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What is ISO 10993? How is it Different from USP Class VI?

April 22, 2014

One of our most popular posts is “What is UPS Class VI Testing and Why is it Important?”. But did you know that while USP Class VI testing is widely used and accepted, some view as the minimum requirement a raw material must meet in order to be considered for use in a medical application? In fact, USP Class VI has been largely superseded since the release of ISO 10993 in 1995. This post will take a deeper look at what biocompatibility is and how it is defined by the International Standards Organization.

To begin, let us address just what biocompatibility is. Biocompatibility is the materials lack of interaction with living tissue or living system by not being toxic, injurious, or physiologically reactive. A material that is biocompatible does not cause an immune response in a host. One thing biocompatibility is not is chemical compatibility. It does not define how well equipment will perform in an autoclave or when exposed to SIP because humans are not generally steamed in place.

Another thing biocompatibility is not is simple. In fact, no one test can comprehensively describe a material’s biocompatibility. That’s why, through the years, several testing protocols have emerged to characterize a materials biocompatibility. One of the first guides to biocompatibility was published by the United States Pharmacopeia in 1990 was USP <88>, which includes the criteria for USP Class VI Testing.

In an effort to standardize biocompatibility testing worldwide, the International Standards Organization (ISO) developed ISO 10993. ISO 10993 is a 20-part standard that evaluates the effects of medical device materials on the body. The first part of the ISO 10993 standard, “Biological Evaluation of Medical Devices: Part 1: Evaluation and Testing” is probably the most relevant to finding a place to start determining which tests methods should be used to assess a material’s biocompatibility. The rest of the sections mostly deal with appropriate methods to conduct the biological tests suggested in Part 1.

ISO 10993 uses matrices to break medical devices down into three categories: Surface, External Communicating, and Implant and further breaks these categories into subcategories based on exposure time (limited, prolonged, and permanent). Once we identify the device category and exposure time, we can then use the ISO 10993 standard to select a recommended biologic testing protocol. ISO 10993-1 is not a formal checklist, but a guide that should be used to provide the information to get you pointed in the right direction and design a testing program.

As you can see, biologic compatibility testing is complicated and just asking “Is it USP Class VI?” is often a cop out. More detailed characterization and understanding, as outlined in ISO 10993, is essential for proper material specification and selection. Most materials today comply with both USP Class VI and ISO 10993, but few know what this really means. At Holland, we pride ourselves on having the technical knowhow and understanding to interpret the meaning of material compliance and stay abreast to any material changes or compliance issues. If you have questions about the biocompatibility of your single use component, USP Class VI or ISO 10993 standards, contact a Holland Sales Engineer today.

Measuring Temperature in Small Diameter Lines- Direct Immersion RTD’s and Best Practices

April 18, 2014

Measuring and accurately monitoring process conditions is essential in high purity applications. In the over sixty years Holland has spent applying process equipment for the high purity industry, we’ve learned that the process is the product. If we can’t control the process, we can’t control the final product. A critical process parameter that needs to be measured is temperature. This post will highlight some challenges, best practices, and solutions for measuring temperature in a high purity application.

To begin, both the food and pharmaceutical industries rely and platinum RTD’s when measurement of process temperature is critical because these platinum resistance thermometers (PRT’s) offer superior accuracy, stability, and repeatability compared to other temperature measuring devices. Most RTD’s are classified in accordance to either the ASTM E1137 or IEC 60751 standard and are rated either Grade/Class A or Grade/Class B. Grade A sensors have temperature tolerances of +/-0.3 C at 100 C and Grade B sensors have tolerances of +/-0.67 C at 100 C. These tolerances only apply when measured under ideal lab conditions and do not take into account common process variables such as vibration and immersion depth.

The most accurate way to measure process temperature is with a sensor that is immersed directly into the flow. These direct immersion sensors are the preferred because they provide accurate measurement and quick response time. Most often, RTD’s are clamped in to a tee, perpendicular to flow. For small diameter lines, this RTD orientation may not be adequate to get an accurate temperature measurement.

RTD's Work Best When Inserted into the Middle of the Flow Path

RTD’s Work Best When Inserted into the Middle of the Flow Path

A general rule that is used for immersion RTD’s is that the minimum immersion length into the flow should be at least 10 times the sheath diameter plus the length for the sensing element. This immersion depth is required to minimize temperature conduction through the stem of the sensor. Known as stem conduction error, this is the error caused by heat transfer between the sensing element and the ambient conditions at the back of the sensor.

