WEBVTT 00:00:00.000 --> 00:00:02.779 ever stop to think, like really think, about 00:00:02.779 --> 00:00:06.459 how a pill or a liquid medicine, whatever you 00:00:06.459 --> 00:00:08.699 or someone you know might take, how it always 00:00:08.699 --> 00:00:12.419 seems to be just the right dose. Not too strong, 00:00:12.460 --> 00:00:15.000 not too weak, and it works the same way every 00:00:15.000 --> 00:00:17.839 single time. But how do we actually know that's 00:00:17.839 --> 00:00:19.780 gonna happen? How do they make sure? So that's 00:00:19.780 --> 00:00:22.739 a great question. Today, we are diving deep into 00:00:22.739 --> 00:00:25.640 a world that, honestly, most folks probably don't 00:00:25.640 --> 00:00:29.920 think too much about, but is so crucial. analytical 00:00:29.920 --> 00:00:32.740 methods in formulation testing. You know, those 00:00:32.740 --> 00:00:35.320 tests and checks that scientists do to make sure 00:00:35.320 --> 00:00:37.759 every single dose of medicine is exactly what 00:00:37.759 --> 00:00:40.060 it should be. Now, looking at all the stuff you 00:00:40.060 --> 00:00:42.359 sent over, especially that transcript, what was 00:00:42.359 --> 00:00:45.219 it called? 99 analytical methods in formulation 00:00:45.219 --> 00:00:47.340 testing. I think it was from season seven, episode 00:00:47.340 --> 00:00:49.560 nine. Yeah, that's the one. It's obvious this 00:00:49.560 --> 00:00:52.369 whole area is like... the bedrock of pharmaceutical 00:00:52.369 --> 00:00:55.170 quality. So our mission in this deep dive is 00:00:55.170 --> 00:00:57.369 to break it all down, you know, make it clear 00:00:57.369 --> 00:00:59.250 how these methods work, but more importantly, 00:00:59.850 --> 00:01:02.049 why they matter so much for the medicines we 00:01:02.049 --> 00:01:04.670 depend on. OK, let's unpack this. Absolutely. 00:01:04.969 --> 00:01:07.569 So. To start with, we've got to understand that 00:01:07.569 --> 00:01:09.609 analytical methods are really the foundation 00:01:09.609 --> 00:01:11.810 for making sure any drug, like whether it's a 00:01:11.810 --> 00:01:14.209 pill, a capsule, an injection, whatever, has 00:01:14.209 --> 00:01:17.109 the right identity, we'd be 100 % sure what that 00:01:17.109 --> 00:01:19.349 substance actually is. Right. And then, of course, 00:01:19.469 --> 00:01:21.810 its strength, or what we call potency, which 00:01:21.810 --> 00:01:23.930 basically means the exact amount of the active 00:01:23.930 --> 00:01:26.420 ingredient in it. And of course, there's the 00:01:26.420 --> 00:01:29.060 whole quality thing. Does it meet all the standards? 00:01:29.260 --> 00:01:33.299 Is it pure? Meaning, does it have any nasty contaminants 00:01:33.299 --> 00:01:35.040 in it? Makes sense. So we'll be looking at some 00:01:35.040 --> 00:01:38.459 of the key techniques that scientists use, both 00:01:38.459 --> 00:01:40.700 when a new drug hits the market for the first 00:01:40.700 --> 00:01:43.099 time and then... you know, how they keep checking 00:01:43.099 --> 00:01:45.659 it over time to make sure it stays stable and 00:01:45.659 --> 00:01:48.040 effective. Okay. And a really important part 00:01:48.040 --> 00:01:49.959 of this whole thing is of course the industry 00:01:49.959 --> 00:01:53.140 standards. Those super strict rules and the expectations 00:01:53.140 --> 00:01:55.200 set by those regulatory bodies like the FDA, 00:01:55.920 --> 00:01:58.060 they're the watchdogs making sure drug companies 00:01:58.060 --> 00:02:00.900 are doing everything right to keep patients safe. 00:02:01.099 --> 00:02:02.760 So basically we're talking about the science 00:02:02.760 --> 00:02:04.700 that makes sure every medicine you pick up from 00:02:04.700 --> 00:02:07.239 the pharmacy is safe and it actually does what 00:02:07.239 --> 00:02:09.659 it's supposed to do. Precisely. And by the end 00:02:09.659 --> 00:02:11.900 of this deep dive, hopefully everyone listening 00:02:11.900 --> 00:02:14.439 will get a much better grasp on, you know, the 00:02:14.439 --> 00:02:17.300 hows and the whys behind drug quality and why 00:02:17.300 --> 00:02:19.520 all these processes are in place to protect us 00:02:19.520 --> 00:02:23.020 as patients. So let's kick things off with the 00:02:23.020 --> 00:02:26.900 big question. Why are these analytical methods 00:02:26.900 --> 00:02:30.500 so essential? It all boils down to quality and 00:02:30.500 --> 00:02:33.860 performance. Okay. Making sure that every single 00:02:33.860 --> 00:02:37.789 batch of a drug that's made Every single one 00:02:37.789 --> 00:02:41.330 consistently meets the exact specifications. 