Marketing Authorization Applications

In this chapter, the regulatory requirements relating to data on development pharmaceutics and process validation will be discussed. The discussion will be limited to Marketing Authorization Applications (MAAs) for the European Economic Area and many central and eastern European countries. 

The basis for applications will follow the principles laid down in basic European level legislation for the pharmaceutical sector. This is more or less common regardless of the actual mechanism used to gain an approval. The basic requirements for pharmaceutical marketing authorization applications are laid down in Directive 65/65/EEC (as amended). There are no specific requirements for pharmaceutical development or process validation included in the text of that document. 

Readers may also be aware that under the auspices of the ICH a document is being developed on the organization of the Common Technical Document. It is intended that this will result in a common format (and, to at least some extent, content) of marketing authorization applications in the jurisdictions of those party to the ICH process (Japan, the EEA, and the United States). At the time of writing, a draft document had been circulated for comment. When adopted and implemented, this will result in a considerable amendment to the format and sequencing of information in a marketing authorization application. 

In the earliest development pharmaceutics guideline it was indicated that development pharmaceutics studies may be needed to support a marketing authorization application. Subsequent documents have made it clear that such data will be expected to form part of the application. 

The draft guidelines give considerable information on how an applicant can submit relevant data to request parametric release. However, since this is unlikely to be accepted until considerable manufacturing experience of the product concerned has been gained, it is probable that this will be submitted as a later variation application rather than in an initial marketing authorization application. 

In 1993, a significant advance in simplifying the procedures relating to drug marketing authorization applications in the EU was made. At that time, the legal basis of a new drug approval system... 

Unlike the FDA, the EMEA itself does not directly undertake appraisals of drug dossiers submitted to support marketing authorization applications under the centralized procedure. Instead (as discussed in detail below), they forward the dossier to selected national EU regulatory bodies, who undertake the appraisal, and the EMEA makes a recommendation to approve (or not) the application based upon the national body s report. The overall role of the EMEA is thus to coordinate and manage the new system. The EMEA s annual budget is of the order of 120 million. The key objectives of the EMEA may be summarized as ... 

Upon receipt of a marketing authorization application under centralized procedures, the EMEA staff carry out an initial appraisal to ensure that it is complete and has been compiled in accordance with the appropriate EU guidelines (Box 4.4). This appraisal must be completed within 10 days, at which time (if the application is in order), it is given a filing date. The sponsor also pays an appropriate fee. The EMEA then has 210 days to consider the application. In the case of human drugs, the application immediately comes before the CPMP (which convenes for 2-3 days each month). 

Note GLP = Good Laboratory Practice ICH = International Conference on Harmonization IND = Investigational New Drug JMHW = Japanese Ministry of Health and Welfare MAA = Marketing Authorization Application NCE = New Chemical Entity. 

Similar to the US requirements, there are two regulatory steps to go through before a drug is approved to be marketed in the European Union. These two steps are clinical trial application and marketing authorization application. There are 27 member states in the European Union (as of August 2007) clinical trial applications are approved at the member state level, whereas marketing authorization applications are approved at both the member state or centralized levels. 

Following successful clinical trials, the Sponsor has to apply for authorization to market the drug in Europe. Depending on the type of drug product and the intended market, there are four different types of marketing authorization applications (Fig. 8.8). 

Preparation of Marketing Authorization Application Dossier The application dossier is divided into four parts ... 

Reproducibility represents the precision of the method between two or more laboratories and it is typically assessed during method transfer between laboratories, but may be assessed during method validation when more than one laboratory will be performing the method. Reproducibility would also be reported as the SD or RSD value of the mean results between laboratories. These data are not part of the marketing authorization application. 

Management and follow-up of marketing authorization applications under the centralized procedure,... 

Figure 11.1 An example of the activities that are likely to form the critical path for the development of a drug. MAA is the market authorization application that a company has to submit in Britain in order to produce and market a drug...

According to ICH Guideline Q8 Pharmaceutical Development, the marketing authorization application (MAA) should discuss the excipients chosen and their concentration. The MAA should show the characteristics that can influence the medical product performance and manufacturability relative to the respective function of each excipient. Additionally, the MAA should demonstrate the ability of excipients to provide their intended functionality throughout the intended period of validity of the formulation. Use the information on excipient performance as appropriate to justify the choice and quality attributes of the excipients.26... 

Council Regulation 726/2004/EC (updates and expands the previous regulation 239/1993/EC), which mainly concerns the duties of the European Medicines Agency (EMEA), establishment of the Committee for Medicinal Products for Human Use (CHMP), and the scope and mechanisms of the centralized procedure for marketing authorization applications (MAAs) and pharmacovigilance issues. 

EMEA Guideline on similar biological medicinal products Information requirements for the marketing authorization applications 5... 

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