BPOG Best Practice Guidelines for Mitigating Risk used in Biopharmaceutical Manufacturing
Recently, BPOG (Biophorum Operations Group) has published a guide that relates to mitigating risk in bio manufacturing processes when using single use systems components. A key aspect of the risk mitigation strategy is to consider the potential for chemical entities to migrate from the single use component material into the drug product. Suppliers could aid drug manufacturers with their risk mitigation strategies by generating extractables data on their single use materials. Extractables are typically ‘worst case’ indicators of potential leachables and provide a drug manufacturer with useful information on how to approach future leachables studies.
Key definitions to understand are listed below:
Extractables chemical entities that are able to be extracted from a component of a process system into a solvent under controlled conditions which are usually more aggressive than the normal operating conditions
Leachable’s chemical entities which come from single-use system components that migrate into the drug product during normal use. The single use system consumable qualification process must demonstrate that processing components do not impact the quality of the drug product.
It is important to understand that the product quality should be maintained throughout the drug product lifecycle to ensure that the attributes deemed important to the quality of the drug product are consistent with those evaluated during clinical studies.
One aspect detailed by BPOG and other industry bodies is how to perform risk evaluation. Risk evaluation is based on assessing the risk to patient safety, product impact manufacturing and regulatory approval. The regulations for drug manufacturers specifically detail that the equipment used in manufacturing of the drug substance shall be constructed so that the surfaces that contact the process material or drug product shall not be, reactive, additive or absorptive.
Risk assessment can be focused on either testing of every single use system component or by taking a risk-based approach where only critical single use system components are tested. The approach taken can be determined by considering the following key attributes
- Distance of the single use component to the final drug product or API
- Process temperature
- Process time
- Process fluid interaction
- Dilution effects
If you have additional questions about extractables, leachables, or any single use components, contact a Holland Sales Engineer today.
*A Special thanks to Sade Mokuolu @ WMFTG BioPure for her help in putting this blog together
What Sanitary Gasket Material Should I Use? Check out our Chemical Compatibility Guide!
With so many options available for elastomers it can be hard to make sure you are selecting the one best suited for your application. This post is going to go through a few key questions to point you in the right direction.
Let’s start by asking a few important questions about your application:
- What temperature is your process running at?
- How are you cleaning your system?
- What are you trying to seal?
Once we figure out the answers to those questions, we can start by looking at the three most common elastomers used in the high purity process industry- FKM, Buna, and EPDM. We’re going to leave PTFE out because it isn’t an elastomer- it’s a plastic.
FKM and EPDM are able to handle high temperatures well, and with an upper operating temperature of up to 400 degrees Fahrenheit they are the clear choice for high temperature applications. EPDM is great with steam, but does not mix well with oils. And FKM doesn’t perform as hot at low temperatures, with a lower operating temp of only 5 degrees.
Accordingly, if you are planning on either SIP or CIP, you’ll want to go with FKM or EPDM. SIP uses steam to heat the process line up to at least 250 degrees Fahrenheit, which will cause some strain on your elastomers. If you are going to be running steam frequently through the process line then FKM or EPDM are a good choice for you due to its resiliency against steam and its ability to tolerate the temperature.
For CIP applications, all three elastomers provide good resistance to both acidic and caustic solutions commonly used in CIP procedures although Buna does not tolerate concentrated acids very well.
Before installing a new component you should always make sure that it is chemically compatible with your process fluid. In general, FKM is fairly inert compared to both Buna and EPDM and is well suited to most applications. But a chemical compatibility chart is available here to check your specific application.
By selecting the proper elastomer you may be able to stretch out the time between replacements.When it is time to replace them or if you have any questions please contact a Holland Sales Engineer.
At Holland, we’re no strangers to sanitary batching systems. One of the most common customer challenges we’re asked to solve is a simple batching application. Our customers turn to Holland for a one stop, robust solution that is cost effective and quick to implement. Previous posts have focused on batching systems that are volume based solutions- systems that incorporate a flow meter to control a process. This post will instead focus on weight addition systems and the different system solutions available.
