Process validation approaches

Here you will find answers to the following questions:

  • Which approaches are possible for process validation studies?
    Under which conditions do they apply?
  • How many batches must be evaluated during a prospective or retrospective validation study?
  • What does "critical parameter" mean?
    How can critical parameters be determined?

For carrying out validation studies divers approaches are possible. The validation method chosen - or whether there is any option to chose at all - depends on the object of the validation.

1 Prospective validation

If a new drug product or new manufacturing procedure is planned to be submitted for marketing authorisation, it must be validated. In these cases, validation activities must be performed prospectively (for exceptions, see chapter 3 Concurrent validation). By this, it is understood that proof is established that a manufacturing procedure using the process parameters established on the basis of findings from process development, upscaling/pilot plant leads reliably to a product with the desired or labelled quality on the production scale.

Occasionally, there are attempts within the framework of validation to make up for what is definitively a development matter: the determination or also the challenging of critical process parameters - thus, the experimental determination of limits of a process parameter within which a defined product quality can be obtained (see chapter 7.E.4 Prerequisites for carrying out a validation project). This is a hazardous undertaking at this stage, taking into account that failure can lead to the write-off of a whole production batch. Even the legislators and prevailing guidelines, such as the "Inspection of qualification and validation in pharmaceutical manufacture and quality control" aide mйmoire, continue to emphasise that validation is not development and, thus, determination or "challenging" of critical process parameters is not the object of validation. In contrast, the objective of validation is the confirmation of the normal operating ranges for the critical parameters in a previously evidenced "Proven Acceptable Range", that is, the range within which a process parameter can be varied without affecting the quality of the final product (see chapter 7.E.4 Prerequisites for carrying out a validation project).

Before planned changes in manufacturing technology are implemented, it must be also shown, with the help of prospective validation, that the change does not have a negative impact on product quality.

Figure 1 Definition of prospective validation

Definition of prospective validation

A prospective validation is a validation conducted prior to distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product quality. A prospective validation should be carried out with at least three consecutive batches. The three batches must comply with the specifications.

In the very beginning of a prospective validation project, a risk analysis should be carried out, which evaluates both, the individual product risk and the process risk. On the basis of the findings obtained during the risk analysis, the validation protocol is then compiled. The validation protocol must always refer to specific master production records, or "master formula" or "manufacturing description" as part of the submission file for marketing authorisation). If several master production records are planned to be validated simultaneously, for example for several dosages of the same preparation, this can be done using a "bracketing" concept (see chapter 7.F.1 Validation matrix). However, application of bracketing for a particular instance must be justified. Once a process has been successfully validated, all basic parameters established in the respective manufacturing instruction and in the related validation protocol, e.g. relating to batch size (must correspond to the subsequent production batches; batch sizes which deviate by a factor of more than 10 must be justified in the validation protocol and the impact on the validation result must be assessed), facilities/equipment, sampling plans, IPCs, control procedures and operating ranges, are definitively fixed - i.e. following a successful validation, every change must be recorded and reassessed in relation to the validity of the process.

There must be careful coordination with production planning when the validation protocol is compiled and deadlines are established. In particular, when collaborating with external consultants or contract manufacturers, ambiguity about the enormous amount of time needed until full completion of the validation project (which is not earlier than by the time of approval of the validation report by the responsible person) can lead to false expectations, time pressure or validation forecasts on the basis of partial results that are legally inadmissible (see chapter 17.A Contract manufacture).

2 Retrospective validation

During retrospective validation, the reliability of the manufacturing process is assessed and documented on the basis of historical data which was collected in connection with batches that have already been manufactured.

Figure 2 Definition of retrospective validation

Definition of retrospective validation

A retrospective validation is the validation of the manufacturing procedure for a product already in distribution based upon available production, in-process control and quality control data.

A retrospective validation should be carried out with no fewer than ten batches and must, generally, be supplemented with "prospective cycles".

For drug products that have already been in production for years and about which it has, therefore, been possible to collect a lot of knowledge, this procedure initially appears effective and time saving. In practice, retrospective validation often emerges as unexpectedly laborious and disappointing. The reasons for this are simple: in the past few years, GMP requirements regarding documentation have increased noticeably. There has been an ongoing improvement in the quality of records (batch reports, records, etc.) as a result. Looking at older documents today, one often realises that the records logged are unusable for an interpretation, as they are incomplete or inhomogeneous and consistent traceability is not guaranteed. To be able to use historical data in terms of a retrospective validation, however, the conditions listed in figure 3 must be given:

Figure 3 Requirements for a retrospective validation

Requirements for a retrospective validation

  • Compilation of a validation protocol with risk analysis, definition of critical parameters, establishing of acceptance criteria
  • The facilities and equipment used must be qualified and the measuring points calibrated
  • Traceability of sampling (intervals, sample sizes, etc.) for IPC and quality control
  • Homogeneity of historical records (i.e. all batches considered are manufactured and tested in accordance with the same authorised manufacturing and test procedure. In case of changes have been made to product composition, instructions or equipment, the exact timing must be traceable.
  • Analysis of at least 10 consecutive batches - from the statistical point of view and from the point of view of FDA inspectors, only 20 batches are even acceptable.

