Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Los Angeles District |
Irvine, CA 92612-2608
VIA UNITED PARCEL SERVICE
May 15, 2013
WL # 39-13
Paul R. Wheeler, Pharm.D.
President and Pharmacist in Charge
Custom Compounding Centers, LLC
10525 Humbolt Street
Los Alamitos, CA 90720
Dear Dr. Wheeler:
Between November 14, 2012, and December 13, 2012, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, Custom Compounding Centers, LLC, located at 10525 Humbolt Street, Los Alamitos, CA 90720. During the inspection, the investigators noted that you were not receiving valid prescriptions for individually-identified patients for a significant number of drug products you were producing. In addition, the investigators observed serious deficiencies in your practices for producing sterile drug products, which could lead to contamination of the products, potentially putting patients at risk. These observations and others were noted on an FDA Form 483 issued on December 13, 2012, and displayed on FDA’s website at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm339771.htm. We acknowledge receipt of your firm’s response to the FDA Form 483 dated January 10, as well as your subsequent responses of January 25 and 31, February 5, and March 25, 2013.
On January 22, 2013, we held a teleconference with you to discuss our inspectional observations. Among other things discussed, we expressed our concerns with air quality deficiencies of your aseptic fill area (observation 7 in the issued FDA Form 483) and an overall lack of adequate design and control of your operation to reliably prevent product contamination. We also note that your firm had multiple instances of “cloudy” or “unclear” product that was either rejected, or retested and released, without root cause investigation and remediation. We remain concerned about your failure to conduct sterility and endotoxin testing at the end of your drug products’ shelf lives (observation 2 in the issued FDA Form 483), contrary to your firm’s established procedures. Such tests are important, as they address whether the container-closure systems are adequate to maintain sterility of the drug product throughout its shelf life. Although you indicated your firm has instituted changes in these and other regards, you have not provided sufficient detail about what those changes are, or provided a response that sufficiently establishes that these and other observed deficiencies have been corrected.
Based on this inspection, it appears that you are producing drugs that violate the Federal Food, Drug, and Cosmetic Act (FDCA).
A. Compounded Drugs Under the FDCA
The FDCA establishes agency jurisdiction over “new drugs,” including compounded drugs. See Medical Ctr. Pharm. v. Mukasey, 536 F.3d 383, 393-94 (5th Cir. 2008) (“compounded drugs are not exempt from the FDCA's ‘new drug’ definition, § 321(p)”). The drugs that pharmacists compound are not FDA-approved and lack an FDA finding of safety and efficacy. Because compounded drugs are “new drugs” under the FDCA that are unapproved, the statute generally prohibits their introduction into interstate commerce.
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 U.S. 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 drug, or diluted dosages for children. As a matter of agency discretion, FDA has historically not taken enforcement action against traditional compounding in recognition of the benefit that it affords patients when FDA‑approved, commercially available drugs are inadequate or unavailable.
In 1997, Congress enacted, as part of the Food and Drug Administration Modernization Act of 1997 (FDAMA), a provision that related to pharmacy compounding, codified in section 503A of the FDCA (21 U.S.C. § 353a). In 2001, the Ninth Circuit Court of Appeals declared this section invalid because it included unconstitutional restrictions on commercial speech and those restrictions could not be severed from the rest of section 503A. Western States Medical Center v. Shalala, 238 F.3d 1090 (9th Cir. 2001). The Supreme Court affirmed the Ninth Circuit ruling that the advertising restrictions violated the First Amendment, but it did not consider whether these restrictions could be severed from the rest of section 503A. Thompson v. Western States Medical Center, 535 U.S. 357 (2002). In 2008, the Fifth Circuit Court of Appeals held that the restrictions on commercial speech could be severed from the rest of 503A and that the remainder of 503A is valid and in force. Medical Ctr., 536 F.3d at 404. Thus, the decisions of the Fifth and Ninth Circuits directly conflict on whether the non-advertising provisions of section 503A are valid and in effect.
Your facility is located within the Ninth Circuit where section 503A is invalid, and where FDA continues to apply the enforcement policy articulated in Compliance Policy Guide section 460.200 [“Pharmacy Compounding”], issued by FDA on May 29, 2002 (see Notice of Availability, 67 Fed. Reg. 39, 409 (June 7, 2002)) (the “CPG”). The CPG identifies a non-exhaustive list of factors that the Agency considers in deciding whether to initiate an enforcement action with respect to compounding.
