What Are The Signs of Bioreactor Contamination?

by Oliver Yu

For animal cell culture, look to dissolved oxygen (dO2) for signs of bioeactor contamination.

Animal (and certainly plant) cells grow more slowly than bacterial cells.  A population of animal cells will double once per day (specific growth rate ~ 0.70 day^-1), where as bacterial cells can double as fast as once every 20 minutes (specific growth rate ~ 70 day^-1).

Bacterial cells that make their way into a bioreactor (be it because you failed to kill them or because you failed to keep them out), have less cellular infrastructure to maintain, and when they find a nutrient-rich, oxygen-rich environment, they will multiply until the excess oxygen in their environment is exhausted.

Have a look at this batch:



What's plotted here is dissolved oxygen (blue) and volume (dark blue).  We inoculate the bioreactor and the dO2 falls to set point.  Once it hits setpoint, the controller comes on and maintains the setpoint by adding air or oxygen (blue line goes flat).  But a few days in, you can see that all of the sudden, the dissolved oxygen crashes for no reason.  This is usually the first sign of contamination... when dO2 in the culture gets consumed.

Let's have a look at the same trend, except with dO2 controller output also plotted.

You can see that the controller is gliding along on a slow upward path.  And then all of a sudden, an inflection point and then it shoots to 100%. (She's all I've got captain!)  And even at 100% controller output, the culture's dissolved oxygen still gets exhausted.

Watching the dissolved oxygen trend is a daily task for campaign monitoring.  If you're looking at these trends, you ought to be able to detect a contamination.

Of course, verify that the culture is contaminated by sampling the bioreactor and sending it off to QC Micro(biology).  They'll tell you for certain whether the culture is contaminated.

But you can use these trends to tell you when to suspect contamination.

Additional Reading:

• You Suck At Reducing Bioreactor Contaminations
• Why You Suck at SIP
• Case Study: Large-Scale Bioreactor Contamination

Use #FDA 483s to Your Advantage

If you have a minute...



One thousand FDA Form 483s are in the FDAzilla 483 Store.

As they say, "A smart man learns from his mistakes.  A wise man learns from others' mistakes."

Disclosure: Zymergi LLC receives nothing from FDAzilla sales.  They are a licensee of our software and we think they add signifcant value to commercial cell culture.

Gun Violence Is Not a Univariate Problem

by Oliver Yu

The public seems to have a hard time debating multivariate problems.

I remember the Ford Explorer/Firestone Tires issue years back very distinctly.  Was driving a Ford Explorer the cause of the SUV flipping over?  Those who say Ford was culpable pointed to the fact that few other SUVs were flipping over.  Ford pointed out that there were Explorers that weren't flipping over... just the ones with Firestone Tires.

Firestone was saying that there were plenty of cars driving around on Firestone tires without issue and it was Ford's fault that their SUV sucked.

This debate went on and on.  What my boss when I worked at Genentech Vacaville, Jesse Bergevin, said to me at the time was that this was a classic multivariate problem with one interaction.

Likewise, gun violence in America is a classical multivariate problem: there are not one, not two, but many variables that contribute to these horrific events.  And like most complex systems, gun violence is many variables coming together (interacting) for a specific effect.

• When it comes to gun violence, we know that guns are a factor... as in, were it not for guns, we wouldn't have gun violence. (Yes, we'd have some sort of other violence).
• We also know that mental illness is a factor.  After all, not all gun owners are going around shooting up malls and elementary schools.
• We also know gun-free zones are favorite targets for gunmen with bad intentions
  

We know of these factors.  And we know that they interact.  To treat this issue as a univariate problem will change the response.

The right thing to do is to model the system and optimize for least number of gun-related deaths.

In the meantime, I will be thinking often of the children who died at Sandy Hook Elementary.  When I think of them, there's this vacuous hole that fills my stomach and my skin feels numb.

We must solve the problem of violence in our society; but we can't afford to do it wrong and treat it as a univariate problem (i.e. ban guns and be done with it).

