Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug Substances

The control of the environment around biologics manufacturing has historically been a key consideration for the design and operation of bioprocessing facilities to ensure product quality and safety. Facility design and control considerations for commercial biopharmaceutical manufacturing processes include environmental controls (e.g., temperature, humidity, and pressure), air quality (e.g., particulate and microbiological), facility finishes, gowning and flow procedures, equipment containment, system integrity, and cleaning procedures.

These controls were developed through interpretation of regulatory requirements for both nonsterile and sterile biologics manufacturing decades ago and have been replicated based on successful regulatory precedent. The most common approach taken by the biopharmaceutical industry was to establish a secondary layer of environmental control via the application of area or room air classification. This was in addition to the primary approach of designing and operating contained processes with qualified cleaning, and using sterilization procedures with appropriate microbial and viral controls.

The most widely adopted room classifications in use today range from grade A/ISO 5 (dynamic) through grade D/ISO 8 (static) based on the perceived risk of environmental contamination to the process step (see Figure 1) (1). Room classification is also driven by segregation and environmental, health, and safety (EHS) requirements. Open processing increases the need for stringent environmental controls, while closed or functionally-closed processing decreases the dependence of the process on environmental controls.

Figure 1: Common biopharmaceutical unit operations and the area classifications that contributing manufacturers established around those unit operations. For many of the unit operations, different manufacturers use significantly different area classifications, and in general, no consensus can be drawn from the status-quo data. It is likely that some manufacturers are using risk-based approaches to determine the area classifications while many others are relying on historical precedent.

Advances in process technologies and analytics enable manufacturers to close, contain, and monitor more of their process steps so that environmental controls are less important than they were in the past. Scientific, risk-based approaches can be applied to determine the environmental controls that are appropriate for a particular process step. This article describes a revised approach to defining an appropriate level of control resulting in potentially lower capital investment, operating costs, and a reduced carbon footprint, without compromising product quality or risk of product contamination.

DEFINITIONS

Closed system: A process system with equipment designed and operated such that the product is not exposed to the room environment. Materials may be introduced to a closed system, but the addition must be done in such a way to avoid exposure of the product to the room environment (e.g., by 0.2 µm filtration).

Functionally closed: A process system that may be routinely opened (e.g., to install a filter or make a connection), but is returned to a closed state through a sanitization or sterilization step prior to process use. It is the owner's responsibility to define and validate the sanitization or sterilization process required to return an opened system to a functionally closed system.

Open system: A process system that exposes the product to the room environment. In these systems, the room environment is controlled to minimize the risk of product contamination. For nonsterile, bioburden-controlled processing, open operations are expected to be performed in a classified environment, such as grade C. The process fluid is often filtered for bioburden control within a controlled amount of time after completion of any open process step.

Sanitization: To make sanitary by cleaning and disinfection, but not necessarily sterile. Sanitization reduces viable microorganisms to defined acceptance level. Sanitization can be accomplished by chemical exposure or elevated temperature. Clean-in-place (CIP) procedures may accomplish sanitization, especially CIP procedures that use caustic and hot water rinses (water-for-injection [WFI] or high-purity-water [HPW]). Steam sanitization is a very effective sanitization method and can, if properly designed and validated, achieve sterilization. However, steam is not required for sanitization.

Sterilization: To make free of living microorganisms. In biopharmaceutical processing, sterilization is often accomplished via exposure to saturated steam at temperatures ≥ 121.1° C using a validated sterilization procedure.

Controlled not classified (CNC): A cGMP manufacturing area designed to produce a consistent and controlled environment, but not necessarily monitored to a given environmental classification. CNC is similarly defined by the International Society for Pharmaceutical Engineering (ISPE) Biopharmaceutical Manufacturing Facilities Baseline Guide as "a non-classified room environment where closed processes and their immediate support systems may be located. CNC space is cleanable, access controlled, and served with filtered ventilation air. Procedural controls and personnel garment upgrades may be applied at the Owner's discretion" (2).

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.

