The current economic crisis will undoubtedly spur pharmaceutical firms to curb spending. One strategy that may help achieve this goal is to incorporate process analytical technology (PAT) into manufacturing processes. PAT may reduce costs by helping companies control process variability, improve yields, reduce waste, and produce high-quality therapies consistently. Companies that have not yet embraced PAT may find its potential to reduce expenses a compelling argument in its favor during this time of financial difficulty.

Analytical tools such as near-infrared (NIR) spectroscopy enable PAT to enhance process understanding and control, but they require analytical expertise. “A high-level analytical scientist should be involved in designing, developing, and implementing a PAT system,” say Duncan Low, scientific executive director, and Cenk Undey, principal engineer, both at Amgen (Thousand Oaks, CA). And, laboratory professionals will need training to understand process instruments, process-sampling systems, and data-acquisition systems used in the manufacturing process, says Rod Woods, director of PAT at MannKind (Valencia, CA). 

In addition, PAT “frequently uses statistical tools that chemists and engineers generally don’t use,” Woods cautions, including modeling techniques such as principal components analysis and multiple linear regression. Teaching people the tools is easy, he says, but normally requires additional learning from experience with the statistical method and with the application. The model for the application must be refined through experience and accumulated data. 

For each analytical instrument installed on a production line, a company must have a scientist who understands the data it collects. Online testing “creates an overwhelming amount of data, and you can very quickly get lost in it,” adds Jason Kamm, principal at Tunnell Consulting. “You need skilled people who can read the spectra and understand what’s important and what’s not.”

The challenge of using PAT may not be as daunting as it seems, given that most pharmaceutical companies have the necessary knowledge to implement it. Many firms already use NIR and other analytical devices in quality-assurance and research applications. The industry has a pool of experienced chemists and engineers who can interpret analytical data, says Woods. “PAT implementation will go ahead despite the fact that it requires a skilled scientist to implement,” says Low. 

Using PAT to make decisions and adjust a manufacturing process doesn’t require as much analytical expertise as does implementing PAT initially. “Once the PAT application is fully developed in a commercial environment, process operators frequently make their go–no-go decisions on simplified graphic or alphanumeric output,” Woods explains. “The raw data from the application require only periodic review from the development group or people with suitable skills.” If standard maintenance procedures are in place, analytical experts need only be available for troubleshooting, say Low and Undey.  

On the other hand, a company needs extensive knowledge of the manufacturing process and PAT tools before it can use PAT applications to automatically control a process. Although this technique can provide fine control of difficult steps, it is a challenge that few manufacturers choose to confront, says Woods. Yet, applications such as chemical synthesis with unstable materials, keeping a continuous process in a state of control, and working with valuable actives might justify the cost and effort required for automatic control through PAT.

In the past, Big Pharma’s budgets have generally been large enough to compensate for waste and inefficiency in manufacturing processes. This may no longer be a viable strategy, given the faltering economy.

“I think PAT tools will become more necessary,” says Kamm. “If manufacturers are going to keep their costs down, enhance process understanding, and deal with regulatory constrictions in the new world, they’ll have to [adopt PAT tools].”

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Production Lines

PAT may reduce costs by helping companies control process variability, improve yields, reduce waste, and produce high-quality therapies consistently. Companies that have not yet embraced PAT may find its potential to reduce expenses a compelling argument in its favor during this time of financial difficulty.

A Propitious Period for PAT?


 The “Stratus” PTFE-lined silicone hose from ResistoPure (Marion, NC) features a flared-through design that eliminates the potential for entrapment. The hose incorporates one continuous piece of PTFE liner that is formed over the fitting ends. All of the hose’s wetted parts also are PTFE, which enables it to withstand steam cleaning and harsh cleaning solutions as well provide extended service life and a low cost of ownership.

In addition, because PTFE is a nonstick, low-friction material, it improves the hose’s drainability and reduces the potential that cleaning chemicals will contaminate high-value process streams. 
 The lightweight, flexible hose is appropriate for pharmaceutical and biopharmaceutical applications. The Stratus hose is available in diameters from 0.5 to 2 in.

Millipore
 System purifies water efficiently


 The “Elix Advantage” water-purification system from Millipore (Billerica, MA)

incorporates an ergonomically designed “E-POD” water dispenser that provides pressurized pure water on demand. Unlike traditional deionization systems, the Elix Advantage system uses a small electrical current to continually regenerate the resins in the Elix module. The E-POD provides manual and volumetric dispensing at flow rates as high as 2 L/min. The unit’s graphic display shows information such as water quality and system status. 

The system recirculates water from the storage vessel to the final dispensing point and back, treating it with ultraviolet light before it is stored in a reservoir. Various point-of-use filters can be installed in the E-POD to further purify water for specific applications. 

