Representatives from leading contract research organizations (CROs) weigh in on key challenges tied to the biopharmaceutical R&D, including issues regarding bioequivalence, platform technologies, process analytics, and more. Particpating in the 

 roundtable are: Nancy Gillett, PhD, corporate executive vice-president and president of Global Preclinical Services at Charles River Laboratories; Jon S. Kauffman, PhD, director of Biopharmaceutical Services and Analytical Method Development/Validation at Lancaster Laboratories; Alan Breau, PhD, vice-president of Scientific Affairs–Analytical Sciences at MPI Research; Fiona Greer, Global Director of BioPharm Services Development, SGS M-Scan; and Andrew J. Reason, Group Manager, SGS M-Scan Europe.  

 Biologics are clearly more complex to develop and characterize than small-molecule drug products. What would you say are the key unique challenges associated with biopharmaceutical development and testing?   

 Choice of models is key. Products need to be screened for the intended human activity against targets from one to several models. In addition, they need to be tested for a loss of potency. This testing requires varied technologies for binding and activity assessment–early staging of these tests is important for reducing costs and avoiding unnecessary studies.  

Nancy Gillett, Charles River Laboratories 

Immune reactions on the part of the model to human protein, cell, or gene-based treatments can be complex and are required not only to detect antibodies to drug, but also to interpret toxicology results. Occasionally, this comparison of kinetic, biomarker, and immune-reaction assessments reveal that a drug's toxicity is due to immune reactions. In such a case, the drug can be freed from an "alert" and continued through development without interruption. Without the bioanalytical assays and careful scientific review of assay results, however, a drug program might be terminated for the wrong reasons. 

 One unique challenge is the vast array of testing required to fully characterize a biologic. Assays can range from simple pH measurements to peptide mapping to cell-based potency assays. In some instances, orthogonal techniques are also required. Therefore, the contract laboratory needs to have state-of-the-art equipment and staff with specific skill sets and expertise.  Further, the laboratory needs to have redundancy of high-end equipment and specialized capabilities to be able to support multiple projects on short timelines.  

Another challenge is that the process, not just product, must be characterized and understood. Potential contaminants are not just synthetic chemicals like those found in small-molecule manufacturing. Testing for more complex organisms, such as adventitious viruses, bacteria, yeast, fungi and mycoplasma, along with a wide array of antibiotics, and other additives, may need to be performed.  

 I see three key challenges: handling, analysis, and disposition.  Unlike small molecules, biological drug candidates require ordered secondary and tertiary structures to exert their desired activity, making their storage and handling much more complicated. For example, vigorous mixing of a small-molecule solution usually is not a problem; yet a similar procedure would likely denature a biologic drug, which could compromise its potency.  

Assay development for small molecules usually consists of test article analysis using components and instruments that are generally available, such as extraction cartridges, high-performance liquid chromatography (HPLC) columns, and liquid chromatography/mass spectrometry (LC/MS) systems. Because most biologics are analyzed by immunoassay methods, specific reagents must be developed for a particular biologic. This requires time to produce novel, well-characterized reagents, as well as assay development time, which can lengthen the time needed to complete the full analysis of the studies required to file for product registration. However, in preclinical species, it may be possible to use readily-available antibodies that bind to the constant region (Fc) on a humanized monoclonal antibody (mAb) candidate for immunoassay detection, thus eliminating the need for reagent development.  

Ultimately, the sponsor and CRO must work together to define and fulfill the reagent requirements at the onset of a project to mutually understand the sequence of developmental activities required to meet project timeline expectations. 

Finally, with rare exceptions, small molecules undergo absorption, metabolism, and excretion after administration, using well-defined enzymatic and physiological pathways. The development and regulatory paradigm to evaluate small molecule disposition has been well studied and characterized. The disposition of biologics, on the other hand, is typically not well characterized during development. 

Biologics must be assessed for the potential to develop neutralizing antibodies. There is no appropriate surrogate to assess the clinical development of neutralizing antibodies, which can be critical for endogenous biologic replacement therapy. The development of neutralizing antibodies to an endogenous protein can produce auto-immunity against a key physiological process. The sponsor and CRO therefore must develop a well-designed plan to assess neutralizing antibodies in nonhuman primates and in the clinic, as this is an important component of biologics development, especially when the biologic is meant to serve as a replacement therapy for an endogenous compound.  

