Monday, January 15, 2024

Biopharmaceuticals And Medical Devices: A General Overview I (Drugs)

FOTB (Friend Of This Blog) Leigh from Five Acres and A Dream made the following comment in my update on Week 4 of Hammerfall 3.0:

"Being in the "retired category of folks myself, I feel really out of the loop in understanding such things, but I have to ask why your particular industry seems to be struggling so.  I mean (probably naively), it's in the medical/health care arena, and people always need these things, so it would seem that the demand for the supply should keep the industry thriving.  I'm guessing the answer is extremely complicated but it's one of those things that just doesn't make sense."

It is a fair question - after all, the Pharmaceutical/Biotechnology/Medical Device Industry impacts almost everyone at some point (if you have used an aspirin or a bandage, you have participated).  Hopefully I can shed some illumination.  

For reference how I know about this: I have over 25 years of experience in the industry in Manufacturing, Quality, and Project Management had have worked for almost every type of manufacturer (pharmaceutical, biologic, medical device) for products being developed, products in the approval process, and approved products.

I will start with Biopharmaceuticals and then move to Medical Devices.

(Note 1:  This is a very generalized description of the process.  There is a lot of underlying details and processes which, while important, would rapidly spiral of control.)

(Note 2:  For the purposes of this discussion,  I will just use "Drugs" to describe both pharmaceuticals and biologics.)

The most important thing to remember about all of this is that all Drugs in the U.S., be they small molecule (e.g., generated by chemical or "pharmaceutical") or large molecule (generated by biologic process,  or "biologics") are regulated by U.S. Law.  The history of how we got here is long, but suffice it to say in our day, the US Food and Drug Administration (FDA) is responsible for ensuring that all drugs are safe and effective.  The origins of this authority are found in the 1938 Food, Drug, and Cosmetic Act (FD&C Act) and have been expanded ever since.  The regulations for drug manufacture (and much of biologic manufacture) is found in the Code of Federal Regulations (CFR), Title 21, Parts 210 and 211 (and part 600 for certain biologics).  

Unlike International Standards like the International Standards Organization (ISO) or the International Committee on Harmonization (ICH), these regulations must be complied with (as opposed to the standards, which must be conformed to) - unless the standards have been taken into U.S. law as a consensus standard (which many have been).  Every nation has their own set of regulations that must be complied with:  for example, if you are going to sell products in the U.S. and Europe, you have two sets of regulations to comply with.  Often these are similar, but sometimes there are differences which can be significant and must be planned for.

Thus everything that has to do with drug development and drug manufacture is regulated.  The closer one gets to submission for approval, the more regulated things become.

The second most important thing to remember is that all Drugs have side effects.  Every single one.  Drugs are thus evaluated on a risk/benefit basis: does the benefit of a drug outweigh the risks and impacts?  Everyone is familiar with the impact of chemotherapy on the individual in terms of visible impacts (loss of fast growing cells like hair follicles) and not quite as visible impacts (loss of appetite, nausea, loss of ability to taste, lowered immune resistance).  In this case, the benefit (fighting cancer) outweighs the impacts and risk (all the physical impacts above and, frankly, dying of an infection due to a lowered immune system).

Drugs all start in a lab.  There is a promising compound or a significant unmet need that drives scientists to look for a solution.  After going through hundreds or even thousands of compounds (via lab screening or computer models), they discover one which (maybe) has an effect on a condition on a medical condition.  Most likely it is perceived as a novel impact, as "me-too" drugs have a higher bar to succeed in the market.  Also, multiple labs may be working on the same condition, so the development becomes a race to be first (for a novel compound) or a race to be more effective (where a drug already exists for a condition).

Once a compound is identified, it has to be tested to verify that it has the effect that scientists think it has.  This is done in several ways - in silico ("in silicon", or using computer models). in vitro (literally "in glass", or under controlled laboratory conditions with the target cells or molecules), in vivo ("in the living" or using live animals (only, at this point - live humans come later),  Generally the progression is from in silico (where available) to in vitro (cell studies) to in vivo (animal testing).  At the same time as the product is being tested, a basic manufacturing process is being designed:  what conditions, what medias and buffers, what manufacturing steps have to be in place to make "the compound".  Not only does the compound need to have an effect, it needs to be able to be manufactured.

