Bioavailability documentation

The bioavailability, and hence the toxicity, of metal depends on the physical and chemical form of the metal, which in turn depends on the chemical characteristics of the surrounding water. The dissolved form of the metal is generally viewed as more bioavailable and therefore more toxic than the particulate form. Particiilate matter and dissolved organic matter can bind the metal, making it less bioavailable. What is not well known or documented is the various chemical transformations that occur both within the effluent stream and when the effluent reaches and mixes with the receiving water. Metal that is not bioavailable in the effluent may become bioavailable under ambient chemical conditions. 

EPA. 1996a. Bioavailability of lead in soil samples from the Jasper County, Missouri Superfund Site. U.S. Environmental Protection Agency Region 8. Document Control No. 04800-030-0161. 

Eversole 1980). It is probable that bioavailable concentrations from the water in each test did not exceed 1.0 pg/L. However, delayed mortality frequently occurs for extended periods after exposure, and the potential for adverse effects at the population level remains high (NAS 1978). Latent biocidal properties of mirex were documented for hsh (Van Valin et al. 1968 Koenig 1977) and crustaceans (Ludke et al. 1971 Hyde 1972 Cripe and Livingston 1977). Crustaceans were the most sensitive group examined. For example, the crayfish (Procambarus blandingi) immersed in nominal concentrations of 0.1 to 5.0 pg mirex/L for periods of 6 to 144 h died 5 to 10 days after initial exposure (Ludke et al. 1971). Immature crayfish were more sensitive than adults, and mortality patterns were similar when mirex was administered in the water or in baits (Ludke et al. 1971). 

The physical properties of an API can significantly effect the physical and chemical stability of a formulation, its bioavailability and ultimately they can modify the pharmacokinetic profile of the drug. This issue will be discussed in more detail in section 3.4. For these reasons it is necessary to control the physical form of the API at the Pures crystallization step, and throughout the subsequent formulation steps, to ensure a consistent delivery profile to the patient. This control strategy must be documented in the New Drug Application... 

In the mid-70s, it was a generally expressed opinion that there could be as many as 100 formulation factors that might affect bioavailability or bioequivalence. In fact, most of the documented problems centered around the use of the hydrophobic magnesium stearate as a lubricant or use of a hydrophobic shellac subcoat in the production of sugar-coated... 

Part II Part II is the report concerning chemical, pharmaceutical, and biological documentation. The report details the composition, method of development of formulation, manufacturing processes under GMP, analytical test procedures, bioavailability, and bioequivalence. It should be noted that all analytical test procedures need to be validated, and the validation studies must be provided. 

Bioequivalence Bioequivalence problems have been documented for primidone products marketed by different manufacturers. Brand interchange is not recommended unless comparative bioavailability data are available. 

In addition, for level 2 change, no additional bioequivalence study is required if the proposed alteration matches with the situation for cases A, B, and C. However, if there is any deviation, then documentation containing the results and assessment of a new bioequivalence and/or bioavailability study [if proper in vitro/in vivo correlation (ivivc) has not been established] should be submitted as per the conditions mentioned in the level 3 alteration. 

During the 1990 Washington Conference on Analytical Methods Validation Bioavailability, Bioequivalence and Pharmacokinetic Studies [1], parameters that should be used for method validation were defined. The final report of this conference is considered the most comprehensive document on the validation of bioanalytical methods. Many multinational pharmaceutical companies and contract research organizations contributed to its final draft. This scientific meeting was sponsored by the American Association of Pharmaceutical Scientists (AAPS), the Association of Official Analytical Chemists (AOAC), and the U.S. Food and Drug Administration (FDA). The conference report has been used as a reference by bioanalytical laboratories and regulatory agencies worldwide. 

The most important nutritional use of sesame protein is as a methionine source for complementation of other protein consequently, the low lysine content is not an important consideration with proper complementation (69). Here we see a case where reduced bioavailability of an amTrib acid is documented but is of little practical importance in the mixed diet in which the protein will be only a part. 

These reports document increasing confidence in IVIVC to estimate the in vivo bioavailability characteristics for an ER drug product. In this regard, increased IVIVC activity in NDA submissions has been apparent. StiU, the complete process of developing an IVIVC with high quality and predictabUity and identifying specific applications for such correlations has not been weU defined. 

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