WEBVTT 00:00:00.000 --> 00:00:03.240 Okay, let's get started. You know that amazing 00:00:03.240 --> 00:00:06.139 feeling that spark when a potential new drug 00:00:06.139 --> 00:00:08.640 looks really promising in the lab? Oh yeah, that 00:00:08.640 --> 00:00:12.160 aha moment. Exactly. But that's really just the 00:00:12.160 --> 00:00:14.199 starting line, isn't it? The big challenge comes 00:00:14.199 --> 00:00:17.480 next. And making sure you can actually make it 00:00:17.480 --> 00:00:20.239 reliably, consistently, you know, batch after 00:00:20.239 --> 00:00:22.899 batch when you scale things up. It's a whole 00:00:22.899 --> 00:00:26.739 different ball game. It really is. And how we 00:00:26.739 --> 00:00:30.510 manage that jump from like a tiny lab flask to 00:00:30.510 --> 00:00:32.549 producing medicine for potentially millions of 00:00:32.549 --> 00:00:34.530 people. Well, that's where things get interesting. 00:00:34.890 --> 00:00:37.229 And that's what we're digging into today. The 00:00:37.229 --> 00:00:39.250 analytical tools. The unsung heroes, you could 00:00:39.250 --> 00:00:41.689 say. Definitely. They're like the the vigilant 00:00:41.689 --> 00:00:44.549 eyes watching the whole process, making sure 00:00:44.549 --> 00:00:46.490 the chemistry does what it's supposed to and 00:00:46.490 --> 00:00:48.469 that every single pill or vial has the right 00:00:48.469 --> 00:00:50.710 stuff in it. Right. So for our listeners, think 00:00:50.710 --> 00:00:52.890 of this as your kind of shortcut to understanding 00:00:52.890 --> 00:00:55.939 a really key part of drug manufacturing. We're 00:00:55.939 --> 00:00:57.960 not going to drown in super technical jargon, 00:00:58.020 --> 00:00:59.899 but we want to shed light on how these tools 00:00:59.899 --> 00:01:02.520 give us the essential insights we need during 00:01:02.520 --> 00:01:05.420 that whole process development stage. And we'll 00:01:05.420 --> 00:01:08.620 be drawing on scientific literature, papers from 00:01:08.620 --> 00:01:12.040 drug discovery development, including those practical 00:01:12.040 --> 00:01:14.359 case studies you often find in journals like 00:01:14.359 --> 00:01:17.140 OPRND, Organic Process Research and Development. 00:01:17.450 --> 00:01:20.030 So our mission for this deep dive is pretty clear 00:01:20.030 --> 00:01:22.450 then. Yeah, I think so We want to unpack how 00:01:22.450 --> 00:01:25.629 these core analytical methods the key techniques 00:01:25.629 --> 00:01:28.829 are actually used day in day out to monitor what's 00:01:28.829 --> 00:01:32.049 happening and Importantly to troubleshoot when 00:01:32.049 --> 00:01:34.310 things don't go quite right in developing these 00:01:34.310 --> 00:01:36.890 pharmaceutical processes It's all about making 00:01:36.890 --> 00:01:40.390 sure that initial aha Reliably becomes a safe 00:01:40.390 --> 00:01:43.709 and effective medicine. Okay, so why all this 00:01:43.709 --> 00:01:46.530 focus on monitoring? on consistency. I mean, 00:01:46.549 --> 00:01:48.930 it seems kind of obvious for medicine, but let's 00:01:48.930 --> 00:01:51.030 explore the why a bit more. Well, at its core, 00:01:51.290 --> 00:01:53.049 consistent quality isn't just like a nice to 00:01:53.049 --> 00:01:55.250 have in pharma. It's absolutely fundamental. 00:01:55.530 --> 00:01:57.890 Patient safety depends on it. Right. And there 00:01:57.890 --> 00:02:00.829 are strict regulations for very good reason demanding 00:02:00.829 --> 00:02:03.129 it. Every single batch has to meet incredibly 00:02:03.129 --> 00:02:06.230 tight specifications. It's non -negotiable. Yeah, 00:02:06.269 --> 00:02:08.509 you can't have one batch strong in the next one 00:02:08.509 --> 00:02:12.289 week or with some impurity. Thinking back to 00:02:12.289 --> 00:02:14.870 one of our earlier deep dives, way back we talked 00:02:14.870 --> 00:02:17.050 about scale up, right? Going from the lab bench 00:02:17.050 --> 00:02:20.629 to giant industrial reactors. Exactly. And that's 00:02:20.629 --> 00:02:22.969 where things get tricky. The actual physics can 00:02:22.969 --> 00:02:25.969 change, how things mix, how heat gets transferred. 