Process Revalidation.
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Revalidation requirements should always be considered an integral aspect of an original validation approval. Revalidation may be time based or event based, for example, if time based it may be determined that a process will be subject to a full or partial revalidation every three years, alternatively if event based, a process may be subject to revalidation were there are significant changes, e.g. new equipment introductions, new materials applied, change suppliers, revised specifications, etc..The need for revalidation has been identified by the major regulatory bodies, for example the US FDA and the IMDRF (International Medical Device Regulators Forum).
Per the IMDRF (formerly the GHTF) a process needs to be continually monitored to ensure it remains within a validated state. Any change within a product or process, including changes to personnel, equipment, procedures, etc., need to be evaluated to determine the potential consequences on validation status.
The IMDRF identified potential reasons for revalidation as:
– change within a product or process with potential quality impacts,
– changing or negative trends in quality indicators,
– changes in the design of a product which can impact the associated process,
– transfer of a process between facilities,
– change of the application of a process.
Per the US FDA, the quality system should require a revalidation if changes are to be implemented in product packaging, equipment, formulation or processes which have the potential to impact product effectiveness or characteristics. In addition, where there are changes in the supply chain, the potential for subtle, potentially adverse changes in raw material characteristics needs to be considered, which may necessitate a revalidation.
Product and Process Validation.
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Must all validations be repeated?
As long as a routine process operates in a state of control and no changes have been made to the process or output product, the process may not have to be revalidated. Control may be demonstrated by analyzing day-to-day process control data and any finished device testing data for conformance with specifications and for variability. The quality management system, needs to define the circumstances where a revalidation will be performed. Revalidation may be required based on observed performance of product, process, equipment established during an initial validation. Ideally, an individual should be designated to review all planned changes to personnel, equipment, product, processes and facilities to determine any potential validation impact.
A revalidation may be full or partial. The level of revalidation required will be determined by the nature of the proposed change. It may not be necessary to perform a full repeat of an original validation, however, where only a partial revalidation is to be performed, then there needs to be a clear justification documented outlining the reasons supporting the partial revalidation.
Recurring Validation
Recurring validation is all or a portion of a validation that is required to be repeated periodically, and demonstrates continuing compliance of a validated process or operation. Some critical-process standards include a requirement for re-validation at “defined intervals” and require that those “intervals shall be justified”. (ISO 11135-1).
Examples include EtO sterilization and Aseptic systems.
For recurring revalidations, widespread practice is that such revalidations of critical processes can be extended out to a maximum of 3 years, where reviews of process performance versus the need for a revalidation are performed on an annual basis and the annual reviews do not identify any need for more immediate revalidation.
Revalidation and change management.
It is necessary to define procedures for the management of proposed changes to specifications, methods of manufacture, processes, procedure, products, etc… Per the US FDA “Such changes shall be verified or where appropriate validated before implementation, and these activities shall be documented”.
In all change management systems, where proposed change may impact on validated products or processes, the potential impact of the change needs to be assessed in advance of implementation.
On a day to day basis the potential validation impact would ideally be identified 100% of the time, however in reality unforeseen consequences can arise from a change. Additionally, a series of relatively minor changes in themselves may not have a validation status impact, however the combined effect of such changes may be to impact validation status. Therefore, to counter these risks, it is good practice to have an annual validation status review, where the potential of all change on a product or process can be considered.
Where there are effective monitoring and measuring of processes and products and the control of monitoring and measuring devices can identify changes in the validated status of processes and equipment, then data from such monitoring can be utilized in the annual review for justifying the need for revalidation or for not revalidating (ISO 13485, 7.6, 8.2.3, 8.2.4).
Revalidation needs to be risk based.
Any decision on performing an original validation, the extent of an original validation and revalidation requirements should be based on a risk assessment. A risk evaluation process needs to be in-place which uniformly determines potential risk across processes and products. Where risks exceed a pre-determined threshold, then revalidation should be mandated. The organization will predetermine and justify such risk thresholds. The risk assessment, evaluation, minimization, control and monitoring process needs to be defined, documented and affectively implemented.
Revalidation summary.
The need for revalidation can arise from a number of sources:
– An identification for future and recurring revalidation can arise during the initial qualification validations.
– The ongoing performance of products and processes will continually be monitored and analyzed. Deviations in results performance, change in trends, etc., may highlight the need for revalidation.
– As changes are proposed to processes, equipment, specifications, etc.., revalidation may be required.
– Applicable Standards may demand revalidation of critical processes, resulting in a manufacturer needing to define revalidation cycle times.
– Organization policy may define revalidation expectations as part of an overall organization approach to quality. Equally, a desire to move away from a reliance on verification activities, may demand ongoing revalidation.
– Internal audits may highlight weaknesses in process controls and demand process revalidations.
Product and Process Validation.
- The Validation Master Plan. Performing a Gap Analysis. Validation in the Design Process. Etc..
- How to ensure Validation efforts are aligned with potential Risks.
- How to ensure that Validation activity is appropriately documented, reviewed and aligned with requirements.
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