 3 
D.  ARV Drug Products Needed for PEPFAR .................................................................................. 4 
III.  GENERAL CONSIDERATIONS ................................................................................... 5 
A.  Submitting ARV Drug Product Applications Eligible for Procurement Under PEPFAR 
Through the Appropriate Abbreviated Approval Pathway ............................................................... 5 
1. ANDAs ............................................................................................................................................. 5 
2. 505(b)(2) NDAs ................................................................................................................................ 6 
B.  Changes Made After Tentative Approval of an Application ..................................................... 7 
1. Amendments: Before Final Marketing Approval Request ............................................................... 7 
2. Amendments:  Requesting Final Approval..................................................................................... 10 
C.  Regulatory Procedures that May Expedite the Availability of ARV Drug Products 
Submitted in NDAs Eligible for Procurement Under PEPFAR ....................................................... 11 
IV.  CLINICAL CONSIDERATIONS ................................................................................. 11 
A.  Pediatric Considerations ............................................................................................................. 12 
V.  CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS ............................ 12 
A.  Bioequivalence or Bioavailability Studies .................................................................................. 13 
B.  Assessment of the Effect of Food ................................................................................................ 13 
C.  Waivers of Bioequivalence or Bioavailability Studies .............................................................. 14 
D.  Pediatric Formulations ................................................................................................................ 14 
VI.  CHEMISTRY, MANUFACTURING, AND CONTROLS ......................................... 15 
A.  Drug Master Files ........................................................................................................................ 15 
B.  Manufacturing Facilities and Processes ..................................................................................... 15 
C.  Drug Substance Issues ................................................................................................................. 16 
1. Controls ......................................................................................................................................... 16 
2. Impurities ....................................................................................................................................... 16 
D.  Drug Product Issues ..................................................................................................................... 16 
1. Controls and Impurities ................................................................................................................. 17 
2. Water Content ................................................................................................................................ 17 
3. Markings and Labeling .................................................................................................................. 17 
4. Scored Tablets ................................................................................................................................ 17 
5. Tablets Intended for Dispersion in Water or Other Liquids .......................................................... 18 
6. Packaging ...................................................................................................................................... 18 
7. Stability .......................................................................................................................................... 19 
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8. Stability Storage Conditions .......................................................................................................... 19 
9. Amount of Stability Data ................................................................................................................ 20 
10.  Assessment of Stability Data ..................................................................................................... 20 
11.  Expiration Dating Period .......................................................................................................... 21 
E.  CMC Changes After a Tentative Approval ............................................................................... 21 
1. Addition of a New Drug Substance Manufacturer or Manufacturing Site, Drug Product 
Manufacturer, or Manufacturing Site or Testing Site ........................................................................ 21 
2. Extension of Expiration Dating Period .......................................................................................... 21 
3. Changes in Excipient Specifications .............................................................................................. 22 
4. Changes to the Stability Testing Program ..................................................................................... 22 
VII.  LABELING AND PRESCRIBING INFORMATION ................................................ 22 
VIII.  OTHER REGULATORY CONSIDERATIONS ......................................................... 23 
A.  User Fees ....................................................................................................................................... 23 
1. NDAs .............................................................................................................................................. 23 
2. ANDAs ........................................................................................................................................... 24 
B.  Pediatric Requirements ............................................................................................................... 24 
C.  Adverse Event Reporting ............................................................................................................ 25 
 
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Fixed-Combinations and Single-Entity Versions of Previously 
Approved Antiretrovirals for the Treatment or Prevention of HIV-1 
Under PEPFAR  
Guidance for Industry1 
 
 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
for this guidance as listed on the title page. 
 
 
 
I.  INTRODUCTION 
 
This guidance provides recommendations for applications for single-entity (SE) antiretroviral 
(ARV) and fixed-combination (FC) ARV drug products for the treatment or prevention of human 
immunodeficiency virus-1 (HIV-1 or HIV) infection that are intended for distribution outside of 
the United States under the Presidents Emergency Plan for AIDS Relief (PEPFAR).2  
Specifically, this guidance addresses versions of previously approved SE and FC ARV drug 
products and FC ARV drug products for which the individual drug product components of the 
combination are already FDA-approved (i.e., for which substantial evidence of safety and 
efficacy of the specific individual drug product components or combination already exists).   
 
This guidance discusses regulatory procedures relevant to such applications and makes 
recommendations on how to identify and address common issues.   
 
This guidance revises the guidance for industry Fixed Dose Combinations, Co-Packaged Drug 
Products, and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment of 
HIV issued in October 2006.  When finalized, this guidance will replace the October 2006 
guidance.  Significant changes from the 2006 final guidance include, but are not limited to, the 
following: 
 
  Addition of information about ARV drug products for prevention of HIV infection. 
 
1
 This guidance has been prepared by the Division of Antivirals (DAV) in cooperation with the Office of 
Pharmaceutical Quality, Office of Clinical Pharmacology, and Office of Generic Drugs (OGD) in the Center for 
Drug Evaluation and Research (CDER). 
 
2 For the purposes of this guidance, a fixed-combination antiretroviral drug product is one in which two or more 
antiretroviral drugs are combined in a single dosage form and the contribution of the individual drugs has been 
demonstrated to contribute to the effect(s) of the fixed-combination consistent with the requirements of 21 CFR 
300.50.  For the purposes of this guidance, the term drug product will be used to refer to human prescription drugs 
under section 505 of the Federal Food, Drug, and Cosmetic (FD&C) Act. 
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  Deletion of references to co-packaged products and focus on SE ARV and FC ARV drug 
products currently most needed under PEPFAR. 
 
  Inclusion of a subsection that describes the processes for making changes to applications 
after tentative approval. 
 
  Addition of updated descriptions of regulatory requirements and procedures in the main 
text of the guidance and deletion of Attachment A, which provided hypothetical 
scenarios. 
 
  Reference to other FDA guidances for industry for common regulatory topics instead of 
repeating information. 
 
  Addition of updated information in the section on chemistry, manufacturing, and controls 
to be consistent with other guidances for industry published after 2006. 
 
  Deletion of Attachment B, which listed examples of two and three drug FCs supported by 
clinical data.  Instead, the guidance refers applicants to a separate list3 for ARV drug 
products supported by clinical data and needed for PEPFAR procurement.  This list is 
published in conjunction with the FDAs PEPFAR database.   
 
  Deletion of Attachment C, which listed combinations that were not acceptable for FC or 
co-packaging. 
 
This guidance is not an exhaustive document on FDAs current thinking regarding the 
development and review of ARV drug products eligible for procurement under PEPFAR.  
Applicants can refer to other guidances cited in this document or seek advice from FDA when 
questions arise regarding specific drug development programs.  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
3
 The separate list of ARV drug products, Antiretroviral Drug Products Needed for Use Under PEPFAR, can be 
found under question 6, What PEPFAR products can companies submit for FDA review?, at FDAs PEPFAR 
database on the Frequently Asked Questions web page available at https://www.fda.gov/international-
programs/presidents-emergency-plan-aids-relief-pepfar/pepfar-database-frequently-asked-questions.  This list is 
revised periodically to address current public health needs. 
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II.  BACKGROUND ON HIV TREATMENT, HIV PREVENTION, AND PEPFAR  
 
A.  HIV Treatment 
 
ARV drug products are essential for the treatment of HIV/AIDS (acquired immunodeficiency 
syndrome).  The goals of HIV treatment are to maximally and durably suppress HIV to allow 
recovery of the immune system, reduce adverse clinical outcomes associated with HIV, reduce 
the emergence of resistance, and reduce HIV transmission to others.  In the United States and 
developing countries, simplified HIV regimens in the form of FC ARV drug products improve 
patient adherence and facilitate distribution.  For patients initiating ARV drug product therapy, 
preferred regimens are listed in the U.S. Department of Health and Human Services (DHHS) 
treatment guidelines,4 the International AIDS Society guidelines,5 and the World Health 
Organization (WHO) guidelines.6   
 
B.  HIV Prevention 
 
ARV drug products that are safe and effective for HIV prevention are important for people who 
are negative for HIV but are at substantial risk of HIV acquisition.  The goal of using ARV drug 
products to prevent HIV acquisition is to reduce the morbidity, mortality, and cost to individuals 
and society associated with HIV infection.  Recommendations for initiating HIV prevention, 
including recommended ARV drug products for prevention, are presented in the U.S. Public 
Health Service guidelines7 and the WHO guidelines.8       
 
C.  PEPFAR 
 
PEPFAR is a U.S. Government initiative to help save the lives of those with HIV/AIDS around 
the world, outside the United States.  It was originally announced in President George W. Bushs 
State of the Union address in 2003 and was reauthorized in 2008, 2013, and 2018.  This historic 
 
4
 See the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV developed by the 
DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents  A Working Group of the Office of AIDS 
Research Advisory Council, available at https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-
adolescent-arv.  
 