Assuming we now have the compound, it has to be put through some level of paces to make sure it is worth moving forward with.  Typically the product will be characterized (to learn all they can about it) and placed against a set of criteria that will define if the product meets the anticipated needs of the criteria identified (sometimes called "Target Product Profile") and can be manufactured.  If it meets both criteria, it will move forward (if not, of course, it gets discontinued).   At the point (or slightly before), small scale lots (pilot lots) will be manufactured and animal testing starts.

No-one I know of in the industry is fond of animal testing (also called "Non-Clinical Laboratory" Testing), but the other option at this stage is "testing straight in people", which for some pretty strong historical reasons is a bad idea.  A species which simulates the human system or condition to be tested is selected (typically starting with mice and ending with non-human primates, but other species animals may be used based on the nature of the disease or condition being evaluated) and the product tested per a protocol.  Often, necropsy is performed and the data reviewed, looking for 1) Efficacy and 2) Impact to to the physical systems.  Pharmacokinetics (the movement of the drug through the body) and Pharmacodynamics (the biological, physiological, and molecular impact of the drug on the body) are measured.  For this testing, the controlling regulation is 21 CFR Part 58, Good Laboratory Practice for Non-Clinical Studies (also referred to as GLP).  These test can be either non-GLP (for general data generation or proof of concept) or GLP (required to move the product into clinical trials).

All of this does not come cheaply, of course.  Scientists require labs, and labs required equipment and reagents and personnel to run them.  Small manufacturing lots need a pilot plant internal to the company or an external contract manufacturing organization (CMO) to manufacture them.  And Non-Clinical laboratory studies need to be conducted:  as of last year, a small mouse study ran $250,000 at a minimum and a non-human primate study $1.3 million.  Generally there is more than one mouse study and a minimum of one major animal study (such as non-human primates).   Add to that that scheduling for these studies is anywhere from 4 months (for mice) to 9 months or more (for non-human primates).

If helpful for reference, products that I have worked on to get to this point - not including internal overhead for personnel, lab space, equipment, etc. - have cost between $2 million and $4 million.  Just to get to the point of possibly using it in an early clinical trial.

Assuming all of this data indicates 1) There is some benefit; and 2) The benefit outweighs the impact, and 3)  The compound can probably be manufactured,  the compound will likely be moved to scaled manufacture and clinical trials of the compounds in humans (which we will review tomorrow).


  1. Nylon126:20 AM

    That's quite the post there TB, gave me a lot on info I never knew. The number of side effects on some of the advertised drugs always opened my eyes when I saw those ads. Costs are impressive.

    1. Thanks Nylon12. Leigh's question reminded me that for most people, how we actually get a drug or medical device is probably just as mysterious a concept as how silicon chips are manufactured or skyscapers are erected. That is a shame, really - these things are so impactful on our health that folks really should understand the basics. To your point, one of the major things is cost (we will continue to review as we go on) - they are very high even for failures and the cost compounds the longer the failure is delayed.

      Side effects are something that we also fail to take account of too often. If you get medication, you will either get a Product Insert (PI) physically or a link on line. That is a document which describes the drug, a summary of the studies done on the drug, the mechanism of action (MOA), and all of the side effects. Just for "fun", read one sometime. It can be shocking.

    2. Shepherd6:26 PM

      I found your blog via a link to the Collapse series - very well done, thank you! Perusing the rest of your blog has me hooked on the general content as well, so it's now a daily read.
      Thank you for the excellent summary of the drug/biologic manufacturing process. While not in the field directly, I have colleagues who are. I just retired from almost 50 years in the data storage and semiconductor industries (Quality, Reliability, and Test Engineering roles) and am very familiar with this level of complexity and cost to develop and manufacture items that people use every day that were once very expensive and today have reached commodity status, just like some common antibiotics.
      The reason that items like computers and hard disc drives have a price floor that you cannot go below is the cost of the facilities to manufacture them. A semiconductor ("chip") fabrication facility (a "fab") can easily cost a billion dollars to set up. That process requires ultra-pure water and chemicals, and clean rooms that much cleaner than a hospital operating theater. The equipment needed to produce today's chips with ultra-fine geometries (5-7 nanometers - about 30 or so silicon atoms wide) using X-ray lithography is extremely expensive, not to mention needing extremely stable mounting surfaces and sub-structures to decouple the equipment from vibration. The manufacturing process is so delicate that most of it is automated these days, with robots handling the silicon wafers and tightly sealed "boats" transferring wafers around the facility in sealed transport tubes (think of the air tube that carries your bank business papers at some drive-up locations). Much of this requires very skilled personnel who don't come cheap. And since the process can take hundreds of steps and involve a silicon wafer that contains hundreds of individual chips (in individual die form, on a larger silicon wafer), a mistake or equipment failure at the end of the process can be very expensive. (At one company who used the semiconductor manufacturing equipment my company produced, several of the engineers had a plaque on their wall that showed them to be a member of "The Million Dollar Club". The award was given when you made a mistake that ruined a million dollars worth of wafers during a production run.)

