Fritz-Martin Scholz, Product Manager, Syntegon03.04.20
Containment is all about the safety of the operator. But what exactly is needed to safely and efficiently implement containment requirements in oral solid dosage processing? Only a combination of modern and highly efficient systems with automated cleaning, proven processes and years of expertise form the basis for successful containment.
The development of new drugs for oncology and hormone therapy is increasing the demand for containment solutions. During the processing of these highly potent substances, the protection of machine operators is paramount. At the same time, the quality of the final product is crucial since patients’ health depends on it. But how much containment is necessary? And how can it be implemented economically and flexibly in the cost-intensive pharmaceutical industry?
It all depends on the limit value
By means of NOEL (No Observed Effect Level) and the required safety factors, the Occupational Exposure Limit (OEL) can be determined in micrograms per cubic meter for active substances. The OEL is the time-weighted average concentration of a substance in the air at the workplace at which no acute or chronic damage to the health of employees is to be expected. The regulation is based on eight-hour exposure five days a week during working life. Next to determining the OEL, a classification into bands (OEB, Operational Exposure Band) with ascending activity has proven effective to describe the toxicity of active substances.
A risk-based project approach
If the active substance and the OEL are known, two further factors should be considered for the risk analysis. First, the degree of dilution of the active substance and second, the product’s tendency to be released into the air, for instance dry dust versus wet granules.
In addition to characterizing the active substance and its properties, it is important to describe the leakage potential of the production equipment. The STTWA (Short Term Time Weighted Average) value is applied for all relevant components. This short-time weighted average value is measured over 15 minutes in the working cycle per equipment part and indicates how much product in µg/m3 can be released into the environment as leakage. It is assumed that an operator only absorbs active substance through breathing and inhales 10 m3 of room air per shift.
As part of the risk analysis, the possible exposures, i.e. the ROI (Real Operator Intake), must be estimated and added up conforming to the process steps performed by the operator during his eight-hour working time. At the same time, the selection of suitable components must ensure that the estimated amount of active substance absorbed by the operator is below the limit value (Acceptional Daily Exposure, measured in µg/day).
The crucial points in the manufacturing process
Nowadays, most plants operate with a closed product flow. Suitable dynamic and static seals are continuously monitored to ensure optimum safety. The challenges are therefore primarily filling, sampling and emptying, as the product is transferred and could also be released during these steps. Split valves are the preferred solution to ensure that the process is closed to the outside during these process steps. Split valves are available in different versions and their STTWA value is typically significantly below 1 µg/m3.
Routine tasks such as cleaning and service are just as important – and often underestimated. The operator must be prevented from exposure to product residues on the equipment surfaces. Modern systems therefore have recipe-controlled cleaning with a high degree of automation and a minimal number of parts that must be cleaned manually. A riboflavin test can verify whether the cleaning nozzles are located at the right place. Prior to manual post-cleaning, all surfaces that came into contact with the product must be wetted in order to bind existing product residues.
While the Occupational Exposure Limit (OEL) determines the concentration of a substance in the air at which no acute or chronic damage to the health of employees is to be expected, the Operational Exposure Band (OEB) describes the pharmacological and toxic effects of the substances.
High efficiency with low risk
When choosing suitable equipment, the focus is not only on safety but above all on efficient and flexible production. Those who rely on market-proven technologies, which have been developed following the profitability factor, have a clear advantage. For example, Syntegon, formerly Bosch Packaging Technology, equips its high-shear mixers with the patented Gentlewing mixing tool. The special shape of the rounded, Z-shaped mixer ensures thorough emptying of the product container. Furthermore, the small gap between the container and the mixer minimizes product adhesion to the container wall and thus ensures a high yield without manual intervention.
Additional safety is provided by monitoring the product flow in the plant. An impending blockage of the product transfer from the high-shear mixer into the fluid bed can be detected in advance and prevented by adjusting the transfer parameters. Syntegon (under the name of Bosch Packaging Technology) has, for example, developed a system for the veterinary pharmaceuticals manufacturer Vétoquinol that consists of a high-shear mixer with Gentlewing, a fluid bed system, and a circulation cleaning system (see lead image in the photo slider). The entire production process takes place in a containment system based on split valves.
The path to safe containment
An experienced manufacturer can offer a modular system with different technical solutions. Depending on the framework conditions and the results of the ROI assessment, the individual components can be combined with to form a system that meets customers’ containment requirements, both from an economic and a safety point of view. Personal protective equipment (PPE) for plant operators should only be considered as a last resort.
At the end of the containment evaluation, a SMEPAC test can be carried out during commissioning to evaluate the complete batch process from filling the granulation line to emptying into an IBC. The ISPE Good Practice Guide “Assessing the Particulate Containment Performance of Pharmaceutical Equipment” defines the appropriate framework conditions. In the case of Vétoquinol, the SMEPAC test delivered the expected results: the measured values of all equipment parts were clearly below the required limits.
This containment systematics can be flexibly extended by further components such as isolators, tablet presses, capsule fillers or drum coaters, depending on customer requirements. Combined with the relevant experience as well as documentation and validation expertise, there is nothing to stop the implementation of a safe, flexible and efficient containment project.
