- Delivery Method:
- VIA Electronic Mail
Recipient NameAndrew D. Stoker, Pharm. D.
Recipient TitlePharmacist in Charge
- The Compounding Pharmacy
750 Fourth Street SW
Hickory, NC 28602-3401
- Issuing Office:
- Division of Pharmaceutical Quality Operations II
June 5, 2020
Case # 608400
From March 18, 2019, to April 8, 2019, a U.S. Food and Drug Administration (FDA) investigator inspected your facility, The Compounding Pharmacy, located at 750 Fourth Street SW, Hickory, North Carolina 28602. During the inspection, the investigator noted that drug products you produced failed to meet the conditions of section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353a] for exemption from certain provisions of the FDCA. In addition, the investigator noted serious deficiencies in your practices for producing sterile drug products, which put patients at risk.
FDA issued a Form FDA 483 to your firm on April 8, 2019. FDA acknowledges receipt of your facility’s response, on April 16, 2019. Additionally, FDA acknowledges your written statement, dated April 8, 2019, to immediately cease compounding with chloroform and nitrofurazone. Based on this inspection, it appears that you produced drug products that violate the FDCA.
A. Compounded Drug Products Under the FDCA
Section 503A of the FDCA describes the conditions under which human drug products compounded by a licensed pharmacist in a State licensed pharmacy or a Federal facility, or a licensed physician, qualify for exemptions from three sections of the FDCA: compliance with current good manufacturing practice (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)].1 Receipt of valid prescriptions for individually-identified patients is one of the conditions for the exemptions under section 503A.
Another condition for the exemptions under section 503A of the FDCA is that the licensed pharmacist or licensed physician does not compound a drug product that appears on a list published by FDA at Title 21 CFR Part 216 of drugs that have been withdrawn or removed from the market because such drug products or components of such drug products have been found to be unsafe or not effective (section 503A(b)(C)).
B. Failure to Meet the Conditions of Section 503A
During the inspection, the FDA investigator noted that drug products produced by your firm failed to meet the conditions of section 503A. Specifically, the investigator noted that your firm compounded chloroform and nitrofurazone, which appear on the withdrawn or removed list at 21 CFR §216.24.2
Therefore, you compounded drug products that do not meet the conditions of section 503A and are not eligible for the exemptions in that section, including the FDA approval requirement of section 505 of the FDCA, the requirement under section 502(f)(1) of the FDCA that labeling bear adequate directions for use, and the requirement of compliance with CGMP under section 501(a)(2)(B) of the FDCA. In the remainder of this letter, we refer to your drug products that do not qualify for exemptions under section 503A as the “ineligible drug products.”
Specific violations are described below.
C. Violations of the FDCA
Adulterated Drug Products
The FDA investigator noted that drug products 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, your firm produced drug products with materials that had not been verified to assure that they did not contribute endotoxin contamination that may be objectionable given the product’s intended use.
In addition, the investigator observed the bottom surface of a (b)(4) horizontal laminar flow hood was composed of a porous, particle-generating, and hard to clean material; an unsealed, loose ceiling tile containing a cracked ceiling light cover was observed in the cleanroom; and chipped paint was observed around the door frames of the anteroom leading into ISO 7 buffer room.
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.
Misbranded Drug Products
The ineligible drug products you compounded are intended for conditions 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.3 Accordingly, these ineligible drug products are misbranded under section 502(f)(1) of the FDCA. 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.
D. Corrective Actions
We have reviewed your firm’s response to the Form FDA 483.
Regarding your response related to the insanitary conditions, we cannot fully evaluate the adequacy of the following corrective actions described in your response because you did not include sufficient information or supporting documentation:
1. You stated that you “…will (b)(4) ” which “…will be submitted to an outside testing laboratory for endotoxin testing,” and, you will submit “…(b)(4)…” and that incoming API will be tested for endotoxin. However, no supporting documentation was submitted with your response. In addition, your firm did not address procedures for predetermining the endotoxin burden of the non-sterile components on all your intrathecal drug products.
2. Your stated that the bottom of the hood “…will be painted with an (b)(4) that may exist in the material…” and surfaces will be caulked with a “cleanroom grade (b)(4).” However, we remain concerned with porous equipment in the aseptic processing area which you have not addressed. In addition, it is unclear if the surface can be easily cleaned and disinfected, and if applying paint to the underside of the hood is appropriate and suitable to prevent particulate formation and to prevent the accumulation of microorganisms and other contaminants.
3. You stated that the cracked light cover located in an unsealed, loose ceiling tile in the cleanroom will be replaced and resealed. However, no supporting documentation was submitted with your response.
4. You stated that all chipped surfaces in the anteroom will be repainted and “Door frames will be monitored and inspected during (b)(4) and (b)(4) cleaning to identify any future chipped paint and repaired immediately.” However, no supporting documentation was submitted with your response.
Please be aware that section 501(a)(2)(A) of the FDCA concerning insanitary conditions applies regardless of whether drug products you compound meet the conditions of section 503A, including the condition on compounding drug products that do not appear on the withdrawn and removed list published by FDA at Title 21 CFR Part 216.
In addition, regarding issues related to the conditions of section 503A of the FDCA, your corrective actions appear adequate. During the inspection, you provided a written statement that “The Compounding Pharmacy will immediately cease and desist the production of any compounds that contain chloroform and nitrofurazone.”
Should you compound and distribute drug products that do not meet the conditions of section 503A, the compounding and distribution of such drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the drug CGMP regulations. Before doing so, you must comply with the requirements of section 505 and 502(f)(1) and fully implement corrections that meet the minimum requirements of the CGMP regulations.
FDA strongly recommends that your management undertake a comprehensive assessment of operations, including facility design, procedures, personnel, processes, maintenance, materials, and systems. In particular, this review should assess your aseptic processing operations. A third party consultant with relevant sterile drug manufacturing expertise should assist you in conducting this comprehensive evaluation.
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.
Within fifteen (15) working days of receipt of this letter, please notify this office in writing of the specific steps that 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 you cannot complete corrective action within fifteen (15) working days, state the reason for the delay and the time within which you will complete the correction.
Your written notification should refer to the Warning Letter Number above Case #. Please electronically submit your reply, on company letterhead, to: Shawn Larson - Compliance Officer, at ORAPHARM2_Responses@fda.hhs.gov and Shawn.Larson@fda.hhs.gov.
If you have questions regarding the contents of this letter, please contact Dr. Larson at 214-253-5216.
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations,
Wesley V.A. Waters III - Owner
The Compounding Pharmacy
750 Fourth Street SW
Hickory, NC 28602-3401
Jay Campbell, Executive Director
Krystal Stefanyk, Director of Inspections
North Carolina Board of Pharmacy
6015 Farrington Road
Chapel Hill, North Carolina 27517
1 We remind you that there are conditions other than those discussed in this letter that must be satisfied to qualify for the exemptions in section 503A of the FDCA.
2 The withdrawn or removed list includes chloroform and nitrofurazone.
3 Your ineligible drug products are not exempted from the requirements of section 502(f)(1) of the FDCA by regulations issued by the FDA (see, e.g., 21 CFR 201.115).