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Richard Pearce
Director,
Purification Solutions,
EMD Millipore
We have really been seeing an increased pressure on cost of goods, speed to clinic and the introduction of more personalized therapies with limited patient populations. For developers of monoclonal antibodies (MAbs), this translates into the need for highly flexible manufacturing processes that minimize capital investments and maximize the use of existing facilities. As the demands and challenges associated with the purification of therapeutic proteins increase, new tools are needed.
MAb producers face difficulties maximizing usage of existing facilities, especially as titers and the number of products increase. Some typical constraints include filtration areas, buffer tank volumes, and intermediate hold tank volumes. To alleviate these constraints, developers are looking at a variety of strategies, including higher capacity resins, in-line blending of buffers, buffers that require less volume to adjust, and connecting process steps by direct loading.
We have recently been working on developing a three-step MAb antibody purification process that is free of intermediate holding tanks and does not require buffer adjustments between chromatography steps. In this new process, each column is loaded directly from the previous, thus circumventing costly tanks, better utilizing floor space, decreasing process time, and allowing for a more disposable and flexible downstream purification train.
This process is based on a three-step chromatography purification train using a directly connected Protein A column, followed by a cation exchange column and then an anion exchange membrane adsorber, to provide a purified antibody concentrate. The new process may also be able to perform a low-pH viral inactivation using an on-column holding step.
The resulting process has the potential to improve the plant fit of new processes into existing facilities and offer increased flexibility and convenience in disposable systems.
To learn more about innovative chromatography solutions being developed to help prepare for the future of MAb manufacturing, view Part I of the webinar on the Factory of the Future, called “Developing a Three Step MAb Purification Process without the Need for Intermediate Hold Tanks.”
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David Newman
Director of EHS &
Sustainability,
EMD Millipore
Our 2010 European Biosafety Tour is focused on ensuring the safety of life saving drugs. The month-long road trip will travel across Europe, showing how our products and services deliver process optimization, operational flexibility, product safety and regulatory compliance, and continuous process improvement.
As the tour progresses, traveling an estimated 9,300 kilometers with an itinerary that includes 16 stops in 6 countries, I plan on sharing a number of sustainability initiatives we are taking in Europe. Here are just a few:
> Use of single-use products to save on energy – At our Livingston, Scotland plant, which manufactures clinical diagnostic products derived from biological sources, we adopted a completely single-use disposable manufacturing process using Millipore products. The new process uses less steam and electricity for heating and cooling and less water. Together with significant upgrades to our mechanical facilities, the single-use manufacturing process resulted in a 20 percent drop in electricity use year over year.
> Solvent recovery – Our Cork, Ireland plant, where we cast almost all the membranes for filtration products used worldwide, recently implemented an enormous solvent recovery system. The system recovers, purifies, and reuses thousands of gallons of solvents, significantly reducing solvent purchase and disposal costs.
> Commuting initiatives – In the Netherlands, site of a huge European customer service center, our biggest sustainability impact comes from commuting initiatives encouraging our employees to take public transportation or bicycle to work. At our Molsheim, France plant, which manufactures disposable devices and is the site of a hardware systems operations center, we established Millimoves, an internal website where employees sign up to make carpool arrangements. The plant is also located right next to a train station.
> Reducing packaging – Tremendous progress is being made in the research and development and manufacturing of our lab water products, making them more energy efficient and reducing packaging dramatically.
One final note about sustainability and our 2010 European BioSafety Tour – we recognize that traveling 9,300 kilometers will use a lot of gasoline (petrol). To do this as responsibly as possible, we have placed a great deal of attention on minimizing the tour vehicle’s carbon footprint by using a special tractor uniquely designed to save on fuel consumption.
In my next post, I will be sharing some exciting information on the evaluation of lifecycle impacts of single use technologies based on a detailed comparative analysis of single-use technologies versus stainless steel.
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Sue Walker
Applications Engineering BioManufacturing Sciences Network (BSN)
The implementation of process-ready hardware systems such as Millipore’s Mobius® FlexReady Solutions is becoming increasingly popular not only to aid in rapid facility start-up but also for on-going operational flexibility.
Typically these systems are designed to:
> Expedite facility installation
> Provide maximum mobility
> Accommodate single-use flowpaths to eliminate cleaning validation requirements
The key to maximizing these inherent benefits is efficiently using the systems seamlessly across all unit operations – simple and easy operation from the bioreactor to final formulated bulk drug substance.
But the specific details such as proper component sizing and compatible connections between systems, not to mention optimization of process parameters to achieve overall process and product objectives, can be far from simple or easy. And … what about all those SOP’s?
Millipore’s Applications Engineering team is working to find a total single-use solution for the entire downstream process train – start to finish – including not only those SOP’s but also economic and environmental impact analyses.
