Pharmaceutical compound development

by Hank Rahe

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Development of new compounds for pharmaceutical applications can be divided into four segments. The first is discovery of the molecule, which in today's world takes place more by computer modeling than by the scientist working on the laboratory bench.

The second stage is to produce small quantities of the compound ranging from a few hundred grams to a kilogram.

The third stage is to produce limited quantities for testing in humans—this is called clinical trials.

If the compound is successful in the first three phases it is approved by the FDA and can be marketed by the company (stage four). This sequence from “molecule to marketplace” typically takes six to eight years and represents a one-in-over-one-hundred-thousand chance of success.

Containment of the compound during phases two and three requires a high level of attention because of a lack of information on both long- and short-term exposure effects. The need for containment at these stages is not widely recognized because of the pharmaceutical industry's rapid move to more potent drug compounds. With exposure levels in the low microgram range for many of these compounds, small laboratory quantities of a few hundred grams can represent a major health risk to those exposed without proper protection.

At the laboratory stage of development many different compounds are evaluated in a short period of time and each can have a negative effect on the individuals working with them. It is important to consider not only the individual exposure of a given compound but also the combined effect because many of the compounds are of the same family and target the same organs in the body.

Of special importance is the long-term effect, which may not be evident with the initial toxicology testing, performed on the compound. The longer-term effects many times are not known until late in the phase-three clinical trial testing. At this point more complete data can be evaluated to determine if target organs show negative side effects. Laboratory workers may, by this point in time, have had significant exposure if not properly protected.

The unknown implications of exposure require a change from the open bench top manipulations, which are prevalent in current laboratories, to a higher level of containment. The safety of individuals working in these environments can be at risk. Containment of operations such as weighing, sample preparation and manufacturing of small quantities of final dosage form can be accomplished without major changes to the facility. Containing the potent compounds at the source using closed systems does not restrict individual flexibility if proper ergonomic design is considered.

Some of the more concerned companies are taking action by assuming that any compound being introduced to the laboratory has a low exposure limit until data shows that not to be the case. Most major pharmaceutical development organizations will soon follow this model. The major concern is the smaller companies, which lack the resources to understand the containment issues associated with potent compounds. The thousands of smaller companies working on developing new molecules can put at risk not only individuals working in the laboratory environment but also those with whom they may come in contact.

How can individuals outside the work environment be put at risk? Hands, feet and clothing can track the potent compound to other locations. Testing of a number of laboratory environments has shown presence of potent compounds, which exceed the exposure limits, outside the confines for the laboratory. In some cases materials have been tracked outside the facilities, putting at risk not only family members but also anyone coming in casual contact with the unprotected laboratory worker.

Hank Rahe is director of technology at Contain-Tech in Indianapolis. He has over 30 years' experience in the healthcare industry. He is an expert in the areas of conventional and advanced aseptic processing. He is the past chairman of the board of the International Society of Pharmaceutical Engineers, and is a member of the CleanRooms Editorial Advisory Board.


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