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 (Previously Presented)
II. BACKGROUND (Previously Presented)

III. DISCUSSION (Present Presentation)
For a licensed pharmacist in a State-licensed pharmacy or Federal facility that has not registered as an outsourcing facility and that compounds beta-lactam oral antibiotic suspension products that appear on FDA's drug shortage list, the Agency intends to prioritize its regulatory and enforcement actions with respect to the insanitary conditions provision to focus on the potential for harm to the public health, taking into consideration the public health need for beta-lactam oral antibiotic suspension products at this time.

Complete and comprehensive separation refers to a cross-contamination prevention strategy that consists of: (1) the complete physical separation of beta-lactam production area(s) (including separate air handling system[s]) from production areas for other drugs; and (2) additional design and procedural controls for facilities, equipment, material, and personnel that are necessary to support and maintain the integrity of the physical separation (e.g., dedicated equipment; utilities management [waste flow, including the potential for beta-lactam production exhaust to contaminate an adjacent building air intake, vacuum systems]); people/material/equipment flow; personnel gowning; decontamination; monitoring containment; testing; compliance with procedures; investigations). Although separate buildings could ensure separation of beta-lactam operations from non-beta-lactam operations, it is feasible for one building to contain a dedicated area for beta-lactam production that is completely isolated and sealed off from the rest of the building. For example, separate entries and exits to the beta-lactam segment of the building would be necessary to ensure comprehensive separation. In the limited cases in which this design concept could be considered, a risk assessment should demonstrate that the design provides as much protection against cross-contamination as is achieved by producing in a separate building. See FDA's guidance for industry on Insanitary Conditions at Compounding Facilities. The guidance explains that "processing of beta-lactams" does not refer to mixing, reconstituting, or other such acts that are performed in accordance with the directions contained in approved labeling provided by the product's manufacturer and other manufacturer directions consistent with that labeling, at the immediate point of dispensing for administration to the intended patient.

As noted above, FDA's insanitary conditions guidance describes the processing of beta-lactams without complete and comprehensive separation from non-beta-lactam products as an example of an insanitary condition the Agency has observed. However, during the time that beta-lactam antibiotic powder for oral suspension products are on the FDA shortage list (or for such shorter time as FDA may announce by updating or withdrawing this guidance based on evolving needs and circumstances), based on the Agency's current understanding of the potential for risk of contamination, compounders under section 503A of the FD&C Act that prepare beta lactam oral antibiotic suspension products that appear on FDA's shortage list without complete and comprehensive separation from non-beta-lactam products should take at least the following minimum steps to mitigate the potential risk of cross-contamination and reduce risk to patients. FDA generally intends to prioritize its regulatory and enforcement actions if the following steps are not all followed when preparing beta-lactam oral antibiotic suspension products that appear on FDA's shortage list without complete and comprehensive separation from non-beta-lactam products:

1. Use of FDA-approved beta-lactam tablets and capsules instead of bulk drug substances to compound the beta-lactam oral antibiotic suspension product;
2. Temporal segregation of the compounding of these oral suspensions from non-beta-lactam products;
3. Use of dedicated or disposable equipment, utensils, and personal protective equipment (e.g., gowns, gloves);
4. Segregation and storage in a separate area of any equipment, utensils, and personal protective equipment used in the compounding of these oral suspensions (e.g., glassware, mortar and pestle) from equipment, utensils, and personal protective equipment not used in beta-lactam compounding;
5. Trituration of the FDA-approved product after wetting it with a quantity of the suspension vehicle sufficient to eliminate formation of product dust;
6. Use of proper cleaning procedures after completing compounding, including use of peroxide or bleach solutions to deactivate the beta-lactam ring of any drug residue on surfaces. The use of strong oxidizers should be followed by neutralizers and volatile cleaning agents (e.g., purified water, isopropanol) to minimize damage to these surfaces;
7. Containment and remediation of spills;
8. The beyond-use-date assigned to the compounded oral suspension does not exceed the beyond-use-date of the related reconstituted FDA-approved beta-lactam antibiotic powder for oral suspension product that is on FDA's drug shortage list, as found on the approved labeling; and
9. Storage conditions used for the compounded oral suspension are consistent with those for the related reconstituted FDA-approved beta-lactam antibiotic powder for oral suspension product that is on FDA's drug shortage list, as found on the approved labeling.

Healthcare providers may also consider FDA-approved alternatives to the product in shortage.

FDA also recommends monitoring for reports of allergic reactions, including anaphylactic shock, that might be related to unintentional beta-lactam exposure from the use of non-beta-lactam drugs. If such reports are confirmed, the pharmacy should take appropriate action, which may include notifying patients and medical providers. If there are reports of anaphylactic shock or allergic reactions related to unintentional exposure, the pharmacy should stop compounding beta- lactam products.

FDA encourages consumers, patients, and healthcare professionals to report adverse events or quality problems experienced with the use of compounded drugs to FDA’s MedWatch Adverse Event Reporting program:

• Complete and submit the report online at MedWatch: The FDA Safety Information and Adverse Event Reporting Program; or
• Download and complete the form, then submit it via fax at 1-800-FDA-0178.

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