New England Life Care, Inc. dba Advanced Compounding Solutions — FDA Warning Letter Findings

Pools of unidentified liquid on the floors of classified rooms in clean status.

Your responses to Observation 4D outline a new process that includes a (b)(4) inspection of the cleanroom suite and associated equipment while your maintenance contractor is conducting their (b)(4) assessment outside the cleanroom suite and references a draft policy (SOP-FE-007, Operation & Maintenance of the Production Suite (Draft)). The updated requirements, as outlined in the responses, were not found in the provided draft policy. The draft policy states that the production suite should be inspected (b)(4) or not exceeding (b)(4) , does not assign the inspection responsibility to the Quality Unit, and does not require that results be reviewed by production and quality management.

Your responses to Observation 4A state that you intend to change the classification of the ISO 8 finished product room to clean, not classified. Your responses do not include a product impact assessment or risk evaluation for this change or an anticipated timeframe.

Your responses to Observation 4C include an Incident Report related to the loose case around cables in the “compounding room”, which states that the root cause of the detached casing was being bumped by one of the hoods when the hood was moved back into place after cleaning. There was no discussion of changes to the cleaning process to prevent the hoods from needing to be moved during routine cleaning. There was no discussion of the potential effect on the hoods and unidirectional airflow from movement of the hoods during routine cleaning.

Your responses to Observation 1C indicate that your firm considers the current complaint process and procedure, as outlined in SOP-QA-006, adequate and do not intend on making changes. However, our investigators found the one complaint reviewed during the inspection, that was handled under the new procedure, to be inadequate. Specifically, Complaint Record PQC-21-001 was opened October 20, 2021, and was reviewed by our investigators during the inspection. Our investigators…

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)).

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)).

An operator placed components and equipment within the ISO 5 work area that had the potential to block the movement of first air to critical in-process operations.

Your responses to Observation 5B state you have remediated the blockage of the air returns by removing the laminar flow hood (LFH) located in the southwest corner of the “compounding room.” No updated diagram showing the updated layout and location of the LFHs in the “compounding room” was provided. The Form FDA 483 identifies the LFH located in the southwest corner as 34LFH-07. However, the maintenance record dated May 22, 2022, provided with your firm’s August 2022 response, states, “Removed LFH-05 from the general “compounding room.” LFH-05 is stored in the warehouse.” It is unclear from the information available whether LFH-05 in the maintenance record is the same hood as 34LFH-07 or if it is 32LFH-05. There is no explanation in the response how removal of hood 32LFH-05 would remediate the blockage of the air returns. The responses do not explain whether the remaining hoods were relocated or moved within the “compounding room.” Some of your corrective actions appear deficient…

In your responses to Observation 2B, you provided draft SOP-PROD-011, Filling of Bulk Drug Products, which includes photos to show where air samplers should be located. In (b)(4) (for (b)(4) and (b)(4) ), the air samplers appear to be in the same location as observed during the inspection, in the back of the hood, up against the HEPA filters, which not only blocks first air to any objects placed in front of them, but also does not represent conditions at the critical…

Your aseptic processing areas included areas that were difficult to clean, including but not limited to, scratches on the work surfaces of all (b)(4) laminar flow hoods.

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).

An operator rested their hands on the work surface of the hood during aseptic production.

Your smoke studies do not demonstrate adequate airflow throughout the entire production process, from introduction of materials into the hood through completion of compounding. Your smoke study videos include smoke that is directed only at the given port where an aseptic connection or manipulation is being performed. It does not provide assurance that other movements, activities, operations, or materials placement does not allow or promote the ingress of air from the…

Your firm failed to establish an adequate air supply filtered through high-efficiency particulate air filters under positive pressure in the aseptic processing areas (21 CFR 211.42(c)(10)(iii)). 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…

DEV-22-024, submitted in support of your response to Observation 3B, states your firm will implement random auditing of (b)(4) that will be conducted at least (b)(4) by the Director of Quality or designee as an immediate corrective action. No supporting documentation was provided to determine how the audits will be conducted (in person vs. review of video recordings), the timeframe for their initiation, or how identified deficiencies will be handled.

