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QbD in Practiceâ€“Part 2: The Regulatory Filing

BioPharm International, December 2009 (PDF)

The contract development services business enjoyed phenomenal growth over the past decade, fueled by a doubling of the new product pipeline. Although the industry has experienced a downturn in its fortunes in 2009, a new analysis suggests some significant upside for companies helping to develop biopharmaceuticals. 

PharmSource recently completed a major analysis of the clinical supply chain market. We modeled the spend for clinical trial material (CTM) development and manufacturing, including process development and manufacturing for active pharmaceutical ingredients (APIs), formulation and manufacturing of dosage forms, and associated analytical activities. We conducted extensive interviews with both buyers and sellers of clinical supply chain services to understand the key behaviors and trends driving the industry. The analysis goes into considerable depth on analytical chemistry activities. 

The PharmSource analysis estimates industry-wide annual expenditures on CTM development and manufacture (small and large molecules) at about $9.3 billion, divided almost evenly among process and formulation development, analytical development and testing, and manufacture of CTM. The biggest bucket of spending is in early development (preclinical and Phase 1), thanks to the large number of projects in the pipeline and the high cost of API characterization and process development, especially for large-molecule compounds. 

Of the $9.3 billion in total expenditures, the development and clinical-scale manufacture of large-molecule candidates account for nearly 60% of the total, or $5.4 billion. The development and clinical manufacture of APIs account for 90% of that $5.4 billion expenditure, with development of the drug product (dosage form) accounting for the rest of the spending. 

The most revealing aspect of our analysis is the degree to which contract services have already penetrated the clinical supply chain. We estimate that as much as two-thirds of CTM development and manufacturing expenditures are already outsourced. That's a much larger proportion than we expected when we started our analysis. The principal source of contract services' large share is the small and mid-size bio/pharma companies, which account for 88% of the outsourced spend. Small- and mid-size bio/pharma companies tend to be highly dependent on contract services and account for 75% of the candidates in the new drug development pipeline. By contrast, the large global bio/pharmaceutical companies, which account for a quarter of the new drug pipeline, make up just 12% of outsourced spend. 

For the large-molecule segment, the big market driver has been the large number of candidates in the pipeline and the heavy expenditure on process development and clinical supplies manufacture at the early development stages. There were more than 1,800 large-molecule candidates in development at the beginning of 2009 (excluding vaccines, cell therapy, and oligonucleotide candidates), and 60% of those were in the late discovery and preclinical stages. Costs for process and analytical development for early-stage candidates easily run in the $3–5 million range, even before the candidate gets into human testing, and initial GMP batches will add another $2–3 million. Spending for outsourced API development and manufacturing services exceeds $3 billion, more than 60% of the total industry expenditure (Table 1). 

Table 1:  Expenditures on large-molecule API development (USD, millions) 

The PharmSource model clearly highlights the dilemma faced by contract development and manufacturing organizations (CDMOs). They benefitted greatly as the number of early development candidates grew to over 6,000 at the end of 2008, a 55% increase from 1999, and are now suffering as the number of compounds slips back. Faced with a shortage of capital, early-stage companies have been forced to halt work on many candidates and expend funds on remaining candidates more cautiously. Our model projects that a 20% drop in the number of early development candidates would result in a 10–15% drop in outsourced development spending, which is in line with what we are seeing now. 

Our model points to some substantial upside opportunities for the large-molecule segment of the market, however. The continuing shift in mix from small- to large-molecule compounds will likely be a significant boon to the contract services industry. We expect that if large molecules grow to 30% of the pipeline from their current 22%, total outsourced development spend will grow by 15%. Of course, where that spending takes place will shift as well. CDMOs specializing in large-molecule API characterization, process development, and manufacture will increase their market share while small-molecule API manufacturers will lose share. 

Of course, which companies will be around to participate in the growing biologics market opportunity is still open to question. The contract services market is going through a significant restructuring as it adjusts to changing realities in the world of finance and the bio/pharmaceutical industry. We have already seen one contract biomanufacturer go out of business (QSV Biologics) and one other shut down its manufacturing operations (Wuxi Apptec, which continues to offer cell line development and analytical services). There will be significant opportunities for contract service providers as we come out of the restructuring process, but there will definitely be winners and losers. 

is the president of PharmSource Information Services, Inc. , Springfield, VA, 703.383.4903, 

Outsourcing Insights

A new analysis highlights growth opportunities and challenges for contract development and manufacturing organizations.

CDMOs Benefit from the Growing Biologics Market

The H1N1 pandemic is effectively a test of our preparedness for rapid response to new threats. So it is instructive to review how well the industry has been able to respond in this case. The results are not encouraging. As Prof. Peter Dunnill of the Department of Biochemical Engineering at University College London, notes in a recent article, "If you look at the situation, the amount of vaccine being produced globally is very small."

  The implication is that in the event that H1N1 becomes troublesome, then it is likely that commercial contracts will be broken by governments to ensure that supplies reach the population where the manufacturing capacity is based (most vaccine contracts include a clause allowing them to be broken under extraordinary circumstances, such as a health emergency). In addition, deliveries of vaccine are late and there are reports that deliveries are 50% lower than they should be.

Thus, we see that in the current pandemic, it is taking months for manufacturing to respond, the overall capacity is insufficient for the world's population, and there are problems in ramping up production. It is against this backdrop that suppliers of disposables technologies are offering options. 

In this article—the second of a two-part piece on rapid response—we consider the manufacturing component and the role of disposable technologies. In considering emergency preparedness, however, we need to consider the capability of producing not just vaccines but also therapeutic proteins. The US government is spending significant sums of money to encourage the building of manufacturing capacity in the US to meet short-to-medium term needs while also looking for innovative approaches to put in place truly rapid response manufacturing.

  The main catalyst for innovation is the accelerated manufacturing of pharmaceuticals (AMP) program, run by the US Department of Defense. The program is focused on developing new technologies that will revolutionize the manufacture of protein-based therapeutics. A key component to achieving the goals of this program is the use of disposable technologies in both process development and manufacturing. Yet, if we reflect on the conclusions of Part 1 of this article,

  there are a number of challenges relating to the current use of disposables:  

The disposables supply chain is immature and lacks flexibility to respond to rapid changes in demand. The lack of standardization among disposable suppliers considerably increases the supply chain risk, because in many cases, if a supplier cannot meet a deadline due to lack of available manufacturing capacity, or due to lack of availability of certain components, the vaccine or drug  manufacturer cannot turn to an alternative supplier. 

There is a need to be able to deliver flexible manufacturing to where it is needed. How would this be achieved with disposables, which require an ongoing supply of consumables? Would disposables be stockpiled as a precaution for possible border closure?

Standardization of disposable components is also needed to enable rapid reconfiguration of facilities to manufacture different products. There is currently a lag time, which can stretch several weeks whilst new components are qualified, as Tibor Nemes of Novartis emphasized in part 1.

