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Executive Brief: What FDA is Looking For in Your Tox Data to Ensure Safety · Let's Talk Risk! Podcast

0:00
SPEAKER_01: If you are evaluating a piece of commercial real estate to build
0:04
SPEAKER_01: a massive skyscraper,
0:07
SPEAKER_01: the absolute last thing you want to do is pour the concrete foundation
0:11
SPEAKER_01: without testing the chemical composition of the soil first.
0:14
SPEAKER_00: Right.
0:15
SPEAKER_00: Obviously.
0:16
SPEAKER_01: Because you could have the most brilliant structural engineering on paper,
0:20
SPEAKER_01: but if there's an undocumented acidic compound hidden deep in that soil,
0:23
SPEAKER_01: it's just going to quietly eat away at the concrete over time.
0:26
SPEAKER_00: Yeah, and the entire downstream investment is just structurally compromised before
0:32
SPEAKER_00: the first steel beam even goes up.
0:33
SPEAKER_01: Exactly.
0:35
SPEAKER_01: And you can't salvage a sinking building just by adjusting the top floors.
0:39
SPEAKER_00: No, absolutely not.
0:41
SPEAKER_01: The fundamental data supporting that environment,
0:43
SPEAKER_01: it has to be objective and, well, exhaustive from day one.
0:47
SPEAKER_00: Which brings us to our listeners today.
0:49
SPEAKER_00: Because if you are managing a medical device portfolio,
0:52
SPEAKER_00: or if you're steering a regulatory strategy right now,
0:55
SPEAKER_00: you are essentially building that skyscraper.
0:58
SPEAKER_00: And your soil test, the absolute foundational data set, is chemical characterization.
1:04
SPEAKER_01: That's a really great way to look at it.
1:06
SPEAKER_01: Because if that underlying extraction data is murky, or if, say,
1:10
SPEAKER_01: a contract laboratory cuts a corner,
1:12
SPEAKER_01: your entire biological risk assessment is sitting on very shaky ground.
1:16
SPEAKER_00: Exactly.
1:18
SPEAKER_01: So today,
1:19
SPEAKER_01: we are doing a deep dive into the FDA's recent biocompatibility town hall
1:23
SPEAKER_01: from September 2026.
1:25
SPEAKER_01: The agency really shared a wealth of data
1:27
SPEAKER_01: on how they are evaluating chemical analyses and extraction protocols right now,
1:32
SPEAKER_01: specifically looking at ISO 10993-18.
1:35
SPEAKER_00: And the focus of that data,
1:37
SPEAKER_00: along with the feedback surrounding their recent draft guidance,
1:41
SPEAKER_00: it really highlights a shift in regulatory expectations.
1:44
SPEAKER_01: A pretty significant shift, right?
1:45
SPEAKER_00: Very significant.
1:47
SPEAKER_00: The agency is heavily scrutinizing the actual physical mechanics
1:50
SPEAKER_00: of how sponsors are extracting chemicals from these devices.
1:54
SPEAKER_00: They're looking at solvents,
1:55
SPEAKER_00: they're looking at temperatures,
1:56
SPEAKER_00: and really importantly, how variability is calculated.
2:00
SPEAKER_01: Yeah.
2:01
SPEAKER_00: It's an incredibly technical area,
2:02
SPEAKER_00: but it directly impacts whether a submission moves forward
2:06
SPEAKER_00: or just stalls out completely.
2:08
SPEAKER_01: Which is exactly why we need to translate those technical laboratory mechanics
2:13
SPEAKER_01: into executive strategy today.
2:15
SPEAKER_01: Because frankly,
2:16
SPEAKER_01: understanding how a mass spectrometer reads an extractable profile isn't just trivia
2:20
SPEAKER_01: for chemists.
2:21
SPEAKER_01: I mean, it dictates your speed to market.
2:23
SPEAKER_00: Right.
2:23
SPEAKER_01: It dictates how you govern your testing partners
2:26
SPEAKER_01: and how you build out your ISO 14971 risk management files.
2:30
SPEAKER_00: Yeah, it really does touch everything.
2:32
SPEAKER_01: So let's just establish the baseline here.
2:35
SPEAKER_01: Chemical characterization, or CC, is essentially the gateway to biological safety.
2:40
SPEAKER_01: It feeds directly into the toxicological risk assessment.
2:43
SPEAKER_00: The TRA, exactly.
2:44
SPEAKER_01: Right.
