Warning Letter for US Repacker: Deficienceis in Cleaning and Stabilities

Recommendation

17-19 September 2024

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GMP Compliance and Technology for the Manufacture of Oral Solid Dosage Forms

During an inspection of a US manufacturer's repackaging facility in August 2020, the US FDA discovered various deficiencies which now led to a Warning Letter. The main points of complaint are: Repackaging of products in non-equivalent primary packaging and the lack of cleaning validation of multipurpose equipment. The FDA also disagreed with the function of the company's quality unit.

Missing stability data for primary packaging

The FDA complains that the US manufacturer repackages products in non-equivalent primary packaging. Here, the authority describes a case in which the US manufacturer has repackaged tablets, which according to the USP must be kept 'tight and light-tight', in heat-sealed bags with a transparent side. Although the US manufacturer has recalled all products packaged in this way from the market and wants to do without this type of packaging with a transparent side in the future, this is not sufficient for the FDA. The authority states that opacity is only one important feature of the packaging and other requirements may be important such as the permeability to moisture, to oxygen and the compatibility of the product with the packaging material. The manufacturer also lacks a stability study that would prove the stated shelf life.

Missing Cleaning Validation

The US manufacturer packs its products on non-dedicated lines, so that different products have contact with the product-contacting surfaces of the equipment. The FDA criticizes that there is no cleaning validation for this and therefore no statement about a possible cross contamination. The manufacturer had stated in its response that it would start a cross-validation study using the products that leave the most residues on the surfaces. Samples of these products will then be tested in an external laboratory for possible cross-contamination. The FDA finds this response insufficient. They expect a cleaning validation programme that includes 'worst case' considerations such as products with high toxicity, products with poor solubility in the cleaning agent, difficult to clean parts of the equipment and the determination of the maximum time (hold time) before cleaning is performed.

Inappropriate Quality Unit

Another serious point is the FDA's mentioned failure to establish a quality unit (note: the FDA refers to a Quality Unit (QU) as a quality control and assurance function). The FDA mainly criticizes the final review and the release of batches for the market, which can be carried out by many persons of the company. The FDA does not see a sufficient separation between the groups of people who carry out the repackaging process and the people who are responsible for the release - two functions that must be separated. Although the US company has temporarily appointed an 'experienced person' to take over the quality responsibilities. However, this is not sufficient for the FDA. They state that the independence of this Q function must be ensured. Furthermore, the FDA explicitly points out that the quality unit must be equipped with sufficient authority and resources to fulfill its responsibilities.

Please also see the original FDA's Warning Letter to Calvon Scott & Company for further information.