This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
This guidance has been prepared by the Office of Regulatory Policy and the Office of Compliance in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.
This document provides guidance to drug compounders and the staff of the Food and Drug Administration (FDA) on how the Agency intends to address pharmacy compounding of human drugs in the immediate future as a result of the decision of the Supreme Court in Thompson v. Western States Medical Center, No. 01-344, April 29, 2002. FDA is considering the implications of that decision and determining how it intends to regulate pharmacy compounding in the long term. However, FDA recognizes the need for immediate guidance on what types of compounding might be subject to enforcement action under current law. This guidance describes FDA’s current thinking on this issue.
On March 16, 1992, FDA issued a compliance policy guide (CPG), section 7132.16 (later renumbered as 460.200) to delineate FDA’s enforcement policy on pharmacy compounding. That CPG remained in effect until 1997 when Congress enacted the Food and Drug Administration Modernization Act of 1997.
On November 21, 1997, the President signed the Food and Drug Administration Modernization Act of 1997 (Pub. L. 105-115) (the Modernization Act). Section 127 of the Modernization Act added section 503A to the Federal Food, Drug, and Cosmetic Act (the Act), to clarify the status of pharmacy compounding under Federal law. Under section 503A, drug products that were compounded by a pharmacist or physician on a customized basis for an individual patient were entitled to exemptions from three key provisions of the Act: (1) the adulteration provision of section 501(a)(2)(B) (concerning the good manufacturing practice requirements); (2) the misbranding provision of section 502(f)(1) (concerning the labeling of drugs with adequate directions for use); and (3) the new drug provision of section 505 (concerning the approval of drugs under new drug or abbreviated new drug applications). To qualify for these statutory exemptions, a compounded drug product was required to satisfy several requirements, some of which were to be the subject of FDA rulemaking or other actions.
Section 503A of the Act took effect on November 21, 1998, one year after the date of the enactment of the Modernization Act. In November, 1998, the solicitation and advertising provisions of section 503A were challenged by seven compounding pharmacies as an impermissible regulation of commercial speech. The U.S. District Court for the District of Nevada ruled in the plaintiffs’ favor. FDA appealed to the U.S. Court of Appeals for the Ninth Circuit. On February 6, 2001, the Court of Appeals declared section 503A invalid in its entirety (Western States Medical Center v. Shalala, 238 F.3rd 1090 (9th Cir. 2001)). The government petitioned for a writ of certiorari to the U.S. Supreme Court for review of the circuit court opinion. The Supreme Court granted the writ and issued its decision in the case on April 29, 2002.
The Supreme Court affirmed the 9th Circuit Court of Appeals decision that found section 503A of the Act invalid in its entirety because it contained unconstitutional restrictions on commercial speech (i.e., prohibitions on soliciting prescriptions for and advertising specific compounded drugs). The Court did not rule on, and therefore left in place, the 9th Circuit’s holding that the unconstitutional restrictions on commercial speech could not be severed from the rest of section 503A. Accordingly, all of section 503A is now invalid.
FDA has therefore determined that it needs to issue guidance to the compounding industry on what factors the Agency will consider in exercising its enforcement discretion regarding pharmacy compounding.
FDA recognizes that pharmacists traditionally have extemporaneously compounded and manipulated reasonable quantities of human drugs upon receipt of a valid prescription for an individually identified patient from a licensed practitioner. This traditional activity is not the subject of this guidance. [Footnote: With respect to such activities, 21 U.S.C. 360(g)(1) exempts retail pharmacies from the registration requirements of the Act. The exemption applies to “Pharmacies” that operate in accordance with state law and dispense drugs “upon prescriptions of practitioners licensed to administer such drugs to patients under the care of such practitioners in the course of their professional practice, and which do not manufacture, prepare, propagate, compound, or process drugs or devices for sale other than in the regular course of their business of dispensing or selling drugs or devices at retail” (emphasis added). See also 21 U.S.C. §§ 374(a)(2) (exempting pharmacies that meet the foregoing criteria from certain inspection provisions) and 353(b)(2) (exempting drugs dispensed by filling a valid prescription from certain misbranding provisions).]
