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Validating a Single Use Process System- Sterility Claim vs. Microbial Control

August 16, 2016

As we’ve mentioned in this blog before, both at Holland and the rest of the biopharmaceutical process

Holland Provides a Broad Range of Single Use Components for the Biopharmaceutical Industry

Holland Provides a Broad Range of Single Use Components for the Biopharmaceutical Industry

industry, we’re seeing an increasing number of customers switching to disposable process equipment. This can be scary stuff for stainless guys. Customers, however, are finding safety, time, and cost reduction benefits compelling enough to switch to single use systems for applications ranging from buffer formulation and bulk intermediate, all the way to final fill. For many of these applications, microbial control or even sterility is required to ensure system safety and product purity. Today’s post will take a look at one of the most common sterilization methods for single use assemblies, gamma irradiation, and what standards and methods should be followed to call something “sterile”.

To begin understanding why and where a sterility claim may be needed, we need to look at to the origins of single use process equipment. Disposable products were first used in small scale lab applications where time and cost of stainless equipment was prohibitive. As these lab applications developed momentum and scale, there became a need for presterilized products that could be directly incorporated into critical process applications. In order to validate systems and ensure a sufficiently high probability of bioburden reduction and sterility, the bioprocessing industry has turned to standards established for the validation of sterilization of healthcare equipment by irradiation developed by organizations such as the American National Standards Institute (ANSI), the Association for the Advancement of Medical Instrumentation (AAMI), the International Organization for Standardization (ISO), the ASTM, and BPSA guidance.

We’ve talked about gamma irradiation as a means of sterilization in prior posts, so we will now turn our attention to the difference between sterility and microbial control. To be claimed as sterile, industry standards require, “validation of the efficacy and reproducibility of the sterilization process, based on determination of average bioburden and subsequent sterility testing of systems after minimal radiation exposure”. These systems are also subject to routine auditing that examines bioburden and sterility testing results. For prototype or lab systems, the process to make a sterile claim can be cost prohibitive.  As an alternative to the sterile claim, many systems can be simply exposed to a sterilizing irradiation dose of 25 kGy and claimed as microbially controlled. In sum, components or systems requiring zero or low bioburden when applied to a nonsterile process, do not need to be validated as sterile, but simply validated as microbially controlled. We will spend the rest of this post helping explain when validated sterility is required or when microbial control is appropriate.

Let’s revisit the four basic stages we can divide biopharmaceutical manufacturing into. First, we have “upstream” processing where we mix nutrients and producer cells in a fermenter or bioreactor allowing the cells to produce the target molecule. Next, we go to the harvest stage where cells are separated from the target molecule using methods like filtration and centrifugation. Third is downstream processing where a series of separation, purification, and chromatography steps produce a purified bulk drug product. Finally, we have the formulation and fill stage where the purified bulk is sterile filtered and aseptically filled into containers. This final stage is similar to how synthetic pharmaceuticals are manufactured aseptically.

Through all of these stages, it is important to prevent any unwanted microbial contamination. What degree of control is driven by the end user and international regulations which dictate that products and processes claimed as sterile must be validated to prove sterility. What constitutes a validated sterile process? Validation is by definition, “the process of establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes”. A sterile process, then, is a validated method of sterilizing a product such that the sterility assurance level (SAL) is less than or equal to 10-6 (one in a million!). These regulations do not, however, apply processes claimed as microbially controlled, which also may have zero or low bioburden but have not been validated with a defined SAL. What this means in respect to the bioprocessing steps described above is while the assurance of validated sterility is necessary for bulk drug product and final fill single use systems, preparative stages after which product will undergo additional refining (i.e. sterile filtration) can be operated under the tight microbial control afforded by irradiation.

If it is determined that a process must be validated as sterile, there are a few methods most commonly employed. First, we need to figure out what to test. In applications where a single use system is used, it is common that multiple variations of a system are used in a process. In these applications, it is often only necessary to validate a single product from a family known as a “Master Product”. The Master Product is usually the largest product in a family, but it can also be the product which possesses the most components, the greatest number of materials, or even the one that requires the most handling during manufacture. Simulated or equivalent products may also be used. For more information on what equivalent and similar products are, please refer to the BPSA’s guidance on sterilization and validation of single use process systems.

