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BioPharm International, August 2011 Issue (PDF)

The pharmaceutical industry accounts for about $65 billion of annual expenditure in the US. Each day of product development costs approximately $1 million in expenses and at least $0.5 million in losses from not having yet commercialized that product. These costs are anticipated to nearly double between 2008 and 2012 because of the projected increase in the costs of human and material resources and of meeting regulatory expectations. As a result, improvements in process efficiency and delivery become of paramount importance for a viable business. Process development (PD), technological, and learning capabilities are even more critical for efficiency in commercializing complex biological products (1). In the current economic environment, additional pressure to increase efficiency arises from the need to advance multiple projects through the pipeline without increasing resources.   

The development of chronic therapies for rare diseases proceeds differently than the typical pharmaceutical development paradigm. A two-cycle approach (see Figure 1) is used for clinical development of therapies for rare diseases, which includes a safety and dose-finding Phase I and II clinical study followed by a pivotal Phase III clinical trial. Unlike a typical three-phase clinical development program (a Phase I safety clinical study, a Phase II dose-finding study, and pivotal Phase III trials) where manufacturing process changes are typically introduced at the initiation of each phase, the contrived breakpoints of a two-cycle development model create a higher need to perform PD in advance so that a commercial process can be introduced into the pivotal trial within approximately three years instead of the more common five to six years. Process changes are more difficult to introduce as there are not multiple clinical programs by which clinical experience with the new process can be gained. Introducing postcommercial changes which might affect product quality are even more difficult because of the limited number of patients with these diseases in whom clinical comparability trials can be conducted. The low patient numbers often result in the manufacture of a small number of batches to supply clinical studies and market needs, leading to limited data at the time of commercialization and limited time for the manufacturing group to become experts. The shortened overall development timelines and the small quantities needed result in a greater reliance on development-scale studies to support manufacturing, stability programs, and specifications at the time of licensure.  

Figure 1: Two-cycle development process used in development of enzyme replacement therapies for rare genetic diseases. The typical pharmaceutical product development consists of three clinical development phases: Phase I (safety), Phase II (dose-finding), and pivotal trial Phase III studies, providing time for three-cycle sequential process development and the implementation of manufacturing changes at the initiation of each phase.  For rare diseases, the clinical development is often condensed to two phases as depicted in this figure: a safety and dose-finding combined Phase I and II followed by a dose verification and pivotal trial PII/III study. The shortened time and limited number of clinical studies results in  two-cycle overlapping process development, where the commercial process is developed during tech transfer and implementation of the Phase I process, and requires rigorous front-loaded process development activities.  

To manage the constraints and increase the efficiency of this two-cycle approach to product development of highly glycosylated proteins for rare diseases, the the following three steps were taken: 

1. Technology platforms were developed that were linked to manufacturing capabilities and built on the knowledge gained with each enzyme replacement therapy (ERT) development. Developing process and analytical technology platforms for the highly glycosylated lysosomal enzymes transformed the initial trial-and-error development model to a more cost-effective strategy by establishing a small-scale model in the PD department to represent manufacturing scale. 

2. A systematic and integrated approach to PD, called the PD life cycle, was applied to define the appropriate questions and issues to be addressed at the appropriate time within the clinical-development program. Starting the PD life cycle by determining the technical feasibility of product and process targets, followed by refining the targets and development plans based on the knowledge gained at each phase, enables the efficient use of resources and minimizes rework while improving the ability to handle multiple programs in a consistent manner.   

3. Business processes were developed and applied for integrated PD planning, decision making, and communicating with stakeholders. 

Through the use of the above mechanisms, knowledge gained from the commercialization of one product has increased the efficiency of development of the next product, resulting in continuous improvement. This article describes this three–pronged approach to ERT product development. These concepts can also be applied when developing other types of pharmaceutical products. 

Condensed clinical trials consisting of combined Phase I and II to assess safety, pharmacokinetics, and dose-dependent pharmacodynamics, and Phase III to assess efficacy, instead of discrete Phase I, Phase II, and Phase III clinical studies. 

Clinical trials leading to commercialization of a new drug are typically classified into three phases, each requiring regulatory approval before proceeding to the next: Phase I assesses safety, tolerability, pharmacokinetics, pharmacodynamics, Phase II assesses safety and dose-ranging efficacy in a larger population, and Phase III assesses definitive efficacy of the drug. 

 Structured approach to PD consisting of four stages of defined studies to address the needs of the given product development phase and increase predictability of success at manufacturing scale. The stages are technical feasibility, development, optimization, and confirmation or qualification. 

Target process and product profile (TPPP):

 Detailed, desirable targets for process (e.g., titer and yield to meet manufacturing capacity and supply demand needs) and for product (e.g., protein concentration, excipient, and product quality to meet the dose and administration route requirements for the given patient population). Upon completion of PD optimization, the final (actual) process and product profile (PPP) is defined. 

GAINING EFFICIENCY THROUGH TECHNOLOGY PLATFORMS 

Although process technology platforms have been established for manufacturing monoclonal antibodies over the past two decades, such benefit was not available for other protein products such as ERTs. This section summarizes the evolution and effect of PD platforms established for these complex enzymes to accommodate accelerated development. Such platforms allowed efficient PD and predictable scale-up performance. 

Glycosylation is critical to targeting the cellular uptake of lysosomal enzymes and their localization into lysosomes, requiring the development of platform process technologies to generate such highly glycosylated proteins. One of the systems used for expressing these glycoproteins was a human cell line (2, 3). Expression in human cell lines required building knowledge to improve titer, to grow cells in suspension, to control critical attributes, and thereby to increase production yields and tighten process controls. The cell culture process changed from roller-bottle to bioreactor process, thus leading to increased yields and better process control. The bioreactor cell-culture process could be conducted in either batch or perfusion mode, depending on factors such as the stability of the enzymes in the culture media and the desired product output. Animal-derived serum or plant hydrolysate initially used in the cell-culture media was later replaced with chemically defined media to ensure consistent raw materials and control of the process. To this end, the cell lines were adapted from an attached line on roller bottles to suspension culture, first on microcarriers, and eventually free of any carriers.  These combined changes were implemented over three years and consumed approximately 25 PD full-time equivalents to accomplish. Applying the cumulated process knowledge to build process platforms led to efficiency in development time and lower cost. 

