Compounding Certain 
Ibuprofen Oral Suspension 
Products Under Section 
503B of the Federal Food, 
Drug, and Cosmetic Act 
 
 
This guidance is for immediate implementation.
 
 
FDA is issuing this guidance for immediate implementation in accordance with 21 CFR 
10.115(g)(2).  Comments may be submitted at any time for Agency consideration.  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 document, contact (CDER) Office of Compounding Quality and 
Compliance, 301-796-3400. 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
April 2023 
Compounding 
 
Revision 2 
 
    
Compounding Certain 
Ibuprofen Oral Suspension 
Products Under Section 
503B of the Federal Food, 
Drug, and Cosmetic Act 
 
 
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 
Office of Policy 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
April 2023 
Compounding 
 
Revision 2
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DISCUSSION .................................................................................................................... 4 
 
i  Contains Nonbinding Recommendations 
 
Compounding Certain Ibuprofen Oral Suspension Products Under 
Section 503B of the Federal Food, Drug, and Cosmetic Act 
Immediately in Effect Guidance for Industry1 
 
 
This guidance represents 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 office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
This guidance describes the Food and Drug Administrations (FDA or the Agency) regulatory 
and enforcement priorities regarding the compounding of certain ibuprofen oral suspension 
products by outsourcing facilities to provide to: 1) hospitals and health systems for 
administration within the hospital or health system and/or 2) State-licensed pharmacies 
(including those within hospitals and health systems2), and applicable Federal facilities, to 
dispense to patients for use at home after receiving a valid, patient-specific prescription.  The 
United States is currently experiencing a significant number of infections involving three viruses: 
Coronavirus Disease 2019 (COVID-19), respiratory syncytial virus (RSV), and influenza.  Each 
of these viruses may produce fever in young children.  FDA has received reports related to 
increased demand for pediatric fever-reducing medications, including ibuprofen oral suspension 
products.  Further, FDA has received a number of reports related to hospitals, health systems, 
and State-licensed pharmacies experiencing challenges with obtaining these medications to use 
for fever and pain treatment of pediatric patients as well as for adults who are unable to swallow 
solid oral dosage forms (e.g., persons with feeding tubes) due, for example, to regional 
disparities in infection rates, distribution of resources, or other regional conditions that may 
evolve quickly during the winter months when the incidence of respiratory infections is expected 
to peak.  This guidance revises and replaces the guidance for industry called Compounding 
Certain Ibuprofen Oral Suspension Products Under Section 503B of the Federal Food, Drug, 
and Cosmetic Act that was issued on January 20, 2023.  FDA is continually assessing the needs 
and circumstances related to the temporary policy set forth in this guidance, and as relevant 
 
1 This guidance has been prepared by multiple offices in the Center for Drug Evaluation and Research, in 
consultation with the Office of Regulatory Affairs, at the Food and Drug Administration.  
2 For the purposes of this guidance, the term health system means an organization that includes at least one hospital 
and at least one group of physicians that provides comprehensive care (including primary and specialty care) who 
are connected with each other and with the hospital through common ownership or joint management.  See the 
Agency for Healthcare Research and Qualitys web page Compendium of U.S. Health Systems, 2021, available at 
https://www.ahrq.gov/chsp/data-resources/compendium.html.  
  1  Contains Nonbinding Recommendations 
 
needs and circumstances evolve, FDA intends to update, modify, or withdraw this policy as 
appropriate.3  
 
This guidance is being implemented without prior public comment because FDA has determined 
that prior public participation for this guidance is not feasible or appropriate (see section 
701(h)(1)(C) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 
10.115(g)(2)).  This guidance document is being implemented immediately to bolster access to 
ibuprofen oral suspension products compounded by outsourcing facilities and provided to 
hospitals, health systems, State-licensed pharmacies, and applicable Federal facilities during the 
current surge in respiratory infections, but it remains subject to comment in accordance with the 
Agencys good guidance practices. 
 
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.  
 
II.  BACKGROUND 
 
FDA is aware of reports from hospitals, health systems, and State-licensed pharmacies that they 
have experienced difficulties obtaining certain FDA-approved ibuprofen oral suspension drug 
products used for fever and pain treatment of pediatric patients and adults who are unable to 
swallow solid oral dosage forms.4  FDA is closely monitoring this situation and using all of its 
applicable authorities to work with the manufacturers of approved ibuprofen oral suspension 
drug products to increase supply.  However, we recognize that hospitals, health systems, State-
licensed pharmacies, and applicable Federal facilities have concerns about assuring access to 
these drug products to use for fever and pain treatment of pediatric patients, and adults who are 
unable to swallow solid oral dosage form products, during the winter months when respiratory 
illnesses are likely to be elevated.  Therefore, FDA is issuing this policy to provide temporary 
flexibility to help ensure that treatment options are available when hospitals, health systems, 
State-licensed pharmacies, and applicable Federal facilities are unable to obtain ibuprofen oral 
suspension drug products to use for fever and pain treatment of pediatric patients and adults who 
are unable to swallow solid oral dosage form products.  This guidance addresses ibuprofen oral 
suspension products compounded by outsourcing facilities and provided to: 1) hospitals and 
health systems for administration within the hospital or health-system; 2) State-licensed 
pharmacies (including those within hospitals and health systems), and applicable Federal 
facilities to dispense to patients for use at home after receiving a valid, patient-specific 
prescription.  Fever and pain reducing oral suspension products are needed in the hospital and 
 
