Wednesday, January 31, 2024

Rabbit Fun

In lieu of a serious post, today I thought I would post some of my favorite art of Rabbits in different imaginings.

Hoops (Gamma World 1st Edition, circa 1977):  2.6 meter tall rabbits with telepathy and opposable thumbs.

A different version, simply "Rabbits with guns:

Space Marine Rabbit:

"Cute Rabbit with an Axe.  Valhalla calling:"

Usagi Yojimbo (artist Stan Sakai):

We all have that friend:

Tuesday, January 30, 2024

Tales From Produce (A)Isle: Common Courtesy Edition

As I was thinking through my work search at Produce (A)Isle - and I have a lot of time to think - one thing that struck me was the fact that it is by far one of the most courteous environments I have worked in.  

This struck me as I was thinking about my job search and my past experiences in other companies - which, while not awful (for the most part), really do not rise to the same level.

In all my time there to date (7 months), I have only ever had one "unpleasant" customer - and legitimately he had found an issue (a discrepancy between the sign pricing and the label pricing on the shelf below it, although he was not particularly nice about it).  Other than that, everyone  - customers and fellow employees - has being, well, really polite. 

Contrary to what might be out there on the current relations between practically anyone out there, I have contact with a large swath of people from every conceivable backgrounds and many nationalities.  To a person, the request always starts with "Excuse me, Sir".

Now, maybe the grey hair and the slow shuffling around the shelves suggest I am not a quite in the now-current generation, but I have to admit I am a bit shocked by the level of courtesy shown to me by customers.

I contrast this with my industry work environments.

Not that they are impolite or discourteous on the face of them:  people on the whole generally ask permission and generally do not barge in on one.  But the conversations start less with the equivalent of "May I have a moment of your time?" and more "Hey, I have this problem/discussion point/story I need to resolve/run past you/ tell you to amuse you and make myself feel good".  And sometimes, not even the first name basis is used.  It becomes "Do you have a minute?" and barely waiting for an acknowledgement, the conversation is on.

They lack that moment of simple courtesy and respect.

Are they different environments?  Sure.  But it cannot be argued I am not dealing with a wide variety of people at Produce (A)Isle, including people as well educated and trained as those I deal with in the Biopharmaceutical/Medical Device Industry.  It seems that in one environment, the ability to interrupt and/or deal a bit nonchalantly with people is assumed; in the other it is not.

To be completely honest, some folks at Produce (A)Isle seem genuinely apologetic to interrupt me to find out where the celery is or do we have coconuts.  It is no problem, I tell them:  that really is part of my job.  

It does make me wonder though:  how far would the same sort of simple courtesy and respect go in all places, not just on sandy beach and under the waving palm trees of the (A)Isle?

Monday, January 29, 2024

Nighean Gheal's Return

 Yesterday morning, as I made my way through Japan (Or is it the morning before? Being in Japan, time ahead of the U.S., makes it confusing) Nighean Gheal  moved back home.

You may remember that she moved out in October of 2022 to The Big Big City with a job in hand. She has been there for over a year now, enjoying the sights and sounds and tastes of life in perhaps the most urban of urban environments.  But about four months ago, she reached out to us.

Her job was okay, but it was not quite what she had been expecting.  The industry she is in is a tough one, with jobs being assigned out either randomly or "because you know someone".  In some cases the teams were dysfunctional, reaching out late at night (2300) to go over slides for the next day.  Even though she found a better team with good people, the work was still not that interesting.

However, she had continued to do online tutoring during this time and loved it - as she described to us, she felt energized after finishing the tutoring but exhausted after her regular job.  After giving it a lot of thought, she thought that meant something.

We, of course, concurred.

The final outcome of what she will do is still in the process of application (so no update there at the moment), but she asked us if after the ending of her lease in January, could she move back home for 5 or 6 months until the next step of her career journey was complete?

Of course we said yes.

And so yesterday, she and The Ravishing Mrs. TB made their way back to New Home, with the remainder of her things (she had been ferrying them home for Thanksgiving and Christmas).  Her job is now fully remote, so she was able to get herself transferred to the local New Home office, where she will continue to work until (hopefully) the next step is complete.

I am quite proud of her - not just that she has done well in her job, but that she has the presence of mind to realize that this field is not for her and to do something about it, instead of just making the decision to be miserable at a job for years on end.

Sometimes, even compensation and prestige and The Big Big City is not enough.

Saturday, January 27, 2024

Hammerfall 3.0: Week 6 Report

Period:  21 January to 25 January (truncated due to travel)

Positions applied to:  I applied to 2 position this week.  Total jobs applied to/opportunities investigated are 63 unique positions (more on this below)

Note 1:  As of Monday 22 January, there were less than 50 jobs in total for the entire state that Old Home/The Ranch is in that were listed on one of the job sites I frequent.  Likely this does not include the major Biologic/Pharma manufacturers as they have their own websites, but still - that is a staggeringly small number.

Rejections:  I was rejected for 1 position (12 total rejections).


I had one screening call with a large biologics company, one on-site interview, and two phone interviews.

My screening call on 23 January was for an "individual contributor" position at a major biopharmaceutical company.  To be honest, I am really interested in the possibility of the position after the screen.  Pay would be equivalent to what I had at my last job, so not necessarily a step down.  It went so well (apparently) that I had a follow up call with the hiring manager due to my availability next week.  That went well too, so far as I can tell.  They had several other candidates to screen and would follow up if interest, etc.

My on-site interview for the potential job in New Home was on Monday (22 January 2024).  It was a panel interview of about 40 minutes, a few minutes for me to ask questions, and then a short tour.  Bottom line:  Interview went okay and should hear something by the end of next week.  On the negative side, another round of questions on how do you handle underperforming employees (which now sounds like a problem) and how do you dealing with moving things to closure for competing timelines (You do not; you have a limited time and resource bank and you prioritize).  Also a concern is that they are a service organization focused on a rather small part of the overall ecosystem; long term success may be a concern.

My phone interview was for the higher level out of state site Quality position on 24 January also went well.  Conducted with the hiring manager, it was more a review of my career as well as them explaining the company, the job, and the location.  It went well enough that I will moved forward to a panel interview.

Of note, both out of state positions would put me with a long days' drive of The Ranch.

Job losses:  As of this writing (25 January), only one company, Cara Therapeutics, announced they were laying off 50% of their staff (no numbers) to "extend the cash runway into 2026 (this number keeps coming up).


In summary, it appears I have four reasonably possible candidates at this time. I have begun to build a matrix to evaluate the opportunities against each other with an attempted degree of like for like comparison as it seems likely they are tracking closely together in terms of timing.

The Dog Whisperer sent me something this week that made me think.

The quote is from a newsletter called "The Work Shift" which I guess is somewhere on LinkedOut (I cannot find it):  "Even in this job market where 'job vacancies have come down across the board' amid  a 'higher interest rate environment', job seekers are applying to jobs with 21% more intensity than they were this time last year, (Chief LinkedIn Economist Kim) Kimbrough continued.  That could be because there are currently fewer available positions.  By mid-2023, LinkedIn data showed there was about one opening for every two applicants, down from a peak of one job opening for every applicant."  Note the phrase "mid-2023" - we are well beyond that now. 

Add to that "21% more intensity" that does not necessarily mean "21% better matches".  There is likely and equally a sense of "throw it against the wall and see what sticks", which of course means more applications and CVs incoming, which means increased reliance on automatic screening tools, which means more tweaking to CVs using AI to be "the candidate of choice", which leads to AI reading the AI to catch the AI...not a great environment.

Friday, January 26, 2024

Gone Training 2024 Edition


Friends - As you are reading this, I am on my way to Japan for a week of training in Iaijutsu.

