- Delivery Method:
- VIA Electronic Mail
Recipient NameJoshua A. Eudy
- Family Pharmacy of Statesville, Inc.
208 Old Mocksville Road
Statesville, NC 28625
- Issuing Office:
- Division of Pharmaceutical Quality Operations II
November 6, 2020
Case # 611664
From February 3, 2020, to February 12, 2020, a U.S. Food and Drug Administration (FDA) investigator inspected your facility, Family Pharmacy of Statesville, Inc., located at 208 Old Mocksville Road, Statesville, North Carolina 28625. 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 February 12, 2020. FDA acknowledges receipt of your facility’s response, dated February 25, 2020. 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.
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. For example, the investigator noted your firm did not receive valid prescriptions for individually-identified patients for a portion of the drug products you produced, including (b)(4).
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 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 observed:
1. Your firm did not use a sporicidal agent in the ISO 5 areas.
2. Your firm re-used bottles containing (b)(4), for use in the ISO 5 area, without assurance that the bottles remained sterile after multiple uses. In addition, commercially purchased sterile wipes, for use in the ISO 5 area, were stored in a manner which increases the potential for contamination to be introduced onto the wipes.
3. Your firm handled hazardous drugs products without providing adequate cleaning of work surfaces to prevent cross-contamination.
4. Your facility is designed and operated in a way that may permit the influx of lesser quality air into a higher quality air area. Specifically, material flows directly from an unclassified area into a room in which sterile production occurs via a pass-through window. In addition, the investigator observed dust on the inner door levers of the pass-through, which represent difficult to clean equipment. Furthermore, the anteroom, where gowning occurs prior to aseptic production, did not have HEPA filtration.
5. Your media fills were not performed under the most challenging or stressful conditions. Therefore, there is a lack of assurance that your firm can aseptically produce drug products within your facility.
6. Your firm produced drug products with materials that had not been verified to assure that they did not contribute to endotoxin contamination that may be objectionable given the product’s intended use.
7. Your firm failed to confirm that the quality of water was suitable for its intended use in the production of non-sterile drug products.
Furthermore, the manufacture of the ineligible drug products is subject to FDA’s CGMP regulations, Title 21, Code of Federal Regulations (CFR), parts 210 and 211. The FDA investigator observed significant CGMP violations at your facility, causing the ineligible drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA.
The violations included, for example:
1. 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)).
2. Your firm failed to adequately design the facility with adequate separation or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(b)).
3. 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)).
4. Your firm failed to use appropriate air filtration systems for production areas (21 CFR 211.46(c)).
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.2 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 responses related to the insanitary conditions, some of your corrective actions appear adequate; however, 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. Regarding the use of a sporicidal agent in the ISO 5 areas:
- You state that you have amended your cleaning procedures to include the use of (b)(4) in the ISO 5 areas; however, you did not provide supporting documentation such as an invoice, purchase order, or completed cleaning logs.
- Your cleaning procedure documents a contact time of (b)(4) “for maximum disinfection efficacy” for (b)(4); however, (b)(4) are not adequate for sporicidal efficacy.
- Your cleaning procedure did not address how cleaning will be conducted in response to adverse environmental monitoring sample results (excursions), and your procedure documents the use of a non-sterile and non-cleanroom compliant disinfectant to be used in the “cleanroom facility” ((b)(4)).
- You did not provide evidence of re-training on cleaning procedures such as training materials and training records.
2. You state that you have updated your cleaning procedures to include use of (b)(4) in the ISO 5 areas and (b)(4). However, you did not address the issue of (b)(4) in the non-classified pass-through box, and it is unclear where the newly purchased (b)(4) will be stored when opened and not in use. In addition, you did not provide evidence of re-training such as training materials and training records.
3. You state that you have updated your procedure for hazardous drug cleaning and will (b)(4) to clean the interior of the laminar airflow workbench. However, you did not provide evidence of retraining such as training materials and training records.
4. Regarding the pass-through box:
- You state that you have updated your cleaning procedure to include cleaning of the pass-through box. However, we remain concerned with this set up as unclassified air may be introduced directly into the cleanroom in which sterile production occurs. In addition, you have not adequately addressed the difficult to clean levers within the pass-through box.
- You have not provided evidence (e.g., photographs) of the cleaning to remove dust that was accumulated in the ceiling vent above the pass-through box.
- You did not provide evidence of re-training such as training materials and training records.
5. Regarding the anteroom HEPA filtration, you state that you have contacted a vendor to add a HEPA filter to your anteroom. However, you have not provided an update or a completion date of when the HEPA filter was or will be added to the anteroom. If the HEPA filter has been installed, a cleanroom re-certification has not been submitted post-construction.
6. You state that you now have (b)(4) to closely simulate “the most complex operations” performed routinely at your firm. However, you have not provided a timeframe for completion of (b)(4), and if completed, you have not provided the results for our review.
7. You state that you discontinued the use of (b)(4) in non-sterile drug products. However, you did not provide supporting documentation such as a revised procedure and you did not provide evidence of re-training such as training materials and training records.
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 receipt of a prescription for an identified individual patient prior to compounding.
In addition, you did not address issues related to the conditions of section 503A of the FDCA. Specifically, you have not addressed the compounding of drug products without receipt of valid prescriptions for individually-identified patients.
Should you continue to 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.3
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. 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 produce are neither adulterated nor misbranded. [See 21 CFR 210.1(b), 21 CFR 200.10(b)].
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.
In addition, based on our review of photographic evidence obtained by the FDA investigator during the inspection of your facility, the Agency is concerned with the suitability of the work surfaces within your ISO 5 production area. Specifically, the work surface inside your vertical laminar flow hood appears to have multiple unsealed holes in the critical area, which may be difficult to clean and may allow the influx of lesser quality air. Furthermore, there appears to be multiple ledges inside the ISO 5 area. These ledges appear to have signs of wear, are located in front of the direct compounding area, appear difficult to clean, may increase the likelihood of microbial contamination, and may impact and compromise unidirectional airflow in the ISO 5 area. This is concerning because aseptic manipulations are conducted near the holes and directly in front of these ledges. As part of your response, provide supporting documentation to demonstrate that this hood is suitable for use and that the holes and ledges within the ISO 5 classified area do block or disrupt first pass air.
Your written notification should refer to the Warning Letter Number above (Case # 611664). Please electronically submit your signed reply on your firm’s letterhead to CDR John W. Diehl, M.S., Director, Compliance Branch, at email@example.com and firstname.lastname@example.org.
If you have questions regarding the contents of this letter, you may contact Mr. Thao Ta, Compliance Officer, via phone at 214-253-5217 or e-mail at email@example.com.
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations,
cc: Via Electronic Mail
Joseph M. Eudy, President
Family Pharmacy of Statesville, Inc.
208 Old Mocksville Road
Statesville, North Carolina 28625
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 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).
3 In this letter we do not address whether your proposed corrective actions would resolve the CGMP violations noted above.