Validation automated methods

A dedicated automation specialist or group with necessary skill sets (analytical chemistry, computer literacy, and instrumentation) able to devote sufficient time to automation implementation is critical to take a project to fruition. The success of a robotics program can be enhanced greatly by making it accessible to a large population. Thus, it is essential for automation specialists to work closely with every analytical area to develop and validate automated methods for developmental products. After the technology is well established, the specialists can return to their operating areas. 

The key to successful integration of automation into the modem analytical laboratory is a sound approach to method development and validation. The end result of a well-developed and validated automated method will be a robust analytical method that should pay dividends by being able routinely to produce sound analytical data to support crucial regulatory submissions. 

The analyses of illicit drugs and metabolites in the sampled waters were performed following a previously described and validated fully automated method based on on-line solid phase extraction-liquid chromatography-tandem mass spectrometry (on-line SPE-LC-MS/MS) [19]. 

Part—I has three chapters that exclusively deal with General Aspects of pharmaceutical analysis. Chapter 1 focuses on the pharmaceutical chemicals and their respective purity and management. Critical information with regard to description of the finished product, sampling procedures, bioavailability, identification tests, physical constants and miscellaneous characteristics, such as ash values, loss on drying, clarity and color of solution, specific tests, limit tests of metallic and non-metallic impurities, limits of moisture content, volatile and non-volatile matter and lastly residue on ignition have also been dealt with. Each section provides adequate procedural details supported by ample typical examples from the Official Compendia. Chapter 2 embraces the theory and technique of quantitative analysis with specific emphasis on volumetric analysis, volumetric apparatus, their specifications, standardization and utility. It also includes biomedical analytical chemistry, colorimetric assays, theory and assay of biochemicals, such as urea, bilirubin, cholesterol and enzymatic assays, such as alkaline phosphatase, lactate dehydrogenase, salient features of radioimmunoassay and automated methods of chemical analysis. Chapter 3 provides special emphasis on errors in pharmaceutical analysis and their statistical validation. The first aspect is related to errors in pharmaceutical analysis and embodies classification of errors, accuracy, precision and makes... 

In other words, if an automated method can be considered equivalent in suitability in determining compliance, and if a compendial method does not require validation, then does it follow that an automated method using the same basic chemistry does not require validation of the original chemistry This puts automation closer to the same category... 

Use of unusual automated methods of analysis, although desirable for control testing, may lead to delay in regulatory methods validation because the FDA laboratories must assemble and validate the system before running samples. To avoid this delay, applicants may demonstrate the equivalency of the automated procedure to that of a manual method based on the same chemistry. ... 

FDA Guidance. Submitting Samples and Analytical Data for Methods Validation Appendix C, B. Automated Methods. February 1987. 

The relationship between the concentration of the solute and the peak produced in the chromatogram is, strictly speaking, only valid for peak area measurements, but in most instances it is more convenient to measure peak height. Such peak height measurements should only be used when all the peaks are very narrow or have similar widths. The tedium and lack of precision associated with non-automated methods of peak area measurements may be overcome using electronic integrators, which are features of most modern instruments. 

Li W, Rossi DT, Fountain ST. 2000. Development and validation of a semi-automated method for L-DOPA and dopamine in rat plasma using electrospray LC/MS/MS. J Pharm Biomed Anal 24 325. 

The USP 24 General Notices state that alternative methods may be used to determine that products comply with the pharmacopoeial standards for the advantages in accuracy, sensitivity, precision, selectivity, adaptability to automation or computerized data reduction, or any other special circumstances. Such alternative or automated methods shall be validated However, when disputed, the compendial method is conclusive as it is the official or referee test. In addition, USP Chapter (61) Microbial Limit Tests states that automated methods may be substituted provided they are validated and give equivalent or better results, whereas USP Chapter (71) Sterility Tests states that alternative procedures may be employed to demonstrate that an article is sterile, provided the results obtained are at least of equivalent reliability. 

Accuracy. The accuracy of the method expresses the closeness of agreement between the experimental result and the true value. When converting a validated manual method to an automated procedure, it may not be necessary to perform an accuracy study. Instead, it may be sufficient to rely on the comparison to manual data and on additional supporting validation on the automated procedure. When developing and validating the automated method as the first-intent method, it will... 

Equivalency. This test compares the results of the automated procedure with the results of the validated manual method. If accuracy of the automated procedure has been proven, it may not be necessary to perform the equivalency study. However, if the manual method does not exist, then accuracy and reproducibility data should be used to assess the suitability of the automated method. The recommended testing for content uniformity, assays, degradation and impurity methods and dissolution methods are listed in Table 5.4. 

Manual versus automated methods. When difficulties arise in the development or validation of an automated method, it is often due to a minor difference... 

Design of Validation Experiments. For the validation of an automated assay method based on a validated manual method and involving a technical transfer of the method, the following experiments would be required ... 

The validation of an automated content uniformity method and an automated dissolution method based on a validated manual method can adopt a similar approach where the equivalency data can support the requirements of the other studies involved. When validating an automated method that is not based on a validated manual method, only the repeatability and reproducibility can be combined to reduce the amount of analysis to be done since the equivalency study will not be executed. 

A. Walsh et al., Development and validation of automated methods for finished product testing, Pharm. Technol. Eur., 24(3), 134, 2000. 

An automated method can be run after validation using multiparametric open analysers [1, 11, 17], For example, KONELAB 30 (Thermo Fisher Scientific, Waltham, USA). There is no standard for pyruvate, ACAC or . The results are calculated taking into account the molecular extinction coefficient of NADH (6.3 mmol 1 cm 1). A lactate standard is provided in the kit. 

Often, the robotic process takes longer than the manual process however, significant savings and acceleration of the process is realized by overnight or around-the-clock operation. In these cases, the routine operations can be performed by the automated system, leaving the highly trained scientist to perform the more detailed aspects of the analysis that require experience and real-time decisions. Clearly, standard methods provide a necessary step toward the implementation of automated methods via their focus on routine process steps. The automated approach is implemented and validated by careful inspection and observation of performance. 

Extraction scientist who is responsible for sample preparation should be certified prior to extracting real study samples. The validated extraction method has to be followed exactly. The raw data entries have to be documented promptly such as lot numbers of STD and QC, IS, extraction reagents, matrix, the IDs of automation tool and pipette, the time for study sample removal and return to storage and the completion of extraction. Instrument operator who is responsible for analysis has to perform SST test and assess sensitivity and carryover prior to initialing batch. Instrument operator has to... 

Generally, the analysis of environmental pollutants is considered as a necessary expense that is performed solely if stated by law. With less expensive screening methods and automated modern equipment to analyze suspect samples, the cost of analysis will become much lower. Hence, the attitude towards QA would most probably be more positive and the analytical work much more reliable for the customers. This also strengthens the international competitiveness of European producers. The credibility of the entire monitoring chain (screening methods, reference and standardized methods, as well as CRMs for the quality control of these methods) lies in the adequacy and integration of all three levels of the system. The adequate development and validation of methods is a prerequisite for a harmonized measurement system [80]. 

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