I am excited to be able to go train - for those of you that are newer, the last time we were able to go to Japan for training was January/February of 2020 before the arrival of The Plague (in an interesting course of events, the first cruise ship with Plague sufferers arrived in Japan during our stay - a foreshadowing of the next two years).  So it has been almost four years to the week since we have been able to go.

This will be a shorter session than others have been in the past - 4 days full days. But when we train, we train:  up at 0400, training from 0500-0700, breakfast at 0700 and a small break, training from 0900-1200, lunch and a small break, training from 1400 - 1600/1700.  Shower at 1700, dinner at 1800. Most everyone is in bed by 2000.  On top of this training, we will have some additional training at the honbu (parent dojo).

Sightseeing time will be limited (it usually is).  Usually we try to take in at least one site while we are in Tokyo, often Asakusa with its Senso-ji Temple, as there is a marketplace and sword store there as well.  That said, we are also bound by the available time and being sure we get back to the airport (as the tourist time is usually at the end of the visit).

As usual, I have left a series of posts in my absence.  Although I will have computer with me (job hunting and all), responses will still be delayed as I will be 14 to 17 hours ahead of all of you in the United States - strangely enough, even though I am "in the future", it still does not help me foresee anything.

I would say "mind the rules" but since I have the best commenting and reading group on the Inter-Web, I have no concerns whatsoever.

I laugh a bit as I go, for while this job has been completely paid for by Product (A)Isle, this will be the second time in the space of a year that I have traveled without having a job.  I do not know this is the habit I want to get in, but paid for is paid for and I am going.

Be good, do good, and I will see you all on the other side!

Thursday, January 25, 2024

The Collapse CXXXIII: Packing Up

 29 June 20XX +1

My Dear Lucilius:

This was the day of packing and transporting.

After another breakfast of bacon and coffee (will wonders never cease?), the order of the day was transporting the most valuable items from the previous day’s search back to town for inventorying and distribution. We now had The Looters’ truck; during breakfast the two trucks we had ridden over the mountain slowly rolled up (all of this accommodated, of course, by four 5 gallon cans of fuel from the Looters).

The Colonel set the goals: Load up quickly and head back. And by “load up quickly”, he apparently meant strength and speed.

So I would like to tell you the mechanics of loading and setting up the trucks for transport. But I – and the line that held the bridge – were not there. We were out on the fringes of the development, standing guard. The chances of attack decreased a bit every day, it was explained, but they were not absent until we were gone.

And so I found myself on the fringes of the housing development, looking out from a corner of the house down the long road the led to where The Looters had come from, my rifle and a whistle ready.

It was odd, Lucilius, these complete moment of silence after the events of the previous 48 hours. The silence was mysteriously deafening – and by silence I mean not the complete absence of sound, but the silence of being essentially away from any sort of civilization. A light wind blew, the native grasses rustled. While there was a sense of awareness – necessary for any guard of course – there was not the same sense that was over us as we stood at the bridge. The Looters, if they were still out there, were a threat – but not a “they are coming” threat, but a “they might be out there” threat.

I cannot tell you the amount of time we were out there – two hours, three hours, even four? The sun was well overhead by the time The Leftenant stopped by and called us back in. We met for a quick lunch, then headed back to town.

There was a high level of alert on our way back: men and women marching to either side of the vehicles and/or on the vehicles, an advance guard that went on well before us, a rearguard following behind. The pace was slow but steady, the sun hot but not unbearably so as we made our way back.  As we made our way across the bridge, the wooden cross lashed together  above Blazer Man's grave gave evidence that at least one other person had been there.

We came to the point of the initial ambush – disturbing the vultures that were glutting themselves on the carcasses. The bodies had been laid in rows to either side of road, a warning to those that would advance further.

Our entrance into the town was unremarkable as was our original departure. The trucks stopped and everyone unloaded, the trucks peeling off to some location where the items would be sorted and organized. We continued on, back to the gym where we had only departed a few days before.

The rest of the afternoon was spent in repacking the items that had brought with us and the items we had left. Blazer Man’s things were there; I pulled them together and brought them to The Leftenent – except for his Blazer, which I brought over and asked permission to take with me – which was, of course, granted. In the grand scheme of the modern world, who needs semi-formal wear?

I do, Lucilius. For memories, if for nothing else.

Your Obedient servant, Seneca

Wednesday, January 24, 2024

Anatomy Of A Modern Layoff: The Specialization Paradox

 "Specialization is for insects.  A human being should be able to change a diaper, plan an invasion, butcher a hog, conn a ship, design a building, write a sonnet, balance accounts, build a wall, set a bone, comfort the dying, take orders, give orders, cooperate, act alone, solve equations, analyze a new problem, pitch manure, program a computer, cook a tasty meal, fight efficiently, die gallantly."
        - Robert A. Heinlein (through the character Lazarus Long)

Specialization is part of the requirements of a modern civilization.  At some point, things become too complex for the generalist to make and maintain the things that make our modern civilization go - not just complex things like computers and autos, but what many consider simple things like construction and plumbing.

Using yesterday's post as a leaping off point, I wanted to consider the idea of a specialization paradox in modern employment.  To use this example, I will start with myself.

As most readers know, the bulk of my post college working life has been in a single industry,  biopharmaceuticals/medical devices (88% if you were wondering, less 2% for layoff periods and 10% for non-related careers).   That has given me both a general set of skills as well as a very specific set of knowledge and skills for a very specific industry - not just practices and experience, but regulatory knowledge and industry knowledge.

One question that comes up from time to time is "Can you find work in other industries that have similar titles of work?"  The answer is more often than not, no.  I referenced this last week as well, but in point of fact "Quality Assurance" is a field that encompasses everything from airplane manufacture to cheese manufacture, from computer programs to automobiles.  In some cases there may be some similarities and some similar documentation - for example, the International Standards Organization (ISO) Standards - but like almost anything, there are significant differences in application (the same is true of project management as well).

Additionally, many companies are not that open to the idea of a "generalist" - for example, every food producer I have looked at is very specific in that they want previous food industry experience to consider you.  As in "Do not bother to apply if you do not have it".  Which makes sense, as it makes sense for almost any industry:  after all, they want to bring in individuals that have the knowledge base and just need the specific product and corporate base.  And given the current market, they do not need to lower their standards.

Could one start all over at one of these companies?  I suppose the answer is a qualified yes, given two points.  The first is that the company really needs a "Fill in the Blank" Level I.  The second is that the individual being hired needs to be able to live on the entry level wage. 

The other reality is that, from the corporate side, they do not need to hire the unqualified or generalists.  When I started in the industry, things like Biomedical Engineering was in its infancy.  Now, the ability to get a job in this industry in many functions (though not all) presume a Bachelor's degree or above, mostly in a scientific field - the path I took into the industry simply no longer exists.  Thus be default, more and more people are entering in this industry - and many industries - already heavily slanted towards "I am doing this for a career".

Can someone up and change careers?  Of course it is possible and people have done it.  But it requires a number of factors both personal and professional, including the ability to start over completely and - depending on one's age - acknowledgment of the fact that one may not rise to anything but a lower rung.  It also requires the ability to weather the financial loss of income.

All of that said, let us now apply it to many of the folks currently being laid off.

Like me (and most), likely they have spent a certain amount of time and education and knowledge specializing in a field. Now, they find themselves out in the wilderness of the unemployed, competing not only against others but in some cases their own previous friends and coworkers.  There are some jobs - there always are - but these (right now, at least) are contracting more than they are expanding.  