BIOPROCESSING STEPS REQUIRING RISK MITIGATION

In a closed or functionally-closed system, the process stream is isolated from the environment. These types of designs should be used wherever possible. If there are open operations, however, the process stream could potentially be exposed to chemical or biological contaminants, such as micro-organisms or adventitious agents. Chemical contamination could result in the adulteration of the bulk drug substance (BDS). If micro-organisms enter the process stream or process equipment, they have the potential to propagate. Even if the organisms are subsequently removed by filtration, they may leave behind proteases that could damage the target molecule or toxins that could be harmful to the patient if not removed. If an adventitious virus enters the upstream process, it could potentially propagate in the cell culture and result in a temporary facility shutdown. If an adventitious virus enters the downstream process, there is no mechanism for propagation, and a low-titer contamination could go undetected.

Traditional facilities with classified areas and segregation are also designed to prevent cross-contaminations in which traces of upstream material bypass purification steps and re-enter at a downstream process step. Such upstream-to-downstream cross-contamination could defeat mechanisms in the process to remove host-cell impurities or endogenous agents.

Cross-contamination risks due to open operations may be higher in multi-product facilities (MPF) where more than one product is being produced simultaneously in the same suite. Multi-product operation is not specifically addressed in this article. The risk-based approaches described here are, however, also applicable to multi-product facilities and may be addressed in future articles.

As discussed in the previous sections, state-of-the-art biomanufacturing facilities are largely closed or functionally closed, but some open operations occur. The following are operational examples in biomanufacturing facilities that are commonly open, with suggestions on how risks may be mitigated to enable CNC operation.

Temporary breakable connections

Processes with portable vessels and equipment often use hoses to transfer solutions. These hoses are typically fastened with sanitary clamp connections. In many instances, hoses are connected in a cleanroom environment without subsequent sanitization prior to solution transfer. In these cases, the cleanroom environment provides some protection against airborne contaminants, but does little to prevent contamination due to surface transfer. Cleaning and storage of process hoses can also be an open process, and status tracking of hoses can be challenging. Connections to transfer panels (e.g. via U-bend swing connections) or WFI/HPW drops are often made in an open fashion without subsequent sanitization of the connection point.

Suggestions for risk mitigation: The flow path could be sanitized after an open connection is made (e.g., with clean steam, CIP solution, or hot WFI). If a sanitization step is not practical, rinsing the line with WFI/HPW or a buffer solution may flush bioburden or other contaminants to an acceptable level. The process may also be kept closed by using presanitized hoses or tubing with single-use aseptic connectors.

Open manipulation of the process stream

Some operations, like inoculum expansion, lend themselves to open operations. Inoculum manipulations are typically performed inside a unidirectional airflow hood that is located in a cleanroom environment (typically grade C). The hood, cleanroom, gowning, and the aseptic techniques employed by the technicians are important for preventing contamination of the cell culture while handling during transfer operations. Also, at this early stage in the process, a microbial or viral contamination of the cell culture is likely to be detected, which mitigates risk to product quality and safety.

Suggestions for risk mitigation: While it is feasible to do open inoculum manipulations in an isolator, experience to date favors continuing the current practice of open manipulation in a unidirectional airflow hood located in a classified environment. A number of single-use technologies are available that allow most of the inoculum expansion process to be closed, but open handling may still be required for the vial thaw and preliminary cell culture manipulations.

In some processes, when an in-line process filter clogs, the process is paused, and a new filter is installed. The procedure for installing the new filter is frequently open, and there is a potential for contamination of the process stream that is partially mitigated by the room environment.

Further suggestions for risk mitigation: The most effective mitigation is to size filters so that clogging events are infrequent. However, a contingency plan for dealing with clogged filters may be required. A spare in-process filter could be installed in parallel and sanitized before the start of operations. This could be a costly solution if filter-clogging events are frequent. The system can be designed for a replacement filter to be installed, flushed, and steamed in place while the process is paused. Alternatively, a method of installing a pre-sanitized filter into a closed system could be implemented using technologies such as sterile tubing welding.

Charging raw materials during media or solution preparation

In some instances, solids or liquid raw materials can be added directly to the process stream (e.g., in a downstream process step). In most instances, however, the materials are charged into a vessel and dissolved into water to produce a solution (e.g., bioreactor media or chromatography buffer). Solutions may be dispensed directly from the vessels in which they were prepared or transferred from the preparation vessel into a storage vessel or container. Filtration processes frequently occur during the fluid transfer to the storage container to reduce bioburden or particulates. Raw material charging operations are frequently open processes because the cost of making these operations closed or functionally closed is prohibitively high and is not justified by the risk.

