Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

Ion-exchange chromatography is often a crucial component of the downstream processing of biopharmaceuticals. Innovative new exchangers with new ligand chemistries are making it possible to increase selectivity and capacity. Some also are tolerant of high salt conditions, enabling the elimination of some preparative steps. Jim Powell, business development manager with Asahi Kasei Bioprocess, Estelle Zelter, global product manager of ion-exchange chromatography at EMD Millipore, and Sylvio Bengio, head of scientific communications for the global chromatography group at Pall Life Sciences, spoke with Cynthia Challener, editor of the 

Pharmaceutical Sciences, Manufacturing & Marketplace Report, 

about recent developments in ion-exchange chromatography technology that are benefiting their pharmaceutical customers.

Articles

New ion-exchange chromatography media are more tolerant of varying conditions, making it possible to eliminate process steps.

Advances in Ion-Exchange Chromatography Leading to Increased Efficiencies and Reduced Costs

Drug manufacturers today are increasingly challenged to find new, effective methods for the delivery of active pharmaceutical ingredients, and many are discovering that orally disintegrating technologies can help.

Orally Disintegrating Tablets

While monoclonal antibodies (mAbs) are high-value therapeutic products, the expectation of biopharmaceutical manufacturers is that costs of the processes involved in their separation and purification will come down from current levels. Conventional technologies are designed to be effective for the purification of mAbs coming from low titer upstream processes and are not easily adapted to the higher productivity systems that are more common today. Several new technologies have thus been introduced or are being evaluated by the industry to achieve more efficient and cost-effective commercial-scale separations.

To be effective, all mAb separation technologies must first be reproducible, well-controlled and robust, and any sources of variability must be well understood, according to Paul Jorjorian, manager of purification development with Gallus BioPharmaceuticals. “Such separations must provide the scientifically appropriate purity, activity, yield, impurity profile, viral clearance, bioburden and endotoxin removal, host-cell (expression system) protein and residual DNA removal, and meet international leachable and extractable compliance requirements in order to ensure patient safety,” explains Molly S. McGlaughlin, vice-president of business development for Natrix Separations. 

For biosimilar mAbs, which are predicted to become increasingly common according to Günter Jagschies, strategic customer relations leader at GE Healthcare Life Sciences, separation technologies have the additional need to stay within the range of the critical quality attributes of the original mAb, time after time, in a robust fashion. “Safety and efficacy cannot be compromised and a process will not be approved by regulatory bodies if it does not meet this essential characteristic,” he says.

Ideally, adds Andy Herbert, vice-president of development for PolyBatics, antibody separation technologies are also generic platforms that avoid the need for re-invention for each specific product.

Beyond meeting these performance and quality criteria, commercial antibody separations must also make good business sense. To that end, they must be both economical and scalable in order to meet market demands. “Scalability, flexibility, and redundancy of supply are business requirements; a company must be able to ensure that it can supply the market, regardless of fluctuations in demand, particularly when the product is a first-in-class molecule or a molecule for an orphan or fast track indication,” McGlaughlin notes. In addition, as with any other pharmaceutical manufacturing processes, all environmental, health, and safety requirements must be met.

One of the challenges currently facing antibody manufacturers is the fact that conventional methods for the separation of mAbs are limited by their need to operate at low low titers. “As a consequence, very large volumes of reagents and cleaning solutions are needed, which contribute significantly to the overall cost of the process,” Herbert comments. Adds McGlaughlin: “Traditional methods have been slow to adapt to the scientific development in upstream productivity and high titers.”They have slow flow rates that do not enable efficient processing of large amounts of material. In addition to the high operating cost of these systems, they also require a high level of capital investment in equipment, significant labor costs, and the need to maintain a large resin inventory, and also present a risk of contamination.

Limitations are becoming apparent when individual steps in the process are optimized independently and bottlenecks appear as a consequence, according to Jagschies. He points out that “with higher cell mass and increased product concentrations, membrane areas in any filtration step need to go up to maintain filterability of unwanted debris or particulate matter and sufficient throughput of the mAb product-containing volumes. Centrifuges typically used in mAb processes are also facing issues with clarifying high biomass cell culture broth from the bioreactor to the same levels as before the upstream improvement. Chromatography steps are likewise challenged with increasing protein mass per batch, and larger purification installations may be needed to manage the bioreactor output.” 