Simultaneous measures for standardizing PD were introduced during the past eight years. Rapid screening of chromatographic resins is now performed to more efficiently identify suitable resins and initial conditions. Although each process must be adapted to the unique features of each enzyme, a standard purification process flow has been established; for example, an initial capture step, one or more viral inactivation steps, chromatographic steps, and ultrafiltration or diafiltration steps. In the purification area, small-scale models were developed to systematically learn about the effect of upstream and downstream processes on product quality. To accommodate the large number of samples generated by the process groups, the analytical strategy had to be revised. A decision was made to invest in robotics. Robots were subsequently adapted to perform analytical methods, such as enzyme-linked immunosorbent assay and enzyme-activity assay determinations, at a throughput of approximately 2000 samples per week.   

The organizational structure was changed to define a centralized unit dedicated to supporting PD testing, to remove the conflict between development and routine testing activities. Systems were defined to accommodate sample-in, data-out for multiple projects from multiple stakeholders. Such investment and restructuring allowed for an order of magnitude increase in the sample testing throughput (see Figure 2). Additional automation was introduced in the bioassay development to speed up analytical optimization while addressing the complexity and variability in such assays. The overall effect of the combined changes was a doubling of PD capacity for developing multiple complex enzymes at a time.  

Figure 2: Outcome of organizational redesign to enable faster process development (PD). Sample throughput was increased by orders of magnitude by centralizing dedicated analytical resources to support process development and introducing robotics. These changes enabled development of multiple products in a systematic and more efficient manner. This organizational redesign freed up resources in cell culture and purification PD, allowing analysts to focus on process, and enhanced the efficiency of the analysts by not requiring them to divide their time between development and routine testing priorities.  

A key component of enhanced PD effectiveness was the technical problem-solving approach that provided feedback about gaps between the desired and the actual performance at manufacturing scale. Basic knowledge about the process–product relationship was gained during a decade of developing ERTs, initially through trial and error, later through using previous knowledge to design small-scale or pilot-scale studies that would predict process performance and minimize rework at the manufacturing scale. Specifically, a large-scale development laboratory at pilot scale was built to verify the lab-scale studies before implementation at the manufacturing scale.  Small-scale and pilot-scale studies to characterize the process and to define the design space, process parameters, and process ranges also provided more efficient and effective mechanisms to resolve manufacturing investigations. 

GAINING EFFICIENCY THROUGH PROCESS DEVELOPMENT LIFE CYCLE STAGED PLANNING

Efficiency in PD can be gained by a standardized approach to studies that answers the right questions at the right time, taking into consideration the interdependencies between the different product development functions, including the four PD disciplines for biological products: cell culture PD, purification PD, analytical development, and pharmaceutical development. Although the general questions asked at each product development phase are similar for all projects, the specifics vary depending on the properties of the molecule and the development strategy. This standardized approach aims to optimize the output in terms of overall process/product development rather than optimizing each separate discipline. 

Figure 3: Key elements of process-development (PD) life cycle. The four stages of PD life cycle are depicted on the top left insert, illustrating the exploratory nature of the technical feasibility stage and the increasing predictability of technical success through the other stages as knowledge is gained. The intent and outcomes of each stage are listed on the top half of the schematic. The bottom half depicts the clinical-phase dependent application of each PD life-cycle stage; the time spent in each stage is not drawn to scale (see Figure 4 for scaled timing). Technical feasibility stage is when the boundaries of development and its limitations are defined (square symbol), development stage is tied to the scope/resource/quality (triangle symbol), optimization stage renders the final conditions (star symbol), and confirmation and qualification stage is when successful implementation of the final process is demonstrated (check symbol).  Process characterization and other biological license agreement-enabling studies are done in preparation for process validation and subsequent commercialization of the product.  

Shire's PD department created a PD life cycle that structures development studies into stages according to the needs of each product development phase. Figure 3 depicts PD life-cycle stages with key purpose and deliverables. The cycle starts with a draft TPPP based on customer input to meet the development program's strategy. The exploratory stage of technical feasibility assesses the technical hurdles to achieve these targets. The technical hurdles may require refinement of the program's strategy, including changes to targets or timelines. The predictability of development success increases during progress through the subsequent stages of the PD life cycle because the process–product knowledge base is increased. The definitions of the PD life cycle stages are as follows:   

 In this initial stage, the key technical hurdles are assessed and possible solutions identified. This is a problem-definition stage that determines whether the overall program (i.e., the process and product targets) is feasible and what the development path should be. The draft TPPP is refined based on the technical feasibility stage assessment to guide the development stage. Critical thinking at this stage guides the use of resources and directs efforts to address the right question. More time is spent on this stage during earlier phases of development than during late-stage development programs when further product and process experience has been gained.

 In this stage, unit operations that would achieve the TPPP are defined, potential hurdles to scale-up are determined, and technology transfer is facilitated. Because each process is linked to the manufacturing plant's capabilities, the facility fit is assessed early to allow delivery of long-lead equipment and raw materials and to confirm the production schedule and supply-chain plans. Analytical procedures are developed to support PD and product characterization. The development plan for the given clinical phase is finalized.

 In this stage, the process operational parameters and test procedures for assay qualification are finalized. With finalized actual PPPs, a process description is drafted. Critical process parameters and ranges are drafted. There is less optimization during early stages than during late stages.

Process confirmation and assay qualification stage:

 In this stage, the PPP is demonstrated by running the process intended for technology transfer. This stage establishes technology transfer readiness at all clinical development phases. Assays are ready to be validated.

In anticipation of product commercialization, process-robustness studies are conducted to finalize the design space, denoting readiness for process validation. Studies are then conducted toward submission of a license application, including such information as impurity clearance, photostability, and complete product characterization. 

The PD life cycle is designed to guide the efforts and resources needed by asking specific questions from the four PD disciplines at each stage and by critically reviewing the outcomes as an integrated result before moving to the next stage. The questions asked from each discipline at each stage must relate to the other three disciplines. For example, proceeding from the development stage to the optimization stage for the cell-culture process requires demonstrating that the material can be purified by a prototype process and meet the targets for process yield and product quality.  In this example, a "go" decision to proceed to the optimization stage for cell culture development discipline is not solely based on cell-culture performance, but rather is based on the integrated PD life cycle evaluation by purification and analytical disciplines, obviating potentially wasted efforts in cell-culture development if the material from cell culture does not meet the overall targets of the other two disciplines. The relative duration of each stage is depicted in Figure 4.  

