Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Solid-dosage manufacturing involves a range of processing technologies to take a formulated API through to a finished dose form (e.g., capsule, tablet). A thorough understanding of both the product and the process technology are required for optimization. “The more complex a therapy becomes, the more exacting the requirements of the process technology may be to achieve the required performance,” says Nicholas Johnson, strategic marketing director for Catalent’s Advanced Delivery Technologies.

In the past decade, the quality-by-design (QbD) initiative has brought a new focus on better understanding the raw material, formulation, and processing variables that influence the critical quality attributes (CQAs) needed to make a quality pharmaceutical product. QbD is really a synonym for process understanding, and greater understanding will lead to a better process with less out-of-specification material, said Conrad Winters, director of the Drug Product Development Group at Hovione FarmaCiencia, in a recent article discussing how to apply QbD methods in manufacturing-process development for a bulk powder and subsequent tablets (1). Because there are so many variables involved, process developers should use a risk assessment, based on prior knowledge, to determine which parameters are the most crucial to study further. “Expertise in the process ensures that a sufficiently broad study is completed,” says Winters. “A managed or limited study is of no value if you fail to capture the critical process parameters (CPPs).” Analyzing the results of these studies—by quantifying the impacts of the variables studied and evaluating the uncertainty or residual variability associated with them—allows process designers to establish a reliable design space and an operating space within the design space. 

The focus on QbD has begun to break down the traditional barriers between formulation and process development, but even greater communication between these areas is needed to allow better optimization of the whole solid dosage process, says Tim Freeman, managing director of Freeman Technology. “As an industry, we are still challenged in understanding what attributes of the material are important regarding functionality during tablet manufacturing and attributes of the finished product,” says Freeman. Measuring powder properties, such as cohesion, permeability, density, and flow under gravity, is important for both designing and optimizing the manufacturing process. Powder characteristics must be understood to answer questions such as whether a powder can be processed with direct compression, or if it will require dry or wet granulation. 


Adequate raw-material specifications are currently a missing link in the quest for solid-dosage process optimization. A group from the National Institute for Pharmaceutical Technology and Education (NIPTE) began collaborating with FDA in 2011 on a searchable excipients knowledge database for excipient property measurement data to make more data available to developers (2). Better specifications for crucial raw-material powder properties, such as particle shape and flowability, would allow better control of material inputs and reduce the need to adjust the process to compensate for this variation, says Freeman.


Process analytical technologies (PAT) are now widely used to measure, understand, and improve the solid-dosage process. Real-time monitoring allows processors to identify a need for process adjustments more quickly, which improves process capability. Online monitoring methods, such as near infrared (NIR) analysis, can, for example, help identify the endpoint of the granulation process (3). In roller compaction, ribbon density and particle size distribution measurements can be measured on-line and used for process control, says Winters. In tableting, compression forces can be monitored online, and tablets can be rejected based on atypical compression events rather than actual testing, noted Winters in a webcast (4). Tablet properties such as weight, hardness, thickness, and content uniformity are now able to be measured online. Other important properties, such as powder flowability and particle shape, must be measured off-line or at-line, says Freeman, who notes that this engineering challenge is a focus for equipment and method development. 

Another challenge that the industry is currently engaged in solving is moving beyond process monitoring to using PAT data to actively control the process. Processors are addressing issues such as integrating instrument software with plant equipment and ensuring that PAT measurements are quick enough to allow control of process fluctuations (5). 


The use of continuous operations in solid-dosage manufacturing is growing rapidly. “Process development in a continuous process is much easier and faster than in a batch process,” notes Freeman. “Because the process has a low residence time, you can change variables and explore the results very quickly, in minutes or hours instead of days.” Scale-up is also easier, because the process can be run for a longer time rather than in larger equipment. Continuous processing, combined with PAT, allows for the possibility of closed-loop control. The aim is to have a process that can compensate for variation in inputs, such as water content in the raw materials. 

Hot-melt extrusion (HME) is inherently continuous, and continuous processes for wet or dry granulation (with continuous drying and milling) and direct compression are also in use. GEA Pharma Systems, for example, introduced the ConsiGma continuous, high-shear, wet granulation process using a twin-screw extruder in 2013. In January 2014, GEA and Freeman Technology announced a collaboration to advance the use of continuous wet granulation and drying technology. Data from Freeman Technology’s FT4 Powder Rheometer are being used to quantify the influence of the ConsiGma operating conditions on the bulk characteristics of granules, and these data are then correlated to attributes of the tablets. “The study rigorously investigated the impact of changes in water addition level, granulator screw speed, and powder feed rate,” according to a press release (6). “The results show how it is possible to produce granules of closely defined quality using a series of different operating conditions, and demonstrate how the design space for the ConsiGma can be mapped efficiently for a given tableting blend. Dynamic powder measurements provide the information needed to effectively specify optimal operating conditions. Within a commercial manufacturing environment, they would also provide the information needed for operational decision making within the design space.” 

