Strategies for High Containment - Pharmaceutical Technology

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PharmTech Europe

Strategies for High Containment
Experts share insight on facility design and operations for high-potency manufacturing.

Pharmaceutical Technology Europe

Nettleton (Cambrex): In pharmaceutical manufacturing, there are two primary objectives for containment: to protect product quality and prevent worker exposure. There are underlying design principles that apply to all pharmaceutical manufacturing and analytical facilities at Cambrex. The operational goal is to maintain process isolation using isolators, sealed process vessels, dedicated piping, and single-pass, high-efficiency particulate air (HEPA)-filtered airflow. It also is crucial to design the ventilation system so that potentially contaminated air will flow downstream and away from the process area. Ingress and egress also are controlled to ensure both air and worker traffic moves in a single direction with minimal turbulence. Gowning/degowning vestibules, material pass-throughs and misting showers also are integrated into the flow. Upon ingress, disposable garments are donned, and upon egress, workers are misted with water to tack particulates to disposable garments, which are then discarded before exiting.

With respect to exposure prevention, in many instances, the design strategy for quality protection is the same as exposure prevention. Process isolation using isolators, sealed reactors and dryers and HEPA-filtered airflows are all important. In some cases, however, pressure differentials that protect pharmaceutical quality may not be protective of worker exposure. For example, when opening an isolator, positive pressure in the isolator will prevent cross-contamination, but the pressure release will potentially expel particulate material toward the worker. In these cases, the engineering strategy may include a bag in/out system. It also may be appropriate to include extra personal protective equipment when transferring toxic or potent compounds.

Mockups, training and verification also are key. Because all manufacturing process are different, it is important to verify that a given process design will function correctly and that operators are familiar with the process before a pharmaceutical product is actually manufactured. At Cambrex, it is common for the manufacturing team to develop and conduct mock handling exercises. These mock exercises may include the handling of surrogate pharmaceutical compounds followed by an assessment of potential releases and cross-contamination using wipes, air sampling and appropriate analytical detection. Naproxen is typically used as a surrogate because it has an extremely low detection limit and is easy to clean. At completion, mock exercises will demonstrate that process and containment equipment performs as expected, provide process ownership and training for operators, and identify potential need for design modifications to prevent cross-contamination or worker exposure. Cambrex routinely conducts equipment maintenance and equipment performance verification to ensure isolators, hoods, balance enclosures, airlocks and HEPA systems are working properly.

Müller (Carbogen Amcis): Carbogen Amcis has more than one site and has more than one production facility at its headquarters site in Bubendorf, Switzerland, but the concepts pursued with regard to containment are governed by one common philosophy regarding the handling of HPAPIs: the risks to be controlled regard the patient, the worker, and the environment. Therefore, we are analysing the whole lifecycle from the purchasing of raw materials (which may eventually be highly potent compounds) to the delivery of products and to the creation of waste, the whole set of buildings and installations involved and the whole series of applicable procedures and measures.

The containment requirements are defined in view of the toxicological category (performance-based exposure limit [PBECL], OEL, or acceptable daily exposure [ADE], respectively), whereby Carbogen Amcis is working with a four-categories approach, and strict requirements are applied in case of Categories 3 and 4. They particularly involve with regard to production, separation of the ventilation (room and/or reactor exhaust, i.e., systems), HEPA-filtration of exhaust air, separation of the room (airlocks), pressure cascades, partial dedication of specific equipment to HPAPIs, completely closed processing and separation of the wastestreams. Thus, the focus is on avoiding carryover as well as contamination of the workers and the environment through production equipment (cleaning), through space and through infrastructure systems.

The respective considerations are applied along the whole sequence of activities (i.e., the lifecycle). The details cannot be outlined here, but it can be said in a summary that they include gloveboxes or isolators, respectively, barrier isolation benches, laminar flows and flexible containment with all the activities subjected to their specific risk analysis. Personal protective equipment is eventually used as a safety backup during critical operations.

Cascone (Metrics): The facility and equipment constitute the barriers between the high-potent active agents and their surroundings. A facility designed with one-pass air and multiple airlocks with cascading negative pressure differentials will, in conjunction with other controls, mitigate cross-contamination. Hard- and soft-wall isolation technology demonstrates sufficient containment for the manufacture of solid-oral dosage forms containing compounds deemed to fall within an occupational exposure band of 10 mcg /m3 to 30 ng/m3 (TWA). These systems may be verified by recognised industrial hygiene practices, such as the ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment (1).

Enclosing a particular process or unit operation is reasonably well-established by most equipment manufacturers and isolation specialists. A key challenge is linking the unit operations together with the proper conveyance technology. This is particularly daunting if there is a wide variety of equipment makes and models. It is generally easy to contain powders within a bowl or vessel. Charging and discharging those powders and transporting them to other pieces of equipment is more complex. Examples of conveyance technology that may offer solutions include vacuum conveyance and continuous-liner 'bag-out' systems.

Another challenge related to isolation and containment centres on powder sampling. Process intermediates (e.g., blends and granules) need to be sampled to characterise in-process attributes and/or comply with prescribed regulations. Access to the product via properly designed and contained sample ports is essential.

Doherty (Ferro): First and foremost is the principle to not rely on 'moon suits' for the operators and instead have a strategy and philosophy to use engineering controls to provide proper containment. The key considerations are the OEL of the substance to be handled and, particularly for a CRO/CMO, the stage of the API and the scale of operation. The organisation should have a system in place that uses the OEL to establish the acceptable options available for facility design and equipment selection. For a CRO/CMO, the best and most economical means to handle a potent substance depend significantly on the stage (preclinical, clinical or commercial) and scale. For example, the best means of producing a preclinical small-scale API might be a combination of dedicated laboratory-scale equipment, disposables and a small isolator. In contrast, a commercial product produced at a 50-kg scale might require plant-scale equipment with validated cleaning procedures and test methods.


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