May 21, 2013

Separation Anxiety?

Most labs have used floor mount or bench top centrifuges for separation based assays for decades.  Whether spinning samples to remove air bubbles, spinning down cellular debris or isolating supernatent, there are numerous manual access centrifuges on the market, but when it comes to automation, the choices are limited.

For a number of years, Agilent (formerly Velocity11) has offered the compact VSpin.  VSpin has a two position rotor with buckets for std microplates.   It can spiV11_prod_big_vspinn up to 300o rpm/ 1000g and has an automated door that allows direct access to plates using an offset robot gripper.   Units can be stacked on top of each other for increased  use of vertical workspace.  The Optional Access2 loader can also grab the plate and present it externally to a liquid handler gripper or top loading plate mover like Twister2 or KiNEDx.

Hettich also provides a larger unit called the Rotanta 460 which can accommodate 4 plates at speeds up to Hettich_Rotanta_46_RSC_Front_Hatch6200prm,  but is a bit more of a challenge to integrate as the robot gripper fingers need to reach into the unit from the top.  I have seen this done with Mitsubishi and Staubli robots and Tecan actually integrates this unit under an EVO liquid handler accessible via an open locator in the deck.Ixion3

Sias’s Ixion is a compact unit, similar in size to the VSpin, however plate access (total of two) is through the top just like the Rotanta and can spin up to 2000rpm.   This unit integrates nicely with Sias’ Xantus liquid handlers.

Finally, BioNex offers the HiG centrifuge which can also spin two plates.  The bright orange color makes this unit hard to ignore…and a closer look shows that this unit may be BioNex HiGthe best of the bunch.   With an automated lid that retracts from the top, the HiG does not need a plate loader like the VSpin as plates can be accessed by just about any robot gripper.   At 5000g, BioNex claims this unit to be the fastest robot accessible centrifuge available.

Maintenance requirements for each of these devices is similar.   All include high-speed motors so proper ventilation is a must.   Bearings must be greased, sensors cleaned and pneumatics (door opening, plate loaders) checked for leaks.   Additionally, rotors and buckets should be checked for cracks or other signs of wear.   As noted in previous blogs, rotational speeds can be verified using a digital tachometer but you may need to remove covers to gain access to the rotor (kids, don’t try this at home…call a professional).   As always, if you ignore that last piece of advice, don’t come crying to me when your friends make fun of you because you have a mircrotitre plate permanently embedded in your cheek…

April 5, 2013

A Robot By Any Other Name…

A number of lab systems incorporate robot arms to manipulate consumables (plates, lids, tip boxes, troughs).   Robots, insofar as lab automation is concerned, can be broken down into three categories:

Liquid Handling Robots- Ten years ago or more, if someone in thTecan EVOe lab was talking about a robot, chances are they meant a liquid handler.   Not surprising, since most liquid handler are essentially XYZ robots.  However, unlike their more generic cousins which are used in industrial manufacturing applications, these robots have evolved into application-specific workstations.  That is to say, they come pre-tooled with everything that is needed to perform plate preparation applications.  Even their software is specific to these applications.

Industrial Robots- When moving consumables  off the liquid handler deck, to peripheral instruments (readers, washers, storage…etc) a number of lab systecaliper-staccatoms are built around industrial robots from established companies such as Staubli Robotics,Mitsubishi Electric and Epson Robots.  These robust and increasingly affordable robots were once the exclusive purview of industrial assembly lines or semiconductor manufacturing.   Smaller sizes and lower costs have resulted in widespread adoption by integrators such as Hi-Res BioPAA andCaliper Life Sciences (PE).  Out of the box, these generic devices are not much more than building blocks – requiring tooling (gripper hands/fingers, storage devices, sensors and a good deal of programming and teaching to make them manipulate lab consumables.    However, once tooled up and programmed they are reliable workhorses that require little, if any maintenance.

