Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug Substances - The authors re-examine environmental controls in the context of technical advances in manufacturing. -

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Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug Substances
The authors re-examine environmental controls in the context of technical advances in manufacturing.


BioPharm International
Volume 24, Issue 7, pp. 44-60

THE OPPORTUNITY FOR A NEW WAY OF THINKING

Technological advances have continuously reduced the risk of environmental impact on the process stream. Open processing has been reduced to a select few process steps. For example, portable laminar flow hoods are still employed to create a localized controlled environment during brief open manipulations.

There is a consensus among the authors that the historical and current heating, ventilation, air conditioning (HVAC) design and control elements can be safely reduced without any potential impact to process hygiene provided that appropriate process controls are implemented and are demonstrated to protect the process stream from the environment.

Companies have been hesitant to fully exploit process technology advances mainly due to regulatory precedent. Regulatory guidance documents should be revised to reflect recent advances in technologies and process controls. This is the right time to adopt a scientific, risk-based approach to develop a revised process hygiene control strategy for biopharmaceutical manufacturing. Full credit should be taken for process steps that are closed or functionally closed when determining area classifications.

To date, several facilities have successfully eliminated or reduced area classifications with approval by US and European Union authorities. Significant benefits will be achieved by building on these examples and using accepted scientific approaches. Gaining acceptance for this revised way of thinking among quality personnel and regulatory authorities is critical for the success of the industry as a whole.

THE CONSENSUS FUTURE STATE AND ASSOCIATED POTENTIAL BENEFITS


Table I: Consensus on minimum acceptable baseline for controlled not classified (CNC) space.
The participating biopharmaceutical companies developed a consensus baseline for CNC manufacturing space. This definition was needed to quantify and normalize the benefits of reducing area classifications. Table I is a presentation of the consensus for the minimum acceptable elements for CNC designated space.

The potential benefits to existing facilities include reduced energy consumption (e.g., gas and electricity), reduced environmental monitoring, and lower operating expenses (e.g., HEPA filters, gowning) (see Figure 2). For new facilities, capital costs related to HVAC equipment and ducting and architectural finishes may be reduced.


Figure 2: The potential for cost savings per year based on a typical bulk drug substance biofacility with 180 production operators, 15,000 ft2 of class ’C’ space changing to controlled not classified (CNC), air changes reducing from 30 to 10 per hour, and relative humidity ranges from 45% to 60%. The data provided and analyzed are from the participating companies and cover a range of manufacturing scales and facility ages.
More efficient energy consumption is achieved by reducing air change rates, minimizing outside makeup air, increasing temperature ranges and relative humidity ranges, and eliminating or decreasing the number of HEPA filters. Air-change rates are for personnel safety and comfort, machine safety, and process heat dissipation and do not support classification. Participating companies reported an average $50/ft2/yr cost for gas and electricity associated with operating class 'C' environments. Furthermore, they calculated potential reductions of 50% ( 25%) by moving to CNC.

Environmental monitoring costs are decreased by reducing sampling and testing (e.g., particulate, bioburden, HEPA certifications) and by decreasing the number of investigations for environmental monitoring deviations. Operating costs are also decreased by eliminating expensive garments from the gowning regimen and by simplifying facility cleaning procedures.


Figure 3: Reduced capital cost from a typical scale biofacility concept design (15,000 ft2). This has been projected based on controlled not classified (CNC) requirements compared to "C" class requirements and a change in cost per sqare foot of $100.
Capital costs for new facilities are potentially reduced because smaller areas are needed (ballroom-type design and less unidirectional flow and segregation) and by employing more cost-effective architectural finishes that are cleanable and durable but are not currently accepted for classified environments. Finally, capital cost savings will be achieved through reduced air handler unit and duct sizes, control system simplification, reduced requirements for differential pressure and outside air conditioning, and less expensive filters. A less complicated HVAC system and reduced environmental monitoring requirements will also result in cost savings and shorter timescales during facility qualification (see Figure 3).


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