Reproducibility qualification

C. During operational qualification the analyst or vendor would assess if the equipment works as specified, generating appropriately documented data. The procedures will verify that the instrument s individual operational units are functioning within a given range or tolerance, reproducibly. For the dissolution apparatus, the water bath temperature and spindle assembly and shaft rpm speed would be obvious operational parameters. 

These components, rigorously interconnected, enable analytical chemists to produce accurate and reproducible data when unknown samples are analysed. Especially the two basal compartments are of crucial importance analytical methods validation and analytical instrument qualification. 

The degree of lot-to-lot reproducibility you require from a column is ultimately a function of the needs of a particular assay, which makes it impossible to state definite limits that will be appropriate in every case. Whatever the level of variation, it is important that it be documented. As new lots of media are brought into use over the course of years, their performance vs. the established reference should be included in a master database begun with the original qualification testing. Among other factors, this will allow you to track the column manufacturer s performance over time and possibly detect trends that could affect your assay performance — before a problem occurs. 

Performance Qualification (PQ) This provides documented verification that the equipment and ancillary systems, when connected together, can perform effectively and reproducibly based on the approved process method and specifications. 

Apart from the qualification dossiers provided by vendors there seems, at present, to be very little information published on the performance of an operational qualification for capillary electrophoresis (CE) instruments other than a chapter in Analytical Method Validation and Instrument Performance. The chapter, written by Nichole E. Baryla of Eli Lilly Canada, Inc, discusses the various functions (injection, separation, and detection) within the instrument and provides guidance on the type of tests, including suggested acceptance criteria, that may be performed to ensure the correct working of the instrument. These include injection reproducibility and linearity, temperature and voltage stability, detector accuracy, linearity, and noise. 

A specific requirement of solid propellant binder polymers is the small tolerance allowed in the reproducibility of the product properties. As a result, some polymers that cannot be specified easily must be adjusted lot by lot in accordance with qualification tests. This is illustrated graphically by the data of Figure 1, where different lots of a carboxy-terminated polybutadiene procured to the same specification are compared with the different equivalents of the BITA (butylene imine adduct of trimesic... 

The test sample to use in qualification should be a small molecule that is soluble in water, has a strong UV chromophore, and possesses a charge at the intended separation pH value. A nonvolatile compound is also desirable, especially when used for assessing peak area reproducibility during the detector linearity test. Some examples of test samples that can be used are benzoic acid, 4-hydroxyphenylacetic acid, 4-hydroxybenzoic acid, and 4-hydroxyacetophenone. 

Now I would like to turn to some of the issues of operations within the manufacturing process itself and speak to certain process controls that are expected. In a chemical synthesis sequence, as I mentioned above, intermediates will need to be fully characterized. That characterization will then lead to a set of specifications for the intermediate, that is, its level of purity, its form, etc. Test procedures that demonstrate that the intermediate meets specifications must be established. Some intermediates are deemed to be more important than others and are given specific designation, such as pivotal, key, and final intermediates. In those cases, it is necessary to demonstrate that the specific and appropriate structure is obtained from the chemical reaction and that the yield of the intermediate is documented and meets the expected yield to demonstrate process reproducibility and control. Purity of the substance is to be appropriately documented. And, finally, in reactions which produce pivotal, key, and final intermediates, side products or undesirable impurities are identified and their concentrations measured and reduced by appropriate purification procedures so that the intermediate meets in-process specifications. Thus, those important intermediates become focuses of the process to demonstrate that the process is "under control" and functioning in a reproducible and expected manner. All of these activities ultimately are designed to lead to the production of the actual active ingredient which is referred to then as a "bulk pharmaceutical agent." That final product will need to be completely characterized which then will document that it meets a set of specifications ("Final Product Specifications") for qualification as suitable for pharmaceutical use. 

