Articles

Issue PDF

BioPharm International, February 2011 Issue (PDF)

The quality product steward (QPS) model, a single point of contact model, was created at Genentech to manage the quality of our clinical products. The purpose of the QPS is to provide quality oversight and a single and consistent quality approach for our CMC (chemistry, manufacturing, and control) teams. The QPS function enables efficient communication and decision-making related to the quality of our products to occur. The QPS performs many key quality tasks supporting GMP manufacturing, product testing and release, regulatory filings, and clinical supply. The QPS acquires product-quality knowledge and acts as the quality expert for the product-quality history throughout the development cycle. This model has been implemented in our clinical quality organization for more than three years and proven to be valuable to both project teams and the quality organization during clinical product development.

Since the first recombinant DNA product based on human growth hormone was successfully approved and launched in the mid-1980s, the biopharmaceutical industry has evolved tremendously. Significant advances have been made in manufacturing technologies and analytical and pharmaceutical sciences. Additionally, the global regulatory environment has been constantly evolving. In the last two decades, the compliance environment has grown ever more complex. The pharmaceutical industry is facing increased expectations; and delivering products that meet the global regulatory requirements is becoming more complicated and challenging. In today's drug development environment, research and development (R&D) is not the only critical player that can help a company gain a competitive edge. Other supporting functions such as a quality organization with agile and flexible business processes also contribute to the speed of the development timeline and quality of drug development as well.  

At Genentech, we constantly improve our business processes to enhance efficiency and productivity in all chemistry, manufacturing, and control (CMC) functional areas.

  This is especially important in light of our significant clinical pipeline, the diverse nature of our biopharmaceutical products such as monoclonal antibodies (MAb), MAb-drug conjugates, and drug-device combination products, and the number of global sites and outsourcing activities involved during clinical product development at Genentech. The fast-paced and dynamic environment prompted Genentech's clinical quality organization to reevaluate its business model around quality representation on the technical and manufacturing development team (TDT or project team). As a result, a new functional role, the quality product steward (QPS), was established in Genentech's clinical quality organization. 

The QPS represents all of the quality functions on the project team to enable quick and effective decision-making and to ensure that the quality of a released product meets predefined quality requirements (i.e., specifications). In this article, we will describe the rationale for establishing the QPS role, our experience, and its success. 

Process (i.e., CMC) development is a critical function in pharmaceutical drug development. To manage the many diverse aspects of process development, a project team is formed that consists of representatives from several key functional areas including process development, analytical development, pharmaceutical development, manufacturing, quality, and regulatory affairs (Figure 1). At Genentech, the quality function includes several functional groups that focus on specific quality aspects such as raw materials, environmental monitoring, in-process testing, drug substance and drug product testing, viral and mycoplasma testing, quality systems (e.g., documentation, change control), and quality assurance. All of these functions contribute to the process development of clinical products. Their activities must align with the timeline and overall deliverables of the development goals. As Genentech's product pipeline grew and became more diverse, having a representative from each of the quality function groups on the project team became unrealistic and unfeasible. 

Figure 1. A project team consists of representatives from several key functional areas			

Creating a single quality representative, who provides effective and efficient quality feedback, ensures consistent and cohesive quality oversight. Thus, the QPS role was created. A QPS is assigned to a project team and stays with the project from preclinical development to product launch. Then, the QPS hands the product's quality oversight responsibilities and its development history to the commercial quality steward, who shepherds the product through the commercial environment. 

One of the immediate benefits in creating the QPS role was the reduction of resources needed in the various quality functions. This role also greatly helps the project team by identifying a single point of contact that is accountable for all quality issues. The QPS serves as a quality expert for the product during clinical development and is responsible for making quality-related decisions and playing the role of the liaison between the project team and other quality functions. This model provides a consistent quality voice on the project team and helps the team to reach decisions more effectively and quickly. One QPS can provide quality oversight for two to three products, depending on the development phase and level of complexity of the products. In the following sections, we will describe the QPS role in detail, the responsibilities of the QPS, and the business processes that support the QPS function. 

The difference between the QPS role and the quality control (QC) or quality assurance (QA) functions is that this job is not purely function-focused. It is centered on all aspects of product quality and product knowledge, and on being the single point of contact for communication and accountability. 

It is important for the QPS to be involved when the product enters development, before toxicology campaigns, and to stay with the product as it moves through development. Early involvement by one person from quality who is knowledgeable of the product and its challenges provides a proactive front-end approach to quality, as opposed to the traditional reactive back-end approach. Typically QC and QA become involved after the manufacturing process has been developed and the product is manufactured. It is the responsibility of the QPS to ensure quality is ingrained and built into the process during development. The QPS can foresee and inform the project team of potential product quality issues during process development, manufacturing, testing, and management of investigations/discrepancies, and can provide strategic direction and decisions to the project team. The combined knowledge of the product, processes, and the quality functions makes the QPS the best decision-maker for the product's quality. When resolving a critical quality issue, the QPS does, however, engage the appropriate quality function and upper management to ensure a sound decision is made and issue resolution occurs. 

A biopharmaceutical product can take up to 10 years from initial development to approved commercial product. Along the way, many key functional areas such as process, analytical, and pharmaceutical development have generated and accumulated extensive product-specific knowledge. The importance and value of this knowledge are critical and indispensable for understanding a product and developing a high-quality manufacturing process. 

There is also value in generating product-related quality knowledge during the development lifecycle. Although product-related quality knowledge is not as well defined as other scientific disciplines, it can be considered an interdisciplinary knowledge encompassing product characteristics and development history; and how the physico-chemical characteristics and manufacturing process of products are linked to their quality attributes. It is also about knowing stability profiles, specifications (including methods and acceptance criteria), released batches used in various clinical trials (including Certificate of Analysis results and stability data), and major quality-related investigations and discrepancies. In addition, the product-related quality knowledge also includes quality and cGMP principles and systems and relevant regulatory guidelines. The product-related quality knowledge gathered during clinical development is extremely valuable when developing the commercial manufacturing process and setting the final control system. 

  Because the QPS stays with the product from initial development to commercialization and serves as the single point of contact on the project team, they accumulate a vast amount of product knowledge. Clinical development is a very dynamic environment that requires versatile skills and knowledge. The product knowledge gathered provides the QPS with a solid product history and strategic thinking in the quality approach to deal with the constant changes that occur along the way. 

The creation of the clinical QPS at Genentech was the result of a business need and experimentation with a new quality concept to ensure consistent and effective quality oversight during clinical development. 

Table 1 lists the main roles and responsibilities we have identified as value-added services and tasks that benefit process development. 

Table 1. The quality product steward's (QPS) roles in various CMC-related tasks			

As stated earlier, the QPS is involved in the project team's activities early on in development. During GLP toxicology study stage, our QC is normally responsible for testing and releasing the material. The QPS authors the characterization protocol that defines test methods and acceptance criteria. Subsequently, the QPS also drafts the stability testing protocol when the toxicology study is complete to ensure the material used has been stable throughout the study period. Although the material manufactured may not be GMP, it is often considered representative of Phase 1 clinical material. In this situation, the QPS serves as a central role on the project team, accountable for the generation, release, and maintenance of the reference material. Their guidance and communication provided to the project teams and quality functions is very valuable.  

Resource planning is a critical part of every project and organization. At Genentech, the process development functions have been successfully using standardized resource planning tools to forecast resource needs during product development. By collaborating with various quality-related functional groups, we developed a standardized quality–resource-requirements model based on the type and development stage of the product. With this information, the QPS is able to communicate to the project team early on to ensure that resources in quality are in alignment with the overall product timeline and goals. This standardized approach also ensures consistency and eliminates the need for requesting information from various groups every time milestones move or change. 

