Technical Brief 2011 Volume 4

Potent Compound Handling Operations

Background Pharmacology is the branch of medicine and biology concerned with the study of the interactions that occur between a living organism and chemicals that affect biochemical functions. In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a smaller response at similar concentrations. Occupational health professionals in the pharmaceutical industry have recognized the potential for occupational disease caused by overexposure to active pharmaceutical ingredients (APIs).1 Compounds that are routinely handled in the biotechnology, pharmaceutical and medical device industries (from hereon called pharmaceutical industry) are unique in that they are designed to have an effect on the human body. Environmental, health and safety professionals in the industry have responded to this risk by developing and implementing comprehensive programs for the anticipation, recognition, evaluation, and control of exposure to APIs. This is achieved by ensuring that employees are protected from exposure to potent APIs. The purpose of this technical brief is to provide an overview of the design and implementation of an effective and economical potent compound safety precautions for the industry. The design and implementation of an effective potent compound safety program should follow the same basic process as traditional industrial hygiene programs hazards should be anticipated, activities with drug exposure potential should be recognized and evaluated, and finally these exposures must be controlled. A comprehensive potent compound safety program is active at all stages of product development including research, discovery, pre-clinical development, pre-formulation, initial test batches, pilot plant, scale-up and production. Prior to the introduction of new APIs into the workplace, a thorough literature search on the specific or similar compounds should be conducted. While this may seem Table 1
Figure 1

CONTAINMENT USING ISOLATOR

Isolated process using a negative pressure isolator
Minimal PPE

scheme has been widely accepted across the pharmaceutical industry. The most common modification to the scheme described by Naumann and his colleagues is in the number of bands individual companies utilize for their compounds. Some companies use a four others use a five band system (Tables 1 and 2, respectively). Recognition of Exposure Potential to APIs A potent compound exposure control band provides an array of safety requirements for a specific category and a source of information to determine appropriate handling practices, industrial hygiene targets for air monitoring, and a starting point for final potent compound categorization by an occupational toxicologist. These bands are a concentration range of potent compounds where personnel exposure should be controlled. Naumann, et al (1996)1 discuss the basis for establishing occupational exposure levels (OELs) during the various stages of drug development as well as the criteria evaluated in determining occupational exposure bands (OEB). Toxicologists are frequently required to exercise professional judgment to properly complete a potent compound categorization. Once a relevant dose has been determined, an estimated OEL (contaminant concentration in a given volume of air) can be calculated using the methodologies such as those presented by Sargent (1988)2. After the potential hazards of the API have been identified and an estimated OEL has been calculated, the occupational health professional should identify the potential risk factors associated with its use. These risk factors include: how the API is handled form of API (powder or liquid) quantity of the API exposure duration and frequency In addition to routine laboratory and manufacturing processes, the environmental, health and safety professional should have an understanding of potential exposure

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like a simple task, it often becomes challenging to find relevant hazard information for new discovery compounds. However at this point, the primary focus should be to identify adequate information to allow preliminary classification or categorization of the compound into a control banding strategy such as those proposed by Naumann (et al., 1996)1. With a few minor revisions, this categorization

FOUR BAND OCCUPATIONAL EXPOSURE BAND CONTROL TABLE

OEB
1

OEL
> 500 g/m

Suggested Design Controls

General room ventilation. Conventional open equipment with local exhaust ventilation (LEV). Semi-closed to closed material transfer; laminar flow/directionalized laminar flow, engineered LEV. Transfer using direct coupling & closed systems. Selected use of unidirectional air flow booths.

Properties
Compounds that are not harmful, and/or have low pharmacological activity. Compounds that are moderately toxic and/or have moderate pharmacological activity. Compounds that are toxic, and/ or have high pharmacological activity. NOTE: Chemicals of unknown toxicity, which are believed to have the potential for high to extremely high toxicity or pharmacological activity based on its therapeutic class or other indicators, will be assigned to OEB 3 by default. Compounds that are extremely toxic, and/or have very high pharmacological activity.

10 - 500 g/m

0.03 - 10 g/m

< 0.03 g /m

Totally enclosed processes; direct coupling transfer; barriers/isolation technology.

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situations during non-routine activities, such as emergency repair activities. OEBs that are utilized in discovery and early development are initially assigned based on:

Table 2

FIVE BAND OCCUPATIONAL EXPOSURE BAND CONTROL TABLE

OEB
1

OEL
> 1,000 g/m

Suggested Design Controls

General room ventilation. Conventional open equipment with LEV. Semi closed to closed material transfer; laminar flow/ directionalized laminar flow, engineered LEV.