Plate Mover Robots – Zymark (now Caliper/PE) was one of the first companies to come out with robots dedicated to plate movement.   The Twister plate loader was essentially a miniature version of an industrial cylindrical robot – meaning it’s work envelope was twister-7900cylinder shaped instead of rectangular, like XYZ robots.  What made this robot unique is that it came with microplate gripper and fingers, as well as removable plate storage racks.   My good friends Rick Bunch and Brian Paras did a masterful job of marketing this product (over 3000 were sold) which became the de-facto standard for loading instruments for nearly a decade.   Soon, improved varients emerged such as the Hudson PlateCrane EX, Zymark (PE) Twister II, Thermo CataLyst Express and more recently Peak Robotics(now PAA) KiNEDx/ProNEDx/BiNEDx and Precise Automation PreciseFlex all capable of tending to several instruments (Twister was ideally dedicated to one instrument).  Additionally, unlike industrial robots which generally come with sophisticated controllers with multi-tasking operating systems and proprietary programming languages containing huge command sets with an endless syntax permutations,  plate mover robots come with build in controllers (no separate box or umbilical cords) and a concise command set that is optimized around moving microplates.   Finally, the platemover robots have found dual use as instrument loaders as well as becoming the hub of many integrated systems just like their industrial counterparts noted above.

Last words:  Both liquid handling and plate moving robots are well within the means of many labs both in terms of price and functionality as well as ease-of-use.   Industrialbroken_robotrobots are best left to those with deeper engineering resources or professional integration firms.  Since this is a blog about support…the same holds true in that many labs or third parties are capable of supporting liquid handler and plate movers however, not many  (including integrators) are truly capable of services industrial robots.  That is a task best left to the robot manufacturer.

March 26, 2013

Nervous…System Support

My last post about standardization and open source scheduling software for integrated systems got me thinking more about the post-sales support sidon knottsde of those systems.

As many of you know, systems can be very expensive so end-users are making critical decisions on behalf of their employers, both on how well their money is being spent and what are reasonable expectations as to when the system will begin to show a return on that investment.    There is always concern about that ramp up time and the problems you may encounter along the way, so the question of warranty becomes very important to the lab manager or principal user of the system.

Most system integrators go through a very similar process regardless of who the end user is.   It generally all starts with a customer needs assessment, whereby a sales mabiocelnager (usually accompanied by an Application Scientist) asks a number of questions prior  to generating a system concept proposal.   While it may seem tedious to the end-user, (I know what I want, why can’t these people just give me their quote?) this is a critical step in ensuring long term success.   I have been involved in a number of situations where a customer had budgeted hundreds of thousands of dollars but could not provide a single manual method they wanted to automate.    Not good.

Weeks (more like months) after  the system is designed/proposed and agreed upon/purchased by the customer, a date is usually scheduled for a FAT (factory acceptance test) whereby the customer visits the integrator and goes through a “buy-off” checklist prior to shipment.  This buy-off is best done with beckman systemthe actual customer methods (minus real chemistry) to ensure that the system performs as agreed upon prior to shipment.   Remember, shipment means breaking down the system and packaging so that it can be “re-integrated” yet again upon arrival at the customer site whereupon it goes through the SAT (site acceptance test) which is basically the  same buy-off as the SAT, albeit with actual chemistry.   Once completed, you get a handshake (maybe a hug if it goes really well) and “TA-DA !”you own the system.

Most integrated systems come with a one year warranty.  This can mean different things to different integrators but in my experience, entails parts and labor only (travel is nostaublit included).  It also does not include operator induced failures like crashing a robot into an instrument.  In general, most systems include a fair number of third party instruments that the integrator does not manufacture and they don’t make a lot of money providing them.   These instruments come with their own warranties (usually 1 yr) and the integrator almost always passes these on to the end-user, acting as the first point of contact if a failure occurs.   Since the instruments can often reside at the integration firm for several weeks prior to FAT,  it is important for end-users to understand their warranty…’what is covered?’, for how long?’ and ‘when does the clock start ticking (upon shipment, acceptance)?’.

