Effective and Efficient Weighing of Potent Compounds

The advantages of using an automated powder dispensing system in a ventilated balance enclosure for efficient handling and effective containment of potent compounds are discussed.
Sep 02, 2013

Working safely with potent compounds presents challenges for the pharmaceutical industry because exposure to minute quantities could potentially cause health effects. Typically, an isolator would be the preferred containment technology for working with the most potent (occupational exposure band five [OEB 5]) compounds but it has drawbacks in terms of cost, space, efficiency, and ergonomics. The authors describe the advantages of using an automated powder dispensing system in a ventilated balance enclosure (VBE) for efficient handling and effective containment of potent compounds. A review of the data proves that air and surface contamination is well within the acceptable limits, demonstrating the applicability of the automated powder dispensing unit in a VBE for weighing potent compounds in the pharmaceutical industry.

In recent years, pharmaceutical companies have increasingly begun to work with potent compounds (i.e., compounds that are very active pharmacologically, with efficacy at sub-milligram doses). These compounds allow patients to take smaller doses and potentially experience fewer side effects. While this property is advantageous for the patient, it presents a greater risk to the health of analytical chemists working with these compounds because exposure to very small quantities has the potential to cause health effects. In some cases, the quantity of potent compound that can lead to health effects can be extremely small, being practically invisible in air or on work surfaces, which makes containment of these compounds in the workplace especially challenging. The list of potent compounds of interest to the pharmaceutical industry includes hormones, steroids, and many oncology drugs. These compounds have airborne occupational exposure limits (OEL) ≤ 10 µg/m3 as an eight-hour time-weighted average (1). For handling these compounds in the laboratory, a classification system is used to assign materials into a series of health hazard categories, or occupational exposure bands (OEB), of increasing severity based upon their inherent pharmacological and toxicological properties. This classification system helps companies identify risks associated with handling the compounds and provides guidance on how to manage them (2). While no official industry standard exists around the banding of compounds, companies typically utilize OEB systems with four to six categories (1). Each health hazard category corresponds to a predefined strategy known to provide the necessary degree of exposure control to protect employees and the environment.

To support research and development as well as manufacturing of potent compounds, several contract manufacturers have made significant investments to build facilities to control exposure to potent compounds (3). Merck & Co., like other companies, has been developing potent compounds. Merck’s most potent compounds, known as OEB 5 compounds, typically require an isolator for dispensing milligram to gram quantities to maintain airborne levels below 1 µg/m3 and surface contamination below 10 µg/100 cm2 (see Table I).


Table I: Merck & Co.’s occupational exposure bands. HEPA is high-efficiency particulate air, LEV is local exhaust ventilation.

Occupational exposure bands (OEB)







Slightly toxic

Moderately toxic


Potent, toxic, potentially genotoxic

Highly potent, highly toxic

Occupational  exposure limits (OEL) (µg/m3)

≥ 1000

≥ 100 < 1000

≥ 10 < 100

≥ 1 < 10

< 1

Handling requirements

Good laboratory/ manufacturing  practices (GLP/GMP).  LEV may be needed.  No special  containment.

GLP/GMP.  LEV may be needed. No special  containment.

Virtually no open  handling. Closed  systems and/or  controlled by LEV, hoods or HEPA-filtered ventilated enclosures designed for personnel  protection.

No open handling. Closed systems and/or controlled by LEV, hoods or HEPA filtered ventilated enclosures designed for personnel  protection.

No open handling. High containment required.


User safety at the forefront
Working safely with these potent compounds presents challenges. Employers are required to minimize the exposure risk by following the “hierarchy of controls.” Since substitution is not an option when developing or manufacturing potent drugs, engineering controls are required to be used as the primary control. The preferred containment technology is often an isolator that maintains exposures below applicable limits. Using an isolator for dispensing and weighing small quantities of these compounds, however, presents space, ergonomic, efficiency, and cost challenges for an analytical
laboratory. Merck needed a simple solution to allow analytical chemistry researchers to work in a laboratory environment with OEB 5 compounds. The workflow needed to be safe, simple, efficient, and accurate enough to allow precision weighing while maintaining cGMP compliance.