2:45
SPEAKER_01: We are basically trying to figure out what chemicals might leach out of a device and
2:50
SPEAKER_01: into a patient.
2:51
SPEAKER_00: Yeah, that is the core mechanism of the biological risk assessment tree.
2:55
SPEAKER_00: The FDA's expectation is that you identify and quantify every constituent chemical
3:00
SPEAKER_00: that could result in human exposure.
3:02
SPEAKER_01: Every single one.
3:03
SPEAKER_00: Every single one.
3:04
SPEAKER_00: But the mechanical difficulty there is that we aren't just looking at the bill
3:07
SPEAKER_00: of materials, right?
3:08
SPEAKER_00: We're not just looking at intentional additives or surface coatings.
3:12
SPEAKER_01: Right.
3:13
SPEAKER_01: Because things change during production.
3:14
SPEAKER_00: Exactly.
3:15
SPEAKER_00: We have to account for degradation products and manufacturing residuals.
3:20
SPEAKER_00: So that means identifying the trace amounts of cleaning detergents
3:24
SPEAKER_00: the machining lubricants or even the sterilization gases that sort of hitched a ride
3:28
SPEAKER_00: during the manufacturing process.
3:30
SPEAKER_01: And see,
3:31
SPEAKER_01: from a business perspective,
3:32
SPEAKER_01: that requirement can quickly sound like a completely open-ended,
3:35
SPEAKER_01: infinite research project.
3:37
SPEAKER_00: Oh, absolutely.
3:37
SPEAKER_01: I mean, if you have to identify every single molecule that touched a device across
3:42
SPEAKER_01: a global supply chain,
3:43
SPEAKER_01: you're going to burn through capital and development timelines incredibly fast.
3:47
SPEAKER_00: Yeah, you would never finish.
3:48
SPEAKER_01: Right.
3:49
SPEAKER_01: So the regulatory framework has to have a boundary,
3:52
SPEAKER_01: which really brings us to how ISO 1099312 standardizes this risk approach.
3:57
SPEAKER_00: Right.
3:58
SPEAKER_00: And that boundary is established by focusing on the final finished device.
4:02
SPEAKER_00: The standard framework is designed around a really fundamental reality,
4:06
SPEAKER_00: which is that manufacturing changes chemistry.
4:09
SPEAKER_01: It alters it completely.
4:11
SPEAKER_00: Yes.
4:11
SPEAKER_00: So you must account for all materials after they have gone
4:14
SPEAKER_00: through every manufacturing step,
4:16
SPEAKER_00: every sterilization cycle, and every anticipated user manipulation.
4:21
SPEAKER_01: And I really want to break down why that's so critical,
4:23
SPEAKER_01: because I see this as a major friction point for development teams all the time.
4:28
SPEAKER_01: Say a supplier sells you a pristine, medical-grade polymer resin.
4:31
SPEAKER_00: Okay.
4:32
SPEAKER_01: The second you heat that polymer to mold it into,
4:34
SPEAKER_01: like, a catheter, you are altering its physical chemical characteristics.
4:39
SPEAKER_00: Yes, the heat history.
4:40
SPEAKER_01: Exactly, the heat history.
4:42
SPEAKER_01: It might cause the polymer to break down into smaller monomer units
4:45
SPEAKER_01: that could actually leach out.
4:47
SPEAKER_01: If you just test the raw resin in a vacuum,
4:49
SPEAKER_01: you completely miss the actual chemical profile of the device you are putting into
4:53
SPEAKER_01: a patient.
4:54
SPEAKER_00: And that heat history combined with the chemical interactions of sterilization,
4:58
SPEAKER_00: that creates what we call the worst case profile.
5:00
SPEAKER_00: Right.
5:01
SPEAKER_00: The standard expectation is that you must generate
5:03
SPEAKER_00: the maximum potential extractables for your assessment.
5:07
SPEAKER_00: To do that mechanically,
5:08
SPEAKER_00: you have to utilize the device model or configuration that possesses
5:11
SPEAKER_00: the largest surface area of each material.
5:13
SPEAKER_01: Because more surface area exposed to a solvent equals a higher concentration
5:17
SPEAKER_01: of chemicals pulled into the solution.
5:19
SPEAKER_00: Exactly.
5:20
SPEAKER_01: But, okay, here is the strategic bottleneck for executives.
5:24
SPEAKER_01: Manufacturing hundreds of final finished devices with
5:28
SPEAKER_01: the absolute largest surface area purely to destructively test them in
5:32
SPEAKER_01: a lab is incredibly expensive.