#GoogleMaps for #iPhone at 40,000 feet.

by Oliver Yu

So I'm flying back from a client site yesterday and I'm on one of these Southwest airplanes with WiFi.

It was a 1 hour 20 minute flight and probably less than an hour for web surfing time, so I figured the cost wasn't worth it.

But I connected to the WiFi anyway and Southwest lets you go to their mobile website, track their flights.

Well, earlier in the day, I read that GoogleMaps for iOS6 made its debut and had downloaded it.

So I figure I'd kill five minutes checking it out.  So I'm at 40,000 feet, and it slowly dawns on me that I can zoom in, zoom out and pan to wherever I want in the world.  So I tried to see if GoogleMaps could find my location... and it did.

The GoogleMaps App must be getting data across the Southwest WiFi.  And since Southwest blocks port 80 (i.e. so you cannot surf the internet without paying them their 5 bucks), GoogleMaps must be working off some other port.

Here's me somewhere over a field in California's central valley:



Here's me a few seconds later:



And I'm clear in another field a few seconds after that.



This GoogleMaps visualization was so cool because I could see what the land actually looked like below (in Satellite mode).  I could fly as high or as low as I wanted to (zoom level).

For the remaining 20 minutes of the flight, I was no longer a weary software consultant in seat 17E...  I was Superman blazing across the Central Valley fields.

Too bad we had to put away our electronic devices in preparation for landing, otherwise I'd have watched it the whole way.

Great job, Google Maps... Well done.

Related articles:

• Why Google Maps for iOS6 is Better Than The Old Google Maps.
• GoogleMaps for iOS6 is Number 1 Download  - CNBC

How the @OSIsoftPI System Tracks Time

by Oliver Yu

Here's a primer on how PI tracks time.

GMT

The first thing you need to know is that everything is archived Greenwich Mean Time, so it doesn't matter what timezone the server is in. It doesn't matter what timezone you're in. Everything gets archived GMT.


When you create a PI point, you have to tell the PI server what data type it ought to store with the pointtype attribute. This is important because some data types can be converted to others while others cannot. Date/times happen to be one of those that can be tracked in at least two ways:

Time as Integer

One convention that PI uses to track time is using integers where the numerical value refers to the number of seconds since 31-Dec-1969 16:00. I'm not entirely certain of the significance of this date.... maybe prior to this date, no computers existed? Whatever the case, 0 refers to 12/31/1969 @ 4pm.

To get Jan 1, 1970 @ midnight, that's 8-hours. So 8 hour is the same as 480 minutes... which is 28800 seconds. So if you wanted to write the date 1/1/1970 to PI using integers, you'd send the numerical value 28800 as the timestamp field.

Time as Float32

Another convention that PI follows to track time is using floating points where the numerical value of the floating point refers to the number of days since 1/1/1900. Incidentally, this is the same as the Excel convention.

As an example, Marty McFly goes back on 5-Nov-55 (11/5/1955). To figure out what this is in the Float32 format, you simply do this:

1955 is 55 years after 1900... so 55 years * 365 days per year = 20088 days



Credit ©1985 Universal Pictures

November 5th is the 309th day of the year, so 20088 + 309 = 20398

Handling Local Time

PI uses the local time of the PI server or the local time of the PI client (ProcessBook as it were) to figure out how to display the time.  No data is deleted because all of it archived against GMT.

So take the silly American ritual of Daylight Savings where during the summer hours, we adjust our clocks forward and then in the winter, we adjust the clock back.

On 11/4, when we got to 2am, we set the clocks back to 1am and repeat the time from 1am to 2am.  This is what it looks like on PI:


You can see that in the 1-day period between 11/4 and 11/5, 1.04 days is shown.

You can also see in the sinusoid trend (which is based on local clock time apparently), the trend repeats the hour between 1am and 2am.

In summary:

• PI works off of GMT and the translation to local time depends on your computer or the PI server's local time.  
• PI can store timestamps as integers representing seconds since 12/31/1969 @ 4pm
        - or -
• PI can store timestamps as float32 representing days since 1/1/1900

Get OSI PI Consult

Top Selling Biologics for 2011 by @CellCultureDish

Two weeks ago, The Cell Culture Dish posted their list of top selling biologics for 2011.