Figure 4: Relative durations of process development (PD) life-cycle stages. The length of time spent in the life-cycle stages varies depending on the development phase. Early on, more time is spent on technical feasibility. As process and product knowledge are gained at later clinical phases, more time is spent in optimization.  The type of development work as part of the product life cycle may vary from full development (e.g., going from a serum-containing roller bottle process to an animal-free bioreactor process) to a narrower scope (e.g., manufacturing site change, scale change, additional drug product presentation). The total duration of a development program is dependent on the details of the program.  

GAINING EFFICIENCY THROUGH PD BUSINESS PROCESSES

To better coordinate the generation and execution of an integrated development plan, a structured PD team (PDT) process was established. Each team consists of a representative from each of the four disciplines (i.e., cell culture, purification, analytical, and pharmaceutical development) and from manufacturing technical support. Each team has a leader and a project manager; these individuals are responsible for driving the planning, coordinating activities, and tracking execution against the goals. The team leader is responsible for driving decisions, mitigating problems, and representing the process develpment department at higher level teams, such as CMC teams. One PDT is designated to champion each development program. The teams are sponsored by PD management, who provide strategic input into the project plans, and align and prioritize resources across projects.  

Figure 5 depicts the PDT process for planning, prioritization, execution, and communication.  Based on the inputs from external and internal stakeholders, the PDTs develop an integrated PD life cycle plan for each project, including detailed milestones and success criteria for each stage. The plans, the status, and the decision points for all teams are reviewed and prioritized by PD department management as the plans are being executed by the line functions. Periodic review of status and risks facilitate timely cross-functional decision making, raise awareness of current program problems, and provide cross-functional learning. The deliverables are also communicated or provided to external stakeholders in the appropriate forums, who might then give additional input.  

Figure 5: Process development (PD) team business process diagram. A structured business process allows for consistent planning, prioritizing, and delivery on multiple programs in a resource-constrained and time-limited business. The inputs into process development work (top box) come from a wide range of stakeholders (right tall box) and vary in scope from product development strategy to a specific request such as responding to a regulatory question. The inputs are organized into an integrated process development plan with key goals and milestones (beginning of cycle). The PD teams drive compilation of such goals and milestones and integrating them into a detailed plan through iterative coordination with line functions. Work is prioritized and resources allocated by management and executed by functions. The team updates are one of the outputs of the team, which are periodically reviewed for strategic guidance or realignment as needed. Data, recommendations, and materials are other team outputs that are provided to the stakeholders to complete the circle of product-development interdependencies.  

The effectiveness of PD is enhanced by establishing team structures, optimizing business processes, developing clear expectations for roles and responsibilities, and committing the organization to build, train, and mentor strong teams as centers of excellence in product development.   

PD can be the leverage in product development performance where the speed and effectiveness of learning from each program to develop and implement process technologies can shape the overall cost, timelines, and results of new product introductions. PD life cycle planning enables a disciplined approach to PD for a given product and facilitates learning across programs to minimize rework. Establishing an integrated approach among the four disciplines of PD to answer critical questions early in the development cycle ensures timely and appropriate adjustments to the overall program plan and better use of resources. The development and application of process platforms with small-scale models that are predictive of manufacturing-scale performance leads to cost effective product development. Establishing a business process that facilitates integrated planning and decision making is a precursor to well-coordinated execution. Overall, PD life cycle planning, combined with continuous business process improvements, allows for efficient delivery within the fast-to-market complex biological product development paradigm. 

The evolution of process platforms has been a result of the efforts led by Yas Saotome, previous head of cell culture process development at Shire (currently at Alexion Pharmaceuticals) and David Nichols, head of purification process development. The analytical automation technologies were introduced by the immunoassay and bioassay group (Jeffrey vanDoren and Laura Trubiano, led by Brian Lentrichia). The authors acknowledge the inputs into the PD life cycle by Chun Zhang (current head of cell culture process development), David Nichols, PD project managers (Jennifer Puhlhorn and Jennifer Terew) and Walter Uchendu. The insights of Matt Croughan, Rathmann Professor at Kegg Graduate Institute, on the process development learning modes are highly appreciated. 

Zahra Shahrokh is currently senior vice-president at Aurabiosciences, and Marcio Voloch is currently a biotechnology consultant. 

 was senior director, pharmaceutical and analytical development, 

* is director, process development operations, and 

 was vice-president, process development, all at Shire Human Genetic Therapies, Cambridge MA. *To whom correspondence should be addressed, 

The Development Factory: Unl.ocking the Potential of Process Development.

 (Harvard Business Press, Boston, MA, 1997).  

Features

Achieving multiproduct development within shortened timelines.

Efficient Multiproduct Process Development Case Study

Trends in Asia biomanufacturing stood out this year in BioPlan Associates' 

8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

 (1). The study asked respondents to consider their five-year time horizon to 2015 and evaluate their facility's current plans for international (i.e., nondomestic) capacity expansion. For the first time, China ranked highest in the world with 17% of respondents identifying the country as a potential biomanufacturing outsourcing destination. India was the choice of 13.2% of respondents, and Singapore was selected by 9.5% of respondents. The United States was chosen by 15.1% of respondents (see Figure 1). The results show that the demand for biomanufacturing capacity in Asia in serving regional or domestic markets can outweigh managerial concerns when offshoring manufacturing. This year's survey had responses from 352 global biomanufacturers and covered issues associated with production bottlenecks, budget trends, use of disposables, downstream production, and quality management (1).  

These findings support the continuing rise of Asia as a global biomanufacturing power. In coming years, many biopharmaceuticals originally launched in Western markets in the 1980s and 1990s, including many blockbusters, will be coming off patent. Multiple biosimilar and bio-better versions are likely to be marketed for each product, thereby resulting in a significant expansion of  companies developing and manufacturing biopharmaceuticals. Although the great majority of biopharmaceutical manufacturing and consumption in emerging markets currently involves biogenerics or other copies of products developed by Western innovator companies, these foreign markets, although still relatively small, are growing at a more rapid pace than major Western markets.  

Figure 1: Destination for international outsourcing of biomanufacturing.			

