Development Assurance process limitations

Operating limits are data driven, with the most critical measure being the process variation. They are established by working inward from the registration limits to provide assurance that we will not fail registration limits because of process or assay noise. At this stage of development the process variation will not be completely known, particularly in the hands of the plant, but the noise observed from the DOEs can be a reasonable starting point. 

Of course, if a firm is ISO 9000 acaedited, this already speaks volumes about its commitment to quality, although the limitations of ISO 9001 to software development need to be clearly understood. These shortcomings have given rise to ISO 9000-3 (TickIT), to which over 1,000 firms have now been accredited however, this is a drop in the ocean when viewed against the industry as a whole. The consistent pattern of commercial success enjoyed by TicklT-accredited software houses is no coincidence and should be used by the auditor as a powerful endorsement of the benefits of a quality-assured process in securing the future prosperity of a firm involved in any way with software development. 

ARP4754A (paragraph 3.1) refers to Development Assurance , which establishes confidence that system development has been accomplished in a sufficiently disciplined manner to limit the likelihood of development errors that could impact aircraft safety . Development Assurance is defined as a process involving specific planned and systematic actions that together provide confidence that errors or omissions in requirements or design have been identified and corrected to the degree that the system, as implemented, satisfies applicable certification requirements . 

These process limits are inherently conservative. They are designed to assure operation within known-safe limits. Process limits are based on experimental data and Interpreted by etnalytlcal techniques using where necessary conservative Interpolations cmd modest always conservative extrapolations. The limits will be constantly reviewed and updated as additional information becomes available from operational experience and agressive research and development progrcums. 

Currently the main application of interest for parametric release is to replace the sterility test as a control method in appropriate cases (given the limited value of that test to predict sterility assurance due to statistical considerations, although it is also pointed out that a sterility test provides a final opportunity to identify a major failure, although other means should provide a more reliable way of detecting such failures). The concept is applicable to well-founded methods of sterilization where the product stability is known and development data have identified the critical process parameters. The measured parameters should be such as to ensure that correct processing of the batch provides sufficient assurance that the sterility assurance level intended has been achieved. 

Although a thorough validation cannot rule out all potential problems, the process of method development and validation would address the most common ones. Examples of typical problems that can be minimized or avoided include interferences that coelute with the analyte in liquid chromatography (LC), a particular type of column that no longer produces the separation needed because the supplier of the column has changed the manufacturing process, an assay method that is unable to achieve the same detection limit after a few weeks, or a quality assurance audit of a validation report that finds no documentation on how the validation was performed. 

One approach that QA would use to assure itself that a given process (step) is under control is the effort associated with the concept of process capability. Ekvall and Juran [15] defined the concept as the measured inherent reproducibility of the product turned out by the process. The statistical definition of process capability is that all the measured values fall within a 6-sigma range (i.e., range of the minimum to maximum limits). The information is used to show that the process is under control over a period of time as well as determine whether there is any drifting or abnormal behavior from time to time. Process validation is a QA tool in this case because its data will be used as the origin for the data curve developed for the process capability concept. 

The proposed NCP recognizes the statutory mandate in Section 105(8) to develop risk assessment criteria and a National Priority List by limiting "remedial" actions to releases on the National Priority List ( 300.67(a)). This will put teeth in the mandate of Section 105(8) and will assure the importance of the risk analy-sis/prioritization process. 

While this methodology has been shown to be very useful for many crystallization processes, it is subject to size dispersion and the other nonlinear effects of Fig. 4-24, and has the additional need to assure (perfect) mixing up to and including the product exit line. Use of large amounts of material is often impossible for pharmaceutical products in the early stages of development, so this technique has only limited use in our industry. 

The role of chemical analysis and materials characterization has become a central one in advanced IC fabrication. Starting materials, the raw semiconductor wafer, as well as each gas, liquid, and solid used in the processing sequence are coming under increasing scrutiny to assure the highest standards of purity. As a result, analytical methods for bulk chemicals and materials are often used at their lowest attainable detection limits, and techniques are being developed to meet new demands. 

---