Subhi Sedate (5:00)

What's changed since then on the validation front? Because I. I suppose I had it. Put it together that you went from being a draftsman to basically starting at the bottom of validation, where you're doing the basics and then building. So in. In other words, you did a transition. It was. It wasn't a lateral.

Nathan Roman (5:23)

That's right.

Subhi Sedate (5:23)

You went. You basically restarted in a new. You obviously take your experiences with you wherever you go. But I'm saying it's not like you went from, let's say at a manager level where you have responsibilities. For based on five to 10 years of work, you started out at the early on the basics and you've built up since then. So what's changed?

Nathan Roman (5:44)

My age for one thing. So I started young, we're talking 23 years ago and I was, you know, 21, 22 years old then. So I, I was ripe for learning, ripe for starting over. If as you say, which to me wasn't really starting over, I was like learning new things and I still had so far to grow. But for someone like currently my age right now, if I was in engineering or CAD and I wanted to get into the validation world. Yeah, I guess you're right. It would absolutely feel like starting over. But you can learn so much quickly if you're hungry for it. And I think that's where it's almost okay. Yeah, you might start over per se, but there's so much room to grow, so much, so many things to learn and you sky's the limit sort of thing. And on the pharmaceutical validation consulting quality side.

Subhi Sedate (6:43)

And so from, from a validation standpoint, what's changed in the last 20 some odd years?

Nathan Roman (6:53)

In my perspective, things that have changed are the equipment that we're using for temperature mapping, for example. So in the past we used these big chunky data loggers to, and, and all the thermocouples and we would have to wire up a room, a warehouse with thermocouples and that's hard work. That's a lot in the service chase we're running hundreds of lines of feet of, of thermocouples and now we just place it a simple data logger on the shelf wireless thing. So that's completely changed the way we document and, and, and execute our protocols. Obviously everything in the past still is today on paper based. Right. So draft the protocol in word, get it approved, walk it around to each individual person, you know the deal. Right. So get it approved, get it signed, then copy it or dot control gives you a copy and you go out and execute. And today you could. With systems like paperless, systems like NEAT and, and other things you can, you can do all that generation review and approval and execution all in one platform, not even print anything out.

Subhi Sedate (8:05)

Yeah.

Nathan Roman (8:06)

So those are definitely some changes.

Subhi Sedate (8:08)

Why is temperature mapping important?

Nathan Roman (8:12)

So temperature mapping is important because it's a critical aspect, crit, critical attribute to drug product, to samples, to reagents, to food. It's critical. Right. So if you don't maintain temperature at the required criteria that's specific for that individual item, product, food samples, you, they can Perish, they can degrade, they can spoil, they can become non effective anymore, especially with the vaccines. Right. So that's why it's important. And I, I post a lot about that kind of stuff. The importance, the purpose, why we do on temperature mapping as I guess in.

Subhi Sedate (8:56)

My head it, it's clear to me that temperature is important. That's a factor. The measurement of the temperature is also important as a factor. I think what distinguishes what I was looking for is the exercise of mapping temperature and emphasizing its mapping. What makes it more important than let's say humidity because humidity is also measured, but I don't think it's measured in the same to this, to the same level as temperature. Is that right?

Nathan Roman (9:30)

No, no. Yeah, that's right. So humidity is monitored and measured in applications that require things to be humid, less humid or more humid. So like with your, your stability chambers. Right. There's a humidity aspect to those and that needs to be monitored and measured. And, and in that case it is. And, and we do however we it, we won't put for example stability chamber with thermocouples and humidity sensors. We, we measure the, the humidity and the chambers but not as many sensors because humidity will cover a larger amount of space and it doesn't change as drastically as temperature as, as the temperature requirements. So we don't need to utilize as many humidity sensors and it's not, it's not required. But many people often want to mimic the number of thermocouples or temperature sensors for humidity.

Subhi Sedate (10:31)

Is that right?

Nathan Roman (10:32)

Yeah, Yep.

Subhi Sedate (10:33)

Really? And so they'll say we might as well just do one to one.