00:02:26.770 --> 00:02:29.330 It's not the same in a 10 ,000 liter tank as 00:02:29.330 --> 00:02:31.189 it is in a one liter flask. So you need a way 00:02:31.189 --> 00:02:33.909 to actually see what's going on inside that big 00:02:33.909 --> 00:02:35.930 tank to make sure the reaction is still behaving 00:02:35.930 --> 00:02:38.789 as expected despite those changes? Precisely. 00:02:38.930 --> 00:02:40.979 And how do we get that visibility? How do we 00:02:40.979 --> 00:02:43.719 know reliably that the process is under control? 00:02:44.060 --> 00:02:45.759 Well, that's where the data from analytical tools 00:02:45.759 --> 00:02:47.580 comes in. They give us the hard evidence, the 00:02:47.580 --> 00:02:50.000 numbers, to understand and manage that complexity. 00:02:50.300 --> 00:02:52.180 OK. Makes sense. So let's meet some of these 00:02:52.180 --> 00:02:55.580 analytical workhorses. First one, HPLC. High 00:02:55.580 --> 00:02:57.680 Performance Liquid Chromatography. Sounds pretty 00:02:57.680 --> 00:03:01.159 complex. What's the basic idea? Essentially, 00:03:02.099 --> 00:03:05.280 HPLC is a technique for separating out all the 00:03:05.280 --> 00:03:07.930 different components in a liquid mixture. It 00:03:07.930 --> 00:03:09.770 works based on their chemical properties, how 00:03:09.770 --> 00:03:12.550 they interact with the materials inside the HPLC 00:03:12.550 --> 00:03:15.370 column. Think of it as a very, very sophisticated 00:03:15.370 --> 00:03:18.229 filter, sorting molecules. Okay, like molecular 00:03:18.229 --> 00:03:20.729 sorting. So how does separating molecules help 00:03:20.729 --> 00:03:23.330 us watch a reaction happen? What does it actually 00:03:23.330 --> 00:03:27.110 tell us? Well, what you do is take tiny samples 00:03:27.110 --> 00:03:28.990 from your reaction mixture at different times, 00:03:29.229 --> 00:03:31.250 say every hour. or even more frequently. You 00:03:31.250 --> 00:03:34.150 run these samples through the HPLC and the output 00:03:34.150 --> 00:03:36.469 basically shows you what's in that sample and 00:03:36.469 --> 00:03:38.750 how much of each thing there is. So you can see 00:03:38.750 --> 00:03:40.710 the starting materials decreasing over time. 00:03:40.770 --> 00:03:43.750 As they get used up. Right. You can see any intermediate 00:03:43.750 --> 00:03:46.870 molecules formed along the way appear and then 00:03:46.870 --> 00:03:49.169 maybe disappear as they turn into the final product. 00:03:49.750 --> 00:03:52.330 And crucially, you see the final product increasing. 00:03:52.569 --> 00:03:54.669 So it's like a running tally of all the key players 00:03:54.669 --> 00:03:57.169 in the reaction. Exactly. You get a quantitative 00:03:57.169 --> 00:03:59.750 picture of the reaction's progress. And this 00:03:59.750 --> 00:04:02.129 directly feeds into ensuring that uniformity 00:04:02.129 --> 00:04:04.990 in the finished batch from batch to batch that 00:04:04.990 --> 00:04:07.409 regulators like in the U .S. CFR Title 21 are 00:04:07.409 --> 00:04:09.770 so focused on, you're proving the reaction is 00:04:09.770 --> 00:04:11.909 consistent. Okay. That's clear for tracking the 00:04:11.909 --> 00:04:14.129 reaction itself. What about making sure the final 00:04:14.129 --> 00:04:17.649 drug is pure? No unwanted extras in there. Yeah. 00:04:17.689 --> 00:04:19.949 HPLC is absolutely critical for purity testing, 00:04:20.230 --> 00:04:22.449 too. Because it separates everything based on 00:04:22.449 --> 00:04:24.829 chemistry, it's brilliant at spotting impurities. 