Biotech Manufacturing Software & Support

James T. Kirk, Plant Manager

2013-05-18T15:27:00.000-07:00

If you think about it, the starship Enterprise is a plant (i.e. factory).

It's a plant that manufactures light-years.

Construction of the USS Enterprise NCC-1701 as depicted in Star Trek 2009

Kirk is the Plant Manager.

Spock is the Director of Technology.

McCoy is charge of EH&S.

Scotty is Director of Production (i.e. running the warp drive that produces all those light years).

And the SCADA (supervisory control and data acquisition) system is what they call the Enterprise's "Computer."

Nothing illustrates this better than this one scene from J.J. Abrams' 2009 reboot of Star Trek.

SPOILER ahead... If you haven't seen it, you should stop reading this post and go rent it on Amazon.

Then, you can go look up movie times and get tickets to the sequel(out this week).

Anyway, at some point in the movie, Kirk and Scotty get beamed aboard the Enterprise, but end up in utilities. Scotty gets beamed into the piping so Kirk has to go free him.

Where does he go?

Looks like an HMI (human machine interface) to me....

What's he doing? Oh, manually overriding a valve.

It's hardly recognizable as an HMI with those sexy lights across the top and snazzy faceplate graphics.

I guess they covered basic SCADA training in Starfleet ensign training.

But make no mistake. That looks like either a PLC (programmable logic controller) or a DCS (distributed control system).

And this is just for the utilities. The control system for the entirety of the Enterprise would be far more sophisticated.

I keep reading about how long we have to wait before we get Star Trek technologies... or how long before we have hoverboards...

But the fact of the matter is this. So long as we are minting CS and ChemE grads whose purpose in life is to get internet users to click on ads (as opposed to them creating and deploying SCADA software), it's going to be a long, long time.

At Zymergi, we're doing our part, furthering the deployment of these technologies by helping install, validate, and use these SCADA systems to manufacture biologics.

How about you?

Other reading:

Why Isn't Automation Sexy?

All screenshots are from the Star Trek 2009 movie from Paramount Pictures, Spyglass Entertainment and Bad Robot Productions.

Industrial Centrifugation demonstrated on YouTube

2013-05-17T11:09:00.001-07:00

For large-scale cell culture, centrifugation is one method used to harvest the production cell culture.

Before you can purify your active pharmaceutical ingredient, you need to get rid of the cells (yes, after all that work secreting the API, we get rid of the cells).

Note: some APIs are not secreted, in which case you want to keep the cells, so harvest means different things in different processes.

To separate the cells from the cell culture fluid (CCF), you can filter it or centrifugate it. If you need to process 12,000L or 15,000L in hours, you're doing tangential flow filtration (TFF) or you're using a centrifuge.

If you're using an industrial centrifuge to clarify cell culture, chances are, you're using Alfa Laval.

Three minutes of your time is all it takes to see how large-scale centrifugation works.

Nice work, ~~Alfa Laval~~, Westfalia

Automation Engineer's Take on Wall-E

2013-05-10T09:02:00.001-07:00

by Oliver Yu

I was talking with a buddy from my Cornell ChemE days (who now works in social media) about the odd trajectory of his career. Having had a successful career in biopharma and hospital administration, he's now a social entrepreneur. And it puzzled me that he is fulfilled "not using his degree" in social media.

From his side, he was puzzled that I liked running an automation business helping people get and interpret machine data so their factories operate more efficiently.

As an MBA, he explained, "Business is about people and relationships. I want operate in a world where people matter, and that's what 'social' is."

I have no disagreements with that statement. I did add:

Business is about making money...creating wealth. A world where everyone is wealthy is one where no one has to work; in that world, we have machines at our beck and call. Automation is the means to that world.

Screenshot from Disney Pixar's WALL-E where we find humans have fled Earth in a galactic cruise ship where no one has to work because their life is 100% automated.

Pixar's writers pose the question: What does the world look like when no one has to work?

Don't let Pixar's distinctly American interpretation (out-of-shape, chair-loungers watching TV while robots get us our beverage) distract from the world where everyone gets to enjoy leisure and no one has to work.

Some will jump in and say, "See, employment and working is good for man, else we'll end up all fat and lazy." It's true that some will choose this path, but the vast majority of others would do something else with all that time.

No truer words were spoken when man first uttered the phrase, "Time is Money."

Having vast wealth is synonymous with having vast amounts of time to do what you want; this time to do whatever we choose is called, "leisure." And the purpose of an economy is to lift as many of us from the bonds of employment as efficiently as possible.

As an aside, it's rather hilarious that our politicians run around trying to decrease unemployment. The world where everyone has the luxury of 100% leisure is a world where unemployment is 100%.

And all this leisure can only be possible because we created the machines to automate the tasks that would otherwise be manual.

But back to my buddy: he's also right. Ultimately, business is handled with strong personal relationships. And even after we've automated ourselves into a world where no one has to work, we'd probably spend all that leisure time socializing anyway.

More general commentary:

Cell culture engineers are Keynesian

Bringing In The Big Guns

2013-05-09T13:07:00.004-07:00

In the biotech world, perception can be (and often is) reality. The perception that you brought in the big guns matters as much as the reality that you brought bullets.

It actually reminds me of that scene from the movie, Men In Black where Tommy Lee Jones' character is arming Will Smith's character with this puny gun:

In the movie, this gun is called the "Noisy Cricket" and turns out to pack an enormous punch... the gun's small sizes makes it look unpowerful. Look at Will Smith's face.

What does this have to do with bioreactor sterility or cell culture consulting?

Well when you have a rash of contaminations or when your production campaign is on track for failing to meet ATP, you have actually TWO problems:

Solving the actual problem
Looking like you're solving the problem

A customer once told me, "Oliver, I need both action and PERCEIVED action."

He's right, and here's why:

by Oliver Yu

In claiming to have solved a problem, the first thing people ask you is how you solved the problem. If you tell them the solution and the solution is credible (perceived to be viable), then great, problem solved... let's move on.

If you tell them the solution and the solution seems dubious even though it worked, you will get lingering questions and second-guesses.

Managing the perception is as important and managing the reality.

Play-by-play of Microbial Contamination Response

2013-05-07T05:00:00.000-07:00

As indicated in a previous post, the classic sign of contamination observed in your dissolved oxygen (dO2) trends.

But how does this play out in real-life?

In my experience, the front-lines are the ones detecting contamination. Your operator is typically the first person to see alarms on the HMI.

For cell cultures, they're going to see that the dissolved oxygen (dO2) is at 0%. That pH has also "crashed" to a low number.

In response to these signals, the dO2 controller is max'ed out at 100%, and the pH controller has the peristaltic pump for sodium carbonate (alkali solution) spinning.

The operator (probably on a walkie-talkie) calls out to the front-line technical support group, such as manufacturing sciences campaign support group, to verify... at which point, they'll pull up a trend on PI and see something like this on the dO2 trend:

If the trends look like a contamination, he can recommend that the bioreactor contamination response SOP be executed.

Hemocytometer
courtesy of Jacopo Werther

The bioreactor contamination response starts with pulling a sample and verifying under a hemocytometer as well as sending the sample to QC.

Most quality control have a microbiology department with guys who run the validated tests for detecting contamination or bioburden.

If foreign microbes are confirmed in the samples, the bioreactor decontamination response is executed to inactivate the microbes and send them to the waste-kill pit.

The contamination response SOP also mobilizes all the relevant departments: Production, QA, Manufacturing Sciences, QC, Facilities. For one of those politically-savvy contamination meetings.

No one likes having to go to one because these meetings are a huge bummer. The company just produced scrap. A bioreactor is out of commission. And your workload just increased for this "non-routine" item.