Once we’ve determined which product to test, we need to determine what part of the product needs to be tested. If you’ve used single use processing systems in the past, you know how large these can be and can imagine how difficult it can be quantify bioburden and sterility. In some cases, it is only necessary to test and validate the fluid path. Because the system (ie tubing, bags, ect) can act as its own barrier to contamination, we avoid having to test the entire product and avoid the issue of handling its external surfaces without contamination. Large products can also be sectioned, or split into parts that are easier to test. Each section is then tested and summed to come up with the bioburden of the entire bag.

To test the bioburden of a fluid path or sectioned product, we will partially fill the system with sterile buffer, ensuring all surfaces are wetted, then agitate the article by hand to promote suspension of organisms. The buffer is then removed and tested using standard microbiological methods. Sterility testing is accomplished by a similar method, but a growth media is used in lieu of sterile buffer.

As you can probably tell, validating sterility is anything but quick and easy. Determining whether a process needs to be validated as sterile or microbially controlled is critical in optimizing time and cost requirements for a project, considerations which are ultimately borne by the biopharmaceutical manufacturer. While disposable process equipment offers significant advantages to manufacturers, they are not without significant decisions to be made by all stakeholders. While some applications may only require microbial control, sterile processes must be validated as such. While we covered a lot of ground, the purpose of this post is to help distinguish between sterile and microbial controlled, provide an overview of the sterilization validation process, and discuss where these needs fit into the overall biopharmaceutical manufacturing process. For more questions about your specific application, contact a Holland Sales Engineer today!

Seital Centrifuges and Clarifiers- Applications & Tips for Getting the Most out of Your Craft Brewery

April 18, 2016
Seital Separator

Seital Separator

At Holland, we are committed consistently adding products to our portfolio that will help our customers with their sanitary process needs. By rounding out our product offerings, we are able to deliver novel solutions to complex processing problems our counterparts in the sanitary process equipment industry cannot. Today’s post will focus on one of our newest SPX product offerings- Seital separators and how they can be used in brewing applications to increase productivity and improve beer quality.

To begin, let’s take a look at how a Seital separator works in a beer application- or really any application for that matter. First, the mixture to be separated- usually beer or wort -is pumped in to the centrifuge. It enters the centrifuge through the centrally positioned inlet pipe. A distributor then guides the mixture into the separation area of the system. The separation area is made up of a stack of conically arranged discs. These discs spin at a high RPM. The short distance between discs (coupled with centrifugal force) forces solids through the discs to the outside of the bowl where they are ejected. The remaining beer or wort is then pumped out of the system through the outlet pipe.

So now that we have an idea of how this works, let’s look at why and where we should use a centrifuge for beer or wort clarification. One application where we see clarifiers used in the brewery is following the brew kettle, when the brewer needs to remove the protein and hop solids, or trub, prior to fermentation. In many small breweries, traditional filter media or whirlpools are used to filter the trub. By using a Seital separator, we are able to separate the trub and hop solids with maximum efficiency and yield to get bright and clear wort prior to cooling for fermentation.

Brewers have also found that Seital centrifuges can be gentler to beer than traditional filter media. The advanced sealing systems in the Seital separators minimize O2 pickup. Filter media, such as cellulose or diatomaceous earth, can strip flavor from the beer and have an environmental impact. Why do you think there are so many unfiltered beers on the market today? When used as an alternative to traditional Kieselguhr or diatomaceous earth filtration, we’re able to get the same clear bright beer without stripping out any of the hops characteristics that make a craft beer great. The Seital portable skids are ready for any application where you want all the benefits of filtering without the need for filter media.

Continually, Seital separators properly applied in a brewery quickly pay for themselves. Good, sellable beer is often trapped in the solids that collect in the bottom of fermentation tanks. Seital separators allow for more beer to be recovered from tank bottoms, allowing brewers to ship more beer from the same amount of raw ingredients. This return on investment helps to quickly offset initial cost of equipment.