00:02:41.889 --> 00:02:44.669 It's not enough to just be kind of close. Each 00:02:44.669 --> 00:02:47.310 unit, every tablet, every milliliter has to be 00:02:47.310 --> 00:02:49.909 right on the money. So it's about total consistency. 00:02:50.110 --> 00:02:52.289 Like no matter when you buy that medicine, whether 00:02:52.289 --> 00:02:55.310 it's today or year for now, that first pill is 00:02:55.310 --> 00:02:57.310 going to be identical to the last one. Exactly. 00:02:57.349 --> 00:02:59.409 And there are several pieces to this. First, 00:02:59.550 --> 00:03:02.189 there's verifying the amount of the active ingredient, 00:03:02.349 --> 00:03:03.849 you know, the stuff that actually makes the medicine 00:03:03.849 --> 00:03:07.270 work. Like if a bottle says 500 milligrams, you 00:03:07.270 --> 00:03:09.550 better believe scientists are making sure there's 00:03:09.550 --> 00:03:12.990 exactly 500 milligrams in there, plus or minus 00:03:12.990 --> 00:03:16.550 a tiny, tiny bit. Got it. Then there's the checking 00:03:16.550 --> 00:03:18.990 for. You know, anything that shouldn't be there. 00:03:19.250 --> 00:03:21.270 Things that might form as the drug gets older, 00:03:21.629 --> 00:03:23.949 or maybe got in there accidentally during manufacturing. 00:03:24.330 --> 00:03:26.490 We call those degradation products and impurities. 00:03:27.009 --> 00:03:29.469 Ah, so like making sure there's nothing harmful 00:03:29.469 --> 00:03:31.150 lurking in there, right? Right, or if something 00:03:31.150 --> 00:03:34.849 is there that it's below a safe level. And the 00:03:34.849 --> 00:03:36.949 third part is making sure the physical stuff 00:03:36.949 --> 00:03:39.909 is right too. So like, if it's a cream, does 00:03:39.909 --> 00:03:42.509 it spread easily? If it's a pill, is it hard 00:03:42.509 --> 00:03:44.129 enough to swallow, but will it also dissolve 00:03:44.129 --> 00:03:46.490 properly in your body? That's called dissolution 00:03:46.490 --> 00:03:48.639 testing. Interesting. So it's not just about 00:03:48.639 --> 00:03:50.919 the chemicals themselves, but how the medicine 00:03:50.919 --> 00:03:53.460 is actually put together, you know, its form 00:03:53.460 --> 00:03:55.939 and how that might affect how it works in the 00:03:55.939 --> 00:03:59.159 body. Yeah, absolutely. All this testing is basically 00:03:59.469 --> 00:04:02.550 to guarantee that a drug will do its job properly 00:04:02.550 --> 00:04:04.789 throughout its whole shelf life. Because if it 00:04:04.789 --> 00:04:06.449 breaks down too quickly or it doesn't dissolve 00:04:06.449 --> 00:04:08.330 properly, it's not going to work as well. Makes 00:04:08.330 --> 00:04:11.030 perfect sense. So when does all this testing 00:04:11.030 --> 00:04:13.990 actually happen? I'm guessing it's not just one 00:04:13.990 --> 00:04:16.129 big test at the end. No, you're right. It's a 00:04:16.129 --> 00:04:19.310 multi -stage process. One critical stage is what 00:04:19.310 --> 00:04:22.189 we call product release testing. So these are 00:04:22.189 --> 00:04:24.629 the tests that are done on every single batch 00:04:24.629 --> 00:04:28.279 of a drug before it can leave the factory. end 00:04:28.279 --> 00:04:31.259 up on the pharmacy shelves. Think of it as the 00:04:31.259 --> 00:04:34.319 final quality control check, like the last hurdle 00:04:34.319 --> 00:04:36.439 before it gets to the patients. The gatekeeper. 