5:36
SPEAKER_01: It's a massive drain on resources really early in the development cycle.
5:39
SPEAKER_01: So development teams, you know, they often turn to testing coupons.
5:43
SPEAKER_00: Right.
5:44
SPEAKER_00: Surrogate coupons.
5:45
SPEAKER_01: Yeah, which are essentially just surrogate pieces of the raw material.
5:49
SPEAKER_01: But from everything the FDA is signaling right now,
5:51
SPEAKER_01: relying on a coupon can be a massive regulatory liability
5:55
SPEAKER_01: if it isn't documented perfectly.
5:57
SPEAKER_00: A surrogate coupon is truly only as strong as the gap analysis supporting it.
6:02
SPEAKER_00: If a sponsor decides to use a coupon instead of the final finished device,
6:05
SPEAKER_00: they have to embed a rigorous justification within their risk management file.
6:10
SPEAKER_00: That gap analysis has to prove objectively that the manufacturing differences
6:15
SPEAKER_00: between the final device and
6:16
SPEAKER_00: the flat surrogate coupon won't introduce different chemicals or alter
6:21
SPEAKER_00: the extraction profile.
6:22
SPEAKER_01: You essentially have to prove a negative.
6:24
SPEAKER_00: Basically, yeah.
6:25
SPEAKER_01: You have to demonstrate that the flat coupon went through
6:27
SPEAKER_01: the exact same heat cycling,
6:29
SPEAKER_01: the same physical stresses, and the same sterilization as the complex final device.
6:34
SPEAKER_01: And if that documentation is thin, the FDA is just going to reject the data.
6:38
SPEAKER_00: And we are seeing the results of those thin justifications in real time.
6:42
SPEAKER_01: Yeah, the audit data.
6:43
SPEAKER_00: Exactly.
6:44
SPEAKER_00: At the town hall, the FDA shared data from their fiscal year 2025 pre-market deficiency audits.
6:50
SPEAKER_00: They sampled a set of audited letters to give the industry a really transparent look
6:54
SPEAKER_00: at where submissions are falling short.
6:56
SPEAKER_01: And what were the numbers on that?
6:58
SPEAKER_00: Out of a sampled set,
6:59
SPEAKER_00: 19 audited letters contained 32 specific deficiencies related strictly
7:04
SPEAKER_00: to chemical characterization and toxicological risk assessment.
7:08
SPEAKER_01: Wow.
7:09
SPEAKER_01: I mean, 32 deficiencies across 19 letters.
7:13
SPEAKER_01: That is a dense concentration of focus.
7:16
SPEAKER_01: That's almost two severe chemical characterization deficiencies per letter.
7:20
SPEAKER_00: It is.
7:21
SPEAKER_01: The FDA doesn't just share that kind of data unless they are actively trying
7:24
SPEAKER_01: to signal a systemic industry misunderstanding.
7:27
SPEAKER_01: So let's unpack the specific themes they highlighted there.
7:31
SPEAKER_00: Well, the top deficiencies were inadequate or unclear extraction conditions.
7:35
SPEAKER_01: Meaning what exactly?
7:37
SPEAKER_00: Meaning the lab just didn't use the right solvents or the right temperatures to pull
7:41
SPEAKER_00: the chemicals out in the first place.
7:44
SPEAKER_00: They also flagged incomplete test reports and a really high frequency of unidentified chemicals.
7:51
SPEAKER_00: But perhaps the most complex area of deficiency they noted involved the calculations
7:55
SPEAKER_00: for critical thresholds.
7:57
SPEAKER_00: Specifically,
7:58
SPEAKER_00: the FDA is seeing major issues with how sponsors calculate
8:01
SPEAKER_00: the analytical evaluation threshold.
8:04
SPEAKER_00: Okay,
8:08
SPEAKER_01: let's actually stop and define those thresholds because I think if you're
8:11
SPEAKER_01: an executive reviewing a multi-hundred page testing report from
8:15
SPEAKER_01: a contract research organization,
8:18
SPEAKER_01: a CRO, you really need to know what those terms actually mean in practice.
8:22
SPEAKER_00: That's fair.
8:23
SPEAKER_01: Let's start with the analytical evaluation threshold, the AET.
8:27
SPEAKER_01: As I understand it, the AET is essentially the line in the sand, right?
8:31
SPEAKER_00: Yes.
