Contract Pharma editor-at-large Tom Spurgeon recently interviewed Andy Signore, chief executive officer and co-founder of IPS, a provider of design, construction, validation and commissioning of regulated facilities (www.ipsdb.com). We published an excerpt of the conversation in the October 2006 print issue. The full interview is here:
Contract Pharma: Is there any way you can qualify how important health, safety and environmental (HS&E) issues are for pharma companies wishing to build new manufacturing facilities?
Andy Signore: To start with, HS&E issues have always been a significant planning concern for pharmaceutical facilities. And they are becoming increasingly a greater planning dimension.
Most pharmaceutical companies have dedicated departments that not only look after their hygiene, their daily compliance with HS&E, but also contribute to new projects on a regular basis. It's important for obvious reasons, but clearly for registering new facilities and getting permits and complying with local, state and government codes. They become significant factors because of the possibilities of delays in getting such permits to operate and build.
From a more important vantage point, you have the day-to-day operation of these facilities and the absolute necessity to mitigate and/or totally avoid circumstances that could lead to anything from lost work accidents to exposures to noxious and/or toxic airborne materials, or any contact with materials that people handle or produce as a result of what they're doing in a factory. Then there are any of these accidental, unplanned releases from a facility that could cause harm to neighbors, wildlife and/or the general environmental eco-systems.
Here in the Pennsylvania area, there's a facility that had an unscheduled discharge of a very small amount of material, probably less than 50 gallons. It got into their sewer system, left the plant, got into the local stream, went downstream and killed lots of fish. It was a mess, from the adverse relations on through to the obvious harm that it caused. It takes million of dollars of money to remediate. Who knows what you do to your goodwill and relationship to the community?
So for lots of reasons, HS&E have always been an important part of pharma and biopharma companies -- if not always, than at least for 50 years and more. It's going to become more important because most of the new compounds are drugs that are going to be formulated are going to be even more toxic. They're very special. They're very complicated molecules that are targeted to certain remedies or therapeutic effect. It just turns out that when you characterize these compounds, you find out that they are higher order, complicated, and people can stand less and less exposure to them.
So, for example, the way that this affects the design of a facility includes issues like, "How are we going to contain?" In the business today there's a great deal of concern about containment and isolation. But actually what you're trying to do in one sense is contain or separate the bad stuff from the operators and the environment -- they call that containment. In the other sense you try to isolate and keep it from cross-contaminating any other products. You have a duel responsibility. From the HS&E standpoint, you contain. From a product quality and integrity issue, where you want to make sure the aspirin you take has nothing else in it that was being made in the next room, you isolate and/or separate.
So, HS&E is a big deal in our business.
CP: Is there anything in the regulatory landscape that has become a bigger issue in recent years?
AS: From the HS&E perspective, I'm not aware of any sea changes. There continues to be an organization called OSHA that looks after safety issues, the EPA and then state and local authorities. That is the predominant body of regulatory agencies.
As it relates to external or other guidance, prevalent practice, it is true that it's been changing, but mainly because of good business sense. The extra care has to be taken. The FDA, as an example, who doesn’t have a mandate to deal with HS&E issues but is mandated to guard and ensure products are safe, that it's efficacious to take, that it meets the claim you set. They seem to be more involved with the cost and the economy of it. But their fundamental mandate is safety and efficacy.
They are demanding more and more documentation and demonstration -- in the business they call it validation: that the products are of the highest integrity. So things like containment and isolation become part of their GMPs, and within the GMPs they talk specifically about practices to assure a product remains sterile, for example, with a process that yields a product that is acceptable to be injected into your veins. Or that oral doses -- pills and things that you can take orally -- aren't indeed contaminated by other products to which you might have allergic or other non-controlled contra-indications. So long story short is that the FDA doesn't have HS&E oversight, but by virtue of what they enforce for good manufacturing practices they are really in that business as well because they're looking to protect product. So you do things that way.
CP: It's almost as if you're describing an entire culture that makes pursuing HS&E goals easier because that of the values shared in protecting the environment and the product.
AS: I think in effect that it's easier but in some ways it's also more difficult. While the FDA in this case may be describing these mandates to achieve, they don't describe them in detail. So there's a great deal of interpretation of how to accomplish them. They set goals and then they leave it to the industry to accomplish this through their own means and methods. There's a fair amount of conversation constantly about the "interpretation" of GMPs. What is the prevailing practice, or prevailing acceptable practice? Are they indeed generally accepted as "good" in the sense of "wholesome"?