Better training is needed to help manufacturers understand how disposables make it possible to design facilities differently, enabling fully modular facilities working with standardized disposable systems throughout. Such facilities can be expanded rapidly with minimum effort to add capacity.

The industry needs a better understanding of the infrastructure requirements that are needed when working with disposable technologies (as opposed to traditional systems) to support a rapid response.

None of these issues are addressed directly by the AMP program, but they do need to be addressed if we are to be truly flexible in terms of a rapid response. 

Focusing just on the manufacturing element, the ideal approach would be to have stockpiles of product (a good example in the pandemic is Tamiflu), but in reality, unless we have a clearly identified threat, it is difficult to stockpile. For a generalized response, therefore, we are looking at two options: 

1. Modular deployable manufacturing units. This assumes that we can quickly mobilize and send these to the areas where manufacturing is needed most. This approach may be flawed on two counts, however. First, to run any form of biomanufacturing operation requires skilled people, and in such a situation they would not be readily available. Second, there are likely to be restrictions on movement between countries during a pandemic. 

2. Strategic manufacturing locations. By having established operations strategically located, it should be possible to respond effectively to an emergency once the manufacturing process has been defined. 

The ability to establish strategic manufacturing capacity and redeploy it for use by the government is not new. What 

 new is the potential offered by disposables technologies to make this much easier. To understand why, let's consider some of the issues that make it difficult to reconfigure a traditional facility:   

clean-in-place (CIP) and steam-in-place (SIP) systems

Several of these issues are linked. For example, reusable equipment requires cleaning, sanitization, and sterilization between uses, and this requires a lot of piping and infrastructure, which then requires automation. CIP drives the requirement for high quality water (up to 80% of water for injection is used for cleaning).

  The promise of disposable manufacturing is that by making the processing equipment and flow paths single-use, a lot of the complexity disappears because the building is effectively decoupled from the process. The implications of this are significant:   

Processes can be built up from stand-alone modules that can be reconfigured easily.

Processes are physically independent of the buildings in which they take place, thereby allowing the deployment of a process within any simple building structure.

A process can be upgraded and potentially scaled up with little disruption. For example, if you were using a 1,000-L bioreactor and you wanted to upgrade to 2,000 L, the larger bioreactor could be tested and validated off line and quickly moved in when needed.

Such a setup allows for a facility to be reconfigured for a new manufacturing process quickly—within 2 to 3 months. In addition, a facility can be designed to include cheap "fallow" space that could be quickly configured to provide new cleanrooms for a disposable manufacturing system (in 6 to 9 months) This then would allow a staged response to any emergency. 

We are now in a fortunate situation where a number of suppliers are committed to establishing a disposable manufacturing line that could support the idea of rapid response manufacturing. Listed below are some of the leading companies who are active in this area, along with their main product line that would aid rapid response:  

Figure 1.  An artist rendering of Xcellerex's modular FlexFactory system.  

The companies' approaches vary. For example, Xcellerex provides each piece of equipment within its own process environment (Figure 1), thereby offering the potential of running a process in controlled-not-classified space. GE Healthcare and Millipore, in turn, offer solutions built around modules (Figure 2) that sit in a cleanroom environment. 

Figure 2.  Millipore Mobius manufacturing modules. 

The issues with these approaches are maturity and scale, although now with the advent of the 2,000-L disposable bioreactor, there is  the option to use multiple bioreactors to achieve the desired capacity. The benefits of this approach are significant in terms of flexibility, speed of response, and cost. Xcellerex, for example, says that a greenfield site can be established in 12 to 18 months from start to operation and it would cost 50% less than a reusable facility.

At a practical level, it is clear that rapid response can only be addressed by establishing facilities at strategic locations that could supply the main population centers. Short- to medium- term options should seek to establish some form of revenue-generating facility with the capability of expansion. Ideally, government and industry would collaborate at some level, whereby the response would be a measured one, and to encourage the establishment of this type of facility, regardless of who operates it.  

In the near future, it is easy to imagine that suppliers will be in a position to supply the type of facility described above. If it is to work in the short term, however, compromises are required. First, because of the lack of standardization and interoperability among the systems and components offered by different suppliers, in the short term a facility may have to commit significant parts of its operation to one supplier. 

Second, in the event of an emergency, two factors will affect the ability to ramp up production: the capacity of the supply chain to respond to increased demand and restrictions on the movement of people and materials. Therefore, manufacturers would need to stockpile all necessary disposable components (and other raw materials and specialist consumables) close to their key manufacturing centers. 

At the moment, rapid response strategies and approaches are being developed by governments and interested parties, but we do not have a coherent approach. The goal is to establish meaningful strategies for protecting the population in a pandemic. At the policy level, it is important that we have clear definitions of the scenarios that we want to protect against. These scenarious also must be tested in terms of whether they are real threats rather than "what if" threats; "what if" threats are easy to formulate but are often used as a form of scaremongering. We then have to be realistic when considering how governments will behave when responding to real and tangible threats. If we take all this into consideration, then it is possible to build a viable plan for a staged manufacturing response to a threat.  

Disposable manufacturing technologies will be key to delivering that staged response, but much work needs to be done by the industry and governments to transform this into reality. At the moment, we see developments within the supplier base to provide  the disposable manufacturing systems required, but  this is only part of the solution. Suppliers, manufacturers, and governments need work together to consider how best to develop and deploy disposable systems in the event of an emergency.   

is the vice president of marketing and disposables implementation, both at Biopharm Services, Chesham, Bucks, UK, +44 1494 793 243, 

. Miriam is also the European chair of ISPE's Community of Practice for Disposable Technologies. 

 1. Doubts surface over UK swine flu vaccine supply. Times Online. 2009 July 17 [cited Sept. 16, 2009]. Available from 

http://www.timesonline.co.uk/tol/life_and_style/health/article6718224.ece

 2. Jack A. Baxter behind on swine flu vaccines for Britain. Financial Times [online]. 2009 Sept 10 [cited 16 Jan. 2009]. Available from: 

http://www.ft.com/cms/s/0/c3ba0932-9da0-11de-9f4a-00144feabdc0.html

 3. Defense Sciences Office [homepage on the Internet]. Accelerated Manufacture of Pharmaceuticals. Available from: 

http://www.darpa.mil/dso/thrusts/bwd/act/amp/index.htm

 4. Sinclair A, Monge M. The disposables advisor. The role of disposables in rapid response manufacturing. BioPharm Int. 2009 Aug;22(8): 28–31.  

 5. Sinclair A, Leveen L, Monge M, Lim J, Cox S. The environmental impact of disposable technologies. BioPharm Int. Guide to Disposables. 2008 Nov;21(11) supp, p. 4–15.  