00:04:37.000 --> 00:04:40.060 Exactly. So this is where they confirm that the 00:04:40.060 --> 00:04:42.399 product meets all those standards we talked about, 00:04:42.899 --> 00:04:46.079 identity, strength, quality, and purity. And 00:04:46.079 --> 00:04:48.500 what kind of tools these scientists use for these 00:04:48.500 --> 00:04:50.199 tests? I know the transcript we have for this 00:04:50.199 --> 00:04:52.220 episode doesn't go into a ton of detail about 00:04:52.220 --> 00:04:54.180 the specifics, but I've seen some of the other 00:04:54.180 --> 00:04:56.220 materials you shared, and it seems like they've 00:04:56.220 --> 00:04:58.959 got a pretty amazing arsenal of techniques. Oh, 00:04:59.040 --> 00:05:01.439 absolutely. You're right. The transcript might 00:05:01.439 --> 00:05:03.860 not list every single method, but there are some 00:05:03.860 --> 00:05:06.060 key ones that are used all the time in pharmaceutical 00:05:06.060 --> 00:05:08.430 analysis. OK. Chromatography, for example, is 00:05:08.430 --> 00:05:10.970 a big one. Chromatography. Yeah, especially techniques 00:05:10.970 --> 00:05:13.910 like HPLC, which stands for High Performance 00:05:13.910 --> 00:05:17.850 Liquid Chromatography, and GC, which is gas chromatography. 00:05:18.490 --> 00:05:21.769 Basically, these methods separate out all the 00:05:21.769 --> 00:05:23.550 different molecules in a sample. Like, think 00:05:23.550 --> 00:05:26.009 of it as sorting them by size or some other property. 00:05:26.029 --> 00:05:28.350 Yeah. And that lets us identify and measure them. 00:05:28.410 --> 00:05:32.009 Wow. HPLC is particularly amazing because it 00:05:32.009 --> 00:05:34.930 can separate really complex mixtures, like think 00:05:34.930 --> 00:05:37.430 about all this stuff in a pill. It has incredible 00:05:37.430 --> 00:05:40.389 resolution, which means we can spot even tiny, 00:05:40.449 --> 00:05:43.709 tiny amounts of impurities. Wow. GC is especially 00:05:43.709 --> 00:05:46.110 helpful for those volatile compounds, the ones 00:05:46.110 --> 00:05:48.850 that easily turn into a gas. Huh, interesting. 00:05:49.129 --> 00:05:50.829 And then there's spectroscopy. Spectroscopy? 00:05:51.089 --> 00:05:56.120 Yeah, like UV vis spectroscopy. infrared spectroscopy 00:05:56.120 --> 00:06:00.019 or IR for short NMR which stands for nuclear 00:06:00.019 --> 00:06:02.779 magnetic resonance and that one gives us all 00:06:02.779 --> 00:06:05.480 kinds of information about the structure of the 00:06:05.480 --> 00:06:08.300 molecule. And then there's mass spectrometry, 00:06:08.779 --> 00:06:11.160 which is hinted at in pharmaceutical analysis. 00:06:12.139 --> 00:06:14.500 These techniques basically use different types 00:06:14.500 --> 00:06:17.699 of light or magnetic fields to identify and measure 00:06:17.699 --> 00:06:20.259 different substances based on how they interact. 00:06:20.360 --> 00:06:22.360 Okay. It's kind of like giving each substance 00:06:22.360 --> 00:06:24.500 a unique fingerprint. That's incredible. I mean 00:06:24.500 --> 00:06:26.959 the level of detail and precision they can achieve 00:06:26.959 --> 00:06:30.019 is mind -boggling. It is. But sometimes those 00:06:30.019 --> 00:06:32.139 good old -fashioned methods are still really 00:06:32.139 --> 00:06:34.629 important. Oh really? Like what? Like titration, 00:06:34.649 --> 00:06:36.850 for example. That's a classic technique that's 00:06:36.850 --> 00:06:39.430 been used for ages to figure out the exact concentration 00:06:39.430 --> 00:06:41.290 of a solution. OK. And then there are all those 00:06:41.290 --> 00:06:43.050 physical tests we mentioned earlier, like for 00:06:43.050 --> 00:06:45.209 tablets. There's the dissolution test, hardness 00:06:45.209 --> 00:06:47.529 test, and something called a friability test, 00:06:47.730 --> 00:06:49.769 which basically measures how easily a tablet 00:06:49.769 --> 00:06:51.949 will crumble. So think of everything. They try 00:06:51.949 --> 00:06:54.449 to. Yeah. All of these tests together, all these 00:06:54.449 --> 00:06:56.670 different techniques, give a really complete 00:06:56.670 --> 00:06:59.810 picture of whether a drug is good to go before 00:06:59.810 --> 00:07:02.120 it ever reaches a patient. So that product release 00:07:02.120 --> 00:07:05.319 testing is really like that final safeguard to 00:07:05.319 --> 00:07:07.360 make sure that every medicine that makes it out 00:07:07.360 --> 00:07:10.240 there meets the strictest standards. But once 00:07:10.240 --> 00:07:12.819 it's made and it passes all those tests, how 00:07:12.819 --> 00:07:14.439 do we know it's going to stay effective over 00:07:14.439 --> 00:07:17.639 time? Doesn't it like degrade or go bad eventually? 