Pharma Feels Good

From Allegra to Zantac, there’s a veritable cornucopia of available pharmaceuticals that alleviate conditions ranging from hay fever to heartburn. That being said, there still remain many conditions and serious diseases for which there are no answers. But frankly, that means a steady source of work for those involved behind the scenes of developing and producing new drugs, including the architects and engineers who design these facilities.

“Things are booming,” said Scott Simpson, with Stubbins Assocs. Architects, Cambridge, Mass., a firm heavily involved in R&D facilities.

Such a state of activity and sense of optimism is seemingly odd given fairly recent headlines declaring that production on arthritis wonder drugs Celebrex and Vioxx have been halted due to unexpected side effects.

An economic analysis of key manufacturing sectors by Technology Review, an MIT publication, also painted a not-so-rosy picture. “If there is a single industry in our indices that needs pain relief, it is biotechnology and pharmaceuticals,” declared the magazine.

Specifically, the publication noted that many big pharma stocks have taken turns “receiving poundings” due to a combination of business models deemed past their prime and biotech R&D progressing more slowly than the market had hoped.

These occurrences have created roadblocks, admits Simpson, but he maintains they’re not enough to stop the overall surge of the sector. “There have been some hits—Vioxx and the like—but there’s still plenty of steam in the business,” he said. “And that’s because it really is a business that carries its own momentum.”

That assertation is confirmed in the findings of Technology Review’s report. Despite sputtering performance in the first quarter, the publication readily pointed out that the sector was still No. 1 in its TR Large Cap 100 index, experiencing a 3% gain; and No. 2 in its TR Small Cap 100, experiencing a 3.1% increase.

Simpson explains that’s because the sector very much mirrors the boom and residual strength of health-care construction. “There may no longer be a lot of large facilities still going up, but that doesn’t mean there’s not a lot of work going on,” said the architect.

This phenomenon is generated, in part, by the constant backlog of renovations and reconfigurations required just to stay up to speed with rapid developments on the R&D side.

“Novartis, one of our clients, is already doing a major renovation to a project we just completed in April of 2004,” said Simpson.

Another factor that’s sustaining pharmaceutical work, according to Simpson, is the fact that as long as there is a need to keep fighting diseases like cancer, there will be a need to develop and produce new drugs.

“Science is the real driver,” said Simpson. “So long as there are new innovations and new drugs, there will always be a demand for R&D facilities.”

For example, Harvard Medical School has made progress on a drug that might help people stave off cancer, cystic fibrosis and possibly even HIV. The drug, siRNA—small interfering RNA molecules—most simply explained, “turns off” specific disease-causing genes. If experiments remain successful, it could lead to a whole new class of drugs.

A third driver creating demand for new pharma products, according to George Lombardo, P.E., a vice president with Mineola, N.Y.-based Lizardos Engineering Assocs., is pure economics. “Once you have a pipeline product, all the generics can come out and the big pharmas take a hit,” he said.

Lombardo, whose firm specializes more on the manufacturing side of pharma for clients like Wyeth, agrees with Simpson that, overall, the market is sound, even if it has slowed—but that’s not such a bad thing.

“It has slowed down recently, but we look at that as a chance to really catch our breath,” joked Lombardo.

Seriously, he said, his firm has averaged a new project start per year since 1998, each on basically an 18-month schedule. But while they’re busy, and there’s no doubt the big drug companies are shelling out big bucks on R&D to stay competitive, Lombardo notes the big pharmas have not lost their eye for the bottom line—and that’s a key for A/Es who want to continue to stay busy.

“Pharma owners are very sensitive to cost savings because they need to reflect that to their stock holders,” concurred Simpson.

In fact, he readily notes that the business side has changed, with many owners now more interested with simply getting things up and running. “There’s less of a worry about signature facilities and more about speed. Our clients are really looking for ways to get things done,” said Simpson. “[In fact], we just finished a three-quarters of a million sq.-ft. facility for Novartis, and in just 24 months; it’s pretty amazing.”

Clients are often willing to pay a premium for such accelerated projects, added Lombardo, but for A/Es, it’s a double-edged sword.

“If you do a project on a super-fast-track schedule, say four months, now there’s pressure to do it even faster,” he said.