Another advantage of using a separator is being able to increase production volumes without having to add more people. Seital separators come pre-skidded, prewired, and ready for plug and play use in the brewery. When used with turbidity meters and other automation features, brewers are able to achieve greater repeatability and higher quality standards without having to add additional staff.

In order to continue to improve the quality of one’s beer, a brewer must be willing adjust and refine their methods of processing. Craft brewers across the country are all discovery new applications where Seital clarifiers can be used to improve the quality of their product and the efficiency of their process. By using them to replace traditional filter media, automated, pre-skidded processing allows brewers to maximize throughput without compromising quality. If you have any questions about whether a centrifuge is a good fit for your brewery, contact a Holland Sales Engineer today.

Quattroflow 1200 Provides Drop in Replacement for Peristaltic Pump

February 23, 2016

Many of our followers may have noticed that we haven’t posted a new blog in a few months. Fear not- we have still been working on plenty of interesting sanitary process challenges. In this post, we’ll talk about a recent tangential flow filtration application and how Holland was able to leverage our unique design and build skills to provide a drop in replacement for process pump that just wasn’t up to par.

In late September, Holland was contacted by an OEM who was working with an end user to improve the performance of an existing TFF skid. This particular OEM manufactures a variety of automated and semi-automated portable single use filtration skids for the pharmaceutical industry.

While no stranger to the Quattroflow line of quaternary diaphragm pumps, the OEM was working with a customer who had an earlier iteration of one of their skids that utilized the popular Watson Marlow line of peristaltic pumps. The end user was having problems with the high pressures and tubing performance and compatibility issues that frequently trouble peristaltic pumps.

So the solution seems simple, right? Well, not so fast. If you’ve been following many of our earlier blog posts, you would know that the Quattroflow pump is a positive displacement pump designed specifically for the bioprocess industry. It is a gentle, low pulsation pump that uses a series is four diaphragms and check valves to push and pull media through the pump chamber. Available in both stainless steel and single use pump chambers, the high-turndown Quattroflow pump is perfect for these applications. So what’s so tough? Let us explain.

This client was using a servo motor to drive the peristaltic pump. As clean room suites tend to be as compact as possible, so does the equipment that goes into clean rooms. Because the skid had already been built, Holland was presented with unique challenge- provide a servo equipped Quattroflow 1200 that was a drop in replacement for the Watson Marlow pump that the skid was designed around.

To do this meant designing and fabricating in house a new mounting block to mount the servo motor to. Then, we had to figure out how where to position mounting holes so we could bolt in our pump where the Watson Marlow used to be. Finally, we had to mount the motor and couple it to the pump. And we had to do all of this without the skid. Pulling dimensions from CAD models, slowly but surely, a design developed.

When it was all said and done, about five weeks later, we finished bolting the motor to the mounting block and the mounting block to the base plate. Pushed the two halves of the Love Joy couplings together (located inside of the motor mounting block) and bolted down the QF1200 ring drive, and just like that, we had a Quattroflow 1200 pump with servo drive that was ready to stand in for a Watson Marlow pump that just could do the duty.

Sci Log QF1200 Assembly-REV2

Drawing of Quattroflow  1200S with Servo Drive

By implementing a solution that bridged several core competencies at Holland, including technical expertise, design, and fabrication the end user was presented with a solution that, after calibrating the servo drive, allowed for the replacement of a non-performing technology with a performing technology in less than 20 minutes, preserving the benefits of overall skid design.

So the next time you have a technical question about a Quattroflow or are trying to tackle a difficult design challenge, contact a Holland Sales Engineer. We’d be happy to help.

