[0:05] Intro: Welcome to Measuring Up, Thinking Out Loud, featuring news and information from Testo, your consultative resource for precision measurement technology and digital solutions, serving the pharmaceutical, industrial, and allied industries worldwide.

[0:25] Bill White: Hi, this is Bill White on the Testo Information Network. Today, we're with Sean Merrill of Testo. Sean, thanks for being with us today.

[0:34] Sean Merrill: Thank you, Bill. It's a pleasure to be here. 

[0:36] Bill: Sean is a validation engineer with Testo and a man with credentials that underscore the confidence in what we can expect from Testo when Sean shows up on the scene. Sean, tell us a bit about your background.

[0:48] Sean: I've been involved in commissioning qualification validation for the better part of the last 11 years or so. And this is an area that's very near and dear to me. It's a pleasure to be here and speak about this topic with you.

[01:01] Bill: OK. Well, thanks for that. And, I think we should start at the beginning, as to just what is validation and qualification; it's certainly serious business.

[01:11] Sean: It certainly is. So, there's a common acronym that we utilize, or that you will see utilized, which is CQV. That stands for Commissioning, Qualification, and Validation.

[01:23] Sean: Oftentimes, those are managed within the same group, within an organization. Commissioning, really, when we talk about a pharmaceutical facility, whether that's a manufacturing site or a logistics distribution center, what we're talking about there is just the managed approach to the defining requirements, the startup, and turnover of that facility from the contractor and subcontractors who are responsible for essentially putting that final package together. When we talk about qualification, really what we're talking about there is demonstrating through some sort of testing or verification activity that the system is suitable for its intended use. And when we talk about validation, really, we're talking about validating a process. So that is the day-to-day, what people are doing when they're cleaning or sterilizing or sanitizing or operating a filling line or things like that. 

[02:18] Bill: And all of these relate to the products and services that Testo has brought to the market. Why is all this so important?

[02:27] Sean: So, the primary reason is for patient safety. There was a series of incidents, starting around the 1950s, even before that. But I'm really kind of speaking more of like the more recent history as far as what sparked some of the current regulatory landscape, you know, that we see now. And I'm gonna preface this by saying I am not a regulatory expert. I know the areas in which I operate, but as far as all of the nuance from, you know, various different areas, I'm no expert in regulation, but I do understand these particular areas. So, three notable ones brought this whole thing about, to begin with. And first was, in the 1950s, there was an incident involving the polio vaccine. And this is referred to in a lot of literature as the Cutter Incident. There were about 200,000 or so individuals who became infected with a live strain of the polio virus. And as a result of that, you know, many people developed actual polio and, you know, had the issues that came along with that, right? What ended up happening was that they were inoculated with a live strain. The manufacturing process had failed to properly deactivate the virus, right? To properly kill the virus, as it were. There are probably a few people who listen who may have heard of or remember thalidomide, which was widely available in the US and Europe, and other countries as well, but it was essentially a morning sickness remedy for pregnant women. Unfortunately, a very tragic side effect was that a lot of the infants that were born were born with some fairly severe birth defects. Some of the children had missing limbs or other deformities.

[04:07] Sean: And then in the 1970s, there was, and I don't remember the manufacturer that was involved with this, but there was an incident where there was a parenteral drug, an intravenous drug, that was administered to patients, specifically burn patients, and many of these patients developed a severe infection, and about 50 of these patients died. So, all of that to say, there was a lot of activity and things going on in, you know, about the middle of the last century.

[04:35] Sean: And so, the FDA stepped in, and around 1962, 1963, we see the first GMP regulation. And that really was the regulation that says, ‘hey, before you take a drug to market, you have to have approval from the FDA.’ It was really the first time that we saw that in history. There have been other FDA regulations prior to that. The Food, Drug, and Cosmetics Act was passed in 1937 or 1938 or something like that. But this was the first time where the agency actually stepped in and said, ‘you need approval before you actually market this drug.’

[05:03] Sean: Because of the thalidomide incident and the parenteral failure, there were several investigations that went on within the FDA, but then also, you know, internally within pharmaceutical manufacturing. So, through the mid to late 60s and early 70s, what was determined was a lack of quality control within the manufacturing process or documented quality control measures. And so, what we see in the mid-70s and into the early 80s is the FDA starts to issue guidance, and we start seeing terminology like qualification and validation of process for the first time in agency history. Fast forward a little bit, in 1987, the FDA first publishes the guideline for principles of process validation. I think the document title name was, Guideline on General Principles of Process Validation. That was in 1987. That really wasn't effective until about 2010 when the agency came in and actually revised, kind of did a second revision of that document. The 2011 version is still the effective document today. And then in between there, you know, you have regulations from various countries and regions that are coming together to sort of tackle the same approach just in their respective areas.

[06:16] Bill: OK, so basically, we've learned from some tough lessons in history. Today, we're benefiting from a lot of those very difficult lessons indeed. We'll be back with Sean Merrill right after this.

[06:34] Intermission: You're listening to Measuring Up, Thinking Out Loud, news and information from Testo.

[06:45] Bill: Sean, there's a lot of history, a lot of anecdotal evidence, as well as hard science to back up what we're doing today. Tell us about the approaches that you can take in terms of satisfying the commissioning qualification and validation equation.