As mentioned in prior posts, an extended warranty for an integrated system can often cost 10-15% of the purchase price of the system.   Some integrators offer an incentive (discount) if you purchase such an extension with they system, or prior to expiration of the standard one year warranty.   Should you choose that option?

In short, the answer is no and I will tell you why.   Let’s assume we are talking about a $350K ELISA system that includes a robot mover, bar code reader, liquid handler, plate washer, ambient storage hotels and plate reader.    Those majorbeckman systemcomponents probably account for less than 50% of the price of that system.   The remainder is comprised of  things that don’t wear or break (system tables, enclosures, scheduling software, PC and …labor).   That last one is a biggie.    Integration is hard work and proper design, build, programming and testing prior to  SAT can include hundreds of person-hours.  That is commonly referred to as NRE or non-recurring engineering.   A warranty for such a system could cost upwards of $50K, or more (not including travel) but you really should only care about the instruments…not the other stuff.

So, if you are faced with a decision regarding extending the warranty of your integratedautomateitsystem…push back.  It’s pretty easy to determine the list price for each instrument in a system and request a contract that is based on just those costs.   You could also go directly to each manufacturer and request contract pricing on their product only.   If that is too time consuming or a management hassle you don’t need, you may want to reach out to one of the major MVS (multi-vendor services) providers (ThermoPEJohnson ControlsAgilentGE) or smaller ISO (independent services organizations) like The LabSquad.

Don’t be nervous about system support…be informed.

March 22, 2013

SiLA Love Songs

Time to talogo_silake a break from talking about instrument support and wax philosophically about a bigger support challenge – integrated systems.    A colleague asked me my opinion of the SiLA, a consortium that is creating standards for lab automation instrument interfaces.

As I understand it, the folks behind SiLA have a business model that will define these interface standards and then presumably charge instrument manufactures for the privilege of claiming “SiLA Compliant,” or some such declaration.    I have to admit that my knowledge of this model is sketchy at best, and the SiLA website does not really lend much insight.

This seems a bit like putting the cart before the horse to me.  That is to say, the instrument interfaces are fairly useless without a higher level scheduling software that manages assay workflow, instrument status and data.

In the 1980′s and 90′s, there were many such products from well establishepolarad system integrators such as  RoboCon (acquired by CRS Robotics), CRS Robotics (acquired by Thermo Electron, who merged with Fisher Scientific),  Scitec (acquired by Zymark), Zymark (acquired by Caliper, who merged with Perkin Elmer) and Velocity11 (acquired by Agielnt) — do you sense a theme here?  All this M&A activity happened during the HTS and uHTS craze.  Once that goldrush ran it’s course, it became clear that system integration is difficult in a public company.   It’s hard to take a 16-20 week design/build/install model and cram in into a quarterly revenue model.  Systems needed to become smaller, more standardized and less expensive.

Nevertheless, each integration company created their own assay management and scheduling software and wrote their own libraries of instrument interfaces.  Hundreds of systemsMicrosoft.Net were installed and not a single one required the involvement of SiLA or any other instrument standard.   One common thread that enabled each of these software’s to succeed was the widespread adoption of Microsoft’s COM, OLE and eventually ActiveX  and .NET frameworks.  As long as instrument manufactures included automation “hooks” based on the MS framework, integrators had little trouble creating robust instrument interfaces.   It’s really not that complicated, as you really just need to be able to initialize, start, stop and report error status for most instruments.   Data (from readers primarily) was generally a secondary consideration and not part of the scheduling paradigm.

So flash forward a few years and there are remarkably fewer pure integration companies left.   Caliper/PE and V11/Agilent are still out there, but not perhaps as visible as they once were.   Thermo Fisher now has a more limited presence as well.   To be sure, companies like Beckman, Tecan and Hamilton still build systems but they are primarily liquid handling companies first, integrators second.   Really only HiRes Biosolutions,Process Analysis & Automation Ltd. or PAA and Hudson Robotics still fit the pure integrator definition.