Waukesha Universal Series PD Pump Notes- QR Codes, SPX Connect, & Training Videos

February 15, 2016

Waukesha Universal Series PD Pump Notes- QR Codes, SPX Connect, & Training Videos

Waukesha U2 Pumps Mounted on Polished Round Tube Bases

Waukesha Universal 2 Sanitary PD Pumps

If you’ve been following our blog, you know that one of our favorite products to help our business partners with are Waukesha sanitary centrifugal and positive displacement pumps. Waukesha, the longtime leader is sanitary pumping technology, continues to innovate, offering new features and services to further enhance an already proven product platform. In today’s short post, we’ll highlight a few new things SPX is offering, including where you can find maintenance videos and the new SPX Connect smartphone application.

End users- We have a question for you- have you ever had a piece of equipment you are unfamiliar with go down and everyone looks to you to get it back up and running so production can continue? Most of us know the feeling. We don’t have much choice but to dive in, flip through the product manuals, and speak with customer service representatives or applications engineers. Manuals are often vague or unclear, sometimes you don’t even know if it’s the right one. And even though at Holland we’re all trained to help our customer’s troubleshoot basic PD pump problems, sometimes it can be difficult to communicate. We just can’t always see what you see.

Wouldn’t it be helpful if there videos that showed Universal 1 and Universal 2 pump assembly and disassembly? Fortunately for you, SPX offers helpful YouTube videos that detail everything from gear case assembly, shimming, seal replacement, and bearing housing maintenance. The links to these videos can be found on our website as well on SPX’s YouTube page- just search “SPX Corporation”, or click the link below:

https://www.youtube.com/playlist?list=PLDA57D0A1BE96632F

The second program we’d like to highlight is SPX’s new SPX Connect smart phone app and QR codes. If you’ve purchased a new Waukesha PD pump or Ecopure seal-less centrifugal pump, you might have noticed a QR code on the pump name tag. This QR code isn’t some fancy tool to track pump casings through Kanban flows. Rather the QR codes are a full functioning tool end users can leverage to prevent downtime and give you 24/7 access to the information you need to get your pump back up and running.

Using the free SPX Connect smartphone app, anyone can scan the QR code and identify basic information about their pump, including model, displacement, maximum pressure, and maximum speed. The app can also be used to access pump literature, manuals, and the service videos we talked about earlier in the post. All of this information can easily be shared with colleagues directly from the app. The app allows you to select from a list of common parts and services to submit quote requests and even saves a history of all the pumps you’ve searched, allowing you to quickly retrieve accurate information about what could be any one of a dozen pumps throughout a facility.

So there are a quick couple of tools you can use the next time you have questions about your Waukehsa PD pumps. Have a question you can’t answer in one of the videos or the SPX connect app? If so, a Holland Sales engineer would be happy to help you out.

What is WFI (Water for Injection)?

September 15, 2015
tags:
Typical Multi-Effect WFI Still

Typical Multi-Effect WFI Still

Water for injection by definition is water that is intended for use in the manufacture of parenteral (i.e. injectable) drugs whose solvent is water. The USP (United States Pharmacopeia) defines this as highly purified waters containing less than 10 CFU/100 ml of Aerobic bacteria. These waters should also have fewer than 500 ppb of total organic carbon, fewer than 0.25 EU/ml endotoxins, and a conductivity of less than 1.3uS/cm @ 25 C.

Now that we have the textbook definition out of the way, we’ll spend the rest of this blog post delving a little deeper into WFI, how it’s made, and common pieces of process equipment used to make up WFI.

To begin, let’s start by looking at how Water for Injection is made. The USP allows WFI to be produced by one of two means; either distillation or reverse osmosis. Prior to making it to the still, however, supply water has to go through extensive pretreatment. Pretreatment usually includes various filtration steps, removal of chlorines through the use of activated carbon beds, and percolation of water through ion exchange resins to remove residual ionic compounds. What is the purpose of all this pretreatment? By pretreating the water, we effectively reduce the conductivity of the water, as well as the level of organic contaminants.

Once the water makes it through these pretreatment steps, it goes to the still. What happens in a WFI still? Distillation, of course. When water is distilled, it heated until it is a vapor, stripping the heavier ions, particulates, and endotoxins from the water. There are both single and multiple effect stills and which one is best for you is determined by how much WFI you are trying to generate. There are also vapor compression stills available that can make WFI.  Regardless of what kind of still you are using, the basic process is the same- the water vapor is passed through a series of tubes and recondensed, resulting in WFI.