To put things in perspective, for a typical 0.25” diameter sensor with a 1” long element, the 10 times plus length would require 3.5” immersion into the process. You could make this work on a 4” process line, but good luck on a half inch line. While reduced diameter sensors are available, it’s tough to find one much thinner than 1/8” of an inch. One fix is to insert the sensor perpendicular to the flow. By inserting the sensor into the end of the run of a tee, as opposed to the outlet, we can increase insertion depth.

While this fix addresses stem conduction issues, flow blockage and pressure drop must also be considered. The other big drawback to direct immersion sensors is that in order to remove or replace the sensor from the process line, the line must be fully drained. This isn’t good if a sensor fails mid batch. Direct immersion sensors can also pose problems with sticky, viscous products that are prone to coating and difficult to clean or remove. High flow and turbulence in CIP can also cause drift and affect measurement accuracy. Fortunately, there are ways we can address these challenges, so stay tuned for future posts focusing on non-intrusive surface sensors and indirect immersion sensors. If you can’t wait, contact a Holland Sales Engineer today for help with your next temperature application.

Are the BPE Dimensional Tolerances Always Good Enough for your Systems Needs?

April 17, 2014

The industry wide adoption of the ASME BPE standards have brought a host of benefits to the biopharmaceutical process industry. But,  merely specifying the use of ASME BPE fittings in a piping assembly does not necessarily guarantee proper fit up when building a high purity piping assembly. Recently, Holland worked with a customer t in need of pharmaceutical grade custom piping assemblies and the associated documentation for a piece of downstream bioprocessing equipment they were building.  Their design incorporated custom process piping assemblies as well as many standard ASME BPE compliant grade sanitary clamp fittings.  Holland supplied the standard fittings and fabricated the custom piping in our shop.  All items were inspected at our facility and found to be within ASME BPE standards.

An Example of How the Accumulation of Tolerances Can Affect the Squareness of ASME BPE Fittings

An Example of How the Accumulation of Tolerances Can Affect the Squareness of ASME BPE Fittings

When the piping assemblies were installed there were some significant fit up issues.  The custom assemblies fit up to the machine with no issues.  However, where multiple standard ASME BPE tees clamped together there were fit up issues.  There was such a stack up of tolerances that the piping manifolds were more than ½” off.  This led to pitch angles that were supposed to be 3° down instead being more than 1.8° up.  The piping would never drain.

The tees were within specifications per ASME BPE standards.  The specifications for the angular difference on the face of a 1.5” tee can be as much as 1.3° per end.  This could potentially create a 2.6° difference between the opposing end connections.  Stacking several tees exasperates the problem even more.  The attached picture demonstrates this phenomenon.

We solved the problem by manually straightening all of the tees so that the ferrule faces were now within 0.1° of being straight.

So the question remains, are the ASME BPE dimensional tolerances good enough for bio pharmaceutical processes?  It depends upon your design.  We would recommend:

Avoid designs where multiple clamped fittings are stacked together.

  • If you cannot avoid stacking fittings, check the tolerances of each fitting you are using.  You may need to manually straighten them for you system to fit together.
  • The highest risk of this phenomena happening is when you stack multiple tees.  We would recommend using fabricated manifolds whenever possible.

For questions or comments on this or any of the other topics in our blog, contact us.  We would be happy to discuss.

What Sterilization Method Should I Use? Autoclave, Gamma, or ETO

April 15, 2014

In the high purity process industry, sterilization is the name of the game. Sterilization is the process of eliminating all forms of life, including transmissible agents (such as fungi, bacteria, viruses, and spore forms) present on a material’s surface or contained in a fluid or compound.  For our stainless steel products, sterility measures include cleaning in place (CIP with acids and caustic solutions) or steaming in place (SIP). For our single use products, alternative sterility measures are taken which will be the focus of this post.

The most common forms of sterilization for single use components include autoclaving, ionizing radiation (gamma or electron beam irradiation), and gas treatment (ethylene oxide). Each

has its pros and cons, hopefully this post will help you select which is optimal for your process.