5
 See Saag MS, Benson CA, Gandhi RT, et al., 2018, Antiretroviral drugs for Treatment and Prevention of HIV 
Infection in Adults: 2018 Recommendations of the International Antiviral Society-USA Panel, JAMA, 320(4):379
396. 
 
6
 See the WHOs Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery and 
Monitoring: Recommendations for a Public Health Approach. Geneva: World Health Organization; 2021, available 
at https://www.who.int/publications/i/item/9789240031593.  
 
7
 See the Centers for Disease Control and Preventions U.S. Public Health Service: Preexposure Prophylaxis for the 
Prevention of HIV Infection in the United States  2021 Update, available at 
https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf. 
 
8
 See the WHOs Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery, and 
Monitoring:  Recommendations for a Public Health Approach, available at 
https://www.who.int/publications/i/item/9789240031593.  
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commitment is among the largest by any nation to combat a single disease internationally.  As of 
2012, ARV drug products are also available for HIV prevention, and as of 2015, WHO 
recommends the use of these drug products to reduce the risk of HIV acquisition.  ARV drug 
products for treatment and more recently prevention play a major role in PEPFAR, and it is 
important that resources are spent on products that have been demonstrated to be safe and 
effective.  ARV drug products for treatment or prevention of HIV must conform to regulatory 
standards of safety, efficacy, and quality9 to maximize the success of treatment or prevention and 
to reduce the emergence and spread of resistant virus.  Of note, FDA-approved or tentatively 
approved ARV drug products are eligible for procurement under PEPFAR. 
 
D.  ARV Drug Products Needed for PEPFAR 
 
The FDAs PEPFAR database10 includes a list of ARV drug products that have been tentatively 
approved or approved and are eligible for procurement under PEPFAR, and a separate list11 of 
ARV drug products that are currently most needed for HIV treatment or prevention in the 
developing world and countries supported by PEPFAR.  An applicant should refer to the list of 
needed ARV drug products when considering submitting an ARV drug product application for 
HIV treatment and when evaluating whether to submit a user fee waiver request.12  The list of 
needed ARV drug products for treatment is expected to evolve as HIV research continues and 
program needs change.  An applicant that has access to data supporting the efficacy and safety of 
ARV drug products for treatment that are not included in the list of needed ARV drug products is 
encouraged to discuss with the Division of Antivirals (DAV)13 its rationale for why the ARV 
drug product is important for PEPFAR and may qualify for a new drug application (NDA) user 
fee waiver.  Similarly, an applicant is encouraged to consult DAV when considering submitting 
 
9
 Section 505 of the FD&C Act. 
 
10
 The FDAs PEPFAR database is available at 
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=pepfar.page. 
 
11
 The separate list of ARV drug products, Antiretroviral Drug Products Needed for Use Under PEPFAR, can be 
found under question 6, What PEPFAR products can companies submit for FDA review?, at FDAs PEPFAR 
Database on the Frequently Asked Questions web page available at https://www.fda.gov/international-
programs/presidents-emergency-plan-aids-relief-pepfar/pepfar-database-frequently-asked-questions.  This list is 
revised periodically to address current public health needs.  
 
12
 Under certain circumstances, FDA is authorized to waive user fees assessed under the Prescription Drug User Fee 
Act (PDUFA) for new drug applications (NDAs) and biological license applications (BLAs). In 2006, FDA issued a 
guidance for industry regarding certain user-fee waiver provisions of special relevance to PEPFAR products, User 
Fee Waivers for FDC and Co-Packaged HIV Drugs for PEPFAR (February 2007). In 2023, FDA published a new 
draft guidance for industry PDUFA Waivers, Reductions, and Refunds for Fixed-Combinations and Single-Entity 
Versions of Previously Approved Antiretrovirals under PEPFAR (August 2023).  When final, the new user-fee 
guidance will replace FDAs 2006 guidance and represent the FDAs current thinking on this topic.  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
 For more information on contacting DAV, see the Office of Infectious Diseases web page at 
https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/office-new-drugs. 
 
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an ARV drug product application for HIV prevention and when evaluating whether to submit a 
user fee waiver request.12  
 
III.  GENERAL CONSIDERATIONS 
 
This guidance focuses on tentative approval of ARV drug products for HIV-1 treatment or 
prevention, particularly of those submitted in an abbreviated new drug application (ANDA) 
under section 505(j) of the Federal Food, Drug, and Cosmetic (FD&C) Act or in a section 
505(b)(2) of the FD&C Act.10,12  Because ARV drug products submitted as 505(b)(1) NDAs are 
usually eligible for approval rather than tentative approval, these applications are generally not 
discussed in this guidance. 
 
A tentative approval may be granted for ARV drug products that cannot be marketed in the 
United States because of existing patents and/or exclusivity.14  Drug products that receive 
tentative approval meet the same substantive requirements (e.g., safety, efficacy, and quality 
standards) as drug products that receive final marketing approval. 
 
FDA will not grant a tentative approval action in lieu of final marketing approval when there are 
no patent and exclusivity barriers to final approval.15   
 
A.  Submitting ARV Drug Product Applications Eligible for Procurement Under 
PEPFAR Through the Appropriate Abbreviated Approval Pathway 
 
An applicant should determine whether its application should be submitted as an ANDA or a 
505(b)(2) NDA as discussed briefly in this section and as addressed in detail in the guidance for 
industry Determining Whether to Submit an ANDA or a 505(b)(2) Application (May 2019).16  
That guidance highlights statutory and regulatory criteria for submitting applications under the 
abbreviated approval pathways described in section 505(j) and 505(b)(2) of the FD&C Act, 
identifies considerations to help potential applicants determine which pathway is most 
appropriate, and provides recommendations to potential applicants on requesting assistance from 
FDA in making this determination. 
 
1.  ANDAs 
 
Like all ANDAs, an ANDA for an ARV drug product is submitted and approved under section 
505(j) of the FD&C Act (commonly referred to as a generic drug application).  An ANDA relies 
on FDAs finding that the previously approved drug product, i.e., the reference listed drug 
 
14
 See 21 CFR 314.3(b) and 21 CFR 314.105.  If one or more active moiety in an ARV drug product is protected by 
new chemical entity exclusivity, acceptance of an ANDA or 505(b)(2) NDA containing that active moiety for 
review could be delayed.  See sections 505(c)(3)(E)(ii) and 505(j)(5)(F)(ii) of the FD&C Act; 21 CFR 314.108(b).    
 
15
 See 21 CFR 314.105. 
 
16
 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
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(RLD), is safe and effective.  An RLD is defined as the listed drug identified by FDA as the drug 
product upon which an applicant relies in seeking approval of its ANDA17 and is listed in the 
FDAs Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known 
as the Orange Book).18  An ANDA generally must contain information to show that the proposed 
drug product (1) is the same as the RLD with respect to the active ingredient(s), conditions of 
use, dosage form, strength, route of administration, and labeling (with certain permissible 
differences), and (2) is bioequivalent to the RLD.19  FDAs review process ensures that generic 
drug products perform the same way in the human body and have the same intended use as the 
RLD.  All generic drug products approved by FDA have the same high quality, strength, purity, 
and stability as brand-name drug products.  In addition, FDA inspects facilities to make certain 
the generic manufacturing, packaging, and testing sites pass the same quality standards as those 
of brand-name drug products. 
 