So let’s say you have a recipe for a product you make all the time. A recipe is, by definition, a set of instructions for obtaining a desired outcome. Every recipe has a several ingredients. How we choose to add those ingredients to a receiving vessel is a critical question that must be addressed early in the process design. One way to do it is with a flow meter used to volumetrically measure each ingredient introduced. While this may work well if you only have one ingredient or may be just metering off from a bulk tank, a volumetric system does have its drawbacks. For one, accuracy is limited to accuracy of the flow meter used. In some cases, the meter used is a turbine meter. These can have accuracies that deviate as much as 5%.
Even if the accuracy of your flow meter is sufficient for your application, many recipes call for a mass of product to be added- pounds, kilograms, etc, NOT a volume. To do this, best practice would indicate that we take a direct weight NOT volumetric measurement. When using a volume to add mass, you depend on a density based conversion and depending on processing conditions, fluid density can vary. The only way to do take a direct mass measurement is with a Coriolis meter, which often run well into the tens of thousands of dollars, depending on line size. Can you imagine if you have multiple ingredients, necessitating multiple coriolis meters? You also can’t pass solids or dry products through a flowmeter.
As an alternative to volume based batching systems, let’s consider a weight based alternative. With a weight based system, we use either a floor scale or load cells to measure the weight of either the receiving or dispensing container (a future post will take a closer look at weight by addition vs. weight by loss systems).
For this post, we’ll assume that the receiving vessel is on load cells. With the receiving vessel on load cells, we can add multiple ingredients, liquid or dry, while only measuring one process. This greatly reduces the instrumentation cost of a system. Using a controller, either a PLC or something even simpler, like a Mettler Toledo IND690, valves can be opened and closed, pumps start and stopped once volumes are added. Controllers like the IND690 allow for recipe programming and storage and also have a digital display with tare functions to allow for manual addition if need be.
At Holland, we’re able to take you all the way through system development. We usually start by working with a client to either design and fabricate a batching vessel, or retrofit an existing vessel to accommodate load cells. We then help identify and install auxiliary equipment that is very important AFTER ingredients are batched in- components like mixers, RTDs, and tank outlet valves. Once we identify what you want to measure and how you want to measure it, we can start working on HOW we’re going to add ingredients. This can be by Waukesha PD pump, Masterflex peristaltic pump, or Quattroflow Quaternary diaphragm pump. We can also supply the proper ITT diaphragm or Waukesha seat valve to control flow in. Once that is done, we can work with you to size and select an appropriate floor scale or load cells. Coupled with the right control system, we have a fully functioning batching system, capable of adding a variety of different ingredients and storing several different recipes. So if you have any questions about your next sanitary batching application, contact a Holland Sales Engineer today.
What are Weld Maps and Weld Logs?
If you haven’t figured it out yet, at Holland Applied Technologies, we are in the sanitary component and custom systems market and cater exclusively to the high purity process industry. In the high purity process industry, specifically the biopharmaceutical industry, documentation requirements are a key distinguisher between people who play in the industry and those that live in it. One of the most critical processes our customers trust us with is welding of material to create the fluid transfer paths that carry their products. Weld inspection and logging has been and will always be a key part of any Quality Assurance program. But because of the requirements of the US Food and Drug Administration and guidelines outlined by the American Society of Mechanical Engineers Bioprocessing Equipment Standard (ASME BPE), the weld documentation our customers ask us to provide is even more extensive. This post will focus on proper weld documentation specifically weld logs and weld maps- what they are and what information they provide.
Let’s start with the weld map. Weld maps are isometric drawings of the assembly to be welded showing the location with each weld, each weld having its own unique identifying number. They also contain a bill of material with the part number of each component used in making the assembly. After each weld is completed, it is labeled with a weld number (usually pin stamped on the part) that corresponds to a number on the isometric drawing of the part. When the isometric drawing is reviewed during validation, a third party can use the weld map to quickly identify where on the process piping the weld was performed and then refer to the weld log to ascertain the data discussed above.
Weld logs contain the data specific to each individual weld. Normally a weld log sheet would contain all of the welding information for the welds on a specific isometric drawing. At the top of any weld log, you’ll usually find client specific project specific information, i.e. project number, job number, etc. You’ll also find the drawing number of for the isometric drawing that the log matches up with. You’ll also see a section for gas lot number of the Argonne gas used for the weld purge as well a block with the signature of the welder who is doing the work.