3 FDA understands that outsourcing facilities that compound ibuprofen oral suspension products under the 
temporary policy in this guidance, in response to the urgent public health need, will do so without being able to fully 
anticipate when circumstances related to this temporary policy may evolve to a point where the temporary policy is 
no longer appropriate.  Therefore, FDA intends to publish a Federal Register notice that provides at least 60-days 
notice before the withdrawal of this guidance takes effect.  
4 FDA has received reports related to hospitals, health systems, and State-licensed pharmacies also experiencing 
challenges with obtaining acetaminophen oral suspension products, which also reduce fever and treat pain. FDA is 
not addressing acetaminophen oral suspensions at this time to allow time for the review of additional considerations. 
  2  Contains Nonbinding Recommendations 
 
health system setting to treat patients with acute needs and also in the home setting for 
appropriate treatment of children as well as for adults who are unable to swallow solid oral 
dosage forms.5  The availability of ibuprofen oral suspensions for use in homes may help to 
prevent patients from seeking care in hospitals and health systems when such care is not 
otherwise needed, which could cause unnecessary strain on hospitals and health systems.   
 
Fever and pain reducing oral suspensions, such as ibuprofen oral suspensions, are important in 
the management of pediatric patients who may require more specific weight-based dosing and 
adult patients who cannot swallow solid oral dosage form products.  Fever can make patients 
uncomfortable and is associated with increased metabolic rate, oxygen consumption, carbon 
dioxide production, and demands on the cardiovascular and pulmonary systems.  In certain 
vulnerable populations, untreated high fever could lead to potentially serious or life-threatening 
situations.   
 
Although compounded drugs can serve an important patient need, they can also pose a higher 
risk to patients than FDA-approved drugs.  Compounded drug products are not FDA-approved, 
which means they have not undergone FDA premarket review for safety, effectiveness, and 
quality.  Because compounded drug products are subject to a lower regulatory standard, the 
agency recommends FDA-approved drugs be used to treat patients whenever possible. 
 
Additionally, in 2022 and 2023, FDA received reports of pediatric medication contaminated with 
diethylene glycol (DEG) and ethylene glycol (EG) in several countries.6 DEG and EG are toxic 
 
5 Unlike the version of this guidance that was issued in January 2023, which was limited to administration of 
compounded ibuprofen oral suspension products within hospitals and health systems, this guidance also addresses 
the use of compounded ibuprofen oral suspension products in home settings.  In home settings, special packaging, 
such as child-resistant packaging, is generally required for ibuprofen products intended for oral administration.  See 
16 CFR 1700.14(a)(20).  The Poison Prevention Packaging Act (PPPA) was enacted in 1970 to protect children 
(under 5 years of age) from unintentional exposure to household substances including food, drugs, and cosmetics in 
order to prevent poisonings and deaths that can occur when children access the contents of containers with 
hazardous products.  The regulations implementing the PPPA list special packaging standards (e.g., child-resistant 
packaging) for a wide range of household products, including most oral prescription drug products and many 
nonprescription drug products.  See Poison Prevention Packaging Act of 1970 (PPPA), (Pub. L. 91-601, 84 Stat. 
1670-74), enacted December 30, 1970.   
6 FDA has received and continues to receive reports about fatal DEG poisoning of consumers who ingested 
medicinal syrups, such as cough syrup or acetaminophen syrup, that were manufactured with DEG-contaminated 
glycerin.  Recently (January 23, 2023), the WHO announced that countries have reported several incidents of over-
the-counter cough syrups for children with confirmed or suspected contamination with high levels DEG and EG.  
According to the WHO, the cases are from at least seven countries, are associated with more than 300 fatalities, and 
most involve children under the age of five.  See WHO urges action to protect children from contaminated 
medicines, World Health Organization, Jan. 23, 2023, available at https://www.who.int/news/item/23-01-2023-who-
urges-action-to-protect-children-from-contaminated-medicines. The WHO has issued three global medical alerts 
addressing these incidents focused on the outbreak in the Gambia (Oct. 5, 2023), Indonesia (Nov. 6, 2023), and 
Uzbekistan (Jan. 11, 2023).  See Medical Product Alert N6/2022: Substandard (contaminated) paediatric 
medicines, World Health Organization, Oct. 5, 2022, available at https://www.who.int/news/item/05-10-2022-
medical-product-alert-n-6-2022-substandard-(contaminated)-paediatric-medicines; Medical Product Alert N7/2022: 
Substandard (contaminated) paediatric liquid dosage medicines, World Health Organization, Nov. 2, 2022, 
available at https://www.who.int/news/item/02-11-2022-medical-product-alert-n-7-2022-substandard-
(contaminated)-paediatric-liquid-dosage-medicines; and Medical Product Alert N1/2023: Substandard 
(contaminated) liquid dosage medicines, World Health Organization, Jan. 11, 2023, available at 
 