And besides doing it faster, owners are looking to their consultants to help them save money where possible, including energy efficiency. This is particularly a challenge, noted Lombardo, in that pharma manufacturing facilities are required by Federal Drug Administration mandate to employ Good Manufacturing Practices. On the HVAC side, this means HEPA filters and once-through air schemes where air is immediately exhausted. Given the latter, Lombardo said options on the HVAC side are limited. More efficient chillers are one answer, but Lombardo, a LEED-accredited engineer, said they’ve actually discovered more opportunities experimenting with water.

For example, one way Lizardos cuts down on the pre-cooling requirements for AHUs is by employing an economizer cycle for cooling tower water.

“Basically, we take the cooling tower water and run it through a plate-frame heat exchanger,” said Lombardo.

The firm also tries to take advantage of free cooling where and when possible, including winter-chilled water. But because pharmaceutical manufacturing is so water intensive, he said, there are lots of opportunities for conservation, such as reclaiming distillate. Of course, anytime one works with distillate, special stainless steel tanks and appropriate piping are required, so at the end of the day, “money still talks.”

That said, Lombardo said a number of pharmas are biting the bullet and spending the money in the hope of achieving LEED.

“LEED still tends to be more on the commercial side, but we’re making some headway on the manufacturing side and I think the potential is great just from the PR side alone,” said Lombardo.

Elsewhere, Lizardos is also considering on-site wastewater treatment.

Validate me, please

But water conservation isn’t the only efficiency being employed. The firm is also adding more efficient lighting and more automated lighting controls.

“Controls are a huge factor,” said Lombardo. “But a lot depends on whether it’s [governing] a validated or non-validated system.”

“Validated,” for the record, means a part of the manufacturing process is strictly monitored and documented according to GMP guidelines. In fact, if any single word describes pharma manufacturing, it’s “validation,” according to Jens Feddern, vertical market manager with the Building Technologies Group of Zurich-based Siemens.

Speaking on the pharma market at Siemen’s last international press forum, Feddern said it’s all about GMP.

“The pharma industry is regulated like no other,” he stated. “Compliance is a must.”

And this is the point where R&D and manufacturing facilities really diverge. According to Lombardo, R&D operations involve researchers trying to accomplish the widest array of possibilities. Therefore, designers must account for the greatest flexibility possible. In the case of HVAC, this means a mechanical designer might have to provide air movement that ranges anywhere from 100 cfm to 3,000 cfm, depending on whether the particular part of the building is a lab, an office or something else.

A well-conceived building automation system can go a long way in facilitating such varying demands, but that solution, said Lombardo, doesn’t readily transfer to the manufacturing side.

“There, you’re designing for the actual process itself, meaning there is a much tighter range of requirements,” he said.

Typically, he said, that might only involve a range of 1,000 cfm to 1,500 cfm, which is great news for most mechanical system designers. The trouble is that the standard BAS one uses in commercial and institutional facilities can’t meet GMP requirements. “The rule of thumb is, if it’s a validated GPM room it’s going to be controlled by PLCs,” he said.

Furthermore, non-validated areas, such as office space or the R&D labs themselves, said Lombardo, frequently aren’t in the same building as the manufacturing operation or even on the same campus for that matter.

“More often, you’ll really have two separate systems that will have separate head ends,” he said.

It boils down to data integrity, according to Feddern. He pointed to a case in Denmark where a facility had to destroy an entire batch of insulin because the documentation simply wasn’t there.

Reliability, adds Lombardo, is equally critical. “If you’re in the middle of spraying tablets and the coating pan stops rotating, you end up with a clump that you have to throw away,” he said. “So the plants want everything on emergency power.”

That includes the SCADA systems that control production, which Lombardo said are backed by UPS. “And we’re talking about going beyond just being able to ride it out. You need at least a 30-minute window on that SCADA system because you have to document everything—temperatures, flow rates, etc. It’s all FDA driven.”

Even AHUs for cleanrooms, said Lombardo, must be on emergency power, which is typically provided via 1,500-kW generators. “If a clean room goes down for whatever reason, it’s almost a week-long process to get it back up,” he said.

No gambling on fire and security

Beyond equipment, GMP forces pharmas to adopt an integrated risk-management plan.

From start to finish, Feddern said it typically takes 10 to 15 years to bring a new drug to market. “But once you do, you have only five to seven years to bring it into business. So when you enter production is critical.”

