Medaus, Inc. 1/15/14
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Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
New Orleans District
404 BNA Drive
Building 200 – Suite 500
Nashville, TN 37217
Telephone: (615) 366-7801
FAX: (615) 366-7802
January 15, 2014
WARNING LETTER NO. 2014-NOL-09
UNITED PARCEL SERVICE
DELIVERY SIGNATURE REQUESTED
Steven L. Russell, President and CEO
6801 Cahaba Valley Road, Suite 116
Birmingham, Alabama 35244
Dear Mr. Russell:
During March 18 through 22, 2013, U.S. Food and Drug Administration (FDA) and Alabama State Board of Pharmacy investigators inspected your facility, located at 6801 Cahaba Valley Road, Suite 116, Birmingham, Alabama. During the inspection, the investigators noted your firm was not receiving valid prescriptions for individually-identified patients for a portion of the drug products you were producing. In addition, the investigators observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk. For example, we observed technicians wearing non-sterile laboratory coats, hairnets, beard covers, and facemasks while performing aseptic processing. In addition, investigators observed technicians performing aseptic processing with exposed skin.
Furthermore, the room in which the ISO 5 area is located and sterile drugs are manipulated is not suitable for aseptic processing, in particular the ceiling includes unsealed panels and lacks HEPA filters. The design of the hoods has not been demonstrated to provide adequate protection of the ISO 5 area, and the unidirectional airflow of the ISO 5 area appears to be vulnerable to interference by lower quality room air. In addition, your firm labels your products with expiration dates (in some cases up to 180 days) that have not been established by appropriate stability testing. These observations were noted on a Form FDA 483, issued on March 22, 2013.
Based on this inspection, it appears your firm is producing drugs that violate the Federal Food, Drug, and Cosmetic Act (the Act).
A. Compounded Drugs under the Act
At the time FDA inspected your facility, there were conflicting judicial decisions regarding the applicability of Section 503A of the Act [21 United States Code
(USC) 353a], which exempts compounded drugs from several key statutory requirements if certain conditions are met.
Nevertheless, receipt of valid prescriptions for individually-identified patients before distribution of compounded drugs was relevant for both Section 503A of the Act and the FDA’s Compliance Policy Guide 460.200 on Pharmacy Compounding (CPG) (2002), which was then in effect.
During the inspection, investigators observed your firm does not receive valid prescriptions for individually-identified patients for a portion of the drug products you produce. Based on this factor alone, those drugs were not entitled to the statutory exemptions for compounded drugs described in Section 503A of the Act and did not qualify for FDA’s exercise of enforcement discretion set forth in the CPG.
Since FDA inspected your facility, Congress enacted and the President signed into law the Compounding Quality Act (CQA)
, which amended the Act Section 503A by eliminating the advertising restrictions that had been the basis for conflicting judicial decisions. The CQA otherwise left Section 503A intact, and so clarified the remainder of Section 503A, including the requirement of valid prescriptions for individually-identified patients, is applicable in every federal judicial circuit. Accordingly, the drugs you compound without valid prescriptions for individually-identified patients are not entitled to the exemptions in Section 503A.
In addition, we remind you there are a number of other conditions that must be satisfied to qualify for the exemptions in Section 503A of the Act.
B. Violations of the Act
Because the drug products your firm manufactures and distributes without valid prescriptions for individually-identified patients are not the subject of approved applications, they are unapproved new drugs and misbranded drugs in violation of Sections 505(a) and 502(f)(1) [21 USC 355(a) and 352(f)(1)] of the Act, respectively. In addition, your sterile drug products are prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth, or whereby they may have been rendered injurious to health. As such, all sterile products you manufacture are adulterated within the meaning of Section 501(a)(2)(A) [21 USC 351(a)(2)(A)] of the Act. Furthermore, because you manufacture and distribute drugs without valid prescriptions for individually-identified patients, the manufacture of those drugs is also subject to FDA’s Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211 (21 CFR 210 and 211). FDA investigators observed significant CGMP violations at your facility, causing such drug products to be adulterated within the meaning of Section 501(a)(2)(B) of the Act [21 USC 351(a)(2)(B)].
Unapproved New Drug Products
You do not have any FDA approved applications on file for the drug products for which you have not obtained valid prescriptions for individually-identified patients.
Under Sections 301(d) and 505(a) of the Act [21 USC 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 Section 505 of the Act [21 USC 355] is in effect for the drug. Your marketing of these products, or other applicable products, without an approved application violates these provisions of the Act.