 6. Xcellerex [homepage on the Internet; cited 2009 Sept]. Available from: 

Disposables Advisor

Suppliers, manufacturers, and governments must work together to plan how best to develop and deploy disposable systems for emergency response.

Disposables in Rapid Response Manufacturing: The Next Steps

The International Conference on Harmonization (ICH) Q8(R2), Q9, and Q10 guidelines provide the foundation for implementing Quality by Design (QbD). Applying those concepts to the manufacture of biotech products, however, involves some nuances and complexities. Therefore, this paper offers guidance and interpretation for implementing QbD for biopharmaceuticals, from early-phase development steps such as identifying critical quality attributes and setting specifications, followed by the development of the design space and establishing the process control strategy; to later stages, including incorporating QbD into a regulatory filing and facilitating efficient commercial processes and manufacturing change flexibility post licensure. 

This paper focuses on the factors to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9, and Q10 to biotechnology products. Although biologic and biotechnology products often present a higher level of complexity than small molecules in terms of manufacturing process or product structure, the concepts of QbD are the same as those for small molecules. This paper describes the nuances and complexities involved in implementing QbD in the manufacture of biotech products and offers guidance and interpretation for doing so. The scope of this paper is limited to well-characterized protein products, in which the natural molecular heterogeneity, impurity profile, and potency can be defined with a high degree of confidence.  

Part 1 of this three-part article, which appeared in the November issue, covered molecular design, the use of laboratory and clinical studies to identify critical quality attributes, setting specifications, and developing the design space. Here, in Part 2, we address the use of design of experiments (DOE) to define the design space, unique considerations for process development for biopharmaceuticals, the establishment of a control strategy, and the placement of QbD information in a regulatory application. 

Process parameters that have been identified, through risk analysis, as potentially having a significant impact on subsequent process steps, may be studied using multifactor DOE. DOE is more efficient and effective than traditional "one-factor-at-a-time" (OFAT) experiments. DOE is more efficient because it (1) requires fewer numbers of experimental runs, and (2) covers a broader "knowledge space" than OFAT experimentation. As a result, it is more effective in (1) investigating potential interactions among process factors, (2)  avoiding artifacts such as experimental clustering and run order through randomization, and (3) making use of "hidden replication," and thus in having better sensitivity for detecting important effects. 

The mathematical model that is derived from DOE can be used together with the acceptable boundaries of critical quality attributes (CQAs) to define a design space for a given process step. This is illustrated in Figure 1. Two response factors (X

) are studied across the knowledge space that has been defined by the multifactor DOE. These factors yield a response surface for a CQA (Panel 1). The response surface intersects the lower (Panel 2) and upper (Panel 3) specification limits (USL and LSL) for a subsequent process step, to yield its design space (Panel 4). That space  represents the normal operating ranges for the factors, falling well within the design space (Panel 5). Operating within this normal operating range (NOR) will yield quality attribute measurements that fall within the upper and lower control limits (UCL and LCL in Panel 6). Because the LCL and UCL fall well within the LSL and USL, the process step is predicted to be highly capable of delivering product that meets the requirements of subsequent steps in the process. Excursions outside the NOR are expected to deliver product with quality attributes that are acceptable for further processing, as long as the operating parameters are held to limits defined by the design space. 

Figure 1 illustrates the design space for a single quality attribute. In biotech processes, however, it is typical for a single unit operation to affect several quality attributes. For such cases, the design space for the unit operation is obtained from overlays of the design spaces derived from analyses of multiple attributes, or from a multivariate analysis of the system. In addition, the design space is derived from a mathematical model that is subject to uncertainty and to the limits of the model. With continual verification and updating of process information through information management, the uncertainty is reduced because more data are gathered and included during the lifecycle of a product.  

Unique Considerations for Process Development for Biopharmaceuticals

Process development and characterization studies are primarily performed at laboratory scale to make them cheaper and faster

Therefore, developing a representative scaled-down model is crucial to meaningful process characterization and successful process-fit analysis. For example, scale-down of a fermentation step may involve keeping the scale-independent parameters (such as process temperature, pH, inoculation percentages for each step, and times of feed media additions) at the same control set point as the large-scale process, assuming similar vessel geometries, and changing the mixing and air flow rate to mimic the conditions at large scale. Qualifying such scale-down models before their use in process characterization studies is key to establishing a representative design space. 

Before defining a cell culture process, the manufacturer may perform a clone selection (in the case of mammalian or microbial expression systems). A suitable clone must be selected from a number of available clones for establishment of the master cell bank. The clone selection should be based on the quality target product profile (QTPP) and a risk assessment. Parameters determining the selection will be a combination of product quality attributes (e.g., impurity profile) and process performance (e.g., specific productivity per cell, consistent yield), usually assessed at small scale. Prior knowledge of process parameter ranges, existing cell culture platforms, and literature data will play a significant role in clone selection. This could be combined with a mechanistic approach. Alternatively, DOE could be applied for a multivariate approach if a larger number of parameters are investigated. 

A fundamental part of cell culture process development is the development of optimal cell culture media for the different stages of cell culture (e.g., inoculum preparation, main stage cell culture). This can be achieved using small-scale models. The impact of cell culture media composition can be identified by using tools such as DOE. This also provides information that supports the definition of a design space that includes critical attributes of raw materials. Optimal cell culture media development also may include the testing of critical raw materials (supplements) from different suppliers to develop appropriate raw material specifications to allow for alternate suppliers. 

For cell culture unit operations, a risk assessment should be performed to select the process parameters and the drug substance or drug product quality attributes to be investigated in a systematic approach (e.g., DOE). The risk assessment will take into account the type of host cell and expression system, prior knowledge, platform technologies, and knowledge from the clone selection and literature data, and should include raw materials and their impact on CQAs. Process parameters selected are those that may have an effect on quality attributes that are linked to the identity, strength, quality, purity, or potency of the product and may ultimately relate to the safety and efficacy of the product. In addition, those process parameters are commonly investigated that affect various aspects of process performance, such as product yield. There may be cases when CQAs cannot be measured in the cell culture broth because of interference from other components present in the sample matrix or other limitations associated with the analytical assay. To evaluate the influence of cell culture process parameters on quality attributes for such cases, it may be necessary to process the output from some of these small-scale experiments over the subsequent process steps until adequate product quality determinations can be made.  

The process steps are tightly linked, with the output of the previous step serving as the input to the next step. The focus in cell culture is on consistency, productivity, product integrity, and freedom from contamination. The focus of purification is on purity and freedom from process and related materials. 

For drug substance purification and drug product formulation steps, the same principles, as outlined for cell culture, apply for the establishment of a design space. Whereas in cell culture, the individual steps of the process differ mainly in terms of scale, container type, and culture media, each purification unit operation may comprise a distinct technology. This situation provides the opportunity to establish a design space for each unit operation, as well as to combine several different unit operations in a certain order to ensure the desired quality of the product.  