L.B. Bohle is building a technology center, expected to be completed in mid-2014, to develop and demonstrate continuous wet and dry granulation. At the center in Ennigerloh, Germany, L.B. Bohle processing experts will work with specialists from the Universities of Dusseldorf and Graz and experts from Siemens on measuring, monitoring, and controlling the continuous production process, and these  developments will be used to produce new equipment and optimize current machinery, the company said in a press release (7). 

Optimizing manufacturing processes for improved solubility


With the increasing use of APIs with low solubility or bioavailability, processing technologies for improving solubility are being developed and optimized to meet this growing need. Spray drying and HME for pharmaceutical applications, for example, have evolved over years of research and are now established processing technologies with market precedence for improving solubility, notes Dan Dobry, vice-president at Bend Research, part of Capsugel’s Dosage Form Solutions (DFS) business unit. The QbD methodology is especially relevant to bioavailability-enhancement products because each molecule presents its own unique challenges, which are identified and mitigated using risk-based approaches and by designing quality into the product from the beginning, says Dobry. Optimization of spray drying and hot melt extrusion, for example, involves understanding performance, stability, and manufacturability for a specific API and target product profile. “Performance can be optimized by understanding the dissolution mechanism of a specific formulation and pairing that understanding with a mechanistic biomodel to predict absorption,” explains Dobry. “Stability is optimized by understanding the physical state of amorphous materials and development of predictive models to screen out unstable formulations before they are advanced. Manufacturability is optimized by using first principles and multivariate statistical models that correlate critical quality attributes to key process parameters.” 

Although understanding this interdependence of the formulation and process operating space has influenced the most significant advances in optimizing the manufacture of amorphous dispersions, equipment innovations have also played a role. In spray drying, important innovations have been in drying chamber geometry, nozzle choice, and process parameter ranges, notes Dobry.  Future equipment innovations are expected to tackle the cost of goods for “very” poorly soluble compounds and the handling of potent compounds, predicts Dobry. 

Laboratory-based methods have also improved to the point of being able to predict success in improving bioavailability. “There is enough basis of work to be able to provide good guidance as to whether to continue the development process with an SDD, for instance,” explains Jeffery Basham, vice-president of business development at Metrics. When a CMO uses QbD principles in exploring and documenting chosen formulations, the client has a basis for explaining what and why various decisions were made during the development process, explains Basham. 


Extrusion is a well-understood mixing process in several industries, and this understanding is being applied to optimize the pharmaceutical HME process. Commercial adoption rates of HME are expected to increase as it becomes even more accepted as an effective means to address drug solubility challenges, predicts Nicholas Johnson, strategic marketing director of Advanced Delivery Technologies at Catalent. The company expanded its OptiMelt HME capabilities at its Somerset, NJ facility in September 2013 in response to increased customer interest, particularly in the post proof-of-concept stages of process development and scale up. The OptiMelt technology platform was developed to optimize the HME process through an alliance with polymeric-excipient producer BASF, which involved developing the most effective ways to screen drug candidates and identify the most applicable polymers early in the development process. The technology platform also incorporates Catalent’s experience to effectively integrate the HME extrudate into the most appropriate finished-dosage form (e.g., tablets, capsule and granules, and controlled-release technologies) for customers’ end requirements.

HME has the potential to become more widely applied to a greater variety of formulation challenges, over and above bioavailability enhancement, because of several advantages. These benefits include being solvent free, able to operate as a continuous process, and having relatively compact equipment that allows a more effective use of infrastructure. “One of the largest-scale products we manufacture using hot-melt extrusion is not for bioavailability enhancement but rather addresses a specific formulation challenge for an over-the-counter product that was most readily addressed through hot melt extrusion with downstream processing into a convenient dose form,” says Johnson. “We fully expect to see more such opportunities for the wider employment of hot-melt extrusion in the future.” 