ANDAs are reviewed in FDAs Office of Generic Drugs (OGD).  If an applicant has questions 
about its proposed ARV drug product, the applicant can submit a controlled correspondence to 
FDAs OGD.20    
 
2.  505(b)(2) NDAs 
 
A 505(b)(2) NDA for an SE or FC ARV drug product must contain full reports of investigations 
of safety and effectiveness, where at least some of the information required for approval comes 
from studies not conducted by or for the applicant and for which the applicant has not obtained a 
right of reference or use21 (e.g., the Agencys finding of safety and/or effectiveness for a listed 
drug, published literature).  A 505(b)(2) NDA applicant may rely on FDAs finding of safety 
and/or effectiveness for a listed drug only to the extent that the proposed product in the 505(b)(2) 
application shares characteristics (e.g., active ingredient, dosage form, route of administration, 
strength, indication or other conditions of use) in common with the relied-upon listed drug(s).  
The applicant is expected to establish a bridge (e.g., by using comparative bioavailability data) 
between the proposed drug product and each listed drug that the applicant seeks to rely upon to 
demonstrate that reliance on the listed drug is scientifically justified.  To the extent that the listed 
drug and the drug proposed in the 505(b)(2) NDA differ (e.g., a product with a different dosage 
 
17
 21 CFR 314.3(b).  See also the guidance for industry Referencing Approved Drug Products in ANDA Submissions 
(October 2020). 
 
18
 Available at https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-
equivalence-evaluations-orange-book.  
 
19
 See section 505(j)(2) and 505(j)(4) of the FD&C Act; 21 CFR 314.94, 21 CFR 314.127, and 21 CFR 320.21(b).  
See also the guidance for industry Determining Whether to Submit an ANDA or a 505(b)(2) Application. 
 
20
 See the draft guidance for industry Controlled Correspondence Related to Generic Drug Development (December 
2022) for information on the types of inquiries appropriate for controlled correspondence and on how to submit 
controlled correspondence to OGD.  When final, this guidance will represent the FDAs current thinking on this 
topic. 
 
21
 See 21 CFR 314.3(b). 
 
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form or a product that is intentionally more bioavailable than the listed drug), the 505(b)(2) NDA 
must include sufficient data to support those differences.22  For drug products included in the list 
of needed drug products23 on the FDAs PEPFAR database,24 submission of a 505(b)(2) NDA 
that relies on FDAs findings of safety and effectiveness for approved SE or FC ARV drug 
products may be appropriate if the applicant does not have a right of reference to data 
establishing the safety and efficacy of the SE or FC ARV drug product. 
 
505(b)(2) NDAs for ARV drug products are reviewed in DAV, which is part of FDAs Office of 
New Drugs.25  If an applicant has questions about submission of an application through the 
505(b)(2) pathway, the applicant should contact DAV for assistance. 
 
B.  Changes Made After Tentative Approval of an Application 
 
An applicant can submit amendments to a tentatively approved application that propose changes 
to the application, request final approval, or both propose changes and request final approval.  
This section describes appropriate data to submit in an amendment to the application when 
changes (including significant changes, e.g., addition of new manufacturing sites or important 
new safety information) are made after tentative approval, but before final marketing approval.   
 
1.  Amendments: Before Final Marketing Approval Request 
 
While a drug product that is granted tentative approval is not an approved drug and may not be 
marketed in the United States until final approval,26 a tentatively approved ANDA or NDA for 
an ARV drug product may be eligible for procurement and distribution outside the United States 
under PEPFAR.  Accordingly, an applicant may determine that changes (e.g., manufacturing, 
labeling) to its tentatively approved application eligible for procurement under PEPFAR may be 
appropriate or necessary as a scientific matter.  In general, these changes are processed as 
amendments to tentatively approved applications.  Although the administrative and regulatory 
procedures for handling changes to these tentatively approved applications may differ from the 
procedures for changes to ANDAs and NDAs after final approval, the scientific principles that 
guide the evaluation of these changes generally remain the same.  In other words, FDA considers 
 
22
 See 21 CFR 314.93. 
 
23
 The separate list of ARV drug products, Antiretroviral Drug Products Needed for Use Under PEPFAR, can be 
found under question 6, What PEPFAR products can companies submit for FDA review?, at FDAs PEPFAR 
Database on the Frequently Asked Questions web page available at https://www.fda.gov/international-
programs/presidents-emergency-plan-aids-relief-pepfar/pepfar-database-frequently-asked-questions.  This list is 
revised periodically to address current public health needs. 
 
24
 The FDAs PEPFAR database is available at 
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=pepfar.page. 
 
25
 For guidance on the content and format of or the submission process for an NDA, see the FDA guidance web 
page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents and search using the term NDA 
and select either the Administrative/Procedural or Clinical/Medical topic in the filter. 
 
26
 See 21 CFR 314.3(b) and 21 CFR 314.105.  See also 505(j)(5)(B)(iv)(II)(dd) of the FD&C Act.   
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the assessment of risk and type of change for such ANDA and NDA amendments similarly to 
supplements to approved applications.  Therefore, when proposing changes to these tentatively 
approved applications, FDA recommends that an applicant indicate in a cover letter its view of 
whether the changes are considered a major, moderate, or minor potential to have an adverse 
effect on the quality of the drug product.  FDA expects to review PEPFAR change amendments 
for tentatively approved NDAs as shown in the timelines in Table 1.  FDA classifies 
amendments to tentatively approved ANDAs as unsolicited, and in general, FDA will set a 
review goal consistent with the recommendations outlined in section IV of the guidance for 
industry ANDA SubmissionsAmendments to Abbreviated New Drug Applications Under 
GDUFA (July 2018) (see Table 2).   
 
Table 1. Types of PEPFAR Change Amendments and Review Timelines for Tentatively 
Approved NDAs * 
  Type of Change    FDA  Change Amendment   
Review  Implementation 
Timelines  
  Amendment   4 months  Requires submission   
Major Change  of change and 
decisional action by 
FDA before 
implementation 
  Amendment   6 months  Requires submission   
Moderate Change  of change, but the 
change can be 
implemented 30 days 
after FDA officially 
  Amendment   6 months  
receives the 
Minor Changea 
submission 
  
PEPFAR = Presidents Emergency Plan for AIDS Relief; NDA = new drug application. 
a 
Includes changes that, for approved applications, would be submitted in annual reports per 21 CFR 314.70(d). 
 
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Table 2. Review Performance Goals for ANDA* Amendments27    
Submission Type  Goal 
Standard Major ANDA  90% within 8 months of submission date if 
Amendments  preapproval inspection not required 
90% within 10 months of submission date if 
preapproval inspection required 
Priority Major ANDA Amendments  90% within 6 months of submission date if 
preapproval inspection not required 
90% within 8 months of submission date if 
preapproval inspection required and applicant 
meets requirements described in the GDUFA 
III Commitment Letterb 
90% within 10 months of submission date if 
preapproval inspection required and applicant 
meets limitations described in the GDUFA III 
Commitment Letterb 
Standard Minor and Priority Minora  90% within 3 months of submission date 
ANDA Amendmentsa 
* ANDA = abbreviated new drug application. 
a Includes changes to ANDAs for ARV drug products eligible for procurement under PEPFAR that are 
recommended as moderate type change amendments. 
b See the Generic Drugs User Fee Act (GDUFA) Reauthorization Performance Goals and Program Enhancement 
Fiscal Years 20232027 https://www.fda.gov/industry/generic-drug-user-fee-amendments/gdufa-iii-reauthorization.  
 