From here, you pick your favorite root-cause analysis tool and run through the system.

Our experience is that this tends to work if your contaminations aren't back-to-back. Biotech firms can endure the sporadic contaminations, but if you start getting back-to-back contaminations, faith in the existing contamination response goes out the window and people start looking for 3rd-party consultants.

You call your network... you search the internet... and you end up reading blog posts by some company who's trying to sell their contamination consulting services. You might check LinkedIn to see if you have any connections in common.

You might download a microbial contamination case study and see if they've solved some tough problems.

Then, you might want to call them, but when you do, you can't say too much until you get a non-disclosure agreement going.

After that, you're free to send them information while they prepare a quote for services.

They come in, see things you haven't seen, write up a report, and boo-yah, life is good again. At least that's how it goes if the 3rd-party consultant is Zymergi.

Basic Microbial Bioreactor Contamination Probabilities

2013-05-06T04:30:00.000-07:00

by Oliver Yu

Before my time at Cornell, I heard there was a professor who gave a grade based on the product of a test score and a lab grade. If you got a:

10 on the test and a 9 in the lab, your score: 90.
9 on the test and a 9 in the lab, your score: 81.
8 on the test and a 7 in the lab, your score: 56 (ouch!)

When you get into mathematical situations where the final outcome depends on the product of two numbers being high, you're in a tough situation.

One time, I got tasked with figuring out what the probability of any natural disaster striking a biologics manufacturing plant given an estimate of the individual probabilities of said natural disaster.

So suppose:

5-year probability of disaster happening
Disaster	Probability
Earthquake	5%
Grass fire	10%
Flood	2%

The key to answer this question is thinking in terms of "not."

5-year probability of disaster NOT happening
Disaster	Probability
Earthquake	95%
Grass fire	90%
Flood	98%

So what's the probability that nothing happens?

0.95 x 0.90 x 0.98 = 0.838

Even though your probabilities of the individuals are in the 90% range, the probability that not any of them happen is in the low 80's. You have an 84% chance of nothing happening, which means the probability of something happening is 16%.

So the equation is thus:

1 - ( 1-p₁ ) x (1-p₂) x ... x (1-p_N)

This is one of those huge mathematical bummers... the more things that can go wrong with your process, the success rate odds are stacked against you.

The same is exactly true with contaminations.

If a successful run depends on five separate operations. And the failure rates for those five operations are:

p1 = 1%
p2 = 1.5%
p3 = 2%
p4 = 2.5%
p5 = 3%

Then success rate of the system is:

99% x 98.5% x 98% x 97.5% x 97% = 0.90%

Five measly steps each with failure rates less than 3% and your overall failure rate is 10%.

Next time you're troubleshooting your microbial bioreactor contaminations, think about this math. If your culture success rate is 10%, your status-quo aseptic practices can be executed >97% of the time and you can still contaminate 1 in 10 runs.

Don't wait until crisis mode.

Further reading:

Amgen's Biosimilars Offensive

2013-05-05T10:47:00.000-07:00

Here's an article at Genetic Engineering & Biotechnology News on the top 10 innovator drugs competitors are trying to copy.

Amgen's Aranesp
Amgen's Enbrel
Amgen's Epogen/Procrit
Pfizer's Genotropin
Roche's Herceptin
AbbVie's Humira
Amgen's Neulasta
Amgen's Neupogen
Janssen's Remicade
Roche's Rituxan

This list appears to be alphabetical (by the drug's trade name). As you can see, 5 of the top 10 biologics that are marching inexorably towards patent expiration belong to Amgen.

It's no wonder why Amgen needs to start playing offense. And it's no wonder why they need to start now when the regulatory pathway for biosimilars is still a work-in-progress (WIP).

I'd like to see these companies get more lean and compete on manufacturing agility as well as efficiency.

Processes need to be better specified... the operating space ought to be better characterized (QbD).

Once the technology is transferred to large-scale, there ought to be a program to continuously improve these processes to eliminate variability and increase process understanding (PAT).

All of this manufacturing sciences and technology is already happening, but I have yet to see companies trot it out as a core competency.

It's not sexy, but in a world where your top-line revenues are in decline, focusing on bottom-line numbers is one of many viable paths.

Viral Inactivation of Cell Culture Media HTST

2013-04-24T05:59:00.000-07:00

by Oliver Yu

For all this talk of bioreactor sterility, the vast majority of this contamination talk refers to bacterial contamination.

What about viral contamination?

Viral contamination is mitigated with HTST treatment of cell culture media. This is where you put the cell culture media in continuous flow while subject to a high temperature for a short period time.

High-temperature inactivates the virus.
Short-time ensures that cell culture media components do not denature.

The best time to put the media in continuous flow is when you pump the media from the media prep tank to the bioreactor, so viral inactivation often happens during this transfer. The HTST unit is essentially:

Heater
Hold-tube (insulated pipe)
Cooler

At large-scale, the first plug of media that goes through the HTST may not meet the specification, so this plug of media cannot be permitted to be delivered to the bioreactor. This plug may be sent to drain or recycled through the HTST unit until the HTST unit reaches steady-state.

Once at steady-state, the remainder of the media is pumped (through a sterile-filter and subsequent sterile pipes) into the bioreactor; when batch volume is reached, the remaining media is sent to drain.

Simple enough, right?

The hard part is when your HTST performance begins to degrade:

Perhaps your sterile filter starts clogging
Perhaps your heater controller output maxes out
Perhaps your media-prep post-use is showing problems

As recently as January of this year, Amgen's Drug Product Development published a paper titled, "Identification and root cause analysis of cell culture media precipitates in the viral deactivation treatment with high-temperature/short-time method."

I haven't read the paper, but my manufacturing sciences consulting experience predicts it to say the following:

The calcium phosphate in the cell culture media becomes insoluble at the high temperatures during the HTST. This calcium phosphate precipitate may collect on the surface of the holding-tubes thereby decreasing the heat-transfer coefficient, sporadically causing the HTST to fail.

This calcium phosphate (sandy white stuff) may also clog up the 0.1 micron sterile filter causing a high delta-pressure across the sterile filter, maybe even diminishing the media flow rate.

The problem is that calcium phosphate stays in solution except when both the temperature is high and the pH is high.

Unfortunately, high-temperature is a requirement of HTST; which means the only solution to preventing calcium phosphate precipitation and the ensuing HTST performance degradation and filter clogging is to run the media through at low pH.

See Our Fix

This is a classic multivariate problem where operating in a different range will solve the problem.

See also:

Are You Seeing An Uptick in Bioreactor Contaminations?

2013-04-23T06:43:00.000-07:00

There's been an uptick in the number of requests we're seeing from biotech manufacturers regarding our bioreactor sterility services.

A lot of new biotech manufacturers have questions like:

What is everyone else's contamination rate?
What's a good benchmark to target?
What are "low-hanging-fruit" items I can work on now?

The reality of [bioreactor] contamination response is that it can be un-scientific. And the reason it's hard to be scientific about responding to contamination is because losing run slots can be emotional.

If you're reading this wonkish blog, you know what I'm talking about. The first thing is that there's a lot of work that went into a contaminated batch and all that work is wasted. It's demoralizing. Not meeting campaign goals may disrupt supply of your API. Patients may not get medicine. And worst of all, you might get sucked into convening a contamination investigation.

