Danish Manufacturer receives a so-called Untitled Letter from the FDA due to Deviations from GMP

A Danish pharmaceutical manufacturer of antiallergic products has received a so-called "Untitled Letter" from the FDA after an inspection at his production site in March 2016. The letter was issued because of deviations from diverse GMP rules. Unlike a Warning Letter, an Untitled Letter is issued by the FDA when there is no immediate danger for patients' health if the deviations observed are not corrected immediately. The FDA therefore uses such letters for less serious GMP deviations. By contrast with a Warning Letter, an Untitled Letter contains no statement warning the manufacturer that failure to promptly correct a violation may result in an enforcement action.

A Form 483 preceded the present Untitled Letter. This form contained all the inspection observations which - for the FDA - haven't been sufficiently reacted to. But also repeated deviations which had already been identified during an inspection in 2014 in the USA have been admonished.

In detail, the violations are:

Deviations in aseptic manufacturing due to inappropriate measures to prevent microbiological contamination

• The WFI system has not been properly tested for TOC and endotoxins at the points of use.
• There is no procedure in place to specify how to handle exceedings of microbiological limits.
• Environmental isolates are not used for growth promotion studies of media used in media fill simulations
• No CAPA measures taken after 80 exceedings of microbiological limits (within 2 years).

Insufficient calibration and inspection/maintenance of automatic, mechanical or electronic equipment

• Missing re-qualification of a lyophilizer (since 2000)
• Abortion of a batch due to the leaking of the lyophilizer
• No maintenance measures taken after malfunctions of the filling machine (e.g. overfilling, empty vials, missing stoppers)

Failure in the stability programme

• There is no procedure in place to describe when and where samples have to be selected for stability testing of the product.
• Since 2014, around 125 stability samples of the drug product and the drug substance haven't been tested at the required time points.

Furthermore, the FDA states that the response of the manufacturer to the Form 483 was insufficient. The FDA criticises that the responses to too many deviations was only that the procedures will be updated and training will be improved. For the FDA, there is a need for further discussion.

Please also see the detailed FDA Untitled Letter to the Danish manufacturer of antiallergic products.