Suggestions for risk mitigation: There are methods to substantially close powder charging operations. Raw materials can be pre-weighed into bags, and a protected addition mechanism can be implemented at the preparation vessel. Limiting clean hold times prior to preparation, or the preparation and filtration time itself, can mitigate microbial growth risks.

Equipment preparation

Some equipment preparation operations may be open (e.g., inserting diptubes, installing probes after offline calibration, or attaching vent filters). Processes should be designed so that these operations occur prior to sanitization or sterilization.

Chromatography column packing operations are typically open at some point. The extreme case is when resin slurry is prepared and then poured directly into the column with its top head removed, but pack-in-place procedures are also usually open processes. Some chromatography resins are sanitized with sodium hydroxide after packing or re-packing, but resins that use biologically-derived ligands typically employ milder sanitization agents. Through an open packing process, there is a risk that a biological or chemical contaminant could enter the process stream. When unpacking, there is a risk that endogenous retroviruses, not removed through sanitization procedures, could enter the process area and potentially contaminate downstream purification steps.

Suggestions for risk mitigation: In principle, an engineering solution for closed-system column packing could be developed. Hoses could be sanitized prior to packing or unpacking operations, and residual resin slurry could be flushed from the system prior to disassembly. The cost of such an engineered solution may not be justified. Risk analysis tools should be employed to determine if a segregated area for column packing is needed or if post-packing sanitization procedures are sufficient to mitigate risk. Pre-sanitized, pre-packed columns are available for some resins at column volumes up to 20 L, which could allow on-site column packing to be avoided altogether.

Assembly of depth filters for clarifying a bioreactor's harvest broth is also typically an open process. Traditionally, filter elements are installed in a clean, stainless steel filter housing, and this is still a common practice. In recent years, disposable depth filter cartridges (including housings) have been introduced to the market. However, these cartridges are typically not pre-sterilized (i.e., through gamma irradiation) and are usually assembled in an open operation by the end user. Options for sanitizing the depth filters after assembly are limited. Most depth filters cannot be steam sanitized, autoclaved, or chemically sanitized, so a hot WFI rinse may be the most effective sanitization measure that can be implemented.

Further suggestions for risk mitigation: Depth filters are often flushed before use to minimize leachables and extractables. Upstream and downstream connections could be made prior to this flush. The subsequent hot WFI flush would then sanitize the connection points, hoses, and the filter material before use.

Cleaning or maintenance activities

Manual cleaning procedures are by definition open, but even automated cleaning cycles may involve some manual steps. For some vessels, sprayballs may be installed prior to the cleaning procedure and then removed at the conclusion of the cleaning procedure. Hoses may be open to the environment when they are connected to a cleaning manifold. When opened, soiled equipment poses a cross-contamination risk. Materials could contaminate operators who may then carry that contamination to another part of the process. Contaminants may also be carried by airborne aerosols.

Equipment that is usually closed may be open during maintenance activities and must be cleaned and sanitized or sterilized after maintenance to re-establish the closed system environment.

Suggestions for risk mitigation: Manual cleaning areas should be segregated from process areas to avoid cross-contamination due to disassembly. Procedural controls can be established to minimize the potential for operators to carry contaminants throughout the facility. Functionally closed systems must be designed such that they are not opened until after process fluids have been flushed from the system. Manufacturers must demonstrate that equipment can be brought back into a state of control after maintenance activities have been performed.

In-process sampling

Closed-system sampling systems are available for biopharmaceutical processes, but they can be expensive. Sometimes the risk of contamination does not warrant the use of a closed-system sampling method, particularly if the process is performed inside a cleanroom. Open sampling operations still exist in which the operator opens a manual valve and a sample is collected in an open container (e.g., a centrifuge tube).

Suggestions for risk mitigation: Closed-system sampling devices are now readily available, and the increasing number of vendors offering these systems may lead to lower costs. If open sampling is still used, the owner must show that the risk of contamination is acceptably low and that cross-contamination risks are mitigated.