FDA believes that an increasing number of establishments with retail pharmacy licenses are engaged in manufacturing and distributing unapproved new drugs for human use in a manner that is clearly outside the bounds of traditional pharmacy practice and that violates the Act. Such establishments and their activities are the focus of this guidance. Some “pharmacies” that have sought to find shelter under and expand the scope of the exemptions applicable to traditional retail pharmacies have claimed that their manufacturing and distribution practices are only the regular course of the practice of pharmacy. Yet, the practices of many of these entities seem far more consistent with those of drug manufacturers and wholesalers than with those of retail pharmacies. For example, some firms receive and use large quantities of bulk drug substances to manufacture large quantities of unapproved drug products in advance of receiving a valid prescription for them. Moreover, some firms sell to physicians and patients with whom they have only a remote professional relationship. Pharmacies engaged in activities analogous to manufacturing and distributing drugs for human use may be held to the same provisions of the Act as manufacturers.
Generally, FDA will continue to defer to state authorities regarding less significant violations of the Act related to pharmacy compounding of human drugs. FDA anticipates that, in such cases, cooperative efforts between the states and the Agency will result in coordinated investigations, referrals, and follow-up actions by the states.
However, when the scope and nature of a pharmacy’s activities raise the kinds of concerns normally associated with a drug manufacturer and result in significant violations of the new drug, adulteration, or misbranding provisions of the Act, FDA has determined that it should seriously consider enforcement action. In determining whether to initiate such an action, the Agency will consider whether the pharmacy engages in any of the following acts:
- Compounding of drugs in anticipation of receiving prescriptions, except in very limited quantities in relation to the amounts of drugs compounded after receiving valid prescriptions.
- Compounding drugs that were withdrawn or removed from the market for safety reasons. Appendix A provides a list of such drugs that will be updated in the future, as appropriate.
- Compounding finished drugs from bulk active ingredients that are not components of FDA approved drugs without an FDA sanctioned investigational new drug application (IND) in accordance with 21 U.S.C. § 355(i) and 21 CFR 312.
- Receiving, storing, or using drug substances without first obtaining written assurance from the supplier that each lot of the drug substance has been made in an FDA-registered facility.
- Receiving, storing, or using drug components not guaranteed or otherwise determined to meet official compendia requirements.
- Using commercial scale manufacturing or testing equipment for compounding drug products.
- Compounding drugs for third parties who resell to individual patients or offering compounded drug products at wholesale to other state licensed persons or commercial entities for resale.
- Compounding drug products that are commercially available in the marketplace or that are essentially copies of commercially available FDA-approved drug products. In certain circumstances, it may be appropriate for a pharmacist to compound a small quantity of a drug that is only slightly different than an FDA-approved drug that is commercially available. In these circumstances, FDA will consider whether there is documentation of the medical need for the particular variation of the compound for the particular patient.
- Failing to operate in conformance with applicable state law regulating the practice of pharmacy.
The foregoing list of factors is not intended to be exhaustive. Other factors may be appropriate for consideration in a particular case.
Other FDA guidance interprets or clarifies Agency positions concerning nuclear pharmacy, hospital pharmacy, shared service operations, mail order pharmacy, and the manipulation of approved drug products.
REGULATORY ACTION GUIDANCE:
District offices are encouraged to consult with state regulatory authorities to assure coherent application of this guidance to establishments that are operating outside of the traditional practice of pharmacy.
FDA-initiated regulatory action may include issuing a warning letter, seizure, injunction, and/or prosecution. Charges may include, but need not be limited to, violations of 21 U.S.C. §§ 351(a)(2)(B), 352(a), 352(f)(1), 352(o), and 355(a) of the Act.
LIST OF COMPOUNDING DRUGS THAT WERE WITHDRAWN OR
REMOVED FROM THE MARKET FOR SAFETY REASONS
- Adenosine phosphate: All drug products containing adenosine phosphate.
- Adrenal cortex: All drug products containing adrenal cortex.
- Aminopyrine: All drug products containing aminopyrine.
- Astemizole: All drug products containing astemizole.
- Azaribine: All drug products containing azaribine.
- Benoxaprofen: All drug products containing benoxaprofen.
- Bithionol: All drug products containing bithionol.
- Bromfenac sodium: All drug products containing bromfenac sodium.
- Butamben: All parenteral drug products containing butamben.
- Camphorated oil: All drug products containing camphorated oil.