Nathan Roman (10:37)

Yes, that's correct. Yeah.

Subhi Sedate (10:38)

But it's not, but it's not either from your perspective. It's not really based in I need going to requirements. Are, are there regulatory requirements around the expectations for. For sure you have to have some kind of temperature monitoring and control. But are there expectations outlined in any regulations standard.

Nathan Roman (11:03)

So there is, there's. Right. There's guidance out there. There's regulations out there that speak about temperature control and storage areas for drug products, humidity controls for the products, but also for creature comfort and human.

Subhi Sedate (11:21)

You mean.

Nathan Roman (11:21)

Oh, creature comfort in your house you set your, your thermostat to a certain temperature and it's just, it's creature comfort. That's what I meant. So there are guidelines, there are acceptance criterias that are specified. But it's pretty, pretty wide range. Yeah. So like for instance for, for gowning and ISO eights or ISO type class environments, there's requirements for humidity RH in, in those environments. So you would have to meet those, you would have to test those. If, especially if you're claiming or saying that your clean room is a certain classification you that would need to be tested and need to be verified. Obviously if you're, if you have certain criteria around microbial growth, obviously humidity needs to be controlled. But the guidelines, they have such a wide range of acceptability of 20% to 70 RH. So it really depends on your, your activity, your, Your product and, and your design.

Subhi Sedate (12:27)

Is temperature mapping run just like any normal validation?

Nathan Roman (12:32)

Yeah, I'd say when you say any normal validation planning, it's the preparing of documentation. It's do you have specifications, requirements, execute that protocol, perform the testing, analyze your data, run the report and approve it.

Subhi Sedate (12:49)

But I'm just trying to understand it from a, let's say IQ point of view. Are there utilities that go into there's air?

Nathan Roman (12:57)

Probably so temperature mapping protocol in regards to utilities typically say for refrigerator freezers, you're just going to be dealing with your electricity, verifying your voltage. Right. Your amp flow, things like that.

Subhi Sedate (13:13)

That. Is temperature mapping equal to. Sorry if this is a really dumb way to ask this question, but does temperature mapping equal monitoring cold. Are there any applications where it's used for warm and is there. Is monitoring the temperature for an autoclave considered temperature mapping or is that considered part of sterilization validation because it's a process parameter?

Nathan Roman (13:42)

Yeah, it, it, the answer to your question is yes, it is considered temperature mapping from the standpoint that it's a, an actionable test that's being done for that autoclave for an. SIP study for a, an oven. Right. An incubator is warm. So you're going to perform the temperature mapping, if you will, as a test within that qualification of that equipment. And so the idea is the same. You're, you're going to provide the sensors. You're going to have it in a specified location within the chamber. Whether it's an autoclave, oven, refrigerator, freezer, incubator, cold room, warehouse, you're going to have specified locations for these sensors. You're going to run your study for a certain period of time. Obviously with autoclave it's going to be a little different. You're not running for 24 hours. You, you have a cycle that you're running it for. Right. And you're looking for other things other than just temperature when it comes to an autoclave or something like that with pressure and things like that. But yeah, so in essence it's, it does work with Cold and warm products or equipment or requirements.

Subhi Sedate (14:53)

You said you're not running it for 24 hours. Where are you? The 24 hours would be more on the cold side or is it also for. Do you do deprecination ovens as well?

Nathan Roman (15:03)

When you say ovens, yes, but those type. Certain equipment that are. The operation involves cycles or set parameters or things like that. You're gonna test, you're gonna test that equipment and run that cycle. So deep pies you're gonna look at the autoclaves, you're gonna look at even cryo, cryo freezers that have, that have cycles of. They're warming in a, a sample and then cooling it and then freezing it and then warming it and then freezing it. So you're gonna run the cycle and verify the, the mapping the temperatures through, through that, through that test. But as far as 24 hour goes, refrigerators, freezers, anywhere where there's long term storage, you're going to run at longer periods of a study duration. Refrigerators, freezers, incubators even because you're storing media in incubators, you're going to run at 24 hours. That's the typical duration for those type of CTUs. Controlled temperature units. But then the larger units like cold rooms, you're going to. Typically we run three days. We'll have sensors in there for three days to capture the cycles, to capture airflow variations, changes in the cycle of the compressors and whatnot. And then in warehouses it's the, the typical, the minimal amount of time is a seven day study.

