From The Editor | May 3, 2017

Lights, Camera, Validation! — Preparing For FDA Prime Time

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By Bob Marshall, Chief Editor

Breakdown Of The Basics Of "The Elevens"

This article is the fourth in a five-part series examining vital relationships in each stage of medical device development. Read parts one, two, and three here.

You have proven your concept, fully specified your design, and verified that the design output satisfies your design input requirements. It is time for the most pivotal portion of the product development life-cycle. I like to call this fourth stage “validation/manufacturing transfer.” Here, we move beyond lab-queen prototypes, small sample sizes, and controlled bench testing to prove that the product will fully satisfy user needs under actual or simulated operating conditions. This is the dress rehearsal for commercialization.

How important is this phase? If not executed well, it will delay your release, at the least. During his company’s quarterly earnings call last week, Edwards Lifesciences CEO Michael A. Mussallem explained that Edwards halted enrollment for its CardiAQ valve study earlier this year to “perform further design validation testing on a feature of our valve.” Yeah, it’s that important. You can bet that, when he had to explain this delay during the call, Mussallem wished his team had done more during initial validation of the valve — maybe study enrollment would not have had to be halted.

I want to focus on two vital relationships during phase four of device development: a process validation expert and your contract manufacturer (CM).

No Matter Your IQ, Mind Your P’s And Q’s

A process validation expert helps to ensure that manufacturing processes consistently produce devices that meet company specifications. The expert must have knowledge of manufacturing processes and equipment, which is especially important for the first part of process validation, known as installation qualification (IQ). During IQ manufacturing, equipment is verified for correct installation, proper connections for power, air, and/or water (as needed), and for any required calibrations. This first part of process validation is often trivialized or even overlooked, a big mistake that can have costly consequences.

To my point, let me ask you a question: If you have installed a new refrigerator in your home, how far did you position it from the back wall? Did you even read the installation instructions? Most manufacturers recommend an inch or two of clearance between the back of the refrigerator and the wall to allow for proper air circulation. Without this space, the compressor may labor excessively to cool the interior, leading to premature failure, a refrigerator full of spoiled food, and perhaps some form of food-borne illness. If a piece of manufacturing equipment along a medical device production line is not properly installed, it could lead to anything from a non-conforming product to a recall. Pay attention to the equipment manufacturer’s recommendations!  

The second part of process validation is operational qualification (OQ). For OQ, the process validation expert must be able to understand the product risk analysis, enabling him or her to create process maps and process failure modes and effects analyses, to identify process parameters critical to reducing the risks associated with process failures.

Next, a process validation expert needs a good set of specifications to understand how to conduct the OQ. Don’t let your design engineers and designers off of the hook! I was once brought in as a consultant to a medical device company that was frustrated with its CM. The CM was machining parts and bonding them together to make a subassembly that was added to the OEM’s existing device. The CM created a good process for manufacturing the subassemblies, but about 30 percent of the subassemblies would fail after they were incorporated into the existing device. Specifically, the bond would fail.

I asked the CM if they knew how the subassembly worked on the device, to which they replied, “no.” I subsequently asked the OEM how much force the bonded parts needed to withstand, and they did not know. Unfortunately, this is not uncommon, but it’s easily rectified. The OEM’s engineers were able to measure the force experienced by the subassembly when it was incorporated into the device, and provided a force specification with appropriate margin to the CM. The CM analyzed the bonding process in light of the force requirement and performed an OQ with worst-case parameters to ensure adequate bond strength.      

Finally, a process validation expert needs to have a good knowledge of statistics. Following successful completion of OQ, it’s time for performance qualification (PQ). PQ typically is performed by producing three production lots at nominal process parameters. The size of the production lots have to be determined by statistically modeling a confidence interval and the desired yield. Given the complex skills required for process validation, it is imperative that you have an experienced process validation expert on staff, or contract an appropriate professional for a smooth validation and transfer to manufacturing.

Size Does Matter (When It Comes to Contract Manufacturing) 

As we discussed above, your relationship with a CM is critical to the success of your finished medical device. There are many factors to consider when choosing a CM: location, reputation, financial stability, specific manufacturing experience or skill sets, quality system certifications (especially when product will be sold outside of the U.S.), and size. Of all these attributes, I would recommend to you that size matters most.

If you are a large medical device company and you choose to outsource manufacturing to a small (likely local) CM, there certainly are some benefits, but the CM is unlikely to have the capacity to scale production for you when demand increases significantly. That lack of capacity can open a door to your competition while you miss the opportunity to capture the lion’s share of the market.

On the other hand, if you are a small or startup medical device company, and you become enamored with the idea of securing the services of a large CM, you likely are headed for disappointment and frustration. If a billion-dollar CM is willing to build the 50 devices that you have forecast for your first year of production, business likely is slow and they are looking for work to fill up the plant. You have to ask yourself, “How much of their attention will I get, especially when their work picks up?” Startups, especially, experience hiccups and need to make changes to their first production units. Those needs for flexibility and agility may be challenging for a billion-dollar CM.

Also, be wary of low-priced bids. All too often, a CM may low-ball a project because they need work, only to later lose focus on your project because it does not generate as much revenue as other more lucrative contracts. There also is thinking that a low-ball offer will get the work, and later the CM can request a price increase. By then, the project will be too far along for you to consider moving the work elsewhere — our regulated industry exacts time and cost penalties when production is moved from one facility to the next.

Thus, find a CM to partner with that is similar to you in relative size, and has systems that will mesh with yours. Think of the partnership as a marriage, not a date. Find a CM that has skills to compliment your own, a culture that fits your mindset, and the desire to help get your life-changing device into prime time — and stay there.

Check out other installments in this series here.