Every day in the operational business, problems are dealt with which relate to process validation. For example: Recurring high efforts resolving these. Long release times affecting delays in delivery. Scrap rates from poor process performance leading to further costs.
This article

  • Looks at one of the main reasons why most pharmaceutical and medical devices companies are still not sufficiently successful in exploiting the great potential of risk-based process validation for safe quality and cost-effectiveness
  • Puts forward approaches for discussion which could remedy and which are based on regulatory guidelines (see below)

In validation, there is still too little focus on the really critical parameters of product quality, and process risks are being overlooked. At the same time many things are validated that actually do not need validation from a risk perspective. We observe, that risk-based validation is carried out formally as required by the authorities, but at the same time validation is done the traditional way. The possibilities for economic benefits are by far not exploited!

What do we mean by risk-based?

The classical process validation is based on first determining the requirements for the process and then proving that this process meets the critical and also non-critical requirements in all parts. Risk-based instead means that all risks are systematically identified first and then excluded. And this is why the process delivers a flawless product.

It is obvious that you can save a lot of effort if you only validate what really needs to be validated. It is also clear that processes run safer if a lot of focus is placed on potential risks. Using analytical approaches risk-based validation attempts to effectively eliminate as many of the possible risks as possible right from the outset. Due to the systematic approach risk-based process validation leads to reliable quality with less effort.

It sounds as if this is a straight-forward and simple change of approach.

De facto, risk-based process validation requires a different working style!

In classic process validation, experts check every step of the process and validate primarily on the basis of their technical expertise. Methods are used, but more to guide step-by-step through the process. Deeper understanding of the method is hardly necessary, the methods simply facilitate the work. A typical example are the golden three batches.

In risk-based process validation, expertise must be supplemented by an overview of the entire process from procurement to delivery, from dossier preparation and the purchase of pharmaceutical excipients to incoming goods, sampling and production. Process validation should build on the insights from process development. On this basis, goal-oriented teamwork must be triggered. The expert alone will not be able to identify all relevant risks in a quiet room in the ivory tower.

Really not enough staff capacity?

Staff capacity often seems insufficient to involve the required cross-functional team. Often, there is also a lack of methodical support and practice, which of course means that it actually takes a really long time. Using methods without understanding their background makes it feel even longer and often this approach seems unnecessarily difficult.

Risk assessment is still partly carried out after the validation tests. However, and just in case, shouldn’t all the potential risks be evaluated? Out of this concern – and of course out of old routine – in the end, in parallel to the attempted risk-based validation, classical validation is still often carried out.

Together these efforts are considerably higher.

Economic benefits

Risk-based validation works when there is cross-departmental collaboration to systematically identify risks prior to validation and eliminate them through smart preventive actions or specific statistics. And this is the way to tap into considerable economic advantages.

Those who make use of the guidelines can gain a lot of additional benefits:

  • Well-understood processes lead to fewer deviations
  • Fewer deviations mean less (unproductive) processing effort in all areas and fewer delays in product delivery
  • Understanding the process and the process risks we can systematically reduce controls, measurements and samples which reduces the effort
  • Overall process validation is faster, because only what needs to be validated is validated

And almost the best thing about it: Companies that work together effectively during validation will work together well later on in handling and solving problems. This is as process oversight and collaboration become a matter of course.

Systematically fast with understood methods

Tools and techniques make success repeatable and lead to systematic improvement. It’s key to understand the tools, and to adapt them where necessary. Cleverly adapted, well understood methods help to

  • Change also those behaviors to which one has become accustomed
  • Reduce efforts in complex procedures, and
  • Move systematically and safe on the new terrain

Use of some simple techniques recommended by regulatory bodies

Simple tools for moderating and visualizing processes and risks can make a significant difference:

  • Process Maps: With cross-departmental staffing, procurement and production processes are mapped – including critical requirements and risks. Please note: 3 joint workshops of 30 minutes each are sufficient, everything else can be done by individual experts.
  • Fishbone diagrams / Ishikawa: For all visible representation, which problems could occur at the product and which causes could lead to it.
  • Check Sheets: Should be result of each risk analysis. They translate risk protection into practice for the operational departments.

Whoever sees such techniques in use in the company in the context of risk assessment and risk avoidance in process validation, has at least overcome the first initial difficulties of interdepartmental cooperation!

Also of interest are various statistical methods, especially:

  • Determining CQAs (critical quality attributes): The critical limits within which the process is allowed to move should be driven by the risk or by customer requirements. It is often useful to work with regression analysis
  • Control Charts are the tool of choice for different possible process conditions to determine what the actual risk is. Only on this basis can a concept for reasonable sample sizes be derived. This leads to the next point:
  • Sample Sizes, and Amount of Samples depends on how much a process varies, how close it comes to the allowable specifications, and the defined acceptable quality limits (AQLs). If you build on statistics, you can save a lot of sampling and analysis efforts and even more deviations in the running processes. In this way you can save effort also compared to the traditional approach of three validation batches.

The trick is to be aware of the risks already during process development.


In risk-based validation, the use of tools and techniques with understanding, a good eye and a sense of appropriateness helps to keep costs low and to achieve reliable quality.

Relevant policies referred to here:

  • FDA and EMA: For more than 10 years, the FDA and EMA have been demanding that validation be carried out on the basis of risk, and no longer against requirements
  • EC, GMP, Annex 15: The risk assessment should determine the scope and depth of validation
  • ASTM Standard E2500 – based on ICH Q8, Q9 and Q10: enables a risk-based approach to qualification
  • ISO 13485 – Definition of the qualification phases
  • ICH Q9, Annex I: Methods for risk identification

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