00:04:24.910 --> 00:04:27.589 Things like leftover starting materials, byproducts 00:04:27.589 --> 00:04:31.149 from side reactions, or even degradation products, 00:04:31.370 --> 00:04:34.170 if the molecule isn't stable. So tiny amounts 00:04:34.170 --> 00:04:35.689 of things that shouldn't be there will show up 00:04:35.689 --> 00:04:38.470 as separate signals? Precisely. They appear as 00:04:38.470 --> 00:04:40.889 distinct peaks on the output, the chromatogram. 00:04:41.129 --> 00:04:43.810 And we can quantify them, measure exactly how 00:04:43.810 --> 00:04:46.990 much of that impurity is present. Method specificity, 00:04:47.269 --> 00:04:48.829 making sure the method only measures what it's 00:04:48.829 --> 00:04:51.089 supposed to and can distinguish the drug from 00:04:51.089 --> 00:04:53.730 potential impurities, is a huge focus in regulatory 00:04:53.730 --> 00:04:56.230 guidelines. And I guess that specificity is even 00:04:56.230 --> 00:04:59.649 more critical when you have things like... Like 00:04:59.649 --> 00:05:02.389 chiral molecules those mirror image one. Oh absolutely 00:05:02.389 --> 00:05:05.389 vital Chiral molecules or enantiomers can have 00:05:05.389 --> 00:05:07.930 identical chemical formulas But completely different 00:05:07.930 --> 00:05:10.250 3d shapes like your left and right hands and 00:05:10.250 --> 00:05:13.290 often only one hand has the desired medical effect, 00:05:13.290 --> 00:05:15.769 right? The other might be inactive or even harmful 00:05:15.769 --> 00:05:19.660 exactly So your HPLC method must be able to separate 00:05:19.660 --> 00:05:22.519 those two mirror images and also separate them 00:05:22.519 --> 00:05:25.019 from any other impurities that might be structurally 00:05:25.019 --> 00:05:27.100 similar. It needs to be highly selective. It's 00:05:27.100 --> 00:05:30.019 a real analytical challenge sometimes, but essential. 00:05:30.519 --> 00:05:34.620 OK. HPLC separates and quantifies. Got it. Let's 00:05:34.620 --> 00:05:38.180 shift gears to another major category, spectroscopy. 00:05:38.319 --> 00:05:40.439 That's a pretty broad term, right? It is, yeah. 00:05:40.660 --> 00:05:42.560 It covers techniques that look at how matter 00:05:42.560 --> 00:05:44.759 interacts with electromagnetic radiation light, 00:05:44.879 --> 00:05:46.899 essentially, across different wavelengths. A 00:05:46.899 --> 00:05:49.199 really key example in process development is 00:05:49.199 --> 00:05:52.319 infrared spectroscopy, or IR. Infrared, like 00:05:52.319 --> 00:05:55.839 heat radiation. Sort of, yeah. In IR spectroscopy, 00:05:55.899 --> 00:05:59.240 we shine infrared light through a sample. Molecules 00:05:59.240 --> 00:06:01.839 absorb specific frequencies of this IR light, 00:06:02.199 --> 00:06:04.439 causing their chemical bonds to vibrate, stretch, 00:06:04.939 --> 00:06:08.319 bend, wiggle. Wiggle, OK. Yeah, well... vibrate. 00:06:08.699 --> 00:06:11.399 And the pattern of which frequencies are absorbed 00:06:11.399 --> 00:06:13.800 is unique to that molecule. It's like a molecular 00:06:13.800 --> 00:06:17.980 fingerprint. Ah, okay. So unlike HPLC separating 00:06:17.980 --> 00:06:21.300 things out, IR identifies a molecule by its unique 00:06:21.300 --> 00:06:23.959 vibrational signature when hit with infrared 00:06:23.959 --> 00:06:26.220 light. That's a great way to put it. Different 00:06:26.220 --> 00:06:29.220 types of bonds like carbon -oxygen bonds or nitrogen 00:06:29.220 --> 00:06:32.279 -hydrogen bonds vibrate at characteristic frequencies. 