What to do?  Scrap 10 to 30 years of education and experience to start over?  Try to find a job in a lesser role in hopes that it turns into something more (knowing, of course, that entry level opportunity-hungry and less expensive employees are coming up after you)?  Hold out hope that there will be a turnaround in your industry?  Start your own business and hope it makes it?  Just continue to look for work until benefits cease and you have to take something?

This is paradox of specialization:  having created a civilization that essentially requires it, we are required at some level to invest our lives in some field in order to work in it.  And yet that specialization harms us when we are in a position where there are more people in that specialty than jobs - because many other industries also have that level of specialization which are required and they, in turn, have people that have specialized to that.  Perhaps a bit contrary to Heinlein's point, specialization is not quite a thing to scoffed at for insects only; we benefit greatly from it.

The third option, of course, is the one I have chosen on Produce (A)Isle:  the semi-skilled laborer.  Even less previous knowledge and education required, but must be willing to 1) Take a reduced salary; and 2) Be willing to step down in the social order of things.  

Even when I was working Produce (A)Isle and my day job, the reduced salary was not an issue as it was additional funds (less so now, of course - and it alone would not support us, even at full time).  And the social order of things has never really bothered me - as I have told all that I have interviewed with, I am at a point where I no longer care about what my position is or how I am viewed; I am not building a career or starting an empire or trying to rise through ranks.   I just want a job that pays the bills, lets me follow my hobbies, and allows me to deepen the knowledge of my inidustry.

But I wonder, especially for those that have never done such work or have spent the last years doing their dream jobs which they have specialized in.  Will they be able to pivot if necessary?  Can they flip the switch and re-specialize? Will they be willing to do less if that is what there is?

I do not have answers of course, and as I am in the latter part of my career am probably not the best example for them.   But it strikes me that we are either on the brink of simple destruction or a creative destruction and renaissance.  How that plays out will be fascinating to watch.

Tuesday, January 23, 2024

Anatomy of A Modern Layoff: Social Media Edition

 It occurs to me that as I am spending more time than most around looking for work and layoffs, it might be useful to provide a perspective on what a "modern" layoff looks like.  I say this because the perspective has changed.

Once upon a time, layoffs were conducted essentially invisibly.  Perhaps it was something that was known nationally, like a major manufacturer, or perhaps unrecognized except to the local community.  It was known to the family and possibly friends, although this might not be as true as one might think:  even as an adult, I remember having to have a conversation with Uisdean Ruadh letting him know that it was okay to talk about the fact that he had been laid off as it happened to lots of people anymore and was not some kind of "black mark" on your permanent record.  One went about and found a replacement job quietly, combing the want ads of papers or looking out for the signs in windows.

As with everything else, it is not like that today.

Oftentimes it will start with a post on social media by the individual, running something like thus:

"The news is true:  I and XX number of my fellow employees were laid off at Company Y today.  Hard to believe it was already z years.  We did so much together in our time there.  We are (surprised/shocked/in disbelief/not surprised) at this.  Such an incredibly talented group of of people.

That said, I am now #Opentowork.

I have n number of years doing a, b, c and am looking forward to providing a future employer with the same level of (service/innovation/excellent work) that I have to my former employer.  

Looking forward to doing great things with someone else."

This - or a version of this, there is essentially a template now - will be posted on LinkedOut as well.  If one desires, one can put a small "#Opentowork" sidebar in one's photo.

The whole thing interests me on an intellectual level (beyond the personal level, of course) because of the public nature of it - in fact, people almost seem to transition from the last minute at the office to posting online. 

Full disclosure:  When I got laid off in Hammerfall 3.0, I did make a post on The Book of Face - not so much to advertise for work as to inform friends and family of the fact (sometimes these things are rather public; better to allay fears now), advertise for good thoughts and prayers, and re-emphasize that we are fine (essentially what I do here as well).  But I did not do the same on LinkedOut, other than indicate (invisibly to the public) that I was looking for a job.  Perhaps I am simply old school, but the point of this is to find a job, not to make a fuss about it.

In our social media world, this seems to be less of a concern - as with other things, the idea that we put everything in excruciating detail of our lives out for the public to see is present here as well.  

I will be fair that for most of the posts I have seen, denigrating one's former employer is hardly ever done.  That makes sense to me of course:  in essentially advertising one's current status, the last thing a future employer is likely to want to see is one tearing down one's former employer - makes the new employer a bit concerned, not doubt.

How does this end?  I am not sure.  As layoffs continue to accelerate and become more public, I do not wonder that this sorts of personal informational update posts will take on a more Spartan and informational nature:  "Laid off today.  25 years experience in x.  Looking for work in the following industries".  Part of that, I suspect, is simply that people will want to simply stand out in a world of general updates.

The other part, of course, is that at some point continued economic pressure means the push will be to secure employment - not necessarily the employment one "wants" but the employment one needs.

Monday, January 22, 2024

Tales From Produce (A)Isle: Keeping On Keeping On

 I have not written about Produce (A)Isle in a while - not because it has gone away, but simply because there has not been a lot to write about.

Part of the complication has simply been the holidays in general.  Travel to The Ranch cuts me out a week.  Additionally, when there are paid holidays like Christmas and New Year's, the regular employees need to have their guaranteed minimum hours -which means part-timers like myself lose hours.

The week before Christmas I only worked 12 hours, the week of Christmas 17 hours, then the week after Christmas 4.5 hours.  I then went to Old Home of course, which cuts all my hours.  Last week was another 17 hour week; this week is again 4.5 hours as I will be away starting Friday.

Additionally, we have just seen a drop in overall business.  It is a known cause:  the store is undergoing renovations which have taken significantly longer than anticipated; started in August of 2023 they were anticipated to complete by the end of October.  Here it is almost the end of January 2024 and they are not complete.  Predictably, people get tired of the confusion and the fact that items seem to be constantly moving to another place and choose another location.

In terms of the department itself (our remodels being long done now), we have effectively returned to the original configuration that was present when I started last May.  Apples and citrus fruits have been switched in their rows.  Apples continue to be featured along with mandarins.  No particular shortages, although the tomatoes this time of year are all hothouse grown and thus the palest shade of red I have seen.

In terms of longer term impact due to Hammerfall 3.0, I am not sure.  Obviously if I find a job outside of New Home that is not remote, it ends.  If I find a job in New Home but farther away, likely my hours will drop to 8 (Saturday close) as getting across town at quitting time is a nightmare.  If I get something that is remote, the current schedule could likely stay in place (although remote work seems more and more a remote possibility....thank you, thank you very much).

So a lot of uncertainty about the more distant future.  However, right up to that point I will keep working away, piling up the fruits and vegetables beneath waving palm trees on the sandy beaches.

As the saying goes, it is not much but it is honest work.

Saturday, January 20, 2024

Hammerfall 3.0: Week 5 Report

  Period:  13 January to 20 January

Positions applied to:  I applied to 4 positions this week.  Total jobs applied to/opportunities investigated are 60 unique positions (more on this below)

Note 1:  It used to be that Sundays were the big day for job openings to be published.  Not anymore; if I search on positions posted "in the last 24 hours" on Sunday and early Monday, nothing comes up - and by nothing, I mean a big "0".  

Note 2:  Federal holidays curtail position issuance as well, at least in the US.

Note 3:  I have started looking at the big corporate sites.  Locations are much more limited (generally, based on where major plants are).  Even then, not a lot of positions available.

This week effectively represents the first full month of looking for a new job.

Rejections:  I was rejected for 3 positions (11 total rejections).

Conversations:  I had one screening call with a recruiter for a position which although not in Old Home, is significantly closer. This is a recruiter that has the exclusive listing to the position (instead of the ones that try to "pick off" a non-exclusive position by just presenting a candidate).  The position sounds like a fit and the recruiter is submitting me for consideration; I should know more by Monday afternoon.

