Have you led or supported a QbD project? Then you will agree that Risk Assessment is a critical piece — like the small hinge that a big door (QbD) revolves around. The activity may seem trivial but has major implications. In fact, QbD revolves around risk assessment.
If you are not yet convinced, here are 3 reasons why you should not underestimate the impact of QbD Risk Assessment.
3 Reasons Why Risk Assessment is Key for QbD’s Success
1. The Big Impact of “Small” Parameters in Risk Assessment
As the first step in a QbD project, the seemingly “unimportant” activity of risk assessment during development can have a sizeable impact. Not only can it jeopardize a QbD initiative but also delay the launch of a new product. As an estimate, a drug launch delay may cost the company $1M per day (a rough estimation but heard at a conference) and possibly more for the patients.
“The impact of a poor risk assessment can be severe.” says Tim of Clayton CMC Consultancy.
Tim continues with a personal story:
“I have had the misfortune to be involved in a project where one parameter was considered non critical at an early stage but at a later date found to be of great interest to the regulatory authorities. Eventually the matter was resolved but only after significant extra work and delay to the project. “
2. Risk Assessment molds the First Impression of QbD
As the first step in a QbD project, our colleagues will form their first impression on QbD during this activity. If their first experience is frustrating and inefficient, momentum dies and support fizzles. The rest of the QbD journey becomes a struggle. I have personally experienced this from both sides of the table.Thankfully, this is preventable by using smart facilitation process and asking the right questions. Read on for suggestions.
3. Risk Assessment is the Backbone of QbD
Going one step further, Risk Assessment is not only what QbD revolves around, but it is also the backbone of QbD. Risk Assessment ties QTPP, CQA, CPP and Control Strategy together. We call this Quality Risk Management in the ICH Q9 guideline.
Why is Risk Assessment the backbone of QbD? QbD begins with Risk Identification. At the end of a QbD Risk Assessment activity, we will have a prioritized list of “Critical” Quality Attributes (CQA) and “Critical” process parameters (CPP). Starting with high-risk quality attributes and process parameters, the development team will carry out design space studies (hopefully using design of experiments). These “design space studies” are projects generated from the Risk Assessment. Based on the results from these studies and indirect research (prior knowledge and experience, literature review, clinical data, etc.), the development team can go back to their initial risk assessment and update the risk index. As you can see in the figure below (Ref: aMab), Risk Assessment is (and should be) updated at every step of the development lifecycle.
Before submitting a dossier, we must strive to resolve or reduce the number of high risk items. For the items unresolved by the time of submission, Control Strategy will address how we will manage them.
Risk Assessment is key in the success of QbD. As many readers may know, I emphasize the importance of Design Space in QbD. Sadly, I observed that many QbD projects are set up for failure even before they reach the Design Space stage — due to improper Risk Assessment. Therefore, a proper risk assessment is a precursor to proper design space studies.
To a reviewer, Risk Assessment acts as the compass for a new drug application. Risk assessment reveals where the company focused their efforts on during development and how effective they were.
3 Tips for Better QbD Risk Assessment
As a starter, stop using FMEA blindly: Here is why. If you use FMEA, modify it to your needs.
1. Before the first meeting, prepare a list of QTPP, CQA’s.
As a facilitator, make sure you have the inputs (QTPP and CQA) before the first meeting. As with any model, Garbage in Garbage Out (GIGO) rule applies. Risk assessment is a risk model. We are assuming many things in this activity. What goes in, will come out.
Having said that, the list of QTPP’s and CQA’s need not be perfect in the first meeting. Since the list will change during the Risk Assessment, it’s important to begin with a draft set and make adjustments as we discover new information.
Where to collect the List:
Usually Marketing, Clinical, Regulatory and HEOR (Health Economics and Outcomes Research) will have a set of QTPP’s. Begin there. For CQA’s, you can ask the project leader to point you to an initial list.
If you can not find an initial draft of QTPP’s or CQA’s or just would like to supplement or compare your list, search for them in the FDA and industry case studies. For tablets and aMab FDA published a generic list. I also created a template along with QbD Risk Assessment Software.
2. Prepare a Process Map before the First Meeting.
You can attain a copy of the process map for the product/project by asking the project leader. It may not be a comprehensive but it’s a good start to get the ball rolling. A good process map includes Quality Attributes and Process Parameters. If not, this is where the team will explicitly call them out.
Print this Process Map using a Plotter and post it on a wall. If it is a distributed team, I also use process map web apps such as Lucidchart.
Here is an example of a process map for Immediate-Release Dosage Forms.
3. Frame the Question in the Right Way.
In behavioral economics, Amos Tversky and Daniel Kahneman have shown that how you frame a question can affect the answer. Their research led to the development of prospect theory. How we frame the question matters.
Development scientists don’t speak the same language as the folks in Operations and Manufacturing. After working in both organizations, I learned both have very different KPI’s and educational backgrounds, producing different behaviors.
One of the reasons FMEA doesn’t jive well with development folks is because of this. The questions stated in its original form may seem offensive to a few. For example, FMEA’s main question — “What could go wrong for this process?” — is accusing the person who may have developed the process that they did not do their job correctly. They may be thinking, “Who are you to tell me this process is bad?” and leading to a defensive mode. What’s worse, FMEA throws another punch by asking “Why would the failure happen?” A development scientist may think, “If I knew, I would’ve prevented it.”
Instead of asking what will go wrong, (which may be interpreted as, “Why don’t you do your job correctly so these failures don’t happen?”), you can ask: “How much do you expect this CQA will affect this QTPP? or How much do you expect this CPP to affect this CQA?
FMEA questions and QFD questions are really asking similar questions — just in a different way. So prepare to ask them in the way that attendees want to hear them.
Three Reasons Why Risk Assessment is Key in QbD Success:
- The impact of a poor risk assessment can be severe — $1 M per Day
- Risk Assessment molds the First Impression of QbD
- Risk Assessment is the Backbone of QbD
Three Tips when Preparing a Risk Assessment
- Before the first meeting, prepare a list of QTPP, CQA’s.
- Prepare a Process Map before the First Meeting.
- Frame the Question in the Right Way.
More tips on Risk Assessment — focusing on how to facilitate a risk assessment during meetings and what to do between them — with the goal of making the process smoother and faster for everyone.