High-Purity Processing Demands Contamination Control and Containment

Advanced technologies help pharmaceutical and semiconductor producers achieve excellence

Chemical processors are under increased pressure to achieve operational excellence, which involves a balance of increasing yield, improving quality and reducing waste, while also cutting operational costs. Processors in high-purity industries face these same challenges, but have an additional set of requirements centered around sterility and safety of the process, operators and products, which makes achieving operational excellence even more difficult.

At the same time, trends in the pharmaceutical and semiconductor industries — namely more potent active pharmaceutical ingredients (APIs) for pharmaceutical producers and a growing demand to increase yield by avoiding contamination for semiconductor manufacturers — are leading to the development of equipment aimed at helping pharmaceutical and semiconductor producers edge closer to their operational goals.

“In pharmaceutical and semiconductor production, the goal is to create a clean and safe environment, which means avoiding contamination across all stages of the process,” says Sven Falk, IoT digital product developer and data engineer with Bausch+Ströbel (Ilshofen, Germany; www.bausch-stroebel.com). “Both industries produce products with a very high value, so they need to waste as little as possible and operate in the most efficient way. Achieving this comes down to engineering, training, turnkey solutions and data analytics, which together create safe, clean and reliable production that produces the purest products at the lowest cost.”

Pharma production excellence

“The pharmaceutical industry shares the same pressures as other processors, but there are additional aspects, including the safety of products and operators,” says Dominick Eugster, head of sales and marketing with WAB-Group (Muttenz, Switzerland; www.wab-group.com). [Processors] “must produce in a sterile environment in sterile machines. After production, clean-in-place (CIP) technologies must be able to achieve 100% purity to prevent cross contamination between products and to prevent operators from making contact with traces of product left in the machine.”

Additionally, the introduction of more potent APIs and targeted medications, such as antibody drug conjugates (ADCs) for cancer treatment, require reliable containment solutions to protect the product from contaminants and operators from exposure.

“Producers of ADCs and other potent therapies do not want workers exposed to these products, so they are looking for containment and isolation solutions with higher containment levels,” says Norwin Voegeli, president of Lugaia USA (Ponte Vedra Beach, Fla.; www.lugaia.com).

Stephen Sirabian, executive vice president with Glatt Air Techniques (Ramsey, N.J.; www.glatt.com) agrees: “In pharmaceutical processing, the value of the product, as well as the potential toxicity, may demand very high containment standards, sometimes down to the nanogram level. This sets a high bar in terms of mechanical design and the industry’s validation and qualification requirements make it much more involved.

“Most requirements can be overcome with available technology,” continues Sirabian. “But the challenges lie in increased cost, complexity and operational procedures. For example, equipment running acetaminophen will look different from equipment processing a hormone. While the core process equipment looks similar, the ability to clean-in-place or wash-in-place the components and isolate the process from the operators and environment will require extra equipment in terms of tanks, pumps, valving and controls. There are established engineering solutions for this, but it complicates the design and operation of the facility.”

To address these challenges, equipment providers are developing solutions that maintain high levels of purity and efficiency throughout all stages of pharmaceutical production, helping processors achieve their operational goals.

For example, in closed processes where workers manually manipulate multiple potent APIs or powdered raw materials, work with smaller quantities or frequently change processes, a flexible isolation system may be an ideal solution, says Lugaia USA’s Voegeli. “Traditional rigid isolators protect employees and prevent contamination of very expensive ingredients, but if the processor frequently changes products, they must thoroughly clean and revalidate the isolator between products. That takes a lot of time,” Voegeli explains. “However, our SafeFlex Isolator, allows users to dismantle and dispose of the plastic isolator, install a new one and begin working on another process without having to go through the cleaning and revalidation steps. This is much faster than working with a rigid isolator and increases efficiency while protecting the safety of the product and employee.”

Lugaia’s flexible isolators (Figure 1) are customized to meet specific requirements. They are designed with easy-to-use tabs and snap fasteners. The magnetic base plate on the bottom of the isolators provides a fixed and level platform. Optional ventilation technology enables pressure testing. After operation approval, the dust-free docking of containers can be started.

During operation, the isolator is in negative pressure with constant air exchange. When a production batch is completed and the isolator needs to be replaced, the negative pressure is interrupted and the enclosed air is evacuated. The isolator can then be removed and disposed. The isolator can be equipped with customer-specific docking, special gloves and continuous liners for inward and outward transfer of equipment and product. Direct connections to machines and systems can be implemented as well.

