DoE Flow Chart

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We have seen that the DoE is a integral part of any QbD studies however, we seldom apply it properly during developmental stage. I have seen scientist afraid of using it because, they think that DoE means  more experiments. But in reality what I have seen that they end-up in doing more experiments than that suggested by DoE. To give you an idea, scientist would perform 40-50 experiments if they are investigating 4-5 variables whereas, DoE con do that job in 15-20 experiments. This is because, when DoE experiments proposes 15-20 experiments in a single go, it appears more for the developmental team. Other issue is that the lack of knowledge on how to exploit the DoE using fractional factorial designs, Plackett-Burma or D-optimal etc.

This article describes the flow diagram for conduction a successful DoE.

DoE Flow

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Sequence of Events While Performing Design of Experiments (DoE) & QbD

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As a chemist I was always in a hurry to perform a DoE for optimizing a chemical reaction. More often I failed and gradually I learned that it can’t be done in a hurry, we need to do some homework before that.

Basic concept behind QbD is the Juran’s concept of “building/designing quality into the product”[i] rather than “complying product with the quality”. Designing quality into the product could be achieved by having better control on the process and this can be achieved by proper understanding of the relationship between the CQAs (y) and CPPs/CMAs (x) as shown in Figure 4 and 7. This concept of building quality into the product is based on the quality risk management[ii] where one needs to assess the risk of each PPs/MAs on CQAs. Basic outline of QbD in process development is shown in Figure 9. It involves following steps

For a successful DoE, we need to divide the whole process into two phases

Phase-1: Preparing for DoE

It deals with the preliminary homework, like

what quality parameters we want to study & why?

What are the process parameters and material attributes that can affect the selected quality parameters?

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Phase-2: Performing DoE and analysis followed by proposing the control strategy

Once quality parameters and most probable process parameters and material attributes are identified, its time for performing DoE to establish cause and effect relationship between the two.

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Based on the DoE study, CPPs and CMAs are identified and a design space is generated within which CPPs & CMAs could be varied to keep CQAs under control.

Finally, before commercialization, a control strategy is proposed to keep CPPs/CMAs under specified range, either by proposing a engineering or manual control.


DoE: Design of Experiment

CQA: Critical quality attribute —these qualities of the product is critical for the customers

CPP: critical process parameters — these process parameters affects CQAs

CMA: Critical Material Attributes — These are input material attributes affecting the CQAs.

[i]. Juran on Quality by Design: The New Steps for Planning Quality Into Goods and Services, J. M. Juran, Simon and Schuster, 1992

[ii]. José Rodríguez-Pérez, Quality Risk Management in FDA-Regulated Industry, ASQ Quality Press, Milwaukee, 2012.

A Way to Establish Cause & Effect Relationship …..Design of Experiments or DoE

 

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Mostly what happens during any investigation is that, we collect lot of data to prove or disapprove our assumption. Problem with this methodology is that, we can have false correlation between variables

e.g. increase in the internet connection and death due to cancer over last 4 decades!

Is there a relation between the two (internet connections and death due to cancer)? Absolutely not, so in order to avoid such confusions we need to have a way to establish such relationships. In this regard we use DoE, these are statistical way of conducting experiments which establishes cause & effect relationship. General sequence of events in DoE is as follows

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Why DoE is important at R&D stage?

Just remember these two quotes

“Development speed is not determined by how fast we complete the R&D but by how fast we can commercialize the process”

“Things we do before tech transfer is more important that what is there in tech pack!”

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In order to avoid the unnecessary learning curves, and to have a control on the COGS we need to deploy QbD as shown below

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Details will be covered in DoE chapter

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Concept of Process Robustness — 2

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Earlier we have seen that robustness is inversely related to the slope of the main effect. We dealt with the linear relationship in those cases.

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But some time effects could be of higher order like quadratic, cubic etc.  In such cases principle remains same i.e. select the region with least slope for least variability — at the tip of the parabola.

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Related Topic

Concept of Process Robustness — 1

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ANOVA by Prof. Hunter

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We are excited about the quality of videos available on youtube, on almost every topic. Look at this video on ANOVA by none other than Prof. Hunter himself.  These video was shot in 1966 in black & white but experience the contents.

ANOVA-1

ANOVA-2

Concept of Process Robustness — 1

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Before we understand the concept of robustness, we must understand “How Variance Gets Transmitted To The Out-put (y)?”

Let’s have three scenarios where we are measuring the effect of factor A on the response.

Picture22We can see that as we increase the factor A there is a increase in response Y in all cases. Also in all three cases factor-A got fluctuated by an amount = A2-A1.

Case-1: A small fluctuation in  factor A (denoted by A1 to A2) which could be possible at commercial scale can result in ΔY1 fluctuation in response. This ΔY1 fluctuation is depends on the slope of response. Since the slope in case-1 is least, therefore fluctuation in ΔY1 because of the factor-A fluctuation is least.

As the slope increases from case-1 to case-2, the fluctuation (variance) that is transmitted to response Y (denoted by ΔY2) increases, even though the variation in factor A remains constant (A2-A1).

Matter becomes worst as the slope further increases (case-3).

If we are looking for a robust process during commercialization, we should focus not only on the output of the DoE but also the slope of the response.

Suppose we are optimizing a reaction at two different temperatures as shown below

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Even though temperature-1 can give me better yield if we keep on increasing A, I would prefer to take a hit on yield and commercialize the process at temperature-2 because the slope of the response is negligible and hence the yield of the process would be consistent at commercial scale. 

Summary

  1. A small change (deviation) in input can cause huge fluctuations in the response depending on the slope
  2. Higher the slope of response, more is the fluctuation in response due to slight change in reaction parameter

Related topic

       Concept of Process Robustness — 2

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