It would seem to me that without an Open Source scheduler software standard, there isn’t much need for an Open Source instrument interface standard.    Each of the companies mentioned above already have significant investments in creating their device libraries.  What is the incentive for them to abandon those interfaces (many of which they charge for) in favor of the SiLA standard?   I’m not saying they wouldn’t but I’d like to hear a good business argument for it, other than fear of someone else doing it.   In fact,  I would imagine that an Open Source scheduler could exist nicely even without SiLA, much as the proprietary schedulers have existed.    As users create interfaces to various instruments, they would put them into the public domain for anyone to use…no SiLA required.

A few years back, a number of folks in the Cambridge, MA community came together and started to discuss an Open Source scheduler.    About two years ago,  Caliper donated it’s CLARA/iLink source code to the University of Wales, in Aberystwyth which can still be found on Source Forge under the name  LABUX.   Last fall, two MIT students created a similar effort called Clarity.   I have not followed either of these endeavors closely, but it seems to me that they could either solidify SiLA or bury it.

My opinion?  When I ran the system business at Caliper, prior to the PE merger, I was not a big fan of Open Source scheduling.   I knew the investment we had made in our own software and although I knew it had it’s limitations, it was enabling technology that created significant revenue.   Still, I saw the LABUX initiative as a way of testing the waters.    If an open source scheduling standard did emerge, better that it be something we were familiar with.     Additionally, if we could build systems and not have to maintain the software staff to maintain the scheduling software, we could in theory be more profitable (that public corporation thing again).   Now, two years removed from that role,  there does not appear to be  solid consensus on Open Source scheduling or interfaces.    I have no stake in the game anymore, so perhaps I can now be a bit more candid and say.  I am a big fan of the pure integration model, so I am rooting for HiRes, PAA and Hudson!   I still don’t get the whole SiLA thing.   Seems a bit… SiLLY to me.

March 21, 2013

Is your instrument A-OK? If not, you may want to fix it PDQ (or you may be SOL) – LOL!

Is there an acronym for excessive use of acronyms?  It seems every industry has a long list of abbreviated jargon to capture the essence of what is important to their needs…and the life sciences industry is no exception.   Below are a just a few of the many acronyms that we encounter in our daily support of lab instruments and some brief definitions.

OEM – Original Equipment Manufacturer, generally the name of the company who sold the instrument.  However…there have been numerous mergers, acquisitions and bankruptcies over the past decade or more so your BioRad thermal cycler might be sitting on the bench with an older model with an MJ Research logo, or your Zymark Twister robot could now say Caliper Life Sciences (which is now Perkin Elmer)…you get the idea.

MVS – Multi-Vendor Services, a generic term that describes a single services provider who works across multiple vendor brands and product lines.   Giants include Unity Lab Services (Thermo), PE OneSourceAgilent, Johnson Controls and GE Healthcare.

ISO – Independent Service Organization, anyone other than the OEM.  Typically a local provider who works directly with customers or acts as a sub-contractor to MVS’s.

PM – Preventive Maintenance, sometimes called Periodic Maintenance.  A pro-active service performed prior to instrument failure designed to catch wear items before they escalate into more costly failures resulting in downtime.

MTBF – Mean Time Between Failure, a spec provided by some OEM’s that statistically predicts instrument reliability.   Failures are generally defined as abnormal occurrences that cannot be easily remedied by an operator and render the instrument or system inoperable.

MTTR- Mean Time To Repair, the average time required to repair a failed instrument or system.   Total number of failures / total time instrument/system is unavailable for intended operation.

IQ – Installation Qualification, documents that the correct instrument was received and installed properly. IQ can be performed by the user or the vendor (typically both during the site acceptance of a device or system).

OQ – Operational Qualification, tests that the instrument meets specifications in the user environment. OQ can be performed by the user or the vendor.   Some instrument include simple diagnostic routines that can be run by users, however a number of such tools are password protected or visible only to service personnel.