 Undoubtedly, the main issues associated with biopharmaceutical products have to do with the fact that these products are 'manufactured' in living systems. In addition to being larger and more complex, biologic products are invariably a mixture of closely related proteins with the potential for a large variety of post-translational modifications which are not predictable from the gene sequence. Thus, key challenges include: how to develop a process that will consistently yield a product of defined quality; how to develop sensitive and robust analytical tests to characterize primary and higher order structure of the molecule, including degradents and impurities; and how to predict or detect highly undesirable immunogenicity. These analytical studies are crucial to better predict how the compound will work and enable support of clinical-trial design.  

Another challenge tied to biologics analytical testing is the development and validation of robust and reliable potency assays. Among potency assays, cell-based assays are probably the most adequate predictive as they allow the measurement of the drug's efficacy in an 

 model. However, due to the intrinsic biological variability of cell and the complexity of cellular signaling pathways, it can be difficult to define the correct read-out for an assay. The choice of the right cellular model, biomarker, or physiological activity are important parameters that require expertise and specific technologies, such as flow-cytometry or multiplexing capabilities.      

 In your company's experience, how can a CRO best plan to meet regulatory and sponsor expectations for biologics development and testing? 

 The important message for all biologics developers is that there isn't one plan that all biological products can follow. Some programs, such as those involving embryonic stem cells, are extensive and require tumorigenicity testing, while other programs can be based on purely 

 data. Each program needs to verify that the drug can produce and retain exposure and effects, and that studies gauge the doses where effects turn harmful.  

 Based on the analytical challenges noted above, a contract testing laboratory must have experience developing and qualifying extremely sensitive assays for a broad set of contaminants in complex bioprocess matrices. Further,  because there has been increasing scrutiny of these contaminants from regulators, the laboratory must have a broad familiarity of international regulatory guidelines. 

 To assist clients in meeting analytical challenges, a CRO should be fully aware of the complexity of task. It should be sensitive to expectations of regulatory authorities and have an arsenal of appropriate analytical methods, assays, and clinical-trial techniques that are capable of providing reliable scientific data so that informed decisions can be made regarding product safety and quality. 

 How have sponsor companies' expectations for biopharmaceutical contract R&D and testing changed over the past few years? What do you think has led to these changes? 

 In the past, biologics were developed by mid-sized pharmaceutical firms. Increasingly, we're seeing small virtual firms, or nascent biotech companies, assuming sponsorship and taking compounds from early stages into Phase I and II clinical trials. Additionally, more sponsors are risk-sharing by partnering early in development. In these cases, collaborations can involve multiple consultants, teleconferences, and web meetings. It's especially important to establish communication and primary contacts to ensure a solid and confidential connection. At Charles River, we have increased our support for these companies and find the experience is rewarding on both sides because we learn from each other and bridge gaps that start closer to compound discovery. For example, we often suggest the experiments that sponsors start in university labs, and then transfer the technology to good laboratory practice (GLP) settings when product quality and biomarkers are established. 

The models of development need to shift as well to accommodate changes in public policy, regulatory law, international outsourcing of chemical manufacturing—all of which impact costs. Biopharmaceutics are combining genetic, cellular, device, and nanotechnology. These new approaches require access to specialized facilities and expertise. Although traditional models are in place for Big Pharma, they are shifting to more open collaborations as well. 

: Sponsors are looking for partners to help get their products to the market faster in an environment where regulations are becoming more stringent. At Lancaster Laboratories, many clients are looking to compress timelines and accelerate speed to market. Development of biologics is extremely expensive, so sponsor companies are also looking to consolidate vendors and reduce costs.   

 In the past, most pharmaceutical companies kept preclinical functions, such as assay development, initial GLP studies, and first-in-man human pharmacokinetic analyses in-house, to control these critical components of the development process. Today, many companies have downsized their preclinical departments and rely more on CROs for an ever-increasing array of services.  

In addition, there is increased emphasis on in-licensing from biotechnology companies. Rather than rely on in-house discovery, large pharmaceutical companies have increased the proportion of sponsors in early development that are small biotech or virtual start-up companies. The biotech companies rely on quality CROs to provide input into their study designs and development plans. This shift has led CROs to provide more service offerings, including an expansion of program-management services.  