Autoclave

Autoclave is the process of exposing materials to a combination of high temperature and pressure over a fixed period of time. Autoclave is one of the most utilized processes as it is both effective and economic. It’s something anyone who has taken a microbiology class is familiar with. Autoclaves use pressure to raise the boiling point of water and transfer more energy to “cook” any bugs in the autoclave chamber. The World Health Organization recommends autoclave cycles run between 121 and 124 C for 15 minutes at about 30 PSI. This should be enough time to kill any microorganism. Autoclaves are common place in most labs and are an obvious choice for many applications. Drawbacks include overhead costs for the autoclave, as well as utility costs to run the unit. If autoclaves are to be used, materials selection is critical. Materials that handle the high temperature of autoclaves include acetyls, nylon, polysulfone, PVDF, PTFE, and stainless steel. Materials that aren’t great with an autoclave include ABS, acrylics, polycarbonates, and some polypropylenes.

 

Gamma Irradiation

Single Use Components Pre and Post Gamma Irradiation

Single Use Components Pre and Post Gamma Irradiation

Gamma irradiation involves exposing a material to a specific dose of ionizing radiation. The radiation causes DNA mutations in microorganisms, ultimately resulting in apoptosis and cell death. The primary advantage of gamma is that the material can be placed in its final container and penetrated by radiation. This allows us to preassembled and package a single use assembly in a clean room environment, sterilize it, and assure the end user that the product they receive is sterile when they take it out of the packaging. Gamma irradiation is especially useful in applications where a product is going to be stored for an extended period of time The WHO states that the usual level of absorbed radiation for sterilization is 25 kGy or 2.5 Mrad, although other levels may be employed.

Materials suitable for gamma include ABS and acetyls at low doses, acrylics, polycarbonates, polysulfone, and PVDF. While some of these materials may have slight discoloration following gamma, this does not affect their performance- in fact, some properties of plastics performance is enhanced following irradiation.

The drawback to gamma are costs and working with a reliable subcontractor who has experience in material selection and logistics. That’s where we come in- at Holland, we’ve been working with our pharmaceutical customers to have their products gamma irradiated for over ten years.

Ethylene Oxide- Gas Sterilization

Gas sterilization is the technique of exposing materials to a highly volatile and toxic gas for a controlled amount of time. This process is used when elevating a material to a high temperature or imparting ionizing radiation is not available or practical. This technique imparts the least amount of energy of any of the sterilization techniques discussed.

Ethylene oxide is the most common gas used in these applications. It is often mixed with other inert gases to knock down toxicity and make it more usable. Concentration of gas, humidity, temperature, and time of exposure are monitored to ensure proper disinfection. Because of the low input energy, most plastics are compatible with EtO sterilization.

Concerns do arise, however, with extractables and leachables following EtO sterilization. This is obviously a concern as products absorb gas and can potential leach into processes, ruining batches. This post is a high level overview, we won’t get too detailed about the extractable and leachable concerns, just know that EtO is still considered a safe sterilization method and widely used throughout the industry.

Conclusion

To conclude, a considerable amount of time goes into selecting the correct size, material, and certifications/approvals for each component that goes into a single use process. We’ve spent a considerable amount of time just blogging about each of these topics. While these factors alone can be challenging, sterility compatibility is just as critical. This post should serve as a good primer of the different sterilization techniques Holland offers and has worked with customers on in the past. Contact Holland today with any of your sterility concerns.

Think You Need a Sanitary Progressive Cavity Pump to Meter Non-Viscous Liquids? Think Again.

April 14, 2014

When metering thin fluids, sanitary pump selection often forces the user to make compromises.  Sanitary centrifugal pumps are not designed for metering.  Sanitary PD pumps are not accurate with water like fluids because of slip.  That leaves the user with a choice of other PD pumping technologies, most of which are not ideal.  The reality is that most sanitary metering pumps are derivatives of industrial metering pumps that have been adapted to hygienic applications.  They may work great for waste water applications, but create challenges in sanitary applications.  Double diaphragm and piston pumps all have pulsation issues.  Progressive cavity pumps, while non-pulsing, are expensive to buy and maintain.  The food grade stator materials don’t wear like their industrial brethren and are expensive.  Plus they take up a lot of room.

The Quattroflow Family of  Pumps

The Quattroflow Family of Pumps

Most of the technologies we have described above are at least 50 years old.  As we have been developing our line of sanitary metering systems we have begun incorporating a newer pumping technology that we are very excited about, the Quattroflow Pump.   The Quattroflow pump is a quaternary, four diaphragm pump.  It was developed for the biotech industry several years ago to gently pump shear sensitive biological fluids against high differential pressures and has proven to be very successful in that arena.  But the Quattroflow pump has properties that make it an excellent sanitary metering pump in applications beyond biologics.