00:07:17.720 --> 00:07:19.420 Well, that's where stability assessment comes 00:07:19.420 --> 00:07:22.720 in. OK. So stability testing is all about figuring 00:07:22.720 --> 00:07:25.720 out how a drug changes over time and under different 00:07:25.720 --> 00:07:29.509 conditions. Think about it. Medicines can be 00:07:29.509 --> 00:07:31.529 exposed to all kinds of environments. It might 00:07:31.529 --> 00:07:34.370 get too hot or too cold, too humid, or even be 00:07:34.370 --> 00:07:37.129 exposed to sunlight. Right. So stability testing 00:07:37.129 --> 00:07:39.370 tries to mimic all those different conditions, 00:07:39.949 --> 00:07:42.740 but in a controlled way. So they're basically 00:07:42.740 --> 00:07:45.620 putting the drugs through, like a science -backed 00:07:45.620 --> 00:07:48.259 version of accelerated aging? Kind of, yeah. 00:07:48.660 --> 00:07:50.540 So they store the drug under all these different 00:07:50.540 --> 00:07:53.339 stress conditions, harsher than normal, and also, 00:07:53.420 --> 00:07:55.300 under those ideal conditions, the ones you see 00:07:55.300 --> 00:07:58.079 on the label, like store at room temperature 00:07:58.079 --> 00:08:01.680 for long periods of time. OK. And then... at 00:08:01.680 --> 00:08:04.699 set times, maybe every few months or so, they 00:08:04.699 --> 00:08:07.120 pull out samples and test them using those same 00:08:07.120 --> 00:08:09.079 analytical methods we talked about earlier. And 00:08:09.079 --> 00:08:10.560 that's how they know how long a medicine will 00:08:10.560 --> 00:08:13.600 last, right? Exactly. The stability tests help 00:08:13.600 --> 00:08:16.160 determine the shelf life. which is that expiration 00:08:16.160 --> 00:08:18.199 date you see on the bottle. And they figure out 00:08:18.199 --> 00:08:20.339 the best way to store it too. Like, does it need 00:08:20.339 --> 00:08:23.660 to be refrigerated or kept away from light, things 00:08:23.660 --> 00:08:25.420 like that. That makes sense. Oh, and it's worth 00:08:25.420 --> 00:08:27.860 mentioning that there are internationally agreed 00:08:27.860 --> 00:08:30.579 upon guidelines for this whole stability testing 00:08:30.579 --> 00:08:33.299 thing. You know, like the ICH guidelines mentioned 00:08:33.299 --> 00:08:36.320 in season three, the process of new drug discovery 00:08:36.320 --> 00:08:39.120 and development, and season five, safety evaluation 00:08:39.120 --> 00:08:42.179 of pharmaceuticals and medical devices, international 00:08:42.179 --> 00:08:46.120 regulatory guidelines. ICH stands for the International 00:08:46.120 --> 00:08:48.799 Council for Harmonization of Technical Requirements 00:08:48.799 --> 00:08:51.919 for Pharmaceuticals for Human Use. That's a mouthful. 00:08:52.220 --> 00:08:54.759 It is. But basically, it means that scientists 00:08:54.759 --> 00:08:57.639 all over the world try to follow the same rules 00:08:57.639 --> 00:09:00.100 for drug development and quality. That's good 00:09:00.100 --> 00:09:03.379 to know. So it sounds like there's a very well 00:09:03.379 --> 00:09:06.720 -defined rule book for all of this. But who exactly 00:09:06.720 --> 00:09:10.340 sets these standards for analytical methods and 00:09:10.340 --> 00:09:12.960 all the testing? Well, in the U .S., a lot of 00:09:12.960 --> 00:09:15.539 it comes down to the FDA. The Food and Drug Administration. 