It's a good read.  TheDish points out that though even though CHO is a decades-old technology, it remains the "workhorse" of the biologics industry 20-years after its first application.

Pareto Plot showing CHO rules the Top 10

Of the Top 10 biologics sold in 2011, almost 40 billion dollars were biologics produced from CHO; this figure accounts for 75% of Top 10 worldwide sales.  E.Coli stood at about 12% of total Top 10 list.

How much longer can CHO remain dominant?  According to TheDish, there area 3 areas of work to keep that dominance going:

1. Gene synthesis
2. Media optimization
3. Perfusion

My opinion on the dominance of CHO is simply momentum.  The cost of Genentech/Roche switching off CHO is too great when the infrastructure to produce antibodies with CHO is already in place.

For grins, I made a pareto by company:

And the ranking goes:

1. Roche
2. Amgen
3. Abbott

I know it says BiogenIdec as 3rd, but the Rituxan accounted for 6.7 billion in sales, but not all of it goes to BiogenIdec; I'm pretty sure it is split with (Genentech)/Roche.  So that Roche bar ought to be taller and the BiogenIdec bar ought to be shorter.

Nice read, TheDish... nice read.

C:\Program Files\PI

by Oliver Yu

The default location for installing PI is:

C:\PI

It is actually not the Program Files folder:

C:\Program Files\PI

And please don't put it there.

That stinking space between "Program" and "Files" screws things up.

In fact, if you can, don't install it on the C: drive (which I'm assuming is where your OS files are stored).

If you have another partition like E: then you're petter off putting it there.

The vast majority of installations I do put the PI server on the E: drive.

KEPServerEX OPC Connectivity Suite

by Oliver Yu

I just plunked down some dough for Kepware's KEPServerEX OPC Connectivity Suite. Actually, it was a part of a project for a client, but nonetheless, Kepware makes one of the best OPC servers in the business.

Read this intro to OPC.

So if you've got "Islands of Automation," that is, a diverse ecosystem of PLC and DCS vendors as a part of your operations, getting these systems to talk to PI with OPC is the best way to go.

Most operations aren't intelligently designed from Day 1. Operations tend to evolve. People come and go. Corporations make mid-course corrections to their strategy and even the best automation systems evolve into silos of automation.

OPC breaks down these silos and enables communications, and none better than Kepware's KEPServerEX.

Each modern PLC vendor writes an OPC Server for their PLC. In the diagram to the left, those are the blue computers at the bottom.

The OPC Server allows OPC clients to connect and get data. This is where the KEPServerEX OPC Connectivity Suite comes in. One part of the server is an OPC Client (the yellow puzzle piece in the diagram).

And the other part of the KEPServer is the OPC Server. In a sense, this makes the KEPServerEX the "One-stop-shopping" for OPC data.

So from here, you get to send the data to wherever you want to go.

Biotech/pharma companies typically choose OSIsoft's PI System. And to connect there, you just need the PI OPC Interface, which is an OPC client.

You could've connected PI directly to the OPC Server of the PLCs, and a lot of people do. But if you want a separation of duties between your systems, Kepware OPC is where I've seen a lot of people meet success.

But here's the really cool part. Kepware has impeccable technical support. They're a small company so you're not getting routed around the globe for your tech support calls... you're usually talking to the same guy to follow your issue to solution.

Evaluating their systems is worth your while if you're looking to upgrade your automation.

Download Demo

Disclosure: I have no business relationship with Kepware and receive nothing if you buy their products.  Also, I didn't get paid anything to write this post.

5 Things About Connecting To DeltaV OPC Server

by Oliver Yu

Configuring an OPC client to talk to DeltaV's OPC Server is a chore. And surprisingly, there's not a lot of Google-ready goodies on the matter.