As an employee, I've sat in on innumerable contamination responses. And when we've brought in outside consultants, we were in crisis mode. These guys are generally pretty good at helping everyone keep calm and help people walk through whatever system of thinking:

Kepner-Tregoe
Six-Sigma (DMAIC)
5 Why's

These guys are usually generalists, and that's fine. A lot of times, applying a problem-solving system will help get the emotions out and the science back into contamination response. And if you're a big biotech, there's the perception that you have all the experience in-house and it's a matter of applying the resources properly.

by Oliver Yu

The reason we offer biotech veterans is because large-scale sterility operating principles get lost through the years. A lot of companies operate off tribal knowledge. There's that one guy that's been there for 25-years and he's about to retire. Or that your memorandums are stuck on some share drive (or worse, LiveLink or SharePoint) where you can't find them.

Sometimes, good sterility practices are coded into the automation or written into SOPs and the reason for these changes are stuck in the change-control system where most people can't get to it. Institutional knowledge gets fragmented and lost through the years.

This is why we offer biotech veterans for contamination responses. We will deliver:

Statement of Most Probable Cause (MPC) of acute contaminations
Rank-ordered list of sterility risks
Summary/Assessment of operations

With this report, you get both action to actually solve the problem. And you get perceived action to help you "manage up."

So whether your a new Korean CMO or NJ Biopharma, the big question is: can you afford to wait until crisis mode before bringing in veteran contamination consultant?

See offer

Compile Error in Hidden Module: modAddin (x64)

2013-04-12T08:21:00.003-07:00

You're here because of this:

...and because you're using a 64-bit system (x64).

The fix, like the 32-bit solution is to un-register and re-register the mscomctl.ocx.

But it's slightly different on a 64-bit system.

The mscomctl.ocx file is located here:


c:\windows\sysWOW64\mscomctl.ocx

Un-register and re-register that file and you'll be gold.

p.s. - Thanks for all the commenters with this.

How To Interpret Distributions (Histograms)

2013-04-05T11:19:00.000-07:00

Here's a set of Y-Distributions (histograms) I saw on the data visualization sub-Reddit.

On the left side, we have Polish language scores. On the right, we have mathematics.

Each row is a year... 2010 through 2012.

According to the notes on the page, these are the high-school exit exam scores for which passing is to receive 30% of the total available points.

Most people know what a "bell-shaped" curve looks like and those Polish language scores don't look like bells. In fact, it looks like right around the 30% mark, someone took the non-passing scores that were "close enough" and just handed out the passing score.

We sometimes see this in biotech manufacturing... where in order to proceed to the next step, you need to take a sample and measure the result. If there is a specification, you'll see a lot of just-passing results. What is euphemistically called, "Wishful sampling."

The process is the process and if the sampling is random, you expect a bell-shaped curve. In the case of Polish high school students, their Polish skills are what they are. What you're seeing is an artifact of the people grading the tests. I would bet a fair amount of money that teachers or schools are rewarded according to the number of students who pass this test.

Let's look at the mathematics scores. This "wishful grading" is going on in mathematics, but is far less pronounced. What is crazy is how different the distributions look from year to year (compared to the language histograms).

It's hard for me to think that mathematics skills of students across Poland vary that much from year to year. Like the U.S. News and World Reports rankings of schools, it's more likely that the difficulty of the test changes significantly from year to year... in this case with 2011 tests with particularly difficult questions.

by Oliver Yu

Histograms say quite a bit about your process. What they never tell you is that the histograms also tell you quite a bit about your process specifications and how truthful your measurement systems are.

If I were the FDA... and I wanted to be mean about it, I'd request a distribution of measurements for every single process specification, and if I saw something like this "Polish language" test, someone has some explaining to do.

Get Biotech Manufacturing Consulting

Dr. Tom Little - Stats Ninja

2013-04-01T04:30:00.000-07:00

by Oliver Yu

There is an epidemic of statistical dunderheads working in the biotech industry. This epidemic probably plagues other sectors of the economy as well, but I'm not qualified to speak to that.

The reason for this complete lack of statistical knowledge (I think) is that statistics is not a part of the standard engineering curriculum. You get differential and integral calculus like crazy, but just one semester of basic engineering statistics and here's your diploma.

And as with most of undergraduate academia, it's not practical.

At my first job, we used the statistical software program - JMP - a lot. We were making a minimally invasive glucose monitor called the, GlucoWatch® Biographer and my entire job as a research engineer was to run in-house clinical studies and correlate the biographer performance against over-the-counter glucose meters. So we did a lot of linear correlations, I got to understand what p-values meant. And I figured out the primary purpose of engineering a system was to figure out what was signal and what was noise.

I think I might have even landed my second job because I knew how to use JMP. In fact, my second week on the job, the boss had his entire group go get JMP training in San Francisco where I had the luck of sharing a computer terminal with him.

Whatever the case, understanding enough statistics to know what tests are applicable when is really important. And when your group gets big enough that sending your team to off-site training becomes impractical, there is Dr. Thomas Little who will send practical stats gurus to train you.

Dr. Tom trained us (in a computer room) setting and a lot of this stuff was new at the time I learned it. ANOVA... Multivariate Analysis. Why use backwards stepwise regression... how to read the normal quantile plot... Capability... Control Charting.... All the things that are relevant to monitoring a production campaign.

When you get out of the class, you've leveled up in the world of biologics manufacturing and you look around and wonder why maintaining spreadsheets of cell culture data qualifies as plant support. You also start wondering why process development spends more time swinging male genitalia over higher titers rather than defining critical process parameters (CPPs) and identifying proven acceptable ranges (PARs).

Dr. Tom is pretty well-known in the world of biologics. I run into his team of consultants every third place I go. If your team isn't making statistically-sound, data-drive decisions, you seriously need to give him a call.

Call Dr. Tom

@zymergi

Did We Find the Holy Grail for Cancer?

2013-03-29T04:00:00.000-07:00

A year ago, the American Association for the Advancement of Science (AAAS), through their website: ScienceMag.org, is reported the of a discovery of a drug that can kill all tumors.

It breaks down like this:

There's a protein called CD47 that tells your immune system, "Don't eat me."

Our immune system patrols our bodies looking to find and destroy foreign biological entities. And apparently, one of the ways that our immune system recognizes foreign vs. self is this CD47 protein.

The discoverer of CD47, Stanford biologist Irving Weissmann, found that normal cells express CD47, but that leukemia cells express CD47 in higher concentrations.

Some blood cancers have been cured with anti-CD47... an antibody that binds to CD47 thereby blocking this "Don't eat me" signal emitted by cancer cells.

But that's not the news. According to Weissmann,

What we've shown is that CD47 isn't just important on leukemias and lymphomas. It's on every single human primary tumor that we tested.

You can read about the simple A/B experiments they did with anti-CD47, but the basic gist is that they've shown in vitro that anti-CD47 helps macrophages recognize cancer cells.

They have been able to cure cancer of all types from the feet of mice.

The only question remaining is whether or not this works in humans...

Antibodies (mAbs) were 5 of top 8 best selling biologics

2013-03-15T13:14:00.000-07:00

According to @CellCultureDish, 8 of 20 top selling drugs from last year were biologics.

by Oliver Yu

#1. Humira (adalimumab)
#2. Remicade (infliximab)
#3. Enbrel (etanercept)
#4. ~not biologic~
#5. Rituxan (rituximab)
#6. Lantus (insulin glargine)
#7. Herceptin (trastuzumab)
#8.~not biologic~
#9. Avastin (bevacizumab)
#10.~not biologic~
#11.~not biologic~
#12. Neulasta (pegfilgrastim)

Source: Genetic Engineering and Biotechnology News

It's also interesting to point out that 5 of the 8 are monoclonal antibodies (mAbs). You can easily tell from the chemical name of the biologic because the chemical name ends with -mab.

