Finished Product Testing For Lyophilized Products

There are several aspects of finished product testing which are of concern to the lyophilized dosage form. These include dose uniformity testing, moisture and stability testing, and sterility testing.

Dose Uniformity

The USP includes two types of dose uniformity testing: content uniformity and weight variation. It states that weight variation may be applied to solids, with or without added substances that have been prepared from true solutions and freezedried in final containers. However, when other excipients or other additives are present, weight variation may be applied, provided there is correlation with the sample weight and potency results. For example, in the determination of potency, it is sometimes common to reconstitute and assay the entire contents of a vial without knowing the weight of the sample. Performing the assay in this manner will provide information on the label claim of a product, but without knowing the sample weight will provide no information about dose uniformity. One should correlate the potency result obtained form the assay with the weight of the sample tested.

Stability Testing

An obvious concern with the lyophilized product is the amount of moisture present in vials. The manufacturer’s data for the establishment of moisture specifications for both product release and stability should be reviewed. As with other dosage forms, the expiration date and moisture limit should be established based on worst case data. That is, a manufacturer should have data that demonstrates adequate stability at the moisture specification. As with immediate release potency testing, stability testing should be performed on vials with a known weight of sample. For example, testing a vial (sample) which had a higher fill weight (volume) than the average fill volume of the batch would provide a higher potency results and not represent the potency of the batch. Also, the expiration date and stability should be based on those batches with the higher moisture content. Such data should also be considered in the establishment of a moisture specification.

For products showing a loss of potency due to aging, there are generally two potency specifications. There is a higher limit for the dosage form at the time ofvrelease. This limit is generally higher than the official USP or filed specification which is official throughout the entire expiration date period of the dosage form.

The USP points out that compendial standards apply at any time in the life of the article.

Stability testing should also include provisions for the assay of aged samples and subsequent reconstitution of these aged samples for the maximum amount of time specified in the labeling. On some occasions, manufacturers have established expiration dates without performing label claim reconstitution potency assays at the various test intervals and particularly the expiration date test interval. Additionally, this stability testing of reconstituted solutions should include the most concentrated and the least concentrated reconstituted solutions. The most concentrated reconstituted solution will usually exhibit degradation at a faster rate than less concentrated solutions.

Sterility Testing With respect to sterility testing of lyophilized products, there is concern with the solution used to reconstitute the lyophilized product. Although products may be labeled for reconstitution with Bacteriostatic Water For Injection, Sterile Water For Injection (WFI) should be used to reconstitute products. Because of the potential toxicities associated with Bacteriostatic Water For Injection, many hospitals only utilize WFI. Bacteriostatic Water For Injection may kill some of the vegetative cells if present as contaminants, and thus mask the true level of contamination in the dosage form. As with other sterile products, sterility test results which show contamination on the initial test should be identified and reviewed.