Millipore’s BioManufacturing Sciences Training Center (BSTC) in Billerica, MA provides the perfect place to generate the necessary applications testing data over a range of process scales on relevant process streams. The BSTC allows us to replicate our customer’s experience to understand what challenges they will face before they have to face them. It really is a proverbial engineer’s playground and perhaps, this is every engineer’s dream job
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Vikas Gupta
Group Product Manager, Mobius Single-use Products & Services
This blog entry will focus on some of the misconceptions about assessing extractable and leachables (E/Ls) risk. By extractables, I mean chemicals that can be induced to leach in a test lab under worst-case conditions, versus leachables, which are chemicals that leach under actual working conditions.
New users of single-use technology often do so with a high level of concern, including the risk posed by extractables and leachables from single-use components. This can result in seemingly endless and exhaustive analytical studies of extractables. The pursuit involves countless manpower hours spent conducting largely avoidable, extensive animal studies (and no “brownie points” from PETA!).
Unfortunately, due to the relative newness of single-use components and the lack of “check box” regulatory guidance, there is a heightened sense of unease around E/Ls. The irony is that at Millipore, many of the plastic materials used in single-use assemblies have been in use for decades in the manufacture of our filtration products. Most of our customers have been absolutely comfortable using these filters and have established their own risk-assessment approaches for addressing any E/L concerns for their use of the devices.
There are many naysayers who would have you believe that it’s absolutely essential to identify every single chemical that shows up on your drug’s chromatogram. Not helping the cause is the fact that industry conferences feature the same misguided presentations over and over again on the topic of E/Ls and single-use products.
Frustrated by the lack of fresh thinking on this topic, we decided to question the status quo. Why go after the identification of every single extractables? Why are some of our customers using PQRI guidelines for E/Ls thresholds and applying those to parenterals when they are clearly meant for OINDP? Does an extract warrant a complete identification profile even when the overall TOC levels might be below the Threshold of Toxicological Concern (TTC)?
Talk to any quintessential toxicologist and his/her favorite adage, attributed to Paracelsus, the Father of Toxicology, is, “All things are poison and nothing is without poison; only the dose permits something not to be poisonous.” Armed with this truism, we delved deep into scientific data and rationale that would help us develop a risk-based approach to extractables and leachables from single-use components. One of the most useful approaches is the Threshold of Toxicological Concern.
To put it simply, TTC states that chemicals -- when present below a certain threshold in a patient dose -- do not present any substantial risk to the patient’s health. Various regulatory bodies have established specific thresholds of acceptable values for chemicals that are carcinogenic, genotoxic and other categories.
Let us take a very simple example to illustrate how one can use the TTC approach. TTC establishes the maximum amount of a genotoxic compound at 1.5µg/patient/day. Assume that we know that none of the materials of construction are carcinogenic and pass the basic compendial tests like USP <87> and USP <88>. If the overall extractables when calculated for the resulting total amount per dose show that the amount is less than the 1.5µg/patient/day, which is per compound anyway, we can say with a high degree of confidence that the extractables do not present any toxicological risks and do not warrant further identification of all the extractables.
Furthermore, many other safety factors can help us discount some of the risks from extractables and allow us to perform a more pragmatic evaluation of leachables. The location of use of single-use assemblies is important, as the majority of the leachable chemicals upstream of a UF/DF step can be easily reduced by several logs of concentration. Realistic assumptions for temperature, contact period, concentration levels, pH, filter flushing, route of administration, etc., can also result in significant reduction in the amount of chemicals present as leachables.
Bottom line, I would like to reiterate that the task of assessing the toxicological impact of E/Ls is not as insurmountable as it seems! Just as we assess any other concern in our biopharmaceutical process today -- by looking at adjusting a variety of factors that can bring the risk down to an acceptable level -- a similar pragmatic approach should be applied to analyzing E/Ls from single-use components.
To see case studies that highlight the use of this concept in more detail, view the webinar on Risk-based Assessment of Extractables & Leachables in Single-use Systems.
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Damon Asher
PhD, Senior Scientist, Bioprocess R&D Virology
I had the privilege of working with a team of industry and regulatory experts to author PDA Technical Report No. 47: Preparation of Virus Spikes Used for Viral Clearance Studies. This document is an outstanding resource for the biopharmacological industry because it demystifies some of the “black magic” that surrounds the virus preparations needed for viral clearance evaluations. These scaled-down simulations are designed to assess how much virus could be eliminated by a full-scale drug product purification scheme in the very rare event of virus contamination.
To determine how much virus the process can remove, virus is added to, or “spiked,” into drug feed material, and reduction of the virus across the individual scaled-down unit operations (such as chromatography, low pH inactivation, or virus filtration) is measured. These reduction values are then added together to quantify the total level of virus safety assurance for the entire production process.