00:06:32.839 --> 00:06:35.620 So by looking at the IR spectrum, the plot of 00:06:35.620 --> 00:06:37.920 absorbance versus frequency, we can tell what 00:06:37.920 --> 00:06:40.660 kinds of bonds or functional groups are present 00:06:40.660 --> 00:06:42.420 in the molecule. So you can use it to confirm 00:06:42.420 --> 00:06:44.120 you've actually made the thing you intended to 00:06:44.120 --> 00:06:46.819 make. Yes, absolutely. You can confirm the formation 00:06:46.819 --> 00:06:49.459 of the desired product by seeing its characteristic 00:06:49.459 --> 00:06:52.139 peaks appear. You can also monitor the disappearance 00:06:52.139 --> 00:06:54.420 of starting material peaks. And importantly, 00:06:54.620 --> 00:06:57.040 you can sometimes spot unexpected changes that 00:06:57.040 --> 00:06:59.500 might signal a problem, like the formation of 00:06:59.500 --> 00:07:02.600 an unwanted structure. And this fingerprint idea... 00:07:02.720 --> 00:07:05.899 How does that get used routinely? Well, because 00:07:05.899 --> 00:07:08.279 the IR spectrum is so characteristic, it's a 00:07:08.279 --> 00:07:11.420 fantastic tool for identity confirmation. You 00:07:11.420 --> 00:07:13.800 use it to check incoming raw materials. Is this 00:07:13.800 --> 00:07:15.980 really what the label says it is? You compare 00:07:15.980 --> 00:07:19.480 its spectrum to a known standard. Same for intermediates 00:07:19.480 --> 00:07:22.319 and the final drug. It's a quick and powerful 00:07:22.319 --> 00:07:26.199 check. OK. Now I've also heard about X -ray diffraction, 00:07:26.439 --> 00:07:29.160 XRD being important, especially for solid drugs 00:07:29.160 --> 00:07:31.639 like in tablets. How does that fit in? Is it 00:07:31.639 --> 00:07:34.079 related to spectroscopy? It's another way of 00:07:34.079 --> 00:07:36.519 probing material structure, but using X -rays 00:07:36.519 --> 00:07:39.379 instead of IR light. And it's specifically for 00:07:39.379 --> 00:07:42.500 crystalline solids. It's less about the individual 00:07:42.500 --> 00:07:45.420 bonds within a molecule and more about how the 00:07:45.420 --> 00:07:47.379 molecules pack together in a crystal lattice. 00:07:47.399 --> 00:07:50.060 Ah, the crystal structure. Why is that so important? 00:07:50.160 --> 00:07:52.439 Because many drug substances can crystallize 00:07:52.439 --> 00:07:54.439 in different forms. This is called polymorphous. 00:07:54.319 --> 00:07:57.060 Think of it like carbon forming, both graphite 00:07:57.060 --> 00:07:59.319 and diamond. Same element, different crystal 00:07:59.319 --> 00:08:01.620 structure, very different property. For drugs, 00:08:02.199 --> 00:08:04.379 different polymorphs can have different solubilities, 00:08:04.579 --> 00:08:06.620 different stabilities. They might dissolve at 00:08:06.620 --> 00:08:08.939 different rates in the body, or even process 00:08:08.939 --> 00:08:11.339 differently during manufacturing, like when making 00:08:11.339 --> 00:08:14.019 cablots. So if you don't control which crystal 00:08:14.019 --> 00:08:16.579 form you're making, you could end up with a drug 00:08:16.579 --> 00:08:20.040 that doesn't perform consistently. Exactly. One 00:08:20.040 --> 00:08:22.199 batch might dissolve quickly, another slowly, 00:08:22.740 --> 00:08:24.079 leading to different effects in the patient. 00:08:24.959 --> 00:08:27.519 So XRD is used to confirm that you are consistently 00:08:27.519 --> 00:08:30.259 producing the correct polymorph, the one with 00:08:30.259 --> 00:08:32.120 the desired properties that was used in clinical 00:08:32.120 --> 00:08:34.879 trials. It's another critical layer of control, 00:08:35.340 --> 00:08:36.919 especially highlighted when you're transferring 00:08:36.919 --> 00:08:40.059 technology or ensuring consistency after processes 00:08:40.059 --> 00:08:42.500 like milling, which can sometimes induce changes 00:08:42.500 --> 00:08:46.360 in crystal form. Okay, so we have HPLC separating 00:08:46.360 --> 00:08:49.240 and quantifying, IR giving a molecular fingerprint, 00:08:49.639 --> 00:08:52.460 and XRD checking the crystal structure. These 00:08:52.460 --> 00:08:54.279 all sound great for monitoring when things are 00:08:54.279 --> 00:08:56.259 running smoothly. But what about when they're 00:08:56.259 --> 00:08:59.559 not? How do these tools turn into, well, detectives? 