Amorphous dispersions (made using HME or spray drying) can be compressed into tablets or filled into capsules. Another option for improving solubility is using a liquid or semi-solid approach that incorporates combinations of lipids, water-soluble surfactants, and co-solvents in a softgel or liquid-fill hard capsule (LFHC) finished dosage form. “The choice of delivery platform is based on a combination of many factors, including dose/potency, the API’s physicochemical properties, and customer preference on dosage-form presentation,” comments Dobry. “Lipid technology can be especially useful for extremely lipophilic compounds and where there is a need for induction of fed-state, reduction of efflux, promotion of lymphatic absorption, or decrease in hepatic or luminal metabolism.”  

Liquid filling offers a more straightforward manufacturing process with more reliable scaleup than dry-powder filling or tableting, adds Stephen Brown, managing director of the Capsugel DFS Livingston, Scotland site. For LFHC, Capsugel has developed a specialized liquid-filling and sealing process that eliminates product leakage.  The capsule design has two capsule ring-barriers at the top of the sealing zone and eliminates dimples to remove low cap–body contact areas that could affect the sealing process. Capsugel’s proprietary Licaps Fusion technology system lowers the melting point of gelatin, which allows fusion at moderate temperatures. “The combination of capsule design and the use of fusion technology results in fewer capsules removed during post-vacuum inspection and zero subsequent leaking capsules during pre-bulk packaging inspection,” says Anthony Macci, senior vice-president of Global Operations at Capsugel DFS. 

Catalent’s new OptiShell technology increases the range of excipients that can be used in softgels, and further advances are expected to provide more options (8). Traditionally, limits to soft-gel encapsulation include use of fill temperatures below 40 °C, neutral or acidic fill formulations, and excipient limitations. OptiShell non-gelatin shell technology, however, allows fill temperatures up to 70 °C and semi-solid and highly viscous fills. The OptiShell shell is less susceptible to crosslinking and can accommodate a wider range of excipients and surfactants, as well as more basic pH fill formulations, explains Ted Andrew, product manager for Catalent’s RP Scherer Softgel. Softgel technology is well optimized with the experience gained over 80 years of formulating and manufacturing, says Andrew. 


  1.	C. Winters and F. Neves, “APIs Excipients, & Manufacturing” supplement to 

. 37, s14-18 (2013). 
  2.	PharmaHub, “

Explore the NIPTE-FDA Excipients Knowledge Base

,” accessed Feb. 5, 2014.
  3.	C. Challener, “

Granulation Method and Process Monitoring Matter

Pharm. Sciences, Manufacturing & Marketplace Report,

 Sep. 25, 2013.
  4.	C. Winters and F. Neves, “

Optimizing Quality by Design in Bulk Powders and Solid Dosage

,” webcast on www.pharmtech.com (March, 2013). 
  5.	J. Markarian, "

Process Analytical Technology and Process Control in Solid-Dosage Manufacturing

. 37 (4) 56-61 (2013). 
  6.	Freeman Technology, “Freeman Technology and GEA Pharma Systems collaborate to advance continuous manufacturing for pharma,” Press Release, Jan. 28, 2014. 
  7. 	L.B. Bohle, “New L.B. Bohle Technology Center Advances Development of Continuous Pharmaceutical Process Equipment,” Press Release, Nov. 26, 2013.
  8. 	C. Challener, “

Advancing Softgel Technology for Poorly Soluble or Highly Potent APIs

Pharmaceutical Sciences, Manufacturing & Marketplace Report

Articles

Quality-by-design principles enhance a thorough understanding of both product and process technology, which is needed for optimization of solid-dosage manufacturing, including processes for improving solubility, such as hot-melt extrusion, softgels, and liquid-filled capsules.

Optimizing Solid Dosage Manufacturing

Microencapsulation is a promising drug delivery technology in which APIs are encapsulated with a natural or synthetic material that targets delivery by controlling the API’s release. Microsphere drug-delivery systems are used commercially and in many developmental products for both small molecules and biopharmaceuticals. 

Conventional technology for microencapsulation involves emulsification in a specially designed homogenizer. Although current technologies enable adequate dispersion, the ability to easily scale up to commercial production is a significant hurdle, says Frank de Jong, CEO of EmulTech, which has developed a new technology that solves the scale-up challenge and has advantages in reproducibility and process control. EmulTech's microfluidic platform was a finalist for best innovation in formulation in the 2013 CPhI Pharma awards. The Emulsion Technology for Microencapsulates (ET4ME) technology produces highly uniform microspheres, and the process can be controlled to make spheres of any size. 