The problem with the virus stocks used for spiking stems from the fact that they are often loaded with biological debris. Because viruses must be grown in cell culture, they are contaminated with proteins, lipids, and nucleic acids derived from cells and media. Virus purification and concentration can be challenging, and virus suppliers have variable degrees of success with the clean-up. In most cases, the impurities far outweigh the virus, leaving the virus a minority component of the stock solution. I think that if you, in any other circumstance, told a process engineer that you were going to deliberately defile her pristine drug material with undefined biochemical junk, she would, depending on her temperament, either politely excuse herself or hit you on the head with a wrench. In the case of virus spiking, however, the industry lives with this pollution because there has been no alternative.
Virus stock impurities are significant because they can have profound impacts on the performance of the unit operations being studied. For example, the amount of membrane surface area that must be used for full-scale virus filtration is determined by the rate of flow of the drug process fluid across a miniature, fixed-size version of the filtration device. Unfortunately, the impurities that accompany the virus spike can foul the filter, causing a dramatic reduction in the rate of flow. When this happens, the full-scale filter cannot be sized based on how it handles the actual drug feed, which is the relevant, realistic consideration. Instead, the filter must be upsized to accommodate a throughput limitation imposed solely by the dirty virus spike used in the study. Hitting the filter with uncharacterized impurities along with the virus clearly makes the evaluation study less representative of the true application, which subverts the entire purpose of the scaled-down model. This creates a frustrating situation where what is essentially an experimental artifact largely controls the study outcome, resulting in missed performance targets and inflated full-scale production costs.
Virus stock purity is definitely an issue, but equally important is the consistency of spikes. The quality of virus stocks tends to vary significantly from supplier to supplier and from lot to lot. Often, insufficient characterization data is provided for the user to assess the variability or estimate the potential impact of the virus spike on the all-important validation study. As it stands now, the virus spike is like your crazy cousin Larry whom you have to invite to your wedding, but you don’t know if he’s going to behave or end up on the roof naked again. That kind of unpredictability in a viral clearance validation is a real problem. It has genuine costs in terms of time, money, stress and, most tragically, confidence in overall virus safety.
This is why Millipore is committed to the development of new methods to produce virus stocks that are extremely pure, high titer, and well characterized. These ultrapure virus preparations will enable higher virus reduction claims without impacting unit operation performance. The biopharm industry needs virus stocks that are of such high quality that no filter need be fouled by virus spike impurities ever again. Think of it as an intervention for Larry.
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Ranjeet Patil
Process Engineer
The use of redundant filtration operations for bulk and final fill operations is becoming increasingly common. Redundant filtration is a type of serial filtration in which a sterilizing-grade filter is added after the first filter as a backup in the event that the first filter fails. Millipore has initiated the single-use redundant filtration (SURF) assembly project to identify a disposable bioprocess solution for this operation.
Due to the potential risks of filtration as a sterilization method, regulatory agencies highly recommend redundant filtration for filling operations. Other drivers for redundant filtration include long processing times, high product value and inability to reprocess the product due to filter integrity failure. Regulatory agencies require post-sterilization and pre-use integrity filter testing to ensure process integrity. The in-place sterilization required by stainless steel set-up increases preparation time. For both steel and disposable assemblies, the wetting step is limited by the catch bag/tank volume.
Single-use redundant filtration assembly offers an efficient, flexible alternative to stainless steel redundant filtration systems. Unlike traditional systems, a disposable option eliminates the need for CIP and sterilization steps. Preparation time is significantly reduced due to the ease of handling and pre-sterilized format. In addition, the end user can perform redundant filtration operations in multi-product facilities without the extra validation time often needed for non-disposable systems. Disposable assemblies can handle the same pressures and flow rates as stainless steel, while maintaining similar utilization sequences.
Millipore offers a wide range of products that can be used to build a gamma-sterilized, single-use redundant filtration assembly. It is easier to perform filter wetting, air blow-down and pre-use integrity testing while maintaining a sterile envelope by adding a Millipak filter a capsule filter with hydrophobic and hydrophilic membranes.
The SURF assembly project identified the best design for redundant filtration operations by utilizing Millipore’s single-use products and standardized assembly components. The design was finalized with input from a global Millipore technical and quality team to comply with international regulatory requirements. This study also demonstrated the capability of the system to withstand the high pressure used for integrity testing and drying these assemblies.
An optimum utilization sequence of the preparatory steps was designed and tested. All preparatory steps and filtration operations can be performed on this system without breaching the sterility of the gamma-irradiated assembly. Pre-use integrity testing was performed on both filters without compromising sterility. With implementation of the Millipak filter on the assembly outlet, flush volume limitations due to catch bag/can size were eliminated. System specifications such as leachables and extractables, hold-up volume, and flushing requirements were established for a single-use assembly utilizing Opticap XL10 capsules with a 0.22 µm Durapore filter.
To learn more about the SURF assembly and several other next-generation single-use products from Millipore, visit the Life:Expressed tour bus at a stop near you.
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