Searching for CTQ (Critical to Quality)

This post was inspired by a question from a colleague in the medical device industry. To summarize the question:

How can you find previously unknown critical to quality variables (CTQs) to drive preventative action instead of reaction?

I think there are 5 general steps to approaching this question.

1. Define critical to quality (CTQ)
2. Setup a methodology to find unknown CTQs
3. Engage your team and focus your method on a single product line, code, feature, or process step depending on the level of product/process complexity
4. Test the hypothesis of an unknown CTQ with extreme variations to the current nominal and evaluate the impact.   
• If the impact is low, then it's not likely a CTQ.  
• If the impact is high, then more detailed analysis is warranted to confirm a CTQ.
5. Repeat

Step 1: What is critical to quality (CTQ)?

• What is critical to quality (CTQ)? Information. 
• I know that seems simplistic, but it leads me to this question: How many of the issues you have worked on were a result of a lack of information?  I would guess all of them since you performed an investigation. 

Ever heard these phrases during those investigations?

• The design is fine, there must be something else
• We didn't think that would have any impact (so we didn't characterize it)
• Nothing's changed from when we ran the qualification  
• Each one of those phrases is a result of lack of information.  Whether it's considerations that weren't made during the design process, variables that were overlook during a qualification effort, or drifts in tribal knowledge, at the core they are all a lack of information.  

• I think any organization struggles with defining what truly is critical to quality and what is not.  I think the biggest reason for the struggle is because of the wide variety of products and processes across the medical device industry.  Everyone's looking for the end answer when usually every product or process requires a deep dive to truly understand what is critical to quality for that particular product or process.

Step 2: How can you find CTQs?

• Start with a simple question: Where do we have a lack of information?

While that once again may seem simplistic, it can help your team focus discussions on what's important when searching for CTQs.  Some of the questions below can help guide a deeper dive and discussion to determine if there is not enough information to answer the question.  If there isn't enough information to answer the question, then there could be an unknown CTQ variable lurking around. 

Good places to start:

• Manufacturing procedures
• Ask the question: If you handed the procedure to a co-op with all the necessary components and tooling, would they be able to properly make the end product? 
• I use the example of a co-op because often asking someone this question who has less knowledge about a product or process will help guide your search.  The questions they ask when trying to follow a manufacturing procedure will let you know where there is room for interpretation and drift in process steps. 
• If the team thinks that step could be a CTQ, I would talk with each operator performing that action and determine if they have a particular method they all use that isn't clearly defined in the procedure then it could be a CTQ. 
• How many manual steps does the procedure require?
• How long are operators typically trained? 
• How much experience does the average operator for this product have? 
• Lots of experience means lots of tribal knowledge that may or may not have been captured. 

• Raw material specs and incoming inspection records
• How large is the allowable band on the various material components?
• What's the range and standard deviation of the components analyzed on materials certs?
• There are two situations that come to mind:

1. High variation in raw material composition

1. Have you had historical issues with specific or concurrent lots of product that don't have?  A CTQ may be found when correlating those lots to raw material compositions. 
2. Have you had no historical issues with the product?  Probably a lower chance of a CTQ.  

 

1. Low to no variation in raw material composition

1. Little variation of material composition is indicative of a potential CTQ.  If you have never received a lot of raw material outside of a narrow band within the allowable spec, then you don't know how your process will behave if your vendor's process shifts (they want to improve their quality too, but could shift their composition if they change their standard process window)

• Qualification documentation
• What variables were measured during the qualification for both process and product?
• Could more have been measured that may have seemed non-critical at the time?
• How long ago was the qualification run?
• Are the people who performed the original qualification still around? Has tribal knowledge about that product drifted?

• Manufacturing environment
• Are any components or raw materials stored in an uncontrolled environment prior to final assembly?
• Do raw material and component vendors have uncontrolled storage environments?
• Are any of the product components or materials sensitive for humidity or temperature changes?
• Adhesives, Nylon, rubbers, etc.
• Are there any operations that would be affected by static changes?
• Adhesives, inks, coatings, etc.

