A major pharmaceutical micronizing company needed a mobile, high-containment isolation system suitable for housing 4-, 8-, 12-, or 15-in. micronizing jet-mill systems during the loading, milling, and offloading processes. The company consulted Telstar’s technology center in Dewsbury, United Kingdom, for help with this large project, which involved several engineering challenges.

Milling and micronization operations sometimes involve the size reduction of highly potent active pharmaceutical ingredients (APIs). The company’s system therefore needed to reduce the operator exposure level to less than 1 µg/m

 throughout the operation, and above background levels, with defined sequences of operations (SOPs).

Such containment systems must allow the operator to conduct normal operations successfully using gloves. Operators also must be able to clean the isolator and milling equipment in an enclosed environment while wearing gloves. Ergonomic trials play a major role in ensuring that the final design is the best possible solution for operation and provides a high level of containment.

The company’s micronizing mills varied greatly with regard to size, weight, air consumption, and product usage. The 4-in. mill weighed approximately 10 kg and consumed air at a rate of about 125 m

/h at 120 psi. The 15-in. mill weighed more than 50 kg, and its air consumption was roughly 760 m

/h at 120 psi. In addition, the equipment associated with each mill (e.g., mill support, product feeder, product-feed hopper, air-supply pipes, controls, and outfeed product bag) had to be housed and contained.

Telstar and the company discussed various proposals regarding the containment system’s design and operation, and the final plan was to create a three-chamber mobile isolator with a main chamber that could house any of the mills and associated equipment. The 4-in. mill could operate independently in this isolator. The 8-, 12-, and 15-in. mills, however, required a large, fixed, three-chamber cyclone isolator connected to the mobile isolator to handle the large airflows and product discharges. 

The three-chamber mobile micronizing isolator incorporated a transfer chamber, a micronizing chamber, and a discharge chamber. It was designed to provide a high containment barrier for each size of micronizing mill when personnel loaded, micronized or milled, and offloaded APIs. The isolator limited operator and environmental exposure to the API to less than 1 µg/m

 throughout the operation, and above background levels, when defined SOPs were followed. Controls allowed personnel to monitor and adjust the environmental conditions inside the isolator through the various modes of operation. 

A drum-docking system was fitted to the transfer chamber and sealed with an inflatable seal to enable personnel to load raw-material drums. A small weigh scale was included within the main chamber for measuring samples, and a safe-change pass-out port also was added so that samples could be passed out safely. A larger weigh scale was fitted in the discharge chamber for weighing the milled product, and a safe-change connection port also was added to enable a safe-change pipe to be connected between the mobile isolator and the cyclone isolator when necessary. Wash guns and spray balls were provided to enable safe cleaning of the isolator after use.

The three-chamber fixed-cyclone isolator consisted of a filter sock–cyclone hopper chamber, a middle rotavalve chamber, and a lower discharge chamber. The fixed-cyclone isolator was designed to provide a high-containment barrier when connected to the mobile micronizing isolator during the offloading of APIs. Operator and environmental exposure was limited to less than 1 µg/m

 throughout the operation, and above background levels, when defined SOPs were followed. Isolator controls let personnel monitor and control the environmental conditions inside the isolator. 

A rotary valve was fitted between the cyclone and discharge sections to enable exact amounts of product to be discharged without intervention. A safe-change connection port also was added to the cyclone chamber to enable a safe-change pipe to be connected between the mobile isolator and the cyclone isolator when necessary. Safe-change pass-out ports also were added to the sock chamber and middle chamber so that samples and waste bags could be passed out safely. A large weigh scale was fitted in the discharge chamber for weighing the milled product, and wash guns and spray balls were provided to ensure safe cleaning of the isolator after use. To enable access to all parts of the 18-ft tall cyclone isolator, various access platforms and stairs were integrated into the construction.

A drum lifter tipper was provided to assist the loading of large drums of product into the isolator. The drum lifter tipper lifts the drums and docks them onto the transfer chamber of the mobile isolator through an inflatable seal to prevent operator exposure. Personnel can remove the drum lid from inside the chamber and transfer product safely into the isolator. Some of the mills weighed more than 50 kg and were difficult to lift into the isolator. To overcome this challenge, the drum lifter was given a flat lift bed that enabled the mill to be loaded safely from the floor to the correct height.