00:09:15.799 --> 00:09:17.919 Yep. And other countries have their own regulatory 00:09:17.919 --> 00:09:21.220 agencies, too. These agencies are responsible 00:09:21.220 --> 00:09:23.360 for public health, so they have very, very strict 00:09:23.360 --> 00:09:26.019 rules for how analytical methods are used in 00:09:26.019 --> 00:09:28.080 drug testing. They don't mess around. I bet. 00:09:28.460 --> 00:09:30.580 So one thing you mentioned was this process called 00:09:30.580 --> 00:09:33.080 validation in the context of these analytical 00:09:33.080 --> 00:09:36.539 methods. What exactly does that mean? So method 00:09:36.539 --> 00:09:39.000 validation is all about proving that a specific 00:09:39.000 --> 00:09:41.519 testing method does what it's supposed to do. 00:09:41.580 --> 00:09:44.740 OK. It has to produce results that are accurate 00:09:44.740 --> 00:09:47.980 and that can be reproduced every time. Right. 00:09:48.059 --> 00:09:50.600 And that means proving several things. First, 00:09:51.039 --> 00:09:53.059 accuracy, meaning that the method actually gives 00:09:53.059 --> 00:09:55.259 you a result that's close to the real value. 00:09:55.620 --> 00:09:58.779 So if there are actually 500 milligrams in that 00:09:58.779 --> 00:10:01.700 pill, the test better say it's close to 500 milligrams. 00:10:01.820 --> 00:10:04.340 Right. Then there's precision, which means if 00:10:04.340 --> 00:10:07.200 you test the same sample over and over, you should 00:10:07.200 --> 00:10:09.200 get pretty much the same result every time. So 00:10:09.200 --> 00:10:11.200 it's like hitting the bullseye every time is 00:10:11.200 --> 00:10:13.440 accuracy, and then precision is like all the 00:10:13.440 --> 00:10:15.440 arrows being really close together. Yeah, that's 00:10:15.440 --> 00:10:17.580 a good way to put it. Yeah. And both are crucial 00:10:17.580 --> 00:10:21.440 because if a drug is inaccurate, meaning it's 00:10:21.440 --> 00:10:24.379 consistently giving the wrong dose, or if it's 00:10:24.379 --> 00:10:26.679 imprecise and varies a lot from dose to dose, 00:10:26.980 --> 00:10:28.799 that could have serious consequences for patients, 00:10:28.980 --> 00:10:31.159 right? Absolutely. And then there's specificity, 00:10:31.539 --> 00:10:34.059 which means that the test can accurately measure 00:10:34.240 --> 00:10:36.600 just the thing you're interested in without being 00:10:36.600 --> 00:10:38.320 thrown off by anything else that might be the 00:10:38.320 --> 00:10:41.379 mixture. OK. And sensitivity, which is super 00:10:41.379 --> 00:10:43.679 important for drugs that are given in low doses, 00:10:43.820 --> 00:10:46.740 as mentioned in season seven formulation and 00:10:46.740 --> 00:10:49.139 analytical development for low dose oral drug 00:10:49.139 --> 00:10:51.740 products. Right. Because in those cases, you 00:10:51.740 --> 00:10:54.440 need to be able to detect even tiny, tiny amounts 00:10:54.440 --> 00:10:57.519 of impurities. Got it. And lastly, there's robustness, 00:10:57.899 --> 00:11:00.039 which means that the method still works even 00:11:00.039 --> 00:11:01.840 if there are slight changes in the conditions. 00:11:01.899 --> 00:11:04.730 OK. So it's not enough to just have a test that 00:11:04.730 --> 00:11:06.610 seems to work, you got to prove it. You got to 00:11:06.610 --> 00:11:09.149 prove it. Prove it with solid evidence that it's 00:11:09.149 --> 00:11:10.809 reliable and it's going to give you the right 00:11:10.809 --> 00:11:13.809 answer every time. And all of this is regulated 00:11:13.809 --> 00:11:16.769 by those good manufacturing practices or GMP, 00:11:17.210 --> 00:11:19.629 which are highlighted in season six, the Certified 00:11:19.629 --> 00:11:23.059 Pharmaceutical GMP Professional Handbook. GMP 00:11:23.059 --> 00:11:26.200 regulations are basically the rule book for making 00:11:26.200 --> 00:11:29.120 medicines. Okay. And they require the use of 00:11:29.120 --> 00:11:31.659 these validated analytical methods and they require 00:11:31.659 --> 00:11:34.759 super detailed documentation of every single 00:11:34.759 --> 00:11:37.740 step of the testing process. Everything has to 00:11:37.740 --> 00:11:40.360 be recorded and traceable, no cutting corners. 