8:32
SPEAKER_01: It's a calculated concentration limit based on toxicological safety.
8:36
SPEAKER_01: If a chemical extracts at a level below the AET,
8:40
SPEAKER_01: it's considered too low to pose a toxicological risk and we don't have
8:44
SPEAKER_01: to spend months trying to identify it.
8:46
SPEAKER_00: That is the functional application of the AET, exactly.
8:49
SPEAKER_00: It prevents that infinite research project we talked about earlier by establishing a safe floor.
8:53
SPEAKER_01: Right.
8:54
SPEAKER_00: But calculating that floor is highly complex.
8:56
SPEAKER_00: It involves taking the dose-based threshold,
8:59
SPEAKER_00: which is the absolute maximum safe dose of a theoretical chemical for a patient,
9:03
SPEAKER_00: and converting it into an extraction concentration.
9:06
SPEAKER_01: Based on the device itself?
9:07
SPEAKER_00: Yeah, based on the medical device's surface area,
9:09
SPEAKER_00: the volume of the clinical extract,
9:11
SPEAKER_00: and the number of devices a patient might be exposed to simultaneously.
9:15
SPEAKER_01: It's a massive math equation that essentially dictates your entire testing burden.
9:19
SPEAKER_00: It really is.
9:20
SPEAKER_01: But then you also mentioned the limit of quantification, the LOQ, and the uncertainty factor.
9:26
SPEAKER_01: How did those interact with the AET?
9:28
SPEAKER_01: Because if a chemical comes in below the AET, we're supposed to be safe, right?
9:33
SPEAKER_01: But how do we actually know the lab equipment didn't just miss a dangerous chemical
9:37
SPEAKER_01: or misread the amount?
9:39
SPEAKER_00: Well, that is exactly why the uncertainty factor exists.
9:42
SPEAKER_01: Okay.
9:43
SPEAKER_00: Right.
9:43
SPEAKER_00: Right.
9:44
SPEAKER_00: Right.
9:44
SPEAKER_00: Right.
10:12
SPEAKER_01: So you actively lower the AET using the uncertainty factor just to be conservative.
10:17
SPEAKER_00: Exactly.
10:18
SPEAKER_01: And then the limit of quantification,
10:20
SPEAKER_01: the LOQ,
10:20
SPEAKER_01: that's just the absolute lowest concentration the machine can actually measure
10:24
SPEAKER_01: with any kind of accuracy.
10:25
SPEAKER_00: Right.
10:26
SPEAKER_00: The floor of the machine itself.
10:28
SPEAKER_01: So if your calculated AET is lower than your machine's LOQ,
10:32
SPEAKER_01: your machine isn't sensitive enough to prove the device is actually safe.
10:35
SPEAKER_00: Precisely.
10:36
SPEAKER_00: If your safety threshold requires you to detect chemicals at, say,
10:40
SPEAKER_00: one part per billion, but your lab's instrument bottoms out at 10 parts per billion.
10:44
SPEAKER_01: You're flying blind.
10:45
SPEAKER_00: Right.
10:45
SPEAKER_00: Your test is fundamentally inadequate.
10:48
SPEAKER_00: And the FDA is seeing submissions
10:49
SPEAKER_00: where these mathematical relationships are just misaligned or where
10:52
SPEAKER_00: the uncertainty factor wasn't justified by the analytical data at all.
10:56
SPEAKER_01: Another area they flagged in that audit data was the use of surrogate standards.
11:00
SPEAKER_01: I'm going to dive into that for a second because it highlights the reality
11:03
SPEAKER_01: of dealing with unknown chemistry.
11:05
SPEAKER_00: Oh, absolutely.
11:06
SPEAKER_01: When a lab finds a mystery chemical in the extract,
11:08
SPEAKER_01: they have to figure out how much of it is there,
11:11
SPEAKER_01: but they don't have a pure sample of the mystery chemical to calibrate the machine
11:14
SPEAKER_01: against.
11:15
SPEAKER_01: So they have to pick a known chemical,
11:17
SPEAKER_01: a surrogate standard,
11:19
SPEAKER_01: that they hope behaves similarly in the machine,
11:21
SPEAKER_01: and they use that to estimate the concentration of the unknown.
11:24
SPEAKER_00: Yeah, it's a very sophisticated estimation process.
11:27
SPEAKER_00: The deficiency arises when the laboratory selects an inappropriate surrogate standard.
11:32
SPEAKER_01: Like what?