Unexpected breach of a closed-system element

Single-use elements (e.g., tubing or bio-process bags) are commonly used in biomanufacturing processes. These elements can be presterilized by gamma-irradiation There are a number of single-use connectors on the market that enable the sanitization of connection points. Single-use elements offer process designers a number of options for establishing functionally-closed systems and isolating the process from the environment. Single-use elements are, however, subject to breaches or leaks. Bioprocess bags may leak if they are defective or if they are mishandled. Cable-tie connections may fail, and tubing can kink and rupture. Contamination due to breaches in single-use elements may be partially mitigated when the process occurs inside a cleanroom environment.

Suggestions for risk mitigation: As experience is gained by both vendors and operators, the risk of unexpected breaches of single-use systems should be reduced to an acceptable level. Vendors must develop robust systems that resist tears and breaches. Owners must develop engineering and procedural controls to prevent tubing kinks or bioprocess bag breaches. When warranted, pre- or post-use integrity tests can be employed for single-use elements.

Vent filters are often required on process vessels and occasionally on single-use systems, and may be single- or multiple-use. When operating in a controlled cleanroom environment, vent filters are often installed in an open fashion in nonsterile processes. If there is an integrity breach of a vent filter, there is a potential for the contents of the vessel to be contaminated by the room environment. Contamination due to integrity failures of the vent filter may be partially mitigated when the process occurs inside a cleanroom.

Further suggestions for risk mitigation: If the vent filter is attached to a bioprocess bag, the bag and filter may be ordered as a single assembly and irradiated together. If the vent filter is attached to a stainless-steel vessel, it is possible to sanitize the filter and the connection point after the installation of the filter. Post-use integrity testing can be implemented to detect vent filter integrity breaches. A post-use test will protect the patient, but it may not prevent loss of product. Some systems are designed to continuously operate at a positive pressure relative to the external environment to mitigate potential vent filter breaches.

AN EXAMPLE FAILURE MODES AND EFFECTS ANALYSIS

There are a number of potential risks associated with performing operations in a CNC environment. The magnitude of these risks, however, depends on the type of drug substance that is being manufactured, the particular unit operation that is being performed, and the position of a particular step in the overall process. The risk is context-specific, and mitigations should be employed that are commensurate with the magnitude of the risk. Failure modes and effects analysis (FMEA) is a tool that can be used to identify risks for a particular process and to direct design teams toward appropriate mitigating measures. In this section, an example failure mode is examined for illustration.

Consider a process in which the formulation of a BDS is performed by ultrafiltration and diafiltration. The authors are interested in evaluating the risk of an adventitious virus contaminating the BDS at this point in the process. This unit operation has no ability to remove or inactivate viruses and there are no viral reduction steps downstream of this step. The analysis assumes that the manufacturer has many years of experience performing this operation in a Grade C environment and now wishes to perform this same operation in a CNC environment.

Table II shows an FMEA analysis of this failure mode. The impact of the failure is assigned a value of HIGH because viruses could be potentially harmful to the patient. In the next column, possible causes of adventitious viral contamination are listed, and measures designed to mitigate the identified causes are listed in the adjacent column.

Table II: An example failure modes and effects analysis to identify and evaluate risks associated with adventitious viral contamination of a bulk drug substance formulation operation using an ultrafiltration/diafiltration unit operation. (QI is quality impact, QR is quality risk, BI is business impact, BR is business risk, UF is ultrafiltration, PCR is polymerase chain reaction, AVA is adventitious agent assay)

Next, the probability of occurrence is evaluated given the measures that are in place. A value of LOW is assigned to the probability, and the rationale for this value is that there has been no known incident of viral contamination in the history of the operation, and operating in a CNC environment does not increase the probability of contamination.

The detection point is given a value of NO. This means that if the event were to occur, it is possible that the event would not be detected prior to the release of the final container product. Adventitious virus assays may not detect low-titer contaminations and polymerase chain reaction (PCR) testing will only detect selected viruses.

In this case, the team assigned a risk of MEDIUM to this failure mode. The impact is HIGH, the probability of occurrence is LOW, and there is possibly no detection point. The team indicated that more data are needed regarding the effectiveness of caustic sanitization of the ultrafiltration cassettes after installation. They also identify that the raw materials for the diafiltration buffer could potentially carry a virus and that treatment, or other control options for the buffer should be explored. It should be noted that this risk of viral contamination exists regardless of the area classification under which the UF/DF operation is performed.