The EmulTech system uses simple scaleup from a single-channel device that produces in the mg/h scale to a multi-channel device (MCD) with up to 400 channels that produces on the laboratory or preclinical scale of up to 100 g/h. A stack of MCDs can produce hundreds of grams up to the kg/h range, and the company is currently preparing to deliver its first clinical-scale equipment. Because the process parameters are strictly controlled, the process has reproducibility from batch to batch and from smaller to larger scale, adds de Jong. ET4ME operates at a much lower shear and temperature range than conventional technologies, making it useful for sensitive APIs such as biomolecules. ET4ME is a closed system with disposable parts, which simplifies operation under aseptic conditions and allows for easy sterile-suspension production. The ET4ME technology offers high control over droplet formation that produces a narrow particle size distribution. "Particle size control is crucial for microspheres," notes de Jong. "Particles that are too small can cause an immune response that leads to dose dumping. Particles that are too large can block the delivery device." Particles in the 30-90 micron range are used for subcutaneous applications. Particles in the 1-5 micron range are used in inhaled formulations, and particles in the 1-3 micron range are used in vaccines, says de Jong. Particles less than 1 micron are in the nanoparticle range, which puts them in a different category with different requirements.

Filtering, washing, and drying microsphere products


  No matter which encapsulation technology is used, the resulting microspheres must be washed, filtered, classified by size, and dried. Sieving is commonly used to classify microspheres, but, although this method is readily achieved on a non-sterile laboratory scale, it is difficult to scale up to larger production, says Camille Flores, business development manager at Powder Systems Limited (PSL). Scale-up difficulties include mesh blocking, lengthy dry times, poor product recovery, and difficulty incorporating steam-in-place (SIP) sterilization. PSL's Microsphere Refiner was designed to address these challenges and can be used from laboratory through production scale. The Microsphere Refiner combines classification, filtration, cake washing, drying, and sterile product recovery in one system. When necessary, a scalping unit first removes the oversized particles, and then the refiner removes the undersized particles. The desired particles are then washed, filtered, and dried. An agitator and filtration system keeps the microspheres in suspension, which avoids the problem of mesh blocking. The refiner is operated under vacuum using a heated jacket for efficient drying. In addition, the refiner is SIP-capable and is tiltable to accommodate sterile discharge, explains Flores.

Technologies such as these should allow easier scale-up to commercial, sterile production as more microsphere products move from development to commercialization. 

New methods of encapsulation and filtering address scale-up challenges.

Developments in Producing Microspheres

Asset management and redeployment are gaining recognition as important parts of managing pharmaceutical equipment. “We are seeing more formal programs and procedures in place to redeploy unused assets,” says Matthew Hicks, COO of Federal Equipment, which specializes in asset management of process equipment.  “Some companies now have an in-house asset disposition department or, more commonly, a person charged with asset management who will work with a service provider to handle the details.” 

Many types of used laboratory and process equipment are available. Used laboratory equipment (e.g., mass spectrometers, high-performance liquid chromatography equipment) has always been widely available, and the industry is also seeing more growth in available processing equipment than 5 or 10 years ago, comments Roger Gallo, CEO and president of EquipNet, a Boston-based broker and auctioneer of laboratory and manufacturing equipment. Most of what would be needed for a complete solid-dosage or liquids manufacturing and packaging operation is available in the used equipment market, adds Hicks. 
   
  Factors such as budget restrictions and the recognition that assets must be handled efficiently have led to global, mainstream adoption of buying and selling used equipment by both Big Pharma and mid-size and smaller organizations, said Tom Burton, executive vice-president and president of the Capital Assets Group at Liquidity Services in a 

Value-proposition for purchasers of used equipment


Used equipment offers two main benefits for purchasers—cost-savings and quick availability—and buyers are increasingly interested. Original equipment manufacturers (OEMs) have increasingly tight schedules for supplying new equipment, which can make it difficult to get equipment quickly, notes Gallo. Second-hand equipment can be obtained without long lead times.   

“Used equipment can be a good option for anyone who has an urgent need for equipment—anything from having equipment down and needing to replace it to wanting to meet a market need,” adds Hicks.   

Cost savings of used equipment compared to new can be significant, although the savings depend somewhat on the purchase method. Buyers can find used equipment through private transactions made directly with the seller, from the inventory of used-equipment providers, and through online liquidations or auctions. 