  • The pump has no seals
  • Low Pulsation
  • Highly accurate and repeatable
  • Great turndown ratios give the pumps great flexibility
  • Scale- Models available to product flow rates from a fraction of a liter to over 300 lpm
  • Low maintenance

So if you are looking for a sanitary metering pump and don’t want the pulsation of traditional double diaphragm pumps or the maintenance and capital cost of a sanitary progressive cavity pump, take a look at the Quatttroflow.  It would probably be good for you to take a look at new technology every 40 or 50 years.  We offer these pump as a standalone sanitary metering pump or incorporate it into a turnkey sanitary metering system designed to your specifications (including panel mount versions of the QF150).  That is what we do here.  If you want to explore this topic further or have a sanitary metering application you would like to discuss, contact one of our sales engineers.  We are here to help.

Pumping from Drums – Colder Drum Quik Connectors and Double Diaphragm Pumps

April 11, 2014
photo

Colder Drum Quik Dip Tube System with a Graco Husky Double Diaphram Pump

Holland Applied Technologies has been helping customers leverage the synergy of multiple technologies for over 60 years. We’ve found that the only way we can be successful and help meet our customers increasingly high expectations is to prove that the products we offer intersect, not run in parallel to each other. Our product portfolio reflects this philosophy. This post will focus on two technologies we offer- Colder’s DrumQuik dispensing technology and Graco’s double diaphragm pumps- and how we can use them in simple drum unloading applications.

At any given time, millions of liquid filled drums and totes are in circulation all over the world, transporting everything from edible oils and flavorings, to caustic CIP chemicals. These containers provide manufacturers efficient ways to deliver bulk liquid ingredients to end users- who transfer bulk ingredient into smaller containers or fractionate them into batches. Historically, the easiest way to transfer product from these containers has been through “open” dispensing. A spigot or wand is inserted into the container and product is transferred out. This process is messy, resulting in splashes, spills, and product loss. Fumes generated from open systems can be hazardous and product loss is costly.

To solve these challenges, Colder Products (recently rebranded as CPC) has introduced a new closed sealed system, the Drum Quick system. This system is composed of three main components. The first component is the dip tube assembly. This is a drum insert with a threaded plug that replaces a bung plug with a dip tube that extends to the bottom of the container. Inserts are available for a wide variety of bung thread types, as well as both steel and plastic tanks.

The Colder Drum Quik System

The Colder Drum Quik System

The second component is the coupler. The coupler, also known as the dispense head, can be easily affixed to the container. After the shipping plug is removed from the drum insert, the coupling is pressed into the drum insert, the lock ring is turned, and the Drum Quik’s integral shut off valve is engaged. You’re almost ready to pump.

From the coupling, we need to get to the pump. How can we do this? With any one of the several custom hoses we offer. The liquid port on the Drum Quick can be ½” MNPT, hose barb, flare port, or BSPP. However you want to go, Holland can supply a fitting or custom hose assembly to get to your pump. An ideal hose has some sort of reinforcement or braid and should work well in a vacuum application. Hose assemblies made of Teflon, silicone, and food grade rubber are all common for these applications.

The final component in our closed drum unloading system is the pump. There are a few different pumps we can use, but our favorite for these applications is the Graco double diaphragm pump. Graco AODD pumps can run dry, are self-priming, portable, and economical. They are positive displacement pumps that can handle high differential pressures and moderately high viscosities.

Another pump option for metering applications with thin ingredients are Masterflex peristaltic pumps. Peristaltic pumps are also self-priming and when used in conjunction with a digital drive are highly accurate. Peristaltic pumps are great for ingredient dosing or caustic solution make up.

Holland is one of the few companies that can identify and specify all of these components and help you integrate them to improve operator safety, reduce spills and clean up time, and improve accuracy and product recovery. Ideal applications for a system like this abound. Applications range from unloading chemical totes for CIP solution make up to mineral oil unloading and dosing in lip balm applications. Closed dispensing is ideal in any application where safe material management, fast container change out, and clean chemical transfer is required. For your next drum unloading application, contact a Holland Sales Engineer today.

How do We Specify the Optimal Pump for a Sanitary Metering or Dosing System?

April 9, 2014

In previous posts we have gone over different aspects of sanitary metering and dosing systems including defining the criteria for a system, proper use of balance tanks, and sanitary flow meter selection.  Today we will concentrate on another key component of most systems, the sanitary metering pump.