 Our experience at SGS Life Science Services is that sponsors are not just looking for tests to be performed and data returned. They are actively searching for companies with appropriate experience who can guide and advise them during the analytical program. This consultancy might take the form of recommending and providing certain analytical  packages or groups of tests for particular types of products.  

Although sponsors are now used to the 'one-stop-shop' concept, their expectations have grown. Sponsors want to establish that the CRO has in-depth expertise 

 crucial techniques. New emphasis from regulatory agencies to obtain data using orthogonal techniques and to mitigate potential biases from particular methods are also changing the way sponsor companies use CROs.  

 Along these lines, have you witnessed more interest in process analytical technologies (PAT) from sponsor companies? Has your company applied PAT to date or does it plan to? 

 Lancaster Laboratories has witnessed interest from sponsors and contract manufacturing organizations (CMOs) in using PAT for biopharmaceutical production. Quality-by-design (QbD) processes are used in bioreactors, for example. Although rapid sterility and mycoplasma testing approaches are coming to fruition, the technology is not here at this time to measure other important parameters such as post-translational modifications or adventitious viral agents in real time.  

 Not yet. The presumed future increase in the need for PAT services will be driven as FDA's QbD initiative evolves. We have not seen a dramatic increase in the request to characterize raw materials or other process components.  

 What is your take on platform technologies to develop and test biopharmaceutical products? Can you offer a CRO's perspective on the pros and cons of such an approach? 

 In many ways, platform technologies are both beneficial and essential in the CRO setting to enhance productivity. Processes ranging from immunoassay development to telemetered data collection are constantly improved to increase efficiency. These efficiencies evolve into beta testing and standard operating procedures (SOPs). For example, Charles River recently pushed its reporting timelines to a new standard through platform technologies. 

Sponsors could save cost and gain efficiency if one set of 'platform; toxicology data could support multiple products (e.g., a number of agents based on similar chemistry). But implementing this concept is more difficult than it sounds because small chemistry changes can make profound changes in drug distribution and drug effects. Consequently, regulators have been cautious about accepting platform data and generally require individual toxicology programs for each drug substance. We may see a shift in regulatory approach as FDA's modernization program gains momentum and as more data accrues on novel agents, such as gene therapy vectors, or on classes such as biosimilar monoclonals. 

 There are definitely benefits in the platform technology approach. If a process is well understood and can be applied to produce an array of biopharmaceutical products, then it may, for example, be possible for the sponsor to reduce the amount of viral clearance testing performed on all products manufactured using the same processing platform. Transfer and validation of methods also can be expedited and streamlined.  However, one size does not fit all, and it is not always easy to predict when a platform technology will apply. A small change in a process or product may go undetected in a platform method, and this could end up taking more time on the back end to redevelop and validate methods.  

 Novel platform technologies are developed because, presumably, they confer some advantage in certain applications over the alternative competing platforms. MPI conducts a return-on-investment (ROI) analysis to assess whether we should invest in the platform. We are careful in assuring that a thorough assessment is completed before an investment is made. 

Sponsors must be aware that moving forward with a cutting-edge platform that could fail or be removed from the marketplace may cause significant rework and delays in development plans. The sustainability of a new platform must be taken into account, as well as the novel advantages that it may confer.  

Platform analytical technologies, at certain levels are appropriate and can be applied to a wide range of products. However, the more advanced methodologies have to be tailored to suit specific circumstances, particularly with wide variations in formulations, and so forth. 

For example, platform technologies can be applied to all IgG1 mAb products, which are similar structurally, but the methods used to purify these products prior to analysis will vary depending on the product formulation. Other glycoprotein products, such as Erythropoietin and FSH, require more in-depth analysis particularly of their glycosylation. This analysis may require further development of methods to be able to characterize the glycans at each of the glycosylation sites within these products.  

Bioequivalence and biocomparability testing

Have you seen a rise in projects for bioequivalence or biosimilar comparability testing? If so, what unique challenges does that process present? 