For transactions made directly with a seller, much information is available. It could be known, for example, what the equipment was used for, when it was last used, and where it had been stored. Large companies typically keep good records on their equipment, adds Gallo, and a potential buyer might even be able to speak with an engineer who knows the equipment. Purchasing equipment that comes straight from the working environment of a reputable company is one way to know that the equipment has been maintained, noted Burton (1). 

In an auction of a specific facility closure, information would be relatively available about the equipment and how it was used. In an auction that is run by a dealer or an exchange, equipment often comes from various sources, there is less information about the equipment available, and there is greater risk. Pricing, however, generally reflects this uncertainty and risk, and the cost at auctions can be attractive, notes Gallo.

Buyers should consider removal and shipping costs, as well as installation costs at their facility, in their purchase decision, said Burton (1).  


  Most importantly, buyers should know what they are purchasing, because equipment is generally sold “as is.” “A buyer should very carefully read the description and examine the picture of the equipment to make sure that there is no question in their mind as to what is or is not included,” warns Gallo. A picture, for example, may show something in the background that is not part of the sale as listed in the description. 

Buyers should also ensure that the equipment meets their needs, because it may be older technology. Buyers should know if the equipment they are purchasing is supported by the OEM. “We recommend buying equipment that is supported by the OEM for installing, revalidating, and upgrading,” says Hicks. “We have relationships with the OEMs so that if a piece of equipment or its controls, for example, are no longer supported, we can make the buyer aware.”  

If the OEM is no longer supporting the equipment, buyers should be sure that they have someone that is capable of servicing the equipment (e.g., fixing a control panel, calibrating an instrument) and that replacement parts are available, adds Gallo. 

Relatively new equipment can be available, however, from companies that upgrade their equipment on a regular basis, companies that purchase an item and then find they do not need it, or facility closures, explained Burton (1). 

“In process equipment, we are seeing high-quality inventory of late-model equipment that is well taken care of,” adds Hicks. An increase in availability of recent models may be due partly to consolidation and facility closures and partly to the increasing use of asset-management services.  

Buying and selling used laboratory and process equipment has become mainstream; experts offer tips to potential buyers.

Buying Used Equipment

Change is coming to the way biopharmaceutical products are manufactured, said industry thought leaders at the ISPE national meeting in Washington, DC in November 2013. Although how quickly change will occur is uncertain, the manufacturing paradigm is shifting from large, single-product facilities to smaller-scale, flexible, multiproduct facilities that may even be moved to different locations as the need arises. New facility designs that enable flexible, multiproduct production include single-use technologies, the use of controlled nonclassified (CNC) spaces with closed systems, modularization, and continuous processing.

Single-use systems face hurdles, such as a conservative industry mindset and existing investments in stainless-steel facilities, but some companies are moving ahead with increasingly complex systems, such as single-use bioreactors and other single-use unit operations, said Joshua Hays, associate director for upstream sales development at EMD Millipore, in a presentation. Single-use components are an enabling technology for smaller-scale production of biopharmaceuticals as well as cell therapies, such as stem cells, which would otherwise be much more difficult to produce. Because revalidation is costly, the majority of single-use systems are being employed for new products, and many companies choose hybrid facilities with both stainless-steel and single-use components. Hays predicted a big move to single-use components, estimating that as much change would occur in the next three to five years as it has in the past 15 years.  

CNC multiproduct ballroom facilities, which have most unit operations in one room, are not monitored to a specific environmental classification, but are GMP facilities that must use demonstrably closed systems and have other appropriate controls (e.g., quality systems), noted Paul Smock, senior director of quality assurance at AstraZeneca's MedImmune, speaking as a member of the Area Classification team of the Biophorum Operations Group, which is a collaborative community of biopharmaceutical industry experts who meet to establish best practices. Other important considerations for a successful multiproduct manufacturing facility, said Smock, are understanding the process, using advanced controls and testing, and having a flexible organization with good communication.

Modular manufacturing designs, which add flexibility by using prefabricated modules that can be arranged as needed and in the location where they are needed, continue to grow in use in biomanufacturing. Modularization reduces capital cost compared to conventional construction and is also advantageous for construction in developing countries. 

The rate of change in biomanufacturing is increasing, and the new value driver is flexibility, said Parrish Galliher, founder and CTO of Xcellerex, a GE Healthcare Life Sciences company, in a presentation at the meeting. Blockbuster-drug facilities are not flexible enough for the future, which is moving to smaller, multiproduct facilities made "in market, for market". Future technologies, such as cell and organ therapy and personalized medicine, will require even smaller-scale manufacturing, predicts Galliher. These facilities would need to be located "at clinic, for clinic" to have the proximity needed to deliver live products with short shelf-lives. Such technologies have high treatment costs and it is uncertain if they will make a viable business, but the technology is in development. Peering even further into the future, Galliher painted a vision of "on patient, for patient" manufacturing that could include noninvasive real-time diagnostics and real-time, microfluidic laboratory-chip drug synthesis. 

