Validated State

Getting to a validated state requires significant expenditure of time and money. As well as being required for regulatory compliance, it makes good business sense to retain the system under control. A formal set of procedures and systems is required, including the following  

Backup strategy and media storage How backup is done, records to demonstrate that the procedure is being followed, how the backup can be restored and the shelf life of the storage media all need to be considered. It is also prudent to prove that the restore procedure works before it is required. 

Maintenance agreements with the hardware supplier and the systems integrators should be considered. 

Quality reviews of the system are required at the frequency assigned in the Validation Report. They will include reviews of the change control and incident reporting methodology, training, procedures and any outstanding actions from the Validation Report or previous reviews. 

EDMSs are integral in the drive toward a paperless manufacturing environment. EDMSs also provide a useful tool to share information in a way that minimizes duplication and ensures that it is easily accessible when required. 

---

Any validation and verification work performed must always be documented in such a way that the results can be checked and the scope of a method is clear. International standards, e.g., ISO 17025, contain separate sections regarding documentation, which should be observed. The NMKL procedure on method validation states that It is of particular importance that the report includes all raw data from the experimental work, or references to where such data can be found . In some circumstances this complete documentation is impractical. Even where it is practical, it is usually impossible to publish these results together with the methods. 

Constructors should ensure that the newly created objects are in a valid state—that is, that they satisfy the expected invariants. 

The FDA guidance on IVIVC development and validation states that crossover studies are preferred however, parallel studies or cross-study analyses may be acceptable. The advantage of a crossover study is that it avoids bias to any one particular treatment as a result of a period effect. A crossover study also provides the highest probability of successfully validating the IVIVC, since it avoids the variability introduced by cross-study comparisons. 

The current guidelines for IVIVC development and validation state that studies for IVIVC development should be performed with enough subjects to adequately characterize the performance of the drug product under study. Acceptable data sets have ranged from 6 to 36 subjects. 

A formal monitoring system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect validated status and cause corrective action to be taken so that the system retains its validated state of control. 

After an instrument has been qualified, it is ready for production use. The activities in the operational phase support the day-to-day use and maintain the instrument in a validated state. 

The outcome of the review will determine whether the instrument is maintained in a validated state. In the case that the records indicated the instrument is more prone to certain types of failure, a preventive maintenance program may be desirable to avoid system failure during operation. 

The performance of an instrument should be reviewed on a regular basis to ensure that the instrument is reliable and continues to comply with the requirements specified in the user requirements. The review should determine whether the instrument is maintained in a validated state. The review should include records for use, maintenance, services, and performance verification testing. In case the records indicate that the instrument is more prone to certain types of failure, preventive maintenance may be desirable to avoid system failure during operation. The review can also provide useful information to prioritize instrument replacement. 

The structure is fully compliant with structure conventions and the compound transitions to the Valid State. 

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. 

Once a system has been validated, it is considered to be in a state of control. As long as all conditions and control parameters remain unchanged, the system continues in its validated state. It is important for any significant change be recognized before or at the time it occurs, whether the change is to the process,... 

Ensuring that the computer system is maintained in a validated state by ongoing... 

Any corrective actions that are required must be defined and implemented in order to ensure that a validated state is achieved. The corrective actions must be scheduled and follow-up evaluations planned for monitoring and tracking their progress. 

Ongoing evaluation A term used to describe the dynamic process employed after a system s initial validation that can assist in maintaining a computer system in a validated state. 

Periodic review A documented assessment of the documentation, procedures, records, and performance of a computer system to determine whether it is still in a validated state and what actions, if any, are necessary to restore its validated state (PDA). 

As interpreted within the industry, we have implemented programs based upon the classical scientific method, in which we gather information to support the premise. Where the information (read that as validation) supports the premise (that the product is of acceptable quality) we have achieved a validated state for the process. A more contemporary definition is as follows ... 

In this era of restricted headcount (and for any major project) it is common to bring in outside assistance to do some or all of the work. This is certainly acceptable, but firms should maintain some degree of internal expertise to oversee any external support. Once the validation project is completed, the firm is required to maintain the validated state. This is only possible when the core capabilities exist within the firm. The use of prepared forms for data entry during execution can be useful as a means to ensure that the correct information is gathered and promptly recorded. 

Beyond the periodic evaluation of the product, process, or system it is important to assess that the other elements that contribute to the validated state are still in place. This would include an assessment of change controls, calibration, product annual reports (if applicable), process deviations (waivers, alerts, etc.), physical inspection of the equipment, and an evaluation of relevant regulatory guidance. All of these help to augment the data generated in the revalidation study and significantly support the dossier proving successful validation maintenance. 

There should be written procedures to establish systems to manage and control changes that may impact the development, validation, or implementation or affect the maintenance of a validated state for computer systems. Such procedures and controls should apply to all GXP operations and all the systems that support GXP operations. 

Describe or reference the change control system that will be used to maintain the validated state of the VUS after the initial qualification. 

Identify changes that may have influenced the validated state. 

Unlike classical mechanics, a precise simultaneous specification of position and momentum is not possible. Thus, any valid state will at all times obey the Heisenberg uncertainty relation... 

So far the form of 4, has not been specified. While the Schrodinger equation defines clear conditions for valid state functions of the system, it does not offer a practical method to actually obtain the exact solution VP or vPel. As a consequence, iterative procedures have been developed that start with some trial wavefunction, and subsequently improve their quality until some predefined convergence criterion is fulfilled. 

There are no additional or reduced regulatory requirements for closing sites. Computer systems should be maintained in a validated state of compliance up until the very last day of their operational life. GxP records must be archived and stored for the required retention periods. Archived records should be readily retrievable to support critical quality operations like recall, customer complaints, and batch investigation. Computer systems should then be decommissioned, as discussed later in this chapter. Some computer systems may be disassembled and sent for installation at other sites as part of a program of drug product transfers. 

Does the firm maintain a validated state Is validation documentation current and readily available ... 

---