Department of Health and Human Services
Public Health Service
5600 Fishers Ln Rockville, MD 20857
December 4, 2006
Hal's Compounding Pharmacy
3825 32nd St
San Diego, CA 92104
Ref. No. CFSAN-2006-U-3
Dear Mr Keller:
On January 24, 2005, investigators from the U.S. Food and Drug Administration (FDA) began an inspection of your firm, located at 3825 32nd St, San Diego, CA. On March 3, 2005, the investigators completed the inspection. This inspection revealed that your firm compounds human prescription drugs in various dosage forms and strengths.
FDA's position is that the Federal Food, Drug, and Cosmetic Act (FDCA) establishes agency jurisdiction over "new drugs," including compounded drugs. FDA's view that compounded drugs are "new drugs" within the meaning of 21 USC 321(p), because they are not "generally recognized, among experts … as safe and effective," is supported by substantial judicial authority. See Weinberger v. Hynson, Westcott & Dunning, 412 US 609, 619, 629-30 (1973) (explaining the definition of "new drug"); Prof'ls & Patients for Customized Care v. Shalala, 56 F.3d 592, 593 n.3 (5th Cir. 1995) (the FDCA does not expressly exempt pharmacies or compounded drugs from its new drug provisions); In the Matter of Establishment Inspection of Wedgewood Village Pharmacy, 270 F.Supp. 2d 525, 543-44 (D.N.J. 2003), aff'd, Wedgewood Village Pharmacy v. United States, 421 F.3d 263, 269 (3d Cir. 2005) ("The FDCA contains provisions with explicit exemptions from the new drug … provisions. Neither pharmacies nor compounded drugs are expressly exempted."). FDA maintains that, because they are "new drugs" under the FDCA, compounded drugs may not be introduced into interstate commerce without FDA approval.
The drugs that pharmacists compound are not FDA-approved and lack an FDA finding of safety and efficacy. However, FDA has long recognized the important public health function served by traditional pharmacy compounding. FDA regards traditional compounding as the extemporaneous combining, mixing, or altering of ingredients by a pharmacist in response to a physician's prescription to create a medication tailored to the specialized needs of an individual patient. See Thompson v. Western States Medical Center, 535 US 357, 360-61 (2002). Traditional compounding typically is used to prepare medications that are not available commercially, such as a drug for a patient who is allergic to an ingredient in a mass-produced product, or diluted dosages for children.
Through the exercise of enforcement discretion, FDA historically has not taken enforcement actions against pharmacies engaged in traditional pharmacy compounding. Rather, FDA has directed its enforcement resources against establishments whose activities raise the kinds of concerns normally associated with a drug manufacturer and whose compounding practices result in significant violations of the new drug, adulteration, or misbranding provisions of the FDCA.
FDA's current enforcement policy with respect to pharmacy compounding is articulated in Compliance Policy Guide (CPG), section 460.200 ["Pharmacy Compounding"], issued by FDA on May 29, 2002 (see Notice of Availability, 67 Fed. Reg. 39,409 (June 7, 2002)).1 The CPG identifies factors that the Agency considers in deciding whether to initiate enforcement action with respect to compounding. These factors help differentiate the traditional practice of pharmacy compounding from the manufacture of unapproved new drugs. They further address compounding practices that result in significant violations of the new drug, adulteration, or misbranding provisions of the FDCA. These factors include considering whether a firm compounds drugs that are copies or essentially copies of commercially available FDA-approved drug products without a documented patient-specific medical need. The factors in the CPG are not intended to be exhaustive and other factors may also be appropriate for consideration.
1. Topical Anesthetics
During the inspection, FDA investigators documented that your firm compounds and distributes several products that contain high concentrations of lidocaine and/or tetracaine, alone or in combination with other active ingredients (such as prilocaine and benzocaine). These products include : Anesthetic Skin Lotion (lidocaine 10%, prilocaine 2%); Tetracaine 6% in DMSO Gel; and Triple Kwick Anesthetic Gel (benzocaine, lidocaine, and tetracaine). We also note that your firm offers to compound N*E*W* topical anesthetic (lidocaine 30%, prilocaine 2%, tetracaine 4%); Kwick Anesthetic Gel (benzocaine, lidocaine, tetracaine, DMSO); Lidocaine and Tetracaine Demi Gel; and Anesthetic Skin Gel 3+ (lidocaine, prilocaine, tetracaine).
Like a manufacturer, you have developed a standardized line of anesthetic drug products, extolling their effectiveness for all patients. This action is not consistent with the traditional practice of pharmacy compounding, in which pharmacists extemporaneously compound reasonable quantities of drugs upon receipt of valid prescriptions from licensed practitioners to meet the unique medical needs of individual patients.