Continuous biomanufacturing is a game-changing technology for smaller-scale, flexible, multiproduct production that is emerging even now. Sanofi's Genzyme is developing a closed, continuous manufacturing process with the vision of a universal platform for all its protein biologics, said Robert Snow, senior project engineer in Sanofi’s Biologics Development Group, in a presentation at the meeting. The continuous process integrates upstream and downstream unit operations into one process train. Similar to its solid-dosage counterpart, continuous biomanufacturing offers a smaller footprint when compared to traditional perfusion or batch-type systems, and capacity is increased by increasing the number of process trains rather than their scale. The combination of closed, continuous processing and platform approach will result in smaller and more flexible multiproduct manufacturing facilities that can take full advantage of CNC ballroom-type facilities. The concept is being developed using mainly single-use components, but would also work with more traditional stainless steel process equipment, commented Snow.

Facility Trends: Modularization and Single Use

, insights from presenters at INTERPHEX 2013 in the May 2013 issue of  

Flexibility in Biopharmaceutical Manufacturing

, by Simon Chalk of the Biophorum Group in the June 2013 issue of 

New facility designs enable flexible, multiproduct production.

Tracking Biopharmaceutical Manufacturing Facility Trends

Tablet sticking, in which material adheres to the surface of a tablet-punch face, is an ongoing and costly problem in pharmaceutical manufacturing and is a significant issue for drug-product formulators. Analytical methods can be used to troubleshoot sticking problems and develop screening methods. Experts are also seeking to increase fundamental understanding of the underlying causes of sticking and to develop predictive models to more quickly find solutions to specific sticking problems. 
  
  Many variables affect tablet sticking, including formulation (e.g., API, excipient, and other components), granulation properties (e.g., particle-size distribution), tablet design (e.g., tablet shape), tablet-press conditions, tablet-tool properties, and tool maintenance. There are nearly as many possible solutions as there are variables. 
  
  


  Tooling-equipment suppliers have found, for example, that proper tooling and tooling maintenance can help prevent sticking to a certain extent. I Holland champions a rigorous seven-step maintenance method that includes cleaning, assessing for damage or wear, repairing, measuring to ensure that dimensions are maintained, polishing, lubricating, and storing properly (1). 

Microscopy can be used to assess the surface of a punch. “You can’t see a 10-μ scratch with the naked eye, but 2-μ particles will stick to it. Suddenly, you have a film spot that acquires more powder and is then big enough to cause defects,” explains Charles Kettler, director at Natoli, a tooling and equipment manufacturer. “Microscopy allows you to see if the tool has a fundamental problem.” This type of analysis could be used to identify a problem with tool handling, such as whether a polishing technique is more aggressive than it should be. 

Equipment suppliers have also developed special steel types and coatings to prevent sticking. Finding the best material, however, can be a time-consuming process that involves field testing at a customer’s site and laboratory testing to identify a solution to each unique problem. I Holland’s Tableting Science Anti-Stick Research (TSAR) program, in collaboration with the University of Nottingham’s School of Pharmacy and experts from the Laboratory of Biophysics and Surface Analysis, both in the United Kingdom, is developing a predictive tool to identify the best punch or die-coating solution to prevent sticking in a given formulation. The company says that the tool will provide quick guidance without time-consuming tests (2). 

TSAR-program researchers used atomic force microscopy (AFM) to map the adhesive forces on a tablet-punch face, such as the example shown in 

 AFM can elucidate local chemical and mechanical properties, such as adhesion and elasticity, and even molecular bond rupture strength, explains Rob Blanchard, research, development, and quality systems manager at I Holland. Such adhesion maps show differences in adhesion caused by surface topography differences with various coatings at different humidities. The TSAR researchers also used X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and time-of-flight secondary ion mass spectrometry (TOF-SIMS) to visualize the chemical distribution of selected ions on the surface and better understand the interactions involved in sticking. Principle component analysis (PCA), a multivariate statistical technique, is being used to analyze these data and generate correlations to explain how the chemistry of a system affects adhesion with different surface coatings. This understanding of how the formulation components behave and interact to cause sticking will then be used to develop the predictive tool. The predictive tool will be validated using results from compression experiments with various formulations and punch-tip coatings. 