I also have an on-site interview for this coming Monday for a position in New Home. As a practical matter, I would define this potential position  as a step down/lateral move position with less career development potential and less money.

I checked in with my former employer.  It sounds potentially promising and I have been asked (again) to reach out in the event that I have an offer.

Finally, I have a pre-screen for a position on Tuesday.  This would definitely be a step down in position but at a large biopharmaceutical company, which has its own set of pluses as well.

Job losses:  This week in my industry, Lonza announced  for a site closing 218 job losses (interesting, Lonza has only owned the site since 2017 and no longer considers the site commercially viable), ~ 60 jobs losses announced at Allakos (ironically, I had applied there:  this explains that), Dewpoint Therapeutics announced 18 job losses, Ikena Oncology announced 20 job offers for a total of 316.  Adaptive Therapeutics announced layoffs without numbers; they previously also conducted layoffs not once but twice in 2023.  Bayer has also announced "major managerial layoffs" but has given no numbers.  PMV Pharma announced 30% layoffs but no numbers.

Of note, several of these companies still have pretty big war chests: Allakos still has $171 million, PMV has $229 million, Ikena has $175 million.  All are looking at pushing their cash runway into mid 2026, 2.5 years away. 

This certainly seems to suggest that, any news to the contrary, early stage Biopharmaceutical and Medical Device companies see a very limited path to funding in the next two years.


In what a complete lack of confidence building, there have been almost no jobs released this week.

My major check source is LinkedOut.  For 4 days running there no new jobs listed for Quality or Program Management in New Home or Old Home (or remote jobs).  Indeed and Glassdoor were not really any better.  Even for the rest of the week, they have been coming out it dribs and drabs - perhaps one or two total for the entire US for management in Quality Assurance or Project Management.

Yes, fair to say Monday was a federal holiday.  And also fair to say that my search to date is for particular locations.  But almost nothing released?  That sounds a lot like the industry is not in a recovery mode.

Interestingly enough, if I had Software Quality experience or Construction Management experience I might be a stronger case (in case you are wondering, Software Quality is really nothing like Biopharmaceutical Quality so no dice there).  For construction project management, they all (rightly) want some level of experience.

This market reminds me a lot of the 2009 job market. That year, I applied to 210 different positions over a three month period to reach the final stage at three employers and get an offer from a single employer.  At this rate I appear to be well on that track, although the availability of positions may hamper that.

Friday, January 19, 2024

Biopharmaceutical And Medical Devices: A General Overview (Conclusions)

Drugs Part I

Drugs Part II

Medical Devices 

Intellectual Property, Regulatory Submissions, Commercialization

Thanks for your patience in this detour from the normal posting I do here.  I had only intended this to be a one post response to a comment; the subject matter as I wrote really required me to address a great deal more than I had originally intended.

A few closing thoughts:

Caveat Lector

The first thing to emphasize is that the past four days are an overview, and a high level overview at that.  As with any regulated industry, there are a great many permutations and sub-categories that such a high level review cannot handle.  If you have more interest, I would highly recommend the US FDA website.  There is a plethora of information there.  And like most things, knowing how your government impacts products you use is always a good thing.

Success Rate

Commenter LibertyNews asked if there were statistics around failure rates of products.  That might be a little hard to analyze as companies are likely to not announce discontinuation of such products (especially for early compounds) .  A rubric I learned long ago which might still prove useful as a guide is

For every 1000 compounds identified, one will move to Non-Clinical testing.

For every 100 compounds that enters Non-Clinical testing, one will move to Clinical Trials.

For every 10 compounds that enter Clinical Trials, one will move to Regulatory Submission.

For every 5 compounds that enter Regulatory Submission, one will be approved.

I do not have similar statistics for Medical Devices.  In some ways they can be less complex, but I imagine the ratio is in the same ballpark.

E.g.  Starting a Drug or Medical Device in no way guarantees a final approved Drug or Medical Device.

Timing and Cost

Another relevant question is "How long does it take to do this?" and "What is the cost?"

Timing varies (as with anything), but in 2022 an article stated it took 10-15 years to get a new Biopharmaceutical from concept to regulatory approval.  The same article lists the cost anywhere from $985 Million to $2.4 Billion, depending on company size, product market, etc.  In the past, I have used the number $1.5 Billion, which seems to fit in nicely

For Medical Devices, I found the time frame of 3-7 years (which seems a bit low to me in some cases). In 2010 a cost study in the same article suggested anywhere from $31 Million for a 510(k) cleared device to $94 Million for a FDA approved device.  This article from 2022 give a number of $522 Million for a complex medical device (probably a Class III).  I would say double the higher amount from 2010 to $188 Million for a lower end these days.

E.g. It takes a long time and a lot of money to develop and get a new Drug or Medical Device approved for commercialization.

Why This Matters

So back to a version of the question posed by FOTB (Friend Of This Blog) Leigh about the contraction of Biopharmaceutical/Medical Device Industry.  To be clear, these are only my thoughts on the matter and not really based in anything but my opinion and observations.

I will start with a general observation:  the industry goes through troughs and peaks, like any other industry.  2008/2009 was a trough.  2023 was a trough.  There is a chance that we are entering a peak period in 2024 if the JP Morgan Conference from this year is any indicator:  Investment firms are reportedly ready to offer investments again as they have made a lot of money and are looking to invest again. On the other hand, what I am seeing in the industry news suggests companies are hunkering down for another year of frugality.  Mixed signals at best, to be sure.

Hopefully from the past four posts, I have conveyed some of the processes and challenges of the industry.  It is time constrained, labor intensive, and finance dependent. 

Most companies follow the same initial process:  An idea is proposed which is able to gain traction and attract initial funding.  Throughout the life of the process, initial funding is sought to continue to develop the idea through development.  Most companies are able to reach a Phase 1 trial for Drugs or a Design Validation for Medical Devices.  But the outcomes of those can be uncertain (much more so for drugs) and a poor clinical outcome can spell the end of the program and possibly the company.

Cash management is something that not all firms, especially new firms, are as attendant to as they should be.  It is very exciting to be a start-up company have all the start-up perks that similar technology companies do.  It is much less exciting to work at a cash constrained company with restrictive budgets early in the process, but one is more likely to product making it to the finish line than the other.

For all the products that crash and burn, of course, there is likely no recourse.  Occasionally there may be a salvageable product or data that may indicate another path forward, but largely a failure is a failure.  The money is gone, the time is gone.  For most single product companies with no approved products, there is no recovery from this.  Layoffs and "focus" will follow and perhaps their assets will be purchased or merged with a more successful company, but more often that not, the result is the same:  the product and the company disappear, only to appear in the resumes of those who worked there.  

Even if a product does make it to commercialization, the challenges do not end.  Reader Shepherd introduced me to the concept of the "Cost Floor" for semiconductors, the cost below which a thing cannot be produced.  To my mind this is another version of the Cost of Goods Sold (COGS), which is the cost of a drug or medical device to be manufactured and produced.  Additionally, the company has spent upwards of $2.5 billion to reach this point as well as covering costs for the other products that did not make it and to cover new research for new products.  They (and their investors) expect that money to be made back.  And with the exclusivity periods in place, they have a limited time to do it before generics come into play.

Insurance companies and the government get involved as well, dictating what they are willing to pay (or what they believe the price should be).  This may or may not be reflective of the actual costs.

Generics can be a great boon to the consumer, but it should be born in mind that generics only replicate existing products; they do not produce innovative ones.  They can product 20 replicants of azithromycin or acetaminophen, but they will not be producing the next generation or anti-biotics or pain relievers (and, by law, if it is generic is has to be within a very close range of the original product.  If it varies by more than a narrow percentage or is in any way different than the original form, fit or function, it is a new product).  Also keep in mind that a great deal of the cost of the original product is tied up in Clinical Trials, something which is required by law to be done - and which generic companies will not do.