There's a good, healthy intellectual and professional world out here trying to interpret and apply GMPs to existing and novel processes. I don't mean to wander too far afield here, but certain technologies have been around for 30, 40, 60 years. Making a tablet, a coated tablet -- it's well understood, but not trivial. But how do you make a dissolvable filmstrip that you put on your tongue? What are the characteristics? Those are newer products, so now you have to try and understand how sensitive they are, and how to make sure they dissolve uniformly. How about an aerosol? How do you know that every squirt of an aerosol puts out a precisely metered dose of a drug delivery, so that the first squirt you put is as good as the 33rd or the 72nd squirt? Those are technical challenges that come with new, "novel" delivery forms. There is the evolution and even in those preparations and those processes, they bring in new levels of concern or exposure to the chemicals you might be dealing with, to deposit a drug on a surface.
They have drugs now that are delivered like Listerine strips. You stick it on your tongue and it dissolves. It's nice. It's easy. You don't have to take a pill. It tastes good. It's convenient. Those things are made in long ovens. They're basically plastic strips that are spread out and strewn with materials, deposited, dried, laid, dried, almost like making film. There are 15-20 different layers and emulsions on the average piece of film. So those things create new issues for exposure. How do you vent those ovens? Where do you vent them to -- because they're laden with materials and solvent? How do you recover those? Is it okay to put them in the environment? With all new technology comes new challenges to comply with health, safety and environmental issue?
CP: Do these new processes drive the manufacture of new buildings or have an impact on what factors are important in assuring they meet environmental standards?
AS: Many companies have zero or minimum discharge commitments. If currently there's a facility that happens to be in NJ near some suburban water intake or people that live there, they're trying to have the plant be neutral. Literally nothing comes out of the plant. So it's kind of like a submarine. You shut all the doors, you close it down, and no one knows you're there.
So it is driving decisions, not only in how plants are being designed but where they go. Clearly HS&E is a factor in the conceptual planning of facilities, not only in the technologies and configurations but also in physically where they are. There are places where they can't take risks. You wouldn't want to put it next to an elementary school. So you put it where there are fewer people, or no people. When you have an adverse activity in the vent, an emergency, you're a business, so you wouldn't want to expose your business to a loss or to harm unnecessarily. The codes and the practices are driving these facilities: for example, in Puerto Rico some of the water statutes say that if you put a plant here, the discharge of your sewer in many respects has to be cleaner than the water coming into the plant. These challenges definitely affect the way that plants are conceived and/or operated, including the people who have to be trained and be sensitive to emergency back-up plans. If you've got materials you're handling and you want to handle them in a safe way and you want to use your air conditioning or HVAC system to maintain certain flows -- rooms are maintained negatively or positively pressure to adjoining rooms because you don't want power that's being handled in room A to be picked up, blown out the door, run the corridor . . . you're controlling the way air moves in facility. That's okay when it's working, but what if you have a power failure? Suddenly the fans aren't functioning, you lose your pressurization profile. Facilities have redundant systems in them now. They have emergency back-up systems. Generators come on. Batteries come on. Doors close. Dampers and HVAC systems close. There is what they call a hazard operation review, what they call haz-ops. You try to design that away, but if you can't design them totally away, you add systems and devices that would be in effect layers of risk management. That's a big part of our business.
CP: Are there factors that have become particularly pernicious, that by and large can't be designed away?
AS: Yes. If you're going to be handling a substance that in its final form is toxic, for instance some of the drugs that are used for chemotherapy. They have to be delivered to you, the patient, very carefully. They have to be monitored and metered in a way that only a professional can mix them, compound them, put them in a vial, literally sometimes drive them to the point of use and then have someone use them in a day. Radioactive tracers and markers are that way, too.
If you're going in for a test Monday morning, someone's making something for you Sunday night, and dropping it off at the diagnostics or MRI office Monday morning. Those radioactive markers might be active for 12 hours -- they put something in you that works but only for 12 hours before decay. Handling that stuff is a big deal, right? You're handling noxious, toxic stuff that has some value, but only in a controlled way. You get the idea that these are drugs and/or diagnostic agents that are prepared certain ways and have to be handled certain ways . . . but if you're regularly preparing gallons of this stuff, and subdividing it and put it in a vial, you have to be careful with that stuff. You have to be careful with the operators as well as the discharge.