• Product/Process design
• Has anyone ever voiced concerns about an aspect of the product design?
• Is this a legacy product with little change over the long term?
• Has the product or process had many changes over time or very few?  An older product with little to no changes over time likely has a lot of CTQs that are not well defined. 
• How extensive was the process design and development?
• Are there new manufacturing methods or technology that would improve the process that didn't exist when launched?
• How new was the design or process when it was implemented?  Has it been being characterized since that time in detail or only at a high level?

• Project Questions
• How well was the original project run?  Were there many delays?  Many delays is a sign of challenges that can result in a rushed aspects of the project.  Rushed actions make it more likely that something was overlooked. 
• Did the team work well together?  If they did not, then they would be more likely to overlook something.
• Was the product rushed to market?  Could an important variable have been overlooked?
• How much VOC was performed prior to the product being designed?

• What about when there is a lot of information?
• Throughout the analysis there could be situations in which there is a lot of information.  That could mean that a CTQ is already well known and characterized.  It could also mean that because there was so much information, that an important variable was missed.
• In these cases, take a step back and ask the original question.  Where is there a lack of information?  It can allow you to take a step back and evaluate a large amount of data from a top-level view to see what's missing instead of being overwhelmed by a mountain of data. 

Step 3: Engage your team and focus your method on a single product line, code, feature, or process step depending on the level of product/process complexity

• Building the right team and engaging them in the right way will greatly improve the efforts of your CTQ search.  The focus should be able collaborative problem solving. 

• Team Composition
• People with a good bit of knowledge and experience
• Manufacturing engineer
• Line supervisor
• Operator
• Design engineer
• Quality engineer

• People with less knowledge and experience

• At least 2, to provide fresh ideas and unbiased perspective on information
• Ensure they are encourages to ask the team any questions they come up with

• Break the analysis into smaller chunks.  With any CTQ search there will be a lot of information and complexity to work through, so it will need to be guided through smaller chunks by whoever is facilitating the search. 

Step 4: Test the hypothesis of an unknown CTQ with extreme variations to the current nominal and evaluate the impact. 

• Test extreme variations of the CTQ in a simple environment first
• Is it a readily changed process variable (time, temperature, pressure, or speed)?  Make a few runs outside of the current process window in a small scale and compare the results. 

• Evaluate how to proceed
• If the impact is low, then it's not likely a CTQ.
• If the impact is high, then more detailed analysis is likely warranted to confirm a CTQ. 

Step 5: Repeat

In Summary

1. Define CTQ as information.
2. Continually ask: Where do we lack information?
3. Evaluate smaller pieces of the product/process to ensure focused analysis
4. Test the hypothesis of a CTQ by testing extreme variations quickly and iteratively
5. Repeat

I hope this has help spark some thought around what a CTQ analysis method could look like and how to approach the various items that can be analyzed to help predict if an unknown CTQ is likely or not.  I would appreciate any feedback. 

Accelerated Aging of Medical Devices | Part 2: Relative Humidity and Absolute Humidity

Temperature is not the only variable to consider when defining accelerated aging parameters. Humidity must also be considered.  Notice that I only say humidity.  There is absolute humidity and relative humidity (%RH).

• Most people are familiar with %RH, which measures how close the water vapor content of the air is to saturation (raining) at a given temperature
• RH is temperature dependent! 
• Typical temp/RH probes output %RH based upon the temperature they measure, because of this set point must be defined in %RH
• Absolute humidity measures the amount of water water in the air per volume of air and is typically measured in g/m^3 or PPMv (parts per million volume). 
• Absolute humidity is NOT temperature dependent

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Why is humidity important for accelerated aging if it is not part of the Arrhenius equation?

• Incorrectly chosen humidity can cause faster aging than calculated by the standard Arrhenius equation
• Too high or too low can result in faster aging depending on the materials involved
• Poorly controlled humidity can also result in deviations to the Arrhenius calculated aging
• ASTM F1980 recommends ± 5% RH (relative humidity) for accelerating aging limits 

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How can high and low humidity levels affect product during accelerated aging?

