11.06.2013 | LOGFILE Feature No. 03/2012

LOGFILE No. 03/2012 - Process Validation

Process validation from the viewpoint of the FDA

Authors: Dr. Christine Oechslein, GMP Instructor, Germany and Max S. Lazar, FDA Regulatory Compliance Consulting, USA

Current trends in process validation

The significance of the process validation has taken on a new emphasis, since a series of new rules and regulations on this subject have been published, notably

  • EU GMP Guide Annex 15: Qualification and Validation
  • EMA Note for Guidance on Process Validation
  • FDA Guidance for Industry - Process Validation: General Principles and Practices

Last but not least, chapter 12 of EU GMP Guide, Part II covers the topic of validation more extensively than most other rules or regulations. For excipients, the topic of validation is described in the IPEC Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients.

The objective of the EMA Note for Guidance on Process Validation is standardization of the validation documents that must be submitted with the submission file for marketing authorization. This guideline is directed at manufacturers of pharmaceutical products; to some extent, though, the procedure is also transferable to the manufacture of active pharmaceutical ingredients, excipients, biotech or blood products. This paper describes very thoroughly what validation data is expected at the point of submission of the application file for marketing authorization.

The EMA Note for Guidance on Process Validation is to be revised in the course of 2011 in order to incorporate the concepts of ICH Q8, Q9 and Q10. The objective here is primarily to consolidate the various concepts and to clarify questions resulting from this - but not to introduce novel requirements. No additional requirements will result from this for products which have already been approved.

Process validation from the viewpoint of the FDA

The latest FDA document is also only a recommendation: Guidance for Industry - Process Validation: General Principles and Practices. The final version of this has been available to the public since January 2011. In the introduction to this Guidance it is emphasised that the information published in it does represent the current viewpoint of the FDA, but is not legally binding. The FDA expressly points out that alternative solutions are also accepted as long as they comply with the basic legal principles of the CFR. In terms of content the Guidance relates to the validation of human and veterinary medicinal products, biological and biotechnological products and active ingredients.

The long-awaited revision of the Guidance aligns the contents of the predecessor document, which is already 24 years old, with the current views of pharmaceutical quality management, pharmaceutical development and quality risk analysis. However, the FDA stresses that it is not the aim of the document to introduce totally novel requirements for validation. In line with the general trend, this Guidance de-scribes process validation as an integral part of a product's entire life cycle (see also GMP MANUAL chapter 7.E Process Validation and Product Lifecycle).

For this purpose the familiar concepts of the current ICH Guidelines Q8 (R2) Pharmaceutical Development, Q9 Quality Risk Management and Q10 Pharmaceutical Quality System are embraced and applied to the topic of process validation:

  • Extension of validation activities to the entire life cycle instead of selective measures (e.g. "three validation batches")
  • Profound understanding of the processes and risk-based approaches as a basis for the validation activities instead of formal processing of long checklists
  • Continuous process enhancement and innovation instead of predefined processes and parameters
  • Importance of scientific principles (Sound Science) and of knowledge transfer from development
  • Demand for support by the senior man-agement

This list makes it clear that a change in the understanding of process validation has taken place in recent years. The principles mentioned have already been adopted by many companies in their validation concepts and are already in use today. The FDA Guidance consequently has hardly any effect on these companies.

However, the established terms "qualification" and "validation" are given a totally new definition in the FDA Guidance.

The term "process validation" is extended to become a generic term and thus in the sense of the life cycle model also incorporates the up-stream development stage and the subsequent "maintenance phase" during commercial production.

This results in a three stage model (see Figure 1):

  • Stage 1: Process Design
  • Stage 2: Process Qualification
  • Stage 3: Continued Process Verification

In terms of the approach this procedure is definitely consistent and relevant. However, the new FDA terminology also entails the danger of misunderstandings and confusion:

Figure 1 Three stage model of process validation according to FDA Guidance for Industry - Process Validation


The stage generally referred to date as process validation is now concealed together with plant qualification in stage 2 under the totally new title process qualification. The creation of this new term and the reassignment of the content could well carry the confusion of terms which already exists today (as mentioned at the start of this chapter) between qualification and validation to extremes:

"Process validation" thus on the one hand becomes the generic term for "qualification" because the entire qualification of equipment and resources (previously understood as a prerequisite for process validation) is also included in stage 2 "process qualification" of the new validation term. At the same time attributes of equipment and processes which were, for a good reason, previously examined separately and with different objectives in performance qualification (last stage of quali-fication in which the suitability and perfor-mance tests of equipment are conducted over lengthy periods) or process validation are now mixed together with respect to content.

To create greater clarity for the user, the FDA improved the draft of the Guidance and in the final version of January 2011 once again divided the second stage of process validation.

The two sub-steps of process qualification are referred to as:

  1. Design of a facility and qualification of utilities and equipment
  2. Process Performance Qualification, PPQ

The measures to be performed in the new "PPQ" stage are largely the same as those which up until now were understood as "process validation". It remains to be seen how far the proposed extension or redefinition of the terms will prove useful in practice.

"Continuous validation" and the FDA's three-stage process validation model are dealt with in more detail in GMP MANUAL chapter 7.E Process Validation and Product Lifecycle.



Dr. Christine Oechslein 
GMP Instructor, Germany

Max S. Lazar
FDA Regulatory Compliance Consulting, USA

This text is an excerpt from the GMP Compliance Adviser, chapter 7 Process Validation.

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