Complicating this situation is the increasing number of biosimilars being introduced to the market, which by definition require lower manufacturing costs. Both generic and name-brand mAb manufacturers are now looking to reduce the cost of goods by adopting more efficient technologies. In addition, the patient populations are smaller, with many therapeutic antibodies designed for very targeted and specific indications.

“Flexible technologies that not only reduce the material cost of goods, but also improve facility utilization, reduce labor requirements, better ensure that quality assurance requirements are met, and enable quick turnovers between batches or products are being considered and are the true drivers in separation technology,” asserts McGlaughlin (see 

). Herbert agrees. “New technologies employing single-use equipment components that obviate cleaning, and the use of chromatographic media such as ion exchange and mixed-mode resins, are approaches that attempt to reduce cost contributions.”

Another specific technology of interest is depth filtration, according to Jorjorian. “As the industry requires the production of smaller-volume, higher-potency, and lower-demand products and shifts from 5000-L to 20,000-L stainless-steel production facilities to smaller more nimble 500-L to  2000-L facilities, the driver is there to move from centrifugation to depth filtration. Depth filtration offers reduced cleaning and cleaning validation, decreased product changeover times for multiproduct facilities, robust scale-down models, and massively reduced capital costs.”

The development of low-cost Protein A (ProA) is also of interest, because ProA typically accounts for one-third to one-half of the downstream raw material costs, according to Jorjorian. “Recently, comparable products have come on the market at one-third the cost, which can be of particular value for small to mid-sized companies that can’t leverage ProA resin suppliers for preferred pricing.”  He also believes that continuous chromatography will help drive down the cost of the ProA resin. “We are definitely keeping our eye on continuous processing, as it can also allow for a more consistent purification process, because column loadings and other process parameters always remain constant.”

Flocculation and precipitation approaches have found utilization in impurity removal, but they have most power when they can be applied to concentrate the drug molecules themselves, according to Herbert. “There are promising approaches (e.g., using caprylic acid) for monoclonal antibodies that have potential to simplify processes; in general, though, these remain less commonly applied than conventional platforms such as affinity chromatography,” he observes. 

Jagschies also believes that flocculation approaches have shown the greatest promise in helping the filterability of more challenging solutions coming from the bioreactor. “This approach supports elimination of the centrifuge in the process, and thus supports the introduction of fully single-use processing (single-use centrifuges are not available or accepted yet).”

Membrane chromatography and virus filtration are also widely used and offer the attractive advantages of high effectiveness, reliability and scalability. Anion-exchange membranes operated in a flow through modality are well-established for the reduction of DNA and host cell protein contaminates, according to Jorjorian. The introduction of mixed modal or salt tolerant membranes has somewhat addressed the issue of inhibited binding under high salt conditions. There are also certain applications where it is beneficial for the target protein to bind and elute from the membrane. It should be noted, though, that the relatively small device size of membranes can be a challenge. “Even so, membranes offer a cost-effective alternative to chromatography as long as reasonable capacities can be achieved,” Jorjorian concludes. He also notes that single-use membranes offer more control over the cost of goods and reduce operational effort including cleaning validation, column packing, buffer preparation, and more.

One new membrane technology comes from Natrix. Its three-dimensional hydrogel membrane provides significantly enhanced capacity and flow rate. It is a flexible, modular, multi-cycle, single-use disposable technology that can process large amounts of material in a short period of time, according to McGlaughlin.

She also points to two other mAb separation technologies that are attracting interest. Monolith technologies and simulated moving bed systems (or continuous chromatography, and also known as BioSMB) or have both been proven on the research scale but have experienced slow adoption for cGMP manufacture for various reasons, McGlaughlin notes.

Looking into the future, many of these technologies are expected to be further enhanced and eventually more widely adopted for monoclonal antibody separation. Herbert expects to see a continued focus on improving the economics of monoclonal antibody manufacturing. “To achieve this goal, PolyBatics has developed a unique technological approach to reducing the cost of affinity chromatography, one of the main components of the purification platform most commonly used to manufacture monoclonal antibodies. This technology can create low-cost affinity chromatography media ideally suited for the cost-effective manufacture of monoclonal antibodies and biopharmaceuticals in general,” he says.