PQ – Performance Qualification, tests that the system performs the selected application correctly. PQ must be performed by the user, or in the case of some GxP or CLIA labs, a third party that provides hard data.

CV – Coefficient Of Variation (not your curriculum vitae, or resume),  a normalized measure of dispersion of a probability distribution.  Insofar as labs are concerned, this is generally a reference to unexpected errors across a microplate.   The resulting errors or outliers may often be traced back to liquid handling or pipetting performance.

GLP 0r GMP – Good Laboratory/Manufacturing Practices, a set of standard operating procedures (SOP’s) to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of chemical (including pharmaceuticals) non-clinical safety tests.   Insofar as automation of assays is concerned, these SOP’s may contain periodic OQ & PQtesting of individual instruments, using NIST traceable tools and including analytical date (where applicable) .  Techs working in such labs may be required to show tool certificates prior to beginning work and produce validation results.

CLIA – Clinical Laboratory Improvement Amendments, any facility which performslaboratory testing on specimens derived from humans for the purpose of providing information for the diagnosis, prevention, or treatment of disease or impairment, and  for the assessment of health.   As with GxP above, CLIA labs follow stringent SOP’s regarding instrument support or verification, often requiring certified documentation (audit trails).

Did I forget any?  Don’t be shy, let me know.   TTFN!

March 18, 2013

Is it a System or is it a Liquid Handler?

Remember Razzles? – ‘is it a candy or is it gum?,” so the TV commercial went.   (I actually razzlessubmitted a contest entry calling it  ‘Ghandy…a peaceful coexistence of seemly incompatible delights.’  Not bad for 9yrs old and still waiting on a reply.

Servicing liquid handlers can be a lot like Razzles in that you start out thinking you are working on one thing only to show up and find out that you have something else going on.

System Types:

There are essentially three types of plate based automated systems commonly found in life science research labs.

Robot Centric – A robot arm (manipulator) delivers all consumables to/fropaam a variety of plate based instruments and storage devices.   While many such systems include a liquid handler, they along with other instruments are controlled via a separate scheduling software that oversees the assay steps and ensures proper timing.   Common examples are Hi-Res Biosolution ACell , PAA automate.it,  Agilent BioCel and Caliper (PE) Staccato.

Distributed Robots – Similar to above, except that there are multiple robot arms connected via a conveyor belt or other plate transporter.  Each arm is dedicated to a small number of instruments which each carry out the assay in a sequential (first station to last) fashion.  Again, one or more liquid handlers may be present in the system however they contain programs that are initiated 

dim4

by a higher level scheduling software.  Such systems were very popular in the pharma industry (Thermo Dim 4, Zymark Allegro) rush to process more compounds per day (HTS and uHTS) looking for new chemical entities, but nowadays you be hard pressed to find many survivors still in operation.

Liquid Handler Centric- In this instance, the liquid handler is the heart of the system, which is to say, the liquid handler software runs the assay (no higher level scheduling software).   A large number of these types of ‘systems’ consist of just the liquid handler, by itself, simply carrying out pipetting operations.   However, as many mainstream liquid handlers now include robotic gripper capabilities, these devices start to be 

evo-system

stretched into more capable systems that automate more of the assay freeing up lab personnel for more high value operations.   The plate gripper can load/unload consumables for multi-plate runs or can deliver consumables to shaking, heating, cooling or waste locations on the liquid handler deck or may move them off-deck to plate readers, washers, centrifuge, incubators, thermal cyclers, reagent dispensers or storage devices.   Examples can be see from well known vendors such as Beckman CoulterTecanHamilton RoboticsAgilent and Perkin Elmer.

Conclusion – when exploring your options for servicing a liquid handler, be sure to consider any peripheral equipment attached to that device.   If the end-user expects their entire system to PM’d during a routine visit, the service tech may be either the bearer of bad news or a well prepared and valued service provider.