Prospective validation

A computer application which should be used in the context of a GLP study, however, might be a special development for just one or a few test facilities, and therefore any malfunctions, which might occur under special circumstances only, could go imdetected during software development and limited programme testing. As any other apparatus, computerised systems have to be suitable for their intended use, and the user should be able to expect the 

The process of validation, and the determination of its necessary extent may be best understood, if the developmental and operational life-cycles of a computer application or system are considered (see figure 21). 

Whether for a completely new development, or for the simple purchase of a commercially available computerised system, the user requirements have to be defined and compiled in an as specific and complete manner as possible. The new HPLG system, e.g., should be able to detect the test item at a predefined sensitivity and to allow different calculation modes for study-specific 

However, not only the technical aspects will finally have to be addressed, but the whole range of scientific and business, regulatory, safety, performance, and quality requirements will have to be included, amongst which the existence of an audit trail may be cited as an important part. 

The main part of the foregoing paragraphs would probably seem to cover more the demonstration of the suitability for the intended purposes of apparatus in general than the prospective validation of computerised systems. While it may be easy to grasp what is meant by the different steps in a validation process for any such physical apparatus, it may call for some more 

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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. 

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. 

Prospective validation Validation undertaken prior to commencement of routine product manufacture... 

Genetic tests are being prospectively validated as decision-support tools for adjuvant chemotherapy in node-negative patients to identify characteristics of the primary tumor that may predict for the likelihood of metastases and death. 

A combination of retrospective and prospective validation. Performed against an approved protocol but product is released on a lot-by-lot basis. Usually used on an existing product not previously validated or insufli-ciendy validated. 

This validation plan describes the prospective validation of the file Template Content Uniformity by UV (V.Ol).xls. The file is located at Drive E Validated Excel templates Template CU UV (V.01).xls. 

The steps and sequence of events required to carry out a process validation assignment are outlined in Table 8. The objective of prospective validation is to prove or demonstrate that the process will work in accordance with a validation master plan or protocol prepared for pilot-product (100 x size) trials. 

Prospective validation is a requirement (Part 211), and therefore it makes validation an integral part of a carefully planned, logical product/process developmental program. An outline of the development sequence and requirements relevant to process validation is presented in Figure 1. After briefly discussing organizational aspects and documentation, the integration of validation into the product development sequence is discussed. At the end of the chapter there is a... 

An effective prospective validation program must be supported by documentation extending from product initiation to full-scale production. The complete documentation package can be referred to as the master documentation file. 

Prospective validation of a production process utilizes information generated during the entire development sequence that produced the final process. 

A product found to be unsuitable for retrospective validation because of a revised manufacturing process is a likely candidate for prospective validation, which is beyond the scope of this chapter [1], Such a discovery, however, should be brought to the attention of the appropriate authority. In today s regulatory environment ignoring the matter would be imprudent. 

The differing circumstances under which a validation study is prompted often dictate the best approach to be used. Agreeably, prospective validation, for which the validation studies are all completed and approved before shipment of any product, is preferred. There are however, opportunities to complete certain validation studies when producing product intended to be administered to patients. Such circumstances may arise during clinical manufacturing, when exten-... 

Prospective validation, which includes all main validation phase approvals by means of design qualification (DQ), including specification reviews, installation qualification (IQ), operational qualification (OQ), performance qualification (PQ), and ongoing evaluation. 

For new applications or projects a prospective validation based on a recognized life cycle is the most effective and efficient approach. The life-cycle methodology can also be adapted for existing systems that do not have adequate documented records to support a retrospective validation. 

The process for implementation and prospective validation of computer systems outlined in Figure 3 depicts the system application activities within each life-cycle phase and identifies key issues and considerations for each step. The process includes for evaluation of both the computer system product and the system supplier s working methods. The same life-cycle approach may be applied to validate the associated control and monitoring instrumentation [9]. 

The next concern raised by the question is the determination of whether prospective or concurrent validation is appropriate. This decision should be based on the nature of the PV activity. For a new facility, there is only one possible decision namely, prospective validation. When certain process changes are made, however, it may be appropriate to choose the concurrent validation approach. 

The effort required for prospective validation makes it necessary that QA principles are satisfied. The effort should bring together all the technical functions engineering, which documents and qualifies the process equipment, the facility, and the systems production, which checks that its operating systems are working properly QA, which builds on the database that had been accumulated during the development phase and development, which certifies that its process performed as designed. In short, the objective of the work is to show that the product may be routinely produced with confidence. 

As I indicated earlier, prospective validation is used when a new chapter in manufacturing is about to be established. As such, it requires a sound game plan to document the transition from one stage to another (e.g., process development to full-scale production, the inclusion of new equipment, or the inclusion of a modified or new facility). The generated data must support the fact that the new process or facility ought to be used routinely in production. The successful validation provides the documentation that the developmental quality standards for the procedures and operations are adequate to manufacture a quality product in production. Finally, it becomes the basis for the quality standards, which must be maintained throughout the product s lifetime. 

These benefits make prospective validation a QA tool, but QA is not a stagnant activity. It consists of snapshots of distinct activities, yet when all the snapshots are put together, a kaleidoscope of the life of a process and/or of a series of changes results. It may also include the investigative process, when a deviation occurs, and the corrections implemented to re-establish the validated state. To support such an effort, the trends shown by the data for each batch are documented. Prospective validation should thus be viewed as the anchor for the QA effort. 

Performance qualification steps in a sterilization validation project usually require a prospective approach. The most common steps in prospective validation are the following ... 

Prospective validation is establishing documented evidence that a system does what it purports to do based on a preplanned protocol. 

All new computer systems must be prospectively validated before going into production. For existing computer systems, concurrent validation may be considered where limited documentation on the appropriate technology exists, and where an acceptable level of confidence can be established by reviewing and documenting the operating history. 

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. 

Once a legacy system has achieved a satisfactory, documented Part 11 compliant state, any subsequent changes can be prospectively validated. 

Prospective validation Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product s characteristics. (FDA)... 

The testing carried out in the development environment is not sufficient to verily the integrity and performance of the system. The application software must also be tested under actual conditions of intended use in the target or production environment. If the application is to be supplied by a third party in accordance with the end-user s requirements specification deliverable, it should be possible to carry out a completely prospective validation, as would be the case for a system developed in house, providing the requirement for validation is identified at the beginning. As with all systems, the responsibility for validation lies with the system s owner. 

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