For each new or changed drug substance and drug product GMP campaign, the QPS authors a product-specific sampling and testing plan. This document defines QC testing requirements at each manufacturing step. It contains sampling quantity, test codes and names, and the corresponding control limits for all of the key intermediates and release steps. Sampling instructions (e.g., aseptically or not) are also included in this document. It is used as the primary source information by manufacturing, QC testing and sample management, and LIMS, ensuring the appropriate samples are pulled, verified, submitted, logged into the sample tracking system, and tested. 

Collaborating with key CMC stakeholders, especially analytical chemistry, the QPS proposes an overall control strategy for GMP drug substance and drug product. The control strategy covers in-process, release, stability testing, and their respective acceptance criteria (i.e., limits). The proposal is usually presented to an upper management analytical review committee, which consists of key CMC functional directors, and is implemented only after the committee's endorsement. After this endorsement, the QPS is responsible for drafting and approval of the formal drug substance and drug product specifications documents in the QA documentation system. In this capacity, the QPS works with our regulatory affairs and analytical chemistry groups to ensure the overall quality control strategy meets the standards of the relevant regulatory agencies (FDA, EMA, etc.). This task requires that the QPS be familiar with relevant ICH, FDA, and EMA guidelines and take into consideration the quality requirements that are appropriate for the development stage of a clinical product. 

Although the QPS is not directly involved in analytical characterization and method development, they are expected to be familiar with all of the methods used in the control system (including in-process, release, and stability testing). The scope of these methods covers analytical, physical, microbial, and viral testing methods. With this knowledge, the QPS understands why and how these methods are used for monitoring and controlling the quality attributes at each manufacturing process step. 

In collaboration with various QC testing and analytical chemistry groups, the QPS is responsible for proposing the overall method qualification/validation strategy appropriate with the phase of development and internal quality standards. At the conclusion of method qualification/validation studies, the QPS also drafts a final report that summarizes all of the method validation/qualification studies. This report is a useful reference during regulatory agency inspections. It also serves as a valuable source for the lifecycle management of analytical method development. 

Another key responsibility of the QPS is managing the reference materials. During biopharmaceutical development, a product-specific reference material often needs to be generated because there is no international standard available. The reference material serves as the standard for the product and the control for many QC methods. In this capacity, the QPS is responsible for authoring and approving the qualification protocol and coordinating the reference material manufacturing, testing, and release. Afterwards, the QPS continues to maintain the reference material and summarizes the reference material data from QC testing groups to evaluate its stability. These responsibilities can go to outside companies in special cases such as when a contract manufacturing organization (CMO) is used to manufacture and maintain the corresponding reference material. In this case, the QPS will interact with the CMO to ensure the relevant activities are completed from the quality perspective. 

Valuable product knowledge can be acquired during development by strategically managing discrepancies, investigations, and change controls. Because the QPS is involved in quality aspects of their product, they are in the position to take full advantage of these experiences. The QPS is responsible for identifying major quality-impacting discrepancies that occur during GMP manufacturing and testing. Quality-related investigations involve the identification of a possible cause, determination of the impact (or not) on quality, and corrective-action implementation. The QPS leads the effort in presenting a conclusion to and seeking endorsement from the appropriate clinical quality review committee (i.e, quality review board, QRB) and seeking the support of senior quality management to bring the investigation to a successful conclusion. They begin with discussions with the QRB chair to determine if the issue is serious enough for a formal QRB meeting. If needed, they coordinate with various stakeholders to present to the QRB, participate in the QRB meeting discussion and decision-making, facilitate the QRB for endorsement and recommendation, and execute the QRB recommendation. The QPS can also be involved in discrepancies or investigations by performing a quality assessment and providing relevant history and recommendations to the QRB committee to facilitate an effective and efficient outcome. 

Ultimately, the quality-related discrepancy investigation history is valuable when building the design space in support of Quality by Design. By formally evaluating and documenting these deviations and their conclusions, they can be used as unplanned design of experiments, and they may sometimes represent possible manufacturing variations. 

Change control is a quality system that documents changes that impact GMP activities. Its goal is to ensure that the proper assessment is conducted to systematically evaluate potential impact before implementing a change. In this process, the QPS sometimes initiates a change-control record and also participates in the assessment related to the QPS activities stated above. Because the QPS is the quality single point of contact on the project team and knows the product quality history, many proposed changes are often evaluated by the QPS to see if their potential impact on quality has been thoroughly assessed. For various tasks, we have developed a corresponding business process to maintain consistency. As drug candidates advance through development, the manufacturing process usually experiences many changes. The change control system becomes a very valuable source of development history. By capturing and analyzing the development history using discrepancy management and change control, the QPS builds a robust history database that includes all quality aspects of the product. 

Because the QPS is actively involved in establishing the release specification, stability strategy, reference material, and QC testing and control during manufacturing, they author the relevant sections of an investigational new drug (IND), IND amendments, and regulatory filings for other countries. The QPS is also responsible for addressing quality-related questions from various regulatory agencies. Clinical development is a dynamic environment. Regulatory and quality requirements are quite different from those of commercial products. In addition, different countries may have different expectations regarding these requirements for clinical trials conducted in their countries. The QPS is expected to be familiar with these different requirements during clinical development and ensure their product meets them. 

For clinical trials conducted in Europe, the product specification file is required by a qualified person (QP) for releasing the investigational drug. This document generally includes and refers to such information as specification and analytical methods for starting materials, intermediates, bulk and finished products, and packaging materials; the manufacturing process and in-process testing methods; stability data, storage, and shipment conditions; and relevant clinical trial protocols. The information in the product specification file forms the basis of the assessment of the suitability for certification and release of a particular batch by the QP. Thus, the product specification file contains comprehensive information about the manufacturing process and controls. Because of their comprehensive role in quality, the QPS authors this document. In this capacity, the QPS collaborates with various process-development functions and quality groups. This document is valuable not only for QP release but also for many internal customers because it contains key manufacturing and control information in a single source. 

The QPS is accountable for the GMP stability program of the clinical product. The GMP stability study is a critical element of the overall control strategy during clinical development. The data from the study are used to support the expiration dates of drug substance and drug product used in clinical trials; a product quality evaluation in the event of a temperature excursion during shipment and storage; and acceptable ranges that are established for critical quality attributes at the time of the commercial regulatory filing. The QPS is accountable for drafting the study protocol, reviewing and approving the time point data, trending the stability data, and managing the out-of-trend or out-of specification (OOS) investigations. In addition, the QPS participates in the review committee for setting the overall stability strategy throughout the product lifecycle. 

The QPS proposes the product's shelf life based on updated GMP and supportive R&D data (generated by pharmaceutical development) and generates the appropriate documents to justify the proposed shelf life. The shelf life of a clinical product is critical to ensure the successful completion of clinical trials. As stability studies are continuous, the QPS is responsible for updating the shelf life of the drug substance and drug product. In this role, the QPS collaborates with QC testing and pharmaceutical development to evaluate stability data to determine if a product meets its quality requirements. Certain non-US countries require either notification or a formal approval process for updating shelf life. The QPS ensures that, before labeling the product with the newly proposed shelf life, it is approved in those countries where the clinical trial is conducted. In this regard, regulatory affairs is responsible for notifying and filing with the relevant countries to obtain approval. 

Ensuring uninterrupted clinical supply is critical to achieve a successful clinical trial. In this regard, the QPS also plays key roles. During shipping to and storage of clinical materials at clinical sites, temperature is usually controlled to a certain range to ensure product quality. However, temperature excursions often happen because of various reasons. This is especially true if it is a global trial involving multiple countries on different continents. When such an event occurs, the QPS is responsible for assessing if the materials impacted can still be used for the intended clinical trial. The QPS uses available stability data obtained from stability-indicating assays to determine whether the temperature and duration the material was exposed results in potential degradation that warrants quarantine of the material, or is not significant as to impact the product quality. During the evaluation process, the QPS interacts with a formulation scientist for technical discussion and QA for capturing the event in a QA discrepancy system. In addition, the QPS is accountable for timely communication to clinical operations on the quality decision made at a quality review board meeting to reduce impact on the clinical material supply. Under this scenario, once a discrepancy is discovered and under investigation it may affect the timely shipment of clinical materials. The QPS will work with the clinical operation group closely so that they are informed of the material's suitability for use. 

