Containment Case Study of a Tabletting Operation Using Isolation Technology
Original case study appeared in Pharmaceutical Engineering – July August, 2001
1212Glenn Snow, Daniel Liberman, Christopher Lockwood, Mary McConnell-Meachen,
131Eugene McNally, Hank Rahe, Kevin Shepard,
12 Departments of Pharmaceutics and Environmental Affairs and Safety Research and Development
Boehringer Ingelheim Pharmaceuticals, Inc.
900 Ridgebury Road, P.O. Box 368
Ridgefield, Connecticut 06877-0368
3EnGuard Systems, Indianapolis, Indiana 46239
Since the early 1990’s, the pharmaceutical industry has been discovering and developing increasingly more potent drugs. This increase in potency of new drug
substances has reduced patient dosage for new drug approvals. While this trend is a positive outcome for the patients requiring the medication, it has created increasing problems for individuals involved with the development of these potent new chemical entities (NCEs).
The trend toward increased potency of the active drug substance not only includes cytotoxics but also most major categories of pharmaceutical compounds. With this increase in potency of NCE’s comes the need for greater safety measures to protect workers developing these compounds. Traditionally, formulation and process development work with NCE’s has been performed in open laboratories with scientists wearing personal protective clothing and respirators to guard against skin contamination and inhalation exposure during dusty processing operations. However, this dependence on personal protective equipment may be inappropriate when the exposure limit for some of these compounds is in the sub-microgram region.
A number of companies have adopted a strategy that does not rely on Personal Protective Equipment (PPE) to protect their workers. They have adopted the philosophy of containing the potent material at its source, the processing
equipment itself. Using barrier isolators, contaminants are confined to the equipment that generates the contaminants. In this way, very low exposure levels can be achieved and the dependence on PPE to protect the workers can be minimized or even eliminated.
Not all isolators are manufactured to the same protection standards and it is critical to understand the basics of isolation technology as a background to this case study. Isolators are made up of four components:
1. The shell or enclosure
2. The air handling system which includes the filtration and blowers
3. The people interaction technologies such as glove ports or half suites
4. The product interaction or how the materials move in and out of the
Each of the components can impact the containment capability of the isolator system.
The design of the shell of the isolator needs to address both the integrity and functionally of the system. Integrity of the system included assuring that all penetrations are designed and fabricated in such a manner to not create a breach in the system. Functionally addresses the ergonomics of the system that is critical the proper operation of the isolator. A poorly designed system is the major cause of improper use leading to personnel exposure.
The air handling system provides circulation of air or other gasses through filtration to capture particles generated by the handling of materials inside the isolator. The airflow patterns, velocities and quality of the filtration system are all factors in designing the proper system for the defined application. The machine or activity occurring inside the isolator generates airborne particles of potent compound that need to be contained both inside the isolator and the exhaust system used to support the filtration system. The case study showed an important example of breach of containment in the exhaust system and how important it is to treat the containment as a complete system. Choice of filters and the design of safe filter change are critical elements that need to address based on quantity of contamination and particle size range of the potent compound.
Interaction by personnel has always been necessary be it for adjustment of the process equipment, sampling or addition of the potent powder. Robotics may be the best approach but in a batch process industry such a pharmaceuticals it has not been achieved. Interaction by personnel that occurs primarily through glove ports allows the hands and arms to move inside the controlled environment without exposure. The gloves and sleeves are manufactured in two forms: one piece and two piece systems. Each system has advantages and disadvantages. The advantages of the one piece system are a single seal with the shell of the isolator and disadvantage is the loss of feel and dexterity created by a typically thicker hand section. The disadvantage of the two piece system is the additional seal required to attach the glove to the sleeve and the advantage is the flexibility of better touch and feel as well as lower replacement cost. Half-suites are the other
means of allow personnel to interact and are have the advantage of greater reach and ability to lift heavier objects inside the isolator. The disadvantage is difficulty in entry / exit and the feeling of confinement experienced by some operators.
Movement of materials and equipment are also critical to maintaining the containment during set-up, operation and cleaning. Equipment can be placed in or removed from the shell of the isolator either through a door or by removal of a panel. The approach selected is determined by the frequency and equipment size and weight. Movement of materials such as product and tools can occur using three approaches: RTP’s ( Rapid Transfer Ports); airlocks or bag rings. The RTP is a technology developed for the nuclear industry and is the most closed transfer system however, testing has shown that it does leave small levels of contamination. The disadvantages of the RTP are the round shape required by most designs and the durability of the seals. The airlock approach offers the most flexibility in that it can be made in a variety of sizes and shapes to accommodate the materials being transferred. Airlock systems have been validated to provide containment in the low nanogram range. Bag rings offer a means of contained transfers that is sometimes refereed to as “bag tricks” and can be used for both primary and secondary
containment. It is not unusually for a combination of material transfer technologies to be used in the same isolator system.
The isolator used in this case study had a 316L stainless steel shell with engineered plastic viewing areas, a HEPA filtered air handling system with special covers for the
HEPA’s to facilitate cleaning, glove ports for personnel interaction and airlocks and bag rings for materials transfers.
The case study describes an approach for processing potent compounds using pharmaceutical solid dosage form equipment. Isolating the worker from the potent compound prevents worker exposure without relying on personal protective equipment. We will describe the isolator systems, the work practices necessary to maintain containment of the potent material and the validation data generated that demonstrate containment has been achieved.