To rectify that situation, here's a list of the Top 5 things you need to know about OPC.DeltaV.1

5. OPC Remote - required client software

OPC Remote refers to the software you need to install on the OPC Client to be able to talk to DeltaV OPC.  I found this strange because when I was the PI OPC Interface to a KEPServerEX, OSI provided all the software for the OPC client and Kepware provided all the software for the OPC server.

Whatever the case, you need to execute OPCRemote.exe on each machine you designate as an OPC client. This package contains the requirements and diagnostic tools like OPC WatchIt.

4. OPC WatchIt! - diagnostic tool

This Windows application is a single form that let's you connect to the DeltaV OPC Server.  It's installed on the DeltaV Application Station and you ought to run it there to see if the OPC Server is up.

If it's working on the App Station, but not on the client machine, you know that you have a connectivity problem.  If it's working on the client machine, you know you're close to getting data flowing.

3. FrsOpcDv

The DeltaV OPC Server does NOT run as it's own Windows Service.

 As in, if you type services.msc and go hunting through that list, you won't find anything that resembles the OPC server.   But if you type taskmgr and look through the programs that are running, you'll see FrsOpcDv.exe.  That, right there, is the DeltaV OPC Server.

This means that when you're setting up DCOM settings that you need to visit this entry in DCOM Config.

2. Local User Account is Your Only Option

There's only one way to connect to DeltaV OPC Server and that's with a local user account.  The one that's pre-configured is called, "DeltaVAdmin."  This account has to exist on the DeltaV App Station as well as the PROPLUS for the data to get sent.

What's crazier is that DeltaV is hard-coded to block anonymous access, which means your OPC client must be running as DeltaVAdmin (or equivalent).  If you're connecting DeltaV to a PI-OPC Interface, make sure the interface is running as "DeltaVAdmin".  This is basically your only option to getting it to work: you cannot use the local SYSTEM account.

1. DeltaVAdmin Needs DCOM Permissions

It follows that you need to create a local user on your OPC client called DeltaVAdmin.  It also follows that you need to grant this local DeltaVAdmin user Local and Remote authorities:

• Local Access
• Remote Access
• Local Launch 
• Remote Launch
• Local Activation
• Remote Activation

That's basically the list of things I wish I knew going into connecting to a DeltaV system via OPC.


Need A Pro Onsite?

CGMP.CO (without the M)

Anyone that engage(s) in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs shall register and submit a list of every drug in commercial distribution [to the FDA]

The above statement is the text of 21 CFR section 207 and appears to be the way the FDA gets a list of all drug facilities they need to inspect.  Incidentally, the FDA provides a way to search that here.

Search for Lonza Biologics:



and you get this:



Whoop-dee-do.

Now check this out.  Here's the same query over at cGMP.co:

http://cgmp.co/biotechpharma/directory/search?q=lonza+biologics

Click into the Hopkinton, MA result and you see wayyyyy more information:




Quite frankly, you can cross-reference the address with Google Maps to get a picture of where this place is.

You can cross-reference this facility with the list of FDA inspections that happened there.  Perhaps a list of 483s or warning letters that was issued there.

You can see all the other facilities that are owned by Lonza as well as the other cGMP companies located in Hopkinton.

So what's this have to do with Zymergi?

Well, for one, this was built with our software: Zymergi SQL Tool.  We eat what we bake.

For two, I'm interested in finding more leads that I can turn into customers.

For three, I'm interested in owning web-properties that can help connect cell culture/fermentation/cGMP folks.

Let me know how I can improve it.

disclosure: cGMP.co is owned and operated by Zymergi LLC.

Congrats, #RedBull #RedBullStratos and @BaumgartnFelix!

My bladder is having a hard time with my eyes just LOOKING at this picture:




Congratulations to RedBull and Felix Baumgartner for an amazing, remarkable, historic... (insert your "wow" adjective here) jump!

Here's the Yahoo article on the space jump.

Cell Culture Engineers are #Keynesians

by Oliver Yu

It occurred to me today that the cell culture/fermentation engineers are to genetically engineered cells what Keynesian economists are to the modern economy.