11:33
SPEAKER_00: Well, if you're trying to quantify a complex,
11:36
SPEAKER_00: highly polar degradant,
11:38
SPEAKER_00: but you calibrate your instrument using a simple nonpolar surrogate standard,
11:42
SPEAKER_00: your estimated concentration will be wildly inaccurate.
11:46
SPEAKER_01: Oh, wow.
11:46
SPEAKER_00: Yeah.
11:47
SPEAKER_00: So the FDA is demanding objective justification for exactly why
11:50
SPEAKER_00: a specific surrogate was chosen to represent an unknown chemical.
11:54
SPEAKER_01: You know,
11:54
SPEAKER_01: if we pull all of these deficiencies together,
11:56
SPEAKER_01: the delicate threshold math,
11:58
SPEAKER_01: the surrogate standards,
11:59
SPEAKER_01: the unidentified chemicals,
12:01
SPEAKER_01: to me this sends a massive signal for post-market change control.
12:04
SPEAKER_00: Oh, for sure.
12:06
SPEAKER_01: If the AET is that sensitive, it means our post-market triggers need to be airtight.
12:11
SPEAKER_01: A supply chain manager cannot just swap out a manufacturing lubricant to,
12:14
SPEAKER_01: say, five cents a unit without running it through a biocompatibility lens first.
12:19
SPEAKER_00: Definitely not.
12:20
SPEAKER_01: The chemical profile is deeply tied to the continuity of your manufacturing
12:22
SPEAKER_01: and supply chain processes.
12:23
SPEAKER_01: A single,
12:23
SPEAKER_01: undocumented change on the factory floor can literally invalidate years
12:27
SPEAKER_00: of toxicological safety data.
12:41
SPEAKER_00: Which naturally leads us to how organizations actually execute these extractions in
12:45
SPEAKER_00: the first place.
12:46
SPEAKER_00: Because most device manufacturers do not maintain a fleet of mass spectrometers in-house.
12:51
SPEAKER_01: No, they contract this work out to specialized testing laboratories or CROs.
12:55
SPEAKER_00: Right.
12:56
SPEAKER_01: And this is exactly where QA and RA executives need a really concrete action plan
13:01
SPEAKER_01: for governing those testing partners.
13:03
SPEAKER_01: You can't just sign a statement of work,
13:05
SPEAKER_01: hand over the devices,
13:06
SPEAKER_01: and assume the resulting report is going to meet current FDA expectations.
13:10
SPEAKER_00: You really can't.
13:11
SPEAKER_01: You have to audit their mechanical protocols,
13:13
SPEAKER_01: particularly around the concept of replicates,
13:15
SPEAKER_01: which I know the FDA spent a significant amount of time addressing at the town hall.
13:19
SPEAKER_00: They did.
13:20
SPEAKER_00: The mandate here revolves around differentiating between an analytical replicate and
13:24
SPEAKER_00: an extraction replicate.
13:26
SPEAKER_00: They serve entirely different diagnostic purposes.
13:29
SPEAKER_01: Break that down for us.
13:30
SPEAKER_00: So an analytical replicate assesses the variability of the laboratory instrument itself.
13:35
SPEAKER_00: The lab takes one single device,
13:37
SPEAKER_00: prepares one batch of extract solution,
13:40
SPEAKER_00: and then injects that exact same solution into
13:42
SPEAKER_00: the mass spectrometer three separate times.
13:45
SPEAKER_01: Okay, so that gives you three different data points,
13:47
SPEAKER_01: but it only tells you how consistent the machine is.
13:50
SPEAKER_00: Exactly.
13:51
SPEAKER_01: It tells you absolutely nothing about
13:52
SPEAKER_01: whether your manufacturing line is consistently producing safe devices.
13:56
SPEAKER_00: Which is why the FDA requires extraction replicates to assess device variability.
14:02
SPEAKER_00: To do this, the lab must take three distinct final finished devices.
14:07
SPEAKER_01: Three separate devices.
14:08
SPEAKER_00: Right.
14:09
SPEAKER_00: And they must subject each of those three devices
14:11
SPEAKER_00: to its own separate extraction process in its own separate vessel of solvent.
14:16
SPEAKER_00: This yields three completely independent extract solutions.
14:19
SPEAKER_01: Okay.
14:20
SPEAKER_00: The agency's stated best practice expectation To capture robust data
14:24
SPEAKER_00: while remaining least burdensome is to perform the extraction in triplicate and
14:29
SPEAKER_00: then analyze each of those three extracts individually.