The ICH Q10 definition for control strategy indicates that controls for a product consist not only of process controls and final specifications for drug substance and drug product but also controls associated with the raw materials, excipients, container and closure, manufacturing equipment, and facility. It is a state of control in which all of the "planned controls" work together to ensure that the product delivered to the patient meets the patient's needs. Design space boundaries, as described above, are an integral part of a comprehensive control strategy. The control strategy for a product is expected to evolve through the product lifecycle. As product knowledge evolves, there is the likelihood of less reliance on end-product testing.  

The purpose of a control strategy for a product is to ensure that sufficient controls are in place to maintain the risks associated with the product at a tolerable level. Thus, the concepts of risk management and control strategy are intimately connected. Product risk is synonymous with potential risk to the patient. The risk from a product is measured in terms of the amount of harm (or losses because of the inability to supply the market) it can potentially cause. This harm is created by hazards that are associated with the product and its manufacture and supply. The control strategy builds in layers of protection that reduce the risk of the hazards creating actual harm. Given that each layer of the control strategy will not be perfect, it will always be possible for hazards to find a way through the controls to create harm. This concept is illustrated by the "Swiss Cheese" model of risk shown in Figure 2.

  Each control strategy layer can have holes, and if the holes line up, a hazard can become a harm (or loss). The following are four considerations that must be addressed when evaluating the ability of a control strategy to manage risks: 

1. Are there enough layers of protection in the control strategy? 

2. Are there some layers that are not required because they do not protect against any harm? 

3. Does each layer of protection function adequately? 

4. Does the control strategy itself introduce any new hazards? 

This integration of risk management and control strategy can be done in conjunction with the principles described in ICH Q9. Coupled with the principles of QbD defined by ICH Q8 and the appropriate Quality Systems (ICH Q10), the effective use of risk management will dictate a sufficient level of controls to protect the product without introducing new failure modes (for example, from inappropriate product sampling) or without incurring excessive cost that is passed along to patients. A well-designed control strategy that results from appropriate leveraging of Q8/Q9/Q10 principles, then, leads to reliable product quality and patient safety profiles. Although firms may not choose to leverage these principles in exactly the same way, all effective product control strategies use at least some of the elements of risk management. 

For biotechnology products, a holistic approach to control strategy is of particular importance because the complexity of biopharmaceutical products makes it unlikely that product quality can be adequately controlled simply by ensuring that end-product specifications are met. Although it has often been said that the quality of a recombinant product is dictated by the process rather than driven by specification testing, with QbD the quality is designed into both the product and process, and a combination of in-process controls and end product specification testing is used to verify that quality. The integral link between process and product defines unique challenges for the development of robust control strategies for biotechnology products. Some of these challenges for biotechnology products are:  

Many recombinant products are heterogeneous species rather than a single component as in organic synthesis of an active pharmaceutical ingredient (API).

The analytical characterization of recombinant products has evolved significantly over the years. However, the state-of-the-art for analytical science for bioproducts is not as mature and capable as it is for synthetic API characterization.

Microbiological and viral controls (e.g., host cell proteins, bioburden, mycoplasma, adventitious viruses) are critical aspects of biopharmaceutical manufacturing.

Essentially, all recombinant products are parenteral products that 1) require aseptic processing during drug product manufacture, and 2) emphasize container closure delivery systems.

Cold chain management is vital in maintaining product quality throughout the distribution channels because of the potential instability of recombinant proteins at room temperature.

Proteins have a higher order structure that must be maintained throughout processing and shelf-life, and assessed by complex bioassays.

A holistic approach to the control strategy helps minimize the probability of a negative impact on product safety and efficacy. In addition, establishing a comprehensive control strategy can further reduce risk by taking the following elements into consideration:  

Consider a monoclonal antibody (MAb) that was derived from a Chinese hamster ovary (CHO) cell culture and directed against rheumatoid arthritis. The QTPP for this product indicates that a typical patient needs the product to be delivered in a pen that may be held at room temperature for at least one week. A stable single-use solution drug product using a pre-filled syringe for once-weekly dosing meets the QTPP. The patient population typically has reduced manual dexterity and the pre-filled syringe means there is less need for patients to perform manual product manipulations before dosing (i.e., the product has been designed to meet patient needs). The amino acid sequence for the selected MAb with the greatest efficacy has a methionine in the complimentarity determining region (CDR). Oxidation of this residue in the drug product results in loss of potency, which affects product efficacy. Purity with respect to oxidation, then, is a CQA for this drug product. The formulation design and manufacturing control strategy must be developed for this CQA to minimize the oxidation of the methionine residue during manufacture and shelf storage. Appropriate preformulation and formulation DOE studies must be conducted to define the variables affecting the oxidation of methionine, such as pH or dissolved oxygen (DO), or peroxide or trace metals from raw materials or container closure systems. These studies lead to the identification of the design space where product stability is acceptable. Additional controls define the appropriate control strategy during manufacture as well as for incoming excipients and packaging components. For example, the presence of peroxides in excipients (e.g., surfactants) or potential leachates from packaging components can increase the susceptibility to oxidation and require careful monitoring (e.g., vendor qualification) and control. Controls in manufacturing such as monitoring levels of DO using appropriate in-line process analytical technology (PAT) measurements and temperature controls may be instituted to control the oxidation and stability CQA to obviate an end testing specification. Similarly, processes should be designed such that every batch delivers a safe, efficacious product, consistent with the product design intent outlined in the QTPP.   

Development of biotechnology products based on the QbD principles presented in this paper will require modifications to the current application format and content. It is expected that the standard common technical document (CTD) format, for the most part, will be retained in a "QbD" application or supplement but that the content of specific sections in Module 3 will reflect "knowledge rich" information required to support a QbD biological product. The extent of these modifications will depend on how much QbD information individual sponsors may wish to present in their applications. For the purposes of this discussion, we have assumed the sponsor will be maximizing the amount of QbD information to cover manufacture and testing of both the drug substance and drug product. Sponsors may decide to limit QbD to the drug substance, the drug product, or even individual unit operations of either the drug substance or drug product.   

There are a number of principles one must consider when preparing and optimizing quality information in the application. In addition to providing a comprehensive "reviewer friendly" data package that meets regulatory requirements, a strong focus on the data required to establish the relationships between the CQAs and the resulting control strategy for drug substance and drug product is essential. This focus should also include the design of key development studies and the risk assessments that were considered in the design of these studies, as well as a summary of the key findings and conclusions. Every effort should be made to avoid the tendency to include every piece of data to support one's conclusions. "Knowledge rich" is not a data dump but a more focused, strategic presentation of the data synthesized into information to allow a comprehensive review and understanding of the product and manufacturing process.   

The following section presents a recommendation for incorporating QbD information into a CTD format. A sponsor might choose to apply some or all elements of the recommendation. The regulatory landscape for QbD applications will likely continue to evolve in the future. 