Like many other pharmaceutical companies we have developed a classification system for describing the level of potency of materials. Table 1 summarizes our five-category classification system for NCEs and the criteria used in assigning a classification to a compound. All relevant data about the compound are reviewed. This includes chemical, physical, pharmacological and toxicological data from both human and animal subjects. A hazard assessment is conducted and a determination is made as to which Hazard Category is the "best fit." Team members collectively apply their expertise in industrial hygiene, toxicology, pharmacology, occupational medicine and clinical medicine to review the data for the pharmaceutical active ingredient and make the hazard category assignment. Both acute and chronic data are considered and the assignment relies on professional judgment. To assess potential acute effects, both the toxicity and pharmacological activity of the compound are evaluated. The type of
pharmacological effect(s) expected, the mechanism of action and the dose required to produce these pharmacological effects are important considerations, as is the severity of acute (life threatening) effects. This latter assessment is a determination of whether medical intervention might be required and how rapid the response must be if an overexposure occurs. This information in conjunction with the results of acute toxicity studies in animals provides the likelihood that the compound may produce immediate adverse effects. Compounds with a high order of acute toxicity and poor or delayed warning properties are of particular concern.
A determination is made on the likelihood and severity of possible chronic effects. This weight-of-evidence evaluation is based on the results of genotoxicity assays in cell culture, in vitro experiments, in vivo studies in laboratory animals that are designed to determine the potential for the material to produce target organ effects, reproductive or developmental toxicity, cancer or other chronic effects. Where possible the results of clinical studies in humans are used as well. A key piece of information is the dose required to produce these effects, or preferably, the highest dose that does not produce a toxic or pharmacological effect (i.e., the NOEL or “no observable effect level”). In the event that a NOEL cannot be defined, we attempt
to define a “no toxic effect level” or NOTEL.
A judgment is made regarding the severity of chronic effects and whether they may have disabling consequences or the potential to cause early death. A very important consideration is whether effects are reversible or irreversible.
The procedure that we follow in developing occupational exposure levels (OEL) consists of the 5 steps outlined in Table 2. Often the hazard category assignment is conservatively based on the most sensitive health effect endpoint, especially when there is potential for life threatening, disabling, or other irreversible chronic effects. During the early discovery phase of a compound, toxicological profiling is limited by the small quantities available. In the absence of valid toxicological information, research compounds are provisionally assigned to Category 3, unless the molecular structure or other indicators suggest a higher or lower classification. As additional data defining the risk of exposure becomes available the categorization of the new chemical entity can be changed.
The equipment and containment devices that will be described have been designed to handle material in categories 1-3 without the use of PPE. Category 4 compounds will require additional evaluation of both the compound and the containment devices to determine if they can be processed safely. Additional decontamination techniques, the use of PPE and direct exhaust of the isolator are areas, which would reduce potential personnel exposures and allow for the safe processing of compounds in Category 4 . The derivation of occupational exposure levels for therapeutic substances is not a precise scientific exercise; it is a matter of judgment involving medical, toxicological and industrial hygiene disciplines.
Processing of Potent Compounds
At larger scale (50 kg and above) pharmaceutical equipment can be purchased with containment options that limit worker exposure to dust during processing; transport
of materials between unit operations can be accomplished by vacuum transfer between closed bins. However, such containment options are not available on smaller capacity laboratory equipment used when making the first solid dosage form for a NCE at the 200 g – 1 kg scale. At this small scale, past practice has been to work in a chemical fume hood, or in an open lab wearing some form of respirator to prevent inhalation of dust. However, our goal was to be able to work with small-scale equipment in the lab in either a contained or non-contained manner without the PPE and the facility clean up issues. This will allow us to develop all levels of compounds in-house.
When performing analytical testing, we need to treat potent compounds as hazardous and work with them in a properly contained environment. This means that for processing operations that generate considerable amounts of dust (i.e. dispensing active, mixing, granulating, milling, tabletting), we needed to develop containment strategies in order to do prototype formulation development work. We found that we needed to develop criteria to guide our decisions. These criteria evolved as we learned the advantages and disadvantages to various isolation/containment approaches. The initial criteria were:
1. Safety of Personnel working with the potent material and those scientists in
adjacent labs not involved with these materials
2. Flexibility for using lab for both potent and non-potent compounds. 3. Ability to work on a scale of 200 grams to 2 kg.
4. Ability to adopt new process equipment into the lab without redesigning
5. Allow development on compounds with an OEL on the order of 0.1
micrograms/cubic meter of air.
A discussion of how our containment strategy evolved is informative since it identifies the approaches that were evaluated and abandoned due to their impracticality. Our first generation concept was to construct a down draft booth that would be used in conjunction with personal protective equipment (PPE). It was felt that this would be a quick solution for handling potent compounds. However, based on achievable particle capture, this approach would not be useful for
operation was complete, the entire laboratory would potentially have to be cleaned, and we would need to engineer a means of entry and exit into the lab for workers to safely remove their PPE.
The second generation approach was adopted to decrease our reliance on PPE and to minimize the need to clean a large laboratory space upon completion of an operation. We envisioned that all work would take place in a HEPA filtered lab fitted with airlocks and mist showers to contain the material within a smaller lab space. This would allow personnel to exit and then remove their PPE safely. All material transfers and dust generating operations would be performed in a glove box within the HEPA filtered laboratory. One large glove box would accommodate the