Guidance for FDA Staff and Industry
Compliance Policy Guides Manual
Sec. 460.200
Pharmacy Compounding
Submit written comments regarding this guidance document to the Dockets Management
Branch (HFA-305), 5630 Fishers Lane, rm.1061, Rockville, MD 20852.
Additional copies of this document may be obtained by sending a request to the Division
of Compliance Policy (HFC-230), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, or from the Internet at:
http://www.fda.gov/ora/compliance_ref/cpg/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Office of Regulatory Affairs
Center for Drug Evaluation and Research
May 2002
Contents for Page Navigation
Introduction
Background
Discussion
Policy
Regulatory Action Guidance
Appendix A
Compliance Policy Guide
Compliance Policy Guidance for FDA Staff and Industry1
CHAPTER - 4
SUB CHAPTER - 460
Sec. 460.200 Pharmacy Compounding
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.
INTRODUCTION
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.
BACKGROUND
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.
DISCUSSION
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.
2
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.
POLICY:
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:
1. 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.
2. 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.
3. 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.
4. 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.
5. Receiving, storing, or using drug components not guaranteed or otherwise determined
to meet official compendia requirements.
6. Using commercial scale manufacturing or testing equipment for compounding drug
products.
7. 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.
8. 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.
9. 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.
Issued: 3/16/1992
Reissued: 5/29/2002
APPENDIX A
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.
3
1 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.
2 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).
7 |