Cover

Second in a three-part series that discusses the complexities of QbD implementation in biotech development.

Quality by Design for Biotechnology Products—Part 2

Just about everything involving expression systems has been patented, and the use of anything more than basic technology often requires coughing up a fee for a license.  Certainly, inventors deserve credit and reward for their hard work, but the complexities and layers this can add to a manufacturing strategy, on top of keeping track of what product is using whose licenses, can make licensing a legal nightmare. Knowing who has ownership can require some research.

Today, most biotherapeutics are manufactured using 

, Chinese hamster ovary (CHO), or yeast-based expression systems, and these work-horse systems do the job. However, even these older systems have newer, add-on improvements that may require licenses for commercial applications (including basic commercial research). For example, some 

 strains and CHO cells are generally used with licensed technologies that improve performance, such as newer vectors, promoters, and selection and amplification systems. So, even though the older technologies may be soon coming off patent, meaning they can be used without licenses or paying any fees, many users are willing to pay royalties or license fees to access improved performance.    

Most companies expecting to manufacture a recombinant protein or antibody get legal advice on how to license technologies. Licensing involves a series of generally predictable tasks, however, starting with an evaluation of the options. 

One must decide whether to use one of the old, predominant host systems (e.g., 

, CHO, yeast), or seek out a newer system likely offering advantages such as increased yields, cost savings, and adaptability to the use of disposables. A large number of technologies are available for commercial-scale recombinant protein expression. The book, 

Biopharmaceutical Expression Systems and Genetic Engineering Technologies Directory,

 is one source of information on licensable expression system technologies. There is also considerable scientific literature related to expression systems. Whether one sticks with an older technology or goes with a newer one, you still may need one or more licenses to get what you really need.  

Despite biopharmaceuticals being one of the most complex commercial products, many companies remain short-sighted and either do not explore their options or settle on using the same technologies they've been using. Old technologies can be good enough, particularly if long-term costs of manufacturing are not a major concern. However, by using old technologies you might lose out on efficiency (e.g., higher yield, increased speed), adaptability, and cost-effectiveness in the long term. For example, yields over 30 g/L are now being reported in perfusion culture with the PER.C6 human host cell system from Percivia (Crucell/DSM), compared with the single g/L range in older technologies. Often, older systems involve the use of large fixed stainless steel vessels, whereas newer technologies are more adaptable to modern bioreactors, often including single-use systems. Systems like DowPharma's Pfénex expression technology, a 

-based platform, is flexible and can be used to produce therapeutics at very high titers. Selexis (Geneva), developed a technology to improve yield of production cell lines in mammalian cells in suspension and in serum-free media more than 20 fold. There are over 300 other technologies awaiting evaluation.

  So, a first step is simply to be aware of what is available. 

Some licensors create complex rules in an effort to get their technologies widely distributed while still ensuring that commercial organizations pay for access. RTC (Tucson, AZ), for example, licenses its 

 platform to more than 120 companies. A license is required for even research-only use of this technology. Companies can get short-term use of a 

 kit for evaluation. A commercial license for R&D, however, costs more than $50,000. Moreover, if you commercialize a product, fees can be $75,000 plus 3–5% of revenues. Also, if you buy a kit from a third party, you might end up blocking the rest of your organization from testing the technology until you pay the licensing fee. Similarly, Jena Bioscience GmbH (Jena, Germany) provides its 

 expression system without a license to any academic or public institution but charges a license for commercial purposes. 

After you have identified expression systems relevant to your product, you then have to deal with licensing the technologies. Licensing or intellectual property (IP) professionals are employed or hired by the company to work with the licensor. Many of these professionals are attorneys, not all of whom have in-depth technical knowledge of the systems they are working with. This can pose a communication problem between scientists and corporate executives. The community of licensing and technology transfer professionals tends to be rather insular, sometimes preferring to deal with others with the same professional credentials. "Technology transfer has been described as the 'ultimate contact sport,' a game of complex signaling, posturing and negotiations among those in this exclusive gentlemen's club," says Ronald Rader, president of the Biotechnology Information Institute. It is also important to make sure that licensing professionals will use broad networking resources, and not restrict their efforts to their network of fellow professionals.   

The next step is to negotiate the license. Nonexclusive licensing agreements, with the same technology also licensable by others, are generally the simplest to negotiate. Many organizations will have boilerplate legal forms set to go, while others will require multistep exchanges of proposals. IP and licensing professionals prefer more complete, complex agreements to cover more situations. The licensing fees and royalties (usually a percentage of annual sales revenue) for most expression systems and related technologies will generally be around 3–5%, but can be significantly higher, depending on the deal. There typically is an option to either pay higher fees upfront in exchange for lower royalties after commercialization, or vice-versa. Paying more upfront with lower royalties can result in significant savings (profit) for products attaining a high level of sales. It's always advisable to have an expert review any agreement. 

According to the Licensing Executives Society's 2008 royalty survey, fixed royalty rates were used for most deals related to preclinical products. According to the survey, the average fixed royalty rate for preclinical products was 4.3%, with the rates for biologics slightly higher than for small molecules. The range for tiered royalty rates ran from 5–8% for preclinical to 14–18% for post-proof-of-concept. For these deals, 88% were exclusive, 54% included a fixed royalty, and 80% included an upfront payment. About half the deals estimated maximum sales of less than $100 million.  

Patent infringement, although definitely illegal, is commonplace.  Using technology that is patented by another party without a license is reported to be done at even the largest companies. Some companies adopt a "don't ask, don't tell" or plausible deniability approach to their manufacturing and discovery technologies. "IP attorneys at biopharmaceutical companies recognize that their scientists and executives avoid asking about the patent status of manufacturing-related technologies," says Rader. "This can allow a company to claim it isn't knowingly infringing patents." Thus, some companies ignore licensing certain manufacturing-related patents, assuming that most patent assignees considering a costly infringement suit will prefer to settle out of court or drop the suit. Licensing patents and technologies is sometimes simply not done because public disclosure may preclude anyone from knowing about a company's manufacturing processes.   

Licensing often can provide access to know-how, regulatory documentation, and expertise from the licensor that is not available without a license. In addition, many licensors are eager to support their licensees, because they are interested in proof-of-concept for their technologies. Patent infringement, even if a company does not realize it is doing it, could result in legal prosecution, triple damages, other fines, and, theoretically, prison for responsible executives.   

 is president and managing partner at BioPlan Associates, Inc., Rockville, MD. He is also the editor of 

Advances in Biopharmaceutical Technology in India

1. Rader RA. Biopharmaceutical expression systems and genetic engineering technologies: current and future manufacturing platforms. BioPlan Associates; 2008 Nov. Available from: 

In Table 1 of the June column, PharmedArtis GmbH was incorrectly listed as the commercial source of Arxula adeninivorans. It should have said that the expression platform is exclusively marketed by ARTES Biotechnology. 

