	Analyzing the rheology or flow behavior of materials involves evaluating initial movement to flow under different conditions to a final state when flow ceases and the material holds its final position.  Whether the product is a liquid, cream, paste, or powder, flow analysis is needed to show the product’s ability to pump, mix, transfer, store, and fill. Use of pharmaceutical products by humans also requires flow analysis because the consumer will use a variety of actions to spread ointments, chew pills, and swallow liquids.


	Scientists use flow curves to show how materials move. The control parameter that causes movement for liquids and semi-solids is shear rate, which can be graphed vs. resistance to movement (i.e., viscosity or shear stress as shown in 

	Using a cone/plate rheometer, shown in 

, a sample is placed on the plate, which is temperature controlled, and the cone spindle with its virtually flat bottom comes down to make contact. The instrument has the capability of shearing the material over a continuously broad range of shear stresses and/or shear rates and can handle many types of materials, ranging from thin liquids (e.g., eye solutions) to viscous semi-solids (e.g., petroleum jelly and other skin ointments). A rheometer can perform a battery of tests, such as yield stress measurement when the material is at rest, full viscosity flow curve with thixotropy calculation (i.e., time sensitivity to being sheared) when the material is in motion, creep/recovery (i.e., low force flow behavior), and temperature profiling (i.e., how the viscosity property changes with temperature).


	For powders in a bin or containment vessel, consolidating stress is the driving force and reflects the self-weight of the powder pushing down on the material in the hopper section to force it out the bottom. 

 shows a graph of consolidation stress vs. resistance to movement (i.e., failure strength). 

	The data in this graph are measured using a standard flow function test with a powder flow tester and a shear cell, as shown in 

A powder sample is placed in the trough which then sits on a turntable in the powder flow tester. The lid (vane-type with pockets) comes down on top of the trough and compresses the powder. The trough rotates through a very small angle and measures the frictional force between powder particles in the trough and those trapped in the vane pockets. This measurement analyzes the force needed to allow relative movement between particles (i.e., flow discharge out the bottom of the hopper in a bin or containment vessel).

	Most hoppers operate in “core” or “funnel” flow. The material at the topmost level in the hopper moves down through the center of the hopper and discharges before the material around the outside, so that the last powder put into the hopper is the first to discharge. The material around the outside experiences some degree of compaction while it waits its turn to flow out. Sometimes, this compaction may be sufficient to prevent the powder from discharging when its turn finally comes to start flowing. Powder testing can predict this degree of compaction (i.e., rathole diameter) as well as the “arching dimension”, which is a prediction of whether the powder has enough strength to bridge the hopper opening. These numbers can be helpful in determining whether the hopper will experience flow problems.


	Robert G. McGregor is general manager, Global Marketing & High-End Lab Instrument Sales at Brookfield Engineering Laboratories, 

, tel: 1.508.946.6200, fax: 1.508.946.6262, 

Articles

Troubleshooting

A rheometer and powder flow tester can measure how pharmaceutical materials, such as powders from a hopper, flow.

Understanding the Flow Behavior of Materials

	Improving manufacturing efficiency and quality are high priorities, and new technologies-including continuous manufacturing and data analytics-can help the pharmaceutical "facility of the future" achieve these goals, said experts at a recent International Society for Pharmaceutical Engineering (ISPE) event held by the New Jersey and Delaware Valley ISPE Chapters (Princeton, NJ, Sept. 30, 2015).

	"Big data analytics will help the industry to focus on what's important," suggested James Breen, vice-president of Worldwide Engineering & Technical Operations at Johnson & Johnson and member of the ISPE International Leadership Forum. The supply chain is one crucial area for the pharmaceutical industry that can be helped by data analytics. "Slow-moving, obsolete inventory is a big problem and an opportunity for change," said Breen.

	Next-generation facilities need to be more flexible and agile to reduce inventory by more quickly adapting to market demand, using technologies such as modular manufacturing systems and continuous processing. For example, the Portable Continuous Miniature Modular (PCMM) system-built as a collaboration between Pfizer, G-Con, and GEA-is a standardized platform that allow production on demand of flexible batch sizes, explained Rick Mitzner, senior director, Pfizer Global Engineering, in a presentation at the ISPE event. A PCMM was assembled in a Pfizer warehouse in only four days, and the project duration was 14 months from kickoff to delivery. Pfizer envisions an even more accelerated timeframe for future assemblies built with standard modules.

	"The PCMM is targeted for low to mid-volumes in areas such as orphan drugs or oncology," noted Mitzner. The portability of the system, which is built in containers (i.e., PODs), allows a company to recover assets should it close a facility and enables in-country manufacturing without green-field construction, he noted. Another significant benefit is technical transfer. Using the PCMM for clinical (Phase II and Phase III) and commercial volumes streamlines scale-up.