Although proper maintenance and optimized coatings are essential, the root cause of sticking is often the formulation properties or particle size. If these properties are already set, manufacturers must find a solution in the tablet press or tooling. Ideally, however, the drug could be formulated to have a lower tendency for sticking. 


Various methods are available for assessing sticking problems and screening for sticking propensity, but the use of these tools has been limited by their complexity. Many instead rely on subjective visual inspection, which limits the ability to screen consistently. To address this deficit, researchers at Pfizer developed a simple, quantitative screening tool for drug-product tablet-sticking propensity that can be used to rank the degree of sticking for many formulations and their ingredients using a custom tableting punch with a tip that can be removed to measure the amount of adhered powder (3). “This gravimetric method has been successful for classifying sticking severity during drug product design and has significantly reduced risk during scale up,” says Matthew Mullarney, principal scientist at Pfizer. “We can customize both our API and drug-product formulations to ensure they do not exceed in-house threshold values in the laboratory before manufacturing any bulk-tablet supplies.” The screening method can also be used to plan for manufacturing campaigns (e.g., tooling/tablet inspection frequency or cleaning requirements) and to troubleshoot the root cause of sticking problems in large-scale manufacturing. 

Equipment supplier Natoli finds this gravimetric method useful for predicting the sticking tendency of formulations at or prior to clinical-scale production and has tested small amounts of API with a given formulation, tablet design, and tool steel and coating for propensity to sticking (2). Further work using this method will be performed by researchers at the Natoli Institute of Industrial Pharmacy Development and Research in partnership with Long Island University’s Arnold and Marie Schwartz College of Pharmacy in New York. Laboratory facilities for the institute are currently being constructed at the university and are expected to open in late 2013 with fully qualified equipment, reports Kettler. Various projects at the institute will be used to further develop fundamental understanding of tableting problems and formulation studies.

“Now that simpler tools are available for screening and classifying, both pharmaceutical companies and academic groups can focus on relating other material properties, such as molecular structure, particle size, and mechanical properties, to sticking and building models that describe the sticking mechanism,” adds Mullarney. “We may soon find that sticking is multimechanistic, and a variety of molecular chemistry, particle, and bulk-powder characterization tools and models will be needed to parameterize the sticking mechanisms of different powders.” Once these mechanisms are understood, APIs and drug products can be designed to reduce sticking propensity. Current work at Pfizer is focused on understanding why some APIs appear stickier than others and investigating the contribution of a solid API’s molecular attributes (e.g., surface chemistry and morphology) to sticking. “Both computational models and experimental approaches will be necessary to get us closer to the root causes. Additionally, tooling designs and surface treatments are also being studied,” notes Mullarney.


  Work on building models to describe sticking is progressing. Marcial Gonzalez and Alberto Cuitino at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers, the State University of New Jersey, have developed mechano-chemical models and computational methods that predict the evolution of microstructure and interparticle forces during powder compaction. Because most properties of a compacted tablet can be attributed to its microstructure, the models can be used as tools to understand and predict how manufacturing process variables affect product performance. 

The tendency of powders for sticking and picking is described by the adhesion of powder to die walls and tool surfaces and can be explained by a competition mechanism between interparticle bonding and particle-wall adhesion, explained Cuitino (2). If particle-wall adhesion is stronger than interparticle bonding, the weaker interparticle bonds will break when the tablet is ejected and cause sticking or picking. If particle-wall adhesion is weaker than most interparticle bonds, internal cracks might occur. Ideally, if enough bond strength was developed during compaction, no defects will occur. If the network of particle-particle and particle-wall forces are known, competing effects can be quantified, said Cuitino. Because this measurement is not possible with current experimental techniques, the researchers developed a nonlocal formulation of contact mechanics that more accurately describes the powder system (4). This fully discrete model is based on particle mechanics and describes every particle in the powder bed as an individual entity. “The collective rearrangement and deformation of the powder bed is resolved by the fully discrete model and the microstructure of a compacted specimen is then predicted,” explains Gonzalez. 

These computational models are capable of resolving and tracking the micro-structural evolution of a powder bed compacted into relative densities close to 1 (i.e., into a solid tablet with porosities close to 0, which is typical of pharmaceutical products). 

 shows a compaction curve predicted by the model; the black line corresponds to the pressure applied by upper/lower punches in order to achieve a given relative density, and the blue line corresponds to the pressure experienced by the die wall as a result of powder compression. The right-hand side of the insert in 

illustrates the microstructure of the tablet with spherical particles of different sizes. In the left-hand side of the insert in 

, lines illustrate the network of interparticle forces and particle-wall forces predicted by the model, with stronger forces indicated by thicker lines. 