In this example, the operators wear dedicated shoes and change into a plant uniform. The UF skid is sanitized prior to each batch and the connections to the skid are steamed after the connections are made. The mitigations are specific to a particular product, operation, facility, and manufacturer. Different facilities and manufacturers will implement this process step differently. For example, a different manufacturer may not choose steam sanitization for the skid. The FMEA tool allows manufacturers to evaluate the details of their particular operation and determine whether or not additional mitigating measures are required to enable CNC operation.

PROVING THE EFFECTIVENESS OF SANITIZATION METHODS

If a manufacturer only has experience performing a particular unit operation in a grade C or grade D environment, data may be required to convince internal stakeholders and external regulators that CNC operation is acceptable.

Functionally-closed systems require a sanitization step after the system has been opened, and the effectiveness of the sanitization step is key to proving that CNC operation is feasible. Clean steam is a well-established mechanism for sanitizing process equipment. Steam sanitization is not, however, always feasible or economical. If other sanitization methods are used to establish functionally-closed systems (e.g., caustic solutions or hot WFI), data must be shown to support the effectiveness of those methods. Some data are available in published literature, but demonstrating the effectiveness of the sanitization method in the configuration that is proposed may also be needed. Deliberate contamination of process equipment is not desirable, but a relatively inexpensive test system could be constructed to simulate conditions in the target process equipment.

Consider the case in which the test system is used to challenge the connection of a single-use element to stainless steel equipment. The test system would initially be clean. Prior to making the connection, the single-use element would be contaminated with a known amount of a biological contaminant (e.g., bacterial, fungus, yeast, etc.). After connection, a caustic solution sanitization regimen would be applied and then flushed from the system. Then, a process fluid would be pumped into the system and circulated. The fluid would be chosen to represent fluids used in the manufacturing process. After the circulation period, a sample would be withdrawn from the system and tested for the presence of the target organism. The concentration of the microorganism in the sample would provide information regarding the effectiveness of the sanitization method. The premise is that if the sanitization method is sufficient to remove a deliberate contamination, it will be sufficient for operation in a CNC space.

ENDORSEMENT BY INTERNAL QUALITY REPRESENTATIVES AND HEALTH AUTHORITIES

Facility design for bulk biopharmaceutical manufacturing is a direct descendent of regulatory expectations for biologics manufacturing. Design principles for BDS manufacturing have been extrapolated from guidance documents and regulations developed for aseptic processing (i.e., final product manufacturing). Historically, this design precedent has been copied, repeated, and considered "industry standard" based on successful licensure of products sourced from these facilities. Facility design concepts have remained essentially stagnant while process enhancements continue to provide additional assurance that the drug substances will consistently meet their quality attributes. The following arguments should be considered when seeking endorsement for CNC processing from internal quality representatives or from external regulators.

Process design and capability for clearance

Bioburden and viral clearance steps in the process should be emphasized when considering measures that mitigate risk. For example, the use of bioburden reduction and viral filters within the process can provide assurance that in-process intermediates and the final BDS will meet its predetermined quality attributes.

Precise and specific knowledge drives contamination control strategy

Supportive controls such as air cascade designs, gowning procedures, and cleaning regimens can reduce variability in the manufacturing environment. Risk analysis should lead to a comprehensive microbial control strategy. Knowledge and understanding of the variables that may impact process quality should be the foundation for the microbial control strategy.

Routine in-process microbiological testing

In-process bioburden testing of intermediate process steps should be established to ensure process control. Microbiological alert levels should be established for each process step based on demonstrated process capability. Action levels should be established to identify excursions that may impact final BDS quality. Data should be actively trended to identify any shifts or changes in the variability of the process.

Critical quality attribute testing

Microbial, biochemical, and adventitious agent testing should be in place for the final BDS with established alert levels and specifications. The alert levels should be indicative of the process capability and the specifications of the quality attributes. Data should be actively trended to identify any shifts or changes in the variability of the process.

Procedural control and compliance

Closed or functionally-closed systems should be considered first when designing connections. If a closed-system design is not practical or possible, temporary breakable connections can be controlled through robust procedural controls that ensure consistency. Biopharmaceutical manufacturers have extensive experience in implementing manual procedures, and ensuring compliance with those procedures through training programs and internal auditing.

