Validation potency

The R isomer of moxalactam will be the first to elute with a k of about 4.5. The S isomer of moxalactam will elute at a k of about 7.0. For quantitative purposes, the responses of both peaks must be combined to provide a valid potency for the moxalactam standard or sample. 

Solubility The soluble active ingredient should be added to the liquid phase that will be its carrier vehicle. Data of solubility have to be determined as part of the process validation. Potency uniformity has to be tested by demonstrating satisfactory distribution in the emulsified mix [20],... 

These inhalation studies demonstrate the feasibility of evaluating the potency of drugs with different pharmacological actions following inhalation exposure. The comparison of pharmacological effects after both inhalation and IV administration revealed very similar dose-response relationships for each of these three drugs. However, valid potency comparisons can be made between inhalation and IV administration only... 

To demonstrate the feasibility of this approach, the authors have chosen to detenuine the volatilization and dosimetry of heroin for the purpose of making valid potency comparisons between IV and inhalation exposure. 

Edgren carried out a number of studies in which bioassays were used to compare the widely differing potencies of a number of analogues of 17/i-oestradiol that were modified in the 18-position. Commenting on the use of potency ratios, Edgren concluded that they were only valid for specific substances and test systems and useless for product safety testing . These problems could have important consequences for any attempt to establish the potency of specific environmental EDs or environmentally relevant mixtures. 

Drug substance/drug product purity, potency, and other testing Drug substance/drug product stability testing Method development, validation, and transfer Drug product formulation development... 

In this chapter we consider the situation where this assumption is no longer valid, because the affinity of the inhibitor for its target enzyme is so great that the value of K w approaches the total concentration of enzyme ( / T) in the assay system. This situation is referred to as tight binding inhibition, and it presents some unique challenges for quantitative assessment of inhibitor potency and for correct assessment of inhibitor SAR. 

In vitro tools could be used alone or in test batteries with increased potency of the description of cellular events and changes. The chapter provides a brief introduction on the components of an in vitro system, the main differences between models for research and models for testing and a list of validated alternative methods according to the European Centre for the Validation of Alternative Methods (ECVAM) (http // ecvam.jrc.it/, http //ecvam.jrc.ec.europa.eu/) evaluation. 

Another crucial problem for any neurochemical model is cause and effect. Neuroleptics have a high affinity for dopamine receptors, particularly the D2-subtype. There is also a highly significant positive correlation (r > +0.9) between this receptor binding and their clinical potency (Seeman, 1980). But, this does not necessarily implicate elevated dopamine levels as the cause of schizophrenia. Moreover, blockade of dopamine receptors happens very rapidly, whereas clinical benefits are only seen after chronic treatment. Rose (1973) has criticised the reductionist statement that an abnormal biochemistry causes schizophrenia because it relates cause and effect at different organisational levels (namely, the molecular and behavioural). But, while it can be legitimate to discuss cause and effect at the same level that chlorpromazine blocks dopamine receptors (one molecule altering the response of another), it is not valid to infer that increased dopamine activity causes schizophrenia. Put another way ... 

But in order to understand what needs to be changed, we first need to understand the current situation. In order for a pharmaceutical company to use any analytical method for certifying the properties (efficacy, potency, etc.) of their products, the analytical method has to be validated. Validation , in the parlance of the FDA, is a far cry from what we usually call validation when developing a multivariate spectroscopic method. In fact, what we call validation in spectroscopic calibration (which usually means calculating an SEP, or an SECV) is a far cry from the dictionary definition of validate , which is to make legally valid , where valid is defined as having legal efficacy or force [11],... 

The near-IR technique has been used very successfully for moisture determination, whole tablet assay, and blending validation [23]. These methods are typically easy to develop and validate, and far easier to run than more traditional assay methods. Using the overtone and combination bands of water, it was possible to develop near-IR methods whose accuracy was equivalent to that obtained using Karl-Fischer titration. The distinction among tablets of differing potencies could be performed very easily and, unlike HPLC methods, did not require destruction of the analyte materials to obtain a result. 

Knowing the impact of smoke toxic potency on escape from a fire is of sufficient importance that it has been the subject of research for over twenty years. As a result, we now have a realistic picture of proper contexts for the use of toxic potency data and a series of first-generation tools for measuring it. We also have a vision of the key technical issues to be resolved developing a proper small-scale fire simulator, relating rodent results to people, and validating the small-scale data. 

The past 3 years have seen tremendous advances in both the design of Cat K inhibitors and in our understanding of the effect of Cat K inhibition on bone remodeling. The structural diversity of Cat K inhibitors has expanded considerably from simple peptidomimetics to non-peptidic derivatives and even non-covalent inhibitors. The potency, selectivity and pharmacokinetic properties of key compounds are very attractive and seem well-suited to further development. The disclosure of clinical validation of the effect of Cat K inhibition on bone mineral density, plus the provocative data suggesting a decoupling of bone resorption and bone formation provides a compelling framework for further development of Cat K inhibitors for the treatment of osteoporosis. 

Two approaches that have been validated for HIV inhibitors, nucleoside 5 -phosphonates [48] and 1,3-dioxolane analogs [49] have proven unsuccessful when applied to HCV inhibitors. Phosphonodiphosphates have been synthesized and are incorporated by NS5B RdRp, but Vmax/Km for these chain terminators is 10-100-fold less than for ATP, and potency must be greatly improved for analogs of this type to have utility [50]. A small series of 1,3-dioxolanes also failed to afford active inhibitors of HCV, or HIV, despite the addition of a 5-methyl substituent to impose the desired conformational preference [51]. Ring expanded nucleobases [52,53] and AICAR analogs have also been synthesized as HCV inhibitors which provide only weak replicon activity [54]. 

A further option to investigate the phototoxic potential of substances is the use of reconstructed human skin models. The evaluation of the cell viability is based on the MTT-assay that is sensitive for the mitochondria activity in cells. Currently, these in vivo substitutes are still under validation and are not approved as full standard test methods for the investigation of the phototoxicity potency of a test chemical. However, several existing models are in use for prevalidation studies and are described elsewhere in more detail [92],... 

Analytical methods are important not only in the development and manufacture of commercial biopharmaceutical drugs, they also play a vital role in the whole drug development life cycle. Drug discovery and preclinical research require development and application of analytical methodologies to support identification, quantitation, and characterization of lead molecules. It is difficult to perform a comparative potency assay on lead molecules if one does not know how much of each is going into the assay or how pure the molecule is. Analytical methods are typically developed, qualified, and validated in step with the clinical... 

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