Central Admixture Pharmacy Services, Inc. — FDA Warning Letter Findings

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

Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

Your firm failed to establish adequate written procedures for production and process control designed to assure that drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and to follow all of your written production and process control procedures (21 CFR 211.100(a) and (b)).

Regarding your firm’s failure to thoroughly investigate instances of acceptable quality limit (AQL) failure of the 100% visual inspection process, you stated that Section 6.4.7.A of SOP-CAPS-4000688, Visual Inspection, was revised “ (b)(4) .” SOP-CAPS-4000688, Version 13.0, provided in your response, states in section 6.4.7. “ (b)(4) .”, and section 6.4.7.A states “ (b)(4) per SOP-CAPS-4000693, ‘Notification of Quality Event’.” The procedure does not appear to ensure an investigation will be performed per S…

In your response, regarding your firm’s failure to establish an adequate system for monitoring environmental conditions in aseptic processing areas, you stated that all relevant personnel at the remaining two 503B facilities would be retrained, and that SOP-CAPS-4000582, Environmental Monitoring-503B, would be updated, (b)(4) . You did not provide documentation of employee training, or the updated SOP showing this change.

In your response, regarding your firm’s failure to ensure adequate aseptic technique and disinfection of materials used in aseptic processing, you stated the following, however, supporting documentation was not provided: a. SOP-CAPS-4000175, Aseptic Technique-503B, will be updated to address compounders setting the ISO 5 hood (b)(4) to mitigate gowning sleeves from touching the hood surface. b. SOP-CAPS-4000582, Environmental Monitoring-503B, will be updated to enhance the testing location of gown sleeves to cover the (b)(4) gown that may come in contact with surfaces within the ISO 5 classified spaces, and employees will be trained on the update. c. CAPS commits to studying the use of (b)(4) gloves to mitigate excess gowning sleeve material from hanging on the hood surface. d. CAPS will require (b)(4) skills requalification and testing for all its aseptic production employees. (b)(4) requalification using TM-CAPS-4000388 was updated in the (b)(4) system beginning September 1, 2023.

Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188).

Your response states that your firm is evaluating the current sterility testing method validation in order to address formal (b)(4) per Change Control CCR-4000319, (b)(4) for Sterility and Endotoxin Testing. However, you have not provided supporting (b)(4) documentation demonstrating your firm’s (b)(4) sterility test method is suitable for its intended purpose. Therefore, there is no assurance that your (b)(4) sterility test method is able to provide valid results prior to release of each drug product lot.

Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow such written procedures (21 CFR 211.22(d)).

Surface sampling was conducted after disinfectant was sprayed on surfaces. Therefore, surface sampling results are not representative of the aseptic processing environment and may not provide meaningful results. FDA investigators 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…

In your response, regarding your firm’s failure 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: a. You stated you revamped your investigation report template, RPT-CAPS-4000048, “which provides a thorough investigation into non-conformances that are escalated to a full investigation.” However, you did not provide RPT-CAPS-4000048 in…

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. 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…

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)).

In your response, regarding your firm’s failure to establish and follow adequate written procedures for 100% visual inspection, you stated “CAPS has committed to creating additional visual inspection standards to ensure that operators are qualified using standards covering major and critical defects found in injectable drug products. There will also be documented assurance that these defects are all represented in ‘positive’ samples of CAPS visual inspection standards used for visual inspector qualification. Updated visual inspection standards have been prepared, and CAPS will retrain and requalify all inspectors at the Phoenix and Lehigh Valley facilities by December 15, 2023.” However, you did not provide complete documentation of such, including employee retraining and requalification, and documentation to show which critical and major defects are represented in “positive” samples in visual inspection standards used for inspector qualification.

In your response, regarding your firm’s failure to exercise appropriate controls over access to the HIAC Particulate Matter system, you state that “Control of GxP Laboratory Systems in a GMP Environment (SOP-CAPS-4000857, Exhibit 10-4) will be revised to further clarify the (b)(4) . The (b)(4) and (b)(4) audit trail reviews will help CAPS ensure that (b)(4) .” However, you did not provide documentation of the SOP revision, employee training, or audit trail reviews. Additionally, you stated that “ (b)(4) ”, and “ (b)(4) .” You did not provide the procedures or master plans for review. Some of your corrective actions appear deficient…

Your firm failed to document at the time of performance required laboratory control mechanisms (21 CFR 211.160(a)).

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).

In your response, regarding your firm’s failure to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow such written procedures: a. You discussed, but did not provide documentation of, updates to SOP-CAPS-4000343, Supplier Qualification, FRM-CAPS-4000352, New Supplier Material Selection Request & Approval, and up to date qualifications of critical suppliers in accordance with those documents. b. You stated you are…

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

Your response, regarding your firm’s failure to document laboratory data at the time of performance, did not include documentation to show employee training on COP-CAPS-4000014, Data Integrity Requirements, and training and implementation of the referenced SOP-CAPS 4000390, Controlled Data Sheets, at CAPS remaining 503B sites.

In your response, regarding your firm’s failure to establish and follow an adequate written stability testing program to ensure that drug products remain sterile through the labeled expiration date, you stated that “CAPS shall implement (b)(4) sterility testing … per Change Control CCR-4000317, (b)(4) Sterility and Endotoxin Testing for (b)(4) Stability Program … and update all associated SOPs.” However, you did not provide data to show performance of (b)(4) sterility testing of stability batches, updated SOPs, or employee training records.

You failed to adequately disinfect containers of sterile drug components immediately prior to puncturing critical sites for use in operations.

Your response, regarding your firm’s failure to report and investigate all out of specification finished product test results, states that “ (b)(4) personnel at the two remaining facilities will re-train on SOP-CAPS-4000317 ‘Investigation of Out of Specifications Results for CAPS Quality.’” Documentation of employee training for this SOP was not provided. Additionally, your response provided updated test procedure TP-CAPS-4000041, “ (b)(4) .” However, your response was not clear on whether training would be performed, and documentation of employee training was not provided.

Operators dragged the underside of their gowning sleeves on the work surface of the ISO 5 hood during aseptic production. This practice may introduce contamination into the ISO 5 work area.

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)).

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)).

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

Some of your facility’s drug products, including Ephedrine Sulfate, Fentanyl Citrate, Hydromorphone Hydrochloride, Ketamine Hydrochloride, Succinylcholine Chloride, Vecuronium Bromide, and Lidocaine Hydrochloride did not include the following on the label: the established name of the drug product.

Your facility did not 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 . For example, you failed to submit adverse event reports identified in NEQ-US32-211028-093 and NEQ-US32-221031-167. Because your compounded drug products have not met all of the conditions of section 503B, they are not…