A second thought to be born in mind is that higher costs subsidize lower costs elsewhere.  For example, companies can offer diphtheria vaccines or AIDS drugs at a much lower cost than they may charge developed countries - but the cost of that manufacture does not go down because the price charged goes down. That cost has to be made up elsewhere. 

So in a real sense, the cost comes down to cost of the research, cost of the product, cost of the clinical trials, and cost of manufacturing.  But these are not nameless costs:  they are facilities and equipment and people and supplies, both directly involved in the process and indirectly involved in the company (we have not touched on it, but all of the normal business functions - finance, accounting, non-manufacturing purchasing, janitorial service, administrative - have to exist as they do with any company).

The Biopharmaceutical/Medical Device Industry falls into what almost every politician defines as a "good (insert country of choice) job":  generally the pay is good, there are benefits, and involves manufacturing and technical development. It can employ both the highly educated and the high school graduate.  It produces products which genuinely improve human lives.  Likely everyone reading this article knows of a friend or family member whose life was saved or quality of life improved by a Drug or Medical Device.  To counter that, the industry is expensive, time consuming, and more often generates failures than successes.

Is there a model that perhaps prevents this trough/peak outcome?  Hard to say.  Remove the profit motive, and the flow of innovative products may not completely shut down but it will decrease significantly.  Initiate severe enough price controls and companies will shut down production or begin to find ways to accept more risk to cut costs even more (which can look like offshoring).  

Like most things, I suppose, there is no "answer".  There is merely trying to find and address the balance between patients, companies, investors that fund the advancements, and governments that regulate the products and protect patients - while continuing to enable innovative solutions to be discovered.

Thursday, January 18, 2024

Biopharmaceuticals And Medical Devices: A General Overview IV (Intellectual Property, Regulatory Submissions, Commercialization)

Drugs Part I

Drugs Part II

Medical Devices 

Today I would like to review some processes which are across both Drugs and Medical Devices. These processes happen across multiple portions of the processes.

Intellectual Property

(Note: I  am not a lawyer.  This is not legal advice.  These are observations based on my experiences in the industry.)

The key to the entire biopharmaceutical is intellectual property (IP):  without the sole right to a particular compound or device, there is little incentive to develop it due to costs and time. 

Timing of the filing of the patent (in the U.S.) is critical.  There needs to be enough information to clearly differentiate the compound or idea from all others.  But U.S. patents run for 20 years:  do it too early and you will lose market time due to overall time lengths of development (more on that tomorrow); do it too late and the risk is that another company or individual will be first to file the patent.

As part of this process, when a compound or concept is believed to be viable, a patent search is conducted to make sure that the thing has not already been patented.  These are searches are critical and are not as bullet proof as you might think.  Sometimes development work happens and it is discovered that a patent already exists for the compound, costing time and money (and sometimes, the jobs of the people that missed it).

Once the patent is secured, IP becomes a tightly guarded secret.  Access is limited.  There are annual trainings to remind all employees about the importance of it.  Does industrial espionage happen?  Possibly, although you do not hear a lot about it.  You are more likely to read about patent infringement, where one company believes another company has used part or all of its patent (of note, this is most often with large corporations and highly profitable products.  No-one, for example, is fighting over the antacid market.).

Another way IP is used is to purchase the right to use parts of a patent.  This can help where certain things like particular device attributes are already developed by another company or where there is already an existing cell line or cell scaffold; why reinvent the wheel?  For these items there is usually an up front payment, a series of milestone payments based on advancing through the development process, and then a percentage of any profits.

Regulatory Submissions

Ultimately, the purpose of all of the development and clinical trials/clinical validation is to have an approved product. To do this, one must get the approval of the appropriate regulatory body.  For the U.S., it is the Food and Drug Administration (FDA).

To be clear, no company shows up at the end of the process and says "Here is our submission!  Approve away!"  Interactions with the FDA - often referred to in the industry as "the Agency" - start very early in the process.

The FDA encourages this sort of interaction.  It serves the primary purpose of protecting human health (by preventing bad ideas or products from moving forward) and moving products to market in an expeditious fashion (by providing guidance).

While one cannot just ring up the FDA for an ask, there are definitely defined touch points.  One has to get an identification number for the Drug or Medical Device, which will start the process.  To allow the product into clinical testing, one files an Investigational New Drug Application (IND) or Investigational Device Exemption (IDE).  After each phase of the clinical trial, the FDA is usually consulted (So called "End of Phase X" meetings).  Other interaction may occur due to need or due to specialized programs where the FDA encourages interactions to speed up the process, such as Breakthrough Therapies or Breakthrough Devices.

But hopefully, after all the work is done, a final approval submission can be made.

The submission packages, of course, are standardized (for Drugs, they are now globally standardized).  For a New Drug, one files a New Drug Application (NDA).  For a New Biologics, one files a Biologics License Application (BLA).  For a generic Drug, one files an Abbreviated New Drug Application (ANDA).  For a New Medical Device for which there is no previously existing similar device ("Predicate Device"), one files a Pre-Market Approval.  For a New Medical Device for which there is a previously existing similar device, one files a 510(k).

A short description is that everything about the Drug or Medical Device is put into the submission characteristics, mechanism of action, supporting studies,  proposed use, manufacturing process, raw materials, testing, Non-Clinical Study Data, Human Clinical Study Data, proposed documentation to be provided to the Physician and Patient, labeling and all commercial materials.  These are now submitted through a portal at the FDA; at one time these were submitted physically.  It is within my memory of copying, binding, and sealing up multiple banker's boxes of submission to be sent to the FDA (I am likely the last generation that did this).

The FDA will review the submission.  There will be questions and comments.  There may be hearings.  There may be direct interaction with the FDA. At the end of it, there are two outcomes:  an approval (either with or without modifications from the original submission), or a Complete Response Letter, which is a rejection of the application with specific items that need to be addressed (up to and including an additional clinical trial).


Great!  A company has received approval for its Drug or Medical Device and ready to make money!  

Well, of course it is not that easy.

Early on, a target market was identified.  That market now has to be actualized.  

What is the name of the product?  Most products end up with two names, the trade name and the original company.  In the U.S., you will see this in advertising;  For, example Ozempic® (semaglutide).  Ozempic is the trade name, semaglutide is the name it was developed and filed under.  A rather large amount of time and money is spent on this.

What is the "vibe" of the product?  All marketing materials including labeling, advertising, and provided inserts need to be designed and approved by the FDA.  They need to be different enough to distinguish them from other products and unique enough to be memorable.

How big is the market?  The company as part of its manufacturing process should have estimated the commercial launch needs and have validated the process.  Nothing more embarrassing than to launch a product and not have enough of it.

A sales force will need to be developed.  Insurance companies and Pharmacy Benefit Managers will have to be contacted to get the product on the formulary or allowed devices. If not, the company has to plan for how they will make the product available.  Distribution networks will need to be identified and activated.

Then, of course, physicians will have to prescribe the product.


After all of this - all of this post and the previous three posts - the company will start to generate revenue.  Not profit - this has been a significant investment, as we will review tomorrow, but revenue.  Profitability is still a ways off.

Tomorrow we will look at some conclusions, including success rates, timing and costs, and why all of this matters.

Wednesday, January 17, 2024

Biopharmaceuticals And Medical Devices: A General Overview III (Medical Devices)

Drugs Part I

Drugs Part II

(Note:  As with Drugs above, this is a very high level view of a very complex and multi-year process and is only intended as an overview.)

