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

Cynthia A. Challener

Although traditional  powder-characterization methods, such as Carr’s Index, the Hausner Ratio, flow  through an orifice, and the angle of repose, provide some information, these  techniques may have limited value given the processing technologies in use  today in the pharmaceutical industry. John Yin, an applications specialist with  Freeman Technology, spoke with Cynthia Challener, editor of the 

Pharmaceutical Sciences, Manufacturing &  Marketplace Report

, about the importance of newer powder-characterization  techniques for optimizing pharmaceutical product development and manufacturing  processes.

Powder  properties affect processing behavior

Pharmaceutical  Sciences, Manufacturing and Marketplace Report

: Why is powder characterization so important for the pharmaceutical  industry? When is it used and what impacts does it or can it have?

: Understanding and characterizing  powder behavior is critical for the production of solid-dosage formulations,  and there are many key properties of powders that determine how they will  behave in a hopper, when being filled into a die, and compressed into a tablet.  Understanding the variables and processing conditions involved in relation to  what powders are required to do is therefore relevant during all aspects of  development and manufacturing, and can provide information that can be used for  formulation development, process optimization, and improvement of the quality  of the final drug product.

: What advances in powder characterization have been achieved in recent  years? What drove these developments; what unmet needs were addressed? 

: In the past, much of the focus on  powder characterization has been at the single aspect level where one standard  or number is expected to dictate ‘good’ or ‘bad’ once and for all. In reality,  we rely on multiple techniques for explaining behavioral differences when being  subjected to many processing conditions. While some information can be obtained  with traditional methods, such as bulk-tapped density, flow through an orifice,  and angle of repose, these techniques are not at all representative of the  conditions that powders see under process conditions and, therefore, are not  able to provide process-relevant and differentiating information given the  process technologies in use today in the pharmaceutical industry. 

The multivariate  approach for characterizing powders has made it possible to gain much greater  insights into how the combination of powder physical properties and external  variables affect their behavior. Dynamic testing for example, which measures  the flow energy of a powder with respect to external conditions, such as  aeration, flow rate, and consolidation, is a newer technique enjoying considerable  industrial uptake. Advances in shear testing are also improving both the  precision and reproducibility of this important analytical method.

More meaningful data  equals more control

: What specifically does Freeman's new system bring to the pharma  industry?  What were the reasons for its development? How is it  differentiated from other systems on the market? 

: The FT4 Powder Rheometer can conduct  seven direct measurements that fall into the three major categories of bulk,  dynamic, and shear powder properties. In addition, we have developed software  that incorporates state-of-the-art mathematical modeling of powder properties  in order to help customers use the data to predict the compatibility between a powder  and manufacturing equipment (i.e., a hopper). 

In the bulk-property  category, we can determine bulk density, compressibility, and air permeability,  all of which affect the ability of the powder to undergo tableting processes.  Shear properties are measured to predict how the powder will behave in a  hopper. Dynamic flow properties are designed using special blade methodology that  measures flow energy as a function of aeration, flow rate, and consolidation. 

Importantly, the  system is designed to condition a powder first before making any measurements.  Conditioning involves the generation of a standardized packing condition  through gentle displacement of the entire powder sample in order to loosen and  slightly aerate it. The result is a homogenously packed powder bed with no  precompaction or excess air. 

The system is automated  and has been demonstrated to reproducibly deliver reliable data that correlate  with process performance. Because we are able to measure a meaningful and  relevant set of powder properties, this information can then be used to numerically  describe, rationalize, and better understand core powder-processing operations.  It has, for example, been used at line to very rapidly correlate the impact of  the moisture content in a powder to the properties of a final, formulated  product and to characterize powders and their behavior in order to quickly  optimize continuous granulation and tableting processes.

: What limitations remain with respect to powder-characterization  technology for the pharma industry? Why are these issues important? 

: One of the biggest limitations at this  point is the lack of understanding of powder behavior at the level needed to  describe such behavior mathematically or from an axiom perspective. There are  so many variables, not just particle size and density, which are often  perceived as the only critical factors that influence powder behavior, but also  the surface texture, particle shape, stiffness, and porosity as well as  external influences, such as air, moisture, consolidation stress, and flow rate,  which can all contribute to the picture. There is much work to be done in this  area and it will be a steep learning curve. A second challenge is the need to make  the pharmaceutical industry and other powder-processing industries (that share  similar challenges) aware of the benefits of more comprehensive powder characterization.  We are working on addressing both issues.

: What advances in powder-characterization technology might be expected?  What specifically is Freeman working on? 

: The adoption of continuous  manufacturing for the production of solid dosage forms will have an impact on  powder-characterization technology. In addition, as the amount of data gathered  on different powder systems increases, we will continue to gain more knowledge  about powder properties and behavior and be able to expand our insight into  performance with respect to different processing conditions. 

 At Freeman, we always  seek room for improvement based on the feedback that we get from current users.  We are learning a great deal and using that new knowledge and experience to  improve both our software and instrument design. At this time, however, it is  not possible to provide any specifics.

Articles

Dynamic testing and advances in shear testing provide better insight into powder physical properties and external variables that affect powder behavior.

Multivariate Approaches for Powder Characterization

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.

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.