Studies to support the control strategy in a CNC environment

There are numerous supporting studies that can be used to support the robustness of processes operating in a CNC environment with respect to microbial and adventitious agent control. Unit operations can be evaluated to assess the impact of planned breaks to process closure using surrogate bacteriostatic buffers or media to quantify impact from the environment. Demonstration and quantification of bioburden reduction through efficacy studies for cleaning, sanitizing, and sterilization processes can eliminate the sources of microbial contamination from the environment.

A review and assessment of historical process contaminants versus environmental isolates can provide evidence that disassociates microorganisms found in the external environment from process contaminations. The qualification and validation of assays ensures that the sensitivity is suitable to detect all levels of microbial contamination.

The most compelling justification for operating under CNC conditions is a full-scale demonstration of the process. Data generated from such a demonstration will most likely address the concerns of internal quality assurance and external regulatory representatives. Such a demonstration is relatively straightforward to organize during engineering or development batches for a new product. Economic and product supply considerations as well as the estimated probability of success would be key variables in the decision to demonstrate CNC operation for currently commercialized products. Small-scale or pilot-scale data may be required to convince internal stakeholders to authorize a full-scale demonstration.

THE WAY FORWARD– A ROADMAP FOR THE INDUSTRY

Current good manufacturing practices evolve with new technologies, continuous improvements, and science-based evaluations of the status quo. Regulatory expectations are often slower to evolve. Process improvements are reviewed on a case-by-case basis until sufficient experience is available for a consensus opinion. In the case of BDS manufacturing, the following actions are recommended to advocate for this new industry paradigm of functionally closed manufacturing in a CNC environment:

• Keep an eye on the leaders—monitor pharmaceutical and regulatory websites and journals for facility information

• Influence decision-makers and build consensus—attend meetings in industry organizations, particularly those attended by health authority representatives

• Participate in industry groups and consortia to share and learn from others

• Design facilities using formal risk assessments specific to processes, validation, and testing

• Partner with the agencies and actively advocate a scientific, risk-based approach and solicit feedback via design review meetings.

CONCLUSIONS

Biopharmaceutical manufacturing in classified cleanrooms is the current status quo across the industry for many BDS process steps. Technologies for processing in closed or functionally closed systems have evolved rapidly in recent years. These technologies were developed to address the risks of open cleanroom operations, and they now call into question the need for classified environments. It is time to rethink the approach for controlling contamination risks in biopharmaceutical processes so that safe operations can be executed at lower cost and with less impact on the external environment. Scientific, risk-based approaches should be employed when determining the required environmental conditions for a particular process step. Significant opportunities are within reach if the industry moves, in concert, away from historical precedent toward a methodical, scientific, risk-based approach for the design and operation of biopharmaceutical manufacturing facilities.

ACKNOWLEDGMENTS

The authors thank the following for their input by reviewing the article and providing benchmark information: Thomas Dazkowski, vice-president of process technology, healthcare at Bayer Technology Services; Raul Santiago, head of engineering at BMS; Steven Kreisher, head of engineering at Janssen; Paul Smock, head of quality at MedImmune; Petra Wawra, manager, downstream operations at Merck Serono; Carl Johnson, principal engineer at Genentech; Benno Steinweg, head of technical compliance at Sanofi; Thomas Sauer, head of new products and industrialization at Sanofi; and Beth Junker, senior director bioprocess R&D at Merck. We also thank Marc Reifferscheid, Rene Fischer, and Markus Schneider from Novartis for their significant contribution during the benchmarking phase of the collaboration.

Simon Chalk* is director at BioPhorum Operations Group, Ryan Taber is business unit leader, biologics manufacturing at Abbott, Scott Probst is a principal technology specialist at Bayer Technology Services, Paul Gil is in global regulatory affairs at Bayer HealthCare, Tim Palberg is a venture manager at Bayer HealthCare, Matt Kennedy is manager, process engineering at GlaxoSmithKline, Joe Rogalewicz is a quality director at GlaxoSmithKline, Jeff Johnson is engineering director, Global Engineering Services at Merck, and Ken Green is director, bioprocessing at Pfizer. *To whom correspondance should be addressed, simon@biophorum.com.

REFERENCES

1. ISO, ISO 14644-1, Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness Cleanroom Standards (1999).

2. ISPE, Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities, Vol. 6: Biopharmaceuticals (ISPE, June 2004, Glossary, Updated June 23, 2010).