To make a risk assessment of a proposed change amendment (e.g., determine whether a change 
has a major, moderate, or a minor potential to have an adverse effect on the identity, strength, 
quality, purity, or potency of the drug product) and to determine what information or data should 
be submitted to support the proposed change amendment, FDA recommends that applicants refer 
to the following guidances for industry: 
 
  Changes to an Approved NDA or ANDA (April 2004)  
 
  Changes to an Approved NDA or ANDA: Questions and Answers (January 2001)  
 
  Immediate-Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes:  
Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo 
Bioequivalence Documentation (November 1995) 
 
  PAC-ATLS: Postapproval Changes  Analytical Testing Laboratory Sites (April 1998) 
 
After review of a change amendment for an NDA or an ANDA, FDA generally sends the 
applicant one of two types of notifications noted below.  In either case, the original application 
remains tentatively approved. 
 
27
 See the guidance for industry ANDA SubmissionsAmendments to Abbreviated New Drug Applications Under 
GDUFA.  Note that review goal percentages refer to all ANDAs, not just those for drug products eligible for 
procurement under PEPFAR.  
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The possible types of notifications are:   
 
  A PEPFAR Permitted letter, if the change is found acceptable  
  A PEPFAR Denied letter, if the change is found unacceptable  
 
Implementation of a change submitted as a minor or moderate change amendment before 
issuance of a PEPFAR Permitted letter is at the risk of the applicant.  If FDA determines that a 
change submitted as a minor or moderate change amendment is a major change amendment, 
FDA will notify the applicant not to implement the change until a PEPFAR Permitted letter is 
issued for the major change to the tentatively approved application.  
 
For approved applications, applicants must submit postmarketing reports (e.g., annual reports);28 
although this requirement does not apply to tentatively approved applications, FDA recommends 
that applicants submit information related to the distribution outside the United States under 
PEPFAR of a product described in a tentatively approved ANDA or NDA as an amendment 
designating the information as an annual update.  An annual update provides the FDA reviewer 
with background information that may be useful in reviewing other changes to the application.  
Information that is useful in an annual update includes distribution data, stability updates (e.g., 
on original registration batches, commitment batches, and annual batches), a copy of the current 
labeling (including a representative container label), and a cumulative list of all change 
amendments submitted through amendments after tentative approval.   
 
Recommended format for the cumulative list of change amendments with their current statuses 
(e.g., pending, permitted, denied) can be found in the guidance for industry Format and Content 
for the CMC Section of an Annual Report (September 1994).   
 
See section VI.E., CMC Changes After a Tentative Approval, for examples of changes to 
tentatively approved applications.  
 
2.  Amendments:  Requesting Final Approval 
 
When the period of patent and exclusivity protection is ending or has ended, the applicant may 
submit an amendment to a tentatively approved application requesting final approval.  The 
amendment should include final labels and labeling that comply with all applicable U.S. 
regulations (e.g., uniqueness of drug product appearance in accordance with 21 CFR part 206; 
child-resistant packaging in accordance with 16 CFR part 1700).29  The amendment should also 
 
28
 21 CFR 314.81. 
 
29
 In addition, for ANDAs, if the prescribing information includes reference to the antiretroviral pregnancy registry 
contact number, then the prescribing information for the generic product must also include the same antiretroviral 
pregnancy registry reference.  See, for example, section 505(j)(4)(G) of the FD&C Act; 21 CFR 314.127(a)(7).  
Including the pregnancy registry contact in the prescribing information means that a sponsor has joined the 
antiretroviral pregnancy registry.  For 505(b)(2) NDAs, the need to include a reference to the antiretroviral 
pregnancy registry will be decided on a case-by-case basis depending on what is known about the risk and benefit of 
the use of the ARV drug(s) in pregnant females. 
 
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either describe all significant changes to the drug product and manufacturing processes made 
since tentative approval or certify that no significant changes have been made.  A guidance for 
industry is available that provides recommendations for seeking final approval of tentatively 
approved ANDAs.30 
 
C.  Regulatory Procedures that May Expedite the Availability of ARV Drug 
Products Submitted in NDAs Eligible for Procurement Under PEPFAR31 
 
To facilitate rapid development and review of NDAs for ARV drug products eligible for 
procurement under PEPFAR, DAV interacts with applicants early in the development stages to 
discuss the appropriateness of the SE or FC ARV drug product, the dosing strength, and the 
appropriate nonclinical and chemistry, manufacturing, and controls (CMC) data.  In addition, 
some of the regulatory procedures for expediting review of NDAs may apply to ARV NDAs, 
such as fast track designation and priority review designation.  Applicants should refer to FDAs 
guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 
2014) for more information on these expedited programs. 
 
 
IV.  CLINICAL CONSIDERATIONS 
 
FDA believes adequate clinical studies confirming safety and efficacy have already been 
conducted for ARV drug products needed for PEPFAR and listed on the FDAs PEPFAR 
database;32 therefore, in general, new clinical studies are not needed to support applications for 
these drug products when the doses of the approved ARV drug products are unchanged.   
 
Proposed SE and FC ARV drug products should be relatively well tolerated and easy to 
administer, provide potency and a barrier to the emergence of drug resistance, and have available 
clinical safety and efficacy data that support use of the drug product.  Proposed FC ARV drug 
products for HIV treatment intended to be eligible for procurement under PEPFAR should 
contain two or more components of an established fully suppressive ARV regimen that are 
recommended as a preferred or alternative regimen (or regimen component) for treatment-naive 
patients with HIV in treatment guidelines.33  Proposed ARV drug products for HIV prevention 
 
30
 See the guidance for industry ANDA Submissions  Amendments and Requests for Final Approval to Tentatively 
Approved ANDAs (September 2020).   
 
31
 These approaches do not apply to potential ANDA submissions. 
 
32
 The FDAs PEPFAR database is available at 
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=pepfar.page.  In general, SE and FC ARV drug 
products listed on the FDAs PEPFAR database were evaluated in at least one study conducted under good clinical 
practices that evaluated changes in HIV-RNA and CD cell counts for at least 48 weeks and showed statistical 
4 
noninferiority, or superiority, of the ARV drug product or regimen to an accepted control at the time the study was 
conducted.    
 
33
 See the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV developed by the 
DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents  A Working Group of the Office of AIDS 
Research Advisory Council, available at https://clinicalinfo.hiv.gov/en/guidelines; and the WHOs Consolidated 
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eligible for procurement under PEPFAR should represent a prevention option as recommended 
in treatment guidelines.34       
 
Proposed drug products that change the dose of an approved ARV drug product could, as a 
scientific matter, need additional clinical studies to support the change as compared to the relied 
upon listed drug.  Potential applicants should request advice from DAV in this situation. 
 
A.  Pediatric Considerations 
 
FDA encourages applicants to review consensus pediatric guidelines and focus development 
efforts on the types of drug products most needed.  Drug products distributed under PEPFAR are 
used in some countries where liquid drug products may pose significant challenges.  Families 
with pediatric patients may travel long distances to and from a clinic making it difficult to 
transport bulky, heavy bottles of liquid medication.  Many families may not have a place to store 
liquid formulations, particularly if refrigeration is required.  Thus, alternative suitable pediatric 
formulations are preferred, such as tablets for oral suspension or oral pellets that can be mixed 
with food.  To allow maximum flexibility in dosing, another desirable dosage form is a scored 
tablet that can be crushed and dispersed in liquid or food vehicle if the patient cannot swallow a 
solid dosage form.  Scored tablets can include a single score that bisects the tablet or multiple 
score lines, allowing the tablets to be divided into halves, thirds, and/or quarters.  Applicants 
should refer to the guidance for industry Tablet Scoring: Nomenclature, Labeling, and Data for 
Evaluation (March 2013).   
 
Dosing instructions for ARV drug products intended for pediatric patients typically include 
dosing recommendations by weight band.  For FC ARV drug products submitted as a 505(b)(2) 
NDA, it may not be possible to match the U.S. approved dose for each component across all 
weight bands.  If the application proposes doses for weight bands that differ from such 
previously approved doses, the safety and efficacy of such proposed doses at the limits of weight 
bands should be supported by clinical study data or scientific literature.  Potential applicants 
should request advice from DAV in this situation. 
 
