Stability profile

The specification development process is a data-driven activity that requires a validated analytical method. The levels of data needed include assay precision, replicate process results (process precision), and real-time stability profiles. A statistical analysis of these data is critical in setting a realistic specification. Most often, aggregation and fragmentation degradation mechanisms are common to protein and peptide therapeutics. Therefore, the SE-HPLC method provides a critical quality parameter that would need to be controlled by a specification limit. 

Fig. 4.3.1 Effect of pH on the total light emission of phialidin (A), and the temperature stability profiles of phialidin (minute open circles) and aequorin (solid line) (B). In A, each buffer contained 0.1 M CaCl2 plus 0.1 M Tris, glycine or sodium acetate, the pH being adjusted with NaOH or HC1. In B, the photoprotein samples in 10 mM Tris-EDTA buffer solution, pH 8.0, were maintained at a test temperature for 10 min, and immediately cooled in an ice water bath. Then total luminescence activity was measured by injecting 1ml of 0.1 M CaCl2/Tris-HCl, pH 7.0, to 10 pd of the test solution. From Levine and Ward (1982), with permission from Elsevier.

Molecular structure and weight Melting point Thermal profile Particle size and shape Hygroscopicity potential Ionization constant Light stability Optical activity pH solubility profile pH stability profile Polymorphism potential Solvate formation... 

An elastomeric closure is a packaging component that is, or may be, in direct contact with a drug product. Elastomer selection for parenteral packaging principally involves consideration of chemical, physical, and biological properties, with emphasis on the stability profile of the drug/container system. Typical elastomeric closure compositions are listed in Tables 1 1. Although certain packaging applications frequently call to mind certain elastomer types, it is not feasible to prescribe specific... 

It was found that decomposition is in part due to transesterification and that substitution increases stability. The effect of gamma radiation on aspirin has been described.184 The pH stability profile of aspirin according to Edwards has been made the subject of a student experiment.185... 

Compound stability in a variety of matrices including varying pH buffers, plasma, and liver microsomes is an important consideration related to the success of the compound being developed in the clinic. Low stability profiles in these environments will lead to poor pharmacokinetics of a potential candidate. These stability results can be used by medicinal chemists to optimize the labile portion of the structures to further improve stability. 

It must be ensured that a drug product within a produced batch contains the same amount of the active ingredient, the same stability profile, and the same bioavailability. Furthermore all batches produced should be comparable in their properties as mentioned before. 

Typical n-alkyl ligand densities that can be achieved with -alkylchlorosi lanes are within the range of 2.5-3.2pmolm-2, whilst with disilazanes, ligand densities approaching the limited values can be reached under optimized conditions, i.e. between 3.50 and 4.20 pmolm-2. Surface-modified zirconia or other metal oxide based RPC sorbents can be similarly prepared by either of the above two strategies. Compared to n-alkylsilicas, these ceramic RPC sorbents show different selectivities with synthetic peptides, as well as different chemical stability profiles. Consequently, RPC sorbents based on these types on surface-modified, porous metal oxide materials fulfill useful and complementary roles, but at this point in time, have achieved a more limited range of applications for the resolution of synthetic peptides due to their limited availability. 

For long-term studies, frequency of testing should be sufficient to establish the stability profile of the drug product. For products with a proposed shelf life of at least 12 months, the frequency of testing at the long-term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed shelf life. 

Developing stability data for an ANDA product generally requires fewer laboratory studies than those required with an NCE. The primary goal of an ANDA should be to mimic the stability profile of the innovator product, barring any intellectual property issues that might prevent the generic manufacturer from formulating a sim-... 

Some of the most significant data that the PAI team confirm is the stability profile of the product most likely the raw data would be examined if the presentation of the summary data appears flawed. 

A quick means to identify whether or not a drug may be more suitable for solution or suspension is to overlap the pH-stability profile with the pH-solubility profile. This overlap creates a window, which may suggest which dosage form might be most desirable and subsequently the type of excipients needed. The overlapped figures below demonstrate for aspirin (which is a weak acid) that the pH of greatest stability is also the pH at which there is low solubility (Fig. 1). 

Stability profile of the product Produced during process development Primary packaging specification... 

The assessment of material quality normally starts with comparing a material s attributes to the specifications established by the purchasing company. Once the material satisfies established specifications, efforts are made to assess the stability of the product or intermediate manufactured with the material. Typically the determination of raw material process stability is made during the product development activities. Once a vendor or vendors have been selected, three distinct vendor lots of a given raw material will be purchased. Development batches of the product are then produced using these lots, and samples from the three batches are placed on stability. The thought is that if the materials from the three lots result in product with suitable stability profiles, the raw... 

Gamache, P., McCarthy, R., Waraska, J., and Acworth, I. N. (2003a). Pharmaceutical oxidative stability profiling with high-throughput voltammetry. Am. Lab. 35 21-25. 

Stamper GF, Lambert WJ. Accelerated stability testing of proteins and peptides pH-stability profile of insulinoptropin using traditional Arrhenius and non-linear fitting analysis. Drug Dev Ind Pharm 1995 21 1503-1511. 

In general, if an API form has stability problems in the bulk form, it is best to solve these issues via salt and form selection studies designed to discover and identify more thermodynamically stable forms prior to any excipient compatibility evaluation. It is known that different polymorphic forms and hydrated/solvated forms can have dramatically different stability profiles (23-26). 

Drug discovery Lead candidate Screening Protein identification natural products identification metabolic stability profiles molecular weight determination for combinatorial/ medicinal chemistry support. 

Fink, S. W. Rourick, R. A. Whitney, J. L. Volk, K. J. Klohr, S. E. DiDo-nato, G. C. Kerns, E. H. Lee, M. S. 1997. Accelerating drug development using automated predictive stability profiling methodologies. Annual Meeting of the American Association of Pharmaceutical Scientists (Boston, Massachusetts), 590. 

---