Compounding Certain Beta-Lactam Products in Shortage Under Section 503A of the Federal Food Drug and Cosmetic Act

NOVEMBER 2022

IMMEDIATELY IN EFFECT

Final

I. INTRODUCTION

This guidance describes the Food and Drug Administration's (FDA or the Agency) regulatory and enforcement priorities regarding preparation of beta-lactam oral antibiotic suspension products that appear on FDA's drug shortage list by a licensed pharmacist in a State-licensed pharmacy or Federal facility. There is currently an acute shortage of amoxicillin oral antibiotic powder for suspension. Amoxicillin oral antibiotic powder for suspension products currently appear on FDA's drug shortage list. Amoxicillin is widely used for the treatment of bacterial upper and lower respiratory infections in the pediatric population, among other uses. As a result of this shortage, there is an urgent need to increase the supply of these beta-lactam oral suspension products. FDA has received a number of reports related to increased demand for amoxicillin oral antibiotic suspension products in particular. FDA has also received requests for clarification about preparation of compounded versions of those products from FDA-approved tablets and capsules.

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 31 701(h)(1)(C) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 32 10.115(g)(2)). This guidance document is being implemented immediately because of the public health need for amoxicillin oral antibiotic suspension products, but it remains subject to comment in accordance with the Agency's good guidance practices.

In general, FDA's guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's 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

Compounded drug products are not FDA-approved, which means they have not undergone FDA premarket review for safety, effectiveness, and quality. Section 503A of the FD&C Act (21 U.S.C. 353a) provides that a drug product compounded by a licensed pharmacist in a State-licensed pharmacy or a Federal facility or by a licensed physician can qualify for exemptions from requirements under three other sections of the FD&C Act: adequate directions for use (section 502(f)(1) (21 U.S.C. 352(f)(1)), new drug approval requirements (section 505 (21 U.S.C. 355)), and current good manufacturing practice (CGMP) requirements (section 501(a)(2)(B) (21 U.S.C. 351(a)(2)(B))) if all of the conditions in section 503A are met.

One of the conditions in section 503A of the FD&C Act is that each drug product must be compounded for an identified individual patient based on the receipt of a valid prescription order or a notation, approved by the prescribing practitioner, on the prescription order that a compounded product is necessary for the identified patient. If an FDA-approved drug product is on FDA's drug shortage list, it may be compounded by an outsourcing facility in accordance with section 503B of the FD&C Act or by a licensed pharmacist in a State-licensed pharmacy or Federal facility in accordance with section 503A of the FD&C Act.

See section 503A(a) of the FD&C Act. See also FDA's guidance for industry Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act (December 2016). We update guidances periodically. 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.

The provision in section 503A of the FD&C Act that applies to compounding a drug product that is essentially a copy of a commercially available drug does not apply to compounding a drug on FDA's drug shortage list because FDA does not consider products on FDA's drug shortage list to be commercially available. See section 503A(b)(1)(D) of the FD&C Act, and FDA's guidance for industry Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act (January 2018).

Insanitary conditions are conditions that could cause a drug to become contaminated with filth or rendered injurious to health. The drug itself need not actually be contaminated. A drug that is actually contaminated with any filthy, putrid, or decomposed substance is deemed to be adulterated under section 501(a)(1) of the FD&C Act (21 U.S.C. 351(a)(1)).

Under the FD&C Act, a drug is adulterated if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health (section 501(a)(2)(A) of the FD&C Act (21 U.S.C. 64351(a)(2)(A)) (insanitary conditions provision). Section 503A of the FD&C Act does not provide an exemption from the insanitary conditions provision. Drug products prepared, packed, or held under insanitary conditions could become contaminated and cause serious adverse events, including death. Processing of beta-lactam drugs without complete and comprehensive separation from non-beta-lactam products is an example of an insanitary condition that FDA has observed.

In addition to penicillin, all beta-lactam drugs can be sensitizing agents; therefore, cross-contamination between any beta-lactam drug and other drugs could initiate the same types of drug-induced life-threatening allergic reactions that penicillins can trigger. Therefore, any handling of any beta-lactam drugs should be done in a manner to prevent cross-contamination with non-beta-lactam drugs, thereby reducing the potential for drug-induced, life-threatening allergic reactions.

The current shortage of amoxicillin oral antibiotic powder for suspension products and increased demand for beta-lactam oral antibiotic suspension products could lead to potentially serious or life-threatening situations in particular in the pediatric population, especially during the upcoming fall and winter months when the incidence of upper and lower respiratory infections is expected to peak. Therefore, based on risk management principles, in order to address access concerns while also minimizing the potential for cross-contamination and the resulting hypersensitivity or allergic reactions, FDA intends to prioritize its regulatory and enforcement actions regarding the preparation of beta-lactam oral antibiotic suspension products that appear on FDA's drug shortage list by compounders under section 503A.

This discussion will continue next week.

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