Candidate methods

Fig. 2.3 Flowchart of NMR structure determination using the Candid method for automated NOE cross peak assignment.

Based on the evaluation of the screening results, a candidate method is identified and will be optimized. This method is selected on the basis of its being able to monitor all components of interest. It is additionally ideal that no minor peaks elute in close proximity before and after the API. 

A supportive method that is orthogonal to the candidate method is also selected on these terms. The elution order of the supportive method is by definition significantly different from the candidate method. Ideally the method screening experiments will provide two sets of conditions, as shown in Figure 4. The utilization of the supportive method maximizes the probability that new unknown related compounds, which possibly co-elute in the candidate method, will be detected and taken into account when evaluating results for subsequent batches of DS or new DP formulations. 

Following selection of the candidate method, the method is optimized for resolution and run time. As discussed previously, this is readily performed using software tools such as DryLab. The approach may... 

During proactive method development, special attention should be drawn to four key areas, as shown in Figure 8, prior to issuing the candidate method ... 

Following validation, the candidate method is referred to as a level 1, 2, or 3 method depending on the level of pharmaceutical development that the method is intended to support (see Table 1). 

The candidate method is used to support drug synthesis, excipient compatibility, and ultimately to evaluate candidate formulations. Such support typically involves analyses of stressed materials to identify degradation trends. These studies are conducted in the solid state by exposing the DS and DP to relative humidity, temperature, light, and oxidizing... 

Paur, R. Comparison of uv photometry and gas phase titration as candidate methods for absolute calibration of ozone gennator output in the subpart-per-million range. Paper Presented at the American Society for Testing and Materiab Conference on Calibration in Air Monitoring, Boulder, University of Colorado, Aug. 5-7, 1975. 

Step 3 Feasibility assessment Detemiine (via literature search, consultation, etc.) suitable candidate methods and assess the feasibility of these methods. The purpose of this step is to collect enough information to accurately define (or scope ) and prioritize the project. The amount of information required may vary considerably, depending on the magnitude of the proposed project. Significantly less information is required to develop a new method for an existing off-line analyzer than is required to justify spending several million dollars on a major installation of on-line analyzers. (The capabilities and limitations of NIR process analyzers are discussed in Section 15.2.4.)... 

Independent Methods. In the absence of appropriate certified reference materials one may have to rely upon in-house materials that can be analyzed by independent methods (other than the candidate method). These independent methods should include a reference method and other methods that utilize different physical/chemical principles for analyte quantification. Reference methods are generally arrived at by concensus following extensive accuracy testing by a large number of laboratories. The American Society of Testing Materials (ASTM) is one of the largest compilers of reference methods. Additional information on the use of reference methods may be found in a paper by Cali and Reed (.2),... 

Referee Laboratories and Spike Recovery Testing. Outside laboratories, with demonstrated performance records, can be used to evaluate the suitability of a candidate method when none of the other accuracy testing options is feasible. However, This technique provides a very weak form of accuracy assessment. Indeed, it provides a comparability check, not an accuracy measure. Similarly, spike recovery tests provide only weak evidence of method accuracy. Quantitative spike recovery only indicates that the added form of the analyte was recovered. If the added form responds differently toward sample preparation or detection the utility of spike recovery testing remains doubtful. 

Accuracy is an expensive commodity. It involves exhaustive testing of the candidate method. Thorough delineation and careful control of analytical variables is essential to accurate analyses. 

Jones, S.A., Moore, L.B., Wisely, G.B. and Kliewer, S.A. (2002) Use of in vitro pregnane X receptor assays to assess CYP3A4 induction potential of drug candidates. Methods in Enzymology, 357, 161-170. 

Wet Wall Electroinertial Precipitator. The wet wall electroinertial precipitator (WWEP) air cleaner was developed to meet the requirements of high operating efficiency, low maintenance, low operating cost, and simplicity of design. To achieve high efficiency with low pressure loss, an electrostatic precipitation was the best candidate method. A wet wall was desirable to flush the precipitate away and to minimize maintenance. Inertial effects were added to assist in moving material toward the wall and to improve the cleaning action of the water on the wall (20). 

Continuous Sampling and Determination. There are no truly continuous techniques for the direct determination of sulfuric acid or other strong acid species in atmospheric aerosols. The closest candidate method is a further modification of the sensitivity-enhanced, flame photometric detector, in which two detectors are used, one with a room-temperature de-nuder and one with a denuder tube heated to about 120 °C. Sulfuric acid is potentially determined as the difference between the two channels. In fact, a device based on this approach did not perform well in ambient air sampling (Tanner and Springston, unpublished data, 1990). Even with the SF6-doped H.2 fuel gas for enhanced sensitivity, the limit of detection is unsuitably high (5 xg/m3 or greater) because of the difficulty in calibrating the two separate FPD channels with aerosol sulfates. 