 
V.  CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS 
 
This section describes the types of clinical pharmacology and biopharmaceutical data that are 
particularly relevant for ARV drug products eligible for procurement under PEPFAR.  For 
additional details, applicants should refer to other guidances for industry cited in this section. 
 
 
Guidelines on HIV Prevention, Testing, Treatment, Service Delivery and Monitoring: Recommendations for a 
Public Health Approach, available at https://www.who.int/publications/i/item/9789240031593. 
 
34
 See the Centers for Disease Control and Preventions U.S. Public Health Service:  Preexposure Prophylaxis for 
the Prevention of HIV Infection in the United States  2021 Update, available at 
https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf.  
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A.  Bioequivalence or Bioavailability Studies35 
 
Bioequivalence or bioavailability studies are needed to bridge FDAs finding of safety and 
efficacy of U.S. approved drug products to the PEPFAR drug product. 
 
For a drug product submitted in an ANDA (under section 505(j) of the FD&C Act), applicants 
must demonstrate that their drug product is bioequivalent to the RLD.  In addition, applicants 
must use the reference standard (RS), which is selected by FDA, in conducting any in vivo 
bioequivalence testing required to support approval.36  The RLD and RS are identified in the 
Orange Book.  Applicants should refer to the guidance for industry Referencing Approved Drug 
Products in ANDA Submissions and the draft guidance for industry Bioequivalence Studies With 
Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA (August 2021).37  For 
additional information on recommended bioequivalence studies to support submission of a 
particular drug product, ANDA applicants can also access the OGD web page, Product-Specific 
Guidances for Generic Drug Development, available at: 
https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm.  
 
For an SE or FC ARV drug product submitted as an NDA (under section 505(b)(2) of the FD&C 
Act), a relative bioavailability study or studies may be necessary as a scientific matter.  
Applicants should refer to the guidance for industry Bioavailability Studies Submitted in NDAs 
or INDs  General Considerations (April 2022).   
 
All bioanalytical methods should be well characterized, fully validated, and documented.  For 
additional details, applicants should refer to the guidance for industry Bioanalytical Method 
Validation (May 2018).  
 
B.  Assessment of the Effect of Food  
 
It is important to evaluate the effect of food on the absorption of the active ingredients of the 
ARV drug products eligible for procurement under PEPFAR. 
 
For ARV drug products submitted under the ANDA pathway (section 505(j) of the FD&C Act), 
applicants should refer to the Product-Specific Guidances for Generic Drug Development 
resources38 and the draft guidance for industry Bioequivalence Studies With Pharmacokinetic 
Endpoints for Drugs Submitted Under an ANDA.39 
 
 
35
 See generally 21 CFR part 320, Bioavailability and Bioequivalence Requirements.  
 
36
 See 21 CFR 314.3(b). 
 
37
 When final, this guidance will represent the FDAs current thinking on this topic. 
   
38
 Available at https://www.fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-development. 
 
39
 When final, this guidance will represent the FDAs current thinking on this topic. 
 
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For ARV drug products submitted under the 505(b)(2) NDA pathway), applicants should refer to 
the draft guidance for industry Assessing the Effects of Food on Drugs in INDs and NDAs  
Clinical Pharmacology Considerations (February 2019)40 and guidance for industry 
Bioavailability Studies Submitted in NDAs or INDs  General Considerations.  
 
C.  Waivers of Bioequivalence or Bioavailability Studies 
 
There are circumstances in which an in vivo bioequivalence or bioavailability study can be 
waived.41  For FDAs current thinking on such waivers, applicants should refer to the following 
guidances for industry:   
 
Draft guidances42 
 
  Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an 
ANDA 
 
  Bioavailability Studies Submitted in NDAs or INDs  General Considerations 
 
Final guidances 
 
  M9 Biopharmaceutics Classification System-Based Biowaivers (May 2021) 
 
  Dissolution Testing of Immediate Release Solid Oral Dosage Forms (August 1997) 
 
  Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage 
Form Drug Products Containing High Solubility Drug Substances (August 2018)  
 
D.  Pediatric Formulations 
 
Results from bioavailability studies should be included in NDA submissions supporting pediatric 
formulations.  Bioavailability studies, which are typically conducted in adult patients, should 
evaluate the drug product administered under conditions described in the proposed product 
labeling (e.g., chewed, crushed, dissolved, dispersed, or sprinkled in an appropriate liquid or 
food vehicle43).  In some cases, additional administration conditions may need to be evaluated. 
 
 
 
40
 When final, this guidance will represent the FDAs current thinking on this topic. 
 
41
 See, for example, 21 CFR 320.21 and 21 CFR 320.22.  
 
42
 When final, these guidances will represent the FDAs current thinking on these topics. 
 
43
 See the draft guidance for industry Use of Liquids and/or Soft Foods as Vehicles for Drug Administration:  
General Considerations for Selection and In Vitro Methods for Product Quality Assessments (July 2018).  When 
final, this guidance will represent the FDAs current thinking on this topic.  
 
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VI.  CHEMISTRY, MANUFACTURING, AND CONTROLS  
 
This section highlights certain specific topics with respect to CMC submissions in ANDAs and 
NDAs for ARV drug products eligible for procurement under PEPFAR.  Applicants should refer 
to other guidances for industry cited in this section for additional details on FDAs current 
thinking regarding submission of CMC information. 
 
A.  Drug Master Files 
 
Drug substance manufacturing processes should be well-documented through reference to drug 
master files (DMFs) of the drug substance manufacturers, if complete data cannot be included in 
the application.  Applicants should ensure that DMFs are submitted to FDA for the processes 
used in the manufacturing of the drug substance(s) for both the registration batches of the drug 
product and for the intended commercial drug product.  
If reference is made to a DMF, applicants should ensure that the DMF is submitted to FDA and 
that a Letter of Authorization to refer to this DMF is included in the NDA or ANDA and in the 
DMF itself.44 
 
A single DMF may have multiple manufacturing sites, and each site should be listed in the 
ANDA or NDA even though the DMF number is the same.  Applicants should clarify which of 
the drug substance manufacturing sites in the DMF will be used to produce drug substance(s) for 
the drug product.  Asking DMF holders, before the ANDA/NDA submission, about any changes 
planned for the near future may lessen the need for late change amendments to the ANDA or 
NDA. 
 
When a DMF is changed, the DMF holder should notify applicants to whom Letters of 
Authorization have been issued.  These applicants should submit the appropriate amendment to 
their application(s) that reference this DMF.  For example, notification of a new manufacturing 
site is generally a major change amendment and can extend the review goal accordingly, 
particularly if an inspection is needed.45  When notified of a new manufacturing site by a DMF 
holder during a review cycle, the applicant should contact the regulatory project manager in 
either OND or OGD and the regulatory business project manager in the Office of Pharmaceutical 
Quality immediately.  
 
B.  Manufacturing Facilities and Processes 
 
All facilities used in the manufacturing, testing, packaging, and labeling of the drug substance(s) 
and the drug product are subject to inspection and should be ready and available for inspection 
before approval to assess compliance with current good manufacturing practice.46 
 
44
 See 21 CFR 314.420 for additional information on referencing DMFs. 
 
45
 See 21 CFR 314.60(b).  See also section III.B.1., Amendments: Before Final Marketing Approval Request, and 
21 CFR 314.70(b). 
46
 
 See 21 U.S.C. 351(a)(2)(B), 21 CFR parts 210 and 211.  See also, guidance for industry Q7 Good Manufacturing 
Practice Guidance for Active Pharmaceutical Ingredients (September 2016). 
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The process activities, including actual protocols, sampling plans, and acceptance criteria as well 
as study outcomes, will be evaluated during a current good manufacturing practice inspection.  
Process validation should be complete before the release of the drug product intended for 
distribution.  Applicants should refer to the guidance for industry Process Validation: General 
Principles and Practices (January 2011).  
 
C.  Drug Substance Issues 
 
Scientific issues related to controls and impurities may arise during FDA review of ARV drug 
product submissions intended to be eligible for procurement under PEPFAR.  Applicants should 
refer to cited guidances in this section for additional details on FDAs current thinking. 
 