High humidity can cause the following:

• Hydrolysis, which is material degradation in the presence of water 
• Think about how some materials (salt for instance) dissolve when placed in water
• Also think about how elevated temperature results in quicker or more complete dissolving 
• Degradation of any water soluble or water activated components

Low humidity can cause the following:

• Oxidation
• Ozone degradation (Ozonolysis)
• Drying/cracking of materials with variable moisture content
• Nylon and natural rubber are examples of materials with significantly variable moisture content

So at both ends of the humidity spectrum there can be unintended effects on the Arrhenius aging calculation.  The key point is to discuss with your materials engineer or expert which type of failures your materials are most likely to have.

If you have a device/package with both, I may consider performing half your aging at high humidity and half at low humidity to verify the design at the extremes it will see during its shelf life. 

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How are absolute humidity and relative humidity different?

As stated earlier the key difference between relative humidity and absolute humidity is that relatively humidity is temperature dependent while absolute humidity is not. 

Below is a graph of how absolute humidity increases with temperature (25-60°C) at 50% RH. 

Plot of absolute humidity (g/m^3) with increasing temperature at 50% RH

What's important to notice about the above graph?

• The absolute humidity at 60°C is than the standard conditions (25°C / 50% RH)
• It's actually 5.6 times higher, which a huge difference in the intended amount of available moisture in the air
• If we calculate the %RH at 25°C based upon that at 60°C / 50% RH we obtain 282%, which means there is almost 3 times as much moisture in the aging chamber air than would be required to generate rain at room temperature
• I don't think the intent is to have devices/packages submerged in hot water during storage (water vapor passes through packaging for EO sterilization)

So given that keeping %RH constant at elevated temperatures increases the absolute humidity we will need to reduce the %RH set point as the aging temperature is increased as shown in the figure below.

Plot of constant absolute humidity for standard conditions of 25°C @ 15% (green), 50% (blue) and 85% (red) RH

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What can be done to properly account for humidity when selecting accelerated aging parameters?

1 | Determine the device/package storage conditions

• Controlled Storage
• Use temperature/RH monitoring records from the facility over 1 year to calculate the min, max, mean and standard deviation in temperature and absolute humidity measured
• If data is not available, then a reasonable assumption for room temperature controlled storage is 50% RH at 25°C (standard temperature)  

• Uncontrolled Storage 
• Use temperature/RH monitoring records from the facility over 1 year to calculate the min, max, mean and standard deviation in temperature and absolute humidity measured
• If data is not available
• Obtain data from a local environmental monitoring station (if calibrated)
• A reasonable assumption for the low/high RH bounds could be 15/85% RH at 25°C

2 | Calculate the absolute humidity based upon the determined %RH value at 25°C (or other standard temperature)

• Create a table using a calculator from a calibrated probe vendor to determine the absolute humidity for the standard conditions AND the selected aging temperature (see figure below)
• Rotronic 
• Vaisala
• Note: Typical Temp/RH probes do not account for pressure (altitude) in their calculations of RH, which means you can use an standard pressure (1013.25 hPa) within these calculators consistently and obtain relevant results.  

Table of relative humidity set points for a given absolute humidity at 25°C and 15/50/85% RH

• Create a spreadsheet based upon accepted formulas AND validate it
• Vaisala has a great white paper on the relevant formulas available here
• Going into the details of how to create such a spreadsheet is extensive enough for another post, which I will complete and link if enough interest is generated

3 | Perform your aging study at the calculated set points and appropriate control limits

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Closing Remarks

I hope this has been informative and has help you gain some insight into the importance of humidity when aging devices/packages.  Please feel free to leave comments, questions or suggestions below. 

Accelerated Aging of Medical Devices | Part 1: Aging Temperature and Duration

Accelerated aging is probably not everyone's favorite med device topic, but it's one I enjoy.  Accelerated aging allows medical devices to enter the market before real-time data is available.  Accelerated aging is also known as shelf life, stability, or expiry dating testing.  ASTM F1980 is often the reference that guides this type of testing.