According to BioPlan's recently released Top 1000 Global Biopharmaceutical Manufacturing Index, China holds 8.5% of the global concentration of capacity and employment, India 8.0%, and Japan and other Asian countries 9.2%; these areas are growing more rapidly in biomanufacturing capacity than the global average. Asia-Pacific has one of the largest concentration of global biopharmaceutical manufacturing capacity (2). Asia's combined share of 25.7% of global concentration of capacity and employment virtually matches Europe's share at 26.2% and is gaining on North America's share of 37.5%. These results show that the biopharmaceutical industry is becoming increasingly international in scope and is beginning to move away from its exclusively US and European focus as larger manufacturers locate in emerging markets to support regional markets and provide backup manufacturing for products in major markets. The BioPlan study suggests that biopharmaceutical research and development, both for biosimilars and innovative products, is increasing in China, India, Russia, and select emerging markets (2).  

Also, many large Chinese and Indian companies are developing commercial-scale biopharmaceutical manufacturing facilities to serve domestic and regional needs. This trend is evident in vaccine manufacturing. An important development occurred earlier this year in March, when the World Health Organization (WHO) reported that China's State Food and Drug Administration was shown to comply with international standards for vaccine regulation. With a regulatory system for vaccines documented to comply with international standards, vaccine manufacturers in China are now eligible to apply for WHO prequalification of specific products. Prequalification, which is a guarantee that a specific vaccine meets international standards of quality, safety, and efficacy, is a prerequisite for manufacturers to supply to countries through UN procuring agencies (3).  

Along with biopharmaceutical manufacturing growth in Asia comes increased opportunity for vendors such as providers of equipment and consumables. The BioPlan study shows that  more than half of respondents specifically sell to India and China, and 38.7% of all vendors sell into other Asian markets (2). 

The growth of India, China, and other emerging countries also contribute to a tightening of the global scientific labor markets. This year's survey showed that concerns over hiring are increasing as the global economic downturn stabilizes. Expectations of constraints due to the "inability to hire new, experienced scientific staff" jumped from 19.1% of respondents in 2010 to 27.6% in 2011. The survey, which compiled the factors likely to create biopharmaceutical production constraints by 2015, found that facility constraints (48.6%) topped the list, followed by the "inability to hire new, experienced technical and production staff" (31%) and the "physical capacity of downstream purification equipment" (28.1%) (see Figure 2). This tightening in the market for experienced bioprocessing specialists may be due to expansions in growth of operations and further exacerbated by specialists increasingly spread out over a growing number of biopharmaceutical companies worldwide. 

Figure 2: Select factors creating future capacity constraints.			

is president of BioPlan Associates, tel. 301.921.5979, 

, and a periodic contributor to Perspectives on Outsourcing. 

8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production: A Survey of Biotherapeutic Developers and Contract Manufacturing Organizations 

Top 1000 Global Biopharmaceutical Facilities Index

 3.  WHO, "China's State Food and Drug Administration Gets WHO Approval for Vaccine Regulatory System" Press Release March 1, 2011.

Perspectives on Outsourcing

China rises to the top as a destination for international outsourcing.

Offshoring Biomanufacturing

Biopharmaceutical and vaccine manufacturers are increasingly considering the use of single-use systems for final formulation and filling. These applications have stimulated many questions about the particulate quality of single-use systems and their suitability for use under GMP. Particles in singleuse systems have not historically been an issue because most applications were for media or buffer preparation, intermediate hold, or other applications upstream of final filters. Recently, however, drug developers and manufacturers have begun to apply single-use technology to final formulation and filling, which are downstream of final filters. In this column, I will summarize the regulatory requirements for particles in finished drug products, discuss how they can be related to quality requirements for particles from final filters and single-use system fluid paths, and suggest what suppliers and users can do to ensure that finished drug products meet the regulatory requirements for particulate quality. 

Existing drug and biologics GMP regulations and guidelines that address particulate quality apply either to the external cleanroom environment or to the finished drug product itself, after filling in its final dosage container. In addition to the inspection of final dosage units for visible particles (e.g., per USP <1> Injections), injectable drug products are also subject to lot sample testing for microscopic particles (e.g., per USP <788> Particulate Matter in Injections) (1, 2). Similar tests exist under the European Pharmacopoeia 2.9.19 and Japan Pharmacopoeia 6.06 (3, 4). For global harmonization, these tests have also been incorporated into International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q4B (5). 

In contrast to finished injectable dosage units, process equipment, including single-use systems, is not directly regulated under drug or biologics GMP. Consequently, there are no regulations or guidelines for the particulate quality of final filter effluents, single-use filling equipment fluid paths, final bulk drug containers, or even finished drug product dosage containers prior to filling. By themselves, these components and systems do not fall within the scope of GMP regulations, which focus on finished drug products.  

However, regulatory authorities recognize the potential influence of the process equipment fluid path when in contact with final bulk drug formulation. For example, US 21 

 Part 211.65 states, "Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements"(6). 

While particulate quality of process equipment is not specified, drug manufacturers must ensure that process equipment does not adversely impact the quality of the final drug product. This requires the single-use system user to establish that reasonable controls are in place to ensure that process equipment does not cause the drug product to fail particulate quality specifications. 

According to most GMPs worldwide, injectable drug products are required to be essentially free of visible particles. USP General Chapter <1> Injections states, "Each final container of all parenteral preparations shall be inspected to the extent possible for the presence of observable foreign and particulate matter (otherwise termed 'visible particulates') in its contents. The inspection process shall be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates" (1). Similarly, the 

 (2.9.20) states, "Injectable solutions, including solutions constituted from sterile solids intended for parenteral use, should be essentially free from particles that can be observed on visual inspection" (7). 

The observation of a "visible particle" during inspection of filled drug product will depend on the drug, and container clarity, lighting, particle size, optical density, refractive index, color and contrast, and operator or automated inspection sensitivity and reliability. "Essentially free" is also not defined. Because only those individual drug product containers observed to contain visible particles are subject to rejection, limits can vary for the number of unacceptable drug product containers with one or more visible particles per batch, which can be rejected to meet an interpretation of "essentially free of visible particles" for released dosage units. Whether the regulatory expectation of "essentially free of visible particles" applies to particles recovered from single-use fluid paths that may or may not be ultimately visible in drug products, and to what level, is open to interpretation. 

Suppliers' procedures, processes, and qualifications of single-use systems to minimize particulate contamination vary with components and systems. 

