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
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.
Table I: Consensus on minimum acceptable baseline for controlled not classified (CNC) 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.
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.
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.
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.
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).
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.