The key technologies of note for Jorjorian are membrane chromatography, continuous processing, expanded bed separations, and precipitation of the target IgG and impurities. Meanwhile, McGlaughlin expects to see increasing application of single-use, disposable technologies, and multicycle technologies, higher flow rates and binding capacities, and multiproduct processes with smaller footprints. “Adoption of these types of technologies will lead to the implementation, ultimately, of continuous processing in truly single-use facilities that are flexible and offer significant savings in the cost of goods,” she concludes.

For Jagschies, the future will be about integration. “We will not see as much of ‘what can a science discipline do to improve its part’ but instead more of ‘what is needed to make the overall process deliver safety, efficacy, and quantity, but also a good operational economy’. These two approaches are not always the same, as the former allows the creation of bottlenecks and risks, whereas the latter is more likely to lead to a harmonized design with a business focus to it, i.e., aligned to market demand. As a result, we will see the smart combination of technology rather than the individual use of isolated technologies.” Those combinations will include, in addition to continuous manufacturing, more powerful sensor and at- or inline analytical technologies, and technologies that address purification challenges at the level of selecting the producer cell clone. 

Advances in monoclonal antibody separation technologies are largely driven by the need to increase efficiencies and reduce cost.

Improving the Economics of Monoclonal Antibody Separation

Nick Johnson, strategic marketing director for modified-release technologies at Catalent Pharma Solutions, spoke with Cynthia Challener, editor of the 

Pharmaceutical Sciences, Manufacturing & Marketplace Report,

 about orally disintegrating tablets and other technologies. The editorial podcast is 

In Part One, Nick Johnson talks about the formulating challenges presented by orally disintegrating technologies.

In Part Two, Nick Johnson discusses current effective technologies for addressing the challenges of formulating orally disintregrating products.

In Part Three, Nick Johnson highlights some of the main drivers for the development of new orally disintegrating technologies.

In Part Four, Nick Johnson describes new technologies for orally disintegrating products that are under development in response to these market needs, including projects underway at Catalent Pharma Solutions.

Orally Disintegrating Technology Provides Both Formulating Challenges and Opportunities

Biodegradable polymers make it possible for parenteral drugs to be delivered over an extended period of time. New processing methods may make extended-release parenteral drugs easier and safer to use, especially for therapies based on targeted nanoparticle conjugates. Kevin W. Burton, global head of injectable services with Evonik Industries, spoke with Cynthia Challener, editor of the 

 about current biodegradable polymer technology, recent advances, and where the field is headed.

Well-characterized, safe, and predictable

Pharmaceutical Sciences, Manufacturing and Marketplace Report:

 What are the key attributes of successfully designed biodegradable polymers intended for sustained-release of parenteral drugs? 

 Biodegradable polymers used for the controlled release of parenteral drugs must be well characterized, have an excellent safety profile, a well-defined metabolic pathway, and exhibit very predictable degradation behavior. It is also necessary to be able to tailor the degradation rate in order to customize the release performance for a specific drug. Ideally, this customization is achieved by making simple changes to the polymer composition, terminal group, and molecular weight to effect changes in the physical/mechanical properties of the delivery system.

What types of polymers (in terms of chemistry) have proven most effective and why?

 Polyester-based systems derived from hydroxy acids, particularly poly(lactic-co-glycolic acid) (PLGA), have become the most widely used systems. These systems were first introduced as suture materials several decades ago and are well characterized, have an established safety profile, and their metabolic pathway is well known. In addition, the physical and mechanical properties can be varied by changing the molecular weight, the lactic acid/glycolic acid composition, and/or the terminal end groups. The degradation kinetics are highly predictable and produce predictable controlled-release products because the polymers degrade primarily by hydrolysis.

 How do the polymers function? By what mechanism(s) do they degrade?

 This class of polymers contains hydrolytically degradable ester bonds along the polymer backbone; on exposure to aqueous environments such as biological fluids, they swell as they take up water and then begin to degrade by random hydrolysis of the ester linkages. This random chain-scission process continues over time and results in lowering of the molecular weight of the polymer. Eventually, the molecular weight drops significantly, causing the polymer formulation to lose its mechanical integrity and begin breaking apart.