Sterilizing-grade filters are typically preflushed during manufacturing to wet prior to 100% integrity testing. This flushing also serves to minimize downstream particles. Preflushing of particulate filters used as final filters should be confirmed with the supplier. Final filters and re-usable downstream fluid paths or containers are also flushed by users before filling of drug product containers to further minimize particulate and leachable contamination before final drug filling. This flushing may be done for various other reasons, including pre-use integrity testing of the sterilized filter, priming of the filling lines, and checking for final container fill weights and other quality control tests. Filter manufacturers typically recommend that final filters and their associated downstream fluid paths be flushed with a suggested liquid volume before filling of final dosage containers to minimize leachables and downstream particles that would otherwise be introduced into injectable drug products. Initial filter or system flushing is optional per FDA GMP, but indirectly required by EMA GMP Annex 1, which specifies that the sterilized filter should be integrity tested before drug product filtration. Such integrity testing requires inline flushing to wet the filter, which would also serve to minimize downstream particulates if the flush effluent is discarded before finished drug product filling. 

FDA GMP requires that the final filters used to manufacture injectable drugs are "non-fiber-releasing" in accordance with US 

Title 21, Parts 210.3 (b) and 211.72 (6–8). While this requirement originates from the time when filters contained asbestos fibers, it helps ensure that sterilizing grade filters contribute a minimum amount of fibers of any kind (typically from nonwoven polyester or polypropylene support layers). Filter manufacturers may certify that either the finished element or just the membrane meets this requirement. Downstream cleanliness of supplied cartridges, especially those only claiming the membrane is "non-fiber-releasing" versus the finished cartridge, should be assessed as part of product qualification and selection. Filter samples from each manufacturing lot may also undergo effluent particulate analysis by the supplier.  

Despite these effluent cleanliness qualifications, users should recognise that filters are subsequently dried, packaged, shipped, unpacked, handled, and installed prior to use. All these manipulations carry the potential for visible particles to be generated after the manufacturing flush and quality control tests. Visual inspection of the downstream core of a filter capsule for particles is not possible; thus, most filter manufacturers recommend filters to be flushed prior to use to ensure minimum downstream particles and leachables prior to drug product filling.  

Unlike the manufacture of filters, film extrusion is not an intrinsically particle-generating process. Films used to manufacture biocontainers are typically handled in a Class 10,000 cleanroom where fluid contact surfaces are minimally exposed to a controlled environment. During biocontainer assembly (seam and port welding), sealed biocontainers are typically subject to inspection for visible particles. Samples of assembled biocontainers may also be subjected to rinse and analysis per USP <788> (2). Biocontainers integrated into single-use systems may be further screened for visible particles during system assembly. Visibility of particles may vary with film clarity. 

Sterile connectors and disconnectors are often employed downstream of final sterilizing filters and could potentially contribute particles from the fluid path into final dosage containers. To control this risk, suppliers should sample and inspect molded parts for visible particulates upon receipt, and may also subject samples of assembled connectors and disconnectors to rinse analysis for microscopic particulates. Sterile connectors and disconnectors should be validated to not be significant sources of particles during actuation. When installed on single-use systems, sterile connectors and disconnectors can again be screened for visible particulates. Optically-clear connectors and disconnectors can facilitate the observation of visible particles that may be in the fluid path. 

Tubing and fittings are typically not manufactured with specific claims for particulate cleanliness. However, as with biocontainer films, their manufacturing processes (i.e., extrusion and molding) are not intrinsically particle generating, and particulate contamination can be minimized if manufactured and packaged under controlled, clean conditions. Incoming tubing and fittings from qualified suppliers can be screened for visible particles on a sampling basis, and then rescreened more thoroughly during assembly into single-use systems. Visual inspection for particles within tubing and fittings can be limited, however, by translucency or opacity of the tubing material. Additional testing for particulates in lot samples of tubing and fittings may be performed as part of the quality control procedures for assembled single-use systems.  

Even where particulate matter in single-use components is minimized, there remains a risk for particles entering the fluid path from the cutting of tubing and insertion of hosebarbs into tubing. Systems can be assembled in a Class 10,000 cleanroom, but tube cutting and assembly methods should also be qualified by the supplier to demonstrate that visible particles are not generated and introduced into the fluid path during system assembly.  

To assess the particulate quality of assembled tubing systems, some system suppliers have established quality-control programs where single-use system lot samples, or master systems with "worst case" tubing connections and component combinations, are subjected to rinse fluid analysis for particles. Results can demonstrate that the fluid path rinse fluids meet USP <788> limits for microscopic particles and quantify any visible particles detected.  

Many drug developers have embraced the plug-and-play concept of single-use systems to mean that pre-use flushing of the fluid path can also be eliminated. Whether or not flushing of single-use final filtration and/or filling systems is required to minimize particles in the fluid path must be determined by the end user, as defined by process requirements for drug product quality. Where flushing with water for injection or buffer is desired, systems can be designed with flush collection bags and protocols to minimize residual fluid path hold-up volumes that could dilute initial drug product effluent. Where sterilizing filters are installed, this same procedure can be applied for wetting the filter before pre-use integrity testing, an increasing requirement for the marketing of drug products to some European countries. Alternatively, where appropriate, filters and the downstream fluid path can be flushed with product to minimize losses. Sterilized sterilizing grade filters can be pre-use integrity tested "product wet" with the flush going to initial filled containers that may be used for quality control weight/volume checks or formulation analysis. In that way, initial flush can be accommodated to minimize particles without separate loss of product.  

Particulate quality of post-filtration single-use system fluid paths for final filtration and filling should be considered as part of design requirements. Assessments of recoverable particle sizes and levels should be made in advance of clinical and GMP production. 

If you are considering single-use disposable systems for final filling or any other applications, please email me your questions or suggestions for future Disposable Advisor topics.

 is senior vice-president of Global Scientific Affairs at Pall Life Sciences, Port Washington, NY, and chairman of the Board and Technology Committee at Bio-Process Systems Alliance, tel. 516.801.9086. 

29 General Chapter <788>, "Particulate Matter in Injections." 

, 5.0, 2.9.19  "Particulate Contamination: Sub-Visible Particles" (EDQM, Strasbourg, France, 2005), 253–255.  