Anatomy of the Antibody

For the non-biogeeks out there, monoclonal antibodies are Y-shaped molecules that are naturally produced by our immune systems to fight off foreign germs. Picture doing the "Y.M.C.A" dance and you're doing the "Y".

The Village People emulating the shape of a monoclonal antibody

The significance of antibodies is that they are highly specific, meaning that they will bind to one target and only that target; it's possible because the antibody's molecular "hands" fit only one "glove" (specific antigen).

So the reason why monoclonal antibodies are so useful in medicine is because they can hit the targets that you want and nothing else... so-called, "Smart-bombs." And you'll see a lot of mAbs in cancer treatment (since you want to target only the cancerous cells, but not the healthy cells).

Equivalent of when an antibody comes across an antigen it doesn't recognize

mAbs can be divided into two regions: Fab and Fc.

Fab stands for fragment (antigen-binding). The part of the antibody that binds to the antigen. The Fab is basically everything from your shoulders up.

Fc stands for fragment constant: the rest of your body from your shoulders down to your legs. It's not really constant as it can be one of several classes in humans; but relatively, it's constant.

Early antibodies were engineered from mice. In very simplistic terms, you introduce a foreign biological molecule (antigen) to a mouse. The mouse's immune system will naturally fight off this foreign molecule by producing antibodies, and voila, you have yourself a mAb that can target your antigen. This mAb is 100% murine.

The problem with murine antibodies as medicine is that the human immune system recognizes it as foreign and will reject it. So to be useful, the antibody needs to be "humanized."

Humanizing an antibody means replacing mouse-Fc region with a human Fc region and then trying to make as much of the Fab region as human as possible.

mAb Nomenclature

There's actually a nomenclature for monoclonal antibodies that can tell you from the name, how much of the antibody is murine and how much is human:

In the above diagram, the light-blue antibody is from a 100% murine (-omab). The darkish-red antibody is 100% human (-umab).

The genetically engineered antibodies are the ones that are mixed in color. A chimeric antibody (-ximab) is one where from the "elbow" down is human, and from the "elbow" to the fingertips is murine. Drugs like Remicade (infliximab) and Rituxan (rituximab) are chimeric.

A humanized-antibody (-zumab) is one where only the "fingers" are murine and the rest is human. Drugs like Herceptin (trastuzumab) and Avastin (bevacizumab) are humanized antibodies.

While the more humanized an antibody is, the less rejection it gets as a viable drug, there appears to be no obvious correlation from a revenue perspective (see list above).

What's this have to do with cell culture? Antibodies are secreted by genetically-engineered cells that are grown in cell cultures.

Related posts:

Follow me @zymergi

The Crux of Biologics Manufacturing

2013-03-05T04:30:00.000-08:00

Whether you are making a biologic or a biosimilar, the manufacturing process (for the most part) is the same.

You're going to have cell culture or fermentation in either as a batch or continuous process.

You're going to have a recovery/purification train of 3 or more steps where you're purifying the drug and getting rid of unwanted biochemicals.

You're going to freeze that into huge ice cube and ship it to your fill/finish facility where they're going to thaw it and dispense the drug product into vials.

What biologic you make and how hard it is to make was decided by your Process Development group years ago when they were poking the DNA into cells, growing them and picking the "best" one. (This is a big-time simplification, the wonkish version of expression system selection, cell line development, cell line engineering, platform development, clone selection, process characterization/validation... etc.)

What decides whether you're making bevacizumab or rituximab?

If you inoculated a bioreactor with the cells that were transfected with the anti-VEGF gene, you're going to get bevacizumab.

If you inoculated a bioreactor with the cells that were transfected with the anti-CD20 gene, you're going to get rituximab.

It goes without saying that you must follow the recipe/manufacturing formula for the respective cell lines, which will contain minor differences across upstream and downstream.

The crux of biologics manufacturing is cell line development and what makes biologics manufacturing hard was doing the cell line development right.

What decides whether you're making Rituxan® or Reditux®?

If you inoculated your bioreactor with cells that were transfected with the anti-CD20 gene by an IDEC scientist, you're going to get the biologic: Rituxan®.

If you inoculated your bioreactor with cells that were transfected with the anti-CD20 gene by a Dr. Reddy's scientist, you're going to get the biosimilar: Reditux®.

What no one knew a decade ago (2003) was whether or not the Dr. Reddy's cell line could produce a molecule identical to the IDEC molecule. And even if they could, would this molecule be as safe and as effective as the FDA-approved IDEC molecule?

Is Making Biologics Hard?

This is a very broad question. Is putting cells into a bioreactor and watching them grow hard? ...because that's how the active pharmaceutical ingredients get made.

Is pouring the HCCF down chrom columns and hard? Broadly speaking, I'd say there's no shortage of people who can execute a large-scale biologics manufacturing process.

Is cell line engineering, platform development, clone selection tough...etc hard? The grunt work can be done by entry-level scientists/engineers, but you probably want Ph.Ds leading the team to ask the right questions and to cast aside the technical road blocks.

by Oliver Yu

Can Amgen take market share from Roche, Lilly, Abbvie and Janssen? Sure. Amgen has the right people, the resources and leadership.

Is making biologics so difficult to make that no one else can do it? I don't think so. There's already generic versions of Aranesp, Neulasta and Neupogen in ex-US markets.

Amgen's Biosimilars Gambit

2013-02-19T05:21:00.000-08:00

About a week ago, Amgen rocked the biotech industry's proverbial boat with their announcement that they'd be entering the biosimilars market. Multiple news outlets like Yahoo!, Forbes, and CNBC report that Amgen, starting in 2017, will be making six generic versions of blockbuster biologics:

Abbvie's Humira
Janssen's^{OLY 02/19/13} Remicade
Roche's Avastin, Herceptin and Rituxan
Eli Lilly's Erbitux

This comes as a surprise to many, because for years, Amgen has been saying that biologics really can't be copied.

You see, Amgen is facing patent expiration on it's blockbuster biologics. And unlike pharmaceutical companies, there really wasn't a need to be worried about patents expiring for biologics.

The U.S. Food and Drug Administration has long held that not only must the product meet quality specifications, but also the process that makes the drug must also rigorously meet process specifications.

Well, biologics are made by genetically-engineered microorganisms (cells) that conduct a symphony of biochemical reactions. You give these cells media; you control their environment (temperature, pH, dO2), and the cells do all the work making your protein out of the DNA.

Need to manage your cell culture data?

Since the process specification includes these proprietary cells, it stands to reason that no one can produce the drug product if they don't have your cells. For this reason, biotechnology companies have not been as worried about patent expiration.

Up until this announcement, Amgen has been focusing on defending their superior position by indicating how difficult it is to manufacture biologics and how consumers ought not to trust biosimilars:

Amgen's Challenges of Manufacturing Biologics (YouTube)
Amgen's BuildingBiologics.com website saying that comparing biologics is like comparing snowflakes.
Amgen's membership of SafeBiologics, a lobby against biosimilars

"It's really hard to manufacture biologics."

"When copies of our drugs are made, you can't be certain of their safety/efficacy."

But all of the sudden, our ancient weapons dealer who has been selling us his impenetrable shields has a new offering: his spears that can penetrate anything: 自相矛盾.

Amgen sees the writing on the wall. The FDA is being forced to develop a biosimilars approval pathway as a part of Patient Protection and Affordable Care Act (aka, "ObamaCare"). By law, the only way to do this is to renege on the "product and process" cGMP principle.

by Oliver Yu

One of two things is going to happen:

The FDA is going to allow biosimilars into the US markets.
The FDA is NOT going to allow biosimilars into the US market.

Someone at Amgen put their brain on and decided no matter what happens, they were going to win.

Consistency issues aside, I think Amgen's gambit is genius.