Accelerated aging is an area that each person involved in the product development process should have at least a high level understanding of because it is often on the critical path for new products and design changes.  

The importance of accelerated aging

• Overall, choosing the right aging temperature will avoid the timeline killer of redoing aging 
• Improper aging temperatures can cause changes that would not be seen under normal storage conditions.  
• Having a proper understanding of how temperature can affect materials and products will ensure the fastest time to market.   
• Alternatively, aging can be performed at multiple temperatures if data supporting the thermal thresholds of the relevant materials is not readily available or is not known. 

Selecting an Aging Temperature
Below are the main guidelines that should be used when selecting an aging temperature.  Consult your internal (or external) materials expert if you're unsure if your materials will not undergo abnormal material transitions during aging.  

• Ensure material thermal transitions are not reached.  This includes:
• Glass transition temperature
• Melting temperature
• Heat distortion temperature

•  Evaluate all the materials as a finished product:
• Processing (molding, extruding, thermoforming, etc) could have an effect on thermal transitions.  If you need to your material test it after processing.

• The material in your product with the lowest thermal transition should govern your accelerated aging temperature (T_AA) 

Calculating Aging Duration
In general, the Arrhenius Equation is basis for calculating aging duration.  While the details of activation energy that equation can be discussed, those details are not necessary for the majority of people.  So, the equation below is how we typically calculated accelerated aging durations.  

where:
- T_AA is the accelerated aging temperature
- T_S is the standard temperature 
- Q₁₀ is the aging rate per 10°C.  

• T_AA is governed by material properties and is typically chosen as high as possible to minimize aging time. 
• Typical temperatures range from 40°C to 60°C. 
• Increase aging temperature and you're increasing the power to which the Q₁₀ factor is taken, drastically reducing aging time. 
• T_AA = 55°C is often used because it minimizes aging time while ensuring the 60°C threshold called out in ASTM F9180 is not crossed given ± 2°C in allowable fluctuations. 

• T_S is the mean kinetic temperature (more info here) of the product storage environment (sometimes called standard temperature).  
• Typical values range from 20-25°C. 
• 25°C is usually the most conservative value.

• Q₁₀ is typically 2, which means the your aging rate is doubled for every 10°C increase above T_S.
• Increasing this factor will quickly decrease your aging time, but requires objective evidence the materials being tested follow the higher Q₁₀ factor.  
• Proving this is requires aging studies which take longer than using going with the Q₁₀= 2.
• The safe bet is to always use 2, unless you have knowledge that is doesn't follow Arrhenius or has a higher Q₁₀ factor 
• See Eastman Tritan, which has a Q₁₀ =8.  
• See ASTM D7161, which provides specific guidelines for aging outside of ASTM F1980 for medical gloves.  

Example Calculations
Given T_S = 25°C and Q₁₀ = 2 are the conservative standard, and T_AA = 55°C is the most common aging temperature, look what happens to the overall equation:

Knowing that for most aging you need to divide real time by 8 can help with quick calculations.  Below is a table detailing the number of days needed in a chamber (rounded up of course) at various conditions. 

Looking at the 1 Year RT (Real Time) row you can see that increasing from T_AA 45°C to 55°C halves the aging time required. 

The Impact of 2°C
In general, 2°C sounds like a minor temperature fluctuation, but because temperature differences influence the power to which the Q₁₀ factor is taken, it has a big impact.  

Look at the two calculations below.  One assumes T_S = 23°C and the other T_S = 25°C.  For 1 year of aging this results in 40 and 46 days, respectively.  That's a difference of 13%.  What's 13% of a year?  Over 47 days (~1.6 months), which would have a significant impact on labeling.  So, it can make a big difference if you're storage conditions are truly closer to 25°C. 

Closing
Since you made it to the end here is a link to the Excel file for the aging calculator I made (with bonus finish dates added!).

I hope this has added to your understanding of accelerated aging of medical devices.  Feel free to comment and provide feedback below.  Part 2 will focus on the role of humidity in aging.