Misbranded Drug Products
Additionally, because the drug products for which you have not obtained valid prescriptions for individually-identified patients 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 these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended use, causing them to be misbranded under Section 502(f)(1) of the Act [21 USC 352(f)(1)], and they are not exempt from the requirements of Section 502(f)(1) of the Act (see ,e.g., 21 CFR 201.115). The introduction or delivery for introduction into interstate commerce of these products therefore violates Sections 301(a) of the Act [21 USC 331(a)]. It is also a prohibited act under Section 301(k) of the Act [21 USC 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being misbranded.
Additionally, FDA investigators noted your sterile drug products were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under Section 501(a)(2)(A) of the Act [21 USC 351(a)(2)(A)]. For example technicians were wearing non-sterile laboratory coats, hairnets, beard covers, and facemasks while performing aseptic processing. In addition, investigators observed technicians performing aseptic processing with exposed skin. Furthermore, the room in which the ISO 5 area is located and sterile drugs are manipulated is not suitable for aseptic processing, in particular the ceiling includes unsealed panels and lacks HEPA filters. Additionally, the design of the ISO 5 area does not ensure adequate protection of the ISO 5 area, and the unidirectional airflow of the ISO 5 area is vulnerable to interference by lower quality room air.
FDA investigators also noted CGMP violations at your facility, causing the drug products for which you have not obtained valid prescriptions for individually-identified patients to be adulterated under Section 501(a)(2)(B) of the Act [21 USC 351(a)(2)(B)]. The violations include, for example:
1. Your firm failed to ensure its drug product bore an expiration date that was supported by appropriate stability testing [21 CFR 211.137(a)].
2. Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions [21 CFR 211.42(c)(10)(vi)].
3. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination [21 CFR 211.28(a)].
4. Your firm failed to establish and follow appropriate written procedures that are 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)].
5. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas [21 CFR 211.42(c)(10)(iv)].
6. 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)].
C. Corrective Actions
In your April 4, 2013, response to the FDA Form 483 you reference your purported compliance with the United States Pharmacopeia (USP)-National Formulary (NF) General Chapter <797> Pharmaceutical Compounding-- Sterile Preparations, and you objected to any finding of deficiency in relation to your operations. As noted above, your firm manufactures and distributes a portion of drugs without valid prescriptions for individually-identified patients, and the manufacture of such drugs is subject to FDA’s drug CGMP regulations (21 CFR 210 and 211).
FDA strongly recommends your management immediately undertake a comprehensive assessment of your operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess your aseptic processing operations. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation. You should fully implement corrections that meet the minimum requirements of 21 CFR 211 to provide assurance that the drug products produced by your firm conform to the basic quality standards that ensure safety, identity, strength, quality, and purity.
Please note the violations cited in this letter are not intended to be an all-inclusive statement of violations existing 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 ensure 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.
Within 15 working days of receipt of this letter, please notify this office in writing of the specific steps 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.
If the corrective actions cannot be completed within 15 working days, state the reason for the delay and the time frame within which the corrections will be implemented.
Please address your reply to Rebecca A. Asente, Compliance Officer, at the address above. If you have questions regarding the contents of this letter, please contact Ms. Asente via (504) 832-1290 extension 1104.
Patricia K. Schafer
New Orleans District
cc: Alabama State Board of Pharmacy
111 Village Street
Hoover, Alabama 35242
State of Alabama Department of Health
The RSA Tower
201 Monroe Street
Montgomery, Alabama 36104
 Compare Western States Med. Ctr. v. Shalala, 238 F.3d 1090 (9th Cir. 2001) with Medical Ctr. Pharm. v. Mukasey, 536 F.3d 383 (5th Cir. 2008).  The CPG set forth a non-exhaustive list of factors that FDA considered in determining whether to take enforcement action when the scope and nature of a pharmacy's activities raised concerns. This CPG has been withdrawn in light of new legislation. See below.  See 21 U.S.C. § 353a(a) (granting compounded drugs statutory exemptions if, among other things, “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 . . . .”); 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.”).  Drug Quality and Security Act, Public Law 113-54, 127 Stat. 587 (Nov. 27, 2013). The CQA contains a number of other provisions, including new exemptions and requirements for compounders seeking to operate as outsourcing facilities. A discussion of the CQA and the agency’s plans to implement the new law may be found at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/default.htm.  For example, Section 503A also addresses anticipatory compounding, which includes compounding (not distribution) before receipt of a valid prescription order for an individual patient. We are not addressing anticipatory compounding here.  The specific products made by your firm are drugs within the meaning of Section 201(g) of the Act, [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.