How to Choose Which Design Space Studies to Work On – Why QbD Risk Assessment is Not Just a Risk Assessment

If you ask an average pharmaceutical scientist, “What is QbD?” she or he will mostly likely answer: DOE (Design of Experiments).  As scientists, we are attracted to design space studies (including myself) because it is an extension of our daily work. However the bigger question is – “Which process parameters do I experiment with?” Due to limited time and resources, we can only conduct limited number of experiments before submission. How do we choose which design spaces to study?

Traditionally that decision was made by scientists through heuristics or experience. Agencies learned that relying on intuition and spur-of-the-moment inspiration does not produce a repeatable outcome in large organizations such as pharmaceutical companies.

 

How to Choose Which Design Space Studies to Work On

 

Hence the regulatory agencies and industry are now embracing the Quality-by-Design framework. In QbD framework, QbD Risk Assessment provides the answer to the question: “Which process parameters do I need to study?”

After conducting QbD Risk Assessment (using Lean QbD Software), you can see the “high risk” process parameters and quality attributes.

Below graph shows “High Severity & Low Occurrence” process parameters at the top left quadrant and “High Occurrence & Low Severity” parameters at the bottom right quadrant.

First priority of design space would go to the parameters on the top right quadrant (High Severity & High Occurrence) but we don’t see any on the chart.

 

prioritize design space through QbD risk Assessment
High-resolution of Risk: Severity (Y) and Occurrence (X) Separated Visually

 

You can also use the pareto charts of CQA’s and CPP’s to prioritize your design space studies.

 

Pareto Chart of CQA
Pareto Chart of CQA – Ranked in order of RPN
Pareto Chart of CPP
Pareto Chart of CPP – Ranked in order of RPN

 

QbD Risk Assessment is the backbone that links other QbD elementsdesign space and control strategy – together. In a QbD dossier, risk assessment section serves as the executive summary for regulatory reviewers. As such, Risk Assessment plays an essential role in the QbD framework.

However there are major challenges with risk assessments in Quality by Design.

 

Challenges with QbD Risk Assessment

 

First, it is confusing. Why? Because there are various ways to identify and evaluate risks.

 

1. Which Risk Assessment Tools to Choose?

 

Just looking at ICH Q9 (Quality Risk Management), you are faced with multiple decisions in choosing which tools to use:

  • Flowcharts;
  • Check Sheets;
  • Process Mapping;
  • Cause and Effect Diagrams;
  • Ishikawa diagram or fish bone diagram;
  • Failure Mode Effects Analysis (FMEA);
  • Failure Mode, Effects and Criticality Analysis (FMECA);
  • Fault Tree Analysis (FTA);
  • Hazard Analysis and Critical Control Points (HACCP);
  • Hazard Operability Analysis (HAZOP);
  • Preliminary Hazard Analysis (PHA);
  • Risk ranking and filtering;
  • Control Charts: Acceptance Control Charts (ISO 7966); Control Charts with Arithmetic Average and Warning Limits (ISO 7873); Cumulative Sum Charts (ISO 7871); Shewhart Control Charts (ISO 8258); Weighted Moving Average.
  • Design of Experiments (DOE);
  • Histograms;
  • Pareto Charts;
  • Process Capability Analysis

Which tool(s) should you choose? Also, in which sequence should you deploy them? If you are not careful, risk assessment sessions can turn into a time and effort blackhole.

In order to get a good return on your on your time and effort spent, you need to choose your weapon(s) wisely. 

After experimenting with these tools and testing them, I learned that the optimal mix was a Process Map, Cause and Effect Matrix and FMEA. These tools were embodied in the Lean QbD Software.

 

2. Results Depend on the Facilitator of Risk Assessment

 

Whether you hire a consultant or a black belt, the process and the outcome depend heavily on the facilitator of the risk assessment. This is not good when we are trying to achieve consistent results across our organizations.