  3  Contains Nonbinding Recommendations 
 
to humans when consumed and can be fatal.  Toxic effects can include abdominal pain, 
vomiting, diarrhea, inability to pass urine, headache, altered mental state, and acute kidney injury 
which may lead to death.  Although none of the 2022 reports were regarding products in the 
United States, DEG and EG contamination has been identified in past reports in the United States 
and remains a significant quality consideration for oral suspensions compounded using 
components at higher risk of contamination with DEG and EG.  
 
The policies in this guidance are intended to balance access concerns with risks associated with 
compounded drug products and particularly with compounded oral suspension products.   
 
III.  DISCUSSION     
 
Although FDA is monitoring the global pharmaceutical supply chain and working, within its 
authorities, with manufacturers of approved ibuprofen oral suspension products to bolster supply, 
temporary flexibility is needed to help ensure that treatment options are available to hospitals and 
health systems and children and adults being treated at home during this period of increased 
demand.   
 
Therefore, as a temporary measure, until FDA withdraws or revises this guidance, FDA intends 
to prioritize its regulatory or enforcement action for compounding by outsourcing facilities of an 
ibuprofen oral suspension product (100 mg/5 mL) that is essentially a copy of an FDA-approved 
drug product;7 or that uses a bulk drug substance that does not comply with section 
503B(a)(2)(A) of the FD&C Act;8 or that does not meet specific Current Good Manufacturing 
Practice (CGMP) requirements with regard to the establishment of an initial expiration date 
through product stability testing,9 to focus on the potential for harm to the public health.  In 
doing so, FDA is taking into consideration the need to help ensure that hospitals, health systems, 
State-licensed pharmacies, and applicable Federal facilities have access to certain ibuprofen oral 
suspension products to treat pediatric patients and adults who are unable to swallow solid oral 
dosage forms. 
 
Based on FDAs current understanding of the potential risks associated with compounded 
ibuprofen oral suspensions, outsourcing facilities should take at least the following minimum 
steps to reduce the risks associated with the compounded products.  FDA generally intends to 
prioritize its regulatory and enforcement actions if the following steps are not all followed when 
outsourcing facilities compound ibuprofen oral suspension products:  
 
https://www.who.int/news/item/11-01-2023-medical-product-alert-n-1-2023-substandard-(contaminated)-liquid-
dosage-medicines.  
7 A compounded drug product that is essentially a copy of one or more approved drugs would not meet the condition 
in section 503B(a)(5) of the FD&C Act.  The term essentially a copy is defined for purposes of this provision by 
section 503B(d)(2).  
8 The 503B Bulks List refers to the list of bulk drug substances referenced in section 503B(a)(2)(A)(i) of the 
FD&C Act.  When an outsourcing facility compounds a drug product using a bulk drug substance that is not on the 
503B Bulks List or used to compound a drug on FDAs drug shortage list, the compounded drug product does not 
meet the condition in section 503B(a)(2)(A) of the FD&C Act. 
9 Section 501(a)(2)(B) of the FD&C Act and  211.137 and 211.166, require outsourcing facilities to conduct 
stability studies to support the assignment of appropriate product expiration dates when they begin making a 
compounded product and to ensure the dates are appropriate throughout product expiration.   
  4  Contains Nonbinding Recommendations 
 
 
1.  The ibuprofen oral suspension meets the United States Pharmacopeia (USP) ibuprofen 
oral suspension drug product monograph standard for identity, strength, quality, and 
purity, and is packaged and labeled in accordance with the provisions in the 
monograph.10 One of the critical attributes in the monograph standard is Uniformity of 
Dosage Units.11 
 
2.  The ibuprofen oral suspension product has a concentration of 100 mg/5 mL. 
 
3.  Bulk drug substances that the outsourcing facility uses to compound the drug product are 
in compliance with section 503B(a)(2)(B) through (D) of the FD&C Act (21 U.S.C. 
353b(a)(2)(B) through (D)), regarding conformance with applicable United States 
Pharmacopeia (USP) or National Formulary (NF) monograph standards, sourcing from 
facilities registered with FDA under section 510 of the FD&C Act (21 U.S.C. 360), and 
certificates of analysis.   
 