1.  Controls 
 
If the drug substance is poorly soluble or is a small percentage of the drug product weight, 
applicants should consider drug substance particle size control, according to the 
recommendations described in the guidance for industry Q6A Specifications:  Test Procedures 
and Acceptance Criteria for New Drug Substances and New Drug Products:  Chemical 
Substances (December 2000).  If the drug substance can exist in different solid-state 
polymorphic forms, additional controls may be appropriate.  
 
2.  Impurities 
 
Batch analyses for at least three lots of drug substance produced by the same process that is to be 
used for the material used for the exhibit batch of drug product should be included in the DMF, 
NDA, or ANDA.  If impurities exceed the recommended qualification thresholds on drug 
substance as described by the guidance for industry Q3A(R2) Impurities in New Drug Substances 
(June 2008), additional toxicological justification may be appropriate.  If impurities are below 
the recommended Q3A(R2) qualification thresholds, there is no need for toxicological 
qualification unless the structure suggests unusual toxicology (e.g., there is a genotoxic 
substructure).  If the residual solvents or elemental impurities in the drug substance exceed the 
recommendations in the guidances for industry Q3C Impurities: Residual Solvents (December 
1997) and Q3D(R2) Elemental Impurities (September 2022), additional toxicological 
justification may be appropriate. 
 
D.  Drug Product Issues 
 
This section describes scientific issues regarding the drug product that may arise during FDA 
review of ARV drug product submissions intended to be eligible for procurement under 
PEPFAR.  For more information on pharmaceutical development, applicants should refer to the 
guidance for industry Q8(R2) Pharmaceutical Development (November 2009). 
 
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1.  Controls and Impurities 
 
Drug products should be formulated using excipients that meet internationally recognized 
compendial standards.  Information should be provided to support the safety of each excipient, 
particularly those derived from animals.  Applicants should justify the use of novel excipients, 
using animal toxicity data if necessary.47 
 
Identification of an impurity is not needed if the guidance for industry Q3B(R2) Impurities in 
New Drug Products (August 2006) identification threshold recommendation is not exceeded.  
For an FC ARV drug product, in general, the amount of an unknown peak should be calculated 
as a percentage of the smallest active peak.  
 
2.  Water Content 
 
Given the likely exposure to high humidity in countries supported by PEPFAR, applicants should 
provide a water content specification, or a justification for not providing such a specification, for 
solid oral dosage forms.   
 
3.  Markings and Labeling 
 
There are now a significant number of tentatively approved or approved drug products eligible 
for procurement under PEPFAR and prequalified by WHO, and FDA expects drug products to 
be marked and labeled so that they can be identified by medical professionals.  Each dosage unit 
should be marked so that it can be readily identified, and different drugs from the same 
manufacturer should have distinct labeling.   
 
4.  Scored Tablets 
 
If tablets are scored, testing should be performed to show that split tablets are suitable for their 
intended purpose.  More information can be found in the guidance for industry Tablet Scoring: 
Nomenclature, Labeling, and Data for Evaluation (March 2013) (Tablet Scoring guidance).  An 
applicant submitting a change amendment48 to a tentatively approved application should also 
refer to the Tablet Scoring guidance.     
 
Some RLD tablets are scored but would not be considered functionally scored tablets as 
described in the Tablet Scoring guidance.  In these situations, versions of these ARV tablets 
eligible for procurement under PEPFAR should also be manufactured with a score.  However, to 
support labeling claims for splitting these ARV tablets, the tablets should contain appropriate 
information for functional scoring.  The Tablet Scoring guidance recommends a 90-day stability 
study for split tablets stored in pharmacy dispensing containers (no seal/no desiccant) for a 
period of 90 days at 25oC/60 percent relative humidity (RH).  However, for ARV drugs products 
 
47
 See the guidance for industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (May 
2005). 
 
48
 See 21 CFR 314.60(b).  See also section III.B.1., Amendments: Before Final Marketing Approval Request, and 
21 CFR 314.70(b). 
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intended for use under PEPFAR, such testing should instead occur at 30C/75 percent RH 
because of the conditions that may be encountered in climatic zones III and IV.49  
 
5.  Tablets Intended for Dispersion in Water or Other Liquids 
 
If the labeling indicates that the tablet may be dispersed in water or other liquids, appropriate 
testing should demonstrate that dispersion is feasible for this specific drug product.  The 
following information should be included in the application: 
 
  Information on how quickly the tablet breaks up in water or other liquids (e.g., typically, 
2 teaspoons (10 milliliters) per tablet)  
 
  Appropriate controls on process parameters, in-process tests, or specifications to ensure 
that the tablet will break up in water in a reasonably quick fashion  
 
  Short-term stability data to show that the active ingredient is chemically stable when 
dispersed in water or the other liquids (e.g., to support a statement to drink the mixture 
within a certain time frame) 
 
6.  Packaging 
 
In most cases, FDA recommends child-resistant packaging although such a decision should be 
made after consultation with procuring organizations (e.g., U.S. Agency for International 
Development, U.S. Department of States Office of Global AIDS Coordinator and Health 
Diplomacy) keeping in mind the local laws of the country where the drug product is to be used.   
 
Some applicants have expressed a preference for demonstrating the stability of their drug 
products in non-child-resistant packaging, such as in bottles and blisters that applicants believe 
are acceptable to the regulatory authorities of the PEPFAR-supported recipient countries.  FDA 
believes that issues related to special packaging (e.g., child-resistant, senior-friendly) are best 
approached in the context of the PEPFAR-supported recipient countrys regulations and 
prescribing practices; accordingly, it may be appropriate to grant a tentative approval with this 
type of packaging.  However, when patents and/or exclusivities expire for the referenced drug 
products, applications for final marketing approval in the United States must comply with all 
final approval requirements, including relevant U.S. packaging and labeling regulations.50    
 
Applicants should refer to the guidances for industry Container Closure Systems for Packaging 
Human Drugs and Biologics (May 1999) and Container Closure Systems for Packaging Human 
Drugs and Biologics  Questions and Answers (May 2002) for recommendations on the 
information needed for the container closure systems.51  FDA anticipates that procurement 
 
49
 See the International Council for Harmonisation (ICH) guidance for industry Q1A(R2) Stability Testing of New 
Drug Substance and Products (November 2003). 
 
50
 See footnote 30.  
 
51
 See also MAPP 5015.5 Rev. 1 CMC Reviews of Type III DMFs for Packaging Materials.   
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organizations, applicants, and regulatory authorities will cooperate to share information on the 
equivalence of container closure system protection.   
 
The shelf-life specification should be the same for all packaging configurations.  Different 
packaging configurations may have different expiration dating periods to ensure that the drug 
product meets the specification throughout its shelf life.  It is acceptable to have a tighter internal 
release specification, but the regulatory specification applies throughout the approved expiration 
dating period to all packaging configurations. 
 
7.  Stability52 
 
As provided in 21 CFR 314.50(d)(1)(ii)(a), applicants must demonstrate the stability of the drug 
product.  Generally, this includes accelerated and long-term stability data; the application should 
include stability data obtained from the drug product in the commercial packaging.  
 
8.  Stability Storage Conditions 
 
Drug products distributed under PEPFAR are likely to be used in several countries with hot and 
dry or hot and humid conditions (climatic zones III and IV).53  Given the conditions that may be 
encountered during distribution and storage under programs such as PEPFAR, applicants should 
generate data on the stability of their drug products under the conditions specified by regulatory 
authorities in the recipient countries and WHO.   
 
At present, long-term studies at 30C/75 percent RH and 6-month accelerated studies at 40C/75 
percent RH will cover use and registration in all climatic zones.  If the data obtained at 30C/75 
percent RH are satisfactory, data obtained at 25C/60 percent RH are not generally needed.   
 