The CPG recognizes that traditional pharmacy compounding practice involves receipt of valid prescriptions for individually identified patients prior to distribution of a drug. During the FDA inspection, investigators observed that your firm does not receive valid prescriptions for individually-identified patients for a significant number of drug products you produce. Based on this factor alone, your conduct does not qualify for the agency’s exercise of enforcement discretion set forth in the CPG and remains subject to all of the FDCA’s requirements. In addition, we remind you that there are other factors that FDA considers in determining whether to exercise enforcement discretion under the CPG.
B. Violations of the FDCA
The drug products that you manufacture and distribute are unapproved new drugs and misbranded drugs in violation of sections 505(a) and 502(f)(1) [21 U.S.C. §§ 355(a) and 352(f)(1)] of the FDCA, respectively. In addition, the manufacture of those drugs is subject to FDA’s Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. FDA investigators observed significant CGMP violations at your facility, causing such drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA [21 U.S.C. § 351(a)(2)(B)].
Unapproved New Drug Products
You do not have any FDA-approved applications on file for the drug products you manufacture and distribute, including Methylprednisolone Acetate Sterile Injectable drug (40mg/mL). Under sections 301(d) and 505(a) of the FDCA [21 U.S.C. §§ 331(d) and 355(a)], a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under either section 505 of the FDCA [21 U.S.C. § 355] is in effect for the drug. Your marketing of these drug products, or other applicable drug products, without an approved application violates these provisions of the FDCA.
Misbranded Drug Products
Additionally, because the drug products you manufacture and distribute are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written for them so that a layman can use them safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses, causing them to be misbranded under section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)], and they are not exempt from the requirements of section 502(f)(1) of the FDCA (see, e.g., 21 C.F.R. § 201.115). The introduction or delivery for introduction into interstate commerce of these drug products therefore violates sections 301(a) of the FDCA [21 U.S.C § 331(a)].
Additionally, FDA investigators noted CGMP violations at your facility, causing the drugs you manufacture and distribute to be adulterated under section 501(a)(2)(B) of the FDCA [21 U.S.C. § 351(a)(2)(B)]. The violations include, for example:
1. Your firm failed to establish an adequate air supply filtered through high-efficiency particulate air filters under positive pressure in the aseptic processing areas (21 CFR 211.42(c)(10)(iii)).
2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed (21 C.F.R. 211.192).
3. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).
4. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
5. Your firm failed to establish or follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile and that include validation of all aseptic and sterilization processes [21 CFR 211.113(b)].
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.
In your response to the FDA-483 dated January 10, 2013, as well as your subsequent responses of January 25 and 31, February 5, and March 25, 2013, your firm indicates plans to address our inspectional findings with corrective actions. Because your firm's planned corrections do not meet the minimum requirements of 21 CFR part 211, there is no assurance that the drug product(s) produced by your firm conform to the basic quality standards that ensure safety, identity, strength, quality, and purity. FDA strongly recommends that your management immediately undertake a comprehensive assessment of your manufacturing operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess the acceptability of your aseptic processing operations. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation. Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. Your written reply should be addressed to:
Director, Compliance Branch
U.S. Food and Drug Administration
Irvine, CA 92612-2506
If you have questions regarding any issues in this letter, please contact Ms. Jessica Mu, Compliance Officer, by calling 949-608-4477.
Alonza E. Cruse, Director
Los Angeles District
Virginia Herold, Executive Officer
California State Board of Pharmacy
1625 N. Market Boulevard, Suite N-219
Sacramento, CA 95834
Hugo Cornejo, Acting Chief
California Department of Public Health
Food and Drug Branch
1500 Capitol Avenue MS 7602
PO Box 997435
Sacramento, CA 95899-7435
Attn: FDA Correspondence
 See CPG at 2 (“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.”) (emphasis added); see also CPG at 3 (stating that FDA will consider enforcement action if the pharmacy compounds “drugs in anticipation of receiving prescriptions, except in very limited quantities in relation to the amounts of drugs compounded after receiving valid prescriptions.”).
 Even if section 503A of the FDCA were valid in the Ninth Circuit, your firm would not qualify for section 503A’s exemptions because those exemptions are available only “if the drug product is compounded for an identified individual patient based on the . . . receipt of a valid prescription order or a notation, approved by the prescribing practitioner, on the prescription order that a compounded product is necessary for the identified patient.” See 21 U.S.C. § 353a(a) (emphasis added).
 The specific products made by your firm are drugs within the meaning of section 201(g) of the FDCA, [21 U.S.C. § 321(g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases. Further, they are “new drugs” within the meaning of section 201(p) of the FDCA [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses.