Moisture Matters in Lyophilized Drug Product - Using an alternate moisture-generation method may provide more accurate data for regulatory submissions. - BioPharm International

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Moisture Matters in Lyophilized Drug Product
Using an alternate moisture-generation method may provide more accurate data for regulatory submissions.


BioPharm International
Volume 25, Issue 10, pp. 64-67

DISCUSSION

A few technical points are worth mentioning. First, for easier transfer of the divided cake/powder in the glove bag, vials with an opening of 20 mm (for a 5-mL vial or a 6-mL oven vial from Metrohm) instead of 13 mm (for 2- or 3-mL vials) are recommended.

Second, before performing the actual experiment, one should test the system suitability by selecting at least two cakes with high and low moisture levels (at > 3% and < 1%, respectively) and perform moisture analysis on all six vials from each cake. The percentage of moisture should be identical (or with very low relative standard deviation) for all the replicates.

Third, during a real experiment, one can also include vials/samples with very close moisture content for an accelerated stability study. An observation that the accelerated stabilities are extremely close for samples with similar moisture levels will reinforce the confidence that one is on the right track.

Finally, it is possible that, with extensive product knowledge and process understanding, one can, in a single lyocycle run, achieve cakes with all the desirable spread of moisture contents (between 0.1–7.0%). Therefore, it is not always necessary to perform two lyocycle runs when using the proposed approach.

There is no need for large amounts of product or sophisticated equipment. In addition, generating residual moisture in situ offers a more realistic simulation of an actual freeze-drying run in drug production. Furthermore, the residual moisture of each product vial incubated at accelerated temperatures for predetermined time periods (i.e., in storage stability study) can be measured directly and therefore can be considered more accurate than that inferred from sister vials. Thus, ambiguity in stability studies can be reduced.

CONCLUSION

When manufacturing lyophilized drug product, the conventional wisdom is to aim for no more than 1% residual moisture. Based on the approach outlined here, the moisture specification for two different protein drug products was 3.0% and 2.7%, respectively, thereby providing for a higher margin than the conventional 1% residual moisture for lyophilized drug products. Information generated using this approach can help to strengthen one's data package to support specifications for regulatory filings and manufacturing ranges.

Leu-Fen Lin, PhD, is a senior manager, Formulation Development, and Richard Bunnell, PhD, is general manager, both at SGS Life Science Services, 616 Heathrow Drive, Lincolnshire, IL 60069, tel. 847.821.8900,
and
.

REFERENCES

1. E.D. Breen et al., Pharm. Res. 18, 1345–1353 (2001).

2. N.K. Jain and I. Roy, Pharm. Res. 28, 626–639 (2011).


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