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Chapter 2.9.40 of the European Pharmacopeia is the binding requirement for dosage uniformity. Recently, an additional alternative chapter 2.9.47 has been created titled "Demonstration of Uniformity of Dosage Units using large Sample Sizes".
The European Pharmacopeia has created an additional alternative chapter 2.9.47. Could you tell us more?
Chapter 2.9.40 (Uniformity of dosage units) of the European Pharmacopeia (Ph. Eur.) is based on the text harmonised with the US Pharmacopeia and the Japanese Pharmacopeia in the context of the Pharmacopoeial Discussion Group (PDG), and this will remain the binding requirement. Recently, however, the Ph.Eur. Commission created an additional alternative chapter 2.9.47 titled “Demonstration of Uniformity of Dosage Units using large Sample Sizes”, which is intended for, but not limited to, the evaluation of medicinal products that are manufactured using process analytical technology (PAT) methodology. Compliance with general chapter 2.9.40 Uniformity of dosage units can be demonstrated by using the procedures described in chapter 2.9.47. This new chapter was published in October 2012 in supplement 7.7, and will become official in April 2013.
The chapter allows applicants to use information obtained during the production of tablets, such as from in-line testing by near infrared, to assess the content uniformity of the batch. Background information on this new chapter and the rationale behind can be found in additional articles (1, 2)
How are scored tablets approached in Ph. Eur?
The general chapter, “Uniformity of Dosage Units”, deals with intact tablets and does not include acceptance criteria for scored tablets. However, the Ph.Eur. Commission decided to include requirements on the uniformity of scored tablets in the “Production” section of the general monograph Tablets several years ago. The subsection “Subdivision of tablets” describes how the uniformity of scored tablets should be tested and defines acceptance criteria. These requirements were established in close collaboration with licensing authorities of the Ph. Eur. member states.
How the number of largely deviating units be reduced, and what guidance on the tabletting process as a whole can you offer to manufacturers of scored tablets?
The uniformity of scored tablets depends on the formulation of the tablet itself, including its geometry and hardness and the geometry of the break-line. Hence, specific attention to scorability needs to be paid during the development of both the formulation and manufacturing process. This process is an example of quality by design: the scorability needs to be built into the tablet! This is also acknowledged by the Ph.Eur. and EU regulators, as demonstration of uniformity of halved tablets is only required during development and not as a routine release test.
1. O. Holte and M.Horvat, Pharmeuropa 23.2., 286–293 (2011)
2. O. Holte and M. Horvat, Pharm Technol. 36 (10) 118–122 (2012).