- AnazaoHealth Corporation
- Issuing Office:
- San Francisco District Office
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||1431 Harbor Bay Parkway|
Alameda. CA 94502-7070
Delivery Signature Requested
December 9, 2015
Hal J. Weaver, Vice President, Operations
7465 W. Sunset Road, Suite 1200
Las Vegas, NV 89113
Dear Mr. Weaver,
You registered with the U.S. Food and Drug Administration (FDA) as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353b] on September 23, 2014, and again on December 29, 2014. From January 20, 2015, to January 30, 2015, FDA investigators inspected your facility, AnazaoHealth Corporation, 7465 W. Sunset Road, Suite 1200, Las Vegas, NV 89113. During the inspection, the investigators observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk. For example, the investigators observed that your firm did not use sterile wipes or sterile disinfectants as part of the cleaning and disinfection program for the ISO 7 areas and the ISO 5 hood. Therefore, your products may be produced in an environment that poses a significant contamination risk. In addition, the investigators observed that you failed to meet the conditions under section 503B of the FDCA necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain requirements under the FDCA. FDA issued a Form FDA 483 to your facility on January 30, 2015. FDA acknowledges receipt of your firm’s responses, dated February 19, 2015, and April 15, 2015.
Based on this inspection, it appears your facility is producing drugs that violate the FDCA.
A. Compounded Drugs under the FDCA
The Drug Quality and Security Act (DQSA) was enacted on November 27, 2013. Title I of the DQSA, the Compounding Quality Act (CQA), added a new section 503B to the FDCA. Under section 503B(b), a compounder can register as an outsourcing facility with FDA. Drug products compounded by or under the direct supervision of a licensed pharmacist in an outsourcing facility can qualify for exemptions from the drug approval requirements in section 505 of the FDCA [21 U.S.C. § 355(a)], the requirement in section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)] that labeling bear adequate directions for use and the Drug Supply Chain Security Act requirements in section 582 of the FDCA [21 U.S.C. § 360eee-1] if the conditions in section 503B of the FDCA are met.
An outsourcing facility, which is defined in section 503B(d)(4) of the FDCA [21 U.S.C. § 353b(d)(4)], is a facility at one geographic location or address that — (i) is engaged in the compounding of sterile drugs; (ii) has elected to register as an outsourcing facility; and (iii) complies with all of the requirements of this section. Outsourcing facilities must comply with other provisions of the FDCA, including section 501(a)(2)(B) [21 U.S.C. § 351(a)(2)(B)], regarding current good manufacturing practice (CGMP), and section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)], regarding insanitary conditions. Generally, CGMP requirements for the preparation of drug products are established in Title 21 of the Code of Federal Regulations (CFR) parts 210 and 211.
B. Violations of the FDCA
FDA investigators noted that drug products that were intended or expected to be sterile were prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth or rendered injurious to health, causing them to be adulterated within the meaning of section 501(a)(2)(A) of the FDCA. Furthermore, FDA investigators observed significant CGMP violations at your facility, causing your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA.
In addition, the FDA investigators observed that your facility failed to meet the conditions of section 503B. For example, during the inspection, FDA investigators noted that:
1. Some of your facility’s drug products do not include the following information on the product labels: the statements, “This is a compounded drug” and “Not for resale,” the lot or batch number, the dosage form, the date that the drug was compounded, and storage and handling instructions. In addition, for some of your drug products, neither the labels on the drug products nor the container labels list the active and inactive ingredients, identified by established name and the quantity or proportion of each ingredient. Furthermore, the containers for some of your drug products do not include information to facilitate adverse event reporting (www.fda.gov/medwatch and 1-800-FDA-1088
). [section 503B(a)(10) of the FDCA [21 U.S.C. §353b(a)(10)]].
2. Not all bulk drug substances used by your facility to compound drug products are manufactured by an establishment that is registered under section 510 [section 503B(a)(2)(C)]
3. Your facility failed to submit a report to FDA upon registering as an outsourcing facility in September 2014, identifying the drug products that you compounded during the previous 6-month period [section 503B(b)(2) of the FDCA [21 U.S.C. §353b(b)(2)]].
Because your compounded drug products have not met all of the conditions in section 503B, they are not eligible for the exemptions under section 503B from the FDA approval requirements in section 505, the requirement under section 502(f)(1) that labeling bear adequate directions for use, and the Drug Supply Chain Security Act requirements described in section 582 of the FDCA.
Specific violations are described below.
Adulterated Drug Products
FDA investigators noted that drug products compounded in your facility that were 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. For example, the investigators observed that your firm did not use sterile wipes or sterile disinfectants as part of the cleaning and disinfection program for the ISO 7 areas and the ISO 5 hood.
FDA investigators also noted CGMP violations at your facility, causing your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example:
1. The 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. The firm failed to establish a system for cleaning and disinfecting the room and equipment to produce aseptic conditions (211.42(c)(10)(v)).
