October 30, 2014
When a biopharmaceutical company builds new or renovates existing manufacturing space, the last consideration before turning the production key is the environmental monitoring of the same. This short sightedness is understandable when one considers that a manufacturing environment that is under control is often taken for granted and invisible to the critical success of the process. Although multilayered and complex in design, as the individual responsible for the environment there are three points to immediately consider. The first is the intended use for the space, which requires intimate knowledge of the critical product and manufacturing processes. The second is the personnel, process and equipment traffic patterns in the space, here again knowledge of the space's detailed design, user requirements and functional requirements are key. The third is quite simply the application of controls and common sense. The common thread in all three of these points is process and product knowledge. Not surprising, Stage 1 of the 2011 US FDA Guidance for Industry on Process Validation is one of process design which includes building and capturing process knowledge and understanding and establishing a strategy for control of the same.
The diversity of areas or rooms in a manufacturing space can vary greatly and certainly the expenditure, resources and time spent on will mirror the criticality of the space. But don't write this point off immediately, many manufacturers are cited for lack of proper controls in areas such as warehouses where the outside elements may reach into the staging and storage areas of components such as raw ingredients, excipients, active pharmaceutical ingredients or formulated final products. Likewise, when a manufacturing facility reaches its' capacity and still more is required, even hallways become staging and storage areas for media, buffers and bulk intermediates. Although the microbial and particulate level in the area may have no effect on closed vessels, the temperature in those temporary locations may have serious ramifications on solution characteristics such as precipitation, aggregation and potentially accelerated degradation or spoiling. During space planning and facility design there is always the need to play the "what if" scenarios out to edge of failure. Certainly redundancies in both engineering design and personnel procedures are put in place for areas such as the fill and finish suite of a sterile parenteral drug where all microbial, particulates, temperature or humidity of concern, but similar thoroughness should be checked once valuable materials are finalized for consumer consumption.
Once the environmental conditions in a manufacturing area have been established to process or product requiring levels under static or non-routine operations, the challenge becomes that of maintenance while operators, equipment and the manufacturing process is underway. The permutations of possibilities could be endless of what could perturb the established environmental homeostasis. The obligation to establish controls, whether they are procedural or engineering, is on the manufacturer to reduce the impact generated in or brought into their facilities. The use of a building management system may greatly reduce the manual follow up a manufacturer is required to do for proper environmental maintenance. Building management systems can provide real-time, as well as historical, information regarding differential pressures, temperature, humidity and particulate in a manufacturing facility. This level of automation can reduce but not eliminate the need for the quality control unit to travel the facility and take samples. Microbial or viables monitoring may still be a requirement in order to manufacture goods and products of a specified quality. Unidirectional travel, interlocks on hallways and doors as well as increased gowning, equipment wipe-downs, and sealed exhaust should all be considerations in the maintenance of an environment and cleanliness required of the product and process. For more sensitive processes, isolators or restricted access barrier systems may provide the solution of choice to minimizing the impact of operator and equipment travel on the more sensitive units of manufacturing operations. Careful space planning will not only facilitate smooth flow and operations, it may also add to operator comfort and impact to product and process.
Over-engineering and holding every area to high environmental standards may seem like the simple answer to any future space contingencies, but at what cost? At the design stage of a new or renovation build, a manufacturer should build in redundancy or expansion capabilities to elements such as heating, ventilation and air conditioning. Those may serve the facility well when a reconfiguration is necessary. Furthermore, building management systems are often modular and can allow for expanded monitoring when a facility or area is upgraded due to product expansion or changes. Building a facility of sanitary design makes long term fiscal sense as standards are more likely to become more rather than less stringent but closed, sealed and disposable processes and their technologies will lower the impact of environmental excursions but it will not eliminate the need for due diligence of maintenance and monitoring.
Proper process design and knowledge should lead a manufacturer to establish and maintain a facility that is fit for the intended product and process use. The intended use of the space may not always be part of the initial design but knowing the consequences of the environment on the product and process is incumbent on all manufacturers' facilities and storage space. Likewise the traffic and manufacturing patterns of the equipment and operators in a facility can have the greatest impact on maintaining a manufacturing facility under environmental control and as such all necessary procedural and engineering controls should be employed to minimize that impact. These controls, of course, should be tempered with common sense to address the process and product requirements without over taxing the operators and resource to run the same. The FDA Guidance to Industry on Process Validation is clear on the expectation that process design will lead to process knowledge and a control strategy for the same. Don't leave your environmental monitoring to chance - design, build, qualify and maintain a system that preserves a quality manufacturing process.
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