Retrospective validation

The general principles of process validation involve prospective process validation (also called premarket validation), retrospective process validation, revalidation, and... 

Oscillation of the dried granulation and lubricant was accomplished in every instance using a no. 10 wire screen. Reference to the no. 12 screen, the alternative method for pulverizing the batch, must be deleted from the manufacturing instructions for the process to be validated retrospectively. 

Under certain conditions, a firm may rely on existing production, quality control, and facilities maintenance information, and consumer input to validate retrospectively the processes of marketed products. The end result of this effort... 

For existing computer systems, retrospective evaluation is discouraged. It is extremely difficult to evaluate a computer system retrospectively, being generally more costly and time consuming than prospective validation. Retrospective evaluation should be used only as a corrective measure in response to deficiencies noted concerning prior validation efforts. See Chapter 19 for a brief discussion on this subject. 

Process validation is usually performed before commercialization (Prospective Validation). Exceptionally, it may be necessary to validate processes during routine production (Concurrent or Simultaneous Validation). Processes already in use can also be validated (Retrospective Validation). To validate a process, a previous validation of facilities, systems, equipment, and analytical methods (ICH, 1996a), as well as previous training of operators (WHO, 1996 EC, 2001), are required. 

The quality of the biological data is paramount in the decision as to whether a given chemical is closer to, or further away from, the desired properties. This high level diagnosis is made from data derived from numerous sources. The confidence level is very much determined by the extent to which the chemistry and mechanism of action of the drug has been previously described. Since a disease model is only proven when it has been shown to predict a chemical activity in the human, it is only validated retrospectively. A novel therapy will require untested animal models of disease and so the confidence in the data derived from the model is substantially reduced. Similarly, new chemical entities having unknown metabolites are much more problematic in the prediction of adverse side effects. Therefore a chemist is conservative and more likely to work with classes of compounds previously shown to be safe. 

The main advantage of the modular approach is to make validation projects more flexible and more efficient. In addition, there is a labor reduction in terms of cost and time [18]. In particular, the aspects of between-laboratory reproducibility and predictive capacity are separated. Moreover, the modular design is suitable for prospective validation, retrospective validation, or a combination of both. 

The former solution might have the advantage that the looming problem of having to validate retrospectively the respective instruments might be defused or at least alleviated, while of course the latter option might be cheaper, at least for the moment being. 

VALIDATION—RETROSPECTIVE The conduct of validation studies performed after production has begun and designed to show that tiie processes, procedures etc. are effective and robust (insensitive to variation) within the likely ranges of variables affecting them. The collection of data showing that batches always meet specifications is not in itself, validation. 

The method has been successfully validated retrospectively, on its ability to predict the entire experimental interaction matrix between 13 antipsychotic drugs and 34 protein targets (Box 21.1) [20] and also prospectively on its capacity to correctly anticipate the affinity profile of the drug cyclobenzaprine [21]. 

Filter integrity testing equipment Usually, existing processes are validated retrospectively. Here a representative period is considered in which the process took place without adjustments, e.g. 3 years. 

When looking at these examples, you can see that verification is very much a retrospective activity, where the objective is to confirm that what has happened is correct. In contrast, validation takes a prospective view, with the objective being to establish confidence that a product or process will work satisfactorily going forward. 

Trial validity is also grossly affected by the type of trial carried out. In schizophrenia there are several health-care decision models, retrospective mirror-image analyses (with or... 

To be useful to those concerned with choices in the allocation of health and social care resources, the data for economic evaluations need to be timely, relevant, credible and accurate (Davies, 1998). As a minimum, the costs associated with the interventions should be estimated from activity data, which quantify resources used, and price or unit cost data. Often evidence from well-controlled prospective trials with high internal validity is required to establish whether differences in economic end points are directly attributable to the interventions. However, the economic evaluations of acetylcholinesterase inhibitors estimated costs from retrospective analysis of available datasets Qonsson et al, 1999b), analysis of published literature (e.g. Stewart et al, 1998) and expert opinion (e.g. O Brien et al, 1999 Neumann et al, 1999). This means that it is not clear whether differences in costs were due to the anticholinesterase inhibitors or to other factors such as availability of services in different areas, the living situation of the patient, or disease severity. 

Process validation can be done in different ways, viz. prospectively, by carrying out a planned program of experiments, before routine production is started concurrently, during routine production retrospectively, by statistical analysis of historical data and during scale-up studies (developmental validation). 

Generate and maintain an inventory of all systems utilized by the organization, categorizing them as regulated and nonregulated systems. Identify prospective validation or retrospective evaluation needs for each system and record the current validation status. 

For existing systems, conduct a retrospective evaluation of historical versions. Document the adequacy of the historical documented evidence (historical and current versions) and any actions that will be taken to prove the validation stams of the system. 

Validations fall into two types prospective and retrospective. In prospective validation (see flow chart in Figure 2) the validation is done in a sequential manner, involving installation qualification and operational qualification (IQ/OQ) of equipment (e.g., chromatography instrumentation or column hardware). Appropriate calibrations accompany the IQ/OQ. Process qualification, or PQ, involves formal review and approval of a PQ protocol, execution of this protocol, and issuance of a formal PQ report which includes data analysis and recommendations (i.e., approval/certification of the process). If the process is not approved, the report may recommend a redesign or redoing of the validation protocol and, in some cases, a return of the process to process development for further optimization. 

Retrospective validation uses historical information gathered in actual process runs to evaluate the process. For example, batch records can provide extensive data on column performance and analytical data of fractions and final product can provide valuable information on the efficiency of the chromatographic steps in removing contaminants. Chapman67 cautions that while retrospective validation is a valid and valuable approach, it is not meant to be retroactive — validation must be done before product is released to market. 

Retrospective validation Qualification Validation carried out by review of historical records How an individual element of an overall validation programme performs. When validation of that specific element is complete, it is qualified . When all elements are (satisfactorily) completed the system is validated... 

Retrospective IVIVC development, using studies not designed for this purpose, reduces the probability of successful IVIVC development and validation. Normally such studies are compromised by not including a reference formulation and do not have a large enough range of release rates, thereby requiring cross-study comparisons where subjects have different clearance characteristics that could have been accounted for had a reference formulation been incorporated. 

Another retrospective analysis of already known H DAC inhibitors was carried out by You et al. [68]. They generated a 3D chemical-feature-based pharmacophore model and compared the ligand-based model with the structural-functional requirements for the binding of the HDAC inhibitors. Using this model, the interactions between the benzamide MS-275 and HDAC were explored. The result showed that the type and spatial location of chemical features encoded in the pharmacophore are in full agreement with the enzyme-inhibitor interaction pattern identified from molecular docking. However, also in this study no experimental validation of the modeling results was provided. 

Retrospective validation validation carried out by review of historical records. 

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