With Lean QbD approach, I observed that the results are more consistent because of the systematic approach.

Now adding to the confusion: what we call “risk assessment” in QbD is not merely a risk assessment. What do I mean?

 

3. QbD Risk Assessment is Not Just a Risk Assessment

 

The focus of Risk Assessment in Quality by Design framework goes beyond a traditional Risk Assessment used by other industries.

 In other industries, risk assessment is an effort to identify and analyze potential hazards – namely, what can go wrong. The focus of traditional risk assessment remains on generating a list of potential hazards and how to prevent them. Its goal is not to understand the basic science of how a manufacturer’s process parameters will affect the product specifications.

 

Risk Assessment Process

 

 

4. QbD Risk Assessment Goes Beyond Traditional Risk Assessment

 

Let’s compare this to the Pharmaceutical Quality by Design. QbD’s emphasis is on understanding the underlying science of how process parameters affect drugs and ultimately patients. The scope of QbD risk assessment goes beyond the traditional risk assessments.

Here’s how ICH Q8(R2) Guidance for Industry: Pharmaceutical Development defines risk assessment. Notice the first sentence.

 

“C. Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product CQAs (2.3) Risk assessment is a valuable science-based process used in quality risk management (see ICH Q9) that can aid in identifying which material attributes and process parameters potentially have an effect on product CQAs.”

 

ICH Q8 (R2) clearly emphasizes that risk assessment provides the linkage of Process Parameters and Material Attributes to CQAs (Critical Quality Attributes).

 

5. QbD Risk Assessment is Linking QTPP – CQA – CPP and CMA

 

The point of linking QTPP-CQA-CPP/CMA  is also highlighted in Dr. Lawrence X. Yu’s (FDA) latest publication: “Understanding Pharmaceutical Quality by Design”

“This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; … This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.”

Furthermore, Dr. Yu again emphasizes the link of CQA to patients, expressed as QTPP (Quality Target Product Profile) in his QbR (Question based Review) presentation.

Target Product Profile

  • Target product quality profile

– Beginning drug development with the end in mind

What performance is needed to get clinical benefit and meet consumer expectation

 

Yu uses the expression frequently to show that drug quality is determined as a function of API, excipients and processes.

  • Pharmaceutical Quality = ƒ (drug substance, excipients, manufacturing)

 

Define Target Product Profile

What Does QbD Constitute?

  • Define target product quality profileThe performance needed to get clinical benefit and meet consumer expectation
  • Design and develop product and manufacturing process to meet target product quality profile
  • Identify and control critical raw material attributes, process parameters, and sources of variability
  • The process is monitored and adapted to produce consistent quality over time

 

QbD Questions under QbR

QbD Questions Under QbR

  • Define target product quality profile – What attributes should the drug product possess?
  • Design and develop product and manufacturing process to meet target product quality profile – How was the product designed to have these attributes?

– Were alternative formulations or mechanisms investigated?

– How were the excipients and their grades selected?

– How was the final formulation optimized?

 

  • Design and develop product and manufacturing process to meet target product quality profile

– What are the unit operations in the drug product manufacturing process?

– Why was the manufacturing process selected?

– How are the unit operations related to the drug product quality?

 

You get the point. QbD Risk Assessment provides the first step to linking process parameters to quality attributes and then to target product profiles.

 

Conclusion

 

QbD Risk Assessment is not just a risk assessment. Its scope goes beyond preventing hazards. By providing the linkage, QbD Risk Assessment become the hypotheses list that leads to Design Space studies.

The ultimate goal of QbD is to link QTPP, CQA, CMA, and CPP together.

To do so, I recommend using Process Map, Cause and Effect Matrix and FMEA. You can use them in the Lean QbD Software without a learning curve.

After QbD Risk Assessment, you can proceed with Design Space studies.

In the next post, I will share some frequently asked questions regarding QbD Risk Assessment.

If you have any questions about QbD Risk Assessment, please share them by commenting below.

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