A proposed Medical Device definition is "A contrivance designed and manufactured for use in healthcare, and not solely medicinal or nutritional".  A more "conventional" regulatory definition is here: in short if your item is intended to treat, cure, mitigate, or prevent disease and is intended to impact a human or animal system not using a chemical action internally and/or not activated via metabolic systems, it is a device.

So to answer the question, lots of things are a medical device.  A tongue depressor counts.  So does a scalpel.  So does a hospital bed.  So does an MRI machine.

But, all devices are not created equal and so there are classifications for devices.  In the United States, there are three classes (Class I, Class II, Class II) which are identified based on their risk to patient and user.  Class I is the "least" risky, Class III is the "most' risky.

There are distinct steps for designing a medical device - perhaps unlike Drugs, the process is a lot more standardized.  These steps are found in the US Document CFR 21 Part 820 (Quality System Regulations) and in the ISO Standard 13485 (Medical Devices - Quality Management Systems).


All devices start with identifying User Needs:  what does the end user (patient, medical personnel, even marketing) need the product to do or be?   This is much more of an activity that it may seem, as it can involve getting input from a great many sources.   The User Need will be phrased in the form of a statement - for our purposes today, we will identify a User Need as "The product casing should be blue".

User Needs are then usef to generate Design Inputs, which are "The physical and performance requirements of a device which are used as a basis for device design" (21 CFR 820.3 (f)).  Each Design Input must be individually identified and must be clear, unambiguous, and non-conflicting with any other Design Input. As you can imagine, this will lead to hundreds or even thousands of Design Inputs.  Our example above will be translated into "The product casing must be Pantone Classic Blue Part Number #19-4052".   That may seem very specific - and it is intended to be.  Each input must be able to be objectively verified.

At this point a Design Review Team will be called together.  This will consist of personnel from all concerned departments - R&D, Engineering, Quality, Regulatory, Marketing/Business Development, Manufacturing, Supply Chain - and an Independent Reviewer who is not directly involved in the project but has the educational and scientific basis to assess the project.  All will be reviewed, unclear inputs corrected, additional needs identified.  When all agree on the User Needs and Design Inputs, the project will move to Design Output/Design Verification.

Design Outputs are "the results of a design effort at each design phase and at the end of the total design effort" (21 CFR Part 820.3 (g)).  The outputs will form the basis of the final design documentation - batch records, testing, labeling, etc.).  Each Design Input will have a Design Output which will need to be independently verified.  All of these Design Outputs will be putting into a Design Verification Protocol - again for our example, the Design Output would need to be "Product casing color is verified as Pantone Classic Blue Part Number #19-4052" - likely pulled from the manufacturing documentation for the casing in this case.

Another Design Review will take place to ensure that there are no new User Needs or Design Inputs, that all Design Inputs have Design Outputs, and that the Design Outputs are verifiable.  If approvable, it moves to Design Verification.

Design Verification is (rather straightforwardly) ensuring the Design Input meets the Design Output.  Personnel will move through the Design Verification protocol and verify and/or test every single Design Input.  Each Design Output will be recorded as meeting the Design Input, partially meeting the Design Input, or not meeting the Design Input.  At the end of this process the Design Verification Protocol will be reviewed and those Design Outputs which are found to not fully meeting the Design Inputs will be reviewed for additional clarification, correction, and testing.  In our example, if the manufacturing paperwork could not verify that Pantone #19-4052 was used on the casing, this would need to be resolved by an investigation and perhaps a remanufacture of the part - or, the User Need could be re-examined to see if that shade of blue is really needed, or just any "blue".

Assuming all items have been identified, a Design Verification Report is generated, to be presented to the Design Review Committee for approval. 

As you can imagine, there is a lot of documentation (physical or electronic) generated by this.  One of the most critical items is the Design Trace Matrix, which traces each User Need to Design Input to Design Output to Design Verification Result.  This document allows complete traceability up and down the design process.

A note:  This process takes place for each major component of the system.  For a system that has hardware/instrumentation, software and firmware, and consumables/reagents, every item will have a design history.  

The product is ready to move to Clinical Validation.

Risk Management

As noted above, the consideration of risk is a primary factor in determining the classification of product.  A risk - in Medical Device terms - is the combination of the probability of the occurrence of harm (injury or damage to people, property, or the environment) and the severity (measure of the consequences of a hazard) of that harm.  The ISO standard 14971 defines the risk management standard and is really the gold standard for all risk management (and largely a universal consensus standard).

A very short definition (for a very long process) is that intended use of the device and its use conditions are identified, along with what safety would look like and potential hazards and harms identified (including not just impact on the patient, but on the user (electrical hazards, chemical hazards) and the environment (spills, disposal of reagents)).  Using a numerical system, the risk are graded and evaluated.  Where risks exceed an acceptable level due to impact or frequency, risk mitigation and/or controls will need to be introduced, which may very well impact the Design Inputs/Design Outputs/Design Verification which in turn may then require another Design Review Meeting.

Another useful tool is the Failure Mode and Effects Analysis (FMEA) or the Failure Mode Effects and Criticality Analysis (FMECA).  Every potential failure mode is identified and evaluated against probability of occurrence, severity of that occurrence, and impact of the occurrence (for the FMECA, criticality of the failure is also evaluated).  Again, a rubric is used to evaluate unacceptable levels of failures.

The point of this entire exercise is to identify all risks and move them to acceptable risk levels (sometimes called "residual risk levels").  Like drugs, all medical devices entail some kind of risk; the goal is to remove as much risk of failure as possible and control the rest. 

Using our example above, the risk would be assessed under "What is the impact if the casing is not Pantone #19-4052"?  Possibly nothing - but perhaps in a clinical lab setting, that shade of blue may be not be able to be discerned for certain vision issues and could conflict with other similar pieces of equipment.

As with the Design Process, there are multiple iterations of the Risk Management Process.  The final documents will be held in a Risk Management File, which should contain every known risk for the product.  When a new risk is uncovered (either in development or in use), it should get added to the Risk Management file and assessed - in some cases, it may entail a  redesign.

(A note for general use:  Risk can only be avoided, mitigated, transferred or shared (to someone/something else), or accepted. True in real life as well as in medical devices.)


Validation (or as it is often known "Clinical Validation") is the use of the product in the potential use environment.  The difference between verification and validation, if helpful is:

Verification:  Did we make the thing right (e.g., per the Design Inputs)?

Validation:  Did we make the right thing (e.g. per the User Needs)?

A protocol will be developed and clinical sites engaged as well as all items approved by the Design Review Board.  Similar to the clinical process as identified in Drug Overview Part II, there is a whole set of processes involved to insure patient safety and control of the clinical trial. 

At the conclusion of the Clinical Validation, a final report will be generated. The results of the Design Verification will be added to the Design Trace Matrix so there is complete transparency up and down the design chain from User Need to Design Validation.  Any Design Issues or new Risks will need to be addressed, and possibly a second Clinical Validation conducted  Once all issues have been resolved and the report issued, the product will be ready for regulatory submission.

Quality Systems

Underlying all of this, of course, are Quality Systems. Just as with Drugs, there needs to be a system which ensures that all products are documented, manufactured, and released per written procedures and per the approved Design Documents. Just as with drugs, one needs a Quality Manual (corporate statement and discussion of the systems to ensure Quality), Standard Operating Procedures to cover systems like documentation, manufacture, material receiving and testing, product testing, and release.  Materials have to purchased and verified per specification.  Manufacturing facilities need to be maintained for cleanliness and environmental control.  Manufacturing equipment has to be purchased, qualified, and maintained.  Records have to be retained.  The individual Device History Records (batch records for manufacture) need to be created, approved, and executed.  The Device Master File, including the Design History, the Risk Management File, and all documents need to make the product, needs to be controlled and maintained.  Personnel need to be qualified and trained.  Variances like deviations and nonconformities need to be captured and assessed.  Improvements in the form of Corrective Actions and Preventive Actions need to be identified, investigated, and executed.