And, when it comes to efficiently processing powders that must remain free of contamination and be contained, WAB-Group’s Turbula 3-D shaker mixer (Figure 2) offers high-quality mixing in shorter timeframes, while meeting the highest requirements for safety. Designed for use in high-purity industries, the mixing process takes place in a completely closed container, so the process is free of contamination and the machine does not come into contact with the product, preventing product contamination. Additionally, it offers safe operation via the “ready-to-load” function, which moves the mixing basket to the loading position directly after the mixer stops, helping to meet safety requirements and preventing operator exposure.

Sirabian from Glatt agrees that avoiding contamination and exposure are high priorities: “To avoid cross-contamination and achieve the required safety for the workers on the processes, especially at interfaces, solutions must be able to control to very low acceptable concentrations, which go down to less than 0.1µg/m³ (the concentration obtained when diluting a sugar cube in ten Empire State Buildings).”

Glatt’s split butterfly-valve technology incorporated into their TKS valve allows these low concentrations when a product is transferred from an intermediate bulk container (IBC) to a process machine. The split butterfly valve features a valve disc that is essentially split in half, with the passive valve half at the IBC and the active half with all the necessary actuators on the processor. The two halves are docked and locked together so material transfer can be done safely as the inside surfaces that see the environment never contact the powder.

And, as the need for containment grows with the advent of higher-potency APIs, there is also a trend toward reducing interfaces between various process steps. “Although it is now easier to minimize the dust concentration at an interface using technologies such as split butterfly valves, the trend is to combine individual machines into groups to minimize the number of interfaces,” says Michael Maintok, business development manager key technologies with Glatt Air Techniques. “This led to the development of completely new machines, such as the Glatt TwinPro, which combines the tasks of the granulator and the fluidized-bed dryer in one machine.”

Because it fuses two processes, the Glatt TwinPro (Figure 3) offers a system for total containment applications thanks to a significant minimization of material loss. The TwinPro reduces complexity and maximizes functionality for efficient operation. The functional construction facilitates easy and safe product handling, while smooth, seamless surfaces reduce contamination and ensure optimal cleaning.

Pharmaceutical processors must provide the same high levels of purity for the product and safety for operators, while also increasing throughput during the filling, closing and primary packaging of drugs that have a sterile requirement, says Giacomo Guidi, R&D isolation manager with IMA Life, part of the IMA Group (Ozzano dell’Emilia, Italy; www.ima.it). “At this stage of production, there is a focus on quality and safety, but also on productivity to keep a very high throughput rate so plants may achieve operational excellence,” he explains.

Bausch+Ströbel’s Falk adds: “In the pharmaceutical industry, the first goal is to provide consumers with safe products at affordable prices. Additionally, pharmaceutical production and filling processes create medicines that may be very expensive, so producing batches that can safely be sold is critical. They need to achieve the highest levels of manufacturing excellence to ensure that every batch can go out and, by doing that, less waste is created and it is more cost-effective.”

For this reason, the use of advanced automated equipment is increasing. IMA Life offers a variety of automated aseptic filling and packaging solutions. “For example, the Nebula solution is able to execute continuous decontamination of Ready-to-Use (RTU) material to be introduced inside the aseptic area,” says Guidi.

The high-speed decontamination tunnel manages tubs and trays containing RTU material as they enter and transit isolated production lines in continuous mode. The Nebula platform (Figure 4) integrates seamlessly with IMA LIFE aseptic fill-finish lines. Six-log decontamination is achieved over the entire external packaging surface using aerodynamic containment of highly concentrated vapor phase hydrogen peroxide (HC-VPHP), while material crosses the tunnel in a matter of seconds. This allows for continuous, high-speed tub introduction, up to six per minute.

And the company’s Injecta 36 solution is a robotic fill-finish machine, with some models capable of filling up to 36,000 syringes, vials or pre-capped cartridges per hour. The Injecta series is designed to handle pre-sterilized RTU containers, pre-oriented vials in trays and sterilized vials from the depyrogenation tunnel, allowing flexibility and adaptability. Specialized robots perform all handling activities with no glass-to-glass contact and without operator intervention, resulting in less time spent validating aseptic conditions and agility for multi-product manufacturing.

In addition to automated equipment and turnkey solutions, data analytics play a crucial role in high-purity pharmaceutical applications. “There is a trend toward really looking at and using data,” explains Bausch+Ströbel’s Falk. “Processors understand that they must contextualize the data to obtain information that generates enough insight to create a report that can be used to determine if a batch of medicine can be released to the market so that quality and safety are improved. Additionally, data is used to understand the health of the machine to encourage reliability, uptime and overall equipment effectiveness (OEE). These two things come together to help processors reach the highest level of operational excellence.”

