United States: Human Drug Compounding: FDA Issues Four Guidance Documents

FDA had a busy holiday season, issuing two final guidance documents and two draft guidance documents for industry related to human drug compounding right before the start of the new year. These guidance documents cover prescription requirements under Section 503A of the Federal Food, Drug, and Cosmetic Act (FFDCA); compounding and repackaging of radiopharmaceuticals; and electronic drug product reporting by Outsourcing Facilities under the FFDCA.

Final Guidance for Industry: Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act

This final guidance sets out (1) a definition for "valid prescription order"; (2) rules for when a drug can be compounded pursuant to Section 503A of the FFDCA; (3) rules for when a drug compounded pursuant to Section 503A can be distributed; and (4) guidelines for compounding for office stock and office use.

Compounding Pursuant to a Valid Prescription Order

The final guidance defines a "valid prescription order" as one which is from "a licensed physician or other licensed practitioner authorized by state law to prescribe drugs." The guidance also states that "a valid order or notation made by a prescriber" on a patient's medical record while the patient is in an inpatient setting could be included as a valid prescription order for compounding under Section 503A of the FFDCA. Lastly, the definition includes orders made by a physician who also compounds a drug when properly noted in his or her patient's chart. Regardless of where the valid prescription order is made, the guidance states that to meet the patient-specific requirements of 503A, it must include the identity of the patient. In other words, spreadsheets and orders that include physician names but do not include patient-specific identifying information are not considered valid prescription orders under the guidance.

When a Drug Can Be Compounded Pursuant to Section 503A

A drug can be properly compounded under Section 503A of the FFDCA in two situations: (1) after receipt of a valid prescription order; or (2) before receipt of the valid prescription order, also called "anticipatory compounding," when this compounding satisfies very specific exceptions. Unless the compounding falls within an exception, the compounding physician or pharmacist cannot fill the order without receipt of a valid, patient-specific prescription order.

As mentioned above, to compound before the receipt of a valid, patient-specific prescription order, the compounding physician or pharmacist must be engaging in anticipatory compounding. Under the guidance, anticipatory compounding is permitted when (1) there is a history of receiving valid orders for the compounded drug; or (2) the order is generated within an established relationship between the prescriber or patient and the compounder. Anticipatory compounding must be done in limited quantities, under the belief the compounder will receive a patient-specific order in the context of an existing relationship.

The guidance does not address whether a 503A compounder has exceeded the "limited quantity condition" if the compounder follows the product's BUD requirements and does not retain more than a 30-day supply for distribution, and if the amount compounded is based on historical data for that particular product. It should also be noted that, according to the guidance, FDA will not examine whether a 503A compounder is exceeding the exceptions if it follows the 30-day limitation.

When a 503A Compounded Drug Can Be Distributed

As previously mentioned, under the guidance, a 503A compounded drug may be distributed only pursuant to a patient-specific prescription order. In the guidance, FDA specifically noted that some states' boards of pharmacy permit distribution of compounded drugs via prescriptions without an individual patient's name. While this is permitted behavior in some states, FDA stated that it is not permissible to distribute using such a prescription under 503A. However, it should be noted that a properly licensed and cGMP-compliant 503B Outsourcing Facility may distribute compounded drugs using such a prescription.

Draft Guidance for Industry: Compounding and Repackaging of Radiopharmaceuticals by State-Licensed Nuclear Pharmacies and Federal Facilities

Compounding of radiopharmaceuticals has a long and interesting history. Section 503A of the FFDCA specifically excludes radiopharmaceuticals meaning they are not afforded the exemptions that other drug products compounded by the same entity are, and therefore do not meet the FFDCA exceptions for a "new drug." Similarly, repackaged radiopharmaceuticals are not exempt from any provisions of the FFDCA.

This guidance, related to compounding of radiopharmaceuticals by state-licensed nuclear pharmacies and federal facilities, stipulates FDA's intention not to take action against state-licensed nuclear pharmacies and federal facilities for compounding radiopharmaceuticals in violation of Section 505 (new drug approval requirements), Section 502(f)(1) (labeling with adequate directions for use), and Section 501(a)(2)(B) (current good manufacturing practice (CGMP) requirements) under the following conditions.

