Moisture Matters in Lyophilized Drug Product - Pharmaceutical Technology

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


Pharmaceutical Technology
pp. s41-s43

Aside from the expected shelf-to-shelf differences in moisture content (since each shelf was stoppered at different times), there was also substantial vial-to-vial variability among vials on the same shelf, mainly because those vials were stoppered when sublimation was still in dynamic process and the system was not in equilibrium. These data guide the second lyocycle run (with additional 12 drug formulation-filled vials) in which one can better gauge when to stopper the vials to obtain cakes complementary to those from the first run so that the full range of 0.1–7.0% moisture levels can be obtained (see Table I ).


Figure 1: Moisture content versus stability via SE-HPLC.
From the two lyocycle runs, eight groups of the 5-mL vials, each contains ~1\6 of the cake with known moisture contents (italicized in Tables I and II ), are selected for stability studies. One vial from each group is the t=0 sample, while the remaining 4 vials from each are incubated at accelerated temperatures for predetermined time periods (e.g., 50 C for 2 weeks and 4 weeks; 40 C for 3 months; and 25 C for 24 months) and analyzed by the stability-indicating assay upon reconstitution.


Table II: Vials from Table I selected for stability study.
Stability data using the above approach with two different protein drug products are shown in Figure 1 . The major degradation route for both proteins upon lyophilization was aggregation; therefore, protein stability was assessed by size exclusion high-performance liquid chromatography (SE-HPLC) to measure the recovery of intact native protein (% native). Figure 1A demonstrates that all eight t=0 samples ( Table II ) with 0.3–6.2% moisture content had identical % native protein indicating the residual moisture level had no impact on the in-process stability. However, the 50 C and 40 C storage stability decreased when the residual moisture was ≥ 3.6%. Results in Figure 1A suggest that the moisture specification can be set at 3% for this protein drug product.

Stability data using the same approach with a second protein drug product is shown in Figure 1B . The results suggested a moisture specification of 2.7% is appropriate for this drug product.

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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