For our weld logs, the main body of the document has 9 columns for the weld to complete and 3 for the weld inspector. For each weld, the welding technician first enters the weld number, the date, what piece of welding equipment is being used and which weld procedure is being used. All of our welding personnel are qualified to specific ASME Section IX weld procedures. They then enter the heat number for each of the two components to be welded, the size of the tubes being welded and their own initials.
The rest of each line on the weld log is used by the weld inspector. Each weld is visually inspected by a qualified weld inspector using a boroscope to examine the weld ID. After inspection he completes the log for that individual weld as to whether it had been boroscoped, did it pass the visual boroscope examination, the inspectors’ signature and the date.
Typical Holland Weld Log
Once this process is completed, these documents, as well as the corresponding material test reports of the components used in the assembly, become part of the turn over package that ships with the system. Properly executed, you now have a comprehensive package identifying each weld, who made the weld, what components went into the weld and the corresponding material certs for each one of the components.
As we wrap this blog up, let’s not forget why all of this documentation is important. The systems we fabricate at Holland Applied Technologies are used by our customers to manufacture drug products we literally inject into our bodies. And before the drug ever gets made, the system used to make it needs to be validated. Governing bodies like the US Food and Drug administration use the data provided in these logs and maps to approve the manufacturer and manufacturing facility, protecting public health and giving consumers the peace of mind that the medicines they are taking are made on systems and in facilities that comply with current best practices. So if after reading this blog, you have any questions about high purity process welding or documentation requirements, contact a Holland Sales Engineer today.
What are the NEC Requirements for Conduit Fittings in Explosion Proof Applications?
4 Cable Seal Off
At Holland, we encounter many electrical system design challenges. Between large biopharmaceutical and food modules, smaller sanitary process skids, pump carts with VFD’s, etc., there are many chances to learn. Recently we had an interesting situation that required us to modify our design to meet a portion of the NEC standard for Hazardous Classified location equipment.
Section 500 of NFPA 70: National Electric Code defines the requirements for building equipment in Hazardous Locations. The standard is broken down into three “Classes”-Class 1 deals with flammable gases and liquids, Class 2 deals with combustible dusts, and Class 3 deals with ignitable fibers. For our purposes, we are concerned with Class 1. This classification defines (among many other things) the requirements for electrical enclosures (which must be explosion proof) as well as the conduit lines that carry electrical cables back to these enclosures.
The requirement of the standard is that all conduit lines must have a seal off located within 18 inches of the purged panel enclosure. Seal offs are (as there name implies) a barrier that is filled with a compound that “provides a seal against the passage of gas or vapors through the seal fitting”, and therefore into the enclosure potentially leading to a dangerous situation. Further, the standard requires that only 25% of the cross sectional area of the sealed fitting can be used up by the conductor wiring. Note that this is significantly less that the 40% allowable area that can be used in all the other fittings in the conduit assembly.
In our case, we realized during field installation that although we met the general 40% requirement, we did not meet the more stringent requirement in the seal off. This situation presented a few options that we had to think through. The first option was to increase the size of the seal off. The standard allows for a larger trade size seal when required to meet this requirement. Unfortunately, Crous-Hinds (as well as Gibson and Calbrite) doesn’t offer a seal off in stainless steel that is larger than 1 inch. There are other options for larger seal offs in other materials of construction (Robroy makes a PVS coated metal conduit (Plasti-Bond) in much larger sizes as well as EYX in galvanized iron), but the specification on this job required stainless steel.
Option two was to reduce the size of the cables. The initial choice was a 3 conductor + ground 18 gauge wire. There are some nice advantages to running multiple conductors, primarily being that it gives more flexibility down the road with device choices (think limit switches, more instrumentation, troubleshooting, etc.). However, in this case we needed to figure how to make this work. We opted to use a 2 conductor with 18 gauge wire, reducing the wire size by more than 30%. This choice met the requirement for cross sectional area of the seal off, effectively getting us in “just under the wire” (ok, I have been waiting to use that) to meet the standard.
Electrical design is a big part of our work at Holland. Hopefully this post will give you some ideas if you run into issues with seal offs and related Class 1 work. Contact one of our Holland Sales Engineers a call if we can help you with a project you are working on.
