It’s easy for pharmaceutical professionals to be absorbed in the particular part of the manufacturing process for which they’re directly responsible. Operators concentrate on keeping their segment of the production process running smoothly. But the whole manufacturing line can be improved, even before production begins, if technology transfer is implemented thoughtfully. Effective technology transfer helps to provide process efficiency and control and maintain product quality.

Technology transfer contributes Quality-by-Design (QbD) principles by identifying critical quality attributes, the key manufacturing parameters that affect those attributes, and ways to control those manufacturing parameters, according to Paul Wlodarczyk, vice-president of solutions consulting for 

A company’s development department plays an important role in this process, he adds. Development personnel help identify critical process parameters as part of a general recipe. The process parameters are thus associated with a certain set of manufacturing actions specified for equipment and materials classes, says Wlodarczyk.

A general recipe can be converted into a master recipe for batch control in a specific plant at a given scale. “This conversion is a matter of identifying which recipe parameters are sensitive to scale and replacing class-based parameters with instance-based parameters,” Wlodarczyk explains. 

Ideally, development and manufacturing teams share a common information model for process definitions. “This model would capture process definitions and parameters in a machine-readable format that can be rendered into documents for human interactions,” Wlodarczyk says.

Technology transfer then brings QbD limits and definitions from development to the manufacturing process, explains Mike Power, life-science supply-chain manager at 

 (Mclean, VA). When systems such as enterprise resource planning and laboratory information management are linked to development-process knowledge, says Power, the transfer is accomplished quickly without human error. 

Startup and process definitions directly affect manufacturing yield and waste, Power notes. When technology transfer transmits QbD limits and definitions to manufacturing, “waste is reduced by eliminating trial and error in setting up the process,” he says. By giving manufacturers complete knowledge of the process and a framework for continuous improvement, technology transfer improves yields.

In several ways, technology transfer enables continuous improvement of the manufacturing process. After ensuring that the process is clearly defined with general recipes, technology transfer sets the stage for recipe harmonization. Recipe harmonization, the use of common formats for all recipes across the product life cycle, forms a basis for process-knowledge management, says Wlodarczyk.

In turn, harmonization allows operators to define and reuse repeatable manufacturing actions, which are the building blocks of recipes. This process, recipe normalization, “provides a mechanism for continuous improvement,” he adds.

When technology transfer is performed correctly, it benefits all stages of a product’s life cycle. To begin with, “technology transfer, combined with QbD and programmatic interfaces to commercial manufacturing systems, greatly reduces time to market,” Power says.

Wlodarczyk agrees. “Effective technology transfer affects time to market most during the 12–48-month period it takes to scale up from pilot to commercial scale,” he explains. Recipe harmonization and normalization can reduce the time to achieve commercial-scale production by months, he adds.

Once their product enters the market, manufacturers must scale production up or down during their products’ lives in the marketplace and according to customer demand. “Each time there is a change in scale, there is technology transfer,” Wlodarczyk points out. Technology transfer “is critical for achieving rapid scale-up with control over how the manufacturing process is achieved,” he says.

Effective technology transfer is particularly important when conveying manufacturing-process knowledge about current products to contract manufacturers. “By using recipe-based process definitions, outsourcers can better prescribe not just what to make but how to make it, including control over critical and key parameters,” Wlodarczyk observes.

If a pharmaceutical company gathers process knowledge, communicates it internally, and keeps it current, it has great control over its manufacturing process. By efficiently managing process knowledge, technology transfer provides this control and ensures high-quality products

Articles

Production Lines

A manufacturing line can be improved if technology transfer is implemented thoughtfully. Effective technology transfer helps to provide process efficiency and control and maintain product quality.

Technology Transfer Provides Manufacturing-Process Control

Leistritz
 Extruder processes small batches

 
 The “Nano-16” twin-screw extruder from Leistritz (Somerville, NJ) incorporates a microplunger feeder that enables the unit to process 20–100-g batches. Charles Martin, general manager of Leistritz, explains that the microplunger feeder, a piston, uses positive displacement to feed small samples consistently at low rates. The extruder’s staging of unit operations and feeding are similar to those of a continuous process, Martin says. The machine runs continuously at rates ≤1000 g/h.

 The device’s gearbox can drive 18- or 16-mm screws. Using a 16-mm screw produces an OD/ID ratio of 1.18 and a free volume of 0.9 cm3/diameter. The low free volume decreases the material’s residence time at low rates in the instrument, says Martin.

 Unlike many small-volume extruders, the Nano-16 machine produces results that are scalable to production levels. The unit matches the shear rates of typical production-scale extruders, Martin says. 
 

Millrock Technology
 Freeze dryer is hydrogen-peroxide sterilizable


 Millrock Technology’s (Kingston, NY) “Max” series freeze dryers feature an option that enable them to be sterilized with hydrogen peroxide. T.N. Thompson, president of Millrock, says that this validatable sterilization method is more cost effective than steam sterilization because it requires no additional equipment. In addition, hydrogen-peroxide sterilization achieves “the same log reduction in biological activity” as steam sterilization, says Thompson.

