- Delivery Method:
- VIA Electronic Mail
Recipient NameAbdul Hameed
- American Specialty Pharmacy, Inc. dba ASP Cares
13988 Diplomat Drive, Ste 100
Farmers Branch, TX 75234-8807
- Issuing Office:
- Office of Pharmaceutical Quality Operations, Division II
April 5, 2021
Case # 604003
Your firm was 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 February 14, 2017 and most recently on November 20, 2020.
From August 14, 2018 to August 23, 2018, an FDA investigator inspected your facility, American Specialty Pharmacy, Inc. dba ASP Cares, located at 2414 Babcock Road, Suite 106, San Antonio, Texas 78229. During the inspection, the investigator noted that drug products you produced failed to meet the conditions of section 503B of the FDCA necessary for drugs produced by an outsourcing facility to qualify for exemptions 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 facility on August 23, 2018 and a request for additional information on February 4, 2019. FDA acknowledges receipt of your facility’s responses, dated September 14, 2018 and February 15, 2019. Based on this inspection, it appears you produced drugs that violate the FDCA.
A. Compounded Drug Products under the FDCA
Under section 503B(b) of the FDCA, 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 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.2
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 applicable 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.
In addition, for a compounded drug product to qualify for the exemptions under section 503B, it must be compounded in an outsourcing facility that is in compliance with the reporting requirements in section 503B(b), including the requirement to submit adverse event reports to FDA “in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations)” (see section 503B(a)(1), (b)(5) of the FDCA [21 U.S.C. § 353b(a)(1), (b)(5)]).
B. Failure to Meet the Conditions of Section 503B
During the inspection, the FDA investigator noted that drug products produced by your facility failed to meet the conditions of section 503B. Evidence collected indicates your facility’s drug products were not compounded in an outsourcing facility that is in compliance with the requirements of section 503B(b) (see section 503B(a)(1) of the FDCA). In particular, your facility does not comply with section 503B(b)(5) of the FDCA, which as noted above, requires an outsourcing facility to submit adverse event reports to FDA in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations).3 Specifically, your facility’s procedures for reporting adverse events are inadequate. For example, your documented procedures do not adequately define what constitutes a serious adverse event or unexpected adverse event. Because your compounded drug products have not met all of the conditions of section 503B, they are not eligible for the exemptions in that section from the FDA approval requirements of section 505, the requirement under section 502(f)(1) that labeling bear adequate directions for use, and the Drug Supply Chain Security Act requirements described in section 582 of the FDCA.
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. For example, the investigator observed that:
1. 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.
2. Your media fills were not performed under the most challenging or stressful conditions such as failing to simulate the largest batch size produced at your firm. Therefore, there is a lack of assurance that your firm can aseptically produce drug products within your facility.
3. Your firm’s facilities where sterile drug production occurs is not maintained in an adequate state of repair. For example, the investigator noted a crack in the caulking around the HEPA filter inside the ISO 7 cleanroom ante of Modular 1. Therefore, your products intended to be sterile are produced in an environment that may not provide adequate protection against the risk of contamination.
4. Your firm failed to document and measure pressure differentials during operations to demonstrate proper airflow. Therefore, this indicated a lack of assurance that your firm can aseptically produce drug products in an environment that may not provide adequate protection against the risk of contamination.
The FDA investigator also noted CGMP violations at your facility, that caused your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example:
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 thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
3. Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and your firm’s quality control unit did not review and approve those procedures, including any changes (21 CFR 211.100(a)).
4. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(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 a revised draft guidance, Current Good Manufacturing Practice — 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.
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.
Unapproved New Drug Products
You do not have any FDA-approved applications on file for drug products that you compound.4 Under sections 505(a) and 301(d) of the FDCA [21 U.S.C. §§ 331(d)] a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FDCA is in effect for the drug. Marketing of these products, or other applicable products, without an approved application violates these provisions of the FDCA.
Misbranded Drug Products
You compound drug products that 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 causing them to be misbranded under section 502(f)(1) of the FDCA.5 The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the FDCA. Further, it is also 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 facility’s response to the Form FDA 483.