14:32
SPEAKER_01: Individually.
14:34
SPEAKER_01: So three separate devices,
14:36
SPEAKER_01: three separate jars of solvent, three separate uncompromised instrument readings.
14:42
SPEAKER_00: Yes.
14:43
SPEAKER_01: But here is the critical governance issue that we see.
14:47
SPEAKER_01: Labs are often really tempted to pool those extract solutions before running them
14:52
SPEAKER_01: through the instrument.
14:53
SPEAKER_00: Oh, all the time.
14:54
SPEAKER_01: Right.
14:55
SPEAKER_01: They take the liquid from jar 1, jar 2,
14:57
SPEAKER_01: and jar 3,
14:58
SPEAKER_01: they mix it all together into a single master batch,
15:01
SPEAKER_01: and then run that single batch through the machine.
15:04
SPEAKER_01: It saves the lab time, and it saves money on instrument hours.
15:08
SPEAKER_01: But the FDA explicitly warns against this practice.
15:12
SPEAKER_00: Because pooling completely masks the device-to-device variability that
15:16
SPEAKER_00: the toxicological risk assessment relies upon.
15:19
SPEAKER_01: Think of pooling extracts like taking three separate regional sales budgets.
15:22
SPEAKER_01: Let's say North America, Europe, and Asia.
15:24
SPEAKER_00: Okay.
15:25
SPEAKER_01: You average all three budgets together into one global number.
15:28
SPEAKER_01: And then you try to look at that one single number to spot
15:31
SPEAKER_01: a specific localized overspend in Germany.
15:34
SPEAKER_00: You can't do it.
15:35
SPEAKER_01: You can't.
15:35
SPEAKER_01: You have completely erased the variance data.
15:38
SPEAKER_01: If one out of your three medical devices had a massive spike in
15:41
SPEAKER_01: a toxic residual chemical,
15:43
SPEAKER_01: pooling the liquid just dilutes that spike across the clean solvent from
15:47
SPEAKER_01: the other two devices.
15:48
SPEAKER_00: The localized overspend simply disappears into the average.
15:51
SPEAKER_00: And by the time the data reaches the toxicologist,
15:55
SPEAKER_00: they are looking at an artificially lowered concentration.
15:58
SPEAKER_00: They might clear a device that actually possesses a dangerous intermittent manufacturing defect.
16:03
SPEAKER_01: So the executive action plan here is extremely straightforward.
16:07
SPEAKER_01: Your quality agreements and your statements of work with CROs must explicitly forbid
16:12
SPEAKER_01: the pooling of extraction solutions.
16:14
SPEAKER_00: Absolutely.
16:15
SPEAKER_01: You are paying for variance data to protect your submission and your patients.
16:20
SPEAKER_01: Do not let a laboratory wash it away for the sake of convenience.
16:23
SPEAKER_00: And, you know,
16:24
SPEAKER_00: it is worth noting that for highly novel materials or devices
16:28
SPEAKER_00: with complex geometries
16:29
SPEAKER_00: where standard triplicate extraction protocols might not seamlessly apply,
16:34
SPEAKER_00: sponsors have a strategic avenue available.
16:36
SPEAKER_01: The QSOB.
16:37
SPEAKER_00: Yeah.
16:38
SPEAKER_00: Utilizing the pre-submission or Q-sub pathway allows you to engage the FDA early
16:43
SPEAKER_00: to lock in your extraction methodology.
16:45
SPEAKER_00: Taking the time to align on your solvents,
16:47
SPEAKER_00: your temperatures,
16:48
SPEAKER_00: and your replicate strategy before you execute the final testing,
16:52
SPEAKER_00: that is a profound risk mitigation strategy.
16:55
SPEAKER_01: Absolutely.
16:56
SPEAKER_01: Do not wait until the final pre-market review
16:58
SPEAKER_01: to find out your extraction methodology was misaligned with current expectations.
17:02
SPEAKER_01: Right.
17:03
SPEAKER_01: Now, to ground everything we've discussed so far,
17:06
SPEAKER_01: the FDA actually provided two highly specific real-world product exemplars at
17:11
SPEAKER_01: the town hall.
17:12
SPEAKER_01: And I think these examples really illustrate how tailored this extraction process
17:16
SPEAKER_01: has to be to this specific clinical use case.
17:19
SPEAKER_00: They really do.
17:20
SPEAKER_00: The first exemplar they analyzed was a blood collection or infusion tubing device.