 Unlike comparable products, the Max series freeze dryers feature programmable logic control. Thompson notes that many machines this size incorporate microprocessor control instead, which is more limited. The machines can be provided with 21 

 Part 11 software to meet regulatory requirements.

 of shelf area and a maximum condensing capacity of 30 L. Biotechnology firms can perform sterile production runs with the Max series units, Thompson says.

This issue of Equipment & Processing Report features products from Leistritz and Millrock Technology

April 2008 Editor's Picks: Leistritz and Millrock Technology

Pharmaceutical companies today must produce an increasing variety of products while continuing to meet regulatory demands. In addition, competition within the industry has become more acute. Dave Drew, group pharmaceutical director of Matcon (Moreton-in-Marsh, UK), says that lean production is essential for drugmakers to survive in the current environment.

In his presentation at INTERPHEX (Mar. 26–28), titled “Efficient Material Handling Is the Key to Lean Manufacturing,” Drew recognized that the pharmaceutical industry has unique requirements. He emphasized, however, that its manufacturing challenges can be addressed by lessons that the food, cosmetic, and automotive industries have already learned.

Drew explained that the lean manufacturing philosophy is based on the principles of eliminating waste, reducing inventory, and producing high-quality products efficiently and economically. To achieve lean manufacturing, companies should adopt a “pull” production model, according to Drew. The pull model is based on performing continuous production to meet customer demand, rather than to increase inventory in storage. Pull production requires short lead times and facilitates continuous improvement.

One of the challenges a pharmaceutical company faces, Drew noted, is that a new drug application “locks in manufacturing operations” with regulators before the company can find the optimum manufacturing process. Fortunately, regulators are emphasizing process analytical technology (PAT), which helps producers improve, monitor, and control the process in real time. This constant improvement maintains high quality and facilitates lean manufacturing. Controlling the process is critical, Drew observed, because “Quality cannot be inspected into the product.” 

One important attribute of lean manufacturing is continuous production. Continuous processes proceed without interruption and use automation to reduce human error. In the pharmaceutical industry, compression and packaging are already continuous operations.

Drew turned to the automotive industry for an example of a lean manufacturing process. Toyota manufactures a “batch” of components in parallel and assembles them “in a continuous, timely manner,” he said. The production line only retrieves parts that have been used up, and only parts that have been retrieved are produced and replenished. This organization minimizes waste by producing based on customer demand.

Drug companies can take a parallel approach to batch mixing to achieve continuous, multiproduct production. This approach uses intermediate bulk containers (IBCs) and IBC mixers when production increases, thereby providing flexibility to the process. 

A continuous process, Drew explained, requires a buffer hopper that stores enough product to keep the process in operation and allow sufficient time for manual or automated changing of IBCs. These IBCs can be used on a batch basis with processes such as dispensing and blending, provided the production rate does not starve any of the continuous processes. Operators can use a mixture of batch and continuous methods to monitor product quality.

To achieve lean blending of single products, Drew recommended continuous mixing in a Y- or double-cone blender. These blenders are also appropriate for long campaigns, he remarked. An IBC blender, however, is the best choice for multiproduct production. Y-cone and IBC blenders provide great flexibility, Drew added, but IBC blenders require no cleaning and present less segregation risk.

Drew assessed the relative merits of wet and dry granulation. He noted that wet granulation is expensive and time consuming, making it “the weakest link” in the process. Yet wet granulation is highly effective and presents minimal solids-handling risk. Dry granulation requires only one-quarter of the capital and operating cost of wet granulation, but it presents the risk of bridging and packing at process interfaces. A controlled feed to the dry-granulation process from the IBC is critical in overcoming this risk, Drew said.

Typical pharmaceutical solids-handling problems that affect lean manufacturing include bridging in IBCs, chutes, and infeed hoppers. In addition, flow control in mills, sieves, and roller compactors is sometimes difficult, Drew observed. 

One solution is for IBCs to be fitted with active cone valves that rise into the product and break bridges. Operators can achieve an adjustable flow rate by continuously moving the cone valve up and down. “This method of operation provides a controlled feed to the process and prevents blockage of interconnecting chutes and processes,” Drew explained.

The segregation of blended solids in the discharge from blenders, tablet-press infeed, and capsule fillers can be solved by using IBCs for mass flow and venting displaced air correctly. PAT will not solve these problems, Drew warned.

In the Mixer

Dave Drew, group pharmaceutical director of Matcon (Moreton-in-Marsh, UK), says that lean production is essential for drugmakers to survive in the current environment.

Equipment and Processing Report-04-16-2008

Technology Transfer Provides Manufacturing-Process Control

April 2008 Editor's Picks: Leistritz and Millrock Technology

Lean Manufacturing Begins with Efficient Material Handling