4.  Ingredients other than bulk drug substances (i.e., inactive ingredients) that the 
outsourcing facility uses to compound drug products are in compliance with section 
503B(a)(3) of the FD&C Act, regarding conformance with applicable USP or NF 
monograph standards.   
 
5.  Each shipment of each lot of components is tested for identity and evaluated for 
conformity with appropriate specifications before use in compounding (see  211.84). 
The outsourcing facility only uses components that meet appropriate specifications.12  
 
6.  The outsourcing facility performs a limit test for DEG and EG on all containers of all lots 
of components at higher risk of DEG and EG contamination, due to the serious hazard 
associated with DEG and EG contamination, and only uses components that meet 
appropriate specifications.  Components at higher risk of DEG and EG contamination 
 
10 See sections 501(b) and 502(g) of the FD&C Act. 
11 See USP General Chapter <905> Uniformity of Dosage Units.  We note that in recent years, there was a recall due 
to superpotency of liquid ibuprofen suspension drug products.  See Tris Pharma, Inc Expands Its Voluntary 
Nationwide Retail Recall of Ibuprofen Oral Suspension Drops, USP, 50 mg per 1.25 mL, Due to Higher 
Concentration of Ibuprofen, FDA, January 29, 2019, https://www.fda.gov/safety/recalls-market-withdrawals-safety-
alerts/tris-pharma-inc-expands-its-voluntary-nationwide-retail-recall-ibuprofen-oral-suspension-drops-usp.  
Ensuring uniformity of dose is more difficult in suspensions compared to liquid solutions. For example, there was 
another recall of childrens liquid products in 2010 due to superpotency.  See McNeil Consumer Healthcare 
Announces Voluntary Recall of Certain OTC Infants and Childrens Products, FDA, April 30, 2010, 
http://wayback.archive-
it.org/7993/20170112155136/http://www.fda.gov/Safety/Recalls/ArchiveRecalls/2010/ucm210443.htm. An 
associated Form FDA-483, Inspectional Observations, from an April 2010 inspection at McNeil further describes 
the inspectional issues related to superpotency, https://www.fda.gov/files/about%20fda/published/McNeil-
Consumer-Healthcare--Ft.-Washington--PA-483-issued-4-30-10.pdf.  Process validation is a critical CGMP element 
to ensure that the drug production process consistently produces quality drug product.  See 211.100.  
12 CGMP regulations require the use of validated methods when performing routine testing of components, in-
process material, and finished products (see 21 CFR 211.160, 211.165(e), and 211.194).   
  5  Contains Nonbinding Recommendations 
 
include, but are not limited to, propylene glycol, glycerin, polyethylene glycol, sorbitol 
solution, maltitol solution, and hydrogenated starch hydrolysate.13, 14, 15        
 
7.  The ibuprofen oral suspension formulation contains a level of an antimicrobial 
preservative, based upon scientifically valid literature, that is below a level that may be 
toxic to humans based on the recommended dosage and provides effective microbial 
protection for the duration of the labeled shelf-life.16 Antimicrobial effectiveness testing 
(AET) is conducted once for each formulation and container-closure system on samples 
aged to the proposed beyond-use-date (BUD) or expiration date.  The AET study is 
conducted before the first batch is released.  For the purposes of this guidance, when an 
outsourcing facility uses containers of different sizes, and the materials for the container 
and cap liner are the same, FDA does not expect the outsourcing facility to conduct AET 
studies on more than one container size, provided preservative content testing is 
conducted prior to the release of each batch of drug product, regardless of the container 
size. 
 
8.  The ibuprofen oral suspension formulation is compounded using sterile water that 
complies with a USP sterile water monograph or the outsourcing facility conducts 
specific testing for Burkholderia cepacia complex (BCC) in accordance with USP <60> 
as part of batch release testing.17 
 
9.  The outsourcing facilitys practices regarding stability testing and expiration dates at least 
meet the conditions described in Appendix A to this guidance (Stability/Expiration 
Dating for Compounded Drug Products) and Appendix B to this guidance (Conditions 
Under which FDA Generally Does Not Intend to Take Regulatory Action Regarding 
Stability Testing and Expiration Date Requirements), except that: 
 
a.  The outsourcing facility uses a default BUD of not more than 30 days at room 
temperature when limited stability testing has not been completed before 
release;18 and 
 