This is not to say that cell culture/fermentation engineers are charlatans... but if you were a CHO cell, you'd certainly suspect that cell culture engineers don't exactly have your best interests in mind.

You see, the purpose of large-scale cell culture is not, in fact, to sustain a viable biological system.

We know this because at the end of every production culture, the cells are sent down the drain and suicided in the waste kill system. After outliving their usefulness, the cells are... in fact... waste.

The fact of cell culture is that we are replicating a biological system in a stainless steel tank - a phony environment... stimulating the culture with nutrient-rich media so that the cells can engage in the phony economy of secreting the active pharmaceutical ingredient.

We start with eugenics in the seed cultures. This is where we maintain a high copy count of the genes that produce the active pharmaceutical ingredient. Should an offspring be unable to produce enough API, it will die off from being in selective media. The genetic composition of the cell population is thereby controlled.

We then start a series of stimulate/bailout where we transfer the culture into successively larger volumes. When they've consumed their finite resources and polluted their environment, we bail them out into a larger volume.

The ultimate endgame happens at the production scale where we grow the cells beyond the carrying capacity of the culture - crashing their economy and population - so that we can harvest the fruits of their labor.

As cells don't have feelings or livelihoods, I don't feel so badly as a fermentation engineer. These cells were engineered by us for exactly one reason and the end result tends to be life-saving molecules to treat and cure human disease.

But were I a modern economist advising a stimulate/bailout path-forward so the politicians can get re-elected, I'd be a bit more responsible.

The catastrophic collapse of a population and its economy is as predictable as it is scientifically repeatable.  

Free #FDA 483s Offer Is Over. But @FDAzilla Has Opened A 483 Store

Bad News.  The Free 483s Dropbox Folder Offer has ended.

Earlier this year, I found out that FDA483s.com was offering all of the FDA.gov's free 483s in an organized format in a Dropbox:

http://blog.zymergi.com/2012/03/all-fdagov-483s-for-free_6895.html

My biggest problem using these files was:

• Click through 7 separate pages to see what was free
• When you downloaded the file, it was some gibberish like ucm191924.pdf

So when FDAzilla went through and curated it all and put it in a Dropbox, I was really happy to get access.

Afterall, commercial cell culture that produces API in the US is regulated by the FDA and that means you are subject to FDA inspection... most of which my customers are.

Good News.  FDAzilla has opened a 483 store where you can purchase 483s cheaply, instantaneously and anonymously.

Tony tells me that qualifying purchase will grant you access to the Dropbox.

Pristine Bioproduction

There's a company out there called, Pristine Bioproduction.

And it's run by a Genentech alum named, Tim Matthews.  He's an early-stage contract manufacturing organization and their edge is single-use bioreactors.

Here's the deal.  The global mAb market is valued at 15.6 billion and is projected to double in the next 5-years to almost 32-billion by 2017.  Between now and then a lot of folks are going to be entering the market with products, and a lot of the manufacturing capacity is tied up with big biotech.

The reason you outsource your manufacturing is so you can focus on your core competency: R&D and process development.  You let the big guns handle your manufacturing and commercialization strategy.

Guys like Tim have been down that road.  In fact, the cool part about Pristine is that they offer agility with single-use technologies, which translates to greater speed and lower costs.

Questions Tim gets all the time are:

• How can I be certain my CMC strategy is going to fly?
• How do I best ensure that my manufacturing/supply-chain partner is the best fit?
• How can I be be assured that disposable technologies will work for me?

Those other people's questions

What Are Your Questions?

Patching Windows (OSI PI) Servers

A word to the wise:

When you're patching a Windows Server on which an OSIsoft PI server is installed, this is your worst enemy.



It sucks... big time, and here's why:

When you click Restart Now, it shuts down in a manner that corrupts the PI Event Queue. You're going to have data flowing to the PI Snapshot but doesn't make it into the PI Archives.

Then you have to call OSI TechSupport to dig yourself out of this mess.

Final message? Pay Attention! Click Close and go get yourself some coffee. You saved yourself 2-hours of hassle.

