The European Medicines Agency (EMA) has released two new draft guidelines on, respectively, the quality of oral modified release products and transdermal patches.
The two draft guidance documents replace an earlier Note for Guidance on both topics released in July 1999.
Oral Modified Release Products
The first guideline, Draft guideline on quality of oral modified release products, describes how Marketing Authorization Applications (MAAs) should address the physical form of a product, which can affect the therapeutic activity, toxicity, half-life, shelf life and absorption of the drug.
Application sponsors are expected to have conducted in vitro dissolution testing on their products able to detect whether scale-up post-approval changes (SUPAC) have affected the safety or efficacy of the product. "Pharmaceutical development should establish the link from pharmacokinetic parameters through in vivo drug release to in vitro dissolution rate," explained EMA.
For products that are reformulated as prolonged release drugs, sponsors should be prepared to provide EMA with the rationale for the product, how the product works, as well as its pharmacokinetic and physico-chemical characteristics.
The release rate of the drug should be established through dissolution testing using in vitro models capable of discriminating between what EMA calls, "Critical manufacturing variable which may have an impact on the desired bioavailability." In addition, the testing needs to be able to determine the proposed shelf life of the product, required storage conditions and batch consistency between conducted trials.
Other studies, including bioavailability, dissolution comparison and in vitro and in vivo comparison studies, should all be conducted as well and are described in detail in EMA's guideline.
The second, related guideline, Guideline on quality of transdermal patches, is more extensive than the first and describes the steps necessary to market a transdermal patch intended for systemic delivery of medication. The guideline covers quality considerations as they relate to the description, development, manufacture, characterization, control, packaging and stability of the patches.
Transdermal patches are similar to ingested extended release drug products in principle, but are applied to the skin where the drug product is usually diffused into the body at a controlled rate. Two of the most important considerations for these product classes are the rate at which drugs are absorbed into the body and the side effects of that absorption on the skin. Because the patches typically have an excess amount of the drug relative to what the patient requires, EMA officials said they also have concerns about the patches' impact on the environment once they are disposed of, and on other people who might accidentally come into contact with the patch.
As with oral products, sponsors of transdermal patches should be prepared to give a thorough description of the drug's characteristics and composition, including its strength, uptake, excretion, release rate and instructions for use. Sponsors should also be prepared to describe the patch itself, including its composition, size, area, thickness, adhesive and excipients.
Beyond the physical differences, many of the testing considerations for transdermal products are similar to those expected of oral products, said EMA. Sponsors will need to conduct dissolution testing, show evidence of the drug's stability and consistency, bioavailability, and comparison to earlier studies.
Differences, however, remain. Patches will need to provide in vitro adhesion testing, in vitro skin permeation studies, prove the suitability of their contained closure system, justify the steps in their manufacturing processes and provide a related risk assessment, and have an extensive summary of product characteristics (SmPC) to account for numerous administrative contingencies.
Comments on both guidelines are due by 15 March 2013.