13 For additional information, see FDA guidance for industry Testing of Glycerin for Diethylene Glycol (May 2007).  
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. 
14 Reliance on a certificate of analysis from a component supplier, alone, is insufficient to meet CGMP 
requirements, including with regard to component testing under 21 CFR 211.84. 
15 FDAs regulation at 21 CFR 211.84(a) requires testing of each lot of components; 21 CFR 211.84(b) requires that 
a representative sample of each shipment of each lot be collected for testing and describes that the number of 
containers to be sampled shall be based upon appropriate criteria.  Because DEG and EG contamination presents a 
serious hazard, the Agency recommends that the representative sample collected for testing is of each container of 
each lot.   
16 See USP General Chapter <51> Antimicrobial Effectiveness Testing. 
17 This release testing is in addition to microbiological batch release tests such as microbial enumeration (total 
aerobic microbial count, total combined yeasts/molds count) and tests for specified microorganisms (for ibuprofen 
suspension, the specific microorganism is Escherichia coli). 
18 Compare Table 1 in Appendix A: Default BUDs for Nonsterile Drug Products with Aggregate Batch Size  
5,000 Units. 
  6  Contains Nonbinding Recommendations 
 
b.  The outsourcing facility initiates limited stability testing19 when the aggregate 
batch size20 is expected to exceed 5,000 units.21   
 
10. The ibuprofen oral suspension is labeled consistent with section 503B(a)(10)(A)-(B) of 
the FD&C Act and the label on the immediate container22 of the ibuprofen oral 
suspension product, whether used for administration within a hospital or health system or 
for dispensing to patients for use at home, includes statements in bold type to Discard 
by [insert beyond-use-date] and Shake well before using. 
 
11. The ibuprofen oral suspension product is provided: 
 
a.  directly to a hospital or health system for administration within the hospital or 
health system;23 or  
 
b.  directly to a State-licensed pharmacy (including those within hospitals and health 
systems24), or an applicable Federal facility, to dispense to patients for use at 
home after receiving a valid, patient-specific prescription and without 
repackaging by the pharmacy or Federal facility.25     
 
12. For ibuprofen oral suspension products that the outsourcing facility provides for 
dispensing to patients with a valid, patient-specific prescription for use at home, whether 
the product is provided to State-licensed pharmacies, including those within hospitals and 
health systems, or to Federal facilities: 
 
a.  The outsourcing facility packages the ibuprofen oral suspension product in a 
container that holds no more than 120 mL of ibuprofen oral suspension.  
b.  The outsourcing facility ensures that the labeling on the ibuprofen oral suspension 
products immediate container includes the information in Appendix C.  If the 
ibuprofen oral suspension is packaged in a container that is too small to 
 
19 As described in Appendix B. 
20 As used here, consistent with Appendix A, aggregate batch refers to the sum of all units produced from any 
number of batches over the 6-month period for which a drug product report is submitted.  For more information 
about product reports, see the guidance for industry Electronic Drug Product Reporting for Human Drug 
Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act. 
21 As used here, consistent with Appendix A, units are immediate containers (e.g., vial, bottle) for liquid dosage 
forms. 
22 As used in this guidance, immediate container means the container (e.g., bottle) that holds and is in contact with 
the ibuprofen oral suspension.  
23 Administration within the hospital or health system does not include providing units of ibuprofen oral suspension 
to a patient for use outside the hospital or health system, such as a bottle of compounded drug product for use at 
home. 
24 To help reduce risks including microbial contamination and accidental overdosing, FDA recommends that 
hospital and health system pharmacies that seek to dispense compounded ibuprofen oral suspension products to 
patients for use at home do so in containers procured directly from an outsourcing facility, as described in this 
section, that have not undergone any repackaging at the hospital or health system before such dispensing. 
25 For purposes of this guidance, repackaging means taking some or all of the compounded ibuprofen oral 
suspension product from the container in which it was distributed by the outsourcing facility and placing it into a 
different container or container(s) without further manipulating the product. 
  7  Contains Nonbinding Recommendations 
 
reasonably include all of the information in Appendix C (e.g., this may be the 
case for a container that holds 50 mL), the outsourcing facility provides the 
information in Appendix C by another means such as an outer packaging box.  If 
an alternative means of providing the information is used, the immediate 
container label contains, at a minimum, the active ingredient, dosage strength, 
uses, and directions for use, including the dosing chart.26  
 
c.  The outsourcing facility ensures that the ibuprofen oral suspension product 
complies with applicable requirements under the PPPA, such as special 
packaging standards as applicable.27 
 
13. Outsourcing facilities report adverse events associated with the products compounded 
under this enforcement policy consistent with the FDA guidance for industry Adverse 
Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, 
Drug, and Cosmetic Act (October 2015). 
 
 
FDA encourages health care professionals to report adverse events experienced with the use of 
compounded ibuprofen oral suspension products to the outsourcing facilities that produced the 
products as well as to FDAs MedWatch Adverse Event Reporting program: 
  Complete and submit the report online; or 
  Download and complete the form, then submit it via fax at 1-800-FDA-0178.   
 
