Media simulation trials and the matrix approach

Tim Sandle, August 2010

Media trials are often validated based on the number of vials or bottles filled. The number of vials or bottles filled then sets the maximum number of product vials that can be filled on the filling line (this is often with an upper tolerance of +10%).

It is a matter of debate whether media trials are validated by time. If the maximum number of container is the requirement then it is assumed that, by filling the maximum number of vials during a media simulation trial and having the required shift change-over and typical production filling stoppages, that the length of time for a media trial will be equal or longer than a typical product fill.

The difficulty of simulating small product fills runs with media fill is that a large number of media containers need to be filled to give statistical confidence in a trial where no bottles show growth. However, an artificially increased broth trial may no longer mimic the product fill. Therefore the numbers of contains to be filled is normally established in a way which offers the best compromise between the need for a large batch size and the need to ensure that the media fill simulates the product fill.

Thus it is often the case that a single container and fill volume is used to validate a number of different product presentations. This cannot be applied across all types of products. To capture all product types, the following principles, based on worst case conditions, should be used:

a) The smallest vial and neck diameter.b) The largest bottle and neck diameter.c) Maximum duration time.

For example, a facility with three filling lines:

Product Line fillZenalb®

Vessel fillZenalb®

Gammaplex®

Vigam®

Subgam®

Specific IgGSub-cut IgG

Subgam®

CoagulationFactors

Filling line A A B CFill container size/dose to be used for media fill

500ml/50ml 20ml/10ml10ml/5ml5ml/2ml(rotating)

10ml/5g50ml/20g(rotating)

Product fills validated by these media fill combination

All Line fill presentations

All Vessel fill presentations

All presentations All presentations

Minimum Media fill run units to be incubated

50ml – 20,000500ml - 5,000 20ml - 10,000

10ml - 10,0005ml - 15,000

10ml – 10,00050ml - 5000

Minimum volume of media required to be transferred for container

600L220L 10ml- 60L

5ml- 35L10ml – 60L50ml – 110L

Line speed All VariablesSimulate Freeze-drying No No No YesFrequency Alternating between

combinations Alternating between

combinations Alternating between

combinationsAlternating between

combinationsFilling line frequency

6 monthly for each filling line (32 week expiry from date of fill)

Use sterilising filter type grade applicable to the product being simulated

Yes

Example of different combinations, e.g. for filling line A:

Month Vial Size Fill Volume No. Vials Approximate Duration*

1 50ml 30ml 20,000 12 hours

6 20ml 10ml 10,000 8 hours

12 50ml 30ml 20,000 12 hours

18 500ml 100ml 5,000 9 hours