Inspections, Compliance, Enforcement, and Criminal Investigations

RXQ Compounding LLC 5/19/16

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 

Cincinnati District Office
Central Region
6751 Steger Drive
Cincinnati, OH 45237-3097
Telephone: (513) 679-2700
FAX: (513) 679-2761

 

VIA UNITED PARCEL SERVICE
SIGNATURE REQUIRED
 
WARNING LETTER
CIN-16-419670-16
 
 
May 19, 2016
 
Edward J. Zatta, Managing Partner, Owner 
RXQ Compounding LLC
340 W. State Street, Unit 9
Athens, OH 45701-1564
 
Dear Mr. Zatta:
 
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][1] on January 2, 2015, and December 31, 2015. From August 24, 2015, through September 21, 2015, FDA investigators inspected your facility, RXQ Compounding LLC, located at 340 W. State Street, Unit 9, Athens, OH 45701-1564. 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 failed to demonstrate through appropriate studies that your hood is able to provide adequate protection of the ISO 5 area in which sterile drugs are produced. 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 September 21, 2015. FDA acknowledges receipt of your facility’s responses, dated October 12, 2015, and December 4, 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
 
The investigators noted that drug products that are 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, the 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: 
 
1.    Some of your facility’s drug products do not include the following on the product labels: the established name of the drug, the statement of quantity or volume, as appropriate, and the storage and handling instructions. In addition, for some of your drug products, neither the labels on the drug products nor the containers list the inactive ingredients, identified by established name and the quantity or proportion of each ingredient. [Section 503B(a)(10)(A) of the FDCA [21 U.S.C. §353b(a)(10)]].
 
2.    The containers for some of your facility’s drug products do not include information to facilitate adverse event reporting: www.fda.gov/medwatch and 1–800–FDA–1088. [Section 503B(a)(10)(B) of the FDCA [21 U.S.C. §353b(a)(10)]].
 
In addition, your facility failed to submit a report to FDA upon registering as an outsourcing facility in January 2015, 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.[2] 
 
Specific violations are described below.
 
Adulterated Drug Products
 
FDA investigators noted that drug products compounded in your facility that are 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 noted that your firm failed to demonstrate through appropriate studies that your hood is able to provide adequate protection of the ISO 5 area in which sterile drugs are produced. Therefore, your products may be produced in an environment that poses a significant contamination risk.
 
FDA investigators also noted CGMP violations at your facility, causing your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA.  The violations include, for example:
 
1.    Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)).

2.    Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

3.    Your firm failed to establish 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)).

4.    Your firm does 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’s quality control unit failed to approve or reject all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product (21 CFR 211.22(c)).
 
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.[3] 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; therefore, adequate directions for use cannot be written 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).  The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the FDCA. Further, 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 January 2015, 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 October 12, 2015, and December 4, 2015, responses, you described certain corrective actions in response to the Form FDA 483 observations. Although some of your proposed corrective actions appear adequate, others are deficient or could not be evaluated. 
 
For example, you indicated that your firm made numerous changes to its labels and to its SOP on product labeling and accountability to ensure compliance; however, the SOP does not require labeling to include all of the information required by section 503B. Further, your responses did not address the quality unit’s failure to identify deficiencies with the sterile drug product labels and your rationale for not following the product label information procedure. Additionally, the submitted smoke study did not include a demonstration of the air flow within the ISO 5 hood and a determination could not be made on whether the air return vent directly adjacent to the ISO 5 work surface is disruptive to the unidirectional airflow of the hood.   Moreover, the smoke study video did not provide a clear demonstration of your correction to the (b)(4). Your environmental monitoring procedure lacks clarity; for example, the procedure fails to state which growth media should be used. In addition, your media fill procedures are not representative of all processes used in the production of sterile drug products as they do not consider drug processing steps performed outside of your clean room. Also, your finished product endotoxin testing procedure states that endotoxin testing will be conducted on (b)(4), but is not scientifically justified, and this procedure may put patients at risk. 
 
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).]
 
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, 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. Please address your reply to Stephen J. Rabe, Compliance Officer, at the address above.
 
If you have questions regarding the contents of this letter, please contact Mr. Rabe at 513-679-2700, extension 2163.
 
Sincerely,
/S/ 
Steven B. Barber
District Director

[1] See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).
[2] See, e.g., section 503B(a)(11) of the FDCA [21 U.S.C. § 353b(a)(11)].
[3] 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. 

 

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