26 FDA understands that State-licensed pharmacies sometimes provide dosage cups and oral syringes and 
outsourcing facilities may also provide these items.  Because the dosing directions would be expressed in milliliters 
(mL), FDA notes that it is critical that any products, such as dosage cups and oral syringes, that are intended to 
provide calibrated units of liquid measurement are expressed in milliliters (mL) only. 
27 See 16 CFR 1700 for substances requiring special packaging and the relevant packaging standards.  See also 
footnote 6 of this guidance. 
  8  Contains Nonbinding Recommendations 
 
Appendix A: Stability/Expiration Dating for Compounded Drug Products 
 
1.  Stability Program and Beyond-Use Dating 
 
A stability program must be established to assess the stability characteristics of finished drug 
products, and the results of stability testing must be used to determine appropriate storage 
conditions and expiration dates (21 CFR 211.166).  Stability testing is used to ensure that a drug 
product will retain its quality (e.g., strength, appropriate microbial quality) through the labeled 
expiration date.  A stability program for compounded drug products should use previous 
experience, available literature, and fundamental scientific principles to establish the parameters 
for the program.  An expiration date is established through the conduct of a stability program that 
includes testing to assess the products performance against specifications during and after aging 
to the desired expiration date (21 CFR 211.137); the conditions outlined in ICH guidance for 
industry Q1A(R2) Stability Testing of New Drug Substances and Products are recommended. 
  
FDA understands that a compounded drugs batch size may be small and the frequency of batch 
production may vary considerably.  The policies regarding stability testing and expiration dating 
in this guidance recognize these potential aspects of compounded drug production while 
addressing concerns regarding the quality of these products using a risk-based approach. 
 
Taking into account the unique aspects of compounding, FDA generally does not intend to take 
regulatory action against an outsourcing facility for compounding ibuprofen oral suspension 
products according to the circumstances in this guidance, including those in the remainder of this 
section and in Appendix B, such as using a BUD established through limited stability testing in 
lieu of establishing an expiration date through the conduct of a full stability program required 
under part 211 (21 CFR part 211),28 if the compounded drugs BUD does not exceed 
appropriately established expiration or retest-by dates for any of the components used to 
compound the drug.   
 
Whether you use an expiration date or BUD to be used as an expiration date according to the 
provisions outlined below and in Appendix B, the studies below are required to be completed 
before a batch is released (see  211.166 and 211.167).  Each antimicrobial effectiveness testing 
study only needs to be conducted once for each formulation and container-closure system. 
 
  Antimicrobial effectiveness testing for drug products labeled or intended to be multiple 
dose is conducted on samples aged to the proposed BUD or expiration date.  (Note that 
antimicrobial effectiveness testing is container-closure and formulation specific.)29 As 
noted in number 7 in section III above, for purposes of this guidance, when an 
outsourcing facility uses containers of different sizes, and the materials for the container 
and cap liner are the same, FDA does not expect the outsourcing facility to conduct AET 
studies on more than one container size, provided preservative content testing is 
conducted prior to the release of each batch of drug product, regardless of the container 
size. 
 
28 To meet the conditions under section 503B of the FD&C Act, the compounded drug product must be labeled with 
an expiration date (see section 503B(a)(10)(A)(iii)(VI)). 
29 See USP General Chapter <51> Antimicrobial Effectiveness Testing for more information. 
  9  Contains Nonbinding Recommendations 
 
 
2.  Non-sterile limited stability testing 
 
In lieu of conducting full stability studies required under part 211, for small batches (5,000 
units30 in an aggregate batch31), FDA generally does not intend to take regulatory action if the 
relevant default BUD of not more than 30 days at room temperature when limited stability 
testing has not been completed before release, as provided in this guidance, is used for the 
expiration date and the conditions set forth in Appendix B are met.  Alternatively, for small 
batches, FDA generally does not intend to take regulatory action if limited stability testing is 
conducted to support a BUD longer than 30 days at room temperature in accordance with 
Appendix B, and that BUD is used as an expiration date in lieu of conducting full stability 
studies required under part 211.  For larger batches (>5,000 units in an aggregate batch), FDA 
generally does not intend to take regulatory action regarding stability testing if the relevant 
conditions for the limited stability testing outlined in Appendix B are met.  If, at any time during 
a 6-month reporting period, the total number of units compounded exceeds the 5,000-unit limit, 
the conditions applicable to small batches (i.e., 5,000 units) do not apply. 
 
Table 1. BUDs for Non-Sterile Compounded Drug Products, by Aggregate Batch Size 
Aggregate Batch Size  Default BUD (no testing)  BUD Based on Limited 
(over 6-month reporting  Stability Testing 
period) 
5,000 units  Default BUD, which may be  Data-driven stability 
further limited by literature or  program.  See Appendix B 
other scientific information.   for the conditions that must 
See Appendix B for the  be met. 
conditions that must be met. 
>5,000 units  N/A.  Default BUDs are not  Data-driven stability 
applicable to large aggregate  program.  See Appendix B 
batch sizes.  for the conditions that must 
be met. 
   