Product Focus- Aseptiquik DC and Aseptiquik STC
Aseptiquik DC Sterile Single Use Connectors
For today’s blog post, we’re going to take a look at one of the product lines we saw great growth in 2016- Colder’s line of Aseptic Connectors, Aseptiquik. Specifically, we’ll look at to of the latest additions to the product line, the Aseptiquik DC and Aseptiquik STC. Both products leverage the versatility of the Aseptiquik product line to bring robust solution to very specific biopharmaceutical applications we’ll examine further in this post.
The first product we want to highlight is the Aseptiquik DC connector. This connector is the first all-in-one single technology to offer both a sterile connection AND disconnection. This allows for quick, easy sterile connections and disconnections outside of a sterile environment or laminar flow hood. No sealers, no welders after transfer is complete, just an intuitive click-pull twist. The disconnect is even valved, eliminating the need for a pinch clamp.
Where is this applicable, you may ask? Let’s look at a recent application we helped a customer with. A contract manufacturer recently approached us to prototype a disposable manifold for them. This client had an application where they were recirculating buffer media over the course of a campaign and over the course of the campaign needed to dose into a disposable bioreactor already equipped with Colder Aseptiquik connectors. Because the campaign ran over a period of weeks, multiple ports were required off the manifold. After buffer was transferred into the bioreactor, a sterile disconnect was preferred. So with the help up Holland, the customer was able to implement a five port single use manifold equipped with seven Aseptiquik DC connectors, allowing for a sterile connection to the plastic media bag and (5) separate sterile connections to the bioreactor.
Single Use 5 Port Manifold with Colder Aseptiquik Connectors
The second product we wanted to highlight is the Aseptiquik STC. Available with both gendered and gender less sterile connectors, the Aseptiquik STC incorporates Colder’s Steam Thru II connector. This combination gives biopharmaceutical manufacturers the flexibility to marry single use and stainless technologies.
Why would this be useful? Imagine you have a stainless steel buffer and bulk product or media received in disposable bag. You need to find a way to steam the vessel and maintain the sterile barrier when you connect the media bag. As we’ve highlighted in a previous post, during an SIP cycle, a Steam Thru II connector is in the “steam on” position, allowing steam to flow through the process equipment, through the Steam Thru connector to a trap, creating a sterile connection between the connector and the stainless vessel. The Aseptiquik connector is then connected to a single use piece of equipment with a matching sterile connector. After this connection is made, the thumb latch on the Steam Thru II connector is pushed and the valve is locked into the fluid flow position, allowing for sterile transfer in or our of the stainless vessel, to or from a single use bag. Because we use a Steam Thru II connector, once transfer is complete, the Steam Thru II can be re-engaged and allow for a “steam off”.
In sum, as biopharmaceutical manufacturing becomes increasingly complex, manufacturer next generation therapies, it is critical that our technologies continue to evolve. The Aseptiquik STC and Aseptiquik DC are two new products we at Holland have recently applied to help customers to address difficult process challenges. If you have a specific question about your biopharmaceutical processing application, contact a Holland Sales Engineer today.
Sanitary Jacketed Process Piping Assemblies- Things to Keep in Mind
Jacketed sanitary spools, elbows and a jacked sanitary ball type check valve
Here at Holland, we manufacture all kinds of sanitary components. We make everything from sanitary flow orifices to pump bases, manifolds to filter holders. It’s not often that any two items are exactly the same. We are the very definition of a job shop. One of the most common classes of sanitary fabrication we see are sanitary jacketed fittings, tubing, and valves. It’s a regular occurrence that we get a call from someone asking us to jacket some of their more difficult items- say a Waukesha seat valve. But when we ask about the other components- the sanitary spool pieces, elbows, etc.- the client is often quick to reply, “Oh, we have someone on site for that”. More times than not, this call is followed up by another call asking us to help them out with some of the pieces they thought would be a breeze. This re occurrence highlights the purpose of this post- to provide a brief overview of the challenges and common oversights people make when jacketing sanitary tubing, fittings, and various other components. As they say, the devil is in the details.
To begin, let’s talk about pressure testing. At Holland, we pressure test every single sanitary jacketed component we manufacture. Why is this important? Well, there are at least six welds on every jacketed component. This leaves plenty of places for a pinhole leak. After an integrator hangs each piece, the jumper hoses are installed and the lines are pressure/leak tested. If the system doesn’t hold pressure, going back and checking each spool piece, elbow, tee, and valve can be a huge time sink. The moral of the story is- pressure test each piece before you hang it. We do.