00:08:59.860 --> 00:09:01.539 That's often where they really earn their keep, 00:09:01.759 --> 00:09:04.220 honestly. When a process goes sideways, maybe 00:09:04.220 --> 00:09:06.679 the yield drops or an impurity pops up or the 00:09:06.679 --> 00:09:10.799 reaction just stalls, these techniques are indispensable 00:09:10.799 --> 00:09:13.179 for figuring out why. Okay, let's take an example. 00:09:13.740 --> 00:09:16.539 Say your reaction yield is suddenly much lower 00:09:16.539 --> 00:09:20.899 than usual. How would you use, say, HPLC to investigate? 00:09:21.000 --> 00:09:23.519 Right. So you take a sample of that final reaction 00:09:23.519 --> 00:09:27.200 mixture and run a detailed HPLC analysis. What 00:09:27.200 --> 00:09:30.059 are you looking for? Well, maybe you see a huge 00:09:30.059 --> 00:09:32.100 peak for your starting material still remaining. 00:09:32.419 --> 00:09:34.820 Meaning the reaction just didn't finish? Exactly. 00:09:35.000 --> 00:09:37.960 Or perhaps you see very little starting material, 00:09:38.200 --> 00:09:40.860 but also less product than expected, and a bunch 00:09:40.860 --> 00:09:44.100 of new unexpected peaks. Suggesting side reactions 00:09:44.100 --> 00:09:46.399 chewed up your material. Precisely. Unwanted 00:09:46.399 --> 00:09:48.960 byproducts. Or maybe you see a large peak for 00:09:48.960 --> 00:09:51.139 an intermediate compound that's supposed to react 00:09:51.139 --> 00:09:53.759 further but hasn't. That points to a bottleneck 00:09:53.759 --> 00:09:57.000 later in the reaction sequence. The HPLC quantifies 00:09:57.000 --> 00:09:58.539 all these things, so you're not just guessing, 00:09:58.840 --> 00:10:00.720 you're seeing the molecular evidence of what 00:10:00.720 --> 00:10:03.460 went wrong. It really is like molecular accounting, 00:10:03.639 --> 00:10:05.470 tracing where everything went. What about the 00:10:05.470 --> 00:10:08.330 other scenario? A finished batch fails its purity 00:10:08.330 --> 00:10:11.690 test and unexpited impurity shows up. Yeah, similar 00:10:11.690 --> 00:10:14.149 approach. HPLC is usually the first line of attack. 00:10:14.509 --> 00:10:16.450 That unexpected peak tells you something extra 00:10:16.450 --> 00:10:19.110 is there. The next step is often to identify 00:10:19.110 --> 00:10:21.970 it. Sometimes you can couple the HPLC directly 00:10:21.970 --> 00:10:25.870 to a mass spectrometer, HPLC -MS. Ah, which gives 00:10:25.870 --> 00:10:27.769 you the mass of the molecule. Exactly, which 00:10:27.769 --> 00:10:30.970 is a huge clue to its identity. Or you might 00:10:30.970 --> 00:10:33.690 try to isolate that impurity peak from the HPLC 00:10:33.690 --> 00:10:36.649 and then analyze it using spectroscopy IR, or 00:10:36.649 --> 00:10:40.110 perhaps NMR, nuclear magnetic resonance spectroscopy, 00:10:40.210 --> 00:10:43.009 which gives even more detailed structural information. 00:10:43.669 --> 00:10:45.649 The goal is to figure out the chemical structure 00:10:45.649 --> 00:10:47.950 of that contaminant so you can then trace back 00:10:47.950 --> 00:10:50.009 how it might have formed. It's pretty amazing 00:10:50.009 --> 00:10:52.470 the level of detail you can get. It really highlights 00:10:52.470 --> 00:10:54.830 that making medicines isn't just cookbook chemistry. 00:10:55.389 --> 00:10:57.710 It's incredibly precise science and engineering. 00:10:58.450 --> 00:11:00.470 Absolutely. And all this ties into the broader 00:11:00.470 --> 00:11:03.830 concept of quality by design or QBD in pharma. 