The polymer degradation, in turn, impacts the release rate of the drug, which is typically dictated through an erosion-mediated diffusion mechanism. A drug that is at or near the surface dissolves soon after the matrix hydrates and swells, opening a channel through which the drug can diffuse.  As the polymer begins to erode, pores within the matrix are formed, and the drug migrates through these water-filled pores. As time goes on, additional pores are formed, releasing more material until the remaining drug is depleted. Hydrolysis of the polymer continues until only the individual monomeric constituents remain (glycolic acid and/or lactic acid). Thus, tese polymers are biodegradable and biocompatible because these final breakdown products of the polymers are naturally occurring, endogenous entities.

 What other technologies do biodegradable polymers compete with and what advantages do the polymers offer? When are polymers the optimal choice and why?

 There are other methods for the sustained-release of parenteral drugs. Nonbiodegradable polymers, such as ethyl vinyl acetate (EVA) copolymers, acting as diffusional barriers are used as drug-delivery implants. These systems, however, are best suited when a long release time can be achieved (a year or more) because they do not biodegrade and are generally explanted. Stents coated with nondegradable polymers designed to release drugs from their surfaces have also been used, but interest has waned in the last couple of years due to a variety of long-term safety concerns. Other biodegradable polymers such as polyanhydrides have seen some level of success, but their shelf life is typically limited due to their high moisture sensitivity.

Combining controlled- and targeted-release

What recent advances have been made in biodegradable polymer technology for sustained release of parenteral drugs?

 The real advances with sustained-release polymers have to do more with the delivery platforms rather than the PLGA chemistry. We are seeing a lot of convergence with medical devices, from biodegradable stents where these polymers are used to deliver steroids, antibiotics, or anti-inflammatory agents, to localized sustained-release delivery as an add-on to medical devices such as nanoparticles delivered through angioplasty balloons at the site of the insult.

There is also a lot of interest in targeted drug-delivery devices, where the sustained-release system helps enable the targeted administration of the drug to a specific site. Active targeting systems that have an antibody or antigen bound to the surface of the nanoparticle can be administered systemically and then localized to the site of action, wherein the drug can be released directly to the diseased area, minimizing systemic toxicity. In the last couple of years, there has also been growing interest in IV administration, particularly for passively targeting solid tumors. For these applications, the PLG particles must be below 1 micrometer and ideally 100-200 nm.

While participating actively in all of these areas, Evonik has also developed a platform technology that produces particles allowing delivery through much smaller gauge needles (27G or 29G) while also providing a much higher concentration of solids without compromising the particle size or release characteristics of the formulations. Compared to conventional microparticle technologies currently on the market, which are typically administered through 19-23G needles, our technology offers significant advantages. More drugs can be delivered, which enables a longer release period and higher doses, and in a needle size that makes self-administration possible for drugs that previously required delivery in a doctor’s office or the hospital.

 What limitations remain and what is being done to address them?

 The potency of the drug dictates the amount that can be administered. In a typical sustained-release parenteral product, the drug accounts for no more than 30% of the load, with the remainder being the polymer carrier. That means 100 mg of formulation may only contain 30 mg of the active agent. While the number of higher-potency drugs is increasing, additional advances in platform technologies that enable higher drug loading and higher solids content are still needed.

Block copolymers and nanoparticles lead the way

 What specifically is Evonik working on with respect to biodegradable polymers for sustained release of parenteral drugs?

 We believe the future is very bright for drug-delivery technologies and are actively developing a variety of approaches from exploring novel biomaterials to discovering alternate drug delivery platforms in order to help our clients realize safer and more effective pharmaceutical products and medical devices. Most recently, we have been interested in antibody-drug conjugates and polymer-drug conjugates.

Based on our significant expertise in drug manufacturing and drug delivery, these systems fit well within our core competency. We are also engaged in improving drug delivery through the use of block copolymers. Derived from well-known polymeric components such as PLGA, poly(caprolactone), and/or polyethylene glycol, these polymers have interesting properties that make them viable alternatives for sustained-release delivery systems and medical devices.

New platform technologies and polymer chemistries may facilitate self-administration, longer-term delivery, and targeted delivery of parenteral drugs.