Normally, sanitary jacketed assemblies are ganged together, using jumpers to connect the heating/cooling media from piece to piece. We have seen several cases where customers had media flow rate problems from field fabricated jacketed assemblies. This was caused by the NPT jumper connectors being pushed too far in the jacket annulus, almost to the inner tube wall, effectively choking off the media flow. Make sure your fabricator properly copes the connector properly prior to welding, preventing unnecessary media pressure drop from assembly to assembly.
Another common over site when jacketing sanitary tubing is what steps are taken to ensure the inner product contact tube is centered in the outer utility tube. Especially for long, straight spool runs, it’s important that the product tube is centered within the jacket to ensure efficient, uniform heat transfer. To help achieve this, we always tack spacers to the product tube prior to welding on the outer jacket, ensuring the tube will remain centered at all times.
Most sanitary jacketed assemblies used Tri-Clamp connections. Jacketing as much of the process tubing as possible is obviously important. But that can create problems as well. At some point, you will need to get a clamp around each connection, so don’t weld the jacket too close to the ferrule so that the clamp will not go on. Also we have seen several instances where the ferrules faces warped as they either too close to the weld or the welder put too much heat into the weld.
It’s also not uncommon to see people underestimate how much thin wall steel moves when the tremendous amount of heat required for fusion is applied. How does this present itself as a problem? Well, one component we often see people struggle with is with sanitary seat valves. When the valves are received, the valve stem is seated in the valve body and everything is clamped together and fits fine. When you go to put the jacket on, you have to remove the valve stem. When the jacket (often a crescent moon shaped jacket) is welded to the valve body, the seat where the stem sits can become distorted. To combat this, it is important to minimize the heat applied and also ensure you can correct any out of roundness that does occur. This will save major headaches down the road.
Those a just a few of the common over sites we see all the time when people decide there want to jacket their own sanitary tubing or fittings. Hopefully this post will help you with your next job. Or better yet, save yourself the headache and contact a Holland Sales Engineer today.
C Series Sanitary Pump Seals- An Overview
The C Series Pumps has been a Workhorse in the Sanitary Process Industry for Years
The C series pump is possibly the longest running sanitary pump that has ever come to market. While new centrifugal pump technologies have emerged, the C series has endured. While newer designs offer efficiency gains, magnetic drives, or are better suited for ultra-high purity or CIP applications, the C series pump’s simplicity, ease of maintenance and ability to handle most clean, low viscosity fluids. While the simplicity of the C series pump has kept it around for over 50 years, largely unchanged, there have been new introductions that have allowed the pump to continue to appeal to a variety of markets. This post will focus on some of the seal variations and other modifications we’ve seen and attempt to highlight the differences.
Seals
Type D Seal- the type deal seal is the original and most common seal supplied with the C series pump. It is what we call an “external balanced seal”. What that means is we have a rotary seal (for the series that material is carbon), rotating against a stationary seat. In this case, the stationary seat is the stainless steel backplate of the C Series sanitary pump. While this seal configuration will struggle with slurries or exceptionally hot fluids, it is ideal for beverage, dairy, and even tomato juice applications. Service kits are inexpensive and easy to replace.
Type DG Seal/Seat- While the D seal is great, customers also needed a solution for applications where they may be handling abrasive, non-lubricating products. For these applications, we recommend the Type DG seal configuration. This seal assembly uses a modified back plate to enable us to affix a silicon carbide, ceramic, or tungsten carbide stationary back plate. The type D seal is then assembled so the carbon seal from the regular D seal rides on the stationary seal we’ve just installed. While the carbon vs. stainless configuration of the type D seal is great for most clean fluids, the carbon vs. silicon carbide arrangement provides maximum corrosion resistance for hard to handle products. The stationary seat is reversible and existing Type D pumps can be retrofitted to take a DG seal.
Type E Water Cooled Double Seal- the type E seal is the C series version of a double mechanical seal with flush. While we don’t see it often, it is out there and worth mentioning. The seal is locating within a stuffing box affixed to the pump back plate. The stuffing box is pressurized with a flush fluid, usually water and then taken to drain. This seal configuration should be considered for slurries or sticky and abrasive products where a double mechanical seal would typically be used. This is also the ideal choice for vacuum applications.