In short, everything that was done for Drugs is effectively also done for Medical Devices.

Tomorrow, we will discuss Intellectual Property, Regulatory Submissions, and Commercialization.

Tuesday, January 16, 2024

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

 In Biopharmaceuticals And Medical Devices: A General Overview I, we looked at the underlying basis of all drugs (pharmaceuticals and biologics) and discussed the development of a compound from initial discovery to the completion of Non-Clinical Laboratory Studies and the decision to move forward.  Today, we are picking up with starting clinical manufacture and clinical trials.

There are really three streams here:  clinical trials, clinical manufacture, and regulatory submission.  I am going to defer the regulatory submissions to later in the week as there are some small similarities with the Medical Device process.

Clinical Manufacture

Clinical manufacture is the manufacture of a drug to support a clinical trial.

Typically, clinical manufacture is divided into two phases, the manufacture of the actual compound (called an "Active Pharmaceutical Ingredient" for pharmaceuticals and "Drug Substance" for biologics) and the manufacture of the finished form of the product such as pills, capsules, filled liquid vials, lyophilized solutions, etc. called the  Drug Product.

The work done in the investigatory and pilot plant manufacture will be scaled up in volume to support the clinical trial, for example from a 5 L fermentation to a 50 L fermentation to a 600 L or 1000 L fermentation.  Process Development will work to find the ideal conditions for manufacture and all required buffers, medias, or reagents.  Process Sciences will develop criteria to evaluate the product - called "specifications" - which will allow testing during manufacture ("in process"), after manufacturing ("release"), or over time to evaluate how long the drug product remains "good" ("stability").  They will also identify tests to support these criteria.  

At some point, the developed process and associated tests and specifications will be transferred to the Operations Group.  Here, a variety of operations - Manufacturing, Quality Assurance, Purchasing and Supply Chain, Quality Control - will purchase and test incoming raw materials, write and approve manufacturing records for every part of the process, write and approve testing documents for all identified tests, and create final release documents so the product can be evaluated and made available for clinical trials.  The facility to be used will have to demonstrate that the meet the required regulatory and physical conditions for manufacture including temperature and humidity control, air particulate control, and micro-organism control. The equipment to be used - both manufacturing and testing - will need to be qualified to verify it is installed correctly, works correctly, and works for the process. Likewise, all quality control testing will have to be qualified to verify that the tests are repeatable, give verified data, and can be performed by multiple personnel potentially in different labs.

One note: development of the manufacturing process and manufacturing may be conducted in-house at the company or outsourced to a third party vendor, called a Contract Manufacturing Organization ("CMO") or Contract Development and Manufacturing Organization ("CDMO").  There are trade-offs between time and money; for many small companies they have no choice but to use a CMO as building out and qualifying an in-house manufacturing plant can be expensive and time consuming.

In the background of all of this (and by regulation), every company has a Quality System, which is the System put in place to guarantee that all product manufacture is conducted in such a fashion to ensure the identity, strength, purity, quality, and safety of the product.  This includes instructions on how to do things ("Standard Operating Procedures", or SOPs) for every aspect of the organization that is regulated, how to evaluate issues and failures (Deviations or Nonconformities), how to make improvements (Corrective Actions and Preventive Actions), how to manufacture and test the product (as above), and how to release the product. For all of these documents, evidence of training must exist.

Assuming all of this is in place, manufacturing will start.

Manufacturing will often start with a "non-GMP" batch, sometimes called an Engineering Batch.  This lot cannot be used for clinical trials but can demonstrate that the process can generate the Drug API/Drug Substance/Finished Product at sufficient scale and with sufficient quality.  If successful, manufacturing will move into GMP/ Clinical Trial material mode.

As trials advance (see below) the manufacturing and testing will progress as well.  As more is known about the product, tighter controls will need to be put in place.  Sometimes a problem only reveals itself over time through stability, which may mean going back to development.  Better and more extensive testing will develop.  And the process size will scale up as well to support commercial manufacture; for biological products, up to 20,000 L fermentation vessels exist for manufacturing

Clinical Trials

Clinical trials for Drugs in the U.S. (and largely, the world) are divided into three phases.  Each phase gathers information about the product and its impact on patients, but each phase also has a primary goal:

Phase 1 (also Phase I or P1) evaluates safety, or "Is the product (at a high level) safe?"

Phase 2 (also Phase II or P2) evaluates efficacy, or "Does the product do what we think it should do?"

Phase 3 (also Phase III or P3) evaluates dosing range, or "What is the best dosing level that maximizes benefit and minimizes patient impact?"

The primary concern of all Clinical Trials is ultimately the safety of the patient (this largely derives from World War II, where live in human testing was conducted (Read up on the testing in concentration camps and Unit 731 of the Imperial Japanese Army.  It is horrifying.).  To this end, 21 CFR Part include items specifically around the involvement of patients, physicians, and companies (Parts 50, 54, 56, and 312) as well as the International Committee on Harmonization document E6.  In short, patients must be fully informed and able to withdraw at any time.  Physicians cannot have a significant financial interest in a company for which they are testing a Drug Product.  An Independent Review Board ("IRB") must review all documents associated with a trial and make sure it protects patients, is ethical, and is scientifically justified.

To use an unapproved Drug Product ("investigational drug" in the regulated world) in humans, the company ("Sponsor")  is governed by 21 CFR Part 21 Part 312, Investigational New Drug Application.  In short, one has to provide an Investigational New Drug Application (called an "IND") and have it approved by the US FDA prior to starting the trial.

The IND will provide a description of the product, a history of its development, proposed release and stability criteria,  a summary of the Non-Clinical Laboratory Studies (GLP and non-GLP Compliant), and the proposed Clinical documentation.

Leading up to the IND, the company is developing documentation for the Clinical Trial:  an Investigator's Brochure, to explain the product and the trial to physicians and site staff; a Pharmacy Manual to explain how to prepare the product for patient use; an Informed Consent which explains to the patients about the trial and their potential participation and potential risks; a Clinical Protocol, which explains how the trial is to be conducted, what is to be tested, how patients should be included or excluded based on criteria, and the endpoints of the trial; the Statistical Analysis Plan created, which ensures that the study has the minimum of number of patients to power the study statistically and can deliver definitive data; and the Clinical Trial Documentation, which is used to record all data for the trial (often this is now electronic).  All of the documents are reviewed and approved internally by the company, by the IRB and by the FDA upon submission of the IND.  Any of these parties can require changes to any of these documents, which then need re-approval.

At the same time, the company is also identifying sites which would be willing to conduct the clinical trial. This is a lot more work that it may sound like:  there are always more trials than sites and some sites are more desirable than others.  For each site a contract must be written and signed, a budget prepared and approved (sites are paid to conduct these trials), all the documentation above provided, and supporting supplies provided.

Conduct of the Clinical Trial

Assuming all the product is manufactured and approved, all clinical documentation is approved, clinical sites have been identified and initiated, and the IND has been approved (or revised and approved as needed), the clinical trial can start.

Clinical trials escalate in size and scope as they progress.  A Phase 1 trial can have as few as 20 patients and 3 sites; a Phase 3 trial can have as many as 7,000 patients and multiple sites in multiple countries.  Study progress is based on the ability to enroll subjects - and have them complete the program.  Not all patients can be evaluated.  Patients may be rare, depending on the inclusion criteria.  If an Unexpected Adverse Event or Serious Adverse Event happens - something that causes transient, partial, or permanent damage to the patient including death or disablement - the trial may be stopped temporarily or permanently. 