Properties
Compounds that have low pharmacological activity and are considered fairly safe to handle. Compounds that are harmful, and/or have low pharmacological activity.

toxicological assumptions about

a compound based on limited data be fully developed for a monitoring program 2 > 50 1,000 g/m

analytical methods that may not

These bands are ranges of airborne concentrations of substances as 8-hour time-weighted averages (TWAs). Evaluation of Occupational Exposure to APIs In the initial exposure evaluation process, high priority activities are those where APIs are handled in powder form, such as weighing of powders in laboratories, dispensing, blending, dry granulation, and compression activities. Once the product is either in finished solid dosage or liquid form, the exposure risk is significantly reduced. Monitoring methods for the APIs are then needed to establish the airborne and surface concentration of APIs. Alternatively these evaluations may be performed using a surrogate powder such as Sodium Naproxen. Control of Exposure to Potent Compounds Employee exposure to potent compounds can be through:

> 20 50 g/m

Transfer using direct coupling Compounds that are moderately toxic and/ or have moderate pharmacological activity. & closed systems. Selected use of unidirectional air flow booths. Totally enclosed processes; direct coupling transfer; barriers/isolation technology. Compounds that are toxic, and/or have high pharmacological activity. NOTE: Chemicals of unknown toxicity, which are believed to have the potential for high to extremely high toxicity or pharmacological activity based on its therapeutic class or other indicators, will be assigned to OEB 4 by default. Compounds that are extremely toxic, and/or have very high pharmacological activity. program requires that all elements be considered. Failure to adequately anticipate, recognize, evaluate and control exposures to potent compounds can result in costly program missteps, delayed drug development schedules, or potentially hazardous exposures to workers. To be successful, a comprehensive potent compound safety program will have contributions from safety, engineering, toxicology, industrial hygiene, and operations. References 1. Naumann, Bruce D., et. al., Performance-Based Exposure Control Limits for Pharmaceutical Active Ingredients. American Industrial Hygiene Association Journal. 57: 33-42 (1996). 2. Sargent E.V., Kirk G.D., Establishing Airborne Exposure Control Limits in the Pharmaceutical Industry. American Industrial Hygiene Association Journal 1988; 49(6): 309-313.

1 20 g/m

< 1 g/m

Isolation technology; remote operations; fully automated.

exposure. One example is the use of an isolator (Figure 1). The pressure within the isolator is negative with respect to the environment. This minimizes the contamination potential of the potent compound being manipulated in the isolator. Suggested activities for a successful implementation of a containment program are:

ingestion through mouth or nose transdermal through absorption

through skin tal puncture

Study and document containment requirements for a given activity on personnel as the product for a given activity and testing containment system

intramuscular through acciden mechanical

transfer through mucous membranes due to residues on clothing, equipment

Focus the same level of attention Involve the operator in selecting Consider the following in the system selection: Peak and average containment levels expected for the operation Operability and effects on productivity Effect on product yield and material loss Portability or set up times Cleanability/Maintainability/ Durability Initial Cost/Operating Cost Ability to test containment effectiveness and GMP

ocular through airborne particles

The primary focus of a comprehensive potent compound safety program is to ensure employee safety through effective process containment. Containment is the design and implementation of engineering controls and personal protective equipment (PPE) for use with manufacturing, pilot plant and laboratory operations with the goal to minimize the emission of substances into the work environment limiting potential employee

The activity to be contained needs to be studied and documented in detail. The goal is to control air and surface contamination. When handling highly potent compounds (i.e., OELs less than 1 g/m3) containment must be provided during all laboratory procedures or steps in the manufacturing process. The entire process must be considered including the potent chemical compounds that will be handled, the equipment used and the hazards of those chemicals. Approaches can include modification of the engineering controls and the employee interface. The engineering controls need to be ergonomically designed and user friendly or there will be resistance to their use. Minimize the employee interface in a process and exposure will also be minimized. In addition to engineering, administrative controls such as proper potent compound safety training is paramount and if needed, product-specific medical surveillance may be implemented. Summary of an Effective Potent Compound Safety Program

The authors thank Dr. Joe Nieusma and Dean Calhoun CIH of Affygility Solutions for the use of their Design and implementation of an previously published materials in effective potent compound safety this Technical Brief.
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