You can also get WFI from a process called reverse osmosis. In reverse osmosis, or RO, water is forced through a semi-permeable membrane and the pores in that membrane reject dissolved ions, salts, and organic compounds. This is filtration on a molecular and ionic level. The quality of water, temperature, PH, and flows rates are all critical in RO as the membranes used can foul easily. Reverse osmosis systems rely on booster pumps to increase pressure across membranes, storage tanks, and sophisticated controls for bulk WFI preparation. RO systems are capable of producing 600-50,000 gallons per day of WFI.

So what is done with WFI after it is produced to ensure the water stays at water for injections quality? It either needs to be used quickly (usually same day) or put in a state that allows it to maintain its efficacy. How do you make sure WFI stays as WFI? You need to minimize microbial growth. This is accomplished by maintaining it at high temperatures and keeping it in motion.  Normally WFI is kept at 90 degrees C and recirculated through a distribution loop at a minimum velocity of 5 feet per second.

To ensure there is no contamination of entering or building up in the distribution system, the piping is normally highly polished, at least 20 Ra, often with electropolish.  Any ventilation or vent filters are usually sterile membranes of at least 0.2 uM. Vent filter, commonly found on tanks, are often heat traced or steam jacketed. Why is that? Well, when WFI comes in from the still, it can be very hot. The heat can cause it to flash off and enter the filter. Once the steam makes contact with the vent filter, which if not heat traced will be cooler than the tank, the vapor will recondense and cause the vent filter to blind. When you go to pump that tank out, you would then pull a vacuum and could cause the tank to collapse.

Other common pieces of equipment used to ensure system integrity include double sheet shell and tube heat exchangers and weir type diaphragm valves.  EPDM is probably the most common gasket material we see in a WFI system.

Because the conductivity of WFI is so low, it is considered “ion hungry”, ready to leach ions out of any surface it comes in contact with. That makes the water very abrasive. That means we use centrifugal pumps with single or double mechanical seals and hard seal faces, the most common and robust being either silicon carbide or tungsten carbide.

So to recap, what is WFI? WFI is highly purified water that contains less than 10 CFU/100 ml of Aerobic bacteria. These waters should also have fewer than 500 ppb of total organic carbon, fewer than 0.25 EU/ml endotoxins, and a conductivity of less than 1.3uS/cm @ 25 C.

Why is this important? Well, because as the name implies, WFI is the water, combined with active ingredients used to make drugs that are injected into our bodies. It is also used a the final rinsing agent for any component that comes in contact with the drug such as vials, ampules, caps and stoppers.  How do we make it? Through a series of steps aimed removing ionic and organic contaminants with the final steps being distillation or reverse osmosis.

Once we make it, what do we do? Keep it hot and moving, use it or lose it. We store and transport WFI using ultra high purity process equipment like highly polished tubing, diaphragm valves, sanitary centrifugal pumps with single of double mechanical seals, and double sheet shell and tube heat exchangers.

Any questions? If so, contact a Holland Sales Engineer today.

The Tri Clamp & Sanitary Flange Dimension Guide

June 15, 2015

In previous posts, we’ve discussed how hard it can be to identify what size sanitary flange aka Tri Clamp you have. Today’s post is short and sweet- a simple drawing that should help you correctly identify the size of all of your sanitary fittings.  You can download a copy of this in the Resource Center section of  the fittings page of our website

Tri-clamp dimensional guild

 

Sanitary Fitting Part Numbers- A Cross Reference Guide

June 5, 2015

Have you ever ordered a 2CMP and received a EG2C or a GC2C? Do you know why? In previous posts, we’ve talked a lot about sanitary fittings, what they are and what makes them sanitary. One of the things people struggle with the most, however, is providing the correct part for a fitting and recognizing equivalents. Being able to tell what’s what and who’s fitting is equivalent to who’s can help you the next time you’re in a pinch and need a parts for a job the next morning. Even at Holland, where we deal with these parts all day every day, we forget from time to time. So for today’s post, we’ve put together a useful cross reference guide that will help you identify your sanitary fitting and the different part numbers each manufacturer assigns to them.  You can download a copy of this in the sanitary fittings section of our website.