17:26
SPEAKER_00: Because a patient might be connected to this tubing for days at a time,
17:30
SPEAKER_00: it falls under the category of prolonged patient contact.
17:33
SPEAKER_01: And I noticed they emphasized this specific geometry.
17:36
SPEAKER_01: Like, if you take a long piece of medical tubing,
17:39
SPEAKER_01: you can't just chop it up into tiny pieces and throw it in a beaker of solving.
17:42
SPEAKER_00: No, definitely not.
17:43
SPEAKER_01: Because if you chop it up,
17:44
SPEAKER_01: you are exposing the interior layers of the polymer,
17:48
SPEAKER_01: layers that the patient's blood or fluid would never actually touch in
17:51
SPEAKER_01: the real world.
17:51
SPEAKER_00: That is a critical distinction.
17:54
SPEAKER_00: Chopping the tubing creates an artificial worst-case scenario.
17:57
SPEAKER_00: It leads to the extraction and identification of chemicals
18:00
SPEAKER_00: that pose absolutely no real-world clinical risk.
18:03
SPEAKER_01: Which just unnecessarily clutters the toxicological risk assessment.
18:06
SPEAKER_00: Exactly.
18:07
SPEAKER_00: Instead, the mechanically appropriate extraction method is to simulate clinical use.
18:12
SPEAKER_00: The lab should fill the internal lumen of the tube with the extraction solvents.
18:16
SPEAKER_00: Typically,
18:16
SPEAKER_00: this involves using both polar solvents like water or saline and nonpolar solvents
18:21
SPEAKER_00: to mimic the exact physiological pathway of the blood or fluid.
18:24
SPEAKER_01: You test the specific surface that actually interacts with the human body.
18:28
SPEAKER_01: That makes sense.
18:28
SPEAKER_01: It keeps the data relevant.
18:30
SPEAKER_01: Now, what was the underlying challenge with the second exemplar?
18:33
SPEAKER_00: The second exemplar involved a much more delicate technology,
18:37
SPEAKER_00: a drug-eluting degradable scaffold.
18:40
SPEAKER_01: Oh, wow.
18:41
SPEAKER_01: Okay.
18:42
SPEAKER_00: This represents a long-term contact device,
18:45
SPEAKER_00: which triggers the requirement for an exhaustive extraction using a full spectrum
18:49
SPEAKER_00: of polar, semi-polar, and non-polar solvents.
18:52
SPEAKER_00: But the critical variable here is not just the solvent,
18:54
SPEAKER_00: it is the temperature of the extraction.
18:57
SPEAKER_01: Right, because these devices are designed to sit in the human body at 37 degrees Celsius.
19:02
SPEAKER_01: But labs usually try to speed up extractions by raising the temperature well above 37 degrees.
19:07
SPEAKER_01: Why is that temperature increase such a massive variable for a degradable scaffold?
19:11
SPEAKER_00: Well, because a degradable scaffold,
19:13
SPEAKER_00: by its very nature, is chemically designed to break down over time.
19:16
SPEAKER_00: Oh, I see.
19:39
SPEAKER_01: So the extraction must be aggressive enough to capture the true worst case profile,
19:44
SPEAKER_01: but carefully controlled so it doesn't artificially destroy
19:47
SPEAKER_01: the material it is trying to characterize.
19:49
SPEAKER_00: Exactly.
19:50
SPEAKER_00: It is a massive balancing act.
19:52
SPEAKER_01: And when you look at the sheer complexity of characterizing an absorbable hydrogel
19:57
SPEAKER_01: or an in-situ polymerizing material,
20:00
SPEAKER_01: the executive takeaway points directly back to upstream supplier management.
20:04
SPEAKER_00: Yes.
20:04
SPEAKER_00: Supply chain transparency becomes the ultimate business advantage here.
20:08
SPEAKER_01: Because if you're utilizing materials
20:10
SPEAKER_01: that already have established device master files,
20:12
SPEAKER_01: or MAFs, you are building on a known foundation.
20:16
SPEAKER_00: Right.
20:16
SPEAKER_00: The supplier has already characterized the material.
20:19
SPEAKER_01: Exactly.
20:20
SPEAKER_01: They have already mapped the extraction profile, and the FDA already has that data on file.
20:24
SPEAKER_01: You drastically lower your biological risk profile.
20:28
SPEAKER_01: Compare that to the business cost of buying a proprietary,
20:31
SPEAKER_01: undocumented polymer blend from a supplier who just refuses
20:35
SPEAKER_01: to share their formulations.