Redskins Rule - Statistical Bunk

2013-02-06T08:45:00.001-08:00

So in the case of the spurious relationship, you have two symptoms that appear when there is underlying disease.

Symptom A can indicate symptom B, but
Symptom A does not cause symptom B.

Then there's nonsense like the Redskin Rule which is not even a spurious relationship... it's coincidence.

For those non-(American)-football fans, the Washington Redskins is a football team here in the US. And since this team moved to Washington DC, an incredible coincidence started happening:

If the Redskins win their last home game before the election, the party that won the previous election wins the next election and that if the Redskins lose, the challenging party's candidate wins.

From 1932 to 2000, this "Rule" correctly predicted the outcome of the election.

Seriously?

This is why people say things like, "Lies, Damn Lies, and Statistics."

You can make the numbers "say" anything you want... especially when there's nothing to say.

If you do want to say something technically meaningful and relevant for solving short- and intermediate-term problems, here are some links to read:

Ice Cream causes Swimming Pool Deaths!

2013-02-05T06:00:00.000-08:00

by Oliver Yu

I see this proverbial "Ice cream causes swimming pool drownings" statement made in the world of economics and politics all the time.

It's so prevalent that there's a Wikipedia article on spurious relationships.

[Ice cream] sales are highest when the rate of drownings in city swimming pools is highest.

You can look at the data over and you'll see that this phenomenon happens like clockwork:

Low ice cream sales... fewer swimming pool deaths.
High ice cream sales... many swimming pool deaths.

So there's a correlation, right? Yes.

With that correlation, some go farther to allege that ice cream causes drownings or that drownings causes ice cream sales. (ahem, No.)

To claim that ice cream sales is an indicator of drownings or vice versa also misses the point because ice cream sales and swimming pool deaths are both symptoms of the underlying disease: heat wave.

Unfortunately, this statement of two symptoms indicating one another is seen all the time in the world of cell culture analysis:

Final ammonium (NH4+) is an indicator of culture performance
- or -
Final lactate (Lac) is an indicator of product titer

credit: The Usual Suspects MGM

Seriously...who here doesn't already know that cell growth impacts culture performance? or that cell metabolism impacts culture performance?

Yet we are still publishing papers on how final lactate is an indicator of product titer and concluding that cell metabolism impacts culture performance.

Final ammonium or final lactate are symptoms of cell culture metabolic conditions that produces higher titers.

Unless you can:

Change media components
Change a parameter setpoint (pH, temp, dO2)
Change the timing of culture operations (temp shift, pH shift, timing of feeds...)

that is... recommend specific changes the Production group can execute to improve culture conditions, you've simply uncovered a spurious relationship; there remains no action you can take to improve culture performance.

This is why it is best to start your multivariate analysis by picking actionable parameters... to ensure that you have true factors.

When you pick actionable parameters to model as factors in your multivariate analysis, you have a shot at gaining control of an out-of-control campaign and meeting your Adherence-to-Plan.... as Rob Johnson did.

If you're happy pontificating from ivory towers, keep making true-but-useless statements on how every time Y₁ happens that Y₂ also happens.

Otherwise

Thuperbowl1!!!! (Excel vs. PI continuous vs stepped)

2013-02-04T14:38:00.000-08:00

I was actually pulling for the Niners yesterday primarily because I've lived in the SF Bay Area since 1999; but on balance, I didn't really care about the game: the Pixburgh Stillers weren't playing.

That and because the NFL actively supported SOPA, the bill that aims at restricting our internet freedom:

That said, here's a look how scatter plot of score vs game duration.

Source data: Milwaukee-Wisconsin Journal Sentinel

The awesome thing about Excel is that you get to change the Y-axis increments (I made it 7 since that's how many points are in a touchdown)... as well you can configure the X-axis increments (I made it 15 since that's how many minutes are in a quarter).

It's a nice graph and all, but not terribly reflective of what actually happened. You can see from the start of the game, there's a ramp from 0 to 7 for the Baltimore Ravens. That's not what actually happened. At 4:23 into the first quarter, the score was still 0. At 4:24, the Ravens' score was 7.

Let's look at what this graph looks like in PI ProcessBook with correctly configured tags:

Here, is an accurate depiction of what the scores were at the time they happened: the score goes up in increments forming what looks like "steps".

When you have infrequent data, the most accurate visual representation of the data is to set the step point attribute equal to one (step=1). For cell culture and fermentation, you do this for any offline measurement such as:

viable cell count
viability
offline pH
Osmo
Glucose, Lactate, Ammonium, Sodium

If you have it configured any other way, it may look funky... like that first plot in Excel.

Amgen Singapore : I stand corrected

2013-01-31T11:40:00.000-08:00

by Oliver Yu

In a previous post, I indicated that biotech manufacturing facilities in Singapore costing 200M is cheap.

It turns out that that's par for the course.

My original statement is false, but becomes true when edited thusly:

I think the [Lonza-built] Roche plant cost 290 million and the [Genentech-built] Roche plant cost ~~500~~ 210 million, so if Amgen gets it done for 200 million, that's ~~pretty cheap~~ par for the course.

I got the 290 million figure from multiple sources:

But then I mis-read the $500 million figure from the Roche Singapore About page where it says:

With a combined investment of approximately USD500 million, the site is comprised of two state-of-the-art facilities which use two different production technology platforms to manufacture biologic medicines.

(emphasis mine).

So doing the math.... both facilities cost approximately 500 million USD. One costs 290M, so the other must cost $210M.

Thanks to a savvy reader for this correction.

Origin of Biotechnology - A Genentech Perspective

2013-01-22T05:30:00.000-08:00

I'm rummaging through my things and I just found this little booklet that came with my Genentech employment:

In a "We're Awesome" Way, this booklet goes through how Genentech came to be. In fact, inside the front cover, it says:

This notebook is for disclosure outside of Genentech, and it can be removed from the premises without authorization. Other organizations and companies can read it and eat our dust.

So for those interested in biotech and how it started, I present the GenenLab Notebook:

In 1976, the United States was celebrating its birth as a nation. Technological change was in the air, and increasing attention was being paid to Silicon Valley. At the time, few people noticed that a different kind of company was being born - Genentech. As events transpired, its founding led to the creation of an entire new industry - biotechnology. Silicon Valley was about to have a new neighbor: Biotech Bay.

This was not a formal history of what happened. Rather, it was a series of snapshots, drawn from the memories of some of those who were part of the start of the first two decades.

It all began with an experiment conducted by a team led by Dr. Herbert W. Boyer of the University of California at San Francisco (UCSF) and Dr. Stanley N. Cohen of Stanford University. They proved that DNA could be recombined, meaning, in theory, that genetic material from one species could be successfully introduced into the gene of another species.

Boyer says, "I seem to recall it was a Friday... We lined up the gels on the black boxes... The bands were lined up and you could just look at them and you knew... it had been successful. We had recombined.... I was just ecstatic... I remember going home and showing [a Polaroid] photograph [of the bands] to my wife.... You know, I looked at that thing until early in the morning... When I saw it, and knew it could be done, I knew that you could do just about anything.... I was really moved by it. I had tears welling up in my eyes because it was sort of a cloudy vision of what was to come.

A New Adventure

In January 1976, Robert A. Swanson, who had been a partner at the venture capital firm of Kleiner & Perkins, telephoned Boyer. Swanson believed that recombinant DNA technology (rDNA, for short) could be employed to create commercial products in a relatively short time, but it seemed that nobody - including the overwhelming majority of scientists - agreed with him. Everybody he talked with said it would be 15 - 20 years before that happened.

