Strategies for High-Containment - Pharmaceutical Technology

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PharmTech Europe

Strategies for High-Containment
An industry roundtable representing Metrics, Cambrex, Carbogen Amcis, Euticals, Ferro Pfanstiehl, and SAFC.

Pharmaceutical Technology
Volume 36, Issue 9, pp. s6-s11, s33

Nettleton (Cambrex): Risk management at Cambrex begins with training. All Cambrex employees granted access to areas that manufacture potent or toxic APIs must participate in training and become certified. Training follows a detailed risk assessment and risk-management framework that was developed in collaboration with the Cambrex toxicologist who is board certified and has extensive experience in risk assessment and with the Cambrex occupational nurse. Project-specific risk management recommendations are formalized by the toxicologist into a document known as a Project Safety Dossier (PSD). PSDs are formally reviewed by the manufacturing team before beginning work. In high-containment areas, new process designs are evaluated by certified Cambrex manufacturing teams in mock exercises that verify and document containment. Cambrex is guided by a four-band occupational exposure band (OEB) framework. Every molecule used to synthesize the API is evaluated separately and assigned an OEB. In some cases, where data are unavailable for a particular synthetic intermediate, Cambrex may conduct in silico assessment and in vitro toxicity testing (5).

When making risk-management recommendations and decisions, Cambrex is cognizant that safeguards must balance the conflicting goals of mitigating exposure risk, minimizing the ergonomic hazards imposed by unnecessarily conservative exposure controls, and quality considerations. Safeguards include integration of API-specific toxicodynamic factors into risk-management decisions, appropriate use of personal protective equipment, and containment verification with good hygiene practices.

Müller (Carbogen Amcis): The best practices to be applied depend on the category and amount of the material handled and on the frequency and complexity of the operation in question. For Carbogen Amcis, we are working with dedicated equipment that is firmly installed in many instances and working with flexible containment approaches in others (e.g., when having to dismantle equipment in the context of cleaning or when having to be sure that eventual leakage could be controlled). A realistic assessment of the risk in question is important.

Key practices in analytical monitoring involve swabbing surfaces (e.g., in the laboratory) as well as air-sampling during critical operations. Thereby, we are normally working with a combination of IOM samplers carried by the worker and of stationary samplers adequately placed to provide an idea of the eventual emission's distribution in space. We use surrogates right after installing new equipment and periodically perform analogous sampling and analyzing (i.e., high-performance liquid chromatography) of the true highly potent materials to control routine operations later on. The key parameter to be realistically determined is the exposed person's potential daily up-take in micrograms

Doherty (Ferro): Before moving forward with any project work, a process hazard analysis (PHA) should be conducted. This PHA will evaluate all aspects of the technical challenge and incorporate information, such as safety data sheets, product use, OELs, short-term exposure limits, odor threshold, industrial-hygiene monitoring method and analysis, irritant or sensitizer, toxicological data, primary toxic effect, route/mechanism of exposure, warning signs of exposure, treatment for exposure, cleaning procedures, acceptable surface residual levels, deactivation procedures, flammability/combustability, applicability of transportation regulations, waste disposal consideration, and other regulatory impacts.

Even with the best facility design and equipment selection, the level of containment can be largely determined by operational practices. Therefore, a considerable amount of effort needs to be devoted to writing solid operating procedures, and providing operator training. The organization should have a system in place that uses the OEL to establish the acceptable options for handling procedures and practices. In addition, industrial-hygiene monitoring should be used to verify that the combination of facility design, equipment selection, and operational practices is providing the expected level of containment. Medical monitoring of employees should be included as a verification of the adequacy of the industrial-hygiene sampling program.


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