Interactions with External  Partners and CMOs

As Genentech's clinical pipeline became more diverse, we had an increased need for collaboration with CMOs or partners to use their specialized technologies for process development and clinical manufacturing. To effectively manage the development activities with the CMOs or partner, the project team needs a single point of contact identified from each of the key functional areas (e.g., project management, process development, quality (QC and QA), etc.) to be responsible for the interactions with the CMOs or partners. In this situation, Genentech's external QA serves as the point of contact for the quality assurance function and ensures that the product is compliant, reputable, and reliable for patients, while the QPS serves as the point of contact for quality control function and manages the QC activities from method transfer to various QC testing and QC investigations. In many cases, multiple QC laboratories and sites are involved in the QC activities for a project. This requires the QPS not only to have the ability to manage multiple issues at the same time, but also to have the broad knowledge and technical skills to dive deep into issues when guidance is required. This eliminates the need to have all of the QC groups involved in interactions and ensures quick responses to QC issues.  

The QPS is also involved in the due diligence evaluation for selection of the CMOs. This allows the QPS to identify the gaps and risks from a QC perspective and address them in advance of a contract. 

Features

A successful QPS acts as a single point of contact for consistent product quality oversight.

The Quality Product Steward Model: The Genentech Approach

Fed-batch and perfusion culture are the two dominant modes of operation for mammalian-cell-culture based processes, especially for the production of glycosylated proteins required in large amounts. This article provides an economic comparison for the production of a typical glycosylated protein using the fed-batch, concentrated fed-batch (CFB), and concentrated perfusion (CP) technologies. The CFB and CP processes are based on the ATF System, a platform technology developed by Refine Technology for biologics production.

The market for protein-derived products has grown significantly in the past decade and continues to accelerate at a rapid rate. As more recombinant therapeutic proteins enter development and get through the approval phase, more efficient large-scale production of such proteins is necessary to meet the surging demand. Fed-batch and perfusion culture are the two dominant modes of operation for mammalian-cell-culture based processes, especially for the production of glycosylated proteins required in large amounts.

  Challenges in the industry (such as competitive products for the same indication or desired cost reductions) are forcing many to explore new production options. 

In fed-batch culture, there is a gradual addition of a fresh volume of selected nutrients during the growth–culture cycle to improve productivity and growth. The culture is subsequently harvested and the product recovered. Fed-batch culture has been an attractive choice for large-scale production due to its operational simplicity and familiarity as a carryover process from fermentation. However, fed-batch mode of operation typically also involves high start-up costs, resulting from the need for larger bioreactor plant capacity. 

In perfusion culture, a continuous supply of fresh media is fed into the bioreactor while growth-inhibitory by-products are constantly removed. The increasing interest in the use of perfusion culture can be attributed to the higher product output from a reduced reactor size (hence, simplifying operation, cleaning, and sterilization). The cell densities achieved in perfusion culture (30–100 x 10

  cells/mL) are typically higher than for fed-batch modes (5–25 x 10

  The principal aspect of perfusion operation, which is different from fed-batch, is the added requirement of a cell-retention device. Cell-retention systems add a level of complexity to the process, requiring management, control, and maintenance for successful operation. Perfusion bioreactors can suffer operational difficulties such as malfunction or failure of the cell-separation device, which can lead to shortening of the production run, leading further, to increased operating costs. This has previously limited their attractiveness. 

In recent years, a platform technology has been developed for biologics production—the ATF System, introduced by Refine Technology (Pine Brook, NJ). Used in the alternating tangential flow mode, it is a low shear filtration system that inhibits filter-membrane fouling. This external cell-separation system is able to maintain continuous culture for extended periods of time and offers the capability of rapid filter change without compromising the culture run.

  The ATF System allows increased volumetric productivity and reduced bioreactor size.  

Concentrated fed-batch and concentrated perfusion are two production techniques based on the ATF System, which simultaneously nourishes the culture and concentrates the product within the bioreactor. These manufacturing methods permit great increases in cell and product concentrations as compared with fed-batch and perfusion. For example, in the concentrated fed-batch production platform, one of Refine Technology's pharmaceutical clients has reported a protein product titer of 17 g/L with an unoptimized Chinese hamster ovary (CHO) cell process.

  Higher titers are expected as process optimization continues. In the concentrated fed-batch operation, ultra-high cell densities of (70–200) x 10

  cells/mL have been achieved; similarly, extremely high cell densities in the region of (70–100) x 10

  cells/mL have been achieved in systems using the concentrated perfusion mode.  

The system scales on a linear basis from 1 L to greater than 1,000 L and can be used with traditional or disposable bioreactors and with all cell types including anchorage-dependent lines. Table 1 indicates the working volume sizes for each ATF System in the scale-up process. The figures in the table are provided as guidelines. Actual capacity and vessel size depend on process conditions. 

Table 1. Guideline working volume sizes for each ATF system			

This article compares the economic feasibility of a typical glycosylated protein manufactured using three production techniques—fed-batch (FB), concentrated fed-batch (CFB), and concentrated perfusion (CP). The Excel-based process-cost modeling tool, BioSolve from BioPharm Services (Chesham, Buckinghamshire, UK), was used for the economic assessment. The methodology, assumptions, and key results of the cost model are described. The analysis will use the cost of goods (CoG) metric expressed on a per gram basis for comparability. 

The commercial process-cost modeling software, BioSolve, is used to assess the process economics of the FB, CFB, and CP production techniques. The CoG is a useful metric to quantify the operating costs of a manufacturing option. BioSolve is an Excel-based tool that determines the CoG by accounting for the indirect (fixed) overheads of the facility and the direct (variable) operating costs of the process. The fixed-cost element consists of capital charges, taxes, and insurance, and direct costs include consumables, materials, labor, and waste management. Such an approach to estimate the CoG has been used to evaluate the process economics of disposable membrane chromatography for use in biomanufacturing.

Figure 1 illustrates the basic BioSolve framework, which comprises the user interface, process definition, productivity and cost calculations, and model outputs. The interface allows a rapid assessment of the impact of predefined key input parameters (e.g., process scale, product titer, disposable options) on the model outputs. The core of the cost model consists of the process definition, which includes the mass balances, equipment sizing, operating parameters, and resource allocation. The calculated items include plant productivity, labor requirements, consumable and materials usage, and equipment list. The costs of these components are maintained in a cost database, which is built with data consisting of benchmarking information from several biomanufacturing operations. The key outputs generated by the cost model are facility throughput, bill of materials, CoG, and capital investment. 

The model compares the manufacture of a glycosylated protein in three different production techniques—FB, CFB, and CP. Figure 2 depicts the process sequences for these production methods. The seed train for the FB process is longer because this option requires more steps to scale-up to the production cell culture bioreactor. The FB upstream process information was derived from commercially relevant operations commonly practiced in the industry. The upstream information for the CFB and CP processes was provided by Refine Technology, based on data supplied by its clients. In the FB and CFB processes, the removal of cells is achieved by centrifugation and depth filtration. Such recovery-unit operations are not required in the CP process because the cells are retained in the ATF System. The three processes were assumed to have the same purification sequence. This downstream sequence was selected according to commercial relevance and sourced from details that are available in the public domain. Table 2 summarizes the key operating parameters used in the base case study. 

Figure 2. Process sequence (a) fed-batch (FB), (b) concentrated fed-batch (CFB), and (c) concentrated perfusion (CP) for the production of a glycosylated protein			

For the FB process, all the seed steps included in the model are assumed to be batch fermentations. In the production cell culture step, two additional feeds are added to the bioreactor three days and six days after inoculation. The final growth phase takes about 13 days. 