Swanson persuaded Boyer to meet with him for a few minutes. In fact, the meeting lasted two or three hours because Boyer agreed with Swanson on the commercial feasibility of genetic engineering, not in the distant future, but now.

The previous year, Boyer had told an interviewer, "I think [rDNA] has a lot of implications for utilizing the technology in a commercial sense; that is, one could get bacteria to make hormones, etc."

"When Bob came along," Boyer says, "I thought it was great It was an opportunity for a new adventure, for me, personally..."

"Genentech was a result of the combination of chance and necessity. When Bob and I got together, there was a need out there, a necessity for the things this technology could do. Chance, and our mutual desire to go somewhere with this technology, provided the other ingredient."

By the time their initial meeting was over, the two had agreed to organize a new company. They each put up $500. Boyer also came up with a name for the company, derived from GENetic Engineering Technology. (Good thing, because Swanson's suggestion was the HerBob Company.)

With no assets (as accountants define them), rented offices, rented equipment, and a part-time secretary, they launched the enterprise. It was incorporated April 7, 1976.

At first, Swanson says, "I was working without a salary and collecting $410 a month in unemployment [through insurance]. I was sharing an apartment and my half of the lease cost $250 a month. The least on my car was $107. The rest I lived on."

And not very well. Tom Kiley, who later became Genentech's vice president for Legal Affairs, was with a Los Angeles law firm representing the company. To save Genentech money, he often slept on the couch in Swanson's apartment. "Bob was living in a rather nondescript apartment, although in a good neighborhood. He had a black and white television sitting on a steamer trunk and his mattress sat on a plywood box he used in lieu of a bed frame and springs. In the dining room, instead of a dining room table there was a ping pong table under which bicycles were stored."

In June, on the basis of an eight-page business plan, Kleiner & Perkins agreed to provide $100,000 in venture capital funding, which lasted Genentech nine months. At least Swanson could now take a small salary.

Laying the Groundwork for a New Industry

By September of 1978, Genentech had signed contracts with Kabi AB, the Swedish pharmaceutical firm, covering human growth hormone (hGH) and with Eli Lilly and Company covering human insulin.

But it was still questionable whether the courts would permit the patenting of life forms such as microorganisms whose DNA had been recombined with a human gene to express a human protein: And without patent protection, what company could afford to engage in the costly research and development that genetic engineering required? Representing Genentech, Kiley filed a "friend of the court" brief before a federal appeals court, arguing with General Electric, against the U.S. Patent Office, that a patent should be granted to a GE-developed microorganism that was said to "eat" oil, an application that held the promise of cleaning up after oil spills. Eventually, the U.S. Supreme Court agreed with GE and Genentech, holding that life forms were patentable.

That cleared the way for Genentech, and the biotech industry as a whole, to move forward rapidly.

Genentech contracted with universities to do the early research. By 1996, the exclusive marketing rights Genentech received would generate royalty income to the universities of more than $160 million.

A Revolution in Biology

The first product Boyer and Swanson wanted to develop was human insulin. But when they talked to Arthur Riggs and Keiichi Itakura, biologists at the City of Hope National Medical Center in Duarte, California, Riggs and Itakura said they wanted first to synthesize the human gene for somatostatin, a brain hormone, and insert it into bacteria, to see if the bacteria would then manufacture the hormone. In fact, they had applied to the NIH for a grant for such an experiment, but the NIH had turned them down. The NIH thought the chances of success were too slim. No one had ever before produced a human hormone in a microorganism.

Swanson and Boyer agreed that Genentech would fund the somatostatin experiment. Their reasoning in Boyer's words: "It can be done very quickly. We can show that this technique is feasible, and that's what we really wanted to do. We can always do insulin later." If the experiment succeeded, it would demonstrate that human proteins could indeed be manufactured in commercial quantities using bacteria.

One day, the dual research team, in San Francisco and Duarte, thought it was done - the gene had been made and inserted into a microorganism. Then apparent disaster: "We couldn't see any difference," Swanson says, "I could see my whole career going down the tubes. That microorganism, E. coli. was supposed to produce the protein, but we couldn't see any."

Further investigation indicated that the protein was being made, but the microorganism "was chewing up the peptide as quickly as it was being made." After a month or two, the scientists hit upon a trick, making the somatostatin part of a bigger protein and then clipping it off.

"During that period," Swanson says, "everybody was on pins and needles, not knowing whether this was going to work. But it did! That was it!" They had succeeded before the deadline set by the company's initial financing.

On December 2, 1977, national news media reported, as The Wall Street Journal put it, "Scientists Create a Useful Protein Through Genetics... Synthetic May Be Produced in Bacteria More Easily for Research Medical Use." But the Journal got the name of the company wrong: it said, "The study was funded by Genetech, Inc."

Dr. Philip Handler, President of the National Academy of Sciences, told a U.S. Senate committee that the somatostatin demonstration was a "scientific trump of the first order." Science, the journal of the American Association for Advancement of Science, said it ushered in a new "revolution in biology"

Less than a year later, in August 1978, Genentech was able to announce that it had successfully employed the new technology to produce human insulin. The following year, a similar announcement was made about human growth hormone. Then gamma interferon, and tPA - the stream of new rDNA products was underway.

But it wasn't easy. Scientist Herb Heyneker recalls that under the agreement between Genentech and Eli Lilly and Company, which would manufacture and market human insulin after Genentech developed it, Genentech had to meet specified benchmarks by certain dates. "Ron Wetzel [then in protein chemistry at Genentech] was really a hero to make it happen," Heyneker says. "On New Year's Eve, he demonstrated that we could make 1 mg of recombinant insulin, so that Genentech made the deadline, literally with only hours to spare." It had been, he says, a very tense day.

It was not until November 1977 that Genentech felt that it could afford to sign a 2-year lease for office, lab, and miscellaneous use. The lease covered 8,437.5 square feet in the northwest corner of what is now Building 1. Before long, Genentech occupied half of that building, then the entire building. And still it kept on growing and consuming space. By 1996, the company would occupy close to 3 million square feet in 17 buildings.

Employees

Heyneker had worked as a post doctoral fellow in Bayer's lab at UCSF. He had gone back to the Netherlands, to the University of Leiden, and Boyer and Swanson went there to persuade him to return. In 1976, Heyneker became the first employee of Genentech.

Then came Dennis Kleid, who brought with him David Goeddel. Like the many scientists who followed, all were highly competitive, driven to do the best work they are capable of doing.

To accept an offer from Genentech was not an easy decision for scientists in the early years. Art Levinson, who left UCSF to join the company in May 1980 and has gone on to become president and CEO, recalls, "It was considered almost shameful in the academic community at that time for anybody decent to go into industry. Good people almost never did that. When they did, it was considered to be an act of selling out. When it became known that I was considering coming here, the almost universal response among academics was partly disdain, partly scorn. Some just thought I was confused and tried to talk me out of it, arguing that I was making a big mistake. It was so bad that when I returned a telephone call to one of the people at Genentech before I left the university, I didn't feel comfortable making the call from my laboratory, so I went outside to a pay phone."

But it was a decision made by many of the best and the brightest - the most venturesome, risk-taking, "outside-of-the-box" thinkers - and very early on Genentech acquired a reputation for doing some of the finest science in the world.

"There was a group of thoroughbreds at Genentech," says Dave Martin, Jr., a medical doctor who was the VP of Research for several years. The level of scientific confidence and intelligence was extraordinarily high.

"When I moved from academia to Genentech, one of the things I had been concerned about was whether my scope of exposure to science would be narrowed or restrained. To my pleasant surprise, I found quite the opposite. And I worked! I thought I had worked hard in academia, but I worked harder at Genentech. It was a very intense, competitive atmosphere. Saturday mornings the parking lot was as full as it was on a Friday morning. I would usually leave at 7:00 or 7:30 in the evening, and there were still lots of people there.