Automated powder weighing
Merck’s analytical laboratory originally invested in a semi-automated powder dispensing unit (Mettler Toledo) to address an increasing demand for routine weighing of nonpotent compounds. The system, however, subsequently proved to be an effective solution for handling potent compounds as well (see Figure 1).

Figure 1
Figure 1: Example of an automated powder dispensing unit. (Figure is courtesy of the authors.)

It consisted of an enclosed semiautomated dispensing unit attached to a regular analytical balance. The compound is sealed in a vial with a dosing head attached to the top of the container. The dosing head is inserted into the unit, and the balance doors are closed before dispensing takes place. Dispensing the compound from a sealed container reduces the risk of airborne contamination. Each dosing head contains a radio-frequency-identification (RFID) chip to enable identification and tracking of the compound, providing process security by eliminating the possibility of selecting or dispensing the wrong substance. The dispensing system is able to accurately weigh compounds from 1 mg to 5 g with a 2% variance and dispenses the required amount of material into a container that is securely located on the balance. Once the desired weight has been dispensed, the researcher can remove the container and place another one on the balance for the next weighing step. Alternatively, a 30-position autosampler can be added to automate the change of target container, which enables up to 30 weighing operations to take place without any user intervention. It is also possible to link a solvent dispensing module, which accurately adds the desired weight of solvent into the target container based on the actual amount of solid dispensed to achieve a desired concentration. This method is an even more precise way to prepare analytical solutions. Compared to conventional manual dispensing, the automated process can be as much as 20 times faster.

A key benefit of automated dispensing is that it reduces user exposure by eliminating the handling of the substance with a spatula and minimizing the risk of spillage. It also reduces the manual actions required by the user, by eliminating the need for repeated opening of the balance door and transferring the compound from the main container to the secondary container to achieve the desired weight.

The automated dispensing system was situated within a high-efficiency particulate air (HEPA)-filtered ventilated balance enclosure (VBE) (Pharmaceutical Containment Technologies [PCT]). The VBE has features key to effective containment such as rounded airfoils around the entire face, a waste chute to minimize researcher movement in and out of the face, safe-change HEPA filtration, and a flow alarm to ensure the face velocity does not drop below 60 fpm (0.3 m/s). The laboratory initially used this equipment to weigh less potent, OEB 3 and OEB 4 compounds, a task that the device performed remarkably well. A question was raised as to whether the capability of the unit could be expanded to handle the safe and efficient dispensing of OEB 5 compounds. After several discussions between Merck Global Safety and the Environment and Mettler Toledo, an experimental evaluation plan was created to assess the ability of the system to reduce airborne and particulate surface contamination during weighing of OEB 5 compounds. As part of the evaluation, OEB 5 materials were provided to the analytical laboratory in containers compatible with the dosing heads as historical air and surface contamination data indicated manual subdivision by analytical chemists in a VBE would not maintain airborne and surface contamination levels below applicable limits for some OEB 5 compounds.

Surrogate control performance evaluation
Verification sampling was performed to validate the equipment containment. Personal protective equipment (PPE) worn during the sampling included safety glasses, a disposable laboratory coat, disposable sleeves, and double nitrile gloves. Air and surface samples were collected during the dispensing of 2 g of naproxen sodium, and subsequent cleaning and PPE removal.

Naproxen sodium, a nonsteroidal anti-inflammatory drug, was used because it is recognized by the International Society of Pharmaceutical Engineers (ISPE) as a rigorous challenge agent and a suitable surrogate for assessing containment of potent compounds (4). The sampling protocol included cleaning of the VBE, containers, balance, and the removal of outer gloves and sleeves within the VBE given that proper technique during these activities is crucial to containment and the prevention of surface contamination. Six iterations of the dispensing task were performed, and air and surface samples were collected during each iteration to demonstrate that the controls and the procedures used by the researchers did, in fact, protect them.

