Exela Pharma Sciences, LLC

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You invalidated, without an adequate root cause investigation, failing growth promotion results, which are used to determine suitability of media used for sterility testing of finished drug products. (b)(4), lot (b)(4), was used in the release sterility testing of multiple application drug products, including, but not limited to, ephedrine sulfate injection 5 mg/mL, potassium acetate injection 2 mEq/mL, folic acid injection 5 mg/mL, tranexamic acid injection 10 mg/mL, cupric chloride injection 1 mg/mL, glycopyrrolate injection 0.2 mg/mL, sodium bicarbonate injection 1 mEq/mL, nicardipine HCl 2.5 mg/mL, fentanyl citrate injection 50 mcg/mL, sodium nitroprusside injection 0.2 mg/mL, streptomycin injection, ibuprofen lysine injection 10 mg/mL, caffeine citrate injection 20 mg/mL, palonosetron HCl 0.125 mg/mL, pentamidine isethionate for inhalation, zinc chloride injection, and argatroban injection 100 mg/mL, despite growth promotion testing failing twice and passing on a third test.

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You invalidated, without an adequate root cause investigation, out-of-specification (OOS) results for sub-visible particulate matter testing of (b)(4) batches of sodium bicarbonate injection when one of (b)(4) vials failed. Your investigation documented that (b)(4) were observed in the sample (b)(4) for the failing vial, and the analyst was instructed to (b)(4) the line to clear the (b)(4). When a retest of the vial did not confirm the original results, you prepared new vials which gave passing results. Although you identified the root cause as related to human error, no corrective action or training was implemented to prevent recurrence.

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You failed to accurately document microbiology testing results. In addition, test results are not verified by a second person for accuracy. Specifically, on November 6, 2024, your analyst recorded fewer colony forming units for active air environmental monitoring samples than what was observed by our investigator during the examination. An independent review of the plate count by a second analyst to assure accuracy of the data was not conducted.

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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 (21 CFR 211.100(a)).

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Your firm failed to conduct laboratory testing to determine whether each batch of drug product purporting to be sterile conforms to such requirements (21 CFR 211.167(a)).

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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).

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Laboratory records are deficient in that they do not include the initials and signature of the second person reviewing the record for accuracy (21 CFR 211.194(a)(8)).

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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)).

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Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions (21 CFR 211.25(a)).

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Your firm failed to establish acceptance criteria for the sampling and testing conducted by the quality control unit that are adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release (21 CFR 211.165(d)).

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Your firm used (b)(4) media lot (b)(4) to release sterility testing of Sodium Acetate Injection (in vials). However, two tests of lot (b)(4) were invalidated and the third test was passed without scientific rationale. Your firm's investigation, QE-000487, states human performance was determined to be the root cause of the failed testing events. However, your firm did not document any specific human error identified when testing the (b)(4) media.

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You failed to perform contemporaneous two-person checks during the reading of environmental (b)(4) plates and subsequent data entry of the results in your (b)(4) software system. A single analyst reads environmental plate counts, takes pictures only of the positive counts, and then enters results in the (b)(4) software system. The Quality Control (QC) personnel later review and verify the results in the (b)(4) software system. There is no assurance the analyst read plate counts accurately or entered data in the software system accurately. On November 6, 2024, an FDA investigator observed miscounted plates with discrepancies when compared to the analyst’s count which were later corrected by the analyst.

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Regarding your failing to have stability data to support a six-month expiration date for Sodium Chloride 0.9%, USP packaged in 500 mL polypropylene IV bags from a batch size of (b)(4) produced on the “(b)(4)” line in the (b)(4) building, your firm was not adhering to your SOP-QA-000064, “Stability Policy and Guidelines for Establishing Expiration Date or Beyond Use Date of 503B Product.” Section 6.1.5, of the SOP, states stability protocols will be established, and studies will be conducted for variations of 503B products.

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Regarding your firm’s visual inspection program, you committed to developing improvements to your existing visual inspection program, however, no information was provided of what you will do in the meantime before all the corrections have been made, evaluated, and revised, if needed, along with training. In addition, we have the following concerns with your planned corrections: - You state that your defect rates will be based on (b)(4) Visual Inspection of Medicinal Products for Parenteral Use standards. You did not provide any details explaining your rationale for using the (b)(4) or (b)(4) standards. - Deficiencies on the risk assessment of your visual inspection program and process. i. Your risk assessment explains (b)(4) defects ((b)(4)) were not physically represented in the library of defects and concluded that they did not impact the integrity of the unit and, therefore, would have no impact on the patient. However, no information was provided as to why these (b)(4) defects would not impact the integrity of the unit or why the damaged (b)(4) was classified as a major defect rather than critical. ii. Your risk assessment stated, “From the risk ratings and review of other data, although the test sets did not include an example of each defect type identified in SOP-000266, this assessment provides confidence that the robust training program provided adequate training on the identification of defects through the training hours in conjunction with the visual aid of defects….” This assessment appears flawed as it is based on test sets not including an example of each defect type and based on (b)(4) data rather than data collected during the visual inspection phase. iii. It is not apparent if your risk assessment considered whether particulates could be inherent, intrinsic, or extrinsic in nature. It is not clear whether you have established defect (b)(4) with known inherent, intrinsic, or extrinsic defects for particulates. Therefore, it is not known whether visual inspectors can identify those defects during visual inspection. Furthermore, you are classifying all particulates as major defects, and your rationale for this classification is not provided. - Your training or requalification time of (b)(4) periods does not reflect actual visual inspection conditions as documented in your batch record visual inspection worksheets.