"Lots of post docs. One of the things that Genentech did was to popularize the importance of having post-doctoral fellowships in industry. There had been almost none in industry before that. And we had about 50 post docs."

Genentech always was a different kind of company. Swanson and Boyer had the same philosophy: hire the best people, give them the freedom to do the best they can, trust them, give them the credit.

"It's an incredibly driven group of people," says Laurie May, who came to work in June 1979 and is now a project manager in Product Development. "After 17 years here, I still notice how hard people work... There's tremendous pride in working for this company..."

From the beginning, Genentech's environment was conducive to real commitment. Although many company heads pay lip service to the contribution of their employees, Laurie says, people believed Swanson meant what he said. "He designed this company around the employees as its most valuable asset," she believes.

Norm Lin, a senior scientist now, was responsible for fermentation. One day,he recalls, he told Swanson that the freedom the employees enjoyed was right for research scientists, but now that the company was moving into production, "We need discipline... Have [production] people come in, punch a time clock, like a real production site." Lin laughs, "Swanson says, 'No way, I'm the boss, and there'll be no punch cards. You've got to trust everybody to do their jobs.' That's his philosophy."

Second Generation

Swanson's determination to make Genentech an ideal working environment led him to what turned out, rather unexpectedly, to be a highly controversial proposal, but one that he had had in mind from the beginning: to start a day care center for the children of employee. Linda A. Fitzpatrick, who was then in HR at Genentech, points out, "The average age at the company at the time was late 20's, early 30's..., a time when many employees were having children and really wanted to have an option for day care."

But the day care center, which came to be called Second Generation, would cost quite a bit of money to establish, and the proposal was put forward in a year when finances were rather tight. The company proposed to lease space and furnish it for an initial cost of $100,000. But if the company were to subsidize it an an annual rate if 50%, which it intended to do, there would be still more money spent on it. Genentech's financial commitment for the first year's operating budget, Fitzpatrick says, was about $500,000 - "in [1996] terms close to 1.5 to 2 million."

Dave Martin says that he "and the majority of the people on the management committee didn't want to do it... Bob persisted and stood up against the pressure not to do it. [In retrospect] he was absolutely right..."

Martin says establishing the day care center enhanced the company's reputation and helped in recruiting the best people to work at the company.

At the time the day care was opened, there were very few company-run facilities like it in the Bay Area. Now there are many, but non as large as Genentech's, which is licensed to serve up to 256 children. In fact, it's one of the largest in the U.S. Genentech's Second Generation is one of the many important factors to Genentech having been named one of the top 100 companies for working mothers by Working Mother magazine six times.

Genentech Jolts Wall Street

"Genentech wrote the book on creative financing," Heyneker asserts. The initial alliances with universities were followed by strategic pacts with pharmaceutical companies that produced licensing fees. As R&D costs rose, Genentech created R&D partnerships, which generated a great deal of money. Money was raised from VCs, private placement with corporate investors, and finally by public offering of stock and convertible debt.

On October 14, 1980, Genentech stock was offered to the public for the first time. It was quite a day. The main front-page headline in the final edition of the San Francisco Examiner read: "Genentech Jolts Wall Street." Genentech's stock had opened at $35 per share, rose to $88, and closed at $71.25. The newspaper called it "the most spectacular new stock offering in at least a decade." and all the other media agreed.

Genentech's philosophy, from the beginning, was that all employees ought to be stockholders, too.

Scott Hoag, a construction project manager, like many Genentech people, had received some shares of stock as reward for good work. "My attitude - and the attitude of a lot of people at the time - was, 'Gee, this is real nice, a piece of paper, not worth anything...' You throw it in the drawer... The day we went public I came in real early in the morning, about 6:00. Around 6:30, the telephone was ringing off the wall and nobody else was there. [It was 9:30am on Wall Street.] For a while I just ignored the phones, but they kept ringing, so finally I thought maybe I'd better start answering. People on the phones start asking me, 'Does the company have a statement to make? Can you say anything about the performance of the stock?' But I didn't know what the stock was doing."

One day, after the company went public, Swanson received a note from Nita Knox, one of the office staff. In it she said, "Today, Bob, I had to sell some shares. I hated to do it, but I got a chance to put a down payment on a new house. If I hadn't worked here at Genentech, I would never have been able to do that. I want to thank you for allowing us to be shareholders."

Through option grants and stock purchase plan, Genentech continued its tradition of enabling its employees to benefit from the company's success.

HO HO HO...

Such intensity had to find a release, and it did, often in high jinks and practical jokes. Some of them started at the weekly Ho-Hos, held every Friday. The Ho-Ho tradition began simply with refreshments for employees every Friday afternoon. At the end of one particularly hectic work week, a manufacturing VP said, "Oh, another Friday afternoon, ho, ho, ho, ho." And the name stuck. As individual departments got involved in their production, the Ho-Hos grew in scope and complexity - and in fun.

The Ho-Ho was an occasion for play and absurdity. One time Swanson and Boyer came dressed up as Tweedledee and Tweedledum - the "dumbest thing I ever got talked into," Buyer recalls with a laugh.

But from the start, Ho-Hos were more than just fun. To Swanson, the Ho-Ho was "a wonderful idea, because you need a place where people at all levels of the organization, from the president on down, can get together in their shirtsleeves and talk about the issues, as equals... One of the things you worry about, as you get higher in an organization, is whether people are comfortable telling you the truth about the way they see the needs of the company - where are we screwing up as a company?" Even the silly outfits had a purpose.

"A lot of crazy things we did, like running around in tutus or hula skirts, was to say, 'These guys are really kind of nuts. They can't be all that stuffy that I can't approach them with an idea.'"

At least one Ho-Ho ended up in a custard pie fight, like a silent comedy from the 1920's. Another hosted pigs, which each had the name of a current VP printed on its shanks. Mary Lynn Bell (then Lee), Swanson's assistant at the time, said of the swine guests:

"It wasn't really a big deal. Nobody chased them. They just milled around and joined the crowd. They meandered through people's legs. They didn't seem particularly nervous because the farmer was there.

Then came the practical jokes. Some of the true stories are the stuff of legends: many a GNE employee has heard something about a pink car...

The most elaborate joke involved an old car, a rusty Honda Civic that Scientist Mark Mattucci owned. Mattucci had played many a prank on his associates, and they decided to pull a practical joke on him. Once when he was away on a trip, then Senior Research Associate Mark Vasser and some of his other colleagues had it painted pink, with a "Mary Kay Cosmetics" labeled on the door.

Unfazed, Mattucci went on driving the car after his return. The next time Mattucci was out of town, the prankster got another car - same make, same model, same year - painted it pink, took it to a junkyard to be compacted and trucked the crushed car to the Genentech parking lot. They towed Mattucci's car away, hid it safely, and put the crushed car on the spot where Mattucci's had been parked. Mattucci fell for it. "This time they've gone too far," he said, very seriously, but then discovered that his old pink car remained intact nearby.

Making Medicines

The playfulness was merely a safety valve, to release the pressure from working very hard at the cutting edge of science. Dennis Kleid recalls, "The biggest day for me was the day we got growth hormone expressed. The concept of making a human protein in a bacteria and then having the bacteria fold it up right was just absolutely astounding." He points out that a good had already been known about the structure of somatostatin and insulin, "but the growth hormone was a [much more] complicated molecule."