For a retrospective validation, as for a prospective validation, a validation protocol must first be compiled, in which critical processing steps are defined and acceptance criteria are established. When doing this, one should not be guided by which parameters were recorded in the past and are now available as collections of data. It was not always "critical parameters" that were measured, but often those which could be measured easily. Critical parameters are those which, if changed slightly, can have a significant effect on the quality of the product. If a parameter can be graded as non-critical - due to many years of experience, approval and stability data -, it does not require validation. However, it should be mentioned and justified in the validation protocol that this parameter is non-critical - this avoids queries at a later date, e.g. from contractors or during inspections.

In most cases, it will be realised during a retrospective validation that either some of the critical parameters cannot be justified using the available historical data, or the records are inhomogeneous. In these cases, the data that is missing in retrospect must subsequently be collected with the help of so-called prospective cycles. This means that - concomitant to three consecutive ongoing production batches - the missing process parameters defined in the validation protocol are validated.

Figure 4 Documents required for retrospective validation

Documents required for retrospective validation

  • Batch production records with the results of the in-process control
  • Authorised master production record
  • Certificates of analysis and test protocols
  • Reports on rejected batches, exceptional approvals, releases with restrictions
  • Authorised testing procedure
  • Stability data
  • Log books for the facilities, machines and utilities
  • Results of the environmental monitoring
  • Results of trend analyses (if available)

This same applies for qualification: old facilities are often not qualified or inadequately qualified. Qualification of these facilities must be carried out retroactively during retrospective validation at the latest (see chapter 6 Qualification). This also includes reviewing the available equipment documentation, operating instructions, maintenance procedures, etc. for completeness and checking that they are up to date.

Of course, these facilities can only be qualified in their current state. However, if old log books, calibration reports or similar records are available, it may be possible to draw conclusions from them that the apparatus/facilities were also formerly in a controlled state, so historical process data may, therefore, be used for a retrospective validation.

In contrast, if there are no historical documents available which show that, and how, measuring equipment was calibrated or when changes to facilities were carried out, for example, it is very risky to trust the historical batch records: in this case it is not evident for example, whether different drying temperatures that have been documented are due to different air supply temperatures or are quite simply due to the fact that the thermometer was not calibrated?

In the event that there is an insufficient number of batches to be drawn on for retrospective interpretation, the missing data must be ascertained within a concurrent validation.

A for a prospective validation, retrospective validation is concluded with a validation report that must be approved by the responsible person designated in the VMP, e.g. the head of production or the Qualified Person.

3 Concurrent validation

Under certain conditions it is possible to perform a concurrent validation if the validation program cannot be concluded before the start of routine production.

The "Inspection of qualification and validation in pharmaceutical manufacture and quality control" aide mйmoire points out that concurrent validation should only be used in exceptional cases that must be justified. The same requirements as for prospective validation apply for carrying out and documenting concurrent validation. Here too, a minimum of 3 validation batches must be evaluated.

Concurrent validation sets particular requirements for validation planning and coordination between routine production and validation activities, since the batch release to the market is often time-critical and must not be delayed by validation activities carried out in parallel. At the same time, conducting additional sampling and analysis for the purposes of validation requires longer busy times than are normally scheduled in the production planning for the respective product.

Figure 5 Examples for application of the "concurrent validation" approach

Examples for application of the "concurrent validation" approach

  • Transfer of a validated process to another manufacturing site, e.g. to a contract manufacturer
  • Supplementation of missing data within a retrospective validation
  • Long time interval between the manufacture of consecutive batches
  • Periodic revalidation
  • Validation of small changes to already validated processes that are well controlled (e.g. new dosage or different tablet shape)
  • Validation of variations in batch sizes (upscaling or downscaling)

Figure 6 Requirements for concurrent validation

Requirements for concurrent validation

  • Qualified facilities and equipment
  • Compilation and authorisation of a validation protocol with risk analysis (as for a prospective validation)
  • Compilation, verification and approval of the validation report for each individual batch before the batch is released to the market or for clinical studies.


Prospective validation is the method of choice for all new manufacturing procedures or larger process changes. It is effected with at least 3 consecutive, successful validation batches on the production scale.

For concurrent validation, the validation batches are released for sale when the specifications are complied with. To apply a concurrent validation, special constraints must be fulfilled.

For retrospective validation, the evaluation of production data from at least 10 batches is expected. Missing data must be retrospectively collected in so-called "prospective cycles".