Advances in Biodegradable Polymer Technologies Facilitate Sustained Release of Parenteral Drugs

The choice of possible mixing and blending equipment for the preparation of solid and semisolid dosage formulations is extensive. Therefore, the first step in a successful mixing process is to select the most appropriate equipment. “The choice of mixing equipment is greatly dependent on the products/materials being mixed. Therefore, good blending and mixing equipment will be determined by how suitable the configuration of the blender is for the powders being mixed,” says Wilf Sangüesa, product manager for Quadro Engineering’s IDEX Material Processing Technologies Group.,

 Specifically, good blending equipment for solid dosage formulations offers a large filling span at constant blending performance and provides homogeneous distribution of the API within the formulation using gentle blending conditions that do not lead to destruction of the particles or granules, according to Tobias Borgers, head of marketing for L.B. Bohle. Adds Pär Almhem, president of ModWave: “The mixer or blender must achieve the specified quality of the final product in a very short time using a very stable and repeatable process and with minimal residual product in the machine and good cleanability.”

Some of the different types of mixing equipment used for the preparation of solid and semisolid dosage formulations include ribbon and tumble blenders for dry-powder blends, multishaft mixers for transdermal drug/adhesive mixtures, and double planetary mixers for the processing of wet granulations and viscous gels. “Performance characteristics, such as the shear input, cleanability, ease of discharge, flexibility in terms of batch size and viscosity, vacuum capability, temperature control, and scalability, vary from one mixer design to another and depend on the properties of the particular application as well as the mixing objective itself,” explains Christine Banaszek, an application engineer at Charles Ross & Son Company.

Flexibility is becoming increasingly important as well, notes Sangüesa “The better blending systems are the ones that are able to mix a wide number of powders so that fewer blenders are required in a given facility. Because blending can be a costly and labor-intensive step, equipment also must be efficient and provide the maximum yield possible with few trap points and proper surface finishes that allow the maximum amount of powder to flow out upon completion of the mixing process. Systems also need to readily integrate with upstream/downstream equipment.”

Sangüesa has observed that the drive to reduce the number of components needed to perform a task has been greatly influenced by rising costs for not just capital investment, but also by increasing processing costs, such as cleaning, maintenance, space constraints, safety, product losses, and so on. One solution has been the introduction of blending systems that utilize the same holding recipient (i.e., intermediate bulk container, or IBC) to do both blending and at its completion, product transfer. “In the past,” he says, “powders had to be loaded from an IBC or Supersack to a blender and then, once the mixing was completed , transferred back. Each step adds the potential for powder losses, segregation, operator exposure, higher space needs, and more pieces to clean and maintain. By having the powders inside the IBC, blending them without further handling and then taking the IBC to its next process, many of these concerns and costs are greatly reduced. Companies, such as Matcon have innovative approaches in this area.” 

New mixer designs have also been introduced that have also had an impact. For semisolid formulations, for instance, Banaszek points to double planetary mixers with improved mixing efficiency and diminished contamination risk. “We have developed a custom-fabricated and sealed gearbox that protects the drive assembly from all product contact, including solvent vapors. Newer design helical blades also prevent the ‘climbing’ issue commonly experienced with traditional rectangular planetary stirrers. These blades generate a unique mixing action; each sweeping curve firmly pushes batch material forward and downward, keeping it within the mixing zone at all times,” she notes. 

Ekato Corp. has also introduced new technology for highly viscous materials, such as those used for the production of softgel and hard shell capsules. “Softgel capsule formulations often undergo several physical property changes during mixing, such as from a liquid to a paste or even a solid-like material and then back to a paste again. Such systems require very powerful mixers,” observes process systems sales engineer Rainer Engenhart. The company has adapted its high-torque, high-viscosity mixers to meet the specific sanitary requirements of the pharmaceutical industry and developed customized solutions that include ergonomic loading of solids materials with a low melting point into a hot vessel, elevated designs that allow for gravity transfer of the finished bulk into transfer tanks, and in-place cleaning systems for quick changeovers from one formulation to another. 

Most importantly, the systems address the critical needs for high shear mixing combined with excellent de-aeration in both the shell and fill materials, according to Engenhart. For capsules, if air bubbles remain in the shell material, they can create pinholes that can be sources of potential leaks, while entrapped air in the fill materials can cause fill weight issues. In oral strip products, even a tiny amount of trapped air can lead to the generation of large pores during the drying process. In addition, in capsules, if moisture remains in the fill material, it can migrate from the interior and cause degradation of the water-soluble shell, leading to a loss of integrity. 