00:11:40.519 --> 00:11:42.789 So there's no room for error. Not really. And 00:11:42.789 --> 00:11:44.490 then there are also those pharmacopias like the 00:11:44.490 --> 00:11:47.110 European Pharmacopia, the Japanese Pharmacopia, 00:11:47.289 --> 00:11:49.789 and the United States Pharmacopia, mentioned 00:11:49.789 --> 00:11:54.549 in Season 8, merged U48. What are those exactly? 00:11:54.970 --> 00:11:57.009 So those are like official books, essentially, 00:11:57.669 --> 00:12:01.029 that lay out standard methods for testing lots 00:12:01.029 --> 00:12:03.830 of different drugs and substances. and they provide 00:12:03.830 --> 00:12:07.269 a baseline for quality testing. And there's this 00:12:07.269 --> 00:12:10.509 initiative called ICHQ4B that's trying to make 00:12:10.509 --> 00:12:12.629 sure these pharmacopias are all compatible with 00:12:12.629 --> 00:12:14.809 each other, which would make things a lot easier 00:12:14.809 --> 00:12:17.090 for everyone, especially for companies that want 00:12:17.090 --> 00:12:19.250 to sell their drugs in different countries. It's 00:12:19.250 --> 00:12:20.950 really incredible when you think about it, all 00:12:20.950 --> 00:12:23.149 the layers of checks and balances that are in 00:12:23.149 --> 00:12:25.450 place to ensure the quality of our medicines. 00:12:25.690 --> 00:12:28.370 But I'm guessing that developing these really 00:12:28.370 --> 00:12:31.970 robust and reliable analytical methods is no 00:12:31.970 --> 00:12:34.940 easy feat. especially with all the complex drugs 00:12:34.940 --> 00:12:37.059 out there these days. Oh, you are absolutely 00:12:37.059 --> 00:12:39.639 right. It's a huge challenge, especially when 00:12:39.639 --> 00:12:42.679 you're dealing with formulations that are really 00:12:42.679 --> 00:12:44.799 complex, like, you know, combination drugs that 00:12:44.799 --> 00:12:46.899 have several active ingredients in them, or when 00:12:46.899 --> 00:12:48.720 you have a totally new drug that no one's ever 00:12:48.720 --> 00:12:51.940 tested before. So, like, what kinds of challenges 00:12:51.940 --> 00:12:55.080 do scientists face when they're trying to develop 00:12:55.080 --> 00:12:57.580 these methods? Well, selectivity is a big one. 00:12:58.039 --> 00:13:00.809 Selectivity. Yeah. So remember how we talked 00:13:00.809 --> 00:13:03.330 about how a test has to be able to pick out the 00:13:03.330 --> 00:13:06.049 specific ingredient you're interested in without 00:13:06.049 --> 00:13:08.250 getting confused by anything else that's in there? 00:13:08.610 --> 00:13:10.350 Well, that can be really tricky, especially when 00:13:10.350 --> 00:13:12.509 you've got all these other inactive ingredients 00:13:12.509 --> 00:13:15.629 in the mix, what we call excipients. And then, 00:13:15.629 --> 00:13:17.789 of course, there might be some degradation products 00:13:17.789 --> 00:13:19.990 forming over time, too. So you've got to make 00:13:19.990 --> 00:13:22.929 sure your test can ignore all that stuff and 00:13:22.929 --> 00:13:25.000 just focus on the active ingredient. Right. So 00:13:25.000 --> 00:13:27.580 like separating the wheat from the chaff. Exactly. 00:13:27.919 --> 00:13:29.679 And then there's sensitivity, which we mentioned 00:13:29.679 --> 00:13:31.820 before. If you're working with a drug that's 00:13:31.820 --> 00:13:34.840 given in very small doses, you need a test that 00:13:34.840 --> 00:13:37.120 can pick up even the tiniest amounts of impurities. 00:13:37.500 --> 00:13:39.779 So that could be a big hurdle, too. OK. And then 00:13:39.779 --> 00:13:41.820 there's the stability of the analyte itself. 00:13:42.100 --> 00:13:44.419 The analyte. Yeah, that's just the fancy scientific 00:13:44.419 --> 00:13:45.720 term for the thing you're trying to measure. 