Table 2. Summary of the key base-case process parameters			

The CFB and CP seed sequence is performed using a 200 mL bag carried out in batch fermentation mode, followed by a 20 L bioreactor also run in the CFB mode. 

In the FB and CFB processes, the recovery procedure is centrifugation followed by depth filtration. An ultrafiltration/diafiltration (UF/DF) step is used to concentrate the product stream before the Protein A unit operation. A virus inactivation step occurs. The product stream is subsequently loaded onto an ion exchange (IEX) bind and elute column and passed through an IEX flow-through column. A viral filtration step takes place before the UF/DF step. A final sterile filtration step is used to purify the product. This purification sequence is based on typical unit operations for the production of a glycosylated protein, using typical solutions and timings. The overall yield for the downstream sequence is 50% and 69% for the FB/CFB and CP processes, respectively. 

The analysis in this scenario evaluates the process economics of the three production techniques using the assumptions stated in the previous section. Figure 3 shows the total CoG per gram broken down into fixed capital charges and variable costs such as materials, consumables, labor, and others (e.g., insurance, maintenance). As expected, the FB process has a higher upfront capital burden ($53 million) due to the need for a longer seed fermentation train and larger overall fermentation volume. The CFB and CP options benefit from increased throughput and reduced overall bioreactor capacity, which translates to lower initial investment costs. The CFB and CP technologies offer substantial capital charge reductions of 13% and 32%, respectively, relative to the FB process. The CoG per gram is inversely proportional to the annual product mass with the CP process producing the most product (265 kg/year) and FB producing the least amount of product (130 kg/year). This correlation between low CoG and high annual product mass is expected, because increased throughput of product will result in lower costs per gram produced. 

Figure 3: Cost of goods (CoG) results for the base case. FB: fed-batch; CFB: concentrated fed-batch; CP: concentrated perfusion.			

In the CP process, the materials costs contribute a significant amount to the CoG. This can be attributed to the intensive usage of media over the extended perfusion culture cycle.  

The model results indicate that the CP process (scenario 1c) is the most cost-effective technology with the lowest overall CoG per gram of $87/g. The CFB process (scenario 1b) is slightly more expensive at $118/g. The FB process (scenario 1a) has the highest CoG ($158/g). The CFB and CP options provide cost savings of about 25% and 45%, respectively, when compared to the FB process.  

Scenario 2: Changing the Titer for the CFB Process

The expression levels in the CFB process can vary depending on the type of cell line and duration of cell-line development. In this section, the effect of changing the product titer for the CFB process is examined while keeping the bioreactor size constant at 1,000 L (Figure 4). In the worst-case scenario, the titer is reduced from 17 g/L (scenario 1b) to 10 g/L (scenario 2a). In the best-case scenario, the titer is increased to 25 g/L (scenario 2b). 

Figure 4. Cost of goods (CoG) results for the fed-batch (FB) process and the concentrated fed-batch (CFB) process at 10 g/L, 17 g/L, and 25 g/L (1,000 L bioreactor scale) 			

Reducing the titer, as expected, increases the CoG as the annual throughput is reduced. When the titer is reduced to 10 g/L (scenario 2a), the CFB process appears less economical as the CoG ($184/g) is higher than the FB CoG at $158/g (scenario 1a), as shown in Figure 4. On the other hand, when the titer is increased to 25 g/L, the CoG reduces to $87/g. This improvement in the expression level would make the CFB process much more attractive than the FB process with significant cost savings of 45%.  

Scenario 3: Changing the Bioreactor Size for the CP Process

The bioreactor size used for running perfusion culture mode can vary. This section looks at changing the bioreactor size of the CP process while keeping the titer unchanged at 0.8 g/L. Two other bioreactor sizes (500 L and 750 L) are considered in this analysis. When the bioreactor volume is reduced to 500 L (scenario 3a in Figure 5), the CP process generates about the same annual output (132 kg) as the FB process (130 kg). The CoG of the CP process increases from the base figure of $87/g (scenario 1c) to $133/g (scenario 3a). The CP process at 500 L and 0.8 g/L is still more economical than the FB process. It should be noted that the simplification of material and people flow provided by reduced bioreactor capacity in the CP facility cannot be calculated easily but may provide the key driver to such technology being increasingly used in biomanufacturing. 

Figure 5. Cost of goods (CoG)  results for the fed-batch (FB) process and the concentrated fed-batch (CFB) process using 500 L, 750 L, and 1,000 L (0.8 g/L titer)			

This article has provided an economic comparison for the production of a typical glycosylated protein using the FB, CFB, and CBP technologies. The CFB and CP processes are based on the ATF System. The model results revealed that in the base case, CoG savings of 25% and 45% can be achieved using the CFB (1000 L, 17 g/L) and CP (1000 L, 0.8 g/L) technologies, respectively, when compared with the FB process (10,000 L, 2 g/L). The bulk of the savings is derived from the reduction in capital requirements due to higher productivities, resulting in reduced overall bioreactor capacity in these processes. The use of the CFB and CP technologies would seem a potential approach toward lower upfront capital investment and operating costs. Sensitivity analyses were performed on the product titer in the CFB process and the bioreactor volume in the CP process. The feasibility of the CFB technology reduces at the worst-case product titer (10 g/L) reported in current industrial processes. The CP CoG is still lower than the FB CoG when the bioreactor volume is reduced to 500 L. 

In addition to cost considerations, there are other key factors that may affect the selection of an appropriate process for a drug candidate. The existing fed-batch and perfusion processes are well-known but both have limitations. The CFB mode with the ATF System is recommended if the product of interest is a single concentrated product stream harvested from the reactor. The CP mode can be used to reduce the size of bioreactor required to produce the same amount of product as in fed-batch or perfusion.  

This article has not evaluated the use of the ATF System during the cell banking and seed expansion stages in the upstream manufacturing process.

  Performing perfusion cultures with such a system can generate large cell mass for high density freezing to be used for cell-banks preparation. High cell density freezing reduces the inoculum expansion time by removing the first seed passages and inoculates a small bioreactor directly from the freezer. This leads to reduced manual handling of culture and improved facility use. 

The impact of the use of disposable bioreactors in the cell-culture operations has not been captured in this article analysis. Disposable systems are easier to set up and they eliminate cleaning requirements; hence the turnaround time for such single-use technologies is typically shorter compared with their stainless-steel counterparts. The faster turnaround time could result in increased plant throughput and affect the production costs of the facility. 

 is managing director, both at Biopharm Services, Chesham, UK. 

 is vice-president of sales and business development, both at Refine Technology, Pine Brook, NJ, 793.993.3003, 

 1. Chu L, Robinson DK. Industrial choices for protein production by large-scale cell culture. Curr Opin Biotechnol. 2001;12:180–187. 

  2.  Carstens, Jason. Perfusion! Jeopardy or the Ultimate Advantage? BioProcess International webinar. 2009 Sept.   

  3. Furey J. Scale-up of a cell culture perfusion process. Gen Eng News. 2002;22:62. 

 4.  Mora J, Sinclair A, Delmdahl N, Gottschalk U. Disposable membrane chromatography performance analysis and economic cost model. Bioprocess Int Suppl. 2006:4:38–43. 

  5. Lim JAC, Sinclair A, Kim DS, Gottschalk U. Economic benefits of single-use membrane chromatography in polishing—A cost of goods model. Bioprocess Int. 2007;5(2)48–56. 

Comparing the economic feasibility of a typical glycosylated protein.

An Economic Comparison of Three Cell Culture Techniques

The stunning announcement of a few weeks ago that GlaxoSmithKline (GSK) agreed to pay $750 million to settle civil and criminal charges that it knowingly sold adulterated drugs manufactured at one of its facilities is a much-needed wake-up call for the pharmaceutical industry. It serves as a critical reminder for executives to review their organizations' ethics and compliance programs—especially the communications efforts about their whistleblower programs and the protections those programs afford to employees.  