      Hard disc drives also require a clean room environment, (though not as strict as semi) but that costs money as well. That sets a price floor on those as well.

      Thank you for keeping us posted on this time in your life's journey. As one who has been through the boom and bust cycles in the tech sector I can empathize with your struggle. I'm keeping you in my prayers, that you may quickly find solid, enjoyable employment in your field.

    3. Shepherd - Thanks so much for the kind words and commenting!

      Thanks for the discussion of chip manufacturing (truly a mystery to me). I know a very little bit of the process and the criticality of environments, but not to that level. And yes, facilities and environment are critical in both environments - for drug product manufacture in a ISO Class 5/Class 100 environment, you are allowed not more than 100 particulates at 0.5 microns or above per ft/m3. That includes everything: personal, product, equipment. Regular testing and monitoring is required and in the event of a contamination, the entire run may need to be scrapped and the room cleaned. Depending on if it is a contract manufacturer or not, the liability discussions can be...exciting.

      I had not thought about the concept of a price floor, but that opens a whole new level of understanding for me.

      We have the equivalent of the "million dollar club" in our industry as well. A full scale run at a previous employer was not less than $500,000 and outsourced closer to $1 million for drug substance and $250,000 to $600,000 for drug product, so the numbers in the event of a failure add up quickly.

      Thank you very much for the encouragement and the prayers. It is always good to be reminded that others have also tread this path before me.

  2. Anonymous6:38 AM

    Very interesting. Looking forward to tomorrow’s post.

    1. Thank you! I intended to just do a single post, and then started writing, and then realized one post would not be enough...

  3. I suspect the answer of why your industry is not thriving relates strongly to what is going on in the medical community for the last decade but I'll wait for you to get into that first.

    One thing I have noted is that with A.I., drug companies have been identifying new compounds at a fairly quick rate that might make major impacts in our system. I think a new type of antibiotic was just figured out last week by A.I. though I haven't seen an article written on it yet.

    1. Ed - I will be interested to see where it goes as well. Honestly, this is not something I have thought about before so it makes for a good intellectual exercise.

      The use of AI for the screening of compounds is one of the great promises of AI. Even computer-aided screening was allowing thousands of compounds to be screened where much fewer would have been. And it has other promises as well; the company which I am currently "on furlough" from used AI as part of their system - pretty cool stuff, although highly technical, time consuming, and expensive to set up. That said, identification of the compounds may help with the first stage, but once it moves to the lab I fear we will have the same kind of time and cost constraints unless both industry and government can adapt.

  4. Anonymous9:57 AM

    Really very well put TB! I am now 10+ years retired from the industry but occasionally my friends/acquaintances ask why a new drug is so expensive. I may have to steal your summarization to try to explain!

    1. Thanks so much! That really makes my day.

      I think the knowledge of how much it costs to get to a new drug is not very well known. That is a shame on two levels: The first is that it is not seen as the risky investment for companies that it is. The second is that drugs are so common place now, there is little appreciation for what it took to get to that point.

  5. Something else people generally don't understand is that not every attempt at a drug succeeds. Do you have any statistics on the number of failed attempts vs. successes? eg. you spend $250k on X number of mouse studies that fail for every one that succeeds. Thanks for the posts!

    1. Hi LibertyNews! Thanks for stopping by!

      I have some general stats (actually saving up for Friday's post) but in general, there are far more failures than successes. For example, in 2023 the FDA approved 55 new drugs, where as in 2022 they only approved 37. I can assure you that far more drugs were worked on in the same time frame than ever reached approval.

      I will look for the statistics, but I do not know that there is a linear sort of relationship that could be quantified in terms of X studies to Y successes. Sometimes companies just continue to follow bad compound after bad compound until someone from senior management finally decides this is not a field they can afford to be in.

  6. This is going to be an interesting series to read through, TB. I have some catching up to do!

    1. Becki, I especially hope it is useful to someone like you. Hopefully it will help to explain how we got to the drugs that were used during your recent bout with cancer.


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