Safety Assessment Process

The entire safety assessment process that supports new product research and development is a multistage effort in which none of the individual steps is overwhelmingly complex, but for which the integration of the whole process involves fitting together a large and complex pattern of pieces. This paper proposes an approach in which integration of in vitro test systems calls for a modification of... 

A scientific approach to safety assessment, such as the one presented in this chapter, does have proponents and adherents. Such an approach requires those involved in both the management and conduct of the safety assessment process to continually question (and test) both the efficacy and the validity of their evaluation systems and processes. More to the point, it requires recognition of the fact that we have always done it this way is not a reason for continuing to do so. This approach asks first what is the objective behind the testing, and then it asks how well our testing is meeting this objective. 

All drugs entering the Chinese market are approved by the state FDA (13). The nonclinical safety assessment process of pharmaceuticals in China is very similar to that of other countries. Most up-to-date data requirements for the approval of new drugs are available on the Web site of Center for Drug Evaluation (CDE) of the SFDA (http //www.sfda.gov.cn/). 

A number of practical considerations affect the choice of experimental approaches to address a specific question. In general, these practical considerations tend to have a greater impact on applications to toxicology (where specific endpoints may not be measurable in all cell types) than studies of xenobiotic metabolism (where the principal requirement is enzyme activity). However, applications to toxicology should be considered when making a choice of an experimental approach as specific toxicological issues may develop from the metabolism studies or in other aspects of the safety assessment processes. 

In some instances additional specialized studies may be required to assess drug-specific toxicological concerns. For example, hypersensitivity tests may be required for the -lactam antibiotics FDA has recently been concerned with how this standard human food safety assessment process accurately determines the safe concentration of antibiotic residues based on the traditional toxicological end-points. Of particular concern was the impact of low levels of antibiotics on the intestinal microflora. 

Metal foodstuff packaging continues to develop to make use of new materials, new technologies and new market opportunities. The safety assessment of new materials, technologies and applications will always be a fundamental part of any new development, indeed one of the drivers of new product development is to simplify and improve the safety assessment process without prejudicing the existing food safety attributes of the packaging. 

Although contaminants are not intentionally added, the assessment of contaminants typically begins with the application of the same safety assessment process that is used for the evaluation of food additives. In most instances, such an assessment is sufficient in providing the assurance of safety of the potential exposure to many dietary contaminants. There are, however, other instances where the environmental contaminant is so ubiquitous, and therefore difficult to avoid, that a more informative analysis needs to be considered. The output of such an assessment is intended to describe the degree of harm expected in the population and the degree of uncertainty associated with the estimates. Specific areas of uncertainty can... 

Toxicologists must rely on results obtained from an alternative method if it is to serve as a replacement for an in vivo toxicity test. Two measures of alternative method performance must be known in order to define reliability from a test user s point of view. First, a toxicologist must know it is possible to consistently reproduce the data obtained from the alternative method over long periods of time. A test that does not provide the same results on the same test substance repeatedly would not be useful in the safety assessment process. Second, it must be possible to consistently predict in vivo toxicity endpoints at a known level of accuracy and precision. These measures of reliability are objective endpoints that can be measured experimentally. The part of the validation process that provides the data needed to confirm the reliability of an alternative method as proposed by its developers is the validation study. 

Toxicologists who use alternative methods in the safety assessment process generally utilize three approaches to help decrease the uncertainty of the predictions when mechanistic understanding is weak. The first is to restrict the use of an alternative method to the same chemical classes that were used to develop the prediction model. This is important because similar materials are more likely to act by the same mechanisms of action. If the materials tested diverge significantly from those used to develop the prediction model, then the reliability of the predictions will decrease. This will occur because the divergent materials may exert effects through different toxic mechanisms that should perhaps be tested in different alternative methods that are sensitive to different chemical parameters and that use different prediction models. 

If the alternative method is judged both reliable and relevant at the end of this process, then the new assay should be considered validated. Once validated, the alternative method may be used routinely in the safety assessment process and should be considered for acceptance by regulatory authorities (Figure 1). If the alternative method is judged not relevant, then it should not be used or considered for acceptance by regulatory authorities. The reasons for the rejection should be clearly stated so that the deficiencies can be identified and resolved in follow-up research if such work is likely to be fruitful. 

The notion that demonstrating that a system has undergone a safety assessment process is as important as actually achieving safety. 

Where the outcome of an analysis is unexpected at least some consideration should be given to the possibility that the safety assessment process or its application could be flawed in some way. As part of the action plan it can be prudent to check that the issue is not a figment of the assessment methodology, especially when a CRM process is new and has not been previously tested. For example ... 

ARP4761 - Guidelines and methods for conducting the safety assessment process on civil airborne systems and equipment - 1996 - 4.2 and annex G... 

The FHA is undertaken at the beginning of the aircraft/system development life cycle, it is the first step in a safety assessment process that is performed on both new and modified aircraft programs. 

SAE ARP4761, 1996. Guidelines and Methods for Conducting the Safety Assessment Process on Civil Airborne Systems and Equipment. 

Safety Assessment process, which drives the DAL allocation and the required derived system behaviours. 

A-2 Derived high-level requirements are defined and provided to the system processes, including the system safety assessment process. O o o o SAV Requirements Data 11.9 ... 

The Safety Assessment process assigns the DAL as explored in Step 1 (Section 9.2.1) mentioned earlier. The development assurance outputs from the Safety Assessment process is summarised in Table 9.16. 

The data items in Table 9.15 should be a standard output from the process defined in Fig. 1.2. As this book is all about the Safety Assessment Process (see Table 1.1), it is... 

System Safety Assessment process to mitigate crew errors... 

Within the scope of this chapter then, let us consider the regulatory requirements which drive the integration of crew errors into the Safety Assessment process. 

During the Safety Assessment process, various assumptions might have been made (e.g. MTBF as well as how the equipment will be operated and maintained) hazardous failure conditions would have been identified (e.g. loss of Altitude Display might be Extremely Improbable , but is still possible) and procedures would be prescribed to mitigate risks for through life safety (i.e. how to deal with failure scenarios when they do occur). 

Example manuals/documents that can be considered to be part of the ICA are listed below, many of which will receive safety-related information from the Safety Assessment process ... 

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