To that end, Abbott Laboratories are building two pilot plants: One in Germany to manufacture clinical supplies of injectable drugs for hospitals and doctors, and another in Lake County, Ill., to produce primarily oral solid dosages, along with some oral liquid formulations.

The Germany plant contains five interconnected laboratory suites in a 6,700-sf section of a larger building. Construction is completed, and the building is currently in the validation phase of the project. The Illinois facility, currently under construction, is a $53-million, 64,000-sf stand-alone building with eight major process suites, 8,900 sf designed to process potent drugs and 11,925 sf for standard drugs. The plant will enable up to 15 to 20 researchers; each suite can accommodate two researchers at a time.

Potent drugs were developed as a result of the mapping of the human genome, explains David McAlonan, senior program manager, Abbott Global Engineering Services. In the last five years alone, there has been a significant increase in the amount of potent compounds being developed within the pharmaceutical industry, which track proteins that lead to certain disease cells within the body. Because they are so targeted, the dosages require smaller quantities of drugs for the same beneficial effect.

Potent drugs are defined as pharmaceutical compounds that produce therapeutic effects with a clinical dose less than or equal to 10 mg per day.

In addition, there are drugs—largely cancer drugs—that are not considered to be potent by dose but must be handled as potent due to their toxicity. Drugs are handled inside isolators which are completely enclosed; the only way in is through glove ports.

Employee Exposure Limits (EELs) for people working with these potent compounds cannot exceed 10 micrograms per cubic meter on a time weighted average of eight hours.

“That is not a lot,” says McAlonan. “You wouldn’t even be able to see it. Many times you may not even test the air for these compounds, because devices are not capable of monitoring levels this low.”

The drugs are typically milled—ground as fine as baby powder—then filtered through a screen. Inhalation of dust is the biggest concern, but the liquid drugs are dangerous, as well.

“The Level 4 oncology drugs are extremely hazardous,” says McAlonan. “One drop on you can cause blistering on your skin and could have irreversible health effects.”

Abbott Leads the Way

McAlonan tried to compare data from Abbott’s pilot plants with benchmarking data from other companies’ projects.

“There were four companies with projects that were completed either on a one- or two-suite basis,” he says. “Abbott wanted to build an entire building dedicated to pharmaceutical research and development of potent drugs. We were looking for that level in the pharma industry and couldn’t find it. We were one of the first companies to build a stand-alone building dedicated to development of potent drugs compounds.”

The pilot plant suite with containment cost Abbott about $1,400/sf, including engineering and mechanical support, but not including equipment. Without containment, the cost dropped to about $900/sf. An R&D suite without containment cost about $600/sf, while office, warehouse, and mechanical areas cost less than $300/sf.

One feature that was common among all the companies was the amount of mechanical space required to support potent-drug containment. More that 50 percent of the total square footage is taken up by mechanical space, which makes sense considering that the equipment and the room itself are the employees’ major defenses against exposure to the toxic or potent compounds they make.

The HVAC that serves the potent drug suites is a once-through air design which exchanges the air 20 times per hour. Supply and exhaust systems are HEPA filtered, with a bag-in/bag-out change procedure from the contained rooms. The process rooms are under negative pressure and are separated by air locks. The rooms are designed to be cleaned by wiped down method rather than washed down. The rooms are designed with flush-mounted equipment, sloped easy-clean surfaces, and coved corners where walls and ceilings meet. All solid waste is containerized and shipped out as hazardous waste; liquid waste is collected, analyzed, and neutralized if necessary; everything else is decontaminated in the airlock before leaving the process suite. People will exit the suite through decontamination showers upon leaving the individual process suites.

Abbott will have a roll-around document isolator in the potent compound suites that contains pens and data logs, which the FDA requires in hard copy, signed by the operator. In the future, the batch records will be electronically recorded and the document isolators will be equipped with laptops. The laptops and the paper documents never are exposed to the process room.

“You don’t think about it, but you cannot bring paper in because you have to decontaminate the paper going out,” says McAlonan. “By the time you decontaminate it, it blurs all the writing on it.”

Mechanical access is from outside the potent areas, and the process equipment utilizes through-wall design as much as possible to minimize cleaning surfaces and maximize maintenance activities outside of cleanroom areas. Environmental monitoring includes the critical parameters of temperature, pressure, and relative humidity.

Taking a Cue from Biosafety Labs

Pharmaceutical companies approach the safety of their employees with the same philosophy as researchers who deal with deadly pathogens: “Everybody agrees that engineering controls are where it’s at,” says McAlonan. “You have to design the equipment, then the facility. The personal protective equipment adds a last layer of protection to the employee.

“Personal protective equipment is nothing more than a filter,” he adds. “You still have to have air pass through, and there’s no way it can protect you on a microgram level. And it leaves it up to the person to ensure how well they seal the suit and put on the respirator.”

The pharmaceutical industry has categorized the hygiene levels required for different drugs the same way federal health officials have assigned a BSL level to certain pathogens. Level 1 drugs, such as antibiotics, have an EEL limit of less than 100 micrograms per cubic meter, and require only standard controls and facilities, meaning a person can scoop the material and mill it using just a dust mask. Level 2 drugs can still be handled in a standard facility, but have EEL limits between 10 and 100 micrograms per cubic meter; they require partially contained transfers using sealed drums, because aspiration is more of a concern. Level 3 drugs are potent, with an EEL between 1 and 10 micrograms per cubic meter. They require contained equipment and transfers, and the facility must be contained and equipped with once-through air or local HEPA filters, HEPA exhaust, and decontamination showers. Level 4, the highest potency, with EEL less than 1 microgram per cubic meter, has all the restrictions of Level 3, but the drugs can be handled only within closed isolated systems.

“A lot of what we are doing with our potent drugs in the fourth category is very similar to what other labs are dealing with at BSL-4,” he says.

Facility air supply and return systems for potent drug containment are identical to those in BSL-3 and BSL-4 labs, except for two differences: Many pharmaceutical companies require employees to take decontamination showers upon leaving the cleanrooms, and they require that all materials, such as laptops and paper, be separated from the room by an air lock.

BSL labs also exchange the air 15 times per hour, while the pharmaceutical companies have a change rate of 20 times per hour.

“We have a great susceptibility to aerosolizing dust,” explains McAlonan. “Twenty is almost a baseline for us now for potent compound suites. I’ve seen numbers up to 30 so that we can make sure we have a good air sweep through the rooms. The problem is whenever you put equipment into the room it disrupts your airflow. We have to overcompensate in those cases.”

Transferring Technology

It is critical for a pharmaceutical research company to co-ordinate its technology and equipment with the technology and equipment that eventually will be used in commercial production. Something as simple as how the product is dried can affect its molecular structure. The FDA requires equivalency studies to prove that the different processes do not yield drugs with different efficacies.

“You cannot transition from a tray dryer to a fluid bed dryer to a microwave dryer without equivalency studies,” says McAlonan. “Those studies could take six months to a year. Consistent technology makes for an easy transition from R&D to commercial operations.”

McAlonan says the two most important lessons he learned in making key project decisions are:
• Define the containment philosophy. This drives the client expectations and the cost of the project significantly.
• Find the best Subject Matter Experts for the project team that are available from both inside and outside the company. That will save time and money.

By Lisa Wesel

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ISSN: 1096-4894