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EMA requests more stability data for some manufacturing changes

By Zachary Brennan , 14-Apr-2014
Last updated on 14-Apr-2014 at 16:09 GMT

Drugmakers in the EU making changes to their manufacturing processes will have to submit additional stability data, according to a new EMA (European Medicines Agency) guideline.

The guideline describes the stability testing requirements for variations to a marketing authorisation after approval, setting out the differing requirements for changes to active pharmaceutical ingredients (API) and finished dosage form production.

For instance, the EMA says that for variations to the manufacturing process of the active substance, if the quality characteristics/impurity profile of the active substance is changed in a way that may impact the stability of the finished product, six months data on at least two batches of at least pilot scale batch size are recommended.

If the quality characteristics, such as physical characteristics or the impurity profile, of the active substance are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated testing conditions on the active substance before and after the change:

  • For active substances known to be stable: three months data on at least one batch of at least pilot scale batch size; and
  • For active substances known to be unstable: six months data on at least three batches of at least pilot scale batch size are required.

In case of a change to the immediate packaging of a sterile active substance, the EMA requires comparative stability data using long term and accelerated testing conditions of six months in duration on at least 2 batches of at least pilot scale of the active substance.

But in circumstances where conventional dosage forms are used, and when the active substance is known to be stable, comparative stability data of six months in duration on at least two batches of at least pilot scale are recommended.

Six month stability

For critical dosage forms, such as a modified release, or when the active substance is known to be unstable, comparative stability data for six months in duration needs to be performed on at least three primary batches. Two of three batches should be at least pilot scale, while the third batch may be smaller, the EMA recommends.

If a company makes a change to a manufacturing site for part or all of the manufacturing process of the finished product, the EMA says the following approaches may be considered as acceptable:

  • If the quality characteristics of the finished product are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated testing conditions, on the finished product before and after the change;
  • For conventional dosage forms and when the active substance is known to be stable, comparative stability data, 6 months in duration on at least two batches of at least pilot scale are recommended.

Changes in geographical source, manufacturing route or production will also cause a manufacturer to provide additional stability data, according to the guideline.

The guidance comes as the US FDA also has clarified its guidance regarding the stability of generic drugs.

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