Radiopharmaceutical Compounding That Involves Manipulation Other Than Minor Deviations

  • The product is compounded by or under the direct supervision of a nuclear pharmacist in a facility holding a Resident Acoustic Mixer (RAM);
  • The product is distributed pursuant to a patient-specific prescription;
  • If compounded in anticipation of a prescription, the product is not compounded in a quantity that exceeds expected demand based on historical prescription information, and it is not distributed prior to receipt of the patient-specific prescription;
  • If the product is compounded with bulk substances, those substances comply with an applicable USP or NF monograph;
  • If the product is compounded with bulk substances, those substances must be accompanied by a COA from the original manufacturer;
  • The product is compounded in compliance with USP <795> or USP <797>;
  • The product does not appear on an FDA withdrawn or removed-from-the-market list;
  • The product is not essentially a copy of a marketed FDA-approved radiopharmaceutical;
  • The product is not on the list of products presenting demonstrable difficulties to compound;
  • The product is not sold or transferred by any entity other than the one compounding it;
  • The product is only distributed in states where the compounding of such product meets all applicable state requirements; and
  • The product is compounded in compliance with NRC requirements.

Radiopharmaceutical Compounding That Constitutes Minor Deviations, and Repackaging

  • The product is compounded from an FDA-approved drug product;
  • No additional substances are included in the product unless they are consistent with the FDA-approved labeling;
  • If the product is compounded (not repackaged), the compounding constitutes a "minor deviation";
  • The compounding or repackaging occurs by or under the direct supervision of a licensed nuclear pharmacist in a RAM facility;
  • Compounding or repackaging occurs in compliance with USP <795> or USP <797>;
  • The product is compounded or repackaged in compliance with NRC requirements;
  • The product is distributed only in states where the compounding or repackaging of such product meets all applicable state requirements; and
  • The product must not be sold or transferred by any entity other than the one compounding or repackaging it.

Comments on the draft guidance are due February 27, 2017.

Draft Guidance for Industry: Compounding and Repackaging of Radiopharmaceuticals by Outsourcing Facilities

FDA released the following separate guidance to address the question of how the agency will view compounding of radiopharmaceuticals by a 503B entity. Specifically, this draft guidance addresses the circumstances under which an Outsourcing Facility may compound or repackage radiopharmaceuticals.


Importantly, FDA states that radiopharmaceuticals are not expressly excluded from the definition of "compounding" in Section 503B of the FFDCA. By contrast, radiopharmaceuticals are expressly excluded from the definition in Section 503A of the FFDCA. For this reason, FDA clarifies that "the conditions of section 503B of the [FFDCA] apply to radiopharmaceuticals compounded by an entity that is registered with FDA as an Outsourcing Facility." (Guidance, at lines 117-122.) In addition, the FDA has developed a number of policies applicable only to the compounding of radiopharmaceuticals by Outsourcing Facilities, including those applicable to:

  • Bulk drug substances used in compounding radiopharmaceuticals under Section 503B. FDA initially solicited nominations for bulk drug substances to include on its bulk drug substances list, but only one radiopharmaceutical was nominated, likely because there were still outstanding questions about the regulation of this type of compounding. For this reason, FDA has opened nominations for the 503B bulk drug substances list for radiopharmaceuticals.
  • Compounding radiopharmaceuticals that are essential copies of approved drugs. FDA indicates that it does not intend to take action against an Outsourcing Facility for compounding a radiopharmaceutical that would otherwise meet the definition of an "essential copy of an approved drug" if (a) the product is not compounded from bulk drug substances; (b) there is a "minor deviation" from the approved product labeling; and (c) all drugs are compounded in compliance with all other requirements of Section 503B. A "minor deviation" is defined as "a change from the approved labeling in radioactivity, volume, and/or the step-by-step procedures made when compounding the radiopharmaceutical from an FDA-approved drug product in a patient-ready dose." (Guidance, at lines 211-214)


FDA clarifies what it considers to be repackaging. Specifically, the draft guidance states:

FDA regards repackaging as the act of taking a finished drug product, including a radiopharmaceutical, from the container in which it was distributed by the original manufacturer and placing it into a different container without further manipulation of the drug. Repackaging also includes the act of placing the contents of multiple containers (e.g., vials) of the same finished drug product into one container, as long as the container does not include other ingredients. If a radiopharmaceutical is manipulated in any other way, including if it is reconstituted, diluted, mixed, or combined with another ingredient, that act is not considered repackaging.