 Changes in biologics manufacturing or the development of biosimilars can trigger a regulatory focus on bioequivalence. We support comparability assessment of many types starting in early in discovery, which can include comparison of drug biochemistry, binding and potency curves, and toxicology assessments. These are all used along with clinical data to support a sponsor's claim to comparability and to support international approvals. We expect a rise in these projects as the biosimilars market expands. 

Articles

Features

Representatives from leading CROs weigh in on key challenges tied to the biopharmaceutical R&D, including issues regarding bioequivalence, platform technologies, process analytics, and more.

Meeting Challenges in Contract R&D

Contract manufacturing organizations (CMOs) occupy a special niche in the bio/pharmaceutical industry and therefore face problems not encountered by traditional bio/pharmaceutical manufacturing companies. One particular challenge facing CMOs is how to define the responsibility for Quality in a relationship. Which party, the contract giver or the contract provider, has which responsibilities? Although the answer may be straightforward for companies with their own manufacturing operations, it is quite complicated for a CMO. When defining ownership of "Quality," a CMO must consider the compliance needs and regulatory commitments for multiple clients. The CMO also must look at Quality as a function of product lifecycle—in a similar manner to how their clients would look at Quality if they were manufacturing the product themselves.  

If one views the Quality relationship as a simple mathematical equation, it may look something like this:  

 where A is the CMO needs, B is the compliance needs, C is the client's needs, D is regulatory commitments, and E is defined as the elements of the Quality relationship. By analyzing this equation, it is clear that there are no constants, only variables. Each variable is based on the consideration of certain elements from each party in the relationship. 

A CMO's needs are based on maintaining as much operational consistency as possible when managing internal and subcontracted resources. This approach enables cost management for the CMO and cost savings for the customer. Variable A should take into account the audit, testing, sourcing, and customer-specific requirements needed to manufacture the product. The CMO should make sure these requirements are included as part of the Quality Agreement. When defining auditing responsibilities, consideration must be given to determining the appropriate involvement of the client for internal, external, and regulatory audits and should be somewhat consistent between clients.  

Testing requirements (e.g., final product, raw material, and environmental) should include what is required not only to manufacture the product, but also to maintain the environment in which the product is manufactured. For example, testing requirements might be traditional compendial testing, but may also include product-specific testing as defined by the client. In the case of a raw material, the CMO must consider whether the item is used in multiple products and whether it is available from a single or multiple sources. Consider this example: in some cases, the client may dictate the supplier of the component in question because it has an established relationship. In other cases, the CMO may have the more established relationship with the supplier. In such situations, the CMO, in conjunction with the client, must determine who will be responsible for providing the qualification and follow-up audits of that supplier. This type of scenario should be defined in the Quality Agreement so that there is little confusion between the parties. A well-drafted Quality Agreement can save a lot of confusion and duplication of effort on behalf of the client and contract provider and facilitate productive communication.  

Multiple customers, regulatory agencies, and standard-setting organizations influence compliance requirements maintained by a CMO. Each requirement needs to be implemented to accommodate the broad spectrum of these influences. Variable B of the equation defines the compliance needs for the manufacture of all products at the given facility. Company standard operating procedures (SOPs), customer SOPs, audit observations, and compendial requirements need to be considered in discussion with the client and the CMO. Clients should make every effort to understand their CMO's SOPs.  

It is equally important for the CMO to make sure that its SOPs are robust enough to accommodate multiple clients' needs. It is difficult for a CMO with multiple clients to operate using duplicate SOPs for the same process or procedure. The CMO and the client should therefore spend a sufficient amount of time ensuring that the compliance needs of both parties are defined and met.  

Similar to variable A, variable B also has an audit element to consider. In this case, the effectiveness and appropriateness of a CMO's audit program is considered. The audit program must meet the regulatory expectations for internal and supplier audits while also meeting the client's expectations on these points.  

In addition to these audit requirements, the CMO and the client must discuss the communication expectations for regulatory audits either conducted at the CMO's or the client's place of business. The need for the CMO to communicate with the client when a regulatory audit is being conducted at their facility is evident but it is equally important that the client communicate with the CMO when the positions are reversed. Two-way communication is crucial because each organization could be vulnerable for a regulatory audit based on the outcome of the regulatory audit being conducted at either facility.  