4.  Japan Pharmacopoeia XV, 6.06, "Foreign Insoluble Matter Test for Injectables," in General Tests, Processes, and Apparatuses Section,  p. 110–113.  

Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions — Annex 3 Test for Particulate Contamination: Subvisible Particles

, Title 21, Food and Drugs (Government Printing Office, Washington DC), Part 211.65, "Equipment."   

, 5.0,  2.9.20, "Particulate Contamination: Visible Particles" (EDQM, Strasbourg, France, 2005) 255–256. 

, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 211.72 "Filters."

Disposables Advisor

The author looks at strategies to minimize particle levels in the finished product when using single-use technologies downstream of final capabilities.

Particulate Quality of Single-Use Filling Systems

In a study released in May 2011, US regulatory approvals for biologic drugs and biotechnology products (collectively referred to as "biologics") were reported to have nearly doubled in the past decade, compared with the 1990s. This growing market emphasizes the need for consistent approaches to product quality and public standards. In its upcoming Science & Standards Symposium on Biologics & Biotechnology, "Advancing Quality Standards through Analytics and Assays," taking place October 3-6 in Seattle, the US Pharmacopeial Convention (USP) will lead discussions on standards-setting initiatives related to biologics and the materials critical for their manufacture as a growing number of these types of drugs enter the therapeutic space. 

Setting the stage for the symposium are keynote speakers Steve Kozlowski, director of the FDA Office of Biotechnology Products, and Gillian Woollett, chief scientist at the Washington, DC, law firm Engel & Novitt. Each will discuss the regulation of biologics. The following two-and-a-half days of technical sessions will include presentations from an international panel of industrial, academic, and regulatory stakeholders engaged in the development of quality standards for biologics. USP topic experts will discuss general analytical approaches and what they can do for biologics; quality attributes of biologic drugs by product class; and the US regulatory landscape for these products. An entire track of sessions will focus on bioassays and the assessment of biological potency, critical to all biological medicines. 

Quality standards set by the USP—and enforceable by FDA—have traditionally been developed using what's called a "vertical approach," which is particularly suited for the characterization of small-molecule drugs. Under this approach, documentary standards (or product monographs) have been created for one drug product at a time, with associated reference materials (i.e., pure physical samples used as reference chemicals for testing) developed in tandem with monographs. General chapters in USP's official compendium, 

US Pharmacopeia-National Formulary (USP-NF)

, represent overarching information and testing procedures that apply across all or groups of monographs. These chapters broadly support product-specific (vertical) standards in the determination of identity, strength, and purity. 

Compared with their small-molecule counterparts, biologics are heterogeneous and more complex in their makeup. Thus, analysis and characterization are more challenging and require an even greater portfolio of good analytical procedures that can underpin product characterization. Another important issue for biologics quality is the use of ancillary and process materials that are also complex biologics. Common examples are fetal bovine serum (FBS) widely used in vaccine manufacturing; cytokines like interleukin-4 (IL-4) used in the cell-therapy arena; and materials like protein A, used in monoclonal-antibody manufacturing. The quality of these materials going into the manufacturing process can have a direct impact on the quality of the medicinal product itself, especially when the end product is not highly purified and residual amounts of the ancillary material have to remain. 

Working through expert committees and advisory expert panels, the USP biologics and biotechnology department has been actively revising and developing new chapters in 

. Work has focused on general guidance in the form of information chapters, and also on specific test and product-class chapters that speak to the analysis of quality attributes for certain biologics product classes and the analytical procedures necessary to measure them. The goal with these "horizontal" standards is to provide more broadly applicable quality expectations in areas where analytical platform approaches already exist.  

In deploying a horizontal approach to develop standards for biologics, USP's activities in the following areas are reflected in the themes of session tracks for the Science & Standards Symposium. 

USP has developed a suite of bioassay chapters that includes guidance and information focused on development, analysis, and validation of biological assays. As a companion to these guidance chapters, USP has also developed example bioassay data sets and will make software analyses of the data available to meeting attendees. Case studies on analytical and compliance challenges related to bioassays as well as the assignment to biologics of quantities and values will be discussed. 

Critical quality attributes for biologics

In the development of product-class standards, identification of critical quality attributes (CQAs) that apply across products within a designated class is key. CQAs of <129> Recombinant Therapeutic Monoclonal Antibodies is one example of a USP chapter in development which focuses on CQAs. In addition, USP <90> Fetal Bovine Serum—Quality Attributes and Functionality Tests became official in 

Ancillary materials, including growth factors and process enzymes, are necessary for the manufacture of certain biologics, such as vaccines and cell-based or tissue-based therapies, but generally must be removed from the final product once the manufacturing process is complete. USP <1024> Bovine Serum  addresses quality issues related to the production, sourcing and characterization of this class of ancillary materials, with the intent of supporting its users in conducting risk assessment and implementing risk-mitigation measures.  

The functionality of a protein-based therapy is primarily based on its proper structure as well as correct post-translational modifications. General Chapter Glycoprotein and Glycan Analysis—General Considerations <1084> has been developed to address modifications that result from the process of glycosylation. In addition, USP is working on two chapters addressing compendial procedures for oligosaccharide and monosaccharide analysis, important for the manufacture of glycosylated proteins.  

As technological improvements emerge, capabilities regarding bioassays must be updated to parallel those changes. Transitioning legacy products away from animal-based potency assays is an important issue for manufacturers. USP guidance chapters include USP <111> Design and Analysis of Biological Assays, which provides direction to users on developing appropriate strategies regarding biologic potency. 

The topics of the conference speak broadly to industry professionals engaged in the development, analysis and quality control of biological medicines, as well as to professionals interested in the regulatory and compendial issues related to the latest trends in biotechnology. In support of its nearly 200-year-old mission to advance public health, USP is committed to continuing this global dialog among manufacturers, regulators, and practitioners to address the need for public quality standards for biologic medicines.

 is vice-president of biologics and biotechnology for the US Pharmacopeial Convention.  

USP Insights

US Pharmacopeia promotes horizontal standards and a product-class approach for quality attributes.

Developing an International Dialogue on Biologics Standards

Food and Drug Administration officials acknowledge that its established system for ensuring the quality of medical products marketed in the United States cannot cope with the soaring volume of pharmaceuticals and active ingredients coming into the country from all over the world. Because of the potential for consumer harm from intentional adulteration, fraud, and counterfeiting, these developments require major changes in the way FDA does business. Instead of sending inspectors abroad to scrutinize foreign facilities or trying to examine more products at US borders than before, agency officials seek to collaborate more with other regulatory authorities, to make greater use of third-party auditors, and to establish global-information networks that can better alert officials to potential safety hazards.  