The former executive who blew the whistle on GSK will receive an award of about $95 million, which may be the first of many such awards. Such a situation is a result of a confluence of legal, legislative, and regulatory developments that expand a company's liability risk, while simultaneously providing powerful incentives for whistleblowers who go directly to government investigators, rather than reporting their concerns through their company's internal compliance channels. 

The GSK settlement marks the first time that a whistleblower suit, filed under the powerful False Claims Act (FCA), has been successfully used to hold a drugmaker accountable for violations of government manufacturing standards. Similar cases are likely to be brought in the future because the FCA was beefed up by certain provisions contained in the Patient Protection and Affordable Care Act of 2010 (PPACA), and the government is currently devoting substantial resources to investigations of alleged fraud in the healthcare industry. 

A major concern in the industry about the PPACA is the enhancement of criminal statutes to make prosecutions easier, penalties larger, and the scope of potential plaintiffs wider, given relaxation of former restrictions on who may bring legal actions on behalf of the federal government under the Act. Accordingly, liability exposure for industry participants has greatly expanded, prosecutions are increasing, and whistleblowers can be rewarded.  

Concurrently, whistleblower provisions contained in the Dodd–Frank Wall Street Reform and Consumer Protection Act are receiving an enormous amount of attention among publicly traded companies. Under Dodd–Frank, a bounty program now under development by the US Securities and Exchange Commission (SEC) would reward individuals who provide "original information'' to the SEC with up to 30% of any enforcement action recovery that exceeds $1 million. In early November, the SEC set aside $452 million to reward tipsters under the whistleblower program authorized by the Dodd–Frank law. 

The whistleblower provisions under Dodd–Frank have provoked serious concerns among business-advocacy groups, such as the US Chamber of Commerce, which recently issued a statement warning that the SEC program "threatens to undermine existing corporate compliance programs that the federal government has long advocated as an important component of responsible and effective corporate governance.'' 

It is important to note that the GSK whistleblower initially followed the company's internal control mechanisms and reported up the chain of command about numerous quality-control issues at a manufacturing facility. She and her reports were dismissed. In the end, the legal, monetary, and reputational consequences were enormous. 

The solution to the conundrum presented by this confluence of events, laws, and regulation is both simple and complex. At its core, the challenge deals with culture and communication. If an organization is a reflection of its leadership, then those at the top must walk the walk of uncompromising commitment to compliance—and they must relentlessly communicate this commitment at all levels of the organization. These leaders must turn an unblinking eye toward their internal controls and compliance program and make an honest assessment of its rigor and effectiveness. 

 is an associate, both in the litigation department of Sherin and Lodgen LLP, Boston, MA, 617.646.2220, 

Final Word

Those at the top must walk the walk of uncompromising commitment to compliance

The Powerful Lesson of the GSK–Whistleblower Case

Recently, a friend of mine shared with me a story about his daughter and how she and her three college friends managed to turn what should have been a wonderful spring break vacation into a miserable two-week trip that all of them would rather forget. It seems they had decided to take a "leisurely drive" from their college in Washington State to visit another friend in California, stopping along the way to visit mutual friends and enjoy the scenery. Their excitement and enthusiasm was short-lived, however, and the trip resulted in them getting lost numerous times, mechanical failures and breakdowns, sleeping in the car most nights, bad food, missed meetings with friends, and strained relationships among the passengers. In fact, two of the girls do not speak to each other to this day.  

What went wrong? Lack of planning, limited funds, poor communication, and unrealistic expectations are only some of the mistakes that were made before they even turned the key in the ignition. We think they are foolish and immature young people, and rightfully so. But how often do we hear of small biotech companies committing many of the same mistakes in their early-phase drug development business with stakes much higher than a failed road trip? 

Planning for success in early-phase drug development is in many ways similar to the planning of a successful road trip. Positive outcomes depend on preplanning and critical decision-making as quickly and as accurately as possible. The high costs associated with the lack of planning can include the loss of valuable time and money, outright failure of the project, potentially serious damage to the reputation of the company, and in the worst-case scenario, business failure. 

In today's high-cost, highly competitive drug development environment, no biotech firm can afford to enter Phase 3 and commercial production without solid data gathered from early-phase development. Given today's complex regulatory environment and the limited financial resources at so many biotech companies, the pressure to develop new and profitable molecules is tremendous. Although many compounds are screened for their therapeutic potential, few prove suitable to move forward for clinical evaluation, while even fewer ever reach Phase 3 and commercialization. 

Having in place a well-integrated project management strategy developed in concert with a contract manufacturing organization (CMO) is the key to allocating resources, creating a top-notch project management team, satisfying regulatory authorities, and advancing the compound to Phase 3, and then getting the drug to commercial production and finally to the patients who need it. For injectable products, often considered the most technically challenging and expensive drugs to develop, the project management process is especially vital to success. Today, the small biotech company that understands the value of an integrated project management strategy has taken the first big step in reducing a drug's time-to-market, optimizing costs, and increasing their return on investment.  

Is your company ready for its road trip? Here's what you need to know.  

Like any well-planned trip, no compound should enter into early-stage development without a good road map. Plan your trip before you get behind the wheel. 

What does the road map for an integrated project management strategy look like? Generally, it includes four phases: 					

initiation: objectives, project scope, and deliverables are defined, and the project team is put together

planning and coordination: a plan is designed that outlines tasks and individual responsibilities; potential risks and means to address them

controlling: the project itself is executed, and any potential problems are quickly addressed and eliminated

closing: at the end of the project, lessons learned are documented, reported, and applied to current and future projects.

In the present biotech business, each phase of the project is becoming more and more challenging, and risks, particularly financial risks, are increasing exponentially. Engaging a highly experienced CMO to help develop a project management strategy for drug development can be very helpful.  

The key to getting this process in motion—and keeping it moving—is the project manager. The ideal project manager will have a background in natural sciences and significant experience in assembling and directing teams that include researchers, technical, and economic experts. The project manager will pull together a team of highly skilled individuals who are ready to solve existing and potential problems from the laboratory to the production line.  

A diversity of specific skills among team members is vital and should include individuals with experience in:  					

regulatory affairs (including a range of US, European, and other national and regional bodies)

Because small biotech companies often lack the staffing and the expertise to assemble their own project management teams, the CMO and its designated project manager are critical and will create a team that suits each project's specific needs, keeping in mind that small-biotech staff members may not be familiar with all the details involved in bringing a drug to the clinic. This may be particularly true in the case of regulatory issues where a CMO can provide extensive regulatory expertise and bring even greater value to the project. 

Putting in the time and effort to develop a thoroughly integrated plan during the early phases of drug development will reap many benefits by identifying and eliminating existing and future problems before the plan is initiated. This time is well spent, and will not only help avoid crises during the later phases, but will help shorten time-to-market and maximize return on investment.  

The road to a sound partnership and project success is paved with clear and regular communications. The project manager is responsible for ensuring that every step of the work plan and its execution is thoroughly documented and accessible to team members. The importance of good communication among team members cannot be overstated. Executed consistently, clear channels of communication will help prevent misinformation from developing and spreading, reduce or eliminate risks, and promote collaborative team relationships. Regular and pre-prepared conference calls and team meetings that are well-documented help ensure project transparency and the free flow of accurate information. Creating a simple communications plan that includes a list of phone numbers and contact info of whom to call in case of emergency, project issues, etc., is well worth the little effort needed to construct it, and is a valuable tool not just for communications as a whole, but to help speed up decision-making in the event of a crisis or other problem.  

