Stabilization, samples

Product specification documents and analytical test methods—In preclinical development, these are important documents and they evolve along with the development phases. Drug substances and products for clinical trials are tested based on these documents, and so are the stability samples. It is critical to ensure that the analyst will perform the right tests against the right specifications with the correct version of the test method. Therefore a mechanism must be in place to control these documents. This can be done manually or with TIMS. A manually controlled system would require the analyst to sign out hard copies of the documents from a central location. After the testing is done, the analyst would have to return these controlled documents to the... 

We expect that the focus of pharmaceutical QC/QA will be broadened in the near future. Traditionally we have concentrated on the quality of products at the time manufacture is complete, with stability being very largely evaluated from retained stability samples. It is probable that more attention will be given to monitoring the quality of products in the channels of distribution and even, in some instances, under conditions... 

Stability — Samples remain stable for at least 468 days when frozen at -20°C. They are stable for at least five simulated freeze-and-thaw cycles and approximately 28 hr at room temperature. The analyte is viable for at least 6 days in a reconstitution solution stored in the autosampler (temperature set point at 10°C). A dried-down batch (sample process stopped at dry-down step) was stable at least 5 days in a refrigerator (temperature varied from 4 to 8°C). A stock solution of paricalcitol is stable for at least 11 months. Stock solution of internal standard is stable about 4.5 months under refrigeration. 

Inman, B.L. et al. 2006. Solid phase extraction as a faster alternative to HPLC Application to MS analysis of metabolic stability samples. J. Pharm. Sci. 2006, Nov. 8, Epub., ahead of print. 

Fixation procedures are necessary when biohazardous samples are analyzed, and are sometimes used to allow access of membrane impermeant fluorochromes, or to stabilize samples for short-term storage. Optimal fixatives are those that have low autofluorescence and do not significantly affect staining. Paraformaldehyde, at concentrations of 0.5-2%, and ethanol (70%, 4 C) are widely used fixatives for flow cytometry. Combinations of paraformaldehyde with Triton X-100 or saponin have been employed in procedures that fix and permeabilize cells. 

FIGURE 19 HPLC separation of the same stability sample shown in Figure 18 under gradient conditions showing better resolution and increased sensitivity of trace impurities, degradants (DG), and excipients (Exc). Reprinted with permission from Reference 19. 

Method development samples (appropriate DS batches, formulations (active and placebo), and stability samples) are available. 

More recendy, a number of tests of chemical stability of the latex concentrate have been developed. Chemical stability variance in the raw concentrate has considerable effect on the dipping characteristics of latex compounds, and can also affect mechanical stability of the compound. A broad rule is that, while latex MST can be increased or decreased without necessarily affecting its chemical stability, any change in the latter always is reflected in the MST. A new test, in which chemical stability is determined by measurement of the effect of weak zinc acetate solution added to a second mechanical stability sample and the result contrasted with the original MST, is available to numerically quantify chemical stability (56). 

Matrixing design [10] may involve elimination of some stability sample pull time points to achieve reduced testing strategy. For example, a one-half reduction in time points eliminates one in every two time points from full study design, and one-third reduction eliminates one in every three time points. However, such a scenario must include full testing at initial, 12-month, and final time points under a 36-month shelf life study [10]. 

The stability samples should be stored in the same packaging configuration used for the final drug product to be marketed. 

Typically, a stressed sample of about 10 to 20% degradation is used to demonstrate the resolution among degradation products. A 10 to 20% degraded sample is used because it has a sufficiently high concentration level of critical related substance. Therefore, these related substances can be detected easily. In addition, 10 to 20% degradation is not too excessive, and the related substance profile should be close to that of a typical stability sample. 

Freeze and Thaw Stability. Analyte stability should be determined after three freeze-thaw cycles. At least three aliquots at each of the low and high concentrations should be stored at the intended storage temperature for 24 h and thawed unassisted at room temperature. When thawed completely, the samples should be refrozen for 12 to 24 h under the same conditions. The freeze-thaw cycle should be repeated twice more, then analyzed on the third cycle. If an analyte is unstable at the intended storage temperature, the stability sample should be frozen at —70°C during the three freeze-thaw cycles. 

General information Product, including description (e.g., tablet, dose) method name, including revision and technique (e.g., HPLC) project information concerning sample(s) (e.g., stability samples three months) date of test and lot number equipment identifier column raw data file name of computerized system and analyst. This general information will be transferred to each spreadsheet. 

The samples (ca. 2500 g for each sample) were spray dried in a Niro Utility drier with the inlet temperature at 200 C and outlet at 100 C. The drier temperatures were allowed to stabilize before samples were collected for analysis. The dried samples were analyzed for total oil, surface oil, moisture, emulsion size and emulsion stability. Samples were also stored at an elevated temperature for shelf-life determination. Sensory analysis of rehydrated powder from the coarse and Microfluidized emulsions was performed to determine if differences in emulsion size affects the perceived flavor intensity. 

---