Source: https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm537064.htm
Timestamp: 2019-04-21 06:50:58+00:00

Document:
Mr. Luis R. De Leon, Pharm. D.
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 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.
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.
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.
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.
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)).
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.
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.
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)].
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.
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.

References: § 353
 § 353
 § 353
 § 355
 § 352
 § 360
 §353
 §353
 § 331
 § 353
 § 331