Expression Systems

Gaining a license can be a complex process, but a few key tips can help you avoid common pitfalls and patent infringements.

Licensing of Expression Systems

The vaccine business is booming, spurred by worldwide efforts to halt the AIDS epidemic and to contain the global influenza pandemic. Government agencies have rushed to place orders for millions of H1N1 flu vaccine doses, prompting manufacturers to ramp up production along with investment in R&D. Public–private partnerships, many funded by the Bill & Melinda Gates Foundation, are developing vaccines to counter infectious diseases that kill or disable millions of people in third-world nations. Since 2000, the global vaccine market has almost tripled to reach more than $17 billion (2008) and is projected to top $20 billion by 2012. Yet, delays in producing the millions of doses needed to prevent a worldwide influenza pandemic this winter raised questions about continued reliance on decades-old production methods and on private-sector manufacturers. 

The good news is that a record 120 vaccines now are available to meet the health needs of people all over the world, and a significant number of vaccine candidates are moving through the research pipeline. Over 80 new products are in late-stage clinical testing, including some 30 that target untreated diseases, according to the "State of the World's Vaccines and Immunization" report released in October by the World Health Organization (WHO) and UNICEF. The surge in vaccine R&D over the past decade has produced new vaccines for meningococcal meningitis, rotavirus diarrheal disease, pneumococcal disease, and cervical cancer caused by human papillomavirus (HPV). The PATH Malaria Vaccine Initiative recently announced Phase 3 trials for a promising, but only partially effective, anti-malarial vaccine developed by GlaxoSmithKline (GSK), plus plans to continue the search for a more effective, four-year preventive. Merck has linked up with Britain's Wellcome Trust to develop more affordable and heat-stable vaccines for third-world countries. 

There's also progress on the HIV/AIDS vaccine front, despite initial reports that over-hyped the benefits of an AIDS vaccine being tested in Thailand. Analysis of data indicated a low infection rate among 16,000 participants; the results were inconclusive, but generated optimism that they may provide insight that will lead to a preventive against AIDS infection.  

The increasingly healthy vaccine business is attracting more Big Pharma investment. Johnson & Johnson has linked up with Crucell NV of Holland to jointly develop vaccines. Abbott Laboratories is buying Solvay's vaccine and drug business, and Pfizer's acquisition of Wyeth makes it a lead player in the field. Sanofi-Aventis CEO Chris Viehbacher recently announced plans to double the company's vaccine business over five years. These companies may be interested in products like the anti-smoking vaccine NicVAX being developed by Nabi BioPharmaceuticals with support from the National Institute on Drug Abuse. Moreover, the search for cancer vaccines is going strong, supported by the FDA draft guidance on how to conduct clinical trials to test new vaccines to treat cancer.  

Although much of the growth in vaccine sales reflects purchases of newer, more costly products in western countries, the market expansion also supports higher immunization rates around the world. A record 106 million children were administered the traditional roster of childhood vaccines in 2008, according to the WHO report. Global immunization has reached 82%, up from only 20% coverage in 1980. But international health officials warn against complacency. They note that about 24 million children still do not receive routine vaccines, a shortfall that would cost just $1 billion more a year to address. The Global Alliance for Vaccines and Immunization strives to fill the gaps, currently with a campaign to immunize 130 million children against pneumonia with Hib and pneumococcal vaccines.  

Amidst all this progress, the initial H1N1 vaccine shortage in October brought home the perils involved in vaccine development and production. Last July, US government officials predicted that vaccine makers would produce 80–120 million doses by mid-October, and public health agencies ramped up for a major vaccination drive. Government leaders and vaccine producers suffered a sharp loss of credibility when it appeared that only 16 million doses would be available early in the fall. Health and Human Services (HHS) secretary Kathleen Sebelius said she relied on industry predictions that turned out to be wildly overoptimistic, while manufacturers claimed they kept health officials informed of technical problems and anticipated delays at every step in the production process.  

The crisis prompted broad re-examination of vaccine manufacturing and product formulation. One culprit is the continued reliance of US manufacturers on chicken eggs to grow the influenza vaccine. The process took longer than expected with the H1N1 vaccine, and the yield was much lower than with seasonal flu vaccine, a problem not quickly recognized because of difficulties developing a suitable potency test for the new product.  

Vaccine supplies don't go so far in the US, moreover, because of the high demand for single-dose syringes that avoid use of the preservative thimerosal. Multidose vials can be filled and distributed more efficiently, but unfounded fears about side effects from mercury-containing vaccines forces producers to supply thimerosal-free products. AstraZeneca's MedImmune was able to produce ample supplies of its nasal-spray flu vaccine, but was limited by shortages of nasal dispensers. US health officials also pressed for a one-dose vaccine, which requires a high-strength product.  

European manufacturers overcame some of these problems by authorizing vaccines with adjuvants that require less antigen for each dose. Novartis and GSK have licensed pandemic flu vaccines with adjuvant in the EU, but these products still are being tested in the US. Former FDA official Scott Gottlieb, now with the American Enterprise Institute, would like the FDA to do more to make adjuvants more readily available as components for new vaccines and to spur development of new assays that can better detect impurities in vaccine batches and speed up the release of final products.  

However the pandemic plays out, it is spurring more investment in vaccine manufacturing, testing, and regulatory initiatives. Novartis has received considerable government funding to establish a new facility to grow a flu vaccine in animal cells. Several small biotech firms such as Protein Sciences, Novavax, and FluGen are developing flu vaccines that use cell-based production systems.  

The need to quickly develop and produce a vaccine to meet global health needs also is focusing attention on the vaccine regulatory process in the US and abroad. Although FDA officials garnered praise for being proactive in streamlining testing and data requirements for H1N1 vaccine candidates, vaccine makers would like to see a more coordinated international approval process. The WHO vaccine prequalification process takes approximately 18 months, in addition to all the work involved in licensing a product with the FDA or European authorities.  

FDA officials are taking steps to encourage industry development of vaccines to counter global infectious diseases. The guidance issued in 2008 explains regulatory processes that can speed up the review of important treatments and clarifies that the FDA can and will license vaccines for use outside the US. The FDA recently was designated a WHO "reference" national regulatory authority, which enables it to facilitate WHO prequalification of vaccines for distribution to developing countries by United Nations agencies.  

In this capacity, the Center for Biologics Evaluation and Research (CBER) can help manufacturers develop and license vaccines to protect against infectious diseases, including those not endemic in the US, explained CBER Acting Director Karen Midthun at a November conference on global vaccine development sponsored by the Drug Information Association. The FDA is working with the WHO to help build regulatory capacity in developing countries and participates in a number of advisory committees on vaccine development and safety, noted Marion Gruber, deputy director of the CBER's Office of Vaccines Research and Review. The agency further supports vaccine development by providing advice to manufacturers and regulatory authorities on assay validation, clinical trial design, statistical issues, and manufacturing challenges. 