In step 5, the qualification stage, the critical issue is that the protocol for IQ/OQ of the equipment and the facility include the established method and acceptance criteria. The IQ/OQ report should include the maintenance program to keep the equipment in good condition for reproducibility of the product. For qualification of the equipment and process for terminal sterilization, the following standards should be referred to ISO 13408-1 [6] and 11138-1 [7] for general issues, ISO 11134 [8] and 11138-3 [9] for moist heat sterilization, ISO 11135 [10] and 11138-2 [11] for ethylene oxide sterilization, and ISO 11137 [12] for radiation sterilization. 

Operational qualification is the step in a validation process that will ensure the reproducibility and acceptability of the packaging process. Formally, it is an investigation of the control of variables in any given individual piece of equipment or in a given subprocess. In this way it is possible to verify that the sequencing of events is in the proper order and that the process equipment is operating consistently within the design limits. 

Evaluating composite performance requires test methods for mechanical properties of the constituent materials (fibers, tows, filaments, and matrices) as well as the composite materials themselves. The types and quantities of tests to be performed, and the selection of testing parameters, depends on the information desired. For material development, the tests may be much simpler and less numerous than those that would be chosen for design qualification, but may encompass a greater range of test parameters than would be expected in service. In the case of materials development, it is the trends in the data and the mechanisms by which failures occur which are most important, and it is crucial to examine the extremes of behavior. For component design and qualification, it is more important to know the reliability and reproducibility of the material under conditions which resemble the expected service conditions. 

Process Qualification FDA (1995) Establishing confidence that a process is effective and reproducible. 

In experimental freeze-drying plants small amounts of products are dried to demonstrate that it is possible to freeze-dry a product and to get an overall impression about its solubility and other qualities. For the development of a process, the freeze-drying plants should have a number of certain qualifications, and this is even more necessary if the data have to be documented. It is absolutely necessary that the qualifications of the plant can be measured, are reproducible, and the single steps of the freeze-drying process can be measured, controlled, and documented. 

The purpose of carrying out a performance qualification of the target cycle is to demonstrate that the product can be manufactured in a reliable and reproducible manner using the selected freeze-drying process. In order to substantiate process reproducibility, it is commonly accepted that three consecutive successful runs is adequate. 

In a well-designed validation program, most of the effort should be spent on facilities, equipment, components, methods, and process qualification. In such a program, the formalized, final three-batch validation sequence provides only the necessary process validation documentation required by the FDA to show product reproducibility and a manufacturing process in a state of control. Such a strategy is consistent with the FDA preapproval inspection program directive. ... 

Recalibration of the instrument response function reduces or eliminates most of the instrumental factors that lead to relative intensity variations over time. For example, a luminescent standard could be used at the beginning of each session as described in Section 10.3.3. Use of the same standard and correction procedure during qualification could establish the true value of one or more peak ratios for future reference. Table 10.9 shows results for this approach applied to the example of calcium ascorbate. The ratio of the 767- and 1587 cm" peak intensities was monitored after calibration of the response function with a luminescent standard. The standard deviations listed in Table 10.9 for the 767/1582 peak height ratio provide indications of the reproducibility of the response correction and sample spectra. 

Qualification of critical equipment, process validation and change control are particularly important in the production of herbal medicines with unknown therapeutically active constituents. In this case, the reproducibility of the production process is the main means for ensuring consistency of quality, efficacy and safety between batches. 

Mass spectrometry has become more useful In the support of electronic development and manufacturing processes. Fourier transform mass spectrometry, the latest advance in this analytical method, Is another step forward in versatility, sensitivity and reproducibility in analytical characterization, qualification and quantification of raw materials and contaminants as used in electronic devices. A review will be provided of basic instrument hardware and interfacing, significant operating parameters and limitations, and special inlet systems. Emphasis will be placed on material evaluation, process control and failure analysis. Data handling will be reviewed using appropriate examples encountered in material and failure analysis. 

The observations made during the execution of the VMP provide strength to significantly reduce the regulatory risks related to the systems and initiation of the proactive corrective actions required. The plan provides visibility for the completion of individual tasks and assures system evaluation, process validation, equipment validation, facility and utilities qualification, documentation, environmental control, and monitoring implementation and execution of the VMP assures process reproducibility control over the applicable changes and modifications as a result in facilities, equipment, personnel, and materials. 

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