FDA Warning Letter: Combination of Returned Capsules from Various Lots into New Batches

At the end of January 2022, the U.S. Food and Drug Administration (FDA) published a Warning Letter dated December 29, 2021, to Health Plus Inc., following an inspection at the firm's drug manufacturing facility in California conducted from June 23 to July 1, 2021. The Warning Letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals.

Handling of Returned Drug Product

According to 21 CFR 211.204, it must be ensured that returned drugs meet appropriate standards of safety, identity, strength, quality and purity prior to redistributing. During the inspection, it came out that the company "combined returned capsules from various lots into new batches with new lot numbers. These new lots did not have uniform character and quality, including capsules that would expire in less than three years." However, the company "then assigned these comingled batches new lot numbers and granted them an additional three-year shelf life."

The company also could not provide documentation of adequate inspection and investigation of the returned product. Apparently, the company has only conducted organoleptic examination on the returned product that was subjected to unknown conditions before return. This procedure is quite rightly classified as unacceptable by the FDA.

Process Validation

Another aspect of the Warning Letter concerns the process validation. According to the FDA, the firm did not adequately validate the process used to manufacture an over-the-counter (OTC) drug product. After changing the formulation, including the removal of multiple components, the company continued to manufacture and release batches of the drug product without issuing a process validation protocol and associated analytical testing report. Thus, successful process qualification studies that are necessary before commercial distribution were not available.

The FDA has drawn up a whole list of actions to be taken, including a detailed summary of the validation programme for ensuring a state of control throughout the product lifecycle and a comprehensive, independent assessment of the change management system.

Method Validation

The company also failed to adequately validate the method for the assay used for the drug product release specification.

For example, the validation of a spectrophotometer method was performed at a different wavelength than the one used during release testing. Thus, the method validation was not conducted at the correct wavelength. In addition, the method validation report did not include system suitability.

Stability Programme

The company's stability programme is also considered inadequate by the FDA. The company failed to perform any stability testing since at least September 2017. Furthermore, no stability data for drug products manufactured using the new formulation could be provided.

The company tried to excuse itself with restrained resources for the Quality Unit (QU) that caused the delay in conducting a stability study. This was, of course, not accepted by the FDA. According to the FDA, the firm has been aware of the inadequacy of its stability program since an inspection conducted in 2013.

Quality Unit 

Finally, the company "failed to establish, review, and approve all procedures, including those which may impact the safety, identity, strength, quality, and purity of your drug product." Specifically, the QU failed to implement SOPs for operating the equipment used to manufacture the drug product.

Based on the inspectional history, the FDA concludes that the company's QU is not fully exercising its authority and responsibilities.

For more detailed information, please see the original FDA Warning Letter to Health Plus Inc.

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