3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).
4. The firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. FDA has issued a draft guidance, Current Good Manufacturing Practice — Interim Guidance for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act. This draft guidance, when finalized, will describe FDA’s expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211 until more specific CGMP regulations for outsourcing facilities are promulgated.
Under section 301(a) of the FDCA [21 U.S.C. § 331(a)], the introduction or delivery for introduction into interstate commerce of any drug that is adulterated is a prohibited act. Further, 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 and results in the drug being adulterated.
Unapproved New Drug Products
You do not have any FDA-approved applications on file for your drug products.
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 or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FDCA is in effect for the drug.
Misbranded Drug Products
You compound drug products that are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, and 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 uses, causing them to be misbranded under section 502(f)(1) of the FDCA, and they are not exempt from the requirements of section 502(f)(1) of the FDCA (see, e.g., 21 CFR 201.115). It is a prohibited act under section 301(k) of the FDCA 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 and results in the drug being misbranded.
Failure to Report Drugs
As noted above, your facility failed to submit a report to FDA upon initial registration as an outsourcing facility in September 2014, identifying the drug products that you compounded during the previous 6-month period (Section 503B(b)(2) of the FDCA [21 U.S.C. § 353b(b)(2)]). The failure to report drugs by an entity that is registered with FDA in accordance with section 503B(b) is a prohibited act under section 301(ccc)(3) of the FDCA [21 U.S.C. § 331(ccc)(3)].
C. Corrective Actions
In your February 19, 2015, response you committed to correct the observed 503B labeling deficiencies by including all information required under section 503B on product labels and containers for your facility’s sterile patient-specific drug products, indicating that such information was currently included on labeling for your facility’s non-patient-specific or “outsourced” sterile compounds. However, we reiterate that 503B labeling requirements apply to all drug products produced at your facility, both sterile and non-sterile, and regardless of whether the drug is dispensed or distributed pursuant to a prescription for an individual identified patient (except the statement “Office Use Only” is required only for drugs dispensed or distributed without a patient-specific prescription).
In addition, your February 19, 2015 and April 15, 2015, responses state that you will take or have taken certain corrective actions in response to the Form FDA 483 observations. Although several of your proposed corrective actions appear adequate, others are deficient. For example, the investigations into the sterility failures did not extend to other batches that may have been affected, and the source of the bacteria has not been identified. The updated procedure for your cleaning and disinfecting program does not include specific dwell times for all disinfectants or does not include appropriate scientific justification for the frequency with which a sporicidal agent is used in your facility. Moreover, some corrective actions described in your response do not appear to have been implemented in a timely manner or did not include any appropriate interim actions to address the deficiencies. Specifically, your firm committed to implementing the use of sterile disinfectants by March 1, 2015. The inspection closed on January 30, 2015, and it is unclear what corrective action you undertook regarding the use of non-sterile disinfectants for the interim one-month period.
FDA strongly recommends that 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 necessary corrections in order to ensure that the drug products produced by your firm conform to the basic quality standards that ensure safety, identity, strength, quality, and purity.
In addition to the issues discussed above, you should note that CGMP requires the implementation of quality oversight and controls over the manufacture of drugs, including the safety of raw materials, materials used in drug manufacturing, and finished drug products. See section 501 of the FDCA, as amended by the Food and Drug Administration Safety and Innovation Act (Pub.L. 112-144, Title VII, section 711). We note that you have chosen to hire a contract testing laboratory to perform some of the required testing of your finished drug products. If you choose to contract with a laboratory to perform some functions required by CGMP, it is essential that you select a qualified contractor and that you maintain sufficient oversight of the contractor’s operations to ensure that it is fully CGMP compliant. Regardless of whether you rely on a contract facility, you are responsible for assuring that drugs you introduce into interstate commerce are neither adulterated nor misbranded. [See 21 CFR 210.1(b), 21 CFR 200.10(b).]
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, including 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. FDA intends to re-inspect your facility to verify corrective actions have been completed.
Within fifteen 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 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. If the corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time frame within which the corrections will be completed. Your written notification should refer to the Warning Letter Number above (WL: 460480). Your response should be addressed to:
Lawton W. Lum, Director of Compliance
FDA San Francisco District Office
U.S. Food and Drug Administration
1431 Harbor Bay Parkway
Alameda, CA 94502-7070
If you have questions regarding the contents of this letter, please contact Russell Campbell at 510-337-6861.
Kathleen M. Lewis, J.D.
San Francisco District Director
U.S. Food and Drug Administration
Larry L. Pinson, Executive Secretary
Nevada Board of Pharmacy
431 W. Plumb Ln.
Reno, NV 89509
 See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).  See, e.g., section 503B(a)(11) of the FDCA [21 U.S.C. § 353b(a)(11)].  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 and/or because they are intended to affect the structure or any function of the body. 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.