FDA recommends in-use stability studies for ARV drug products containing amorphous 
dispersions (e.g., products containing ritonavir) and/or tenofovir prodrugs (e.g., products 
containing tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)).  These ARV 
drug products have a sensitivity to moisture, and studies could support bottles that are intended 
to be dispensed to patients and then opened daily for 90 days or 180 days.  By combining results 
from long-term and in-use stability studies at 30C/75 percent RH, applicants can predict the 
amount of a particular degradant by summing the following values: 
 
  The amount of degradant present in freshly manufactured drug product 
 
 
 
52
 For more information, see the guidances for industry ANDAs: Stability Testing of Drug Substances and Products 
(June 2013) and ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers (May 2014) 
and the ICH guidances for industry Q1A(R2) Stability Testing of New Drug Substance and Products and Q1C 
Stability Testing for New Dosage Forms (November 1996). 
 
53
 Deitz, R, K Feilner, F Gerst, and W Grimm, 1993, Drug Stability Testing  Classification of Countries 
According to Climatic Zone, Drugs Made in Ger, 36:99103. 
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  The amount of degradant likely to be formed as the sealed bottle sits in storage (rate of 
degradation (percent degradation per month) times expiration dating period (in months)) 
 
  The amount of degradant that is formed during the in-use study 
 
The amount of degradation (or reduction in assay) predicted at the end of expiration can be 
compared to the acceptance criteria for stability.  Depending on the outcome of these studies, it 
may be appropriate to tighten the release acceptance criteria for major degradants (or assay) to 
ensure that the acceptance criteria for stability are met.  If desiccant is included in the bottle and 
retained during the in-use study, FDA in general would recommend a labeling statement such as, 
Store and dispense in original bottle, protect from moisture, and keep bottle tightly closed.  Do 
not remove desiccant. for NDAs for ARV drug products eligible for procurement under 
PEPFAR. 
 
FDA recommends a storage labeling statement such as Store below 30C (86F) for NDAs for 
ARV drug products eligible for procurement under PEPFAR if supported by data obtained at 
30C/75 percent RH.  In general, ANDAs for ARV drug products eligible for procurement under 
PEPFAR will follow storage recommendations for the RLD. 
 
These recommendations apply to the drug product.  Because the drug substance is generally held 
at more controlled conditions (e.g., at the manufacturing site) it is typically tested under less 
stressful conditions (e.g., 25C/60 percent RH). 
 
9.  Amount of Stability Data 
 
Currently, FDA recommends that at least 6 months of stability data obtained under long-term 
(e.g., 30C/75 percent RH) and accelerated (e.g., 40C/75 percent RH) conditions be submitted 
with the initial application.  These data should be obtained for at least three batches of drug 
product manufactured by a process representative of the intended commercial process.54  At least 
two of these batches should be a minimum of 10 percent of the intended commercial scale, 
unless otherwise justified.  When appropriate, the design of stability studies can incorporate 
bracketing and matrixing.55  Additional stability data may be requested by FDA during the 
review cycle.  If a 24-month expiration date is desired, 12 months of stability data should be 
submitted by the middle of the review cycle. 
 
10.  Assessment of Stability Data 
 
Assessment of stability should include assaying each active ingredient to meet acceptance 
criteria of 90 to 110 percent of labeled strength, determining individual and total impurity levels, 
 
54
 See the guidances for industry ANDAs: Stability Testing of Drug Substances and Products and ANDAs: Stability 
Testing of Drug Substances and Products, Questions and Answers and the ICH guidances for industry Q1A(R2) 
Stability Testing of New Drug Substance and Products and Q1C Stability Testing for New Dosage Forms. 
 
55
 See the ICH guidance for industry Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug 
Substance and Products (January 2003). 
 
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and measuring dissolution rates.  Applicants should submit data on moisture uptake in the dosage 
form, which is important if the drug product is to be packaged in polymer/foil blisters that are not 
as impervious to moisture as high-density polyethylene bottles or foil/foil blisters.   
 
11.  Expiration Dating Period 
 
Applicants should provide justification of the proposed expiration dating period based on actual 
stability data for the drug product in the application, supportive stability data for pilot batches or 
similar drug products, qualitative or statistical analysis of trends, etc.  Applicants should include 
sufficient time points on the stability protocol to cover any anticipated future extension of 
expiration.  To facilitate the effective delivery of drug products distributed outside of the U.S. 
under PEPFAR, FDA encourages applicants to extend the expiration dating period to 36 or 48 
months, once sufficient supporting stability data have been acquired.  An applicant could 
acknowledge its commitment to submit amendments after tentative approval for extension of 
expiration in a timely manner by including a statement in the original application (section 
3.2.P.8.2, Postapproval Stability Protocol and Stability Commitment, of the common technical 
document is recommended).  Once sufficient stability data have been obtained (typically 24 or 
36 months of data), FDA encourages applicants to submit an amendment after tentative approval 
to extend the expiration.  Applicants should include the wording Priority Review Requested in 
the submission and the cover letter and should not include other changes in the expiration-
extension amendment.  See section VI. E., CMC Changes After a Tentative Approval, for 
recommended approaches to extending the expiration dating period. 
 
E.  CMC Changes After a Tentative Approval 
 
This section addresses some of the common CMC changes after tentative approval of ARV drug 
products eligible for procurement under PEPFAR. 
 
1.  Addition of a New Drug Substance Manufacturer or Manufacturing Site, Drug 
Product Manufacturer, or Manufacturing Site or Testing Site 
 
A new manufacturer (supplier) of the drug substance should be submitted as a major change 
amendment.  A new manufacturing site for an existing manufacturer that has not been previously 
inspected by FDA should also be submitted as a major change amendment.  In contrast, a new 
manufacturing site for an existing manufacturer that has been previously inspected by FDA 
should be submitted as a moderate change amendment.  An inspection may take place, even if 
previously inspected, depending on review of the submission.  Note that the manufacturing 
process needs to be validated at the new manufacturing site, regardless of previous 
manufacturing experience at other sites.  A Letter of Authorization to allow an applicant to 
reference the DMF should be submitted to the DMF, with copies submitted to the relevant 
application(s).   
 
2.  Extension of Expiration Dating Period 
 
Depending on the data available to justify the extension, the two following approaches are 
examples of what may be appropriate:  
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a.  Submitting a major change amendment proposing to extend the expiration dating period 
for the drug product on the basis of real-time data plus extrapolation using acceptable 
statistical methods,56 for example, extrapolating to a 36-month expiration dating period 
based on statistical analysis of 24-month stability data on the original three registration 
batches. 
 
b.  Proposing extension of the expiration dating period through a minor change amendment 
based on real-time stability data from pilot-scale or larger/commercial-scale batches 
following the acceptable stability protocol for an application that has already received a 
tentative approval action, for example, proposing a 36-month expiration dating period 
based on 36-month stability data on the original three registration batches. 
 
3.  Changes in Excipient Specifications 
 
Applicants should submit a change made to comply with U.S. Pharmacopeia/National Formulary 
(USP/NF) that adds a new test or tightens existing acceptance criteria in an excipient 
specification in a minor change amendment.  Applicants should submit deletions of tests or 
relaxation of limits as a moderate change amendment if the relaxation or deletion is in 
compliance with an updated USP/NF monograph.  Applicants should submit other deletion of 
tests or relaxations of limits as major change amendments. 
 
4.  Changes to the Stability Testing Program 
 
Applicants should submit any changes to the stability testing protocol after tentative approval as 
major change amendments, except the addition of time points or deletion of time points beyond 
the approved expiration dating period, which may be submitted as a minor change amendment.  
 
 
VII.  LABELING AND PRESCRIBING INFORMATION 
 
ARV drug products eligible for procurement under PEPFAR must comply with all applicable 
labeling requirements.57  This section highlights certain labeling considerations specific to ARV 
drug products eligible for procurement under PEPFAR.  For pediatric dosage forms, the 
proposed labeling for the drug product should provide clear instructions so that the patients 
caregiver can administer the appropriate dose of the drug product.58  In some cases, it may be 
appropriate for written and pictorial Instructions for Use intended for caregivers to be included in 
the prescribing information.59 
 
56
 See the ICH guidance for industry Q1E Evaluation of Stability Data (June 2004). 
 
57
 See generally section 502 of the FD&C Act; 21 CFR part 201, Labeling.  
 
58
 See, for example, 21 CFR 201.57(c)(9)(iv) and 201.80(f)(9). 
 
59
 See the guidance for industry Instructions for Use  Patient Labeling for Human Prescription Drug and 
Biological Products  Content and Format (July 2022). 
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The inclusion of product-identifying information (e.g., National Drug Code (NDC) numbers), if 
relevant, on the labeling (e.g., container labels, carton labeling, prescribing information) of 
tentatively approved drug products eligible for procurement under PEPFAR can assist with drug 
product differentiation.  . 
 