Subhi Sedate (16:35)

Aren't there data loggers that are used for continuous monitoring? I think I've seen that for warehouses.

Nathan Roman (16:44)

No, you're absolutely right. Sure. You're required to have monitoring sensors in your warehouse. For example, there's even a monitoring sensor in the fridge or a freezer or, or a cold room. Not as many as when done performing the testing to, to. To look at the complete uniformity of the area or the space that's being tested.

Subhi Sedate (17:06)

Okay, so the is. Is temperature mapping typically the end all be all validation or does it typically feed into another. I suppose I'm trying to understand. Let's use the example of a deep hyrogenation oven or a. I suppose it makes sense if it's just a. You said control temperature unit. That just means a storage area where temperature is its main perimeter thing. So. Yeah. Okay. And so basically a refrigerator incubator warehouse. Actually warehouses are typically not controlled, are they? They're monitor not controlled.

Nathan Roman (17:48)

No warehouses. I mean there are, there are Warehouses that aren't, um, you know, being. Maintaining any type of temperature, they're ambient or if you will, or something like that. But there are warehouses that are controlled. H VAC is controlled, you know, the temperature. Um, absolutely. So what, so what, going back, what was the question that you had?

Subhi Sedate (18:08)

Um, I'll ask it in a second. But ambient temperature, is that a formal definition?

Nathan Roman (18:16)

Yeah, USP says that is 15 to 30 degrees is the acceptable range, like you had mentioned. But is there, in my experience, is there something tighter that is completely up to you and your equipment and your product storage. The other thing they say is to, to make sure that your acceptable range, your acceptance criteria is based on your products, what's labeled on your products, and what's the temperature range they're to be stored at? Let's say you, you want to store something at 25 degrees C. Your range, you put 25 plus or minus 5 degrees C would be your range. You go from 20 to 30. But if you have something that you're wanting to store at 22.5 degrees. So it would be based upon your need and your product's requirements.

Subhi Sedate (19:10)

Sure. So going back to the last question, is temperature mapping typically a subset of an overall validation or is it the. The kind of. Is it on its own? The reason that I asked this question is in my experience, there's a few different validation buckets. So in my experience, let's say if you're working on a large program, there'll be the process validation bucket for the product, and there'll be the sterilization validation for the cycle. There'll be the environmental setting up the clean room as a validation. Those would be like very big buckets. That would be months of work to, to generate all the protocols, gather all of the data, review. In many cases, you may have a bunch of different teams working on those things. I haven't seen temperature mapping looked at in that big bucket. Or is it typically just a subset of one thing?

Nathan Roman (20:11)

So I think it's both. So obviously you and I, we come from different sectors of the industry, maybe where a lot of the stuff we do does intertwine at times. But in my experience, temperature mapping has been its own thing, its own standalone item. So there's temperature mapping where a team can just come in to a lab and verify temperature for their fridges and freezers or their storage area. And they're just, they set up the sensors, they run the study, they print the report and hand it to you, and that's all that you're given is A report of the data. Right, but. So that's temperature mapping. But then the equipment qualification of that freezer or fridge is going to go more in more depth on the. Install the control parameters, the screens, does the button work, how is, what is it plugged in at, how many shelves does it have? And then run the temperature mapping studies. Right, so whether it's an empty chamber, a loaded chamber, they have other tests about. Open that door for a certain period of time, allow the temperature to collect, you'll see the temperatures rise. Shut that door, you'll see the temperatures come back into spec. How long does that take? All that kind of stuff? Shut the doors, allow the temperatures to equilibrate while you're recording, pull the plug, turn the power off, simulate a power failure. How long do. Do the temperatures maintain the acceptance criteria until they drop out? What is that information? So during the equipment qualification, we're doing way more than just the temperature mapping. That's, that's an aspect of the qualification which is the same for the autoclave that you're talking about, or a deep buy, or a bioreactor. We're going to run temperature studies and, and the bioreactor in the tanks he runs and all that kind of stuff. So it's an, it's definitely an aspect of the qualification or validation. But, but it, it, it can also stand as its own as well.