Washington editor, Chevy Chase, MD, 301.656.4634, 

Regulatory Beat

Vaccine research and development is surging, but continues to face manufacturing and regulatory challenges.

The Promise and Perils of Vaccines

Now that my Honda Accord has 230,000 miles on it, I'm shopping for a new car. Gas mileage is a factor, of course, not just to save money but also to assuage my environmentalist guilt over my 60-mile round trip commute. So I'm considering a Prius. My husband, however, thinks a bigger car would be more comfortable. So in trying to convince him, I emphasized the gas consumption numbers. 

"The Prius is a bit small," I said, "but as a hybrid it averages 48 miles to the gallon. And some people even get 55 mph or more!"  

"But you wouldn't be one of those people," he replied. "When I drive your car, I get 34 mpg, but you only get 29." 

Dismayed, I asked for tips to improve my mileage. He told me to accelerate slowly, spend more time in a cruising gear (even if that sacrifices a little power), and watch traffic further down the road, to avoid braking and then speeding up repeatedly. In other words, I needed to smooth out my changes in speed. 

My gas guzzling habits, I realized, arise from my desire to reach my destination quickly. The funny thing is, my husband can drive anywhere in less time than I do. This was a reminder that not only does haste make (fuel) waste, but it may not even make things faster.  

Some people in the pharma industry, however, are way ahead of me in learning this lesson. One of them is Nick Warne, PhD, director of formulation development at Pfizer (formerly Wyeth), in Andover, Massachusetts. At this fall's AAPS conference, he gave a talk on how the Andover group has developed a platform to accelerate drug product development. Many companies use platforms, of course, but one particular aspect of the Andover approach intrigued me: They doesn't go for all-out speed. 

A year or so ago, the group reduced the development timeline, from gene to IND, to 17 months (and have since shortened that further). "This is not the fastest possible," Warne said. "But time is not the only important factor. It is also about reproducibility and robustness."  

The chosen platform, he explained, not only allows the team to hit its deadlines consistently, but also ensures consistent quality (e.g., low levels of high molecular weight species) and the production of sufficient drug quantities (e.g., for toxicology, clinical trials, stability testing). "For example, I know that at a prescribed week, the purification group will give me 4.5 g of drug to test," he said. In other words, they are smoothing out the changes in speed, and getting better returns overall.  

This approach also balances speed and resource investments. "Industry statistics teach us that 90% of these products will likely fail in the clinic," Warne reminded the audience. "Not only does this platform get products into the clinic faster, but by standardizing our approach, we also avoid overinvesting in processes and formulations for products that will never reach the market." 

The classic project development triangle says that of the three key elements—time, cost, and quality—you can only get the desired result on two out of three. Applied to pharma manufacturing, where you clearly can never sacrifice quality, this paradigm instructs you to choose between saving money or saving time. 

 Warne's results, however, like the driving example, seem to say that by balancing things right, you may not be able to reach the 

 of low cost or high speed, but you can get pretty close to your goals on both—reaching your endpoint faster, with the same or fewer resources—while maintaining quality. 

From the Editor

Do we really have to choose between saving money and saving time?

Speeding Up Slowly

This paper compares two project alternatives for the construction of a new 100 kg antibody plant, based on a real case. The chosen hybrid approach, which integrates disposable and stainless steel technologies, is compared with an equivalent stainless-steel model, in terms of capital investment, operating costs, and net present value.

Disposable technology has gained importance in recent years. One of its significant advantages is that it reduces the initial capital burden and spreads out capital costs more evenly over the life of a manufacturing project.

  A fully disposable plant is still a technological dream, however. That concept has some potential applications in small-scale production, or in pilot plants for process development, but seems less likely to have a significant impact on the current paradigm for large-scale biotech plants that have fermentation capacity greater than 100,000 L.

There is less doubt nowadays, however, that a combination of disposable and reusable equipment is beneficial for process economics in both new and existing manufacturing plants. Such hybrid models can be applied with different degrees of disposable integration, and that degree generally depends mainly on process scale and the biotech manufacturers' experience with disposable technology. Mid-size plants will probably benefit the most from the use of this hybrid model, but data from real case studies are not yet available to validate this hypothesis. 

The Center of Molecular Immunology (CIM), in Havana, Cuba, has built a strong pipeline of new antibodies and cancer vaccines. Some of these products are in early research, and others are in clinical development or commercial distribution. Several years ago, to meet this growing demand to produce therapeutic grade antibodies, CIM began the design and construction of a new plant with an annual capacity of 100 kg. 

CIM has integrated disposable technologies into its biopharmaceutical processes for more than 10 years, and the use of disposable technology has been a key element in CIM's approach to process innovation, cost control, and regulatory robustness. Current applications include plastic culture ware and disposable systems for formulation operations and medium handling up to 2,500 L. Based on this practical experience, a new antibody active pharmaceutical ingredient (API) production plant was designed to integrate disposable technology to the extent that it has been validated in our processes. This approach was chosen to maximize our antibody production capacity in a context of limited capital availability. 

In contrast to most large facility investment projects carried out by biotech companies, CIM's manufacturing project is based on continuous perfusion culture rather than the more widespread fed-batch fermentation. Because of the higher productivity of perfusion, production levels similar to those of the fed-batch mode can be achieved with smaller fermentation volumes. However, the high medium turnover required for the continuous operation of perfusion requires the use of several medium and harvest storage vessels for each production fermenter. A large-scale perfusion operation also involves almost daily purification runs (usually hundreds of lots per year) with intensive buffer preparation and storage operations. In our case, all this led to a smaller, but more sophisticated, manufacturing facility compared to a typical biotech plant. 

This paper discusses the economic comparison of two project alternatives for the construction of a new 100 kg antibody plant, based on a real case. The antibody plant, with its significant integration of disposable technology, will be referred to as the "hybrid project" (HYB) and will be compared with an equivalent stainless-steel (SS) project based on reusable equipment. The two project alternatives will be compared in terms of capital investment, operating costs, and net present value. 

The basic production process used in the new plant is very similar to standard reported antibody production schemes. Cell culture and fermentation are carried out in a continuous perfusion mode that lasts for several months, with harvests being collected at regular intervals. The purification scheme starts with a capture step based on Protein A chromatography, followed by several chromatography steps for contaminant removal and product polishing. Adequate viral reduction is achieved by viral (nano) filtration as well as by viral inactivation steps along with the chromatographic operations. 

The plant was designed with two segregated production trains, which each have 2,000 L of fermentation capacity. This setup allows two products to be manufactured simultaneously. The layout was organized to facilitate liquid handling in bags at large scale, based on experience with our current process. Cell culture medium and buffers are stored in a central service corridor, from where all the process rooms are fed through a closed liquid distribution system (Figure 1). This open space allows for flexible allocation of movable pallet tanks with bag containers up to 2,500 L. Larger bags are not available, however, so fixed stainless-steel tanks are used for volumes of 3,000 L and greater. A significant reduction of highly controlled cleanroom space was achieved with this approach. 