	In biopharmaceutical manufacturing, continuous downstream processing is needed to handle the volumes coming from more highly productive upstream processes, with a smaller footprint and faster cycle times to reduce inventory, commented Bruce Snyder, director of process automation for IPS, at the ISPE event. Availability of the needed process analytical technology is a concern for bioprocesses, he noted. Another potential challenge is ensuring the mechanical reliability of single-use components for the timeframe of the process (e.g., 60 days). Process automation is a crucial piece of a continuous process. In a bioprocess using continuous multi-column chromatography, the output from this operation is technically discontinuous, but an intermediate container (e.g., a single-use bag) can be used to isolate the unit operations and allow a steady flow to the downstream operations, explained Snyder. Although equipment may be controlled by a variety of systems, a distributed control system is required to integrate the pieces in a continuous process, concluded Snyder. 

	Analysis of "big data" has many applications in the pharmaceutical industry, one of which is to improve risk assessment of manufacturing facilities. "Unstructured information from FDA- including 483s, inspection details, recalls, warning letters, and the 

-can be examined to help identify compliance risk and determine what problem areas to address first, to avoid past mistakes, or to audit vendors," explained Rafi Maslaton, president at cResults Consulting, in a presentation at the ISPE event. His company has developed a platform called FDAAWARE, which creates a database of these public data and uses software to analyze and extract useful information, in conjunction with an advanced projection algorithm to assess specific sites and overall company compliance related risks.

Employing continuous manufacturing and data analytics will help improve the efficiency of pharmaceutical manufacturing in the facility of the future.

Giving a Boost to the Facility of the Future

	With attention from FDA and other regulatory agencies focused on visible particulates in parenteral drug products, the industry is actively working to find a solution. The problem is especially difficult to control because particulates can come from many sources, including external (people as well as secondary packaging), internal (primary packaging), and inherent (formed in the drug product solution) (1). The challenge of achieving zero visible defects (i.e., particulates) in parenteral drugs will require a coordinated effort at all stages of the supply chain, particularly in the production and filling of primary containers.

	"Zero particulates will require a dramatic shift in how the industry operates," said Chris Sellards, general manager for Schott's glass packaging manufacturing, in a presentation at Schott's Forum for Ready-to-Use Solutions in Aseptic Manufacturing. "Lean, six-sigma, and Kaizen [continuous improvement activities] can't be only buzzwords, but must be how we do business every day." The goal of "engineering by design" (the component-suppliers' equivalent to a drug-product manufacturer's quality by design) is to first prevent problems, beginning with the glass tubing and extending through container conversion to fill/finish. Proper design requires understanding how the container will be used. "For example, with the use of camera inspection, the way the bottom of the container is formed is now more important than it was 10 years ago. We have tight control of the tooling to minimize dimensional defects for both the crown and the bottom of the container," noted Sellards.    

	West Pharmaceutical Services, which manufactures packaging components for injectable drugs, is working to decrease particulates by partnering with their suppliers and by adding automation wherever possible, explained Peggy Frandolig, director of technical customer support, Pharmaceutical Packaging Systems, North America, at West, in a presentation at the same conference. West's NovaPure product line of stoppers is supplied with both visible and subvisible particle specifications. Using a quality-by-design process, West chose the best of current materials and designs and added additional control strategies to meet the narrower specifications of this product line.

	Another new technology that helps reduce particulates is nested vials, which prevents the glass-to-glass contact that occurs with traditional bulk processing. Although syringes (for prefilled syringes) are commonly supplied as ready to use in nested tubs, the deployment of ready-to-use, nested vials is just beginning. Schott developed nests for different sized vials, using the standard industry tub to allow use in existing equipment, explained Gregor Deutschle, product manager for Schott, at the conference. Schott's adaptiQ RTU vials will be available in nests by the end of 2015 for some sizes, with other sizes available in 2016. The vials can be lyophilized without being removed from the nest, as Benjamin Kammerich, product manager at GEA Lyophil, demonstrated in a case study at the conference. In addition, new, RayDyLyo push-fit, vial caps for RTU nested vials from A. Raymond offer advantages in the lyophilization closure process, including eliminating the crimping process, which can generate particles.

Packaging

The challenge of achieving zero visible defects (i.e., particulates) in parenteral drugs will require a coordinated effort at all stages of the supply chain, particularly in the production and filling of primary containers.

Equipment and Processing Report-10-21-2015

Understanding the Flow Behavior of Materials

Giving a Boost to the Facility of the Future

Partnering to Address Particulates