 
30 Units are immediate containers (e.g., vial, bottle) for liquid dosage forms. 
31 For the purposes of this guidance, batch size has been considered by defining aggregate batch as the sum of all 
units produced from any number of batches over the 6-month period for which a drug product report is submitted.  
For more information about product reports, see the guidance for industry Electronic Drug Product Reporting for 
Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic 
Act. 
  10  Contains Nonbinding Recommendations 
 
Appendix B: Conditions Under which FDA Generally Does Not Intend to Take Regulatory 
Action Regarding Stability Testing and Expiration Date Requirements 
 
Enforcement Policy Regarding the Use of Limited Stability Testing to Assign a BUD 
Stability testing is intended to confirm the stability performance of a compounded drug product 
held under the labeled storage conditions for the duration of the BUD.  Procedures established 
for assessing the stability of drug products compounded by outsourcing facilities must achieve 
the following ( 211.122, 211.160, and 211.166): 
 
  Incorporate stability-indicating test methods that are reliable, meaningful, and specific. 
 
  Evaluate samples of the drug product in the same container-closure system and with the 
same or representative label and adhesive that will be affixed to the container in which 
the drug product is marketed. 
 
  Evaluate samples for stability that are representative of the batch from which they were 
obtained and are stored under suitable conditions. 
 
  Incorporate testing to evaluate antimicrobial effectiveness for drug products labeled or 
intended to be multiple-dose.  If antimicrobial effectiveness has been previously 
established for the formulation and container-closure system, a test for preservative 
content may be used in lieu of a full antimicrobial effectiveness study. 
 
FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
stability testing and expiration date requirements if the outsourcing facility uses the approach 
outlined below describing a number of lots and a set of testswhich should be conducted at lot 
release as part of normal operationsto be performed at the time of the desired BUD.  
 
The following conditions apply: 
 
  Samples are evaluated following aging under the long-term storage conditions (i.e., 
temperature and humidity) in ICH Q1A(R2). 
 
  The data from each time point are evaluated against the established specifications for the 
compounded drug product. 
 
  The BUD is not longer than 12 months. 
 
  If the data for any test fall outside of the established specifications, the BUD is restricted 
to the last time point at which the data remained within specifications. 
 
Because of the possibility that a sample may not meet specifications at the final time point, FDA 
strongly recommends the inclusion of testing at least once at an interim time point.  If the data at 
the final time point do not confirm the stability of the product at the desired BUD (e.g., some 
measurements fall outside of the established specifications), but the data at the interim time point 
  11  Contains Nonbinding Recommendations 
 
are acceptable (i.e., measurements meet the established specifications), a BUD equal to the 
interim time point meets the second condition above. 
 
Under this policy, samples from one lot are tested.  Each unit subjected to one or more tests that 
compromise the integrity of the primary container-closure is only tested at a single time point 
(i.e., not at additional time points).  If a single unit is to be used for multiple discrete tests to 
minimize destructive testing, the unit dosage is subdivided into multiple aliquots that are not held 
longer than the time to complete the testing (typically not longer than 48-72 hours) and the 
aliquots are placed into appropriate testing containers (e.g., high-performance liquid 
chromatography vials or sample tubes) that protect the sample from being compromised (e.g., 
from exposure to air, light, evaporation). 
 
A.  Nondestructive tests 
 
The following test is conducted: 
 
  Appearance. 
 
B.  Destructive chemical tests 
 
The tests to be conducted include: 
 
  pH. 
  Assay.32 
  Appropriate specifications.33 
 
C.  Microbiological tests  
 
The tests to be conducted include: 
 
  Antimicrobial effectiveness testing/preservative content testing at expiry. 
  Microbial enumeration34 (USP General Chapter <61> Microbiological Examination of 
Nonsterile Products: Microbial Enumeration Tests). 
  Test for specified organisms35 (USP General Chapter <62> Microbiological Examination 
of Nonsterile Products: Tests for Specified Microorganisms).36 
 
32 If the API is known (from literature or other scientific information) to have the potential to form genotoxic 
degradants as discussed in ICH guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) 
Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk, the presence of the impurity or impurities 
should be evaluated as part of the assay or, if the assay method is not sufficiently sensitive, using a different test. 
33 For ibuprofen oral suspension products appropriate specifications include the additional tests in the USP 
monograph: Identification, dissolution, uniformity of dosage units, deliverable volume, and impurities. 
34 See, for example, USP General Chapter <1111> Microbiological Examination of Nonsterile Products: Acceptance 
Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use. 
35 See, for example, USP General Chapter <1111> Microbiological Examination of Nonsterile Products: Acceptance 
Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use. 
36 If sterile water is not used, USP General Chapters <60> Microbiological Examination of Nonsterile Products  
Tests for Burkholderia cepacia complex. 
  12  Contains Nonbinding Recommendations 
 