Part of the problem is that although the concept is intuitively obvious, it is sufficiently multifaceted that a concise but truly complete and rigorous definition (i.e., one that leaves all questions answered) is difficult to craft. Another part of the problem is that many definitions seek to define the term in a way that predisposes it to a certain method of determination. It is a simple statement of fact that there is a diversity of opinion on the answers to questions related to the issues associated with the subtle aspects of the LOD and that there are numerous mathematical methods that have been devised, which get at the essence of the LOD. The challenge is to draft a definition that acknowledges that these differences exist and then handles these differences not by specifying which of literally tens of candidate methods and approaches are correct but rather by requiring that the methods and approaches used be specified as part of reporting the LOD. Such a definition follows ... 

The selection of appropriate methods for clinical laboratory assays is a vital part of rendering optimal patient care, and advances in patient care are frequently based upon the use of new or improved laboratory tests. Ascertainment of what is necessary clinically from a laboratory test is the first step in selecting a candidate method (Figure 14-1). Key parameters such as desired turnaround time and necessary clinical utflity for an assay can often be derived by discussions between laboratorians and clinicians. When introducing new... 

In evaluation of the performance characteristics of a candidate method, precision, accuracy (trueness), analytical range, detection limit, and analytical specificity are of prime importance. The sections in this chapter on method evaluation and comparison contain a detailed outline of these concepts and their assessment. The estimated performance parameters for a method can then be related to quality goals that ensure acceptable medical use of the test results (see section on Analytical Goals), From a practical point of view, the ruggedness of the method in routine use is of importance. Reliable performance when used by different operators and with different batches of reagents over longer time periods is essential. 

Various categories of candidate methods may be considered. New methods described in the scientific literature may require in-house development. Commercial kit methods, on the other hand, are ready for implementation in the laboratory, often in a closed analytical system on a dedicated instrument. When reviewing prospective methods, attention should be given to the following ... 

Following selection of a candidate method, further stability studies are desirable for both drug substance and drug product (or drug substance mixed with excipients, if a dosage form is not available). These studies should be con-... 

As was the case for the forced-decomposition samples, the solid-state stability samples should be monitored using both PDA and MS detection to ensure that specificity of the candidate method is maintained. Analysis of the samples using an orthogonal method to further verify specificity is also recommended. If the method is, at this point, shown to provide separation among the API, all drug synthesis process impurities, and all degradation products, no additional method development is required at this juncture. When coelution is observed between components, development using additional column/mobile-phase combinations may be considered (see Section III.E). Alternatively, the use... 

Review Figure 4.1, which places in context most of the validation concepts and steps for a candidate method that we have discussed. We will discuss quality control in the context of quality assurance below. 

Finally, the possibility of obtaining bonding with a candidate method must be determined to decide whether agglomeration can be carried out binderless (potentially, by making use of an inherent binder in the material and/or high pressure or elevated temperature) or requires the addition of binders. 

Thus, a broad range of sometimes complementary analytical techniques is available at present for the characterisation of the various PAH/POM emissions. For standardisation purposes, candidate methods must be tested extensively in a collaborative exercise to determine and evaluate repeatability, reproducibility and recovery criteria before final definition and approval. (Recently, the method detection limit, defined as the concentration which can be detected at a specific confidence level, was proposed as one criterion for assessing the performance of an analytical method (18)). 

The syndiesis of nanomaterials is being pursued via a number of methods. Physical mediods include sonication and ball milling of solids ((f). Chemical techniques include vqwr condensation methods (7-P), micellular synthesis, chemical reduction (//), sonochemical syndiesis (/O), and the sol-gel methodology (12-20). For nanomaterials to have a notewordiy impact in the area of energetic materials processes for dieir syndiesis must satisfy significant production specifications such as cost, health and safety, and reproducibility. The sol-gel mediod provides another iqqnoach to nanomaterials syndiesis for energetic nanoconqiosites and, in some reflects, it is a more suitable candidate method than those Ascribed previously. 

Based on the number of produced units it may be determined - e.g. with the sudden-death-test method or the Eckel-candidate-method (Eckel, G. 1977) - the... 

Subsequently, it is possible to calculate a prognosis regarding the expected damage cases in the field. Based on the numher of produced units N = 36.000, the damage probahihty can be determined e.g. with the sudden-death-test method or the Eckel-candidate-method (state of the art, Bertsche, B. et al., 2004) - at each life-span area with respect to the known coolant pump population in the use phase. 

Caruso A, Frances N, Meille C, Greiter-WiUce A, Hillebrecht A, Lave T (2014). Translational PK/PD modeling for cardiovascular safety assessment of drug candidates methods and examples in drug development. J Pharmacol Toxicol Methods 70 73-85. 

---