The real effort in moving a drug forward in the early stages of the project is in the development and validation phases. In this stage, the plan's tasks and responsibilities yield the actual product. Throughout these phases the project manager is responsible for checking on the progress of the project, anticipating needs, overseeing costs, identifying and addressing any issues that may crop up, and ensuring the project is progressing as planned. Regular communication in these phases is critical. Milestones should be kept in sight and adjustments made to be sure they're reached. The project manager that can cultivate a trusting and collaborative environment between the CMO and the customer is a major asset to the project. The focus on each others' needs beyond the project at hand will make for a better outcome now and in the future. 

CHALLENGING ROAD TRIPS FOR SMALL BIOTECHS

At small and emerging biotech companies, the challenges and risks involved in project management during early-phase development can differ in both type and degree from those at major biotech companies. For example, smaller biotech companies often prefer the selection of a CMO that they can work with through the entire process of a project, from Phase 1 through to commercial production. Thus the selection of a CMO by the small biotech company is crucial to the success of the project. There are many issues to consider and questions to ask before a final selection is made to be certain the CMO and the company are well suited. These include how swiftly can the CMO move a project ahead? How effectively will the supplier handle the company's active pharmaceutical ingredient? Is the CMO financially stable and flexible? Will the CMO understand the company's overall goals beyond the project at hand? Is there a sense that the relationship will be trusting and collaborative? In many cases, the smaller biotechnology companies are less experienced in many of the technical and regulatory issues that must be addressed in bringing a new compound to the development phases and then to market. Because these problems tend to occur more often during early-phase development, these companies may need to frequently update project specifications when unexpected roadblocks appear. For many of the complex new compounds being developed today, there exists a significant risk that a project may be cancelled at any point in the process. For these reasons, the depth of experience, capacity for innovation, and flexibility an experienced CMO can bring to the smaller biotech company will lend vital support to the successful management of early-phase development. 

For smaller biotech companies that typically lack the financial resources that larger companies bring to bear, the selection of a CMO can make the difference between the success or failure of not just the project underway but, possibly, the very company itself.  

The troubling financial situation over the last several years has resulted in tightened credit markets and the reduction in the flow of necessary capital. Moreover, the enforcement of increasingly stricter licensing regulations that pose especially high hurdles for small biotechnology firms, especially those lacking the internal expertise to address them, also has created a more difficult environment. Today, small and emerging biotech companies feel particularly pressured to get a drug development project underway and through the early phases as quickly as possible.  

Often, because of their size and limited capabilities, the smaller company may only learn about the many problems surrounding the early drug development process as they move forward. They also may be unaware of potential problems between the laboratory and the market and their own limitations in addressing them. Small biotech companies with little experience in bringing a product to market are less likely to have acquired the knowledge of how the development process works. In such cases, working with a CMO that is willing and capable of adapting its support services to changing circumstances is essential.  

A high-quality CMO can contribute critical consulting and production support to help manage the difficult procedures and decision-making inherent in early-phase development. Together with a well-integrated project management team, a small company can maintain its milestone schedule and keep a project on budget. 

Another consideration is how important the size of a drug company is in determining decision-making processes. At smaller biotech companies, the CEO may not have a scientific background. However, this function is central to the decision-making process. Typically, large firms assign the decision-making process to contract management, purchasing, or outsourcing departments. The small biotech CEO's central role and the personal nature of decision-making underline just how important it is for a CMO and its customer to cultivate personal relationships and develop close partnerships among key staff members. Cultivating comprehensive relationships that last beyond the fulfillment of the initial project is critical. A CMO that helps the customer's business as a whole becomes more successful and will lead to huge payoffs in developing a productive partnership and an ongoing business relationship. 

Biotech project management is a complex issue, and many of the greatest challenges and risks come during the early phases of drug development. However, moving from the early phases into Phase 3 and commercial production, companies will have a much better shot at success with a well-integrated project management plan and team in place from the very outset. The key features of the plan include: 					

a deep appreciation of the small biotech's unique challenges, strengths and limitations, and decision-making processes

a clear focus on sound project planning and management

a consistent, hands-on approach in every phase of the project

development of specific project tools for the planning and controlling phases

Perspectives on Outsourcing

Biotech companies will have a much better shot at success with a project management plan and team in place from the very outset

Driving your Product to Profitability with Project Management at the Wheel

This is the first of a series of columns that I have agreed to write about singleuse manufacturing technologies and issues for 

), which are sister publications. I want to start by acknowledging former 

 Editor-in-Chief Laura Bush, who invited me to contribute and to welcome Editorial Director Michelle Hoffman, with whom I look forward to working with. I also want to acknowledge Andrew Sinclair and Miriam Monge, who edited this column in 

 over the past several years and who have set a high bar. 

I've written several editorials and articles for 

 in the past, and I am also a member of the editorial advisory boards for both of these publications. For those who are not familiar with me, I've been in the biopharmaceutical industry for more than 31 years and have worked in filtration process development and validation with many pharmaceutical and biotech companies since before the biotech revolution. As an active member of the Parenteral Drug Association (PDA), the International Society for Pharmaceutical Engineering (ISPE), the American Society for Mechanical Engineering–BioProcess Equipment Committee (ASME–BPE) and the Bio-Process Systems Alliance (BPSA), I've been a contributor or reviewer on numerous industry guides and standards, and have conducted training for regulatory agencies in the Western hemisphere, Europe, and Asia. In my present role as chairman of the board and the Technology Committee of the BPSA, I have had the opportunity to interact with suppliers and users of single-use technologies worldwide and look forward to sharing that perspective here. 

Over the past 10 years or so, we've seen singleuse technologies explode from production-scale filter capsules, tubing, and simple biocontainers to encompass sterile connectors, membrane-chromatography adsorbers, bioreactors, mixers, and integrated platform systems with increasing levels of sensors and automated controls. Many articles have been published, and singleuse conferences have become regular events, with topics evolving from fundamental technologies to user evaluations, and on to process and facility integration.  

The main issues today include implementation, quality, security of supply, regulatory expectations, system design, integrity/installation testing, QbD, PAT, quality agreements, standardization, disposal and environmental issues, and economic justification. As this column progresses, let me know what singleuse issues and topics you would like to see further explored. This month, I will touch on some recent developments in standardization and quality agreements, and provide an update about some of the latest BPSA initiatives in this area.  

Standardization of singleuse components has become a frequent topic in articles, on chat boards, and at conferences. Interest has been expressed in standardizing the materials for films and tubing, as well as the dimensions of sterile connectors, hose barb, and sanitary flange fittings. When considering standardization of singleuse components, it is important to bear in mind that although some aspects of singleuse components can be standardized (e.g., approaches to sterilization, characterization of extractables, particle and endotoxin testing, tubing ID, hose barb, and flange dimensions), it is unlikely that any materials or design features will become a commodity subject to standardization because of the proprietary nature of many singleuse components. Other than ASME–BPE and ASTM International, none of the primary industry professional or trade associations (PDA, ISPE, and BPSA) or regulatory bodies issue formal standards. Pharmaceutical standards bodies, such as the US or European Pharmacopoiea or the International Organization for Standardization, tend to focus on the final drug product and packaging. These can be extrapolated or adapted to singleuse equipment, but the industry organizations themselves primarily issue best practice recommendations and technical guides rather than formal or obligatory standards. 

One of the key roles of BPSA, in addition to producing its own best-practice guides, is to stimulate other organizations to also develop guides or standards that facilitate implementation of singleuse equipment. For example, BPSA recently submitted a letter to ASME, encouraging a review of the ASME–BPE standard for sanitary flange fittings with regard to using polymeric material instead of traditional metal alloys. The current ASME–BPE standard for sanitary flanges was developed with stainless steel in mind and specifies dimensions and tolerances that are costly to achieve in a variety of polymers. A modified standard addressing the properties of polymer-based flange connectors that maintains critical fitment requirements, while accommodating the unique properties of molded polymers, could reduce cost of ownership and ensure that all parts can work with singleuse and stainless steel systems. For flange-connector manufacturers, tooling and production costs also could be reduced if more liberal tolerances were allowed.  