During the trial, company personnel from the Clinical, Medical Affairs, Regulatory Affairs, and Quality Assurance departments work intensely with the sites.  Clinical Trial Monitors or Clinical Trial Associates contact and/or visit sites frequently to check up on the trial and audit documentation and product.  Medical Affairs personnel assess data and answer questions.  Quality Assurance evaluates potential complaints.  Regulatory Affairs reports any Unexpected or Serious Adverse events to the Regulatory Authorities.  Meanwhile as needed, Manufacturing, Purchasing and Supply Chain, Quality Assurance, Facilities, and Quality Control continue to do their jobs to ensure that Drug is available for the study.

Periodically the trial may be evaluated by statisticians to evaluate the data.  There may be a reason to cut the trial short, either because the data is overwhelmingly indicative of the endpoints or the data demonstrates no progress to the endpoints or is even risky.


As you can hopefully see, there is a lot to "testing the product in a person".

Perhaps unsurprisingly, a main factor is cost - not just of the all the work to make the product and get to the clinical trial, but for the clinical trial itself.  I would hesitate to provide a number for even the most basic of clinical trials, but it is easily in the millions of dollars for a Phase 1 trial - and goes up from there.  

And the cost escalates of course.  Phase 2 trials are more expensive than Phase 1 trials, and Phase 3 trials are even more expensive.  And the cost of scaling up manufacturing and testing increases as well.  

The funding of a company really determines its future at these stage. Most companies have enough funding to complete a Phase 1 clinical trial.  The hope is that the data from that Phase 1 trial will support getting additional funding to continue to Phase 2, then Phase 3.  Obviously, a failed Phase 1 trial pretty much can spell doom for an early stage company and many layoffs occur after a "setback" in the Phase 1 trial.

But it can happen at any step.  Phase 2 trials fail as well, and Phase 3 also.  The cost of those failures is significantly increased in terms of money as well as prestige:  a Phase 3 trial means that at some point, some signal was missed in an earlier trial.  This can reflect poorly on the company's executive management and scientific basis.  Established companies with commercial products can survive this; most non-commercial companies cannot.

And we have still not arrived at the ability to sell a single Drug Product and thus generate any revenue for all of the work done to date.

Tomorrow we will turn our attention to Medical Devices and how they reach this same point of pre-submission.

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).

Sunday, January 14, 2024

Obeying In Absence


Obedience to God is itself a challenge at times.  Obedience to God when there seems to be no evidence of God, even more challenging.

As I read this quote of Lewis', I ask myself how often this has impacted me:  How often I have been in a universe where I have seen no evidence of God actively out there and continued on?   The reflection is not a good one: more often than not, I can barely obey God (or have failed to obey Him) when I am quite aware of His presence (and what He expects of me).  

Have I ever been completely bereft of the presence of God?

A hard question.  That I can consciously think of, no.  Even when there situations where I felt that I was completely abandoned (due to existing circumstances), there was never that sense that there is no God.  But that probably speaks more to the ease of my own life rather than any real circumstance that I found myself in.

Which likely says one of two things:  Either it really has never happened, or God really does not trust me to do so in such circumstances due to my weakness of belief.

Saturday, January 13, 2024

Hammerfall 3.0: Week Four Report

 Period:  06 January to 12 January

Positions applied to:  I applied to 25 positions this week.  Total jobs applied to/opportunities investigated are 56 unique positions.

Rejections:  I was rejected for three positions, two within a week of submitting to the position.  The third one was a six hour turnaround, which is my new record.

Conversations:  I had  one phone interview and one phone screen.

The phone interview was an initial interview with the hiring manager for a position in New Home consisting of 30 minutes.  I should know soon if I advance to the next round.  I will confess I am ambivalent about the position.  Based on what I heard, it sounds there is a tangled mess of overdue actions they expect the position to come in and sort out.

The second was for a 1 year contract position.  It was with recruiters - recruiters are always gamble as they are super excited and hurry-hurry to get you interested and in line, and then you may never hear from them again.  I always take it with a large grain of salt.

Job losses:  This week in my industry, job loses were announced at Organon, Affimed (German company), Exelixis, C4 Therapeutics, and Nevro:  283 Job losses confirmed plus "percentages" of others.  Possible layoffs were announced at Lifescan.  Angiodynamics announced closure of their Queensberry, and Glen Falls NY plants in Q2 2025 with up to 350 workers impacted - interestingly, they are closing down a corporate owned site and moving to a outsourced manufacturing site, something which I suspect will become more widespread this year..

Mood:  Although I have had my down periods this week (Thursday afternoon was bad), on the whole it has been an okay week.  Partially, of course, being up here at The Ranch has been therapeutic and seeing "my people" has been refreshing (as I often joke, 90% of my in-person social group is here, not in New Home).

Sending things off into the InterWeb sphere is not a very rewarding process.  Things go off and the feeling that nothing is happening is oppressive at times.  Things are happening of course; it is just that I cannot see them going on.  Sometimes just waiting for the process to work and trusting God feels like the bigger struggle than just not having a position.

Friday, January 12, 2024

On Using A Wood Stove and Independence

 During my stay here at The Ranch, I had a bit of a problem to deal with.  The dryer had gone out.  I had arranged for a visit by the local repairman (Sears seems to be the one in the area).  Sure enough, the heating element was gone and it has not been upgraded like many other parts (I suspected the heating element, but after watching some Tube of You videos, suddenly there were a lot more possibilities).  

The part was ordered.  Sure enough, it was a three day turnaround which might get here but turned out to be a 7 day turnaround (so after the part arrives, I will ask Uisdean Ruadh to open the house up and then lock it back down).  Which meant I had a week's worth of laundry that needed doing before I left

Enter the wood stove.

T-shirts and socks on ironing board; skivvies (not pictured) on hearth

It is not an ideal system of course; things will take a while to dry and likely will be drying until tomorrow.  But it was a ready solution to a problem.

Which got me to thinking about something like the wood stove.

It has a multitude of uses.  It heats the house of course - well, mostly the living room and the office and to a lesser extent, the dining room and the kitchen (bedrooms, you are out of luck).  And I use it to heat water when I am here for tea (ideally if I had a french press, for coffee as well).  When the power went out last year, I used it to make dinner (noodles) and used it just for fun while I was here to make ramen.  And now, I have found another (albeit not completely ideal) use.

It represents independence, the ability to make do for one's self.  As long as there is the stove and a supply of wood (and an occasional chimney sweep), one is not dependent on the larger system for several things.

The drier is a great convenience of course, and I do love the way clothes feel coming straight out of it.  And so is the central heating that we have here.  But I can make do (at least during my visits) without both). 

A useful thing, that wood stove.  But more useful still for what it represents.

It is freedom.

It is freedom from a lot of things.  Freedom from dependence on the power grid.  Freedom from dependence on the company that runs the power grid and the governments (local, state, federal) that are somehow involved with overseeing the power grid.  Freedom from fear in the event of a power failure.  Freedom from freezing at night.  Freedom from being unable to cook anything.

Freedom to roast a marshmallow if I desired as well, I suppose.

It strikes that this freedom, this lack of dependence, is what Our Political And Social Betters (OPASB) hate.  They hate the idea that people can live their lives without oversight.  They hate the fact that people can provide for themselves instead of relying on the social constructs, companies, and government.  They especially hate the fact that those who do such things are not "leaning in" to the idea of centralization but are "leaning out" - sometimes as quickly as they can.

Perhaps, someday, someone will make a flag for the independent lifestyle.  Might I suggest we plant a wood stove in the middle of that?  It is a symbol of both independence and independent living.