The human growth hormone project had special meaning for Herb Boyer. "When my oldest son, Doug, was growing up," he recalls, "the pediatrician said, 'Doug's in the short stature profile, so I'd like to run some tests to check his growth hormone levels.' It turned out his growth hormone levels were normal and everything was fine. As a teenager, he reached normal height.

But I remember the physician saying to me, if he had a growth hormone deficiency, there was not much that could be done about it, because there was only enough growth hormone to treat kids in the most pathological states of growth retardation. I said at the time - we had just had the breakthrough with recombinant DNA technology - we could make that stuff with this new technology."

It takes varied talents and skills - in science, scale-up process, engineering, production, quality control, law, regulatory liaison, marketing, sales, and many more - to get medicines to patients and for the company to succeed. For example, before Genentech could get any of its products to market, it had to be able to carry the technology from laboratory to the manufacturing plant. "This was a little company with no established infrastructure," now VP of Process Sciences Rob Arathoon points out. "And yet we accomplished scale-ups that nobody had achieved before. As one of many examples, in 1985 we developed serum-free 12,000-liter cell culture processes, 50% greater than anybody had done before. The first day that we successfully worked at that level was tremendously exciting - the whole thing came together then. Genentech is still the world leader in this area."

In selling human growth hormone, start-up Genentech's small, newly formed sales force had to compete head-to-head with Eli Lilly's sales force - one of the biggest and most respected sales organizations of the well-established pharmaceutical companies. The result: Genentech won about 75% of the market, which it would maintain into 1996.

In the end, of course, it came down to creating products that would serve humanity. Diane Pennica worked 9 months without taking a day off during the successful attempt to clone tPA; her name is first among the authors of the research paper published in the scientific journal Nature. But the full implications of what her team had accomplished didn't really come home to her until the day that one of the Genentech marketing people stopped her in the hall. he introduced her to Steve Birnbaum, the first heart attack patient who was treated with tPA. "Birnbaum just grabbed me and hugged me and said, 'Thank you. Your drug saved my life.' That was the high point of my whole career."

Steve Shak, who led the Pulmozyme (dornase alfa) inhalation Solution project from its inception, had a similar experience. During the first clinical study of the drug, he visited a young woman with cystic fibrosis in the hospital. She had just received a dose of Pulmozyme.

"I asked her what it was like, how she felt. She said 'I take a breath now and it feels as though the air goes all the way down to my toes.'"

Though Pulmozyme had not yet been proven to be safe and effective (the FDA licensed it for marketing in December 1993) this experience made Shak realize that this protein might really work for CF patients, just as he anticipated.

Beyond Genentech, Beyond [1996]

Genentech's most important impact has been on its patients. But it has also had a tremendous impact on the biotechnology industry that it founded. Dave Martin observes, "Genentech has really seeded the biotech industry around the Bay Area and California as a whole... Those people who were drawn to Genentech were initially different, more intense, more on the edge.... The number of spin-offs from Genentech is at least an order of magnitude the number of spin-offs from [another company that is larger than Genentech].... Many biotech companies - not all, but many have stemmed from Genentech. In fact, the number of companies spun off from Genentech is about 25.

By 1996, at the 20th anniversary of its founding, Genentech reported 1996 assets of more than 2 billion, revenues approaching $1 billion (with the passing of that milestone anticipated for 1996), and net income approaching $150 million. It was marketing six products, and five additional products stemming from its research were being marketed by licensees. It had a dozen very promising products undergoing clinical testing, targeting many serious medical conditions, from cancer to asthma to diabetes. It was providing nearly $26 million worth of pharmaceuticals yearly free of chart to those qualified patients who were uninsured or under-insured. And it continues to provide a challenging and rewarding opportunity for more than 2,800 employees.

And the biotech industry that sprang from Genentech's success has also shown astonishing growth. The industry as a whole had 1995 sales revenues of about $10 billion, and increase of nearly 800% in just the past 10 years. As Genentech turned 20, there were more than 1,300 biotech companies employing some 108,000 people.

In 20 years one start-up company, with initial capital of $1,000 revolutionized pharmaceutical science and the interaction of academia and industry, created an entire new industry with exciting employment opportunities, and helped hundreds of thousands of sick people. Many people contributed along the way. As a result, many children breathe easier, get sick less often or grow to normal heights. Many adults get a second chance at life. Where will the next 20 years lead?

This was published in 1996. I joined Genentech in 1999.

2016 is coming up, so we'll know the answer shortly ;)

Biotech Manufacturing in Singapore

2013-01-17T05:30:00.000-08:00

Note: The original post has been corrected; this post is the result. OLY/Jan31,2013

Amgen is going to build their first Asia plant in Singapore. Here's the link from Amgen.

The current list of Singapore Biotech Companies includes:

Pfizer
Roche - Built by Genentech then acquired^{OLY 1/31/13}
Novartis
Schering-Plough
~~Genentech (~~Lonza ~~built this)~~^{OLY 1/31/13}

All these plants are clustered in the Tuas Biomedical Park on the west side of Singapore:

(image from Google Maps)

Zooming in, you can see that these plants are basically right next to each other.

... and right next to Malaysia.

I think the Genentech plant cost 290 million and the Roche plant cost 500 million, so if Amgen gets it done for 200 million, that's ~~pretty cheap~~^{OLY 1/31/13} par for the course.

Rising Trends With FDA 483s

2013-01-15T06:00:00.000-08:00

by Oliver Yu

Manufacturing Quality Assurance and Regulatory Affairs professionals are no longer the only people spying FDA Form 483s.

In their latest blog post, FDAzilla reveals a rising trend that hedge funds, law firms and reporters are requesting these documents at greater frequency:

http://blog.fdazilla.com/2013/01/4-trends-the-rise-of-the-fda-483/

Deadlock detected : aspnet_isapi.dll

2013-01-14T06:30:00.000-08:00

Customers are reporting errors of the variety:

ISAPI 'c:\windows\microsoft.net\framework\v2.0.50727\aspnet_isapi.dll' reported itself as unhealthy for the following reason: 'Deadlock detected'.

Our web applications use ASP.NET, which is a multithreaded application. When tasks execute in parallel (as opposed to serial), but require the same resource, this is a deadlock.

In many cases, the reason for this deadlock is because insufficient threads are allocated by the IIS 6.0 default. To allocate more threads, you open up Internet Information Services (IIS) by typing Start > Run > inetmgr.

Right-click on the application pool that your website is using and you'll get a dialog with 4 tabs:

Recycling, Performance, Health and Identity. On the Recycling tab you get to "reset" the tread by duration, by the number of requests or by clock time.

The recycling schedule should match the loads on your web application.

Select the Performance tab and you get:

This is where you can set the number of threads for the web app. In my case, I've set a total of 5 maximum threads.

Changing these settings will alleviate your Deadlock detected errors for ASP.NET applications.

FREE Replacement for Your Gen 1 iPod Nano

2013-01-11T21:30:00.001-08:00

So it turns out that there is a manufacturing defect in the battery of the iPod Nano.

Turns out I'm a proud owner of one of these bad boys. In 2000, Genentech had these five corporate goals that we needed to hit by the year 2005... Management called it the 5x5 goals.

We hit 4 out of 5 and Art handed out iPod Nanos to every employee. Art is now the chairman of Apple's board, but at the time, he was an Apple board member probably trying to help out his AAPL shares.

Whatever the case, we got these kick ass color-screened iPods that were small as heck. They went great with the Nike+ shoe dongle.

Guess what. There's a manufacturing defect with the battery such that it overheats.

Worse, the overheating gets worse with age. So Apple is offering a modern iPod Nano in exchange for your current iPod Nano.

Trade in Gen 1 iPod Nano

So dig up that Nano you don't use so you can trade it in for another iPod Nano that you're not going to use.