Nanoparticles are gaining the pharmaceutical industry’s attention as research and practical experience demonstrate their many uses. Among other applications, nanoparticles have proven suitable for anticancer medications and microarray platforms for genomics and proteomics. The oral, parenteral, transdermal, transmucosal, ocular, and pulmonary drug-delivery routes can effectively use nanoparticles, and implants can incorporate these particles, too. In a 2007 study, research firm Freedonia Group concluded that demand for nanotech-based medical supplies and devices in the US will exceed a value of $110 billion by 2016.


  Creating nanoparticles can be challenging and requires appropriate equipment and techniques. Broadly speaking, nanoparticles are substances that are smaller than 100 nm. In the pharmaceutical industry, the term applies to substances as large as 500 nm. Media milling or grinding is the best-established manufacturing method for nanoparticle production. Its many benefits include:

Equipment scalability from benchtop to production

Limited or no contamination of the active ingredient

Fulfillment of current good manufacturing practice production requirements.

Fine-bead mills are popular because of their simplicity and scalability. These machines are less expensive than alternative technologies (e.g., precipitation process techniques) and are often used in conjunction with plasma-gas process techniques. With the proper stabilizing agents, bead mills efficiently disperse output to discrete, submicrometer particle-size, stable dispersion (see Figure 1). 

In bead mills, impact and shearing forces between moving beads grind suspended solid particles. The agitator shaft within the machine’s stator housing transmits kinetic energy to the grinding media.

Stress intensity and the number of contact points are the main factors that determine particle fineness. Stress intensity is influenced by the kinetic energy in the grinding beads. To produce a fine particle-size distribution, a process must have a high number of contact points. The smaller the grinding media, the more contact points touch the product. The rule of thumb is that particle size is equal to 1/1000 the size of the grinding media.

Achieving repeatable nanoparticle dispersions


  Creating repeatable distributions of submicrometer-sized particles is essential for effective formulations. But nanoparticles’ tremendous surface areas and energy make it difficult to disperse them in liquids. Economically creating stable nanoparticle suspensions or dispersions requires a comminution process, which grinds particles into a fine particle-size distribution range, using 70–125-µm beads. This process, known as mild dispersion, relies on multiple mild contacts instead of one strong contact that could break or destroy the particles.

As bead size decreases, the stand-off distance (i.e., the space between the beads) decreases. Reduced stand-off distance works as a filtering mechanism that holds back large agglomerates and breaks them apart. The stand-off distance is roughly 44 µm for 1-mm beads and about 2 µm for 0.05-mm beads. Using 70–125-µm beads yields a stand-off distance of about 4 µm. Mild dispersion uses small beads that provide a small stand-off distance, thus holding back large particles and shearing them apart to their primary (i.e., nonagglomerated) size. This technique ensures particle-size uniformity, reduces particle damage, and maintains productive work speeds.


  Selecting appropriate equipment is key to developing a repeatable process and creating an efficient workflow from the laboratory to full-scale production. New mills use beads as small as 100 µm in diameter and offer enhanced functionality such as an improved media-separation system and an ergonomic machine design for easy disassembly for cleaning. New mills also facilitate adequate product throughput at slow, low-energy motor speeds, thus preventing particle damage.

The ideal mill has “plug flow,” which refers to a hydraulic condition where all the molecules or particles move through the bead mill at a uniform velocity. Plug flow thus maintains a uniform grind and residence time. On the other hand, turbulence (i.e., intermixing between the grinding zones) in bead mills usually means that particles mix at a broad velocity range and requires manufacturers to perform rapid multiple-pass operations to achieve a narrow particle-size distribution (see Figure 2). 

Selecting suitable construction materials for the grinding media and chamber prevents batch contamination. Grinding-zone parts made entirely of yttria zirconia, a high-strength ceramic, offer metal- and contamination-free grinding. Grinding beads made of plastic, glass, ceramics such as aluminum oxide and zirconium oxide, steel, and tungsten carbide are also available. 

With the right media milling equipment, researchers can cost-effectively create nanoparticles for drug delivery that are uniform and readily available. The advantages of working with nanoparticles will help reduce the time and cost of product development while improving drug performance and patient outcomes.

Harry Way is a technical director, and Chris Esterly is a pharmaceutical sales specialist at NETZSCH Fine Particle Technology.

Articles

In the Mixer

Creating nanoparticles can be challenging and requires appropriate equipment and techniques. Media milling or grinding is the best-established manufacturing method for nanoparticle production.

The Challenges of Manufacturing Nanoparticles through Media Milling

More and more, pharmaceutical companies are choosing to outsource their manufacturing projects. This trend is likely to continue for the foreseeable future. To reap the full benefits of this strategy, a drug company must evaluate the performance of its contract manufacturing organizations (CMOs) and determine whether it meets industry and regulatory standards. Quality and compliance information are particularly important to this evaluation.

A pharmaceutical company’s information technology (IT) infrastructure could potentially facilitate the appraisal of CMO performance. A drug company’s enterprise resource planning (ERP) system is the system of record for regulatory purposes, says Jim Sabogal, vice-president of the life-sciences industry business unit at SAP America (Newtown Square, PA). This designation is based on the fact that batch information, quality information, and information relating to good manufacturing practices are stored as part of an ERP system’s record. 