The company was pleased with the results of this large, bespoke, and challenging high-containment project. The team proclaimed the effort a huge success.

John Hargreaves is a project engineer in Telstar’s Technology Centre for Containment Systems in the UK (Telstar ACE),

Articles

In the Mixer

A major pharmaceutical micronizing company consulted Telstar when it needed a mobile, high-containment isolation system suitable for housing 4-, 8-, 12-, or 15-in. micronizing jet-mill systems during the loading, milling, and offloading processes.

A High-Containment Isolation System for Micronizing Jet Milling

Q: My drug failed a light-obscuration test, but after I filtered the drug for microscopic particle counting, I couldn’t see any significant particulate on the filter. What might have caused the failure, and why is it not visible?

A: One possibility is that what caused the failure was not solid particulate. A light-obscuration test can respond to droplets of suspended liquid (e.g., silicone oil in an aqueous product or water in an oil-based product), or even to air bubbles, as if they were solid, discrete particles. Air bubbles, of course, vanish completely upon filtration, water evaporates, and residual oil typically is not visible on the standard mixed-cellulose ester (MCE) filters used for 

 <788> microscopic particle counts. Even on a membrane filter made of a smooth material such as polycarbonate, oil residue from a filtered product may not be visible. 

The other possibility is that solid particulate was present in the liquid, but that its morphology prevents it from being seen easily on the filter. Very fine precipitates, as opposed to randomly sourced environmental particles, may be difficult, if not impossible, to see on an MCE filter because of its surface texture. Even on a smooth membrane filter, very fine particulate may form a layer that is too thin to be seen readily with ordinary oblique top lighting, even at a low angle. The same difficulties can occur with the stringy or amorphous precipitates that form in proteinaceous drug products, or with thin flakes of glass delamination. Using a smooth-surfaced membrane filter and a microscope equipped with episcopic or coaxial illumination (i.e., light directed down through the objective at a 90° angle to the filter surface) will allow particulates of these types, not apparent under other conditions, to be adequately visualized. 

—Scott Stoeffler, senior research microscopist at McCrone Associates

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Troubleshooting

My drug failed a light-obscuration test, but after I filtered the drug for microscopic particle counting, I couldn?t see any significant particulate on the filter. What might have caused the failure, and why is it not visible?

Invisible Particulate

Pharmaceutical companies historically have had confidence in the safety of their nonsterile drugs. The products are made through processes generally regarded as reliable and well established. But developments during the past several years have led many industry professionals to question whether these dosage forms are being produced in a state of control. 

In September 2001, Greenstone Brand glyburide tablets were recalled because raw materials used to make them had been contaminated with fungal organisms. Drugmakers gradually perceived a trend of similar problems during the years following that incident. The most recent, and high-profile, example occurred in April 2010, when Johnson & Johnson recalled lots of children’s liquid medications, including Tylenol and Benadryl. This recall was prompted by the discovery that raw materials used to make the products had been contaminated with gram-negative bacteria. 

Other factors have increased attention to contamination in nonsterile drugs as well. The industry has noted a growing emphasis on inhaled formulations and dermatological products, both of which carry potentially higher risks to the patient than other dosage forms. In addition, the patient base has expanded to include more individuals with potentially compromised immune systems, such as infants and elderly people, than before.

These considerations have helped generate broad support among manufacturers for enhancing environmental-monitoring programs and finding ways to reduce the risk of microbial contamination in nonsterile manufacturing suites. The US Pharmacopeia (USP) Expert Committee on Microbiology is nearing completion of an informational chapter that will provide general guidance on the development of an environmental-control program for nonsterile production suites. And the International Organization for Standardization’s working group 209 is rewriting the ISO 14698 standards for biocontamination control. 

Although drugmakers have begun to perform environmental monitoring in their nonsterile manufacturing facilities, many companies are uncertain about how to interpret the data and develop alert and action levels, says Leonard W. Mestrandrea, principal consultant at Mestrandrea Consulting and chair of the aforementioned USP subcommittee. The industry should record the types and numbers of microorganisms that it identifies in its environmental-monitoring programs and evaluate the information on a quarterly basis, he says. This strategy could provide guidance, based on scientific rationale, for assessing and controlling the risk of contamination.