[07:06] Sean: Yeah. So, early on in the 80s, 90s, when some of the final guidance was first issued by the agency, the method that was often applied is what we call today the overkill method. And that was essentially, you validate anything that moves and don't move anything that's validated. By that logic, let's say I was qualifying an ultra-low freezer for storing samples of some type, and I have it plugged into a specific spot in my facility, and I've qualified that unit. I've done all of the temperature mapping studies and such. If I'm doing a renovation and I need to just move that unit from one location to another, under that approach, you would say, I need to completely revalidate that ULT again. Validation under the overkill method, there were a couple of, I would say two, unintended consequences. One is that it really discouraged innovation, because validation was such a time and labor-intensive burden. You know, there was very little motivation to try to make any type of improvement or change. 

[08:09] Sean: On top of that, qualification and validation were seen as a necessary evil rather than something that was, you know, truly a value add. And so, that approach, often, you know, we still see some of that mindset in some organizations today. By and large, what we have evolved to over the last, I would say, probably 25 years or so, is more of a risk-based approach, which is sort of an integrated method of commissioning and qualification. And so, taking that risk-based approach really focuses on the life cycle management of the facility or equipment or utilities, and the qualification activities themselves can be integrated as part of the facility, equipment, or utility commissioning. 

[08:57] Sean: And so, essentially, what that looks like is during the commissioning phase, there are lots of startup checklists and things that are completed by suppliers and vendor and engineering groups and things like that. And then what would traditionally happen later on was a qualification or validation group, such as, you know, what I do, would come back in and basically end up rerunning a lot of those initial tests. And so, what the risk-based approach tells us, and by integrating commissioning and qualification together, is that if a test has been completed during commissioning, with some caveats, you know, provided that it's well documented and follows good engineering practices and things like that, you can leverage the testing that was completed during commissioning as part of the qualification. So, there's no need to go back and redo a bunch of testing that has already been done. But again, it does depend on the quality of the documentation that's been provided for that specific exercise. 

[9:48] Sean: Several organizations have published guidance documents. ISPE, which is the International Society for Pharmaceutical Engineering, most notably has a document, or a book really, called Baseline Guide 5, which is commissioning a qualification. It's sort of the modern bible for taking a risk-based approach around commissioning and qualification for facilities. It doesn't touch on process validation that's covered elsewhere. And then ASTM, which is the American Society for Testing and Materials, they also have a guidance document. They use some goofy letters and numbers and very long titles, but it's E 2500 is the ASTM standard around us. It essentially allows us to, to take a risk-based approach to commissioning and qualification to really deliver a truly value-added set of testing and verification to demonstrate that the facility, room, the piece of equipment, or utility, or all of those things combined, will meet end requirements and thus mitigate risk to patient safety and product quality in the end.

[10:49] Bill: So as part of the Testo service to the industry, in addition to a huge buffet of sensors and transmitters and data acquisition devices, there's a consultative approach to working with customers, and that sounds like you're on the point for all of that. Helping these customers determine what they absolutely must do; what they might want to do; what makes sense in the overall equation of risk management.

[11:22] Sean: Yes, correct. So, my role at Testo is really to supplement the efforts that a specific customer might be undertaking on their own. Our services are largely tailored to be modular. So, for smaller organizations or even mid-size organizations, those that don't have an expertise in qualification or validation can utilize any number of our services. So, as you said, we offer a buffet of sensors and other data logging and instrumentation. We also kind of have a buffet of services that we can, we can choose from as well. So, we can offer the full package of going through from drafting, validation, master plans, all the way through conducting performance qualification, or customers are free to pick and choose. So, if they have an internal team that is handling the risk assessment and handling certain aspects, we can step in and assist with temperature mapping, which is part of the qualification exercise as well.

[12:20] Bill: So, Testo is selling not just what they make, but what they know, and that's where you come in.

[12:27] Sean: Yes, that's correct. Traditionally, validation within pharmaceutical manufacturing would generally fall within the quality or engineering group, usually as a liaison between, you know, several different functional areas. But as a service provider, we're here as a third party, as an objective third party, really with the focus and intent to making sure that, you know, whatever you are, you are doing in your facility, you know, logistics, manufacturing, testing, sampling, whatever the case may be, that the intended areas of application are suitable for their intended use, thus minimizing or mitigating risk to patient safety.

[13:03] Bill: That's great. That's great news to know that when you engage Testo, you also engage what you [Sean] know and your experience as well, your expertise.

[13:12] Bill: We're talking with Sean Merrill of Testo. Sean is a validation engineer. We've learned a lot about what that means, and Sean, we are definitely gonna be coming back to you to go take a deeper dive into some of these areas that are critical to the safety and efficacy of pharmaceutical products and services in this country and beyond.

[13:35] Sean: Great, Bill, it's been a pleasure speaking with you today. 

[13:38] Bill: Thanks, Sean. Sean Merrill, Testo, validation engineer. I think he comes with the complete package.

[13:49] Outro: You've been listening to Measuring Up, Thinking Out Loud, news and information from Testo, your resource for precision measurement technology and digital solutions for pharmaceutical, industrial, and allied industries worldwide.