Subhi Sedate (22:11)

Walk me through commissioning qualification validation.

Nathan Roman (22:15)

Okay. CQV commissioning is going to be running the. So, first of all, that's something that has changed from when I had started in the industry, Commissioning qualification validation. And then today's standard of cqv, that has changed. The guidelines have changed. Whereas in the old days, commissioning was a process that you ran all the, you, you tested the equipment, run it through all its paces. It's verifications, it's checks, it's, you know, loop checks, it's, you know, testing the operation of the unit, making sure that it works and it is installed. And then it was always done as an engineering function outside of QA per se approval. And then when you took that and everything passed, you went to that next phase of qualification where. Okay, now that's a go ahead.

Subhi Sedate (23:11)

Sorry to jump in, but before we move into qualification on commissioning, it is. Is commissioning the same thing for, let's say, a refrigerator or something like that, where it's F a T S a T or is it something else?

Nathan Roman (23:27)

So for a refrigerator or a freezer or things like that, there is typically not. We don't. You don't have the commissioning phase. You don't have that step. But for an autoclave or something larger like that, you would have that step because I guess because the autoclave is more of a designed element, designed item. There's features, there's programs, there's. You've built it per se. It's not just like a minus 80 freezer you can look through, you can flip through the manual and pick which one you want and then have it delivered. Right. So there's no necessarily. There's no F18 tests going on for something like that.

Subhi Sedate (24:08)

Okay, then on to qualification.

Nathan Roman (24:11)

Right. So qualification is going to be a step where, okay, now you're getting QA to review and approve your documentation. You're testing. So there it's more of a qualified or it's a quality involvement and, and remember this is stuff that. This was in the beginning, in the past with commissioning, qualification, validation and qualification. You would repeat a lot of the same testing that was done previously on the engineering version of commissioning. So it was a rep. A repeat of functions, repeat, repeat of tests, re verification, The P&ID and all sorts of stuff. And then after the qualification asp, the IQ oq PQ is done, then you would move on to the validation, the process validation side of things. Right. Which that can. It can go on for a long period of time, like you had mentioned earlier. But today standard of CQV is the. They've combined the. The commissioning and the qualification aspect of things together to alleviate all that redundant testing. Right. And quality is a player from the beginning, not, not separated. The C and Q is handled nowadays. If, if you probably looked around at a lot of different companies, C and Q is, is. Is handled within the engine departments, the facilities teams like they're responsible for the C and Q whereas the quality or the. The validation departments with within a site handle the valid, the V, the validation side of things.

Subhi Sedate (25:51)

So in, in your experience, validation feeds in through the quality. Org.

Nathan Roman (25:55)

Yes.

Subhi Sedate (25:57)

And interesting. I think that's maybe something that's a little bit different between Medtech and Biotech. My experience in Medtech is even though validation is approved and overseen by quality in a way that's quite heavy, the actions taken are. Have typically been in operations. But when I moved into pharma I started seeing a lot more validation departments as part of quality.

Nathan Roman (26:23)

Right?

Subhi Sedate (26:23)

Yes. So I wanted to ask about the different temperature ranges and the challenges associated. So you mentioned a minus 80 for ultra cold drugs. The typical ranges are like minus 20 to minus 80, I believe 2 to 80 and then ambient. There's no warm drugs Are there?

Nathan Roman (26:44)

No. Yeah, you have your, your two to eight chambers, your refrigerators, your, your deli boxes if you will, two to eights, which is a five degree set point or something like that. And then you have your, your minus twenties, your minus eighties like you said. You have your cryo storage which is it can be a tank that has LN2 supplied to the tank to, to maintain that, that cryo storage lots of times. Ln2 liquid nitrogen. Ln2, sorry. And so the Ln2 can either be surface level in the tank at the bottom. And what happens is you can store your samples inside of this vessel and they're not submerged in LN2 but they are kept in the vapor phase of LN2. So your, your temperatures are minus 1 40, minus 1 30.