Get a PI Professional

E.Coli Replicating Near Thermodynamic Limits

Here's a fascinating Nature article translating a wonkish MIT paper on how E.coli are hyper efficient at replication.  And that their doubling time of 20 minutes is near the thermodynamic limit.

In all, it's an indecipherable 3-page thought experiment applying equations derived from cited sources, which - no doubt - apply equations derived from further sources.

With regard to cell culture, we already know that the 20-minute doubling time of microbes is the rule and that strange strange contaminants like Leptospira are the exception. 

@CellCultureDish On Eliminating Animal-Derived Components - ಠ_ಠ

by Oliver Yu

In a recent article on key improvements for improving the quality of biopharmaceutical manufacturing, the author, "The Dish" states:

Many problems with respect to contamination are a result of problems with raw materials and too often these raw materials are sourced from animals. Animal-derived products always carry a risk of contamination from adventitious agents, such as viruses and prions. Not only are animal sourced products a safety risk, but also they simply are no longer necessary ingredients in manufacturing.

While I agree that eliminating animal-derived sources will improve the process, this claim is rather spurious.

Let's go through this one claim at a time:

Animal-derived products always carry a risk of contamination from adventitious agents, such as viruses and prions.

This is certainly true... there is always a risk, albeit small.  Peptones and other animal-derived media components are heat-inactivated.  Automation engineers code recipes into the PLC or DCS to make certain this happens.  After the animal-derived media components are added during cell culture media preparation, the entire media is virally-inactivated with a process similar to pasteurization.  Whatever risks were there are significantly diminished before the bioreactor is even batched.

In the case of antibody manufacture, the Protein A chromatography is the step that binds the antibody and throws everything else away.  To present the risks of viruses or prions in the final product as a risk - given the viral barriers and purification capabilities of modern biotechnology - is extremely irresponsible.

What about this claim?

Not only are animal sourced products a safety risk, but also they simply are no longer necessary ingredients in manufacturing.

Is it true that we fully understand the components of animal-derived ingredients?  I'm not aware that this is true.  Perennially, miniferm experiments confirm that cultures that use animal-derived sources produce higher titers than "veggie" media or fully-defined media.

There's that je ne sai quoi in animal-derived media that the cells seem to like.  Some think it is the shear-reduction capabilities; others think it is some magic ingredient that we have yet to fully characterize, but these process R&D managers aren't stupid.  If your process titers are low, and using animal-derived media can increase titers so that you can commercially manufacture the API... you use animal-derived media.  It's that simple.

All this said, The Dish is correct about eliminating animal-derived media components... but for the wrong reasons.

Elimination of undefined media sources will reduce process variability because you've eliminated a potentially huge source of variability.  I've seen titers swing 300% from year to year with no change in the manufacturing formula, no change in manufacturing execution, no change in anything but the lots of ingredients that we get. Using defined media will simply eliminate the lingering question of, "Is it the peptone lot?"

On top of that, variability reduction increases process capability.  Even if using fully-defined media loses out 25% yield to the best performing undefined media, you gain from the predictability of your process.

Now, you can schedule campaigns with greater confidence.  You can manage the supply chain.  You can be assure that there will be fewer disturbances to your manufacturing process... you can keep less inventory... and you can ultimately save in costs.

Variability reduction is the reason you want to eliminate animal-derived media components... not risk of viral or prion contamination.

Process R&D managers that "get it" understand that optimizing titer must be balanced with optimizing process capability.

Single-Use Bioreactors (there's the Mobius by @EMD_Millipore)

Mobius CellReady Single-Use Systems

The concept of throwing away your bioreactor after a single use is quite foreign to me. My professional career grew up on stainless steel bioreactors that sat majestically in these uber-clean processing space in these plants.

But the disposable bioreactor concept appears to be gaining traction.

The idea is this:

You sterilize a plastic bag and you fill it with media. You can mix the contents of the bag. You can control temperature. You have pH and dO2 sensors hooked into a control system that maintains pH and dO2. You have everything that a stainless steel bioreactor has to maintain cell culture. Except when you're done with the operation, you get to throw away the bioreactor, whip out a new sterile bag and repeat.