For example, Feddern’s group has known companies that built plants in Singapore that are now empty, because the drugs, ultimately, were not approved.

In no other industry, he emphasized, is the need for risk management more acute. And perhaps no other industry provides a better argument for integrating life-safety, security and building controls.

In his presentation, Feddern ran through a risk matrix the company developed to measure the probability of an incident vs. its impact on operations. Using this model, he presented a scenario in which faulty data integrity, a false fire alarm and a security breach might affect a facility. He also presented possible solutions.

Regarding the possibility of a false fire alarm, according to his matrix, Feddern said the probability is fairly high, meaning there’s a high potential that an operation could be shut down and the product lost. To minimize this risk, a custom fire-protection system could be designed for each clean room where sensors on custom algorithms could better identify whether the alarm is indeed smoke, fire or something else. Plants can also be broken into zones to contain fires and minimize overall impact.

As for a security breach, where someone tries to contaminate raw materials, what’s the risk and what can be done?

Besides a halt in production, Feddern said there’s a huge risk to a company’s reputation and possibly litigation. Potential solutions might involve installing strict access control directly in the materials storage and similarly vulnerable areas. Video surveillance in these same areas would also go a long way in lowering both the risk of occurrence and loss of production.

Finally, regarding the integrity of data, besides the back up power measures, Feddern said the following can be employed:

• A professional monitoring solution.

• Use of backup strategies.

• Installing alarm solutions to address faults.

Identifying critical areas, critical systems and potential preventive measures from the get-go will go a long way in keeping facilities running.

Specifically, according to Feddern, the checklist should include:

• Identify the real needs of each manufacturing installation in regard to building infrastructure.

• Identify inherent potential risks of the infrastructure; effectiveness of the planned action and acceptance criteria.

• Identify the action necessary (technical, organizational, structural) to reduce the risks.

• Optimize the effort expended to reduce the risks to an acceptable level.

• Justify the solution and relevant documentation.

• Concentrate on fundamental risks.

Of course, integrating these systems into a whole at an early stage, in Feddern’s opinion, best serves the client.

“An integrated and flexible risk management methodology, namely the graduated rating of the probability of an occurrence and its impact on operations and the environment, is suitable for this purpose,” he said. “But the quality of the information depends on how thoroughly familiar the relevant risk managers are with the operating processes and technical functions of the plant infrastructure.”

In the end, carefully planned risk management eliminates surprises. And indeed, Feddern joked that GMP really means “Give me paper.” But the good news is that implementing systems as outlined will automatically do that. And that, ultimately, will make a lot of pharma owners feel good.

New Plant Priority In an effort to promote greater energy efficiency in process facilities, particularly chemical plants, the U.S. Dept. of Energy, Office of Energy Efficiency and Renewable Energy, has issued an announcement seeking applications for cost-shared research, development and demonstration of innovative energy systems that can be widely applied throughout the industry. Areas to be addressed include energy conversion, energy recovery and crosscutting and systems applications. Energy systems are defined as those technologies that produce or transport energy to the process or recycle waste energy streams. Studies show that of the approximate 5.07 quads (10 E15 BTUs) of primary energy consumed annually by the U.S. chemical industry, only about 2.2 quads of heat and power is directly utilized in processes. The document can be downloaded at www.grants.gov or at DOE’s e-Center at https://e-center.doe.gov . Lessons Learned: Lowering H 2 O Loss Fact: pharmaceutical manufacturing is a water-intensive process. Fact: pharmaceutical manufacturing is an energy-intensive process. Fiction: Owners of such facilities don’t care about saving energy and water. “Energy is always an issue,” said George Lombardo, P.E., a vice president with Mineola, N.Y.-based Lizardos Engineering. The problem is that due to strict GMP guidelines, pharmaceuctical facilities typically require once-through air distribution schemes, making it difficult to find low-hanging fruit on the HVAC side. The good news is that water conservation is not as difficult. “A lot of distillate gets dumped down the drain in water-for-injection (WFI) facilities,” said Lombardo. “It’s the same with the wash-down process as well.” One way his firm has been able to recover some of that water is to pump water coming off stills into a storage tank where it can be sent directly to a deaerator for boiler water because it’s already heated. Such water can also be used for cooling towers. Of course, doing so means specialty piping and tanks are required.

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