The call for a new approach to food and drug regulation will have a notable impact on FDA field inspections and compliance operations. The Office of Compliance (OC) in FDA's Center for Drug Evaluation and Research (CDER) has reorganized to heighten its focus on supply chain and international issues. At the same time, manufacturers are supporting new approaches and collaborative efforts to prevent drug theft, diversion, and distribution of counterfeit products around the world. These changes also reflect FDA's need to cope with increasingly tight resources at government agencies and healthcare organizations. FDA faces a potential $250-million reduction in its budget for fiscal year 2012, which begins Oct. 1, 2011, as Congress moves to cut funding for most federal programs. Such a cut would severely limit funds for FDA field inspections in all regions and limit the increased oversight of food producers and imports that has  been mandated by new food-safety legislation.  

The lines between domestic and foreign production are increasingly blurred. The difficulties of ensuring the safety and quality of imported food and medical products in such a world are outlined in the report, "Pathway to Global Product Safety and Quality," which FDA Commissioner Margaret Hamburg unveiled in June 2011. Although the report contains few really new proposals for overseeing food and drug imports and outsourced production, the document is noteworthy for providing a comprehensive overview of the forces reshaping biopharmaceutical product development.  

In the face of pressure to cut costs and increase productivity, pharmaceutical companies are shifting manufacturing to foreign locations and searching for less expensive ingredients. The cost of formulating an active pharmaceutical ingredient (API) is 15% to 40% less expensive in India, than in the US. Consequently, drug manufacturers now import 80% of APIs, primarily from China and India. Imports of pharmaceutical products have increased about 13% per year for the past seven years. This shift is boosting the US trade deficit in pharmaceutical products, which has jumped from less than $2 billion in 2000 to $18 billion in 2008.  

Additional overseas outsourcing, however, fragments the drug-production process. Contract manufacturing has more than doubled during the past decade to an estimated $46 billion business in 2010. China and India now have the largest number of foreign, FDA-registered drug manufacturing establishments. These and other emerging nations also are producing more complex, high-risk biologics, and vaccines and are becoming more prominent in biopharmaceutical research and development (R&D). India and China already have more than 30% of the world's drug master files, and more clinical trials are taking place in these regions. With a growing volume of foreign manufacturers and producers to monitor, FDA concedes that it is not viable to scale up its current regulatory model, even if it had the resources to do so.  

These developments inevitably open the door to more economically-motivated abuse, drug counterfeiting, fraud, and intentional adulteration. For many novice suppliers, the "temptation of economic gain is greater than any concern for risk to human and animal health," the FDA report observes. It has become "difficult to identify the 'source' of a product and to ensure that all players along the supply chain meet with safety and quality responsibilities." The US already has suffered the consequences of adulterated heparin and counterfeit glucose-monitoring strips, and low-quality counterfeit medicines are widely available, particularly in developing countries. Americans feed illegal operators, moreover, by purchasing more pharmaceuticals online, often from unknown sources and without appropriate oversight and safeguards.  

In response, FDA proposes a more collaborative regulatory approach, somewhat along the lines of the International Civil Aviation Organization, which promotes common global standards for aviation safety. Another model is information sharing, promoted by the International Criminal Police Organization (Interpol). Access to international data on manufacturers, pharmaceutical suppliers, and regulatory operations would help FDA identify potential risks that can be monitored and addressed before they lead to public harm.  

Collaboration between regulatory counterparts is not new. FDA and EMA have launched extensive information-sharing activities involving new drug applications, drug safety reports, orphan medicines, and field inspections. A joint FDA–EMA pilot with Australian regulators aims to coordinate inspections of API manufacturers in third countries. Another FDA–EMA pilot involves joint oversight of clinical-research sites. 

Although FDA has been engaging foreign regulatory counterparts in collaborative initiatives, such as those being refined by the International Conference on Harmonization and the Pharmaceutical Inspection Co-operation/Scheme, these partnerships "are not sufficient" to deal with an increasingly complex global environment, the report concedes. What is needed are "global coalitions of regulators" that allow countries to maintain sovereignty in setting standards and making decisions, but rely more on the work of other regulators and encourage the pooling of resources to manage the global pharmaceutical inventory. Increased information sharing with trusted counterparts would be easier if FDA did not need to redact all trade secret information from documents,  for example, a process that seriously stymies the communications process.  

Such collaboration reflects FDA's recognition that its own inspectors cannot reach the growing volume of foreign sites: The average cost of a foreign-plant inspection is $52,000, more than twice the $23,000 outlay for a domestic site visit. More than 54% of foreign drug making facilities went uninspected from 2002 to 2007, and the record is even worse for foreign medical device producers. Even though FDA increased foreign-drug inspections by 27% between 2007 and 2009 and opened a series of international offices, that still falls hopelessly short of covering the field.  

The good news is that collaborative initiatives are proliferating as regulators seek to conserve their own resources. Mexico and Costa Rica, for example, are accepting FDA medical-device review decisions. FDA recently put a company on import alert based on an inspection report from a European agency, and is exploring other ways to streamline operations. EMA reliance on "qualified persons" employed by drug manufacturers to verify the quality and safety of all approved drug batches is an approach worth looking at, says OC Director Deborah Autor*. She's also interested in models for third-party audits for drugs, an option already authorized by FDA for medical devices and food imports. A shift to more reliance on outside auditors, however, requires a more sophisticated review and monitoring infrastructure that can verify the integrity of information received from other regulators and private parties.  

Related initiatives aim to expand the expertise and capabilities of regulatory agencies around the world. The World Bank is providing resources for building regulatory capacity in developing economies so that  less-experienced agencies can better enforce GMPs and other drug quality policies. The US Pharmacopeia similarly is providing technical assistance to help emerging-nation manufacturers comply with GMPs, along with support for regulatory authorities to establish quality drug-surveillance programs. The US Agency for International Development (USAID) funds this $35 million, 5-year program, which now is active in about 30 countries in Africa, Asia, and Latin America. A major impetus for regulatory capacity building comes from donor and health funding organizations, such as the Global Fund to Fight AIDS, Tuberculosis, and Malaria, which increasingly require the drugs they purchase to meet GMPs and World Health Organization prequalification standards. 

