May 9,
2014
VIA UPS
WARNING LETTER
(14-ATL-07)
William B. Cheek, Pharmacist and Co-owner
Nature’s Pharmacy & Compounding Center
752 Biltmore Ave
Asheville, NC 28803-2558
Dear Mr. Cheek:
From November 12, 2013 to November 22, 2013, a U.S. Food and Drug
Administration (FDA) investigator conducted an inspection of your facility,
Nature’s Pharmacy & Compounding Center, 752 Biltmore Ave, Asheville, NC
28803-2558. During the inspection, the investigator noted that you were not
receiving valid prescriptions for individually-identified patients for a portion
of the drug products you were producing. In addition, the investigator observed
serious deficiencies in your practices for producing drug products intended or
expected to be sterile, which put patients at risk. For example, your
compounding procedure for Lidocaine 4% solution/personal lubricant (1:1) Gel
used for urethral injection is to mix sterile lidocaine with non-sterile
lubricant in a non-sterile (b)(4) without any further
sterilization before it is filled into sterile bags and sealed. In addition,
your firm failed to demonstrate through appropriate studies that your
(b)(4) is able to provide adequate protection of the area in
which products intended or expected to be sterile are processed. Therefore, your
products may be produced in an environment that poses a significant
contamination risk. In addition, you do not use sterile disinfectants, including
a sporicidal agent, for disinfection of the area. FDA issued a Form FDA 483 to
your firm on November 22, 2013. Furthermore, a lack of sterility assurance
resulted in a voluntary recall of product on November 13, 2013.
Based on this inspection, it appears that you have produced drugs that
violate the Federal Food, Drug, and Cosmetic Act (FDCA).
A. Compounded Drugs Under the FDCA
At the time FDA inspected your facility, there were conflicting judicial
decisions regarding the applicability of section 503A of the FDCA [21 U.S.C.
§ 353a], which exempts compounded drugs from several key statutory requirements
if certain conditions are met. [1] Nevertheless, receipt of valid
prescriptions for individually-identified patients prior to distribution of
compounded drugs was relevant for both section 503A of the FDCA and the agency’s
Compliance Policy Guide 460.200 (CPG) (2002), which was then in effect
[2] During the
FDA inspection, the investigator observed that 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 FDCA and did not qualify for the agency’s exercise of enforcement discretion
set forth in the CPG. [3]
Since FDA inspected your facility, Congress enacted and the President
signed into law the Compounding Quality Act (CQA),[4] which amended FDCA 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 that 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. [5]
In addition, we remind you that there are a number of other conditions that
must be satisfied to qualify for the exemptions in section 503A of the FDCA.
[6]
B. Violations of the FDCA
The drug products that you manufacture and distribute without valid
prescriptions for individually-identified patients are misbranded drugs in
violation of section 502(f)(1) [21 U.S.C. § 352(f)(1)] of the FDCA. In addition,
your drug products intended or expected to be sterile 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
drug products intended or expected to be sterile that you manufacture are
adulterated within the meaning of section 501(a)(2)(A) [21 U.S.C. §
351(a)(2)(A)] of the FDCA. Furthermore, because you manufacture and distribute
drugs without valid prescriptions for individually-identified patients, the
manufacture of those drugs are also subject to FDA’s Current Good Manufacturing
Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of
Federal Regulations (CFR), Parts 210 and 211. An FDA investigator 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)].
Misbranded Drug Products
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 drug products 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). It is also a
prohibited act under section 301(k) of the FDCA [21 U.S.C. § 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.