Some of your corrective actions appear adequate:
1. Your firm has performed media fills that reflect the largest batch size produced by your firm.
2. Your firm performed smoke studies of its ISO 5 areas under appropriate dynamic conditions.
3. Your firm revised your SOP to reflect the new process for sterilization and marking of (b)(4) goggles used in sterile production.
4. Your firm revised and updated Master Production Records to include intermediate hold steps for any batches that are not immediately sterilized or filled into their final container.
5. Your firm revised your SOP for continuous pressure monitoring in your cleanroom, requiring immediate review of any alarms to ensure detection of any pressure logging issues and at a minimum a (b)(4) download and review of alarm logs.
6. Your firm caulked the loose ceiling tile noted on inspection and repeated the cleaning procedure for the cleanroom with a sporicidal agent.
We are unable to fully evaluate some of your corrective actions due to lack of adequate supporting documentation:
1. You state that you have hired a contract laboratory to develop a validated potency test method for your taurine injection, but you have not provided any timeline for implementing this test method and interim steps that your firm is taking to ensure the potency of your taurine injectable product. Additionally, your firm provided no information on how you will ensure the products produced and released by your facility will be tested for identity, potency and any other release testing requirements for each individual product produced at your firm.
Some of your corrective actions appear deficient:
1. Your firm has not addressed the steps of remediation for positive environmental results found in environmental monitoring reports. In addition, your firm failed to conduct investigations into the impact of these environmental excursions on your sterile products.
2. Your firm failed to validate your (b)(4) by ensuring your process can detect the highest and lowest temperature spots within the (b)(4) which provides valuable information on where to place your (b)(4) to ensure sterility of your products is achieved through the (b)(4).
3. Your firm failed to validate your (b)(4) to ensure it can maintain adequate temperatures to achieve required depyrogenation.
4. Your firm stated that the (b)(4) testing result for your sterile products was set below the product specification without providing any scientific rationale to support this interim passing result.
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).]
Regarding issues related to the conditions of section 503B of the FDCA, we have reviewed the Standard Operating Procedure (SOP), SOP Number 8.013 “Adverse Event Reporting”, which describes the “requirement for reporting adverse events for compounded drug products.” This SOP does not appear to adequately address adverse event reporting. For example:
1) Your SOP does not adequately define a serious adverse drug event consistent with the definitions of serious adverse drug event in section 310.305(b);
2) Your SOP does not adequately define an unexpected adverse event consistent with the definitions of unexpected adverse event in section 310.305(b).
As explained above, a facility must comply with adverse event reporting requirements (section 503B(b)(5) of the FDCA [21 U.S.C. §353b(b)(5)]) in order to qualify for the exemptions under section 503B. Furthermore, your procedures for adverse event reporting must also comply with the requirements as specified in 21 CFR 211.198.
Should you continue to compound and distribute drug products that do not meet the conditions of section 503B, the compounding and distribution of your drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the Drug Supply Chain Security Act requirements.
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 any violations 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 any violations. Failure to adequately address any 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 address any violations. Please include an explanation of each step being taken to prevent the recurrence of any violations, as well as copies of related documentation. If you believe that your products are not in violation of the FDCA, include your reasoning and any supporting information for our consideration. If you cannot completely address this matter within fifteen (15) working days, state the reason for the delay and the time within which you will do so.
Your written notification should refer to the Warning Letter Number above (Case # 604003). 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
Jacqueline Esqueda, PharmD.
American Specialty Pharmacy, Inc. dba ASP Cares
2414 Babcock Road, Suite 106
San Antonio, Texas 78229
Allison Vordenbaumen Benz, Executive Director
Texas State Board of Pharmacy
333 Guadalupe Street, Suite 3-500
Austin, Texas 78701-3943
1 See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).
2 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 503B of the FDCA.
3 For more information, see FDA’s guidance, “Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” which can be found at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM434188.pdf.
4 The specific products made by your firm are drugs within the meaning of section 201(g) of the Act, [21 U.S.C. § 321(g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases and/or because they are intended to affect the structure or any function of the body. Further, they are “new drugs” within the meaning of section 201(p) of the FDCA [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses.
5 Your compounded 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).