Inspections, Compliance, Enforcement, and Criminal Investigations

I.V. Specialty, Ltd 4/21/15

  

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

Public Health Service
Food and Drug Administration
 Dallas District
4040 North Central Expressway
Dallas. Texas 75204-3128 

 

April 21, 2015
 
2015-DAL-WL-16
WARNING LETTER
 
UNITED PARCEL SERVICE
 
Sarah A. Herrington, Owner
I.V. Specialty, Ltd.
3200 Steck Avenue, Suite 330                             
Austin, Texas 78757
 
Dear Ms. Herrington:
 
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 February 26, 2014, and at the time of FDA’s inspection from July 14, 2014, to July 22, 2014, your facility, I.V. Specialty, Ltd., located at 3200 Steck Avenue, Suite 330, Austin, Texas, 78757, was registered as an outsourcing facility. Although, as of the date of this letter, your facility is no longer registered as an outsourcing facility, this letter discusses violations identified during the time you were registered as an outsourcing facility. Because you are no longer registered as an outsourcing facility, in the corrective action section, this letter discusses the conditions a compounded drug product must meet in order to qualify for the exemptions under section 503A of the FDCA [21 U.S.C. § 353a].
 
During FDA’s inspection of your facility, the investigators observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk. For example, the investigators observed your operators processing sterile drug products with exposed hair, ears, and forehead. Your personnel were also observed placing materials in an ISO 5 hood without sanitizing them and using non-sterile wipes in an ISO 5 hood.  In addition, your firm failed to utilize a sporicidal cleaning agent to disinfect the ISO 5 horizontal laminar airflow (LAF) hoods. Your firm also failed to demonstrate through appropriate studies that your hoods are able to provide adequate protection of the ISO 5 areas in which sterile products 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 that applied to your facility at the time of the inspection and that are 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 firm on July 22, 2014. FDA acknowledges receipt of your facility’s response, dated August 4, 2014.
 
Based on this inspection, it appears your firm is producing drugs that violate the Federal Food, Drug, and Cosmetic Act (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 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 [21 U.S.C. § 351(a)(2)(A)]. 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 [21 U.S.C. § 351(a)(2)(B)].
 
In addition, FDA investigators observed that your facility failed to meet the conditions of section 503B, which applied to your facility at the time of the inspection.   For example, during the inspection, FDA investigators noted:
 
1.    Some of your facility’s drug products do not include the following information on the labeling: the lot or batch number and the statements, “This is a compounded drug”, “Not for resale”, and “Office Use Only”. (Section 503B(a)(10)(A) of the FDCA [21 U.S.C. § 353b(a)(10)(A)]). In addition, some of your facility’s drug products do not include information on the container to facilitate adverse event reporting (Section 503B(a)(10)(B) of the FDCA [21 U.S.C. § 353b(a)(10)(B)]).
 
2.    Your facility failed to submit a report to FDA upon initial registration as an outsourcing facility in February 2014, and again in June 2014 and December 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 did not meet all of the conditions in section 503B of the FDCA, they were not eligible for the exemptions under section 503B from the FDA approval requirements in section 505 of the FDCA, the requirement under section 502(f)(1) of the FDCA 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 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 [21 U.S.C. § 351(a)(2)(A)]. For example, our investigators observed your operators processing sterile drug products with exposed hair, ears, and forehead. Your personnel were also observed placing materials in an ISO 5 hood without sanitizing them and using non-sterile wipes in an ISO 5 hood. In addition, your firm failed to utilize a sporicidal cleaning agent to disinfect the ISO 5 horizontal LAF hoods. Your firm also failed to demonstrate through appropriate studies that your hoods are able to provide adequate protection of the ISO 5 areas in which sterile products 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 [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 a system for maintaining any equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)).
 
4.    Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug products from contamination (21 CFR 211.28(a)).
 
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 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)).   
 
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.  
 
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.
 
Misbranded Drug Products
 
You compounded 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 [21 U.S.C. § 352(f)(1)]. As stated above, because your compounded drug products did not meet all of the conditions in section 503B of the FDCA, they were 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 [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 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 February 2014, and again in June 2014 and December 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 response submitted August 4, 2014 to the Form FDA 483, you described certain corrective actions you took in response to the Form FDA 483 observations. Although several of your proposed corrective actions appear adequate, others are deficient. For example, you failed to indicate whether the (b)(4) you intend to spray on packaged materials transferred into the ISO 5 LAF hoods will be sterile. Moreover, you failed to describe how the sporicidal agent for use in cleaning the hoods, walls, and floors will be applied (i.e., contact time), the frequency of its application, and how the cleaning activities will be documented.    Additionally, you failed to describe the sterile gowning components, procedures for donning the components, and gowning training for operators. These corrective actions are necessary to address the insanitary conditions identified at your facility, and must be corrected if you continue to compound sterile drugs, regardless of whether you are registered as an outsourcing facility or you seek to compound drugs in accordance with the conditions of section 503A of the FDCA. Section 503A of the FDCA does not provide an exemption from section 501(a)(2)(A) concerning producing drugs under insanitary conditions. 
 
Because your facility is no longer registered as an outsourcing facility, drug products that you produce are no longer eligible to qualify for the exemptions under section 503B of the FDCA. However, they can qualify for the exemptions under section 503A of the FDCA if they are compounded in accordance with all of the conditions of section 503A. Section 503A describes the conditions under which certain compounded human drug products are entitled to exemption from three sections of the FDCA: compliance with CGMP, section 501(a)(2)(B); labeling with adequate directions for use, section 502(f)(1); and FDA approval prior to marketing, section 505 [21 U.S.C. §§ 351(a)(2)(B), 352(f)(1), and 355(a)]. Receipt of valid prescriptions for individually-identified patients is one of the conditions for the exemptions under section 503A. In addition, there are other conditions that must be satisfied to qualify for the exemptions in section 503A of the FDCA.[3] 
 
During the inspection, the investigators noted that you compound and distribute a portion of your drug products without receiving valid prescriptions for identified individual patients. Those drug products would not be eligible for the exemptions under section 503A, and, if the CGMP violations cited above are not corrected, such drugs would be adulterated under section 501(a)(2)(B) of the FDCA. Similarly, those drugs would be misbranded under section 502(f)(1) of the FDCA unless their labeling bears adequate directions for use or they are otherwise exempt from section 502(f)(1) (see, e.g., 21 CFR 201.115). Furthermore, if you continue to produce unapproved new drugs and distribute them in interstate commerce without first receiving prescriptions for individually-identified patients, such drugs would be introduced into interstate commerce in violation of section 505(a) of the FDCA. Drug products that are intended or expected to be sterile would be adulterated under section 501(a)(2)(A) of the FDCA unless the violations noted above are corrected.  
 
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.
 
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 may 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 firm’s response to this letter should be sent to: Dallas District Office, 4040 North Central Expressway, Suite 300, Dallas, Texas 75204. If you have any questions about the contents of this letter, please contact: John W. Diehl, Compliance Officer, at 214-253-5288. 
 
Sincerely,
/S/ 
Reynaldo R. Rodriguez, Jr.
Dallas District Director 
 
 
Cc: 
 
Gay Dodson, RPh, Executive Director
Texas State Board of Pharmacy
William P. Hobby Building
Tower 3, Suite 600
333 Guadalupe Street
Austin, Texas 78701
 
 
Tom Brinck, Manager
Drugs and Medical Devices Group
Texas Department of State Health Services
8407 Wall Street, S-124
Austin, Texas 78714
 

 
[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] 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.

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