Many singleuse systems integrators now offer standardized singleuse assembly configurations for common functions, or subassemblies that can be custom assembled aseptically with sterile connectors by the user. Such rationalization can help reduce complexity and cost, but further standardization of designs or materials among suppliers is practically difficult and would be a barrier to further product development. Singleuse technology may have moved out of its infancy, but standardization to create commodities needs to be considered very carefully. Establishing standards for equivalency of designs or materials would stifle innovation and conflict with market demands for improved designs and materials. 

One area that can benefit from a form of standardization is quality agreements. In a recent editorial I wrote for 

), I discussed a new initiative by   BPSA to develop a quality agreement template for singleuse suppliers and users. The FDA has provided guidance on establishing quality agreements with contract manufacturers of licensed biologics, and drug manufacturers are seeking similar agreements with all their suppliers, including equipment suppliers.

  The Society of Chemical Manufacturers and Affiliates, home to BPSA, has a Bulk Pharmaceuticals Task Force that has developed a template for quality agreements related to the manufacture and release of substances regulated by the FDA.

 A similar template has been developed by the International Pharmaceutical Consortium on Regulation and Science for use by drug manufacturers and suppliers when addressing raw materials, container closure/device components and packaging materials.

  BPSA, through its Singleuse System Quality Agreement Template Task Force, is adapting the content of these guides to develop a template specific to singleuse manufacturing. This template is intended to simplify and standardize the timeconsuming and sometimes difficult process of negotiating quality agreements between biopharmaceutical or vaccine manufacturers and singleuse system or component suppliers.  

To discuss this topic further and provide an opportunity for users and suppliers to offer input, 

 and BPSA are collaborating to produce a web seminar on quality agreements for single-use manufacturing. The seminar is scheduled for Wednesday Mar 2, 2011 (7 am PST, 10 am EST, 3 pm GMT, and 4 pm CET). For more details, see: 

http://biopharminternational.findpharma.com/webcasts

BPSA also will be hosting its inaugural International SingleUse Summit in Washington DC (Jul 27–29, 2011). The meeting will focus on the future of biopharmaceutical manufacturing, with a specific emphasis on regulatory considerations and perspectives on the effect of healthcare reform on drug markets. Innovations and market drivers affecting the singleuse industry also will be discussed. More information is available at 

In my next column, I'll be reporting on global issues, as well as on the implementation of singleuse components, based on participation as a speaker and panelist at several international meetings, including the ISPE Japan Sterile Products Processing Community of Practice in Japan (Feb 17, 2011), the ISPE Aseptic Processing Seminar in Tampa, Florida (Feb 21–22, 2011), and the IBC Biomanufacturing and SingleUse Systems Asia Conference in China (Mar 7–9, 2011). 

In the interim, feel free to send me suggestions about topics, issues, and technology that affect your implementation of single-use technology. I look forward to hearing from you.  

 is senior VP of global scientific affairs, Biopharmaceuticals, Pall Life Sciences, Port Washington, NY, and chairman of the Board and Technology Committee of the BioProcess Systems Alliance (BPSA), 516.801.9086, 

1. US Food and Drug Administration. Guidance for industry. Cooperative manufacturing arrangements for licensed biologics. Rockville, MD; 2008 Nov. Available from: 

2. SOCMA BPTF. Manufacturer's quality agreement template. 2010 Apr. Available from: 

3. IPAC-RS. Quality agreement template toolkit. 2009  May. Available from: 

The Disposables Advisor

Although some aspects of single-use components can be standardized, it is unlikely that any materials or design features will become a commodity

Trends Toward Standardization

Late last year, Congress approved a sweeping food safety legislation that provides the US Food and Drug Administration with more authority to recall and monitor food products, boosts its inspection force, and strengthens its capacity to halt unsafe imports. But that may be the last time for a while before the legislators bolster FDA's oversight capabilities or authorize added resources. With Republicans taking over the House last month and increasing their clout in the Senate, the legislators are contemplating severe federal budget cuts and more aggressive oversight of the administration's healthcare policies and regulatory programs. The FDA is a ready target as agency critics move to examine an apparent slow-down in new drug approvals and the agency's difficulties in keeping violative products off the market. It's not clear whether Congress even will provide the $1.4 billion over five years, needed to hire about 2,000 additional FDA inspectors to expand food oversight. 

House Democrats continue to support a similar drug safety bill that would give the FDA additional enforcement tools over drugs and biologics, including mandatory recall authority, stiffer civil and criminal penalties, and authority to subpoena records related to drug violations. As with food, there would be a big increase in foreign and domestic inspections and heightened controls on imports and stronger plant registration requirements. But there's not likely to be any action on the measure before 2012, when Congress is scheduled to renew the prescription drug user fee program.  

Instead, new Republican committee chairmen are preparing for extensive oversight hearings on administration health reform legislation and regulatory stances. The Chairman of the House Committee on Oversight and Government Reform, Darrell Issa (R-CA), considers FDA a "broken bureaucracy" and has included the agency on his priority investigation list. Issa was highly critical of FDA officials and pharmaceutical executives at hearings before his committee last year on delays in drug recalls by Johnson & Johnson's McNeil Consumer Products unit. Now as panel chairman, Issa plans to hold FDA officials accountable for such regulatory lapses. In December, Issa sent FDA Commissioner Margaret Hamburg a letter questioning FDA's oversight of a contract manufacturer for J&J, and of contract drug manufacturing practices in general. The new chairman also has his eye on the FDA's expanded authority over food production and its growing involvement in tobacco marketing. And FDA's Office of Criminal Investigations is expected to draw scrutiny following criticism of its operations last year by Congress's Government Accountability Office.  

Similarly, House Energy and Commerce Committee Chairman Fred Upton (R-MI) is preparing to challenge specific health reform policies, along with "job-killing regulations" that block technological innovation. FDA programs and policies are fodder for the E&C Health subcommittee, which is headed by Reps. Joe Pitts (R-PA) and Mike Burgess (R-TX). In addition, the oversight and investigations subcommittee, under Chair Cliff Stearns (R-FL), may continue to probe drug manufacturing problems, such as FDA's handling of heparin contamination and its failure to adequately monitor foreign drug production.  

At hearings last year on J&J's manufacturing problems, the FDA was represented by Principal Deputy Commissioner Joshua Sharfstein, who won plaudits for his command of the issues. Now someone else at FDA will have to fill the hot seat at Congressional hearings, following Sharfstein's surprise departure from the agency last month.  

Sharfstein was lured away by an offer to head Maryland's health department, a move that capitalizes on his public health roots in Baltimore. In moving to the state agency, Sharfstein will manage a $7 billion budget and will be involved with implementing the many health reform programs and policies that require state involvement, including an expansion in Medicaid and formation of new health insurance exchanges.  

At the FDA, Sharfstein helped engineer a get-tough compliance policy designed to curb perceptions that the agency is too cozy with industry. The stronger enforcement stance has produced more warning letters that cite manufacturing and marketing violations and more criminal investigations. Sharfstein also was involved in strengthening FDA's medical device approval process, which is still ongoing, and he advocated establishing tight curbs on using more risky medicines, such as the diabetes drug Avandia. 

Hamburg is using Sharfstein's departure as an opportunity to re-examine the agency's top management structure. Previous commissioners have tried various organizational models of deputy commissioners, chiefs of staff, and special assistants, and Hamburg may move away from the one-deputy arrangement. John Taylor,  counselor to the commissioner, is filling Sharfstein's shoes while Hamburg weighs her options, and he is likely to assume a more visible role at the agency.  

Taylor has had a long career at the FDA in legal, enforcement, and regulatory affairs positions under several FDA commissioners during both Democratic and Republican administrations. He rose to be associate commissioner for regulatory affairs from 2002 to 2005, and then served brief stints at Abbott Laboratories and the Biotechnology Industry Organization. Taylor returned to the FDA in 2009 to be Hamburg's top legal advisor, and the commissioner might very well like to have a seasoned enforcement official represent the FDA before contentious Congressional committees.  