CP: Are those factors specifically resistant to design solutions at the facility manufacture stage?
AS: Certain design solutions come with the process -- if you can avoid or reduce the use of a material because it would be beneficial to. For example, a lot of coatings that are put on tablets, a sugar coating, you can pop them in your mouth because they're semi-sweet even though the ingredient active inside that is so bitter you couldn't stand it. It used to be that most of those coatings were applied using solvents. Over the last 20 years, the industry has moved from solvent-based coating, with methanol and methalyne chloride to water. That was a design specifically brought in to minimize or elminiated use of the solvent -- where you had to be careful to breathe, you had to be careful to recycle, you had to be careful to discharge -- to water-based, where there are far fewer concerns.
There is equipment that is being operated and installed now which basically work within themselves with little or no exposure. Everything happens within a contained environment where the operators are never exposed because multiple steps are concerned -- you can dry it, you can mill it, you can handle it -- closed processing is an example of designing to mitigate or remove exposure. Disposables are another hot item now -- literally doing your process in a plastic bag. Then when you're done, seal it up and throw it out. Don't try to clean the place -- imagine you have a pot on your stove and you're going to cook some beans. What if the pot had a liner in it and the beans never touched the pot, they only touched the liner? You did your cooking. You found a way to transfer the beans from the pot to whatever container or what you wanted to eat with. You close up the side of the things and threw that away, never having to handle a dirty pot. It's one thing for convenience, but what if the beans were danger and you didn't want to handle that pot or clean it. So disposables are being used more and more now because they can be more simply handled. Those are design solutions.
CP: Does this apply all the way back to building the facility itself?
AS: Sure. Facilities are walls, floors, ceilings, right? Rooms that encourage a certain flow of transportation of people and guests and materials and equipment, raw material, work in process, finished goods -- stages of production until something gets packaged. The facility itself can be designed to minimize traffic, the cross-flow of traffic. You can be designing to specifically keep out of certain rooms.
Let's say, for example, you had to use your mixer in the kitchen. The back end of the mixer where the motor is and anything that would be rotating -- what if you stuck that in the wall so that only the blades were in the kitchen and the motor was in the room on the other side of the kitchen? Now the guy who has to repair that item doesn't have to go into the kitchen to repair it. They can come at the item from behind it. You've designed a facility so that maintenance can be handled outside the room, so now you don't have to send someone in there. That's good, right? That's a facilities design issue.
I'll go back to cleaning for a minute, because cleaning happens to be one of the big areas to expose people to safety issues. What if you instead of saying send somebody in to steam down a room with a wand and he's in the middle of it, what if you designed a steam-in-place system, where no one has to go into the room, the room is automatically steam cleaned by some automatic valves, some nozzles and some drains, so that the room can be steamed and cleaned or that equipment could be steamed and cleaned in place, drained washed and rinsed and no one ever had to go in there? That's a mechanical solution that would make things safer to deal with.
CP: It sounds like paying attention to HS&E issues works as an extension of basic problem-solving in terms of seeking greater profit and meeting certain regulatory goals.
AS: With one difference: it's becoming more and more expensive and more and more important to do, so it's not a static picture.
CP: What drives the expense?
AS: Most of the materials that are involved in these remedial activities are expensive. They tend to be exotic materials and stainless steels and lined materials that are impervious or very resistant to abrasion and melting. They're high-tech materials.
Facilities sometimes have to be bigger as a result of these extra steps you take. You have to heat them, you have to cool them, you have to build them, you have to pay for them -- your house is getting bigger. The facilities are sometimes larger. The engineering that goes into these systems is more complex and takes longer to do. And the validation: because systems are more complex. They have more bells and whistles and features, and many of those bells and whistles and features have to be validated to satisfy the FDA. The FDA asks what you're doing, and how you know what you're doing is doing what you want it do. When you have an excursion or emergency or set of circumstances out side your normal limits -- temperature goes up, pressurization changes, electricity fails -- how do you know you didn't contaminate anything else in the place? You have to answer those questions. And to validate it, you have to demonstrate you're in control.
Long story short? More complicated, bigger facilities, more expensive to own and operate.