EMA’dan dozaj değişiklikleriyle ilgili yeni rehber… (İng)



EMA releases new guidance on Quality of Modified Release Products.


The European Medicines Agency (EMA) has released a new draft guideline on, the quality of oral modified release products.


Pharmaceutical dosage forms may be developed in which the rate and/or place of release of active substance(s) has in some way been modified compared with conventional release formulations. Such modifications may have a number of objectives, such as maintaining therapeutic activity for an extended time, reducing toxic effects, protecting the active substance against degradation due to low pH, targeting the active substance to a predefined segment of the gastrointestinal tract for local treatment or targeting active substance release at specified time-points.

The quality of a prolonged release dosage form is continuously improved during the development of a new drug product. The choice of the composition is normally made early in the development based on  small-scale batches and takes into account physicochemical properties of the drug substance, stability  and drug absorption characteristics throughout the gastrointestinal tract. As soon as the constituents are chosen, gradual scaling up of the manufacturing process will start. During this period it is reasonable to expect that adjustments will be necessary to reach full-scale production. These adjustments might be changes in composition, manufacturing processes, equipment or manufacturing site. In some cases these adjustments may have an effect on the properties of the drug product.

The guideline  therefore recommends that an in vitro dissolution test is developed which is able to detect changes which may have an effect on the efficacy or safety of the product. It further advises that Pharmaceutical development should establish the link from pharmacokinetic parameters through in vivo  drug release to in vitro dissolution rate.

There is also a recommendation that the formulation chosen in early development should be tested under different dissolution conditions to determine its sensitivity/robustness to the expected physiological environment after administration. The discriminatory power of the test conditions chosen for routine control may be determined by comparison of the in vitro dissolution data and the bioavailability data of the different formulations. If a Level A in vivo-in vitro correlation (IVIVC) is established, the dissolution test – after proper validation – can be used as a qualifying control method with in vivo relevance, while in the absence of a Level A IVIVC the dissolution test can be used only as a quality control method.

The guideline considers it reasonable  to compare after completed scale-up the laboratory/pilot scale batches with the full  production scale batches in a bioavailability study if the scale-up factor exceeds 10 (compared to the laboratory/pilot scale biobatch) in order to verify that the dissolution test conditions chosen are appropriate for the release of clinical materials, scale-up and manufacture .

This guidance concerns quality aspects, especially pharmaceutical development and in vitro testing, of dosage forms in which the release of active substance is modified. This guideline only covers delayed release oral dosage forms with the principle of gastro-resistance and prolonged release oral dosage forms. Pulsatile and accelerated release dosage forms are not covered by the current guideline. Delayed release dosage forms with other principles, including those designed to release in a specific area of the gastrointestinal tract in response to a specific trigger (e.g. enzymes) or at specific time(s) after ingestion are not specifically addressed.


Draft guideline on quality of oral modified release products