Experimental techniques, such as a tablet-press simulator and a tablet-hardness test, are used to calibrate material properties employed by the model (e.g., elastoplastic constants and fracture toughness of the particles). The model can be used to predict powder behavior and properties for given tablet-press conditions (e.g., tooling geometry and punch displacement) and powder formulation (e.g., the total mass and particle-size distribution of each component of the formulation). 

Other work in the early stages at C-SOPS uses tomography to measure the density gradients across the tablet at different compressions. These measurements can identify internal cracks or other near-surface defects that cannot be detected visually. These defects can be correlated to the shape of the tooling (e.g., punch shape). “Given this information, one can optimize the shape of the punch in order to minimize internal defects or avoid the formation of areas prone to chipping or capping,” explains Gonzalez.


  Current research is adding to the understanding of how adhesive forces and particle interactions cause sticking, and researchers are building models to elucidate sticking mechanisms. Results will be used to find better solutions to sticking problems by optimizing tooling and, eventually, improving API and drug-product formulations. 

. 37 (2) 36-37 (2013). 
  2.	J. Markarian, Equipment & Processing Report (EPR), “Researchers Seek Solutions to Tablet Sticking”, online, Aug. 21, 2013, 

, accessed Sept 6, 2013.
  3. 	M. Mullarney, B. MacDonald, and A. Hutchins, 

. 36 (1) 57-62 (2012).
  4.	M. Gonzalez and A. M. Cuitino,

Screening methods and predictive models address tenacious tablet-sticking problems.

Tablet Sticking Solutions

To enhance FDA’s ongoing efforts to prevent and resolve drug shortages, the agency released a strategic plan and issued a proposed rule requiring certain manufacturers to notify the agency of supply disruptions, FDA announced in a 

. The strategic plan, called for in the FDA Safety and Innovation Act (FDASIA) of 2012, aims to improve the agency’s response to imminent or existing shortages and outlines longer-term approaches for addressing the underlying manufacturing and quality issues that are most often the root cause of drug shortages.

According to the strategic plan, actions FDA will undertake to improve its current efforts to respond to early notifications of a potential shortage include improving communications, clarifying manufacturers’ roles and responsibilities, and updating internal FDA procedures. Longer-term actions to address underlying manufacturing and quality issues include: broader use of manufacturing metrics to assist in the evaluation of manufacturing quality as well as incentives for high-quality manufacturing; internal organization improvements to focus on quality, which would include a proposed Office of Pharmaceutical Quality within the Center for Drug Evaluation and Research (CDER); and risk-based approaches to identify early warning signals for manufacturing and quality problems, the agency reported in the press release.

 requiring all manufacturers of certain medically important prescription drugs to notify FDA of a permanent discontinuance or a temporary interruption of manufacturing likely to disrupt their supply. The rule extends this requirement to manufacturers of medically important biologic products. The proposed rule will be published on Nov. 4, 2013 and will be open to 

The proposed rule implements the expanded early notification requirements included in FDASIA.  “The complex issue of drug shortages continues to be a high priority for the FDA, and early notification is a critical tool that helps mitigate or prevent looming shortages,” said Janet Woodcock, director of CDER in the press release. “The FDA continues to take all steps it can within its authority, but the FDA alone cannot solve shortages. Success depends upon a commitment from all stakeholders.”   Early notification gives FDA time to work with manufacturers to investigate the issue leading to the manufacturing disruption, identify other manufacturers who can make up all or part of the shortfall, and expedite inspections and reviews of submissions from manufacturers of drugs that may prevent or mitigate a shortage, explained FDA. 

 Early notification from manufacturers about possible shortages, as requested in the President’s Executive Order 13588 of Oct. 31, 2011 and then codified into law in FDASIA, has increased sixfold since the issue of the executive order, which has resulted in progress in addressing shortages, said FDA in the press release. The FDA helped prevent 195 drug shortages in 2011 and 282 drug shortages in 2012, leading to a reduced number of new shortages in 2012. The expanded early notification requirements would further enhance the FDA’s ability to address issues prior to the occurrence of a shortage.

FDA releases a strategic plan and issues a proposed notification rule to improve prevention and resolution of drug shortage problems.