Internal Seal- One of the newest seal configurations used introduced for the C series sanitary pump is an internal seal design. Using a recessed back plate, this is the only C series pump seal that is an internal seal, meaning that the seal is located in the product zone. The internal seal (also sometimes known as a John Crane Type 21 industrial seal), has two silicon carbide seals. The stationary seat is pressed into the back plate. The pump impeller then pushes on a spring that is engaged with the rotating seal face to allow seal face contact between the two parts. This seal is great for hot fluid applications where a flush is not practical. It’s also works well in applications where the pump is going to be cleaned in place. That being said, the backplate does create a large sump that cannot fully drain (a no-no for a sanitary application) and what happens if/when the seal fails? Usually, it means seal components entering the product stream- or worse. That being said, we recommend this seal for many different applications and have found it to be an especially useful in brewery applications transferring for transferring hot wort out of the brew kettle.
So there you have a quick pass at the standard seal configurations available for the C series pump. If you have any questions about your C series pump or sanitary pump application, contact a Holland Sales Engineer today.
Case Study: QF4400- NPSHr of a Self-Priming Pump
Quattroflow QF400 Pump
For our first post of 2017, we will be talking about a few issues and from one of most successful products in 2016- the Quattroflow quaternary diaphragm pump. Today’s post will talk about NPSHA, self-priming pumps, and a specific application troubleshooting a QF4400.
Let’s start by taking a look at a problem a client of ours had recently during startup of a QF4400. If you’ve been reading our blog, you’ll know that one of the hallmark characteristics of the Quattroflow line of pumps is their ability to actually pump air and create considerable suction lift. The Quattroflow QF4400, for instance, can generate up to 4.5 meters of suction lift! Just because the pump can generate suction lift, however, doesn’t mean you can’t still see (or hear) cavitation at the inlet of the pump. It is important to remember the NPSH stands for net POSITIVE suction head. You can’t have a “negative” suction head.Thus, every pump will have SOME net positive suction head required. If at any time the pressure at the inlet of the pump drops below the vapor pressure of the fluid being pumped, you will see and hear the pump cavitate, resulting in noisy operation and erratic flow.
This is precisely what happened during a recent FAT. A client was commissioning a skid that used a Quattroflow QF4400 as a supply pump. During the FAT, the skid was connected via hoses to some water tanks about 10’ away from the skid. The water flowed from the tanks, up about 5 feet and then down through an elbow and into the QF4400 bottom inlet. While hardly ideal suction conditions, the Quattroflow was able to evacuate air from the line and draw product to the inlet. Once sufficient speed was reached, however, a noticeable chatter could be heard at the pump.
What was happening? Simple- cavitation. To understand why this was occurring, let us consider how the all Quattroflow pumps move fluid. A Quattroflow pump uses an eccentric disc to nutate the four pump diaphragms. When the diaphragms retract, a vacuum is created within the pump chamber. This actuates each of the four inlet check valves. As the eccentric disc turns, the chamber that was created is now collapsed as the diaphragm is pushed toward the valve plate. This pressurizes the pump chamber and forces fluid through the discharge valve.
As the fluid enters the Quattroflow pump chamber (pulled in by vacuum) and crosses the inlet check valve, the velocity of the fluid increases considerably. This results in considerable pressure drop. Coupled with the vacuum created at the inlet by the diaphragms, the pressure at the chamber inlet can fall below the vapor pressure of water or other aqueous products. When this happens, cavitation will occur. The result is a very noticeable clicking sound that almost sounds like a screw is loose. Rest assured, it is not.
The fix for this is simple- increase the suction head. In this instance, we used a simple centrifugal booster pump to increase the pressure at the pump inlet. We only need to go to approximately 10-15 PSI before the “clicking” sound was no longer audible.
So the next time you have a self priming pump application, remember- net positive suction head can’t be negative. And if the pressure at the inlet drops below the vapor pressure of the fluid, you will hear the pump cavitate. Often times, the fix is easy- follow good piping practices or run the pump slower. If possible, increase the pump inlet pressure as well. If none of these work and you’re convinced you’ve got a defective pump and you’re feeling SOL, contact a Holland Sales Engineer today. We’d be happy to help you out.
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
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!