Inspections, Compliance, Enforcement, and Criminal Investigations

Pharm D Solutions, LLC 12/8/16

 

  

Black HHS-Blue FDA Logo

 

 

 
Dallas District Office
4040 N. Central Expressway, Suite 300
Dallas, Texas 75204 

 

December 8, 2016
 
2017-DAL-WL-06
 
WARNING LETTER
 
UPS OVERNIGHT
 
Mr. Luis R. De Leon, Pharm. D.
Executive Officer and Pharmacist in Charge
Pharm D Solutions, LLC
1304 South Loop West
Houston, Texas 77054
 
Dear Dr. De Leon:
 
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 August 6, 2014, and again on November 6, 2015. Between May 28, 2015, and June 5, 2015, an FDA Investigator inspected your facility, Pharm D Solutions, LLC, located at 1304 South Loop West, Houston, Texas, 77054. During the inspection, the Investigator observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk. For example, the Investigator noted that your firm used non-sterile disinfectants within the aseptic processing areas. In addition, 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 products are produced. Therefore, your products may be produced in an environment that poses a significant contamination risk.
 
In addition, the investigator noted that you failed to meet the conditions under section 503B of the FDCA [21 U.S.C. § 353b] necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain requirements under the FDCA. 
 
FDA issued a FDA 483 to your facility on June 5, 2015. FDA received your firm’s undated response to the FDA 483, and acknowledged receipt of this response on July 2, 2015. FDA also acknowledges your actions on October 12, 2016, to voluntarily recall Testosterone cypionate 200 mg/ml in sesame oil (all lots) and HCG cynacobalam 500 U (lots 09142016 and 09282016) due to mislabeling.
 
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) of the FDCA [21 U.S.C. § 353b(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 investigator 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, the FDA Investigator 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 Investigator observed that your facility failed to meet the conditions of section 503B. For example, during the inspection, the FDA Investigator noted that some of your facility’s drug products do not include the following statements on the label: “This is a compounded drug,” “Office Use Only,” and the date the drug was compounded. Additionally, the containers for some of your facility’s drug products do not include the following 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)]].
 
Furthermore, your facility failed to submit a report to FDA upon initial registration as an outsourcing facility in August 2014, and in 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 have not met all of the conditions in section 503B of the FDCA, they are not eligible for the exemptions under section 503B of the FDCA 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
 
The FDA investigator 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 investigator noted that your firm used non-sterile disinfectants within the aseptic processing areas. In addition, 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 products are produced. Therefore, your products may be produced in an environment that poses a significant contamination risk. 
 
The FDA investigator 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:
 
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 used 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 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 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 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). 
 
In addition, in October 2016, you voluntarily recalled Testosterone cypionate 200 mg/ml in sesame oil (all lots) and HCG cynacobalam 500 U (lots 09142016 and 09282016) due to mislabeling.  Under section 502(a) of the FDCA, a drug product is misbranded if its labeling is false or misleading in any particular. Because the labeling of these drug products was false, they are misbranded under section 502(a) of the FDCA.
 
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 misbranded is a prohibited act. 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 August 2014 and in 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 undated response to the FDA 483 issued to your facility on June 5, 2015, you describe certain corrective actions taken in response to the FDA 483 observations. We also acknowledge your recall of Testosterone cypionate 200 mg/ml in sesame oil (all lots) and HCG cynacobalam 500 U (lots 09142016 and 09282016) due to mislabeling. Although several of your proposed corrective actions appear adequate, others are deficient. For example, your response to our observation of the use of non-sterile disinfectants within the aseptic processing area is not adequate. You stated in your response, “All cleaners used ((b)(4)) are bactericidal agents.” However, we note that these agents are not labeled as sterile or sporicidal, and bacterial and fungal spores may be able to persist within them. The use of non-sterile disinfectants increases the risk of contamination in the aseptic processing area. Your firm also did not commit to perform smoke studies under dynamic conditions.
 
For the remaining proposed corrective actions, some appear adequate but cannot be fully evaluated as your firm did not provide supporting documentation. For example, you did not provide your revised SOPs or log records pertaining to your environmental monitoring, including air and surface sampling as well as records of your pressure differential monitoring during routine production. Furthermore, your response did not indicate appropriate interim actions to address the deficiencies noted until corrections were made. 
 
We acknowledge your stated commitment to correct the observed 503B labeling deficiencies, specifically, to include the statements, “This is a Compounded Drug” and “Office (Hospital) use Only”, on your labels, as well as information to facilitate adverse event reporting on the containers for your facility’s drug products. To clarify, your labeling should state “Office Use Only” not “Office (Hospital) Use Only”. Further, you did not provide documentation that you have made these changes. Please submit the documentation in your response to this warning letter.
 
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 product(s) 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). 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).]
 
E. 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 (2017-DAL-WL-06). Please address your reply to John W. Diehl, Compliance Officer, at the address above.
 
If you have questions regarding the contents of this letter, please contact John Diehl at 214-253-5288.
 
 
Sincerely,
/S/ 
Karlton Watson
Acting Dallas District Director
 
 
CC:
 
Tom Brinck, Manager
Drugs and Medical Devices Group
Texas Department of State Health Services
8407 Wall Street, S-124
Austin, Texas 78714
 
Gay Dodson, RPh, Executive Director
Texas State Board of Pharmacy
William P. Hobby Building
Tower 3, Suite 600
333 Guadalupe Street
Austin, Texas 78701


[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)].

Page Last Updated: 01/17/2017
Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.
Language Assistance Available: Español | 繁體中文 | Tiếng Việt | 한국어 | Tagalog | Русский | العربية | Kreyòl Ayisyen | Français | Polski | Português | Italiano | Deutsch | 日本語 | فارسی | English