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GMP LOGFILE Features

2016-09-14

LOGFILE No. 34/2016 – The Changing Concept of Validation

The changing concept of validation

An excerpt from the GMP MANUAL

by Dr. Christine Oechslein

 

GMP trends that have significantly changed validation

The concept of validation has undergone a major transformation in recent years: from a selective short-term project to an important tool for quality assurance that accompanies a process or product during its entire life cycle.

This in turn mirrors the major changes in our understanding of GMP that occurred around the turn of the millennium. These include three major aspects:

  1. Life-cycle models instead of isolated actions:
    Validation, qualification, maintenance and deviation and change management are no longer regarded as separate entities, but as interacting processes that are carried out over the entire life cycle. This applies to processes, products and systems, i.e. from the start of product development to the withdrawal of the product from the market or from the planning stage of a system until decommissioning/scrapping.
  2. Continuous data evaluation instead of evidence gathering:
    Data accrued on a day-to-day basis during manufacture, cleaning, maintenance, deviation and change notifications, process controls and laboratory testing are no longer archived separately as evidence, but evaluated as a whole on a continuous basis (trending, review). This means that fluctuations and trends can be identified at an early stage and corrective actions can be taken in time. The continuous evaluation of data can also be used to show that processes are running within the defined ranges, which means that the original approach of revalidation/requalification is not required in most cases.
  3. Risk-based action instead of maximum compliance:
    Ensuring quality in a GMP environment no longer means implementing as many measures as possible. Companies can decide which measures are appropriate and required in the individual case based on the individual product risk and the level of experience within the company.

This change in approach is documented in the three key documents ICH Q8 Pharmaceutical Development, ICH Q9 Quality Risk Management and ICH Q10 Pharmaceutical Quality System. Common to all three documents is the idea that quality is the result of an integrated and systematic consideration of a large number of interdependent factors.

All three documents emphasise the importance of pharmaceutical development, but they also specify that processes have to be checked continuously even after the marketing authorisation dossier has been submitted (permanent validation). In addition, all process and analytic data as well as other quality-related information (expiry dates, complaints, fault analysis, etc.) should be evaluated on a regular basis and used as a basis for process improvement. This is done during the product quality review (PQR).

This trend towards a comprehensive approach has affected validation in the following ways:

  • The product quality review (PQR) or annual product review (APR) in the USA provide continuous statements about the validation status of processes.
  • Ongoing process verification (continued process verification in the USA) is a complementary validation concept that accompanies a product even after marketing authorisation has been granted until the product life cycle ends.
  • Continuous process verification (CPV) is an alternative to traditional validation. The process performance during the manufacture of commercial products is continuously monitored and evaluated, e.g. using process analytical technology (PAT). This makes traditional three-batch validation and revalidation redundant because the processes are kept within predefined ranges based on the current process data. CPV requires that the process has been developed in accordance with the QbD concept.
  • Differentiation between prospective, retrospective and concurrent validation is no longer required. Only prospective validation that includes the entire product life cycle is now acceptable. Retrospective validation is not mentioned in the latest guidelines. Annex 15 limits concurrent validation to exceptional cases. It is only permitted in extraordinary situations and must always be justified. In the FDA Guidance for Industry – Process Validation, the term concurrent validation is aptly replaced by the concurrent release of PPQ batches.

Author:

Dr. Christine Oechslein
GMP Instructor, Germany

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