- Carbetapentane citrate: All oral gel drug products containing carbetapentane citrate.
- Casein, iodinated: All drug products containing iodinated casein.
- Chlorhexidine gluconate: All tinctures of chlorhexidine gluconate formulated for use as a patient preoperative skin preparation.
- Chlormadinone acetate: All drug products containing chlormadinone acetate.
- Chloroform: All drug products containing chloroform.
- Cisapride: All drug products containing cisapride.
- Cobalt: All drug products containing cobalt salts (except radioactive forms cobalt and its salts and cobalamin and its derivatives).
- Dexfenfluramine hydrochloride: All drug products containing dexfenfluramine hydrochloride.
- Diamthazole dihydrochloride: All drug products containing diamthazole dihydrochloride.
- Dibromsalan: All drug products containing dibromsalan.
- Diethylstilbestrol: All oral and parenteral drug products containing 25 milligrams or more of diethylstilbestrol per unit dose.
- Dihydrostreptomycin sulfate: All drug products containing dihydrostreptomycin sulfate.
- Dipyrone: All drug products containing dipyrone.
- Encainide hydrochloride: All drug products containing encainide hydrochloride.
- Fenfluramine hydrochloride: All drug products containing fenfluramine hydrochloride.
- Flosequinan: All drug products containing flosequinan.
- Gelatin: All intravenous drug products containing gelatin.
- Glycerol, iodinated: All drug products containing iodinated glycerol.
- Gonadotropin, chorionic: All drug products containing chorionic gonadotropins of animal origin.
- Grepafloxacin: All drug products containing grepafloxacin.
- Mepazine: All drug products containing mepazine hydrochloride or mepazine acetate.
- Metabromsalan: All drug products containing metabromsalan.
- Methamphetamine hydrochloride: All parenteral drug products containing methamphetamine hydrochloride.
- Methapyrilene: All drug products containing methapyrilene.
- Methopholine: All drug products containing methopholine.
- Mibefradil dihydrochloride: All drug products containing mibefradil dihydrochloride.
- Nitrofurazone: All drug products containing nitrofurazone (except topical drug products formulated for dermatalogic application).
- Nomifensine maleate: All drug products containing nomifensine maleate.
- Oxyphenisatin: All drug products containing oxyphenisatin.
- Oxyphenisatin acetate: All drug products containing oxyphenisatin acetate.
- Phenacetin: All drug products containing phenacetin.
- Phenformin hydrochloride: All drug products containing phenformin hydrochloride.
- Pipamazine: All drug products containing pipamazine.
- Potassium arsenite: All drug products containing potassium arsenite.
- Potassium chloride: All solid oral dosage form drug products containing potassium chloride that supply 100 milligrams or more of potassium per dosage unit (except for controlled-release dosage forms and those products formulated for preparation of solution prior to ingestion).
- Povidone: All intravenous drug products containing povidone.
- Reserpine: All oral dosage form drug products containing more than 1 milligram of reserpine.
- Sparteine sulfate: All drug products containing sparteine sulfate.
- Sulfadimethoxine: All drug products containing sulfadimethoxine.
- Sulfathiazole: All drug products containing sulfathiazole (except those formulated for vaginal use).
- Suprofen: All drug products containing suprofen (except ophthalmic solutions).
- Sweet spirits of nitre: All drug products containing sweet spirits of nitre.
- Temafloxacin hydrochloride: All drug products containing temafloxacin.
- Terfenadine: All drug products containing terfenadine.
- 3,3′,4′,5-tetrachlorosalicylanilide: All drug products containing 3,3′,4′,5-tetrachlorosalicylanilide.
- Tetracycline: All liquid oral drug products formulated for pediatric use containing tetracycline in a concentration greater than 25 milligrams/milliliter.
- Ticrynafen: All drug products containing ticrynafen.
- Tribromsalan: All drug products containing tribromsalan.
- Trichloroethane: All aerosol drug products intended for inhalation containing trichloroethane.
- Troglitazone: All drug products containing troglitazone.
- Urethane: All drug products containing urethane.
- Vinyl chloride: All aerosol drug products containing vinyl chloride.
- Zirconium: All aerosol drug products containing zirconium.
- Zomepirac sodium: All drug products containing zomepirac sodium.
This page was posted on November 26, 2005.