 “We have found that the solution for good de-aeration is to bring the bubbles to the surface while pulling a vacuum on the system to remove the air. Because air bubbles can’t move in the very viscous materials used for the production of softgels, we developed a shear laminar flow impeller that gently moves them to the surface (without breaking them into smaller bubbles), where they are removed under a strong vacuum.” 

Other developments have also had an impact on the mixing and blending equipment used for solids and semi-solid formulations. For Borgers, the ability to conduct online analysis of blend homogeneity has helped manufacturers better understand blending behavior and made it possible to detect properly the required blending time. Ekato has found that determination of the end point of mixing using inline techniques such as viscosity, pH, and particle size analysis, but on a bypass loop, enables increased automation. 

Meanwhile, for Almhem and Reiner Lemperle, director of sales with Lödige Process Technology, the shift to continuous processing has been a notable development. “This approach allows the use of smaller equipment, which translates to less expensive production space, reduced product losses, and fewer material surfaces to clean, and eliminates scale-up issues, because the only factor is running time.” Lödige has developed a solution for continuous mixing, granulation, and drying that can be used for continuous mixing with a throughput of up to 200 kg/h, and for granulation and drying from 5 to 30 kg/h. 

Despite these advances, there are still numerous ways in which blending and mixing of solid and semisolid formulations can be improved. Engenhart believes that even higher batch size flexibility is needed to increase efficiency and productivity in the mixing and blending of both solid and semisolid dosage forms. Currently, some Ekato mixing systems can efficiently mix batch sizes that are in the range of 10–25% of the maximum batch size that can be processed in a specific size of equipment. Engenhart is confident that these limitations can be pushed further. 

For Sangüesa, the main issue is segregation. “Blenders can do a great job to ensure that all the powders, even those with varying densities, particle shapes, flow characteristics, etc., are thoroughly mixed inside the blender. But the moment those powders are either discharged or transferred out, segregation can occur,” he explains. “Depending on the surface finish, for example, some powders will flow better than others, thus negating the very benefits the blender had achieved. As powders flow out, there is always the concern that some of the ingredients will no longer be represented in the same percentage throughout the batch.” 

To address issues such as segregation, Borgers would like to see more simulations of blending processes. He believes the ability to effectively simulate different mixing and blending processes will lead to the development of more effective approaches to scale-up of processes and help address equipment transfer questions. “Fortunately, advances are being made in simulation software, and I am thus hopeful that useful software tools will be available in the near future.” 

At the same time, there are a growing number of specialty products and “individual drugs” that are produced in much smaller quantities. “Scaling down production throughput to these small volumes is a challenge. The mixing and blending equipment needed for these niche products looks a lot different than the existing units in use today,” Lemperle notes. To help its customers, Lödige has introduced a mixer designed for batch sizes down to 0.5 kg/batch. Engenhart adds that many of these specialty semisolid formulations, including softgels and oral strip products, involve exceptionally high viscosity materials that require special mixing conditions. 

Furthermore, there is a trend toward the use of non-animal-based shell materials for softgel capsules, and these materials are more challenging to work with, according to Engenhart. In addition to having higher melting temperatures that require an even tighter allowable process parameters during mixing and transfer, these newer shell materials are often of even higher viscosity than conventional materials, and thus higher shear mixing is necessary to adequately disperse some of the solids raw materials. 

There are also general challenges related to the selection of appropriate mixing and blending equipment. Because many mixing technologies today overlap in use and function such that certain formulations can be produced in more than one distinct type of mixer, making sure that the mechanical and physical aspects of the equipment enable safe, repeatable, and sanitary mixing is very important, according to Banaszek. “More often than not, there is no all-purpose, off-the-shelf solution,” she says. 

In addition, manufacturers that are using inherited equipment or procedures because they have worked in the past may actually be at a disadvantage and limiting their production capabilities. “With the greater understanding of mixing and blending processes that we have today, combined with the advances in mixing technology and new equipment, it is generally beneficial in such cases to reevaluate the existing mixing strategy to determine if it is efficient,” Banaszek observes. She concludes that, to identify the best mixer or blender for a particular formulation, it helps to partner with a reliable mixer supplier that offers long-term experience, rental, and testing resources. 

Effective blenders provide efficient, homogeneous mixing and de-aeration for a wide range of formulations