Pharmaceutical companies also are working together to prevent product theft and adulteration and to provide more efficient ways to oversee suppliers and contractors. The Rx-360 coalition aims to ensure product quality through cooperative auditing of suppliers and contractors. More than 50 pharma, biotech and supplier companies are participating in the Rx-360 joint audit program, which uses third-party auditors to examine operations and standards at producers of active ingredients, excipients and other raw materials. A shared audit program encourages pharmaceutical companies to provide their own audits of suppliers to colleagues.  

Separately, several organizations market third-party audit and certification programs for excipients. And a new track-and-trace consortium of manufacturers, distributors, pharmacists, and shippers is working with FDA to develop standards for an interoperable prescription-drug tracking system. The impetus comes from California electronic pedigree requirements, which are scheduled for implementation beginning in 2015.  

With drug manufacturing and clinical-trial activities expanding overseas and at home, CDER's Office of Compliance is being reshaped into a "super" office that can better manage its growing responsibilities. OC now has a staff of 300, compared with 118 in 2005, explained OC Deputy Director Ilissa Bernstein at the Parenteral Drug Association pharmaceutical supply-chain conference in June. Now a string of top aides manages cross-cutting initiatives, including policy and communications, strategic planning and organization development, data analysis, and risk assessment, directly under OC Director Autor. These staff functions incorporate many of the data-management responsibilities of the former Division of Compliance Risk Management and Surveillance.  

The main new OC component is the Office of Drug Security, Integrity, and Recalls (ODSIR), which will oversee import operations, recalls, and a range of supply-chain issues. An Import Operations branch will coordinate import and export compliance activities, including supplies for clinical and preclinical studies. The Division of Supply Chain Integrity  (DSCI) will handle anticounterfeiting strategies, track-and-trace initiatives, product authentication, good importer practices, good distribution practices, cargo-theft prevention, intentional adulteration, and efforts to leverage domestic and international partnerships in these areas, explained Leigh Verbois, who will serve as the DSCI deputy director.  

Among other responsibilities, ODSIR Acting Associate Director Connie Jung will continue to lead agency efforts to develop track-and-trace programs, building on guidance issued in March 2010 that outlines how manufacturers should provide a standard numerical identifier (SNI) on every product as the basis for tracking products through the supply chain. FDA is digesting comments from a February 2011 public workshop on how to develop interoperable standards that will facilitate adoption of pedigrees and tracking systems, hopefully in time to help manufacturers meet California requirements.  

With this reorganization, OC's status is similar to that of CDER's Office of New Drugs, Office of Pharmaceutical Science, and Office of Surveillance and Epidemiology. Most OC divisions will function as before, though with slightly revised names. The Office of Manufacturing and Product Quality (OMPQ) will no longer oversee recalls and shortages, but continues to manage inspections for new and generic drugs and biologics, both domestic and international, to ensure compliance with GMPs. The Office of Unapproved Drugs and Labeling Compliance (OUDLC) oversees drug fraud and labeling and approval requirements for prescription and over-the-counter drugs. The Office of Scientific Investigations (OSI), which monitors clinical trial operations, bioequivalence testing, and patient protections, gains a new division of safety compliance with responsibility for postmarketing activities, including adverse event reporting and risk evaluation and mitigation strategies (REMS) .  

The global market "contains a vast amount of counterfeit and substandard drugs," Bernstein commented at the PDA conference, noting the need for more transparency and accountability in the supply chain, both upstream and downstream. 

OMPQ Associate Director Richard Friedman emphasized that company management is ultimately responsible for ensuring product quality, including use of safe and reliable raw materials and effective monitoring of outsourced activities. A significant reason for the OC reorganization, Autor explains, "is to recognize the challenges of globalization" and to be able to focus more on international collaboration, data mining, and risk analytics. "It fits together nicely and it's the right direction for us to move in."  

  *As we went to press, FDA announced a major reorganization of the Commissioner's office, with Autor becoming FDA Deputy Commissioner for Global Regulatory Operations and Policy. Ilisa Bernstein will serve as the Office of Compliance Acting Director. 

 is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, 		

Regulatory Beat

Rising imports, overseas production spur collaboration and realignment of enforcement activities.

FDA Maps Strategy to Counter Supply-Chain Threats

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. 

 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).  

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. 

 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.  

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. 

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.  

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/ft

/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. 

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. 

 U-bend swing connections) or WFI/HPW drops are often made in an open fashion without subsequent sanitization of the connection point. 

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. 

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. 

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. 

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. 

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. 

 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. 

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. 

The authors re-examine environmental controls in the context of technical advances in manufacturing.

Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug Substances

For years, a glut of successful, well-recognized biopharmaceutical products generated extremely high profits for the industry. The patents for these products and others have expired or are set to expire in the near future. In addition, research and development (R&D) productivity has long been falling, and the industry has little prospect of replacing these blockbusters while healthcare is likely to reform further squeeze margins and drive a shift to outcome-based pricing. 

As a result, the enterprise value of biopharmaceutical companies as a whole has been stagnant. Evidence from Accenture's High Performance Business research, conducted between 2007 and 2009, suggests that the investment community has become disenchanted with the biopharmaceutical industry altogether and is looking at other industries with expected high growth for future investment. This powerful mix of forces has significantly impacted the biopharmaceutical industry's ability to drive shareholder value growth, and the forces are game-changing. 

Scale and diversified portfolios no longer guarantee success for the biopharmaceutical industry. Biopharmaceutial companies need to be bold and decisive to prove their future worth to a skeptical market. According to Accenture's research, which involved analzying the 16 largest pure-play biopharmaceutical companies (i.e., those with more than 75% of their revenue derived from pharmaceutical products) globally, biopharmaceutical companies must focus on what differentiates them in the marketplace and build expertise in these carefully selected areas. Through years of research, Accenture has learned that high performance is definable, quantifiable, and achievable. High performers effectively balance current needs and future opportunities. They consistently outperform peers in revenue growth, profitability, and total return to shareholders. In addition, they sustain superiority across time, business cycles, industry disruptions and changes in leadership. 

Industry may be its own obstacle to success in achieving the desired high-performance state.

BioPharm International-08-01-2011