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September 17, 2020

Case #:    610545 

WARNING LETTER

Dear Mr. Daley:

From July 23, 2019, to August 6, 2019, a U.S. Food and Drug Administration (FDA) investigator inspected your facility, Randol Mill Pharmacy, located at 1014 N. Fielder Road, Arlington, TX  76012.  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 August 6, 2019.  FDA acknowledges receipt of your facility’s response, dated August 24, 2019.  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 that your firm did not receive valid prescriptions for individually-identified patients for a portion of the drug products you produced, including LIPOTROPIC INJ. SOL, BENZ/LID/TET ANHY 20/6/10%, BENZ/LI/TET LIP 20/10/10 C, TCA 30% SOL, and ACETONE/ALC 20%/20% SOL.

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:

1.    Personnel engaged in aseptic processing while exposing skin within the ISO 5 aseptic processing area. 

2.    Your firm did not disinfect materials during transfer from the ISO 7 cleanroom into the ISO 5 hood.

3.    Your firm failed to conduct post-use (b)(4) testing on (b)(4) used to sterilize drug products.  Therefore, you do not have assurance that the (b)(4) was integral throughout use.

4.    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. 

5.    Your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within the ISO 5 area.  Therefore, your products intended to be sterile are produced in an environment that may not provide adequate protection against the risk of contamination.

6.    Your ISO 5 classified aseptic processing area had visibly dirty surfaces.  Specifically, white residue was observed on the HEPA filter in your ISO 5 classified laminar airflow hood.

7.    Your firm handled hazardous drug products without adequate containment, segregation, or cleaning of work surfaces and utensils to prevent cross-contamination.  Specifically, your firm utilized non-dedicated utensils and shared work surfaces to produce drug products with no assurance that your cleaning process can deactivate and remove residual drug product.

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 ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)).

3.    Your firm failed to establish 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 have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(c)).

5.    Your firm failed to establish a written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

6.    Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

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.²  Consequently, their labeling fails to bear adequate directions for their intended uses.  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.    Your response states, “All pharmacy personnel involved in aseptic processing will perform media fill tests that represent the most challenging or stressful conditions.” However, you have not provided a media fill protocol or completed results. 

2.    Your response states, “Our pharmacy will perform smoke studies (b)(4) and maintain records. Clean room certification will be conducted under dynamic working conditions.”  However, you did not provide a description of how smoke studies were performed, or alternatively, provide video for the smoke studies.

3.    Your response states, “Our pharmacy will revise our SOP to include using a deactivator on work surfaces after the production of hazardous drug products (non-sterile and sterile) to prevent cross-contamination.”  However, you have not provided your revised cleaning procedures or the specifications for the deactivation agent.

In addition, you did not address certain observations related to insanitary conditions, for example, you have not specifically addressed the lack of disinfection of some materials transferred into the ISO 5 classified aseptic processing areas.

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 and distributing drug products.  

In addition, regarding issues related to the conditions of section 503A of the FDCA, you have not addressed the compounding of drug products for office stock.

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.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. 

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.  

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 case # 610545. 

Please electronically submit your reply, on company letterhead, to Jose R. Lopez, Compliance Officer, at [email protected]. In addition, please submit a signed copy of your response to [email protected] and [email protected].

If you have questions regarding the contents of this letter, you may contact Jose R. Lopez via phone at (787) 729-8603 or email at [email protected].

Sincerely,

/S/
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations, Division II

Cc:  
Allison Vordenbaumen Benz, R.Ph., M.S.
Executive Director
Texas State Board of Pharmacy
333 Guadalupe, Suite 3-500
Austin, Texas 78701-3903
[email protected]  

_________________________

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