Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Implications of the new CHMP Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products Summary ***

Dr. Herta Reile (Abschlußjahr: 2007)

Medicinal products for inhalation are commonly used for asthma and COPD, but also as locally acting antibiotics and antiviral drugs for lung infections. Recently, inhalation and nasal products gain growing importance due to the advantages of nasal and pulmonary drug delivery to the systemic system over conventional drug delivery routes. These types of products consist of a great variety of technical systems and the aspects of pharmaceutical quality are very complex since these products generally are composed of a drug product formulation together with a delivery device. This implicates many different parameters influencing product performance.

As an effort on harmonization as well as an update of existing regulatory requirements and in order to cover newer types of devices the new Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products has been jointly developed by the EMEA Quality Working Party and Health Canada and came into effect in both regions in October 2006. It replaces the previous CHMP guidelines on pMDIs and DPIs and remedies the former lack of guidance on nebulisers and nasal sprays in the European Union.

In this thesis the changes of regulatory requirements on pharmaceutical quality specific to inhalation products (pMDIs and DPIs) within the EU and the differences to FDA requirements are discussed. Topics for further harmonization between EU/Canada and US are outlined.

In the new CHMP guideline emphasis is placed on characterization of drug substance, drug product, and the device via pharmaceutical development tests ensuring quality by design with less emphasis on end product testing which is in line with the ICH guideline on pharmaceutical development (Q8). In the section on pharmaceutical development and the section on drug product specifications tables with development tests normally conducted for characterization and with tests normally included in specifications give a concise overview on the requirements for the different product types. It is stated that depending on the type of product not all tests (or additional tests) might be required providing high flexibility acknowledging the vast variety of different technical systems. In the new guideline there are now more requirements specified in a higher level of details giving comprehensive and scientifically sound guidance.

The US requirements specific for pMDIs and DPIs are outlined in the Guidance for Industry on Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation which is still a draft since October 1998. Compared to the new EU/Canadian guideline there are some additional tests for drug product pharmaceutical development requested in the draft FDA guidance, but there are also some important tests for product development missing. An essential difference for instance is that the evaluation and control of fine particle mass (the fraction which is actually reaching the lower airways) is not requested by the draft FDA guidance for pharmaceutical development and as specification criterion, although this parameter is very important regarding product quality, affecting product efficacy and safety. The test for particle size distribution which is the corresponding parameter requested in the draft FDA guidance should be replaced by the superior parameter fine particle mass.

The draft FDA guidance requests many individual tests for routine quality control of the finished product including parameters which are already assured during product development and components control, and which should not be required for redundant testing of finished product. Modern quality control theories emphasize that quality cannot be "tested into the product" but rather should be "built in". The goal of this concept is characterizing a new product via extensive development studies and applying that information to select appropriate control tests for the finished product maximizing the value of characterization and control testing and minimizing redundant testing.
 
Updating of the draft FDA guidance from 1998 with the concepts of Quality by Design might dispose the requirements for some unnecessary and redundant quality control tests on the finished product and put more emphasis on pharmaceutical development. This would be a beneficial step for international harmonization of the requirements for inhalation products.

The new CHMP guideline which is harmonized within EU and Canada and already took the US requirements into consideration could serve as a good basis for an urgently required update of the FDA draft guidance from 1998 to align with recent progress in scientific and regulatory developments.

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