What's the Advantage?

The most obvious thing is that you don't need to clean-in-place (CIP) or steam-in-place (SIP) the bioreactor... these bags come sterile. This means that you don't have CIP and SIP validation and the associated quality costs.

This also means that you don't have the piping, the valves, the boilers, the steam traps... all the infrastructure that goes into maintaining CIP and SIP systems.

CIP and SIP consumables don't need to be purchased. WFI systems can be smaller. Your Waste Kill isn't taking on all that acid, alkali and rinse solutions.

Staffing overhead to maintain and troubleshoot these systems don't need to be hired. The PLC logic or DCS recipes don't need to be coded. Control loops don't need to be tuned, so your automation engineers aren't as busy.

What about contaminations? Everyone knows from miniferm experiments that tube welding has low associated contamination risks. Everyone know that your failure rates go up the larger your tank. Is it true that success rates are higher with these single-use bioreactors?

What Stays The Same?

by Oliver Yu

You're still going to need to execute, so your production organization ought to stay the same. You're still going to need to troubleshoot the process, so your Manufacturing Sciences process support stays the same. You still need scheduling, you still need downstream recovery and purification. All that stays the same.

I Still Have A Few Questions...

• Do Single-Use Bioreactors (SUBs) decrease my plant shutdown times?
• What is the turn-around time (from dirty to prepped) on a SUB?
• What commercial products are manufactured with SUBs?
• At what scale are SUBs proven?
• What is the Total Cost of Ownership of SUBs?

If you want to know more, Dan over at EMD Millipore has some answers.

Contact Dan For More Info

How to Use ZOOMS (for OSIsoft PI System)

This was where our OSI PI Search Engine was as of 2008



In a single textbox, you could type in any set of words... just like Google.

And after you typed in a few concepts like:

• Reactor1
• Temperature
• Concentration
• Volume

ZOOMS could figure out that Reactor1 was a unit while Temperature, Concentration and Volume were process parameters.

Not needed, but if you felt like typing in a time-window (in OSIsoft PI-ese), it would simply show you the trend that you meant to see.

Perfect for people who don't have PI ProcessBook installed... which is basically management, scheduling, QA, instrumentation, process engineering... you know, everyone.

Get The ZOOMS Brochure

Dang @Novartis, 9 #FDA 483s Since 2009!? You Should Get With @fdazilla

I was reading this FiercePharmaManufacturing's Article on Novartis' CEO under a Regulatory Cloud.

So I got to thinking... how many FDA 483s are these guys getting?

It turns out, Novartis - across all their businesses has gotten at least nine 483s since 2009.

• 17 observations made at the Liverpool UK site in 2011
• 14 observations at the Emeryville site in 2010
• 8 observations at the Vacaville site in 2011 after 5 observations from 2009
• 5 observations at Suffern NY in 2010 after 4 observations from 2009
• 1 observation at Brea in 2011
• 13 observations issued in 2011 after 2 observations at Lincoln, NE in 2010 

As Eleanor Roosevelt once said, "Learn from the mistakes of others.  You can't live long enough to make them all yourself."

Fierce is doing a good job tracking Novartis' quality problems. I'm just letting you know how to get your hands on their 483s.

Double Block and Bleed - Contamination

When filling up a bioreactor with media (colloquially called, "batching"), the media is delivered through a dedicated pipe.  When the batching is complete, there needs to be a way to contain the bioreactor... which is why there is a "near-to" block valve.

And the excess media (not required per specification) is sent to drain via a bleed valve that is on the non-sterile side of the block valve.



Figure 1: Single Block and Bleed

This is pretty standard for fermentors and bioreactors... in the 1980's.

After the media line has delivered the media, it is dirty because the nutrient-rich media has coated the pipes and will promote growth unless cleaned.

And if you have single-block-and-bleeds, your cleaning and rinse solutions are going to pound against that block valve.  Should it fail, you're going to have a contaminated bioreactor.