Liquid storage in bags accounts for the most extended use of disposable elements in the hybrid facility. Table 1 describes the level of substitution of stainless steel tanks by disposable containers in the various steps of the manufacturing process in this model. Disposable bags replaced 73% of the total liquid storage capacity of the plant, estimated at 117 m

  and distributed over more than a hundred process vessels. Other disposable elements were also introduced, such as chromatographic membranes and disposable viral filtration, but those had a limited effect on equipment cost savings. 

Table 1.  Vessel types used in the stainless steel (SS) and hybrid (HYB) models. 

Figure 2 shows the total capital costs for constructing a 100 kg antibody plant under each project alternative. This calculation started with a detailed estimate of equipment purchase costs (PC) based on recent price quotes. Prices were corrected for volume and currency depreciation where needed. To avoid significant distortions of the results because of land prices and construction costs in Cuba, the total capital costs were calculated using Lang coefficients, as updated by Petrides for the biotech sector.

  This method makes it possible to calculate the various items of the capital cost based on the equipment purchase cost using several multipliers (or coefficients). The use of these coefficients for disposable and stainless-steel technology has been discussed in the past by various authors.

After making the calculations for our case study using the combination of the selected Lang coefficients, we found that direct fixed capital was seven times greater than the equipment purchase cost for the stainless steel project alternative, but only five times greater in the hybrid alternative, similar to the estimates obtained by Farid.

  These results correspond to our experience that a significant reduction in facility complexity is achieved when disposable technology is used extensively throughout the manufacturing process. 

As can be seen in Figure 2, equipment purchase costs in the hybrid project were 34% lower than in the stainless steel project, which in turn reduced the total capital cost by 54% compared to the stainless steel alternative. This result demonstrates the significant capital savings that can be achieved through a broad integration of disposables in a medium-sized biopharmaceutical plant.   

To calculate operating costs based on raw materials and consumables, a detailed mass and energy balance evaluation was carried out to estimate the consumption of chemicals, culture medium, disposable materials, and pharmaceutical water for both technology alternatives, according to a manufacturing schedule of 75% plant capacity usage involving more than 200 purification cycles. Figure 3 shows the profile of daily pharmaceutical water consumption over 90 days. This analysis was used to estimate utility costs and the capacity of water production equipment. As can be observed, the daily water consumption in the hybrid project was significantly lower than in the stainless steel alternative, as a result of much lower demand for clean-in-place/steam-in-place (CIP/SIP) operations after 90 process vessels were replaced with disposable bags (as shown in Table 1). 

Table 2 shows the cost of various elements included in the calculation of the total annual expenses for both projects. Because the breakdown of costs in biopharmaceutical production operations is often different from the breakdown in other industries, the second column in this table shows percentage values of cost items reported elsewhere, for comparison with our calculations.

  In our case study, the cost of raw materials and consumables were obtained separately for the two technology alternatives from the mass balances and adjusted to account for the prices of each item. As expected, the hybrid alternative had a 19% higher cost of consumables and raw materials compared to the stainless steel project. 

Table 2.  Estimated operating costs for both project alternatives. 

To simplify the comparative analysis, the operating costs for labor, quality control/quality assurance (QC/QA), and waste treatment were assumed to be the same for both project alternatives because in previous studies we conducted, the use of disposable materials did not have a significant effect on these costs. Utility costs, however, were 50% lower in the hybrid alternative than in the stainless steel model, as a result of a 57% decrease in water and steam demand.  

Equipment-dependent costs have been reported to be one of the largest cost elements in biopharmaceutical production because of the highly sophisticated nature of biopharmaceutical manufacturing facilities.

  Our estimate showed this cost item to be 30% of annual manufacturing expenses for the stainless steel alternative, which is roughly in the middle of previously reported ranges of 10–70%. In contrast, the integration of disposable technology in the hybrid project reduced equipment-related costs to 18% of annual operating expenses.  

Overall, the data in Table 2 show that for this plant, with an annual production volume of 75 kg, the use of the disposable technology lowered total annual operating expenses by 16% compared to the stainless steel alternative. This represents a reduction in the cost of goods from $768/g to $647/g. 

ECONOMIC EVALUATION OF PROJECT ALTERNATIVES

To compare technologies, several profitability indicators can be used. In addition to the commonly used net present value (NPV), other indicators that can be used include internal rate of return (IRR), discounted break-even point (DBEP) and discounted interest-recovery period (DIRP).

  As pointed out by Sinclair, NPV can be used effectively to estimate the long term economic benefits of introducing disposable technology in the context of a project alternative evaluation.

Figure 4 shows the evolution of NPV of the hybrid and stainless steel investment projects. For this calculation, the start-up time, market penetration, financial terms, and product selling price were all assumed to be the same for both models. The introduction of disposable elements reduced the time required to recover the investment by almost two years. If calculated over a ten year period, the hybrid project alternative showed an NPV almost US $92 million higher than the stainless steel project, because of the lower capital expenses and operating costs. 

This case study demonstrates that integrating disposable and stainless steel technology in a hybrid model has economic benefits. Using this approach in a 100 kg antibody production plant yielded significant savings in capital expenses, a key factor that may determine the feasibility of an investment project for a small- or medium-sized company. The economic model also showed lower operating costs for the hybrid project, compared to a project based on stainless steel, mainly as a result of lower equipment-related costs and reduced demand for pharmaceutical water. The net present value of the hybrid project, calculated over 10 years, was 68% higher than a similar project based on stainless steel technology. 

We would like to thank Danilo Ponassi of Sartorius Stedim Biotech for his significant contribution to the introduction of disposable technology in CIM processes over more than 10 years. 

 is the technical director, all in the Technical Direction department at the Center of Molecular Immunology, Havana, Cuba, +53 7 271 3357, 

 1. Farid SS, Washbrook J, Titchener-Hooker NJ. Decision-support tool for assessing biomanufacturing strategies under uncertainty: Stainless steel versus disposable equipment for clinical trial material preparation. Biotechnol Prog. 2005;21:486–97. 

 2. Darby N. Trends in biological manufacturing: How will our industry change in the next 10 years? 2nd Annual Bioprocess Technology Seminar & Exhibition, Europe; 2008 June 23–25; Stockholm, Sweden. Available from 

http://www.asmeconferences.org/BioprocessEurope08/ASMEDarby.pdf

 3. Lang HJ. Simplified approach to preliminary cost estimates. Chem Eng. 1948;55:112–113. 

A case study compares capital costs, operating expenses, and NPV for a new MAb plant.

BioPharm International-12-01-2009