In accordance with the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation concerning Investigational Medicinal Products in Clinical Trials (CHMP/QWP/185401/2004 final, dated 31 March 2006) this depends on the initially approved IMPD. If this IMPD contains a plan with the criteria for an ongoing stability testing program which is the basis for further shelf-life extensions, a shelf-life extension is not considered a substantial amendment.

Otherwise, shelf-life extensions of an investigational medicinal product will be considered a substantial amendment.

Not less than the following particulars have to be included in the plan for shelf-life extensions:

(In order to make the requirements clear, selected examples of acceptable and unacceptable approaches are given. Please bear in mind that specific particularities with regard to formulation and substance have to be considered when determining the shelf-life.)

1. Basic conditions/minimum outcomes to be fulfilled are to be established.

   1. Example for an acceptable approach:

      • The detected or calculated outcomes remain within the shelf-life specification. An appropriate shelf-life specification was provided.

   2. Examples for unacceptable approaches:

      • No appropriate stability specification is provided.
      • Statements like: "The tests will be adjusted depending on the obtained data".
2. The method by which the shelf-life will be calculated on the basis of real-time data is to be stated.

3. The intended extrapolation period has to be established accurately.

   1. Examples for an acceptable approach:

      • The shelf-life is determined by maximally doubling the period covered by real-time data. The extrapolation duration can be 12 months at the most.
      • The period of stability testing under accelerated conditions is multiplied by 4 in order to determine the shelf-life. This extrapolation is valid for up to 24 months.
      • Furthermore, the shelf-life can be extended based on the results of the long-term testing for no more than 12 months at a time and for a maximum of 5 years in total.

   2. Examples for unacceptable approaches:

      • The shelf-life is calculated based on the outcomes of long-term testing and of testing under accelerated conditions. Therefore, a shelf-life extension will not be considered a substantial amendment.
      • The sponsor will extend the shelf-life to the end of the stability testing, if the outcome of the stability testing is satisfactory and the data (determined or extrapolated) are within the specifications. In accordance with the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation concerning Investigational Medicinal Products in Clinical Trials (CHMP/QWP/185401/2004 final) a change of the shelf-life will not be considered a substantial amendment.

In order to simplify assessment by the BfArM, we ask you to list the manufacturers in the IMPD as follows:

First, the name of the manufacturer including the complete address should be given. Then, all manufacturing activities carried out by this manufacturer are to be listed.

The listing of manufacturers involved in the manufacture of the drug substance is done in chapter S2.1, the listing of manufacturers involved in the manufacture of the drug product is provided in chapter P3.1 of the IMPD.

The listing can also take the form of a tabular overview according to the following example for the drug substance and the drug product. Each manufacturer including the complete address should be entered in one cell of the table.

S2.1

Drug Substance
Name and address of manufacturing site	Function of the manufacturing site
Sample Company Sample Street 00 00000 Sample City Any Country	Synthesis of the drug substance XXX
Sample Company 2 …	...

P3.1

Drug Product
Name and address of manufacturing site	Function of the manufacturing site
Sample Company Sample Street 00 00000 Sample City Any Country	Manufacturing and primary packaging of the XXX tablets
Sample Company 2 …	...