French 2019 Good Manufacturing Practice: larger batchs

F. Rioblanc , A. Sabri, T. Storme, O. Bourdon Pharmacie à usage intérieur, CHU Robert Debré (AP-HP), 75019 Paris, France

Context and purpose
French Good Manufacturing Practice (GMP) published in public inquiry in July 2019 would give the possibility to produce up to 7 500 capsules per batch versus 300 previously.
In anticipation of the implementation of this new GPP, we have considered a new manufacturing process to optimize batch management by increasing from 300 to 1,500 capsules per batch. The objective of this work is to assess the feasibility of such a process at the scale of a hospital pharmacy by comparing it to the process used until now.

Material and method
Feasibility test was made on melatonin capsules. Manufacturing sheets have been updated to produce 1,500 capsules per batch and to includ an automated mixing step using a rotary mixer.
An uniformity of mass testing and an uniformity of content testing were realized in accordance with European Pharmacopoeia requierements. Melatonin content was determined by UV-visible spectroscopy.
Only the batches complying with the two tests were retained. We compared the new batches to batches produced in 2019.
The quantitative variables were presented by the mean. Statistical analysis was done using R® software (Student’s test).

We made 12 batchs of 1 mg, 2 mg, 4 mg and 5 mg with our new process. 4 batchs have been refused because non-compliant. The mean melatonin content were 0.989 mg (n = 40, 2 batchs), 1.963 mg (n = 50, 3 batchs), 4.035 mg (n = 20, 2 batchs), 4.758 mg (n = 10, 1 batch) respectively for the theorical dosage of 1 mg, 2 mg, 4 mg and 5 mg. Capsules made with the previous process had a mean melatonin content of 0.980 mg (n = 70, 7 batchs), 2.009 mg (n = 90, 9 batchs), 4.068 mg (n = 80, 8 batchs) and 4.961 mg (n = 90, 9 batch). Statistical analysis did not show significant difference between the two process.
Time requiered to produce and control a batch is estimated at 2.3 hours with the previous process and at 3.9 hours with the new process.

The new process seems to be realisable at the scale of a hospital pharmacy. This one simplified the weighing step of the powders by allowing a maximal difference of 5% in the quantities of powders to be used. Mixing the powders using a rotary mixer optimized this key step.
Increase the number of unit per batch would reduce the number of circulating batchs and so improve the gestion of the product. Moreover, increasing the size of the batches saves time over all the steps with an equivalent number of capsules produced. Thereby, producing 1,500 capsules would be almost 3 times faster with the new process. However, a non-conformity in a 1,500 capsules batch results in a greater loss. In order to assess this compromise, it might be interesting to compare the number of non-compliant batches between the new and the previous process. These tests have enabled us to think about optimizing the production, control, packaging and management of melatonin batches.

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