FDA GUIDANCE DOCUMENT

Compounding Certain Ibuprofen Oral Suspension Products Under Section 503B of the Federal Food, Drug, and Cosmetic Act

Part 3

FEBRUARY 2023

IMMEDIATELY IN EFFECT

I. INTRODUCTION (Discussed in a previous newsletter.)

II. BACKGROUND (Discussed in a previous newsletter.)

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; or that uses a bulk drug substance that does not comply with section 503B(a)(2)(A) of the FD&C Act; 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, 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 FDA's 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:

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. One of the critical attributes in the monograph standard is Uniformity of Dosage Units.
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.
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 include, but are not limited to, propylene glycol, glycerin, polyethylene glycol, sorbitol solution, maltitol solution, and hydrogenated starch hydrolysate.
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. 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.
9. The outsourcing facility's 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:
   1. 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 and
   2. The outsourcing facility initiates limited stability testing when the aggregate batch size is expected to exceed 5,000 units.
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 container 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:
    1. directly to a hospital or health system for administration within the hospital or health system; or
    2. directly to a State-licensed pharmacy (including those within hospitals and health systems), 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.
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:
    1. The outsourcing facility packages the ibuprofen oral suspension product in a container that holds no more than 120 mL of ibuprofen oral suspension.
    2. The outsourcing facility ensures that the labeling on the ibuprofen oral suspension product's immediate container includes the information in Appendix C. If the ibuprofen oral suspension is packaged in a container that is too small to 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.
    3. The outsourcing facility ensures that the ibuprofen oral suspension product complies with applicable requirements under the PPPA, such as "special packaging standards" as applicable.
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 healthcare 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 FDA's 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.

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.

For the most recent version of the guidance, check the FDA guidance web page at:
https://www.fda.gov/​regulatory-​information/​search-​fda-​guidance-​documents.

Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition