Central Admixture Pharmacy Services, Inc. MARCS-CMS 675065 — March 25, 2024

WARNING LETTER

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• Delivery Method: VIA EMAIL CONFIRMED DELIVERY
• Product: Drugs

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• Recipient: Mr. Jose L. Escobedo; Manufacturing Operations Manager; Central Admixture Pharmacy Services, Inc.; 2200 South 43rd Avenue; Phoenix, AZ 85043-3909; United States; (b)(6), (b)(7)(C)

• Issuing Office: Division of Pharmaceutical Quality Operations IV; 19701 Fairchild Road Irvine; Irvine, CA 92612-2506; United States

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WARNING LETTER

March 25, 2024

 

Dear Mr. Escobedo:

You registered your facility with The U.S. Food and Drug Administration as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353b]1  on March 29, 2018, and most recently on November 8, 2023. From June 21, 2023, to July 31, 2023, FDA investigators inspected your facility, CAPS Phoenix located at 2200 South 43rd Avenue, Phoenix, AZ 85043. During the inspection, the investigators noted serious deficiencies in your practices for producing drug products intended or expected to be sterile, which put patients at risk. 

The FDA issued a Form FDA 483 to your facility on July 31, 2023. The FDA acknowledges receipt of your facility’s responses, dated August 21, 2023, and November 21, 2023. The FDA also acknowledges that your firm ceased production of products on August 4, 2023 and ceased distribution of products on July 28, 2023. The FDA further acknowledges that, on July 14, 2023, and August 17, 2023, your firm initiated voluntarily recalls of drug products intended or expected to be sterile due to lack of sterility assurance. 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 the 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.

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.

B. Violations of the FDCA

Adulterated Drug Products

FDA investigators 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 investigators observed that:

1.    Production areas and equipment were visibly dirty.

2.    You did not perform adequate product evaluation and take appropriate corrective action after microbial contamination was recovered within the ISO 5 aseptic processing area.

FDA investigators noted CGMP violations at your facility, that caused your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example:

1.    Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

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 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)).

4.    Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)).

5.    Your firm failed to establish and follow an adequate 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 establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).

7.    Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. The FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. The FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. The 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 the 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.

C. Corrective Actions 

We have reviewed your facility’s responses to the Form FDA 483. We acknowledge receipt of your facility’s responses, dated August 21, 2023, and November 21, 2023. The FDA also acknowledges that your firm ceased production of products on August 4, 2023 and ceased distribution of products on July 28, 2023. The FDA further acknowledges that, on July 14, 2023, and August 17, 2023, your firm initiated voluntarily recalls of drug products intended or expected to be sterile due to lack of sterility assurance. We are unable to fully evaluate some of your corrective actions due to the lack of adequate supporting documentation:

1.    Your response states initiating Corrective and Preventive Actions (CAPAs) and Notice of Quality Events (NQEs) to address the underlying issues. However, your firm did not provide copies of all completed and retroactive investigation reports for, including but not limited to the following: accuracy of data and records for production and analytical testing; environmental monitoring excursions and events; invalid tests and out of specification results; non-conformance events; and releasing drug products before all testing is completed.

2.    In your response regarding unknown peaks for the UPLC amino acid analysis, in part you state that you have revised your cleaning procedures for laboratory glassware, however, you did not provide a cleaning validation report demonstrating the effectiveness of the new cleaning procedure. 

3.    In your response, you note your firm has cleaned the stains caused by the cleaning agents and buffed all floors, however, you did not provide supporting documentation for remediation of the floor stains in Rooms E and F (ISO 7).

4.    In your response, you note the initiation of Change Control CCR-4000314 to refurbish and passivate the ISO 5 workstations, with a change control completion date of September 29, 2023. However, you have not provided supporting documentation regarding the completion of refurbishing and passivating workstations (ISO 5).

5.    Your response states the implementation of (b)(4) sterility testing in addition to the initial, (b)(4) sterility testing to now be performed for (b)(4) products and (b)(4) stability programs per Change Control CCR-4000317. However, you have not provided completed (b)(4) stability studies, to include sterility, for products with (b)(4) that were previously established using (b)(4) studies in lieu of (b)(4) sterility testing. 

6.    Regarding your firm’s electronic documentation management system, you have acknowledged that previously system access and permissions allowed for unauthorized personnel to make changes. However, you have not provided a completed investigation determining if any data or documents were modified or deleted due to the unauthorized access. 

7.    In your response, we acknowledge your continued evaluation of the current sterility testing method validation to address the formal method transfers. Based on your evaluation, your firm will revise sterility and endotoxin method validation SOPs as needed to include method transfer and revise or create any supporting documentation. In addition, you state training of relevant employees will be performed on the updated documents with a target completion date of May 31, 2024. Finally, you state the supplemental validation is being supported by a third-party subject matter expert and is ongoing with an estimated completion date of April 30, 2024. However, as your firm continues to distribute products you have not provided a completed validation report for your firm’s rapid sterility test method demonstrating the method is specific and suitable for its intended purpose.

Some of your corrective actions appear deficient:

1.    Specifically, regarding the stability data for your oxytocin drug products, your firm’s responses did not address the following: 
a.    You do not address the practice of rounding and averaging individual out of specification results and then ultimately reporting as a passing final result.
b.    You do not address the necessary significant figures needed for raw data before rounding and calculating the final reported result.

2.    In your responses, you acknowledge the need to further evaluate your rapid sterility method. As you continue to distribute products, you have not stated that in the interim you will use a compendial method or another validated method for drug product release. Therefore, there is no assurance that your rapid sterility test method is able to provide valid results prior to release of each drug product lot.

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).]

The 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. 

Repeat Violations at Multiple Sites

The FDA identified similar CGMP deficiencies at other facilities in your company’s network. CAPS Allentown and CAPS San Diego were also inspected and cited for CGMP deficiencies and insanitary conditions. These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs is inadequate. 

Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.

D. 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 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 address 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 you have taken to address any violations, or you may inform us that you do not intend to resume production of drugs. If you intend to resume production of drugs in the future, please include an explanation of each step being taken to prevent the recurrence of any violations, as well as copies of related documentation. This letter notifies you of our concerns and provides you an opportunity to address them. If you believe your products are not in violation of the FDCA, include your reasoning and any supporting information for our consideration. In addition to taking appropriate corrective actions, you should notify this office fifteen (15) working days prior to resuming production of any drugs in the future. 

Send your electronic reply to ORAPHARM4_Responses@FDA.HHS.GOV or mail your reply to:

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612-2506

Please identify your response with unique identifier 675065.

If you have any further questions, please contact Compliance Officer Mariza M. Jafary by email at Mariza.Jafary@FDA.HHS.GOV or by phone at (949) 608-2977. 

Sincerely,
/S/
CDR Steven E. Porter, Jr.
Program Division Director
Division of Pharmaceutical Quality Operations IV

SP: np

cc: Jim W. West, President (via (b)(6), (b)(7)(C))
    901 Marcon Blvd. 
    Allentown, PA 18109

• 1See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).