Modern plants... those with the luxury of building from scratch install two blocks and two bleeds, hence

Figure 2: Double Block and Bleed

by Oliver Yu

In this scenario, when the media is delivered, both block valves shut simultaneously and both bleed valves are opened simultaneously.  The excess media is sent to drain via the valves farther away from the bioreactor.

Subsequent manipulations to that line (e.g. post-use integrity tests, cleaning, sterilization) are isolated from the bioreactor by two block valves... prophylaxis for disturbances to the sterile envelope.

Read About A Successful Contamination Response

Cell Culture Database - Batch Information

You work in biopharma. Maybe you're a fermentation guru... or a cell culture hot shot. Whatever the case...
We muggles don't have the luxury of waving our wands and having protein fold themselves mid-air. There's usually a container where the process happens.
A time-window (starttime to endtime) is when processes happen.

Operators execute process instructions; these procedures is how the process happens.
The execution of process instruction results in an output. The output of the process step is the product and constitutes the what.
Lastly, the process (step) is given a name describing who the batch is.
It stands to reason that the who, what, how, when, where of a batch is characterized by:

• batchid
• product
• procedure
• starttime - endtime
• unit

and fully describe batch information for cell cultures and fermentation.

Organize Your Cell Culture Data

#FDA Inspector Just Showed Up... @fdazilla

It’s Friday. 8:30am. You’re looking forward to a long, nice weekend. Then, you get a call from one of your associates. An FDA inspector is waiting in the lobby. She’s unannounced, she’s experienced, she’s eager, and she’s ready to go.

Do you know the feeling?

#FDA Inspection Readiness: Inspect the Inspector @fdazilla

So get this.  That FDA 483 Store has this uber-awesome feature for inspection readiness:

You can inspect the inspector.

FDAzilla has a page for each of the 772 FDA inspectors involved in their 1,000 Form 483 Reports and cross-referenced two key pieces of information about them:

1. Which cGMP site they audited
2. Who else was with them when they conducted the audit

Which means if an FDA investigator shows up in your lobby, you can search their name on the FDAzilla 483 Store and see:

• See who else they've inspected
• See who they've worked with
• Buy and research their 483 observations to see their core expertise

FDA inspectors have core areas of expertise.  Some focus their work in key geographic areas.  The more you know about your inspector, the better you are able to pass the inspection with minimal 483 observations.

This FDAzilla 483 Store is the only tool I know of that lets you inspect the inspector.  

Anyone know of anything better?

Compile Error in Hidden Module modAddin (Excel 2003, 2007)

You're here because you can't stand seeing this:



anymore.  Your molars are ground flat and deleting the Forms folder didn't work for you.

You're in luck:  a guy who goes by GJBenzie wrote in and provided a solution that worked for my Windows Vista 32-bit and here it is:

Try This for Getting Rid of modAddin Errors

1. Go to Start > Run

2. Type cmd


3. At the prompt, type:

regsvr32.exe /u C:\Windows\System32\MSCOMCTL.OCX

4. Hit Enter

5. Then type:

regsvr32.exe C:\Windows\System32\MSCOMCTL.OCX

6. Hit Enter



Did that work for you?



If you use OSI PI, check out: Want to never deal with this problem again?

1,000 #FDA 483s!?! @fdazilla

Check this out:

http://store.fdazilla.com




It's basically a place where you can search and buy one-thousand FDA 483s reports.

 Here's what a search for Amgen's 483s look like:



Click into the 483 report and see the details:

• Number of observations
• Inspection Time Range
• Investigators

...everything:

Add To Cart and checkout with PayPal.
It's strange because when you're running cell culture production in GMP environments, QA sort of gets these communications and plan their inspection readiness strategy around these 483 reports.

Next thing you know, you're at a change management meeting and you're trying to address all these new requests and can't figure out the drivers for them...

Well, here they are: 483 observations that FDA inspectors make of other plants will also apply to you.

p.s. -  This is, of course, in addition to their FREE 483 offering I wrote about a while back.