(Guidance, at lines 133-140)

The draft guidance also sets out FDA policy on repackaging radiopharmaceuticals:

  • Repackaged drugs are not subject to Section 503B. Thus, repackaged radiopharmaceuticals are not subject to Section 503B or eligible for the exemptions under Section 503B.
  • If an entity only repackages drug products, including radiopharmaceuticals, it does not meet the definition of an Outsourcing Facility.
  • If an entity does meet the definition of an Outsourcing Facility, and the entity also repackages radiopharmaceuticals, "FDA does not intend to take action for violations of sections 505 and 502(f)(1) of the [FFDCA] when the Outsourcing Facility repackages radiopharmaceuticals" if specific conditions are met:

    • The repackaged radiopharmaceutical is approved under Section 505 of the FFDCA;
    • Repackaging occurs under the direct supervision of a licensed, authorized nuclear pharmacist in an Outsourcing Facility with a RAM license;
    • Repackaging occurs in accordance with CGMP requirements;
    • The product is not on a withdrawn or removed-from-the-market list;
    • The repackaged product is not sold or transferred by an entity other than the one that repackaged it;
    • The product is distributed only in states where the production of the radiopharmaceutical meets all state requirements;
    • Repackaging occurs in compliance with all applicable NRC requirements;
    • Specific labeling requirements are met;
    • The product is included on the required biannual report to FDA; and
    • The Outsourcing Facility reports serious adverse events for the repackaged radiopharmaceutical.

Note that the draft guidance does not address the following:

  • "Mixing, reconstituting, combining, diluting, or repackaging of a radiopharmaceutical, or other such acts, performed in accordance with directions contained in the FDA-approved labeling";
  • PET drugs;
  • Non-radiopharmaceuticals;
  • Radioactive biological products subject to the PHSA;
  • Radiopharmaceuticals for animals;
  • Compounding or repackaging of radiopharmaceuticals by non-outsourcing facilities.

(Guidance, at lines 26-34)

Comments on the draft guidance are due February 27, 2017.

Final Guidance for Industry: Electronic Drug Product Reporting for Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act

This final guidance outlines how FDA-registered Outsourcing Facilities must submit drug product reports pursuant to Section 503B of the FFDCA.

Who Must Report and What Must be Reported

A drug product report must be submitted to FDA upon initial registration as an Outsourcing Facility and twice each year (June and December). This includes zero reporting if the Outsourcing Facility has not compounded a drug product in the previous six-month period.

The following information must be included:

  • The active ingredient and strength of active ingredient per unit – "strength" means the strength of the active ingredient per dose;
  • The source of the active ingredient;
  • The National Drug Code (NDC) number of the source drug or bulk active ingredient, if available – this must be submitted in the standard format of 10 numerical digits;
  • The dosage form and route of administration;
  • The package description of the smallest saleable package for distribution;
  • The number of individual units produced (based on the smallest individual saleable packages); and
  • The NDC number of the final product, if assigned.

When to Report

Reports must be filed upon initial registration and twice a year (June and December). The initial report must list products compounded in the previous six months, not including the month of registration. June reporting must include products compounded from December 1 through May 31. December reporting must include products compounded from June 1 through November 30.

How to Report

Product reporting must be submitted using the FDA electronic reporting system, and information must be submitted in the structured product labeling (SPL) format unless FDA has granted a waiver. Outsourcing Facilities must use the Human Compounded Drug Label document type when making electronic submissions. More information about electronic submissions is available at the FDA website.

Confidentiality of Reporting Information

Outsourcing Facility registration information is publically available; however, specific product reporting may be exempt from inspection "unless the Secretary finds that such an exemption would be inconsistent with the protection of the public health." This guidance clarifies that FDA does not intend to exempt some of the product reporting from inspection – including the name of the Outsourcing Facility, the address of the Outsourcing Facility, the name of the active ingredient, the strength of the active ingredient per unit, the dosage form, the package description, and the NDC of the final product (if assigned) – because it would be inconsistent with the protection of the public health. FDA states that:

[t]his information is generally required on product labels or publicly available, but publication of this information will facilitate product recalls when they are necessary, and assist the public in finding outsourcing facilities that have compounded certain drug products, particularly drugs in shortage. FDA intends to publish this information on our Web site. FDA does not intend to publish information about a drug submitted in a product report if an outsourcing facility notes in the report that it has not distributed the drug and has not advised any person of its intent or ability to compound the drug.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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