20:37
SPEAKER_00: Yeah, then you have to reverse engineer and characterize their chemistry from scratch.
20:41
SPEAKER_01: And the cost difference is just night and day.
20:43
SPEAKER_00: Which reinforces the necessity of binding quality agreements with your upstream suppliers.
20:48
SPEAKER_00: You must establish mandatory change notifications for any incoming material controls.
20:54
SPEAKER_01: Because if they change something.
20:56
SPEAKER_00: If your supplier quietly changes the resin formulation
20:59
SPEAKER_00: or even switches their own upstream chemical provider without notifying you,
21:03
SPEAKER_00: your entire chemical characterization profile is instantly compromised.
21:07
SPEAKER_01: It always comes back to governance.
21:09
SPEAKER_01: So let's synthesize the core of what we've unpacked today.
21:12
SPEAKER_01: Chemical characterization is not just some administrative checkbox you leave to
21:16
SPEAKER_01: the lab technicians.
21:17
SPEAKER_00: No, absolutely not.
21:18
SPEAKER_01: It is a strategic business driver.
21:21
SPEAKER_01: By integrating worst-case extraction profiling directly
21:24
SPEAKER_01: into your ISO 14971 risk management files and ensuring your gap analyses
21:29
SPEAKER_01: for any surrogate coupons are airtight,
21:32
SPEAKER_01: you build a regulatory architecture that can actually withstand FDA scrutiny.
21:37
SPEAKER_00: Furthermore,
21:38
SPEAKER_00: maintaining strict oversight of your contract research organizations,
21:41
SPEAKER_00: specifically forbidding the pooling of extraction replicates
21:45
SPEAKER_00: and ensuring they are using appropriate surrogate standards,
21:48
SPEAKER_00: That guarantees that
21:49
SPEAKER_00: the data feeding your toxicological risk assessment is both accurate
21:53
SPEAKER_00: and genuinely representative of your manufacturing variants.
21:56
SPEAKER_01: And finally,
21:57
SPEAKER_01: leveraging supplier transparency in master files protects your development timelines
22:02
SPEAKER_01: and your speed to market.
22:03
SPEAKER_00: Exactly.
22:05
SPEAKER_01: The goal of this deep dive was really to give you the strategic executive framing
22:09
SPEAKER_01: and the technical FDA mechanics to look at your internal processes objectively.
22:14
SPEAKER_01: You know what thresholds are being scrutinized in the audit data,
22:17
SPEAKER_01: and you know how to audit a CRO protocol for hidden variables.
22:20
SPEAKER_00: It's all about proactive governance.
22:22
SPEAKER_01: It really is.
22:23
SPEAKER_01: But as we wrap up,
22:25
SPEAKER_01: I want to leave you with a forward-looking thought regarding all
22:27
SPEAKER_01: of these physical beaker and solvent extractions.
22:30
SPEAKER_00: Okay, what's that?
22:31
SPEAKER_01: Well, the methodology is constantly evolving, right?
22:34
SPEAKER_01: We are spending massive amounts of capital physically destroying devices
22:38
SPEAKER_01: in laboratories to see what chemicals leach out.
22:41
SPEAKER_00: True.
22:41
SPEAKER_01: But as we look toward the future,
22:43
SPEAKER_01: what happens when predictive computational modeling
22:46
SPEAKER_01: and artificial intelligence advance to the point
22:48
SPEAKER_01: where they can accurately simulate material degradation in silica?
22:52
SPEAKER_00: Oh, wow.
22:53
SPEAKER_01: If an algorithm can look at the molecular structure of a drug-eluting scaffold,
22:58
SPEAKER_01: factor in the heat history of the manufacturing process,
23:01
SPEAKER_01: and perfectly predict the extractable profile without a single drop
23:05
SPEAKER_01: of solvent ever being used,
23:07
SPEAKER_01: will physical triplicate extractions eventually become a relic of the past?
23:11
SPEAKER_00: The shift from physical chemistry to computational toxicology is certainly on the horizon.
23:16
SPEAKER_00: It's a fascinating prospect.
23:18
SPEAKER_01: It is something every regulatory strategist should be keeping an eye on.
23:22
SPEAKER_01: But until those algorithms are fully validated,
23:25
SPEAKER_01: make sure your physical foundation inspection is flawless.
23:28
SPEAKER_01: Thanks for joining us on this deep dive.