Your responses fail to address any of the individual investigations and complaints cited in Observation 1. Your responses do not indicate whether the cited investigations were conducted if absent or reopened if previously closed, if product impact and/or risk assessments were completed, or if there were resulting corrective and/or preventive actions (CAPAs).

Your responses to Observation 3B state that your firm determined the scratches observed on the decks of the ISO 5 hoods to be normal wear and are not deep enough to significantly impact the work surface of the ISO 5 space. Your responses failed to provide your documented justification/risk evaluation for that determination.

Your responses to Observation 4 (specifically 4A and 4C) do not address pest control, do not include an evaluation of the damaged rubber gaskets and floor sweeps as they relate to the pests identified in the compounding suite, and do not include any updated pest control plans pending repair of the doors. Your responses did not address what immediate corrective actions were taken, if any, to prevent the ingress of pests into the compounding suite in the over (b)(4) timeframe before the doors were repaired.

Your responses to Observation 3B include a Maintenance report from July 29, 2022 – July 31, 2022, where multiple repairs and updates to the cleanroom and LFHs were documented. The maintenance report email describes unplugging and disassembly of LFHs (removal of (b)(4) and removal of (b)(4) screens to facilitate cleaning of the screens and (b)(4) of the (b)(4) worksurface). Your responses fail to address what actions were taken prior to returning the LFHs to service (e.g., cleanings and requalification) for sterile operations.

Your facility is maintained in a way that may permit the influx of lesser quality air into a higher quality air area and fails to prevent pests from entering classified spaces. Your firm had at least five documented instances where pests were found in the “compounding suite” from June 2020 through September 2021.

Your responses to Observation 3B also state that material sanitization was the primary topic during your (b)(4) CGMP training. No details related to the date, trainer, trainees, or content of training were included in the responses.

Your responses to Observation 2A state that the use of (b)(4) is no longer allowed. The responses included product information for a (b)(4) solution to be used in the (b)(4) and a (b)(4) that you stated should (b)(4) as well. There was no updated procedure provided to explain when and how the (b)(4) solution would be applied during gowning. Your May 19, 2022, response included draft SOP-PROD-017, Gowning and Hand Hygiene, which your response cover letter stated required the use of (b)(4) solution on the (b)(4) . However, that language was not found in the included draft procedure. Your responses also stated that the relative humidity of the general “compounding rooms” was (b)(4) , but no additional details were provided.

Your responses to Observation 3A do not address the differences in your planned disinfectant efficacy study and the approved protocol/completed study from (b)(4) . It is unclear if the remaining variables from VP31.01 will be included in later studies, or what the anticipated timeframe would be. The noted differences between the approved protocol/completed study from (b)(4) and your planned study under VP31.01 include, but are not limited to: • The intended study design was…

Your firm failed to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair (21 CFR 211.58).

Your responses to Observation 3B include an email from your cleaning contractor that included their suggestion on how to prevent standing cleaning fluid on the floors of the cleanroom suite (via a (b)(4) ). Your responses focus on the use of the contractor and fail to discuss the cleaning contractor’s recommendations. No supporting documentation was provided to demonstrate that the proposed corrective actions were implemented.

Your firm failed to establish and follow adequate written procedures describing the handling of all written and oral complaints regarding a drug product, including provisions for review by the quality control unit of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with 21 CFR 211.192 (21 CFR 211.198(a)).

Multiple air returns in your ISO 7 “compounding room” were observed to be either fully or mostly blocked by your laminar flow hoods. 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…

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.

Your responses to Observation 1B appear to solely focuses on improvements to be made to the investigation process. Your responses fail to address any immediate actions that were taken to mitigate the deficiencies pending the implementation of the planned improvements.