Last week, FDA posted two Warning Letters to drug firms. One has already received considerable attention. This one was issued to one of Mylan’s sites in India and is similar to one the company received for another Indian site last year. Additionally, the Warning Letter addresses similar concerns as one issued to a U.S. Mylan site in 2018. That Warning Letter cited issues with solvent recovery and cleaning validation.

Bottom line? Cleaning validation is important and the use of recovered solvents remains problematic as identified in the saratan collection of warning letters from 2018, 2019, and 2020.

Drug Warning and Untitled Letters

Acella Pharmaceuticals, LLC

Acella Pharmaceuticals, LLC (Alpharetta, GA) received a warning letter on August 14, 2020, based on the outcome of an inspection ending January 7, 2020. In addition to the GMP violations, the FDA found the firm’s NP Thyroid drug products adulterated because they failed to conform to compendial standards for strength, quality, or purity. FDA reminded the firm that it is responsible for the quality of drugs made at its CMO regardless of agreements in place with the CMO. NP Thyroid is determined to be a biological product and is being marketed without FDA approval or a valid biologics license. Deficiencies include but are not limited to:

The firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling, and test procedures. Specifications do not meet the USP acceptance criteria for levothyroxine and liothyrinine assay. The firm revised its active ingredient assay specification and stated that no released lots exceeded 110% USP specification during release or stability testing. FDA, however, inspected the CMO who made the product and identified 13 lots made with the previous API supplier that exceeded 100% USP specs during release or stability testing. The firm agreed to voluntarily recall these 13 lots. FDA stated the lots should have been identified in the firm’s earlier investigation and communication.
The Quality unit did not provide adequate oversight of the CMO to ensure the expiration dating claims were supported by adequate data. During the FDA’s inspection of the firm’s CMO there was no long-term stability data to support batches made with API from a new supplier. Validation batches using the API from the new supplier were not placed on long-term stability.
FDA took samples of NP Thyroid 120mg strength and found out-of-specification (OOS) results for both active ingredients.

Mylan Laboratories Limited – Unit 7

Mylan Laboratories Limited – Unit 7 (India) received a Warning Letter based on the outcome of an inspection ending February 28, 2020. Form 483 includes five observations on three pages, an unusually shortlist to result in a Warning Letter.

The warning letter was sent to the company CEO in the United States. The firm’s Unit 8 facility received a Warning Letter on Nov. 5, 2019. In the current Warning Letter, FDA noted that this constitutes repeat deviations at multiple sites and recommended they hire qualified GMP consultants to assist them in coming into GMP compliance. The firm also received a Warning Letter in 2018 that cited failures in cleaning at the firm’s site in Morgantown, W.V.

The firm’s Unit 7 manufactures APIs. It provides one more example of firms cited for inadequate controls, including storage, of recovered solvents. Some of the solvents stored at the site are recovered at CMOs, one of which has been placed on U.S. Import alert and received a Warning Letter. Deficiencies include but are not limited to:

Inadequate cleaning of bulk storage tanks, including those for recovered solvents. The firm did not have adequate cleaning records for a number of non-dedicated bulk storage tanks and used the contents in numerous API processes. The firm admitted that cleaning, storage, and usage records for storage tanks were not documented or maintained prior to October 2019. The firm also stated that impurity profiles of recovered solvents were not performed during the initial evaluation of the solvent recovery CMOs.
Inadequate cleaning and verification program for non-dedicated manufacturing and storage equipment. The method for assessment of cleaning validation was not adequately validated to be capable of detecting and quantitating impurities. The firm referred to corrective actions implemented in response to the November 5, 2019, Warning Letter. FDA stated they remain concerned with practices at the facility, particularly with regard to control of recovered solvents. The firm deemed the cleaning validation program adequate based on the absence of OOS investigations, lack of complaints, and undetected impurity testing. FDA reminded the firm this is not the case, i.e., that testing alone is insufficient to mitigate the potential contamination hazards they observed during the inspection.
The firm failed to implement procedures to evaluate and control impurity risks associated with solvents in the API operations. This included adequate testing of all incoming raw materials to confirm suitability, including establishing impurity profiles for solvents.