The Elix Advantage system recycles reject water across its reverse-osmosis membrane, thus reducing the amount of tap water needed to produce pure water and extending the life of pretreatment cartridges. The system uses 200 times less electricity than conventional distillation equipment, according to the company. 

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the November 2008 edition from ResistoPure and Millipore.

November 2008 Editor's Picks: Products from ResistoPure and Millipore

Final bulk inspection helps ensure the high quality of solid-dose pharmaceuticals. Until recently, automated inspection of solid-dose pharmaceuticals was crude, expensive, slow, and difficult to change over. But technological advances have ushered in a new class of vision-inspection systems that is more effective and more commercially viable than older systems.


For the past 20 years, the best technology for automated inspection has been single-file (or single-stream) optical-inspection systems. These systems are highly effective in detecting and ejecting defective products and foreign matter based on differences in size, shape, and color. Single-file inspection systems carry solid-dose products individually past cameras placed above them and alongside them. The system then turns products over to inspect their bottom surface. 

Despite its efficacy, this technology has not been widely adopted because of its limited commercial viability. The drawbacks of single-file optical-inspection systems include high capital costs, low throughput (often around 50,000 doses per hour), the need for many expensive change parts, and changeovers that take as long as eight hours. These systems are implemented only when the need to ensure the highest product quality outweighs other commercial considerations.


Although the first bulk optical-inspection system for pharmaceuticals was introduced recently, similar technology has been successfully adopted in a majority of the food-processing industry for more than 20 years. Similar to single-file optical-inspection systems, bulk optical-inspection systems effectively detect and remove defects and foreign matter based on differences in size, shape, and color, but they don’t require products to be oriented in a particular way before inspection. 

Bulk inspection systems feature excellent, high-resolution color cameras that detect subtle differences between tablets. The systems cost roughly one-third the price of single-file systems. Bulk optical-inspection systems also are more efficient than single-file systems. The former achieve throughputs as high as 1 million tablets or capsules per hour and can be cleared and cleaned in less than five minutes.

The benefits of bulk optical-inspection systems


A bulk optical-inspection system’s high-performance color cameras perform objective and consistent in-line inspection, thereby ensuring high final-product quality and maximizing production throughput. The system also provides many benefits unrelated to product quality such as reduced labor costs, faster changeovers, greater yield, reduced capital costs, and simplified operation. In addition, the system can be integrated with continuous size-grading, polishing, and packaging technology to provide a complete, continuous-processing solution.

As tablet and softgel dosage manufacturers automate their production lines, they are replacing batch processes with continuous processes because the latter reduce labor and work-in-process inventory. Bulk optical-inspection systems enable the shift to continuous processing and, when combined with other continuous components, achieve fully automated, high-throughput finishing lines.

In addition, modern bulk optical-inspection systems may potentially be part of a company’s efforts to incorporate manufacturing based on the US Food and Drug Administration’s process analytical technology initiative. Because the systems continuously capture real-time data about products on the line, they allow manufacturers to improve upstream operations.


To achieve the operational advantages described above, manufacturers must consider various criteria when selecting an optical-inspection system. A system must be validated to meet FDA requirements, including 21 

 11, and comply with good automated manufacturing practice guidelines. 

A system that offers ultrahigh resolution (i.e., 0.18 mm

 pixels) can detect and remove foreign capsules and those with small color and shape defects (e.g., air bubbles, stains, and deformities). A system with four cameras, located both above and below the product stream, views the product from all sides and provides excellent inspection. Such systems can examine as many as 1 million tablets per hour.

Bear in mind that the system’s effectiveness relies not only on its hardware, but also on its software. Algorithms that define acceptable and unacceptable product greatly influence system performance.

Equipment vendors should also be evaluated. Vendors’ experience and success with optical-inspection systems and the pharmaceutical industry indicate their ability to deliver systems that achieve optimal performance. Vendors should be able to help develop and execute the required qualification protocols. Manufacturers should also consider vendors’ services, including engineering, validation, and support.


Modern bulk vision-inspection systems designed specifically for solid-dose pharmaceuticals will likely assist the industry by enabling continuous processing. Because these systems ensure final-product quality and are commercially viable, both in terms of production throughput and capital costs, they appeal to product manufacturers and contract packagers that seek to deliver consistently high product quality and reduce operational expenses.

Jon Donovan is a product manager at Symetix, 150 Avery St., Walla Walla, WA 99362, tel. 509.394.3321, fax 509.394.3219, jdonovan@symetix.com.

In the Mixer

Until recently, automated inspection of solid-dose pharmaceuticals was crude, expensive, slow, and difficult to change over. But technological advances have ushered in a new class of vision-inspection systems that is more effective and more commercially viable than older systems.

Equipment and Processing Report-11-12-2008

A Propitious Period for PAT?

November 2008 Editor's Picks: Products from ResistoPure and Millipore

Quality Is in the Eye of the Inspection System