 

Manufacturer

VNE Tri Clover/Alfa Laval Waukesha G&H Jensen Steel & O’Brien
Description
Elbow- TC x TC EG2C 2CMP 2CMP GC2C JC2 2CMP
Reducing Elbow- TC x TC EGLC31CC 2CMP-31MP 2CMP-31MP GC2C-31 JC1-J31 2CMP-31MP
Elbow- TC x Bevel Seat w/ Nut EG2FPR 2FMP-14 2FMP-14 GC2F-14 JC2-J31 2FMP-14
TC x TC U-Bend EG2WU GC2WU J2WU 2UMP
Eblow- TC x Threaded Bevel Seat EG2FTR 2FMP-15 2FMP-15 GC2F-15 JC2-15 2FMP-15
45- TC x TC EG2K 2KMP 2KMP GC2K JC2K 2KMP
Tee- TC EG7 7MP 7MP GC7 JC7 7MP
Reducing Tee- TC EG7R 7RMP 7RMP GC7R JC7R 7RMP
Cross- TC EG9 9MP 9MP GC9 JC9 9MP
Standard Clamp EG13 13MHLA P13MHHM GH13FAH K13LG P13MHHM
Double Pin Clamp 13MHHM 13MHHM 13MHHM GC13LAH JC13HC 13MHHM
High Pressure Clamp 13MHP 13MHP 13MHP 13MHP JC13HP 13MHP
Tygon Hose Adapter- TC EG14HT 14MPHT 14MPHT GC14AHT JC14AHT 14MPHT
TC Tank Welding Ferrule EG14W 14MPW 14MPW GC14W JC14AHT 14MPW
TC Welding Ferrule- Long EG14WL 14WLMP 14WLMP GC14WL JC14AHT 14WLMP
TC Welding Ferrule- Medium EG14AM7 L14AM7 L14AM7 GC14AC JC14AM7 L14AM7
TC Welding Ferrule- Short EG2CS 14WMP 14WMP GC2CS JC14X 14WMP
TC x Hose Barb Adapter EG14RT 14MPHR 14MPHR GC14AHR JC14AHR 14MPHR
TC Solid End Cap EG16A 16AMP 16AMP GC16A JC16 16AMP
TC x Bevel Seat w/ Nut Adapter EG17PR 17MP-14 17MP-14 GC17PC JC17-14 17MP-14
TC x Threaded Bevel Seat Adapter EG17TR 17MP-15 17MP-15 GC17TC JC17-15 17MP-15
TC x MNPT Adapter EG21 21MP 21MP GC21 JC21 21MP
TC x FNPT Adapter EG22 22MP 22MP GC22 JC22 22MP
TC Welding Ferrule- Reducing EG31R 31RMP 31RMP GC31R JC31R 31RMP
TC x TC Concentric Reducer EG31CC 31-14MP 31-14MP GC31CC JC31 31-14MP
TC x TC Eccentric Reducer EG32CC 32-14MP 32-14MP GC32CC JC32 32-14MP
TC x Bevel Seat Concentric Reducer EG31PC 31PMP 31PMP GC31PC JC14-C31 31PMP
TC x Bevel Seat Eccentric Reducer EG32PC 32PMP 32PMP GC32PC JC14-C32 32PMP
Thermometer Cap EG23B 23BMP 23BMP GC23B JC23B 23BMP
Lateral Wye EG28A 28AMP 28AMP GC28A JC28A 28AMP
Equilateral Wye EG28B 28BMP 28BMP GC28B JC28B 28BMP

 

Still can’t find what you need? No worries- we plan to continue to add more tools like this that will make specifying sanitary fittings a breeze. Don’t want to wait for our next blog? Contact a Holland Sales Engineer today.

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