Bausch+Ströbel’s Omnia platform includes a holistic approach to data analytics for the company’s pharmaceutical production machines. The modular software encourages machine system IoT readiness and assists users digitally to solve problems and malfunctions faster, ensuring the intelligent connectivity of machines and data, which helps enhance OEE.

Under the Omnia platform is the IoT Gateway, Omnia Connect, which enables faster integration of the machine into higher-level systems. Standard protocols ensure users are equipped for data-driven production by enabling manufacturer-independent data exchange.

Omnia Pi (Figure 5), based on the Aveva Pi Data Historian, is also essential to ensuring uptime and reliability of the equipment and process. The module supports processors with GMP (good manufacturing practices) and process monitoring, automatic troubleshooting support and advanced efficiency, as well as maintenance assessments. Monitoring process data is crucial for successful production and subsequent batch release, including key factors such as temperatures in the sterilization zone and weight values measured at the filling station. Continuous monitoring of process-critical data allows for early identification of deviations from target values. By adjusting production parameters within the permitted range, rejects can be prevented.

“The overall effectiveness of high-purity processing is not just in the equipment, but also in supporting the entire data journey from the machine to the higher-level systems, which enables processors to derive, analyze and understand information from the machines so they can achieve the highest levels of operational excellence,” says Falk. “Additionally, collaboration between machine constructors and pharmaceutical processors is crucial for ensuring efficiency, innovation and delivery of high-quality products, which will further the achievement of operational excellence.

Semiconductor manufacturing

Purity is also essential to achieving operational excellence when producing semiconductors. In this industry, the cost of contamination of the chemicals used in the manufacture of semiconductors is very significant, as is losing yield due to contamination, says Steve Rau, senior technical advisor with Edlon Inc. (Avondale, Pa.), a GMM Pfaudler company (Mumbai, India; www.gmmpfaudler.com). “In this industry, the name of the game is chemical purity and contamination control,” he says. “In the early days of semiconductor development, parts per million levels of contamination was considered pure, but today’s semiconductor fabricators are designing chip sets in line widths below 10 nanometers in order to pack higher densities of processing power into their chip designs, which demands the use of ultra-high-purity chemicals at the level of parts per trillion, so everyone between the chemical production plant and the end user fabrication facility needs to ensure that nothing contributes inorganic contaminants into the stream.

“Success in this industry is all about avoiding contamination, because even the slightest contaminant can impact the quality of the wafers and chips and reduce the yield — a major concern in semiconductor fabs [fabrication facilities],” he continues. “The cost of low yield is unbelievably high because the cost of making them is very high.”

To help ensure purity, the chemistries must be tested for contaminants at every step. “Before chemistries are shipped to the fab, when they are received, when they go into bulk storage, when they go into the day tanks and finally when they are delivered to the process tools, they are tested to ensure they are free of particles and have maintained the highest levels of purity,” says Rau.

One of the best ways to avoid contamination is to ensure that all equipment is built for reliability using materials of construction (MOC) that do not contribute to contamination, says Hisham Abu Samra, product and sales manager with Edlon. “When manufacturing tanks or other equipment for the chemistries used in semiconductor production, you can’t build with glass, stainless steel or Hastelloy because they are too ‘dirty’ and many of the process chemicals used in the chip process will attack these MOCs” says Samra. “Fluoropolymers have proven to be the material of choice.”

“Fluoropolymers are very inert molecules that won’t corrode or contribute contaminants into the chemicals, which makes them one of a few acceptable materials of construction in this industry,” says Rau. “In fact, fluoropolymers clean up with time and are a unique class of materials that gets cleaner the longer it is in service.”

Edlon offers fluoropolymer linings and coatings for process vessels and storage tanks that are used along the value chain for the chemicals that go into semiconductor fabrication. Due to their low ion-particle shedding and chemical inertness, Edlon’s fluoropolymer technologies are the materials of choice for semiconductor suppliers and manufacturers that must remove the last traces of metal ions, silicate and particulate contamination.

The company’s Secure & Pure products (Figure 6) are constructed using high-purity manufacturing skills, such as PureFusion seaming for loose linings and bonded linings, thick ultra-pure electrostatically applied fluoropolymer coatings, rotomolding/rotolining, vacuum forming and thermoforming and machining. Each technology uses a proprietary fabrication technique to ensure maximum levels of product purity while resisting chemical corrosion.

Fluoropolymer equipment for the semiconductor industry is made using cleanroom fabrication techniques and is cleaned with 18MΩ semiconductor-grade deionized (DI)water systems and lint-free wipes to ensure the highest levels of purity so that semiconductor fabrication facilities can avoid contamination, increase yields and achieve operational excellence.