00:13:45.740 --> 00:13:49.059 Right. So some analytes could be. quite unstable 00:13:49.059 --> 00:13:51.379 once they're in a solution. Like they might start 00:13:51.379 --> 00:13:53.360 to break down before you can even measure them. 00:13:53.399 --> 00:13:55.740 Oh, that doesn't sound good. Not at all. If that 00:13:55.740 --> 00:13:57.419 happens, your results are going to be all over 00:13:57.419 --> 00:14:00.399 the place. Right. So what can scientists do to 00:14:00.399 --> 00:14:02.980 get around these challenges? Well, it often starts 00:14:02.980 --> 00:14:05.659 with a lot of trial and error, honestly. They 00:14:05.659 --> 00:14:08.500 have to tweak and refine the testing method until 00:14:08.500 --> 00:14:11.940 they get it just right. OK. And luckily, there 00:14:11.940 --> 00:14:14.700 are always new and better analytical techniques 00:14:14.700 --> 00:14:17.769 being developed. Technology is constantly evolving, 00:14:17.830 --> 00:14:20.330 which helps a lot. And of course, once they think 00:14:20.330 --> 00:14:22.289 they have a good method, they have to validate 00:14:22.289 --> 00:14:24.470 it, remember. I've got to prove it works. Exactly. 00:14:24.570 --> 00:14:26.830 They have to show that it's accurate, precise, 00:14:27.370 --> 00:14:31.429 specific, sensitive, and robust. But the work 00:14:31.429 --> 00:14:34.590 doesn't stop there. Even after a method's been 00:14:34.590 --> 00:14:37.149 validated and is being used routinely, they have 00:14:37.149 --> 00:14:39.610 to keep monitoring it just to make sure it's 00:14:39.610 --> 00:14:41.870 still performing as expected. It seems like a 00:14:41.870 --> 00:14:44.320 lot of work, but it's clearly essential. It's 00:14:44.320 --> 00:14:46.559 amazing to see how much goes into ensuring the 00:14:46.559 --> 00:14:48.879 quality of our medicines. And it's not just about 00:14:48.879 --> 00:14:51.580 testing the final product, is it? I know from 00:14:51.580 --> 00:14:52.759 some of the other stuff we've been looking at 00:14:52.759 --> 00:14:55.059 that these analytical methods are used much earlier 00:14:55.059 --> 00:14:57.700 in the drug development process, too. Absolutely. 00:14:58.159 --> 00:15:00.379 They're really crucial throughout the entire 00:15:00.379 --> 00:15:03.440 process, from the very early stages of discovery 00:15:03.440 --> 00:15:06.220 all the way through to postmarket surveillance. 00:15:06.720 --> 00:15:08.860 For example. In those pre -clinical studies, 00:15:09.860 --> 00:15:11.720 the ones that are done in animals before a drug 00:15:11.720 --> 00:15:14.519 is ever tested in humans, analytical methods 00:15:14.519 --> 00:15:17.259 are used to measure how much drug is in the animal's 00:15:17.259 --> 00:15:20.379 blood or tissues. So they're figuring out, like... 00:15:20.080 --> 00:15:23.080 how the drug moves through the body. Right, how 00:15:23.080 --> 00:15:25.580 it's absorbed, distributed, metabolized, and 00:15:25.580 --> 00:15:28.259 excreted. We call that pharmacokinetics, which 00:15:28.259 --> 00:15:30.779 we discussed in season two basic pharmacokinetics 00:15:30.779 --> 00:15:33.019 and season three basic pharmacokinetics. Okay. 00:15:33.600 --> 00:15:35.740 And then later on when scientists are trying 00:15:35.740 --> 00:15:37.720 to figure out the best way to formulate a drug, 00:15:38.059 --> 00:15:40.039 like whether to make it into a pill, a capsule, 00:15:40.240 --> 00:15:44.190 an injection, or something else. They use analytical 00:15:44.190 --> 00:15:46.549 methods to test things like the solubility of 00:15:46.549 --> 00:15:49.149 the drug, which is discussed in Season 6 Handbook 00:15:49.149 --> 00:15:52.409 of Solubility data for pharmaceuticals. And then, 00:15:52.409 --> 00:15:54.370 of course, they have to test how stable those 00:15:54.370 --> 00:15:56.710 different formulations are. And even in clinical 00:15:56.710 --> 00:15:59.309 trials, when a new drug is being tested in people, 00:15:59.669 --> 00:16:01.690 they use these analytical methods to measure 00:16:01.690 --> 00:16:04.289 the drug levels in the patient's bodies, which 00:16:04.289 --> 00:16:06.129 helps them understand how the drug is working 00:16:06.129 --> 00:16:08.450 and whether it's safe and effective. So it's 00:16:08.450 --> 00:16:11.570 really a continuous process. Wow, that's fascinating. 