For tentatively approved 505(b)(2) NDA drug products eligible for procurement under PEPFAR, 
it is not necessary to revise the product labeling whenever there are minor updates in the labeling 
for the listed drug(s) (on which the 505(b)(2) NDA relied upon for safety and efficacy).  
Applicants must submit updated labeling amendments for the drug products if the following 
scenarios apply (21 CFR 201.57(a)(5)):  
 
  When submitting a chemistry change amendment that affects the labeling 
 
  There is a significant update in the labeling for the listed drug(s) on which the 505(b)(2) 
NDA relied upon for safety and efficacy (e.g., new information for Limitations of Use, 
the BOXED WARNING section, the DOSAGE FORMS AND STRENGTHS section, the 
CONTRAINDICATIONS section, or the WARNINGS AND PRECAUTIONS section 
that is applicable to the ARV drug product eligible for procurement under PEPFAR).  
 
For tentatively approved 505(j) ANDA drug products eligible for procurement under PEPFAR, 
labeling must be the same as the last approved labeling for the RLD, except for differences as 
provided for in section 505(j)(2)(v) of the FD&C Act and 21 CFR 314.94(a)(8)(iv) .   
 
 
VIII.  OTHER REGULATORY CONSIDERATIONS 
 
This section briefly discusses other considerations for ARV drug products intended to be eligible 
for procurement under PEPFAR.   
 
A.  User Fees 
 
1.  NDAs 
  
By law, FDA must assess a user fee on human drug applications and an annual prescription drug 
program fee, subject to certain exceptions.60  However, the law provides that under certain 
circumstances FDA can grant a waiver or reduction in fees.61  Potential waivers for ARV drug 
products eligible for procurement under PEPFAR (for NDAs but not ANDAs) are addressed in 
the draft guidance for industry PDUFA Waivers, Reductions, and Refunds for Fixed-
Combinations and Single-Entity Versions of Previously Approved Antiretrovirals under 
 
60
 Section 736(a) of the FD&C Act; 21 U.S.C. 379h(a). The application fee is the most significant of the fees. 
Application reviews do not begin until user fees are paid.   
 
61
 Section 735(d) of the FD&C Act. 
 
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PEPFAR.62  Drug products that are included in the list of needed ARV drug products63 on the 
FDAs PEPFAR database64 may be considered for potential NDA user fee waivers as 
appropriate.   
 
2.  ANDAs 
 
For ANDAs, application and facility fees are assessed according to the Generic Drugs User Fee 
Act (GDUFA).  Applicants should refer to information found on the FDAs Generic Drug User 
Fee Amendments web page available at https://www.fda.gov/industry/fda-user-fee-
programs/generic-drug-user-fee-amendments for additional information on fee structure and 
amounts.   
 
B.  Pediatric Requirements 
 
The Pediatric Research Equity Act (PREA)65 requires that any NDA66 or BLA, or supplement to 
such application, for a new active ingredient, new indication, new dosage form, new dosing 
regimen, or new route of administration contain pediatric assessments, unless the requirement is 
waived, deferred, or inapplicable.  Such assessments shall contain data, gathered using 
appropriate formulations for each age group for which the assessment is required, that are 
adequate (i) to assess the safety and effectiveness of the drug . . . for the claimed indications in 
all relevant pediatric subpopulations; and (ii) to support dosing and administration for each 
pediatric subpopulation for which the drug . . . is safe and effective.67  Pediatric studies may be 
deferred if (1) the drug product is ready for approval for use in adults before pediatric studies are 
complete, (2) additional safety or effectiveness data need to be collected, or (3) there is another 
appropriate reason for the deferral; and if the applicant submits required information68 to support 
the deferral.69  Pediatric studies will be waived if (1) the studies are impossible or highly 
 
62
 When final, this guidance will represent the FDAs current thinking on this topic.   
 
63
 The separate list of ARV drug products, Antiretroviral Drug Products Needed for Use Under PEPFAR, can be 
found under question 6, What PEPFAR products can companies submit for FDA review?, at FDAs PEPFAR 
Database on the Frequently Asked Questions web page available at https://www.fda.gov/international-
programs/presidents-emergency-plan-aids-relief-pepfar/pepfar-database-frequently-asked-questions.  This list is 
revised periodically to address current public health needs. 
 
64
 The FDAs PEPFAR database is available at 
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=pepfar.page. 
 
65
 Public Law 108-155 (2003), codified at section 505B of the FD&C Act (21 U.S.C. 355c).  Although section 505B 
has been amended since the passage of PREA, by convention, that section is often referred to as PREA, and we 
adopt that convention in this guidance. 
 
66 PREA does not apply to drug products submitted in an ANDA under section 505(j) of the FD&C Act. 
 
67
 21 U.S.C. 355c(a)(2)(A). 
 
68
 Described in 21 U.S.C. 355c(a)(4)(A)(ii). 
 
69
 See 21 U.S.C. 355c(a)(4)(A). See also 21 U.S.C. 355c(a)(4)(C) and (D).  
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impracticable, (2) there is evidence strongly suggesting that the drug product would be 
ineffective or unsafe in all pediatric age groups, or (3) the drug product does not represent a 
meaningful therapeutic benefit over existing therapies and is not likely to be used in a substantial 
number of pediatric patients.70  In certain cases, as appropriate, FDA will grant a partial waiver 
with respect to a specific pediatric age group(s).71   
 
PREA, as described above, applies to NDAs for ARV drug products eligible for procurement 
under PEPFAR.  Generally, most ARV drug products indicated for pediatric populations are 
labeled by weight-band dosing, and DAV recommends designing the PREA assessments 
accordingly.  For some SE or FC ARV drug products submitted under section 505(b)(2) of the 
FD&C Act, available information for the reference drug product may provide sufficient 
information to support pediatric use for at least some part of the pediatric population.  For ARV 
drug products not intended for use in specific pediatric age (or weight) groups, FDA encourages 
applicants to contact DAV about the possibility of a waiver or deferral.    
 
Submission of NDAs for ARV drug products discussed in this guidance are usually not preceded 
by end-of-phase 2 meetings or pre-NDA meetings.  Sometimes, sponsors seek pre-
investigational new drug application (pre-IND) advice regarding design of relative 
bioavailability studies.  Sponsors seeking pre-IND advice should consider providing an initial 
pediatric study plan (iPSP) at that time.72  A sponsor that has not met with FDA or sought advice 
before submission of an application should provide an iPSP, submitted to a pre-IND, to DAV 
when the sponsor submits a request for a user fee waiver.   
 
C.  Adverse Event Reporting 
 
For approved ANDAs or NDAs, applicants must comply with adverse event reporting 
requirements (i.e., reports of serious and unexpected adverse events within 15 days of receipt of 
the information by the applicant or its affiliates).73  For tentatively approved ARV drug products 
to be distributed in PEPFAR-partner countries, a system of collecting and reporting adverse drug 
events by the distributor is encouraged (e.g., through governmental or nongovernmental agencies 
distributing the drug products).   
 
 
70
 See 21 U.S.C. 355c(a)(5)(A). See also 21 U.S.C. 355c(a)(4)(C) and (D). 
 
71
 See 21 U.S.C. 355c(a)(5)(B). 
 
72
 For more information on iPSPs, see the guidance for industry Pediatric Study Plans:  Content of and Process for 
Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans (July 2020). 
 
73
 21 CFR 314.80 and 314.81. 
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