Yet ERP systems historically have been “transactional in nature, and not necessarily built to manage your value network,” comments Hussain Mooraj, research director in healthcare and life sciences at AMR Research (Boston, MA). ERP systems have traditionally focused on a few indicators such as timeliness of delivery and overlooked quality and compliance data.

But the IT environment is changing. SAP’s “Manufacturing Integration and Intelligence” (MII) development platform appears to provide a way for pharmaceutical companies to tap their ERP systems’ previously unused potential. Mooraj calls the MII platform a toolkit that could allow pharmaceutical companies to build an interface for exchanging quality and compliance information with their CMOs. The product helps integrate enterprise-level applications with operational systems such as manufacturing execution systems (MES) and laboratory information management systems (LIMS), even if the latter are not SAP systems.

The MII solution enables integration between a pharmaceutical manufacturer’s ERP and a CMO’s plant-floor systems. MII extracts data about orders, quality, and yield from the CMO’s plant-floor systems (e.g., MES and LIMS) to compute composite metrics such as overall equipment effectiveness, says Andy Dé, senior director of solutions marketing in life sciences at SAP. The solution presents the data to the sponsor company within the context of a role-based dashboard that can be configured to suit the needs of various manufacturing roles. Thus, the MII platform allows monitoring, exception management, and performance management in near-real time.

Using the MII solution does present challenges, however. MII lacks a packaged approach to application life-cycle maintenance and management, Mooraj observes. Nor does the platform contain plug-and-play reporting or analytical applications. Because CMOs’ IT infrastructures differ widely, a pharmaceutical company must use the MII toolkit to custom build the integration with its CMO. “Essentially, you are using MII to build out software,” Mooraj explains.

This strategy has been adopted and executed successfully in other industries. For example, aerospace manufacturer Pratt and Whitney (East Hartford, CT) is using MII to exchange quality and compliance information with its CMOs, says Mooraj.

But so far, no life-science company has taken this approach to CMO monitoring. One reason that the pharmaceutical industry lags behind in this respect could be that it is highly regulated. Additions to pharmaceutical companies’ IT infrastructure must be validated. But in some cases, US Food and Drug Administration rules are ambiguous, and whether a particular application must be validated is sometimes open to interpretation. This confusion discourages the acceptance of IT innovations within the pharmaceutical industry. 

Still, intense competition and the growth in pharmaceutical outsourcing could persuade drugmakers to embrace new IT applications that enable the evaluation of CMO performance. To realize outsourcing’s potential to lower costs, a pharmaceutical company “better have an IT system that fully automates data flow back and forth,” says Sabogal. IT strategies can reduce the potential for human error and provide sponsor companies visibility into their CMOs’ operations.

The MII platform is a solution with good potential, Mooraj admits. But to realize that potential, companies must overcome their resistance to new technologies and accept the added work that the strategy entails.

Production Lines

A pharmaceutical company's information-technology infrastructure could facilitate the appraisal of the performance of contract manufacturing organizations.

IT Strategies for Evaluating CMO Performance

Parker Fluid Control Division 
 Valves provide high flow and long life


 Parker Fluid Control Division (New Britain, CT) offers its high-flow line of NAMUR valves for direct mounting to pneumatic actuators. The durable, compact valves control larger pharmaceutical process-control valves and actuators of all sizes.

 The patented sealing system of the high-flow series features a swimming O-ring design. This design allows valve sealing to increase proportionally as pressure increases. Regulating the seal contact pressure reduces seal wear and fosters long valve life and reliable switching. The valves have a life expectancy of 5 million cycles.

 Built with an anodized aluminum body and a stainless steel spool, the new solenoid valves feature internal parts made of brass. The valves are designed for direct mounting in any position on a NAMUR interface. These high-flow devices operate in a 22–150-psi pressure range.

Watson-Marlow Bredel 
 Pump operates at laboratory and production scales


 Watson-Marlow Bredel (Wilmington, MA) has introduced its “520Di” pump for filtration, fermentation, and dispensing applications. The machine’s ramp-and-drip feature enables a soft start and graduated dosing to reduce splashing and foaming while the product is being pumped. Users can perform periodic dose recalibration without disturbing the flow of the batch.

The 520Di device is suitable for laboratory applications such as preparing benchtop media and reagents. In addition, the unit can accurately perform production-scale filling of pharmaceuticals and biopharmaceuticals. The 520Di machine can perform batch dispensing and automatic or single-shot dispensing of sensitive fluids in sanitary environments. 

Watson-Marlow Bredel’s 520Di pump accepts eight different tubing materials and tube sizes as large as 9.6 mm. The device operates at flow rates ranging from 4 µL/min to 3.5 L/min at pressures as high as 100 psi. 

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the July 2008 edition from Parker Fluid Control Division and Watson-Marlow Bredel.

Equipment and Processing Report-07-16-2008

The Challenges of Manufacturing Nanoparticles through Media Milling

IT Strategies for Evaluating CMO Performance

July 2008 Editor's Picks: Parker Fluid Control Division and Watson-Marlow Bredel