One of Sharfstein's last activities at FDA was to unveil the third phase of the agency's transparency initiative, which he headed as chair of the agency's Transparency Task Force. Launched in June 2009, the program has established an FDA Basics web page with broad information on agency operations and policies, plus an FDA-TRACK program that measures the performances and accomplishments of agency offices. This latest transparency segment aims to provide manufacturers with useful information on relevant agency policies and procedures. The FDA will post more information on key staffers and meeting presentations; will provide a system to answer sponsor questions quickly; and will clarify agency review processes and procedures for developing new guidances and regulations. The agency also seeks comments on a few more difficult draft proposals, such as  whether to set specific timelines for guidance development and how to handle requests from manufacturers to appeal agency decisions. 

Of particular interest are two industry proposals that the FDA is rejecting. There will be no binding advisory opinions in response to specific requests from sponsors for clearer decisions on proposed promotional and scientific exchange practices. The FDA says that it will continue to provide its view on whether promotional pieces for drugs and biologics meet regulatory standards before dissemination, but retains the right to change its opinion later on. The FDA also won't commit to notifying companies in advance of publicly disclosing information about the safety of a regulated product. The Center for Drug Evaluation and Research aims to notify sponsors at least 24 hours in advance of posting emerging drug safety information, but says it may not always be able to do so. 

Sharfstein, moreover, is leaving the FDA without resolving the most contentious issues under review by the Transparency Task Force. A May (2010) report on phase two of the initiative sought comments on proposals to make public a broad range of confidential manufacturer information, such as when a company files an investigational application and whether that application is put on hold, withdrawn, or terminated (see 

, Regulatory Beat, July 2010). The FDA also is considering if it should disclose when a firm submits a market application for a new drug, biologic, generic drug, or medical device, and if such applications are withdrawn or abandoned. Most controversial is whether the FDA should make public refuse-to-file or complete response letters, and if the agency should disclose more information from adverse event reports, import evaluations, plant inspections, and product recalls.  

Those issues raise "very interesting legal issues" and additional resource requirements, Sharfstein explained at his last FDA media briefing. Agency teams are assessing dozens of comments on these proposals, but resolution is not expected anytime soon.

Washington editor, Chevy Chase, MD, 301.656.4634, 

Regulatory Beat

FDA prepares for top-level changes while promoting transparency and product safety

Congress to Scrutinize FDA Rules, Research Policies

Process intensification is the new catchphrase in biotech processing. It includes concepts such as reducing the process time of a particular unit operation, decreasing the overall process time by improved alignment of various unit operations, and reducing plant idle time by improved equipment utilization. Biotech manufacturers are realizing that cost savings from such efforts, which result in improved productivity for a facility, far exceed those from the traditional focus area of raw materials. This article presents an approach for performing process scheduling and debottlenecking.

The combination of rising costs for discovery, development, and commercialization of biotech drugs, and ever increasing pressure on product pricing from the government and insurance agencies has put renewed focus on containing manufacturing costs in the biotech industry. Process intensification is emerging as one way to achieve this desired objective and includes concepts such as reducing the process time of a particular unit operation, decreasing the overall process time by improved alignment of various unit operations, and reducing idle plant time by improved equipment utilization. Individual unit operations (or process stages) and their relationships within the overall process are identified, including an assessment of resource and utility requirements from the host facility. After process models have been constructed, we can investigate complex and integrated biochemical processes and unit operations without the need for extensive experimentation or disruption to existing operations. The method can be used at all stages of process development from conceptual design to process scheduling and optimization.

The above-mentioned activities require process scheduling and debottlenecking using platforms such as Microsoft Excel or commercially available software.

  Some of the most widely used commercial software include, Aspen Technology's Aspen Batch Plus, Hyprotech Ltd's Batch Design Kit, and Intelligen's SuperPro and SchedulePro. These tools can optimize a manufacturing facility's capacity by scheduling the process to decrease batch cycle time and reduce the amount of equipment used, which will ultimately decrease pr2oduction costs. 

Several questions arise when performing process scheduling and debottlenecking. How much would it cost to make a fixed amount of the product? How can I reduce the operational cost of the process? How much product can I make in this plant in a fixed time? What are the bottlenecks in my current process and plant? What is the relationship between capital investment and the resulting capacity expansion? How can I relate the scheduling of a process to changes in priorities or production demand?  

Elements of Biopharmaceutical Production series

, we introduce some of the key concepts of process scheduling and debottlenecking, and present an approach for performing these activities. Two case studies—one for a single- product biotech facility and another for a multiproduct biotech facility—illustrate our approach.  

BASIC CONCEPTS IN PROCESS SCHEDULING AND DEBOTTLENECKING

Process scheduling for a production facility is performed to minimize production time and costs by making decisions about what to make, when to make, with which staff, and on which equipment. The overall aim is to maximize operational efficiency and reduce costs. Commercially available scheduling tools provide the production scheduler with powerful graphical interfaces that can be used to visually optimize real-time workloads in various stages of production, while pattern recognition enables the software to automatically create scheduling opportunities, which may not be otherwise apparent without this analysis.

  Manual scheduling, using available platforms such as Microsoft Excel, also can be effective because the user has the advantage of customizing the tool as required, compared with commercial software that are more rigid. Manually developed approaches, however, may lack the user-friendliness of commercial software.  

Process scheduling can be conducted by backward or forward scheduling methods and can help allocate plants, machinery, and human resources, plan production processes, and purchase raw materials. Forward scheduling involves planning tasks from the date resources become available to determine the shipping date or due date. Backward scheduling is planning the tasks from the due date or required-by date to determine the start date or any required changes in capacity. The benefits of scheduling include a decrease in process changeovers, reduction in inventory, increase in production efficiency, leveling of labor load, accurate delivery of milestones, and ability to gather real-time information.  

Process debottlenecking generally includes identifying and removing bottlenecks in equipment and resources. Equipment-based bottlenecks can be eased or eliminated by adding or removing equipment. Resource-based bottlenecks, however, may be unavoidable and may limit the net productivity of the plant. Feed throughput for a production facility is directly proportional to the batch size and inversely proportional to the cycle time; thus, for constant batch sizes we can reduce the cycle time by extensive scheduling, which will subsequently increase throughput. To increase a batch size, we will need to increase the process efficiency or  perform scale-up of the process.

Economic evaluation is necessary when deciding between in-house production and outsourcing. Building a new production facility to manufacture a biotech product is not only a major capital expenditure, but also a lengthy process. To make this decision, information regarding the required capital investment and time to complete the facility is necessary. Even if the decision is made to outsource production, the above-mentioned cost analysis will still be useful as a basis for negotiating with contract manufacturers.

  Irrespective of the decision on where to manufacture, further scheduling and optimization is always useful for maximizing profitability. In a recent publication, the authors illustrated how process scheduling and optimization for a monoclonal antibody product made in a multiproduct biotech facility was used for performing material and energy balances, sizing equipment and utilities, estimating capital and operating costs, and analyzing cycle times.

AN APPROACH FOR PROCESS SCHEDULING AND DEBOTTLENECKING

This section proposes a simple approach that could be used for process scheduling and optimization. The approach is manual and requires common platforms, such as Microsoft Excel. As mentioned earlier, however, commercially available software also can perform this task. The key inputs for this analysis are the process flow diagram; information on time, labor, buffer, and media (if any) required for each step, and equipment specifications (for existing process).  

Step 1 focuses on evaluating process economics. First, we calculate the net fix, expenditure for each step for a single batch, including recurring cost and non-recurring cost, (eq. 1),  

An approach to reduce batch time, increase productivity, and decrease costs.

BioPharm International-02-01-2011