Stability of Pharmaceutical Bulk Products - Which Data Are Dossier-Relevant?

The requirements for stability testing of finished medicinal products are well known and described in the relevant guidelines, e.g. ICH Q1 (R2). There, one also finds the information what stability data have to be included in the dossier at which points of the CTD structure. However, there are no statements with regard to pharmaceutical bulk products other than the instruction that they have to be stored "in a suitable way". In order to bridge this information gap, the European Medicines Agency (EMA) has added a total of 6 questions and answers on this topic ("Stability issues of pharmaceutical bulk products use in manufacture of the finished product") to the questions-and-answers section of its website. In the following, you can read two examples of these questions and answers:

5. What data should be provided to support bulk storage and transportation arrangements?

Answer: The maximum storage interval for the bulk product should be declared in the MA dossier, or alternatively, the maximum batch manufacturing time from start of product manufacture to completion of packaging in the final primary container for marketing.
When storage is prolonged (i.e., > 30 days for solid oral dosage forms > 24 hours for sterile products) evidence of the suitability of the proposed container and storage interval / transportation arrangements should be included in the dossier. The data to be provided will be dependent on results of development studies that represent the conditions proposed.
In line with the principles described for finished products in the relevant (V)ICH Guidelines, it is expected that data from pilot scale batches (minimum of 2 batches) stored under conditions that represent the storage conditions for the bulk product will be provided to support storage of bulk products. Unless provided in the dossier, these data should be verified in post-approval stability commitments on commercial scale batches.
Where transportation of bulk between manufacturing sites is proposed, the impact of excursions outside of the original storage conditions should be discussed and, where necessary, supported by accelerated stability data.

6. How should the product shelf-life be calculated when a bulk product is held in storage prior to further processing during the manufacture of the finished product?

Answer: Calculation of the product shelf-life should be in accordance with the CHMP/CVMP Note for guidance on the start of shelf-life of the finished dosage form (CPMP/QWP/072/96 & EMEA/CVMP/453/01). If other methods are proposed, these should be declared and justified through inclusion of batches that represent the full proposed holding intervals of the bulk product (intermediate) in the finished product stability programme.

You can find EMA's Q-and-A section with these questions here.

Please note: Stability testing of pharmaceutical bulk products and important dossier-relevant data are two of the topics discussed during the following ECA events:
Marketing Authorisation Procedures in the EU and the US,  19-21 October 2010, Barcelona
Stability Testing for Drug Substances and Drug Products, 30 November - 1 December 2010, Vienna

Author:
Dr Gerhard Becker
On behalf of the European Compliance Academy (ECA)

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