Appendix C: Information for Inclusion on the Labeling of Ibuprofen Oral Suspension 
Products for Dispensing  
 
The following is an example of partial content of the FDA-approved labeling of a childrens 
ibuprofen oral suspension product (100mg/5mL); to label products as described in item 12.b. of 
this guidance, the outsourcing facility would include all of this information on the labeling of the 
ibuprofen oral suspension products immediate container when dispensed to a patient for use at 
home.37, 38 
 
Drug Facts 
 
Active ingredients (in each 5 mL) 
Ibuprofen 100 mg 
 
Purpose (NSAID)* ...... Fever reducer/Pain reliever 
*nonsteroidal anti-inflammatory drug 
 
Uses 
temporarily:  
  reduces fever 
  relieves minor aches and pains due to the common cold, flu, sore throat, headaches, 
and toothaches 
__________________________________________________________________________ 
Warnings 
 
Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to 
aspirin. Symptoms may include: 
  hives 
  facial swelling  
  asthma (wheezing) 
  shock  
  skin reddening  
  rash     
  blisters 
If an allergic reaction occurs, stop use and seek medical help right away. 
 
Stomach bleeding warning: This product contains an NSAID, which may cause severe 
stomach bleeding. The chance is higher if the child: 
 
37 For containers smaller than 120 mL if the container is too small to reasonably permit the inclusion of all of this 
information on the immediate container, the outsourcing facility would provide the information by another means 
such as an outer packaging box.  If an alternative means of providing the information is used, the immediate 
container would contain, at a minimum, the active ingredient, dosage strength, uses, and directions for use, including 
the dosing chart. 
38 To correct a typographical error in the prior version, in Revision 2 of this guidance, the Dosing Chart has been 
revised to reflect 24-35 lb as the weight range associated with the 2-3 year age group.  
  13  Contains Nonbinding Recommendations 
 
  has had stomach ulcers or bleeding problems 
  takes a blood thinning (anticoagulant) or steroid drug 
  takes other drugs containing prescription or nonprescription NSAIDs [aspirin, 
ibuprofen, naproxen, or others] 
  takes more or for a longer time than directed 
 
Heart attack and stroke warning: NSAIDs, except aspirin, increase the risk of heart attack, 
heart failure, and stroke. These can be fatal. The risk is higher if you use more than directed or 
for longer than directed. 
 
Sore throat warning: Severe or persistent sore throat or sore throat accompanied by high 
fever, headache, nausea, and vomiting may be serious. Consult doctor promptly. Do not use 
more than 2 days or administer to children under 3 years of age unless directed by doctor. 
 
Do not use 
  if the child has ever had an allergic reaction to any other pain reliever/fever reducer 
  right before or after heart surgery 
 
Ask a doctor before use if 
  stomach bleeding warning applies to the child 
  child has problems or serious side effects from taking pain relievers or fever reducers 
  child has a history of stomach problems, such as heartburn 
  child has high blood pressure, heart disease, liver cirrhosis, kidney disease, asthma, or 
had a stroke 
  child has not been drinking fluids 
 
Ask a doctor or pharmacist before use if the child is 
  under a doctors care for any serious condition 
  taking any other drug 
 
When using this product  
  take with food or milk if stomach upset occurs 
 
Stop use and ask a doctor if 
  child experiences any of the following signs of stomach bleeding: 
  feels faint  
o
  vomits blood 
o
  has bloody or black stools 
o
  has stomach pain that does not get better 
o
  child has symptoms of heart problems or stroke: 
  chest pain  
o
  trouble breathing 
o
  weakness in one part or 
o
side of body 
  slurred speech 
o
  14  Contains Nonbinding Recommendations 
 
  leg swelling 
o
  child has lost a lot of fluid due to vomiting or diarrhea 
  child is taking a diuretic 
  the child does not get any relief within first day (24 hours) of treatment 
  fever or pain gets worse or lasts more than 3 days 
  redness or swelling is present in the painful area 
  any new symptoms appear 
_____________________________________ 
Directions 
  this product does not contain directions or complete warnings for adult use 
  do not give more than directed 
  shake well before using     
  mL = milliliter 
  find right dose on chart. If possible, use weight to dose; otherwise use age. 
  repeat dose every 6-8 hours, if needed 
  do not use more than 4 times a day 
  discard after [insert beyond-use-date] 
  
Dosing Chart 
Weight (lb)  Age (yr)  Dose (mL) 
Under 24 lb  Under 2 yr  Ask a doctor 
24-35 lb  2-3 yr  5 mL 
36-47 lb  4-5 yr  7.5 mL 
48-59 lb  6-8 yr  10 mL 
60-71 lb  9-10 yr  12.5 mL 
72-95 lb  11 yr  15 mL 
 
  
 
 
  15