Not everyone is convinced that the problem is urgent, however. “I don’t think a scientific reason for increased emphasis on nonsterile product monitoring has been established,” says James E. Akers, president of Akers Kennedy and Associates. Given that companies monitor aseptic environments, it might seem logical that they should monitor nonsterile product environments as well, but “it would be the rare nonsterile product that would require comprehensive microbiological monitoring,” says Akers. “Fundamentally, microbial risk to the patient in the use of nonsterile products is low. There may be good reason to make certain nonsterile drugs administered to high-risk patient categories in controlled environments, but generalizing this requirement to all nonsterile drugs would simply add to the cost of these products with no real public-health benefit.” 

For this reason, “the consensus among expert microbiologists is that microbiological environmental-control level recommendations would be of little benefit for the vast majority of nonsterile products,” says Akers. Many in the industry question the need to change the current practice of nonsterile drug manufacturing. Some fear that if companies tightened their controls, it would trigger a “regulatory spiral” that inevitably would increase environmental monitoring with no real benefit to the manufacturer or the end user, says Akers.

Good quality programs do not require activities unless they have value to the end user, and the question of contamination in nonsterile manufacturing suites should be analyzed thoroughly from a risk- and science-based perspective, says Akers. Any requirements should be based on data derived from assessment of risk and should result in well-designed processing systems with control points defined to mitigate risk. “The focus should be on reducing risk in processing, not on bug hunting,” says Akers.

So far, no regulatory authority has set formal microbial-control standards for the manufacture of nonsterile dosage forms. FDA’s policy is that individual firms must establish the environmental controls necessary for these products, according to a spokesperson for the agency’s Division of Manufacturing and Product Quality. Even after USP publishes its informational chapter titled “Microbiological Control Programs for Manufacturing Non-Sterile Pharmaceutical Drug Product,” individual companies will be free to strengthen their own monitoring regimes or not, according to their own judgments. The debate about the need for enhanced control and monitoring of nonsterile products likely will continue, but both sides seem to agree that decisions ultimately should be based on an analysis of products’ risk to the patient.

Production Lines

Developments during the past several years have led many industry professionals to question whether nonsterile dosage forms are being produced in a state of control.

Manufacturers Recalibrate Microbial Control for Nonsterile Drugs

Alfa Laval
 Diaphragm valve provides long service life


 Alfa Laval’s Unique Diaphragm Valve is designed for aseptic, ultrahygienic, and sterile processes. The valve’s actuator can be fitted with various automation and control units that feature a compact design and facilitate conversion of the control function. The actuator also permits users to adjust the spring pressure to protect the diaphragm against excessive stress. In addition, the manual valves incorporate adjustable overclosure protection. These features help to prolong the life of the diaphragm and increase uptime. 

The T- and tank-outlet valves are available in block and forged versions. The forged version weighs approximately 60% less than conventional T- and tank-outlet valve bodies, according to the company. The valves’ light weight makes them quick to heat up during heat sterilization and minimizes the need for piping support of the system. Alfa Laval manufactures the valve with high-quality components, including valve bodies with low delta-ferrite content and diaphragms for continuous-steam applications. 

GE Healthcare
 Chromatography media enable high throughput


GE Healthcare’s Capto SP ImpRes cation exchangers and Capto Q ImpRes anion exchangers are designed for final biopharmaceutical purification processes. The products are based on a rigid agarose matrix that enables high flow rates, thus increasing volume throughput and reducing processing times. The rigid matrix also allows personnel to use high bed heights and small column diameters that can reduce the equipment’s footprint. The products’ ability to run at high flow rates and high bed heights gives users flexibility in process design.

The media’s small bead size (~40 µm) helps users achieve high resolution. The SP and Q ligands are intended to ensure predictable performance and robust processing. The ligands also are compatible with common downstream-purification buffers and are identical to those in GE Healthcare’s other ion-exchange media. The high resolution is intended to provide high purity and high yields.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the February 2011 edition from Alfa Laval and GE Healthcare.

Equipment and Processing Report-02-16-2011

A High-Containment Isolation System for Micronizing Jet Milling

Invisible Particulate

Manufacturers Recalibrate Microbial Control for Nonsterile Drugs

February 2011 Editor's Picks: Products from Alfa Laval and GE Healthcare