00:16:11.870 --> 00:16:14.590 It really highlights how vital analytical methods 00:16:14.590 --> 00:16:17.330 are to the entire pharmaceutical industry and 00:16:17.330 --> 00:16:19.750 ultimately to public health. I mean, every time 00:16:19.750 --> 00:16:21.789 someone takes a medicine and it works, it's partly 00:16:21.789 --> 00:16:23.730 because of all this incredible scientific work 00:16:23.730 --> 00:16:26.289 that's happening behind the scenes. These methods 00:16:26.289 --> 00:16:29.470 are the unsung heroes of drug safety and efficacy. 00:16:29.710 --> 00:16:31.529 I couldn't agree more. They're the guardians 00:16:31.529 --> 00:16:33.929 working tirelessly to make sure that all those 00:16:33.929 --> 00:16:37.470 medicines out there are consistently safe, effective, 00:16:37.850 --> 00:16:40.289 and top -notch quality. So let's wrap things 00:16:40.289 --> 00:16:42.149 up with some key takeaways for our listeners. 00:16:42.389 --> 00:16:44.210 What are the most important points you want them 00:16:44.210 --> 00:16:47.350 to remember? Okay, so the big picture is that 00:16:47.350 --> 00:16:49.730 analytical methods are absolutely essential for 00:16:49.730 --> 00:16:52.450 making sure that all drug products, everything 00:16:52.450 --> 00:16:54.769 from pills to injections to creams, have the 00:16:54.769 --> 00:16:56.850 right identity, the right strength, the right 00:16:56.850 --> 00:16:59.309 quality, and are free from harmful impurities. 00:16:59.950 --> 00:17:02.269 And this isn't just a one -time check at the 00:17:02.269 --> 00:17:05.109 factory. It's an ongoing process that starts 00:17:05.109 --> 00:17:07.910 when a drug is first made and continues throughout 00:17:07.910 --> 00:17:11.150 its shelf life. those strict industry standards 00:17:11.150 --> 00:17:13.589 and the oversight from those regulatory agencies, 00:17:13.910 --> 00:17:16.349 plus all the work that scientists are doing to 00:17:16.349 --> 00:17:18.869 develop better and better analytical methods, 00:17:19.450 --> 00:17:21.589 all of that comes together to protect patients 00:17:21.589 --> 00:17:23.670 and make sure that the medicines they rely on 00:17:23.670 --> 00:17:26.250 are safe and effective. And that brings us to 00:17:26.250 --> 00:17:28.779 our final thought for you, our listener. Think 00:17:28.779 --> 00:17:30.859 about all those incredible new medicines that 00:17:30.859 --> 00:17:33.200 are being developed these days. Things like biologics 00:17:33.200 --> 00:17:35.880 and nanomedicines, which are mentioned in season 00:17:35.880 --> 00:17:38.299 three pharmacokinetics and pharmacodynamics of 00:17:38.299 --> 00:17:41.059 biotech drugs and season seven nanoparticles 00:17:41.059 --> 00:17:43.980 for drug delivery. These are incredibly complex 00:17:43.980 --> 00:17:45.599 therapies and they're pushing the boundaries 00:17:45.599 --> 00:17:48.460 of what's possible in medicine. But how do you 00:17:48.460 --> 00:17:50.119 think those analytical methods we've been talking 00:17:50.119 --> 00:17:52.779 about today are being adapted to make sure these 00:17:52.779 --> 00:17:55.309 new treatments are safe and effective? How do 00:17:55.309 --> 00:17:57.789 you ensure the quality of something that's so 00:17:57.789 --> 00:18:00.690 cutting edge and so intricate? It's definitely 00:18:00.690 --> 00:18:03.849 something to ponder, isn't it? Absolutely. It's 00:18:03.849 --> 00:18:05.930 a huge challenge, but it's one that scientists 00:18:05.930 --> 00:18:08.630 are tackling head on. And if you're interested 00:18:08.630 --> 00:18:10.509 in learning more about this fascinating field, 00:18:10.970 --> 00:18:13.150 there are tons of resources out there, like from 00:18:13.150 --> 00:18:16.690 the FDA or the ICH. But for now, we'll leave 00:18:16.690 --> 00:18:19.230 you with this question. What do you think is 00:18:19.230 --> 00:18:21.630 the single most important aspect of ensuring 00:18:21.630 --> 00:18:24.369 drug quality through analytical testing? We'd 00:18:24.369 --> 00:18:26.509 love to hear your thoughts. Thanks for joining 00:18:26.509 --> 00:18:28.470 us on this deep dive. We'll see you next time.