Specification limits, routine

The quality of the development effort would be enhanced if the routine scientific activity looked at the worst-case situation. First, the process characteristics would be better understood. Second, the specification limits for the in-process tests would be based on hard data. Third, it would be easier to evaluate... 

Method validations and drug substance or finished pharmaceutical product specifications are intimately linked. To ensure transferability of the method and to ensure the method will operate successfully in a QC site, the method variation (from the intermediate precision) should be known and monitored. The method variation is an estimate of the variation that will be experienced in routine use of the method. More method variation will create unacceptable random failure rates, and provide no room for reasonable product variation or even minor stability changes. The method variation should be less than one-third of the interval from the mean or target (typically the midpoint of the upper and lower specification limit) value to the nearest specification limit, or one-sixth... 

Particulates are critical in sterile filtration, specifically of injectables. The USP 24 United States Pharmacopoeia) and BP British Pharmacopoeia) quote specific limits of particulate level contaminations for defined particle sizes. These limits have to be kept and, therefore, the particulate release of sterilizing grade filters has to meet these requirements. Filters are routinely tested by evaluating the filtrate with laser particle counters. Such tests are also performed with the actual product under process conditions to proove that the product, but especially process conditions, do not result in an increased level of particulates within the filtrate. 

One of the main goals of impurity investigations is to determine which impurities need to have specification limits for routine monitoring. 

The primary hindrance to the universal implementation of UHPLC is, for most laboratories, that the platform often requires new capital outlays to buy instrumentation capable of running at higher system pressures (typically above 400-1,500 bar). Access to properly qualified systems can create a roadblock to routine regulated testing. This limited availability of UHPLC becomes less of an issue each year as instrumentation comes to an end of its depreciation lifespan and gets replaced with newer LC systems. Yet, in the current state, pharmaceutical companies across the industry are less inclined to develop and transfer UHPLC analytical methods until they are convinced receiving laboratories have qualified UHPLC systems available on demand. In addition, not all UHPLC instruments perform to the same specifications (14), making transfer even more difficult as vendor-specific limitations can potentially cripple an analytical transfer. 

ImmunO lSS iy. Chemiluminescence compounds (eg, acridinium esters and sulfonamides, isoluminol), luciferases (eg, firefly, marine bacterial, Benilla and Varela luciferase), photoproteins (eg, aequorin, Benilld), and components of bioluminescence reactions have been tested as replacements for radioactive labels in both competitive and sandwich-type immunoassays. Acridinium ester labels are used extensively in routine clinical immunoassay analysis designed to detect a wide range of hormones, cancer markers, specific antibodies, specific proteins, and therapeutic dmgs. An acridinium ester label produces a flash of light when it reacts with an alkaline solution of hydrogen peroxide. The detection limit for the label is 0.5 amol. 

Specificity is unsurpassed. Traditionally, MS was performed on very large and expensive high-resolution sector instruments operated by experienced specialists. The introduction of low-resolution (1 amu), low-cost, bench-top mass spectrometers in the early 1980s provided analysts with a robust analytical tool with a more universal range of application. Two types of bench-top mass spectrometers have predominated the quadrupole or mass-selective detector (MSD) and the ion-trap detector (ITD). These instruments do not have to be operated by specialists and can be utilized routinely by residue analysts after limited training. The MSD is normally operated in the SIM mode to increase detection sensitivity, whereas the ITD is more suited to operate in the full-scan mode, as little or no increase in sensitivity is gained by using SIM. Both MSDs and ITDs are widely used in many laboratories for pesticide residue analyses, and the preferred choice of instrument can only be made after assessment of the performance for a particular application. 

Applications Sollinger and Sawatzki [793] have reported the use of TLC-Raman for routine applications, e.g. TLC of hydroxybenzenes (including hydro-quinone and pyrogallol) on conventional, silica gel and specific Raman-TLC plates (coated with spherical silica gel). Databases were used for identification of substances. Typical detection limits were in the low p,g region per application, Micro-Raman spectrometry has been employed in analysing TLC fractions from polymer additives within a detection limit... 

It is easy to look back from today s vantage point and assert that the spectral patterns produced by pyrolysis were not sufficiently dissimilar for different organisms, or that pattern recognition (or computational) approaches were not advanced enough to provide the specificity needed for routine application of PyMS to bacterial characterization. Such criticism misses the important point that these methods did work within certain limitations. Indeed, research... 

The QA/QC lab, then, would particularly benefit from LIMS technology which would mechanize the collection and analysis of data from routine tests, which would assure and document adherence to appropriate test methods and specifications, and which would include automatic limit checking and pass/fail determination. 

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