While extracting QTPP, CQA and CPP’s from the A-Vax case study, I noticed some authors used “uncertainty” instead of the popular “occurrence” for their QbD Risk Assessment.
What this means is that the Risk Priority Number (RPN) equation:
RPN = Severity x Occurrence
RPN = Severity x Uncertainty
(You can add detectability at the end. But here’s a reason why it’s unnecessary during the development phase.)
So is it Uncertainty or Occurrence in QbD Risk Assessment?
What is the Rationale for using Uncertainty?
At development phase, we usually don’t have enough data to determine the probability of occurrence. That is mainly why using uncertainty can make sense.
Uncertainty can help us identify where our knowledge gaps are. This helps us prioritize process parameters for the ensuing design space work.
Here are a few examples of how some QbD practitioners use Uncertainty in QbD Risk Assessments.
- Process Validation TR 60 from PDA (Process validation)
Here, PDA uses a simple decision algorithm for both Severity and Uncertainty.
- Low: Large amount of in-house knowledge, large body of knowledge in literature
- Medium: Some in-house knowledge and scientific literature
- High: No or little in-house knowledge, very limited information in scientific literature
- Low: Marginal Patient Impact
- Med: Moderate Patient Impact
- High: Catastrophic Patient Impact
Here’s another example of using Uncertainty in QbD Risk Assessment.
- Application of the quality by design approach to the drug substance manufacturing process of an Fc fusion protein: Towards a global multi-step design space (Eon-duval et. al, Journal of Pharmaceutical Sciences Volume 101, Issue 10, pages 3604–3618, October 2012
Here, Eon-duval et al used the following definitions for Severity and Uncertainty similar to PDA’s example:
- Low: No Effect
- Medium: Effect is significant but manageable
- High: Effect is significant and non-manageable
- Low: Data on Molecule available or strong scientific rationale
- Medium: Data on similar Molecule available or literature information
- High: No information available
How can You Apply This?
After learning that some of our LeanQbD users were already using Uncertainty, we had to do something.
So we updated Lean QbD Software to be able to accommodate “Uncertainty” users.
1. Use Occurrence or Uncertainty
Now, you have the option to select between Occurrence or Uncertainty. Mathematically, it doesn’t change the results.
You just ask a different question while facilitating the risk assessment. Instead of asking, “How likely is this process parameter to fail?” you are asking, “How little do we know about the effect of this process parameter?”
Below is a screenshot of how you can change your preference between occurrence and uncertainty. (Example from A-Vax template)
You can choose to use “Occurrence”
2. Simpler Rating Scale for Occurrence or Uncertainty: Low-Medium-High
Let’s not stop here. Let’s go one step further.
Remember the correlations between QTPP-CQA and CQA – CPP were “(none) – Low – Medium – High” while the rating scale for occurrence was 0-10? Some of you asked: Why do we need a 10 scale rating just for occurrence or uncertainty?”
You are absolutely right. At development stage, let’s keep the discussion simple and practical. Even PDA endorses the 3-level rating scale.
So we updated the rating scale to be consistent: (none) – Low-Medium-High.
Now you can ask, “How much (or little) knowledge do we have regarding this process parameter?”
If the answer is “very little,” then prioritize it for a design space study as many case studies suggest.
For our Current Users:
If you have been using the 1-10 scale, how will this affect your work? For now, we suggest that you revisit this section to update it.
If you’d like, we can automatically change the numbers to transform based on rating bands, i.e. 1-3: Low, 4-7: Med, 8-10: High.
But before we proceed, we wanted to confirm with you first. Would you like this feature or would you like to update it manually? Let us know!
We will continue to support both versions upon request.
Quality by Design is a goal. Its tools should be tailored to support the goal of understanding the design space.
You can use either “Uncertainty” or “Occurrence” in QbD Risk Assessments with confidence.
So my questions to you: For QbD Risk Assessment, which do you use?
Uncertainty or Occurrence?