00:11:04.289 --> 00:11:06.870 The idea isn't just to test quality at the end, 00:11:07.250 --> 00:11:09.690 but to build it into the process by understanding 00:11:09.690 --> 00:11:12.009 how different factors affect the outcome. And 00:11:12.009 --> 00:11:14.509 these analytical tools provide the data to build 00:11:14.509 --> 00:11:17.309 that understanding. Exactly. They let you monitor 00:11:17.309 --> 00:11:19.590 the critical parameters in real time or near 00:11:19.590 --> 00:11:22.490 real time, understand the process deeply, and 00:11:22.490 --> 00:11:24.970 control it to ensure consistent quality batch 00:11:24.970 --> 00:11:27.779 after batch. It's proactive. not just reactive. 00:11:28.340 --> 00:11:30.259 So let's sort of wrap this part up. We've seen 00:11:30.259 --> 00:11:32.620 how these analytical tools, things like HPLC 00:11:32.620 --> 00:11:35.240 and spectroscopy IR and XRD included, are just 00:11:35.240 --> 00:11:37.700 fundamental. They're the eyes and ears during 00:11:37.700 --> 00:11:39.700 pharmaceutical process development. They watch 00:11:39.700 --> 00:11:41.779 the reactions. They check the quality. They ensure 00:11:41.779 --> 00:11:44.639 consistency. And they play that crucial detective 00:11:44.639 --> 00:11:47.340 role when troubleshooting is needed. They let 00:11:47.340 --> 00:11:49.639 scientists understand what happened at a molecular 00:11:49.639 --> 00:11:52.500 level and figure out how to fix it or prevent 00:11:52.500 --> 00:11:55.679 it from happening again. You see countless examples 00:11:55.679 --> 00:11:58.740 of this detailed analytical work underpinning 00:11:58.740 --> 00:12:01.580 process improvements in journals like OPRND optimizing 00:12:01.580 --> 00:12:04.460 conditions, controlling tricky intermediates, 00:12:04.759 --> 00:12:08.110 solving scale -up impurity issues. That's where 00:12:08.110 --> 00:12:10.350 the practical application really shines. Right. 00:12:10.409 --> 00:12:13.169 So it's this detailed monitoring and troubleshooting 00:12:13.169 --> 00:12:16.649 underpinned by sophisticated analysis that ultimately 00:12:16.649 --> 00:12:18.830 ensures the medicines people rely on are both 00:12:18.830 --> 00:12:22.330 safe and effective every single time. It really 00:12:22.330 --> 00:12:25.710 is the bedrock of quality, which maybe leads 00:12:25.710 --> 00:12:27.970 to a final thought to chew on. Go for it. Well, 00:12:28.009 --> 00:12:29.669 we've talked about these established techniques, 00:12:30.230 --> 00:12:32.009 but analytical technology is always advancing, 00:12:32.190 --> 00:12:34.059 right? Things are getting faster, more sensitive, 00:12:34.120 --> 00:12:36.679 more automated. And now we're seeing things like 00:12:36.679 --> 00:12:39.120 AI and machine learning starting to be applied 00:12:39.120 --> 00:12:41.460 to analyze the massive amounts of data these 00:12:41.460 --> 00:12:44.639 instruments generate. So the question is, how 00:12:44.639 --> 00:12:47.779 might these future analytical capabilities, maybe 00:12:47.779 --> 00:12:50.759 even smarter tools combined with AI, how might 00:12:50.759 --> 00:12:53.279 they further revolutionize our ability to develop 00:12:53.279 --> 00:12:55.740 complex medicines and guarantee their quality 00:12:55.740 --> 00:12:59.279 even more robustly? What new levels of understanding 00:12:59.279 --> 00:13:02.389 and control might become possible? That's a fascinating 00:13:02.389 --> 00:13:05.490 question. Moving beyond just monitoring to maybe 00:13:05.490 --> 00:13:07.789 even predicting and autocorrecting processes 00:13:07.789 --> 00:13:10.309 in real time using that data. Definitely something 00:13:10.309 --> 00:13:11.809 to think about. Yeah, it's an exciting space 00:13:11.809 --> 00:13:12.210 to watch.