Fritz-Martin Scholz is product manager at Syntegon, a global process and packaging technology provider. Formerly the packaging division of the Bosch Group, the company, headquartered in Waiblingen, Germany, has offered complete solutions for the pharmaceutical and food industry for over 50 years.
The development of new drugs for oncology and hormone therapy is increasing the demand for containment solutions. During the processing of these highly potent substances, the protection of machine operators is paramount. At the same time, the quality of the final product is crucial since patients’ health depends on it. But how much containment is necessary? And how can it be implemented economically and flexibly in the cost-intensive pharmaceutical industry?
It all depends on the limit value
By means of NOEL (No Observed Effect Level) and the required safety factors, the Occupational Exposure Limit (OEL) can be determined in micrograms per cubic meter for active substances. The OEL is the time-weighted average concentration of a substance in the air at the workplace at which no acute or chronic damage to the health of employees is to be expected. The regulation is based on eight-hour exposure five days a week during working life. Next to determining the OEL, a classification into bands (OEB, Operational Exposure Band) with ascending activity has proven effective to describe the toxicity of active substances.
A risk-based project approach
If the active substance and the OEL are known, two further factors should be considered for the risk analysis. First, the degree of dilution of the active substance and second, the product’s tendency to be released into the air, for instance dry dust versus wet granules.
In addition to characterizing the active substance and its properties, it is important to describe the leakage potential of the production equipment. The STTWA (Short Term Time Weighted Average) value is applied for all relevant components. This short-time weighted average value is measured over 15 minutes in the working cycle per equipment part and indicates how much product in µg/m3 can be released into the environment as leakage. It is assumed that an operator only absorbs active substance through breathing and inhales 10 m3 of room air per shift.
As part of the risk analysis, the possible exposures, i.e. the ROI (Real Operator Intake), must be estimated and added up conforming to the process steps performed by the operator during his eight-hour working time. At the same time, the selection of suitable components must ensure that the estimated amount of active substance absorbed by the operator is below the limit value (Acceptional Daily Exposure, measured in µg/day).
The crucial points in the manufacturing process
Nowadays, most plants operate with a closed product flow. Suitable dynamic and static seals are continuously monitored to ensure optimum safety. The challenges are therefore primarily filling, sampling and emptying, as the product is transferred and could also be released during these steps. Split valves are the preferred solution to ensure that the process is closed to the outside during these process steps. Split valves are available in different versions and their STTWA value is typically significantly below 1 µg/m3.
Routine tasks such as cleaning and service are just as important – and often underestimated. The operator must be prevented from exposure to product residues on the equipment surfaces. Modern systems therefore have recipe-controlled cleaning with a high degree of automation and a minimal number of parts that must be cleaned manually. A riboflavin test can verify whether the cleaning nozzles are located at the right place. Prior to manual post-cleaning, all surfaces that came into contact with the product must be wetted in order to bind existing product residues.
While the Occupational Exposure Limit (OEL) determines the concentration of a substance in the air at which no acute or chronic damage to the health of employees is to be expected, the Operational Exposure Band (OEB) describes the pharmacological and toxic effects of the substances.
High efficiency with low risk
When choosing suitable equipment, the focus is not only on safety but above all on efficient and flexible production. Those who rely on market-proven technologies, which have been developed following the profitability factor, have a clear advantage. For example, Syntegon, formerly Bosch Packaging Technology, equips its high-shear mixers with the patented Gentlewing mixing tool. The special shape of the rounded, Z-shaped mixer ensures thorough emptying of the product container. Furthermore, the small gap between the container and the mixer minimizes product adhesion to the container wall and thus ensures a high yield without manual intervention.
Additional safety is provided by monitoring the product flow in the plant. An impending blockage of the product transfer from the high-shear mixer into the fluid bed can be detected in advance and prevented by adjusting the transfer parameters. Syntegon (under the name of Bosch Packaging Technology) has, for example, developed a system for the veterinary pharmaceuticals manufacturer Vétoquinol that consists of a high-shear mixer with Gentlewing, a fluid bed system, and a circulation cleaning system (see lead image in the photo slider). The entire production process takes place in a containment system based on split valves.
The path to safe containment
An experienced manufacturer can offer a modular system with different technical solutions. Depending on the framework conditions and the results of the ROI assessment, the individual components can be combined with to form a system that meets customers’ containment requirements, both from an economic and a safety point of view. Personal protective equipment (PPE) for plant operators should only be considered as a last resort.
At the end of the containment evaluation, a SMEPAC test can be carried out during commissioning to evaluate the complete batch process from filling the granulation line to emptying into an IBC. The ISPE Good Practice Guide “Assessing the Particulate Containment Performance of Pharmaceutical Equipment” defines the appropriate framework conditions. In the case of Vétoquinol, the SMEPAC test delivered the expected results: the measured values of all equipment parts were clearly below the required limits.
This containment systematics can be flexibly extended by further components such as isolators, tablet presses, capsule fillers or drum coaters, depending on customer requirements. Combined with the relevant experience as well as documentation and validation expertise, there is nothing to stop the implementation of a safe, flexible and efficient containment project.
Fritz-Martin Scholz is product manager at Syntegon, a global process and packaging technology provider. Formerly the packaging division of the Bosch Group, the company, headquartered in Waiblingen, Germany, has offered complete solutions for the pharmaceutical and food industry for over 50 years.