Subhi Sedate (27:42)

Is it all the same or are there unique challenges that come with as you get colder or as you get warmer?

Nathan Roman (27:50)

So definitely it's not all the same. There are unique challenges to, to the different temperatures. Things that you need to be careful of. Obviously with cold or hot you need to protect, be safe. Right? Protection. Especially with Ellen or steam. The use of your equipment doesn't react the same with the cold, super cold or hot. So you can't just. I can't be temperature mapping a LN2 unit, pull my probes and then go do a incubator. You know what I mean? You need to be cognizant of the, the temperatures that you're utilizing your equipment in and what they can actually be used for. Because not all equipment can be used for these extreme temperatures versus the mid range temperatures that we just mentioned.

Subhi Sedate (28:40)

What about shipping ranges? I I know that it for, for temp control drugs, data loggers are included in, in the shipping containers. Whether it's on on a controlled truck or in the boxes I think I've seen before, but can you talk about that?

Nathan Roman (29:04)

So data loggers that are put into shipping containers or or shipping cartons, shipping packages. So there's shipping validation that that exists and that's to, to verify the, the criteria for your product that your shipping is, is maintained and and doesn't degrade over time. And the shipping studies that are used, they have data loggers that are transmitting the data or recording the data that when you, when the package is received at its location, you can download download that data and verify your you've been within spec during your run. And then there's those real time monitors that are providing that feedback to, to a cloud server so that you can monitor that study during the actual shipment. They Are temperature ranges can vary from like a 2 to 8. It can be a minus 20, it could be a minus 80 requirement to, to maintain that shipment, they'll pack that thing in dry ice. They'll pack the box up with ice packs. And, and so that's the whole purpose of the shipping validation is to verify, make sure that what you, how you're packaging your products or your equipment can actually maintain that temperature requirement.

Subhi Sedate (30:21)

Are the data loggers the same?

Nathan Roman (30:24)

Are the data loggers the same?

Subhi Sedate (30:25)

Like for the ones that are included as part of, let's say, commercial distribution, are they disposable or are they expected to be sent back?

Nathan Roman (30:35)

So it really depends. So the answer is yes. But to, to all that, it really depends on what you purchase, right? You can purchase a single use sensor that really the only function it is to you purchase it. It's calibrated, it's set up for your study, it's set up with alarms high and lows so that it can create that feedback for you and you hit start and you ship and then when it's done, it's, it's it. So that's a lower price type of a sensor. And, and I guess it boils down to pricing, right? And how many shipments are you going to be using? There's multiple use sensors where you can use them multiple times throughout the life of the sensor. And then there's the, the sensors that are, they don't have a, a life cycle if you like, a life expectancy, if you will, as long as you're maintaining calibration yearly and you're keeping the equipment up in good standards with maintenance and whatnot. But yeah, absolutely, you. There's different sensors, but can they be used in a refrigerator or a warehouse or a shipping container? I can use the same, I can use the same data loggers for those items. The accuracy and things like that is, is what matters for us when we use these data loggers.

Subhi Sedate (31:54)

So Nate, where can people find you?

Nathan Roman (31:57)

People can find me online LinkedIn I @ Nathan Roman on LinkedIn I posting like you mentioned earlier in the podcast, 7:30 every morning. Maybe you didn't actually say that we talked before, sir, but yes, people can find me online LinkedIn. I'm posting 7:30. It's an automatic posting, so I'm not necessarily typing it out every morning but, but I'm there looking to see if I need to provide any comments, feedback, engagement to folks. But people can definitely find me there. You can find me at ISPE events, you can find me at our typical industry networking events.

Subhi Sedate (32:36)

Yep. Thank you for coming on. This was fun.

Nathan Roman (32:39)

Yeah, I appreciate it. Let's. Let's talk again soon. Yep.