Unless you’re starting a new company you will need to plan on a variety of approaches.
Prospective validation occurs before the system is used in production, concurrent validation occurs simultaneously with production, and retrospective validation occurs after production use has occurred.
In this article we will discuss all three and also discuss the role the master validation plan (MVP) performs for each one.
1. Prospective Validation
Prospective validation is establishing documented evidence, prior to process implementation, that a system performs as is intended, based on pre-planned protocols.
This is the preferred approach.
Production is not started until all validation activities are completed.
The MVP need not go into much detail about this approach since it’s the standard method, however, prospective validation follows a step wise process illustrated here.
The process commences with the development of a Validation Plan and then passes through the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed which are followed by a final report.
After which the instrument or equipment will be subject to preventative maintenance and requalification on a routine basis.
On a periodic basis all instrumentation and equipment should be reviewed. This review is intended to identify any gaps which may have developed between the time it was last qualified and current requirements.
If any gaps are identified a remediation plan will be developed and the process will start again.
The MVP may need to describe what is done with product produced during prospective validation. Typically, it is either scrapped or marked not for use or sale.
The product may be suitable for additional engineering testing or demonstrations, but appropriate efforts need to be made to ensure this product does not enter the supply chain.
Ideally, all validation is done prospectively; i.e., the system is validated before use. However, there are cases and conditions which may prevent this.
2. Concurrent Validation
Concurrent validation is used to establish documented evidence that a facility and process will perform as they are intended, based on information generated during actual use of the process.
In exceptional circumstances (for example, in a case of immediate and urgent public health need) validation may need to be conducted in parallel with routine production. The MVP needs to define how product is managed throughout the process.
Typically, the product batches are quarantined until they can be demonstrated (QC analysis) to meet specifications.
The Right Decision?
The decision to perform concurrent validation should not be made in a vacuum. All stakeholders including management, Quality Assurance and the government regulatory agencies should all agree that concurrent validation is an acceptable approach for the system under consideration.
As always the principal requirement is patient safety is not compromised. The rationale to conduct concurrent validation should be documented along with the agreement to do so by all the stakeholders. This can be part of the Validation Plan or documented as a deviation.
The concurrent validation process is identical to that of prospective validation. The process starts with the development of a Validation Plan, followed by the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed, ending with a final report.
Again, routine preventative maintenance, requalification and periodic review are performed.
3. Retrospective Validation
Retrospective validation is validating a system that has been operating for some time. There are various schools of thought on how to approach retrospective validation. Some may feel that a full-blown validation is required to assure the system is functioning properly.
Others may feel that since the system has been in use, presumably without issues, validation is not necessary and a memo to file justifying why validation is not necessary may be issued.
Doing a full validation may not be required, since you already have proof that the system functions as required – at least in the situations in which production was conducted. Doing nothing, though, is a risk.
It’s likely that the controls haven’t been challenged so there may be some hidden flaws that haven’t been identified that could lead to non-conforming product, hazardous operating conditions, extended delays, etc.
Historical data can certainly be used to support validation. For example, if there is detailed and statistically-significant evidence that production runs are well controlled you could rationalize and justify not doing full validation.
During retrospective validation, it’s advisable that existing product be quarantined, and production put on hold until validation is complete.
As an exception, producing product as part of the validation exercise would follow concurrent validation. This may not be practical since product may have already been distributed, but caution is advised for the reasons outlined.
The general process for retrospective validation follows the same process as for prospective and concurrent validation except DQ is seldom performed, as the system has already been in use for some time.
Instead a survey and review of available information is performed. This normally occurs before the validation plan is created.
The MVP should also provide guidance on managing inventory during retrospective validation.
One Major Issue
One potential major problem that can occur with retrospective validation the determination of what action should be taken if an issue is found with the system during retrospective validation?
As with everything else, a risk-based decision is warranted. This could be anything from product recall, to customer notifications, to just documenting the justification of the decision why nothing was done.
Again, the MVP should provide guidance on dealing with situations concerning out of specification conditions revealed during retrospective validation, which should also definitely include involving regulatory support.