Adulteration Charges
Additionally, an FDA investigator noted that drug products intended or
expected to be sterile 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 FDCA [21 U.S.C. § 351(a)(2)(A)]. Examples of these
conditions include that your compounding procedure for Lidocaine 4%
solution/personal lubricant (1:1) Gel used for urethral injection is to mix
sterile lidocaine with non-sterile lubricant in a non-sterile (b)(4)
without any further sterilization process before it is filled into
sterile bags and sealed. In addition, your firm failed to demonstrate through
appropriate studies that your (b)(4) is able to provide
adequate protection of the area in which products intended or expected to be
sterile are processed. Therefore, your products may be produced in an
environment that poses a significant contamination risk. Furthermore, you do not
use sterile disinfectants, including a sporicidal agent, for disinfection of the
area.
An FDA investigator 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 FDCA [21 U.S.C. § 351(a)(2)(B)]. The violations include, for example:
1. 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)).
2. Your firm failed to establish an adequate
system for cleaning and disinfecting the room and equipment to produce aseptic
conditions (21 CFR 211.42(c)(10)(v)).
3. Your firm failed to establish an adequate
system for monitoring environmental conditions in aseptic processing areas (21
CFR 211.42(c)(10)(iv)).
4. Your firm did not have, for each batch of
drug product purporting to be sterile and/or pyrogen-free, appropriate
laboratory determination of satisfactory conformance to final specifications for
the drug product (21 CFR 211.167(a)).
5. 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)).
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)).
7. Your firm failed to ensure that
manufacturing personnel wear clothing appropriate to protect drug product from
contamination (21 CFR 211.28(a)).
It is a prohibited act under section 301(k) of the FDCA [21 U.S.C. §
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 adulterated.
C. Corrective Actions
We acknowledge your action on November 13, 2013, to voluntarily recall all
sterile products within expiry, as well as your written response to the Form FDA
483 on November 26, 2013, notifying FDA that you have permanently ceased all
sterile compounding operations.
FDA strongly recommends that if you decide to resume production of sterile
drugs, 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 and design. A third party consultant with relevant sterile
drug manufacturing expertise could be useful in conducting this comprehensive
evaluation.
As discussed above, your firm has manufactured and distributed drugs
without valid prescriptions for individually-identified patients, and the
manufacture of such drugs is subject to FDA’s drug CGMP regulations, 21 CFR
Parts 210 and 211. Before resuming such operations, you should fully implement
corrections that meet the minimum requirements of 21 CFR Part 211 in order to
provide assurance that the drug product(s) produced by your firm conform to the
basic quality standards that ensure safety, identity, strength, quality, and
purity.
You should also correct the violations of FDCA sections 501(a)(2)(A) and
502(f)(1) noted above.
D. Conclusion
The violations cited in this letter are not intended to be an all-inclusive
statement of violations 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.
If you decide to resume sterile operations, 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. FDA may re-inspect to verify
corrective actions have been completed.
Within fifteen working days of receipt of this letter, please notify this
office in writing if you have taken any specific steps to correct violations, or
you may inform us that you do not intend to resume production of sterile
drugs. If you intend to resume production of sterile drugs in the future, please
include an explanation of each step being taken to prevent the recurrence of
violations, as well as copies of related documentation. If you do not believe
that the products discussed above are in violation of the FDCA, include your
reasoning and any supporting information for our consideration. In addition to
taking appropriate corrective actions, you should notify this office prior to
resuming production of any sterile drugs in the future. Your written
notification should be addressed to:
Marie Mathews, Compliance Officer
FDA Atlanta District Office
U.S. Food and Drug Administration
60 8th Street, N.E.
Atlanta, GA 30309
If you have questions regarding any issues in this letter, please contact
our office at 404-253-1161.
Sincerely,
/S/
Ingrid A. Zambrana
District Director
cc: Michael Rodgers, Pharmacist and Co-owner
Nature’s Pharmacy & Compounding Center
752 Biltmore Ave
Asheville, NC 28803-2558
[1] 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).
[2] 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.
[3] 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.”).
[4] Drug Quality and
Security Act, Public Law 113-54, 127 Stat. 587 (Nov. 27, 2013).
[5]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.htm1.
[6] 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.
quote from here
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