Moreover, the agency is concerned with the public health risks associated with the compounding and sale of products that contain high doses of lidocaine and/or tetracaine. There have been at least two non-fatal reactions and two deaths attributed to the use of compounded topical local anesthetic creams containing high dose of local anesthetics. Local anesthetics may be toxic at high dosages, and this toxicity can be additive. Further, there is a narrow difference between the optimal therapeutic dose of these products and the doses at which they become toxic, i.e. they have low therapeutic index.
Adverse events consistent with high systemic exposures to these products include seizures and cardiac arrhythmias. Specifically, risk of systemic adverse events from tetracaine products includes (1) a systemic allergic response to p-aminobenzoic acid (PABA) which, at worst, could lead to cardiac arrest; or (2) excessive systemic absorption following repetitive or extensive application, especially for 4 and 6% products, which could ultimately lead to convulsions. Tetracaine is associated with a higher incidence of allergic reactions than other anesthetics, such as lidocaine. The risk of systemic toxicity is greatest in small children and in patients with pre-existing heart disease. Factors that may increase systemic exposure are time and surface area of the exposure, particularly when the area of application is covered by an occlusive dressing. Benzocaine and prilocaine have an additional toxicity not seen with lidocaine. This toxicity, which is called methemoglobinemia, is an acquired disease in the oxygen-carrying capacity of the red blood cells. Further, patients with severe hepatic disease are at greater risk of developing toxic plasma concentrations of local anesthetics because of their inability to metabolize them.
Your compounded local anesthetic products are drugs within the meaning of section 201(g)(1) of the FDCA (21 USC 321(g)(1)). These products are misbranded under section 502(f)(1) of the FDCA (21 USC 352(f)(1)) in that their labeling fails to bear adequate directions for its use. These products are not exempt from this requirement under 21 CFR 201.115 because they are new drugs within the meaning of section 201(p) of the FDCA (21 USC 321(p)) and they lack approved applications filed pursuant to section 505 of the FDCA (21 USC 355).
Depending on their labeling, these products may also violate section 502(a) of the FDCA (21 USC 352(a)). A drug or device is misbranded under section 502(a) if its labeling is false and misleading in any particular (e.g., if the labeling for your local anesthetic products fails to reveal the consequences that may result from the use of the products as local anesthetics).
2. Copies of Commercially Available Drug Products.
The inspection also revealed that your firm is compounding several products that appear to be copies or essentially copies of commercially available FDA-approved drug products. These products include, but are not limited to, progesterone 100mg capsules, retinoic acid cream (tretinoin) 0.05% cream, and retinoic acid 0.1% cream. As stated in the CPG and noted above, FDA typically does not exercise its enforcement discretion for the compounding of copies of commercially available FDA-approved products. We remind you of your commitment to our investigator that your firm will only compound such drugs upon written instructions and justification from the prescriber of the medical need for the particular variation of the compound for an individual patient.
Like the topical anesthetic products, the progesterone and retinoic acid products that your firm compounds are drugs within the meaning of section 201(g) of the FDCA They, too, are misbranded under section 502(f)(1) of the FDCA (21 USC 352(f)(1)) in that their labeling fails to bear adequate directions for their use. These products are not exempt from this requirement under 21 CFR 201.115 because they are new drugs within the meaning of section 201(p) of the FDCA (21 USC 321(p)) that lack approved applications filed pursuant to section 505 of the FDCA (21 USC 355)
Please note that, under section 301(a) of the FDCA (21 USC 331(a)), the introduction or delivery for introduction into interstate commerce of any drug that is misbranded is prohibited. Under section 301(d) of the FDCA (21 USC 331(d)), the introduction or delivery for introduction into interstate commerce of a new drug that has not been approved under section 505 is also prohibited.
The above violations are not intended to be an all-inclusive list of deficiencies. You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in additional regulatory action without further notice. These actions include, but are not limited to, seizure of your products or injunction against you or your firm. Federal agencies are routinely advised of the issuance of warning. letters so that they may take this information into account when considering the award of government contracts.
Please notify this office in writing within 15 working days of receipt of this letter, of any steps you will take to correct the noted violations, including an explanation of each step being taken to prevent the recurrence of similar violations. If corrective action cannot be completed within 15 working days, please state the reason for the delay and the time frame within which the correction will be completed.
You should address your reply to this letter to Samia Nasr, Team Leader, Compounding Team, Office of Compliance, Division of New Drugs and Labeling Compliance (HFD-317), 5600 Fishers Ln, Rockville, MD 20857.
Mike M. Levy Director
Division of New Drugs and Labeling Compliance
Office of Compliance
1 Although Section 503A of the FDCA (21 USC 353a) addresses pharmacy compounding, this provision was invalidated by the Supreme Court's ruling in Thompson v. Western States Medical Center, 535 US 357 (2002), that Section 503A included unconstitutional restrictions on commercial speech. And those restrictions could not be severed from the rest of 503A. In Thompson v. Western States Medical Center, 535 US 357 (2002), the Supreme Court affirmed the Ninth Circuit ruling that the provisions in question violated the First Amendment.
This page was posted on February 12, 2008.