Table II: Containment verification data: Air sampling results. VBE is ventilated balance enclosure, < is less than the laboratory limit of detection.

Iteration 1-6  sample numbers

Sample location

Results in micrograms per cubic meter of air (µg/m3)

02S, 07S, 12S, 17S, 22S, 27S

Personal breathing zone samples

< 0.0025 - < 0.0030

03S, 08S, 13S, 18S, 23S, 28S

Left side of VBE face 200 mm from opening

< 0.0025 - < 0.0030

04S, 09S, 14S, 19S, 24S, 29S

Right side of VBE face 200 mm from opening

< 0.0025 - < 0.0030

05S, 10S, 15S, 20S, 25S, 30S

1.8 m from VBE face at height 1.5 m

< 0.0025 - < 0.0030

06S, 11S, 16S, 20S, 26S, 31S

VBE exhaust 200 mm from outlet

< 0.0025 - < 0.0031


In total, six personal air samples and 24 area air samples were collected. All samples collected were below the laboratory limit of detection and well below OELs for the OEB 5 compounds currently being handled in the laboratory (see Table II). Additionally, all wipe samples were below the surface contamination limits (see Table III).

Table III: Containment verification data: Surface sampling results. VBE is ventilated balance enclosure.

Iteration 1-6  sample numbers

Sample location

Results in micrograms per 100 centimeters square on the surface (µg/100 cm2)

05S, 09S, 13S, 17S, 21S, 25S

Floor below VBE face opening (right)

< 0.010

6S, 10S, 14S, 18S, 22S, 25S

Floor below VBE face opening (left)

< 0.010

7S, 11S, 15S, 19S, 23S

Horizontal airfoil (left)

< 0.01



I08S, 12S, 16S, 20S, 24S, 27S

Horizontal airfoil (right)

 < 0.01


A review of the air and surface contamination data showed that exposures are low, generally nondetectable. It was concluded that researchers can safely utilize the automated dispensing system to dispense up to 2 g of OEB 5 compounds with OELs > 3 ng/m3, provided that the VBE is properly sited in the laboratory and use of the system is coupled with appropriate personal protective equipment, a written procedure, hands-on training on proper handling of potent compounds in a VBE, good handling practices, and an annual preventative maintenance program for both the dispensing system and the VBE.

Automated powder dispensing offers an efficient combination of both strategies of containment and improved sample handling techniques. Combining the dosing head, a HEPA-filtered VBE, and good potent compound handling techniques can eliminate the need to use an isolator to precisely weigh OEB 5 compounds for analytical testing. An added benefit is that any researcher can undergo simple training and be qualified to operate the automated system, which also removes user variability from the process. Overall, the use of the automated dispensing system in a VBE affords accurate and reproducible weighing of potent compound while keeping researchers safe and protecting the laboratory environment from contamination.

F. Hermann et al., Chemistry Today, “Focus on CROs/CMOs” supplement, 29 (4) s20-23 (2011).
R. Harris, “Formulating High Potency Drugs,” Contract Pharma, Oct 2012, pp. 46-50.
P. Van Arnum, Pharm. Technol. 35 (12) 36-40 (2011).
ISPE, Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment, 2nd Edition (Tampa, Florida, May 2012) pp. 70.

About the Authors
George Hartford  is laboratory technician/inventory coordinator for labeled compounds in analytical chemistry, Patty Cheung  is associate principle scientist in analytical chemistry, Karen Whitaker  is senior specialist, Rahway Safety and the Environment, and Roy Helmy, PhD,  is director of analytical chemistry, all at Merck Research Laboratories, 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065-0900, USA; Joanne Ratcliff*, PhD,  is communication project manager, Laboratory & Weighing Technologies at Mettler Toledo AG, Im Langacher 44, P.O. Box LabTec, CH-8606 Greifensee, Switzerland, Joanne.Ratcliff@mt.com. 
*To whom all correspondance should be addressed.