Waukesha Univeral Pumps can be Run at Slow Speeds, Minimizing Shear

Waukesha ECP Pump

We have a large toolbox of pumps to choose from for our sanitary metering systems.  These include Waukesha ECP pumps, Quattroflow quaternary diaphragm, Masterflex peristaltic, Axiflow twin screw, and Graco double diaphragm and sanitary piston pumps.   So how do we decide which is the right pump for the specific metering application?  We have 6 major pieces of criteria we look at.

Here are the key factors we look at when specifying a sanitary metering pump:

  • Range of flow rates (minimum and maximum)
  • Differential Pressure requirements
  • Rheology
  • Seal and seal support requirements
  • General product compatibility
  • Accuracy requirements
  • Cost

Let’s take a closer look at these individually.

Flow Rates

For very precise, low flow rates, several of these pumps can be eliminated.  The piston, diaphragm and twin screw pumps are not designed to pump efficiently at fractions of a liter per minute.  Quattroflow, peristaltic, and in some cases, Waukesha PD pumps can.  Conversely, peristaltics do not do well in high flow applications or differential pressure applications.   Piston and double diaphragm pumps also are normally not suited for flow rates over 100gpm.  For high flow rates (100gpm+) we normally look at Waukesha PD pumps, Axiflow twin screw, or Quattroflow diaphragm pumps in pharmaceutical applications.

Quattroflow Quaternary Pump

Quattroflow Quaternary Pump

Pressure Requirements

If you we rate these metering pumps for pressure output capabilities, lowest to highest, it would go peristaltic, Quattroflow, double diaphragm, twin screw, sanitary lobe then piston pumps.

Rheology

The biggest rheological issues we are normally concerned with are viscosity and shear sensitivity.  Here is an overview of how these sanitary metering pumps rate.

  • Peristaltic:  Cannot pump higher viscosities but they are gentle on shear sensitive products
  • Quattroflow:  Similar to peristaltics, these do not do well with viscosity but are extremely gentle on the product. Their low pulsation, volumetric efficiency, and accuracy come from the pumps short stroke length. The short stroke length also limits the pump to products with a viscosity of approximately 200 cps.
  • Double Diaphragm:  When sized properly these can handle higher viscosities and are considered low shear pumps. They are also uniquely suited for drum unloading and batching applications.
  • Twin Screw:  Excellent for both shear sensitivity and viscosity.  Sanitary twin screw pumps, when       properly sized also handle particulate well.
  • Sanitary ECP PD Pumps:  Excellent with high viscous liquids, if sizes properly they can be relative low shear

 

Masterflex Peristaltic Pump

Masterflex Peristaltic Pump

Seal Requirements

The Quattroflow, peristaltic and double diaphragm pumps have no mechanical seals.  Twin screw, piston and Waukesha sanitary pumps do.  A broad choice of mechanical seals are available for these.  But if maintaining absolute sterility is an issue, the non-seal pumps may be preferable.

Accuracy

The accuracy of the actual pump may or may not be an issue depending on how the rest of the sanitary metering system is configured.  As a general rule of thumb, maintaining consistent accuracy in a metering pump is a good thing.  By design, if properly maintained the Quattroflow, Waukesha PD and piston pumps are consistently accurate, with exceptionally low slip.  The accuracy of peristaltic and double diaphragm pumps will degrade as their tubing and/or diaphragms wear.

So that is the matrix we start with when specifying a pump for a sanitary metering or dosing systems.  Like most things in life, there are a lot of tradeoffs with each pump.  Our goal is to work with our clients and help them define the critical aspects of their systems and what quality by design features they want to incorporate into their system.  Sometimes, none of these pumps will work and we will do our research and come up with something else.

Besides the criteria described above, we have to also look at the system as a whole before specifying a bill of materials for the metering pump or any other part of the system.  This includes the meters, instrumentation, and controls.  We do not take a cookie cutter approach to this.  We look at each system as a standalone project and try to engineer the best solution for that specific application.

You’re probably wondering- why didn’t we address the economics of each technology?  For most people cost is a big deal.  It is for us as well.  Providing as the greatest value to our customers is paramount in all of the systems we design and build.  We always look for the most cost effective solution that meets our customers goals.  We wouldn’t have been in business over 100 years if we didn’t.

As always, if you have any questions or comments on this post or any others, contact us.  We are here to help.

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