Sterile Manufacturer receives Warning Letter from US FDA

Recommendation

17-19 September 2024

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

Following an FDA inspection, a manufacturer of sterile medicinal products in the UK has received a Warning Letter due to serious violations of GMP. As often in such cases, the inspection - which took place in March 2016 - was preceded by another one where GMP deviations had been observed but to which the company had responded insufficiently. The first inspection was performed in January 2015 already. The GMP deficiencies have remained in spite of a writing to the company and a meeting with the FDA. Both the company's management oversight and control over the manufacturing process are considered inadequate by the FDA who - thereupon - drafted a Warning Letter. This Warning Letter addresses violations of GMP in the manufacture of both medicinal products and (biotechnological) APIs.

Here are the violations in detail:

Insufficient failure investigation of batches
Particulate matters were found in a batch of a lyophilized product. The cause for that was identified in the manufacturing process of the stopper supplier. The sole measure taken was the addition of a new subcategory of particles in the SOP on the testing of medicinal products. For the FDA, measures concerning the stoppers - i.e. their manufacturing process itself - were missing.

In another batch, fibres were discovered. Here again, the CAPA measures were considered inadequate by the FDA as the potential sources of these fibres - described as paper or cardboard - hadn't been investigated.

Particulate matters found in two other batches were described in the batch record with likely another cause than the stoppers mentioned above. Furthermore, the FDA criticised the lack of strict action limits for certain defects in the visual inspection including extrinsic particles. As a consequence, the FDA called into question the ability of the company to prevent its products from contamination.

Missing Change Controls in the manufacturing of APIs and intermediates
The FDA criticised the missing i.e. inappropriate change management of working cell banks and the associated insufficient assessment of the acceptability of the new cell bank for commercial production. Besides, cell banks were used for commercial production before they had been released. This is a critical element for the FDA as changes - e.g. in the cell line - may have consequences on the identity, purity, quality of the product manufactured.

Please also see the original Warning Letter to Porton Biopharma Limited.