In addition to SOPs and audit requirements, compliance to the compendia must be considered under variable B. The client should confirm that the CMO has a process in place for reviewing and updating test procedures to maintain compliance with the applicable monographs, test chapters, and informational chapters maintained by the United States, Japanese, and European pharmacopeial authorities.  

Customers bring requirements to the table that may be needed due to factors that are not within the purview of the CMO. These requirements might be influenced by development data, regulatory registration commitments, sourcing strategies, or partnerships. Under variable C, the CMO must consider the needs of the client in order to effectively provide them service. For example, the phase of drug-product development and whether the client is virtual or has in-house capabilities are elements that may affect the allocation of responsibilities within the Quality Agreement. If the product is under a cooperative arrangement with multiple companies, there may be more than one Quality Agreement associated with the manufacturing, packaging, and labeling of the product.  

If this is the case, the client should let the CMO know of these agreements and of the expectations when the product is passed to another responsible party during the manufacturing process. In addition, it is important that the client communicate with the CMO whether another contract provider is having regulatory difficulties. Finally, the client and the CMO need to determine whether any special testing protocols are needed for products in Phase 2 or 3 of the development process. If the testing of excipients used in the product is being performed by another organization other than the CMO client, this fact should be disclosed to ensure that excipient compendial requirements are met. The same situation is important with regard to where the material is sourced—whether it be a single source or multiple sources.  

Regulatory commitments are an evolving body of knowledge that may necessitate flexibility to adapt to CMO and client interpretations of new or impending regulations. Variable D considers the regulatory commitments of the client and/or the CMO. CMOs can indicate which regulatory authorities have audited their facilities, when they were last audited, and the outcome of these audits. A CMO must also communicate to their clients the changes and commitments made to their Quality Systems based on the responses to the regulatory audits because these changes may affect the regulatory filings of the clients. Each client will have its own interpretation of how to comply with the audit observation and what filing strategy should be used to update their filings, if any.  

The CMO must ensure that its responses to regulatory audits do not jeopardize any of their clients' commitments. On the other hand, clients must communicate with the CMO regarding commitments they have made in their registrations. Among other information, they should disclose to the CMO whether they are using novel excipients as opposed to compendial excipients and whether any special specifications or testing must be performed.  

The solution to the equation noted above (A+B+C+D) is E, which represents Quality as a function of product lifecycle. The document that contains the information defining the various responsibilities that comprise E is the Quality Agreement. This master document should define the CMO's needs, the client's needs, the compliance needs for the product and both parties, and any pertinent regulatory commitments. The Quality Agreement should be a living document that is reviewed and revised as often as needed to clarify the responsibilities of the client and the CMO as the product progresses through its lifecycle. The Quality Agreement is akin to a marriage license between two parties and should clearly identify the roles and responsibilities needed for a successful partnership.  

In general, Quality Agree-ments are legally binding agreements between the Quality functions of the contract provider and the contract giver. Many companies use a matrix approach for defining these activities which can include but are not limited to compliance, manufacturing, packaging and labeling, documentation, change control, nonconformance, out of specification (OOS), deviations, complaints, recalls, and auditing. Each document should be tailored to address the expectations of the specific operations to be undertaken by the CMO as well as external actions that may have an impact on those operations. Clients and CMOs should communicate frequently to make sure that the product being manufactured meets the necessary specifications required to meet the minimum Quality requirements. In order for the relationship between the client and the CMO to be effective, the two parties should communicate often. 

Defining the Quality relationship between a CMO and a client is complex and requires extensive discussion and attention to detail. The relationship should be open and communication between the two parties should be as frequent as required to assure that the product being manufactured meets the highest Quality standards for the client and for the patients. 

is vice-president of Quality at OSO Biopharmaceuticals, 

The author describes an equation that can be used to define the Quality relationship between a contract manufacturing organization and a client, including how to factor in both party's needs and regulatory commitments.

Managing the Quality Relationship for a Contractual Agreement: A CMO Perspective

  Avenue in New York City sits one of the greatest skyscrapers ever built. At 1453 feet, the 103-story Empire State Building is not only a magnificent architectural structure, but also a marvel of engineering especially considering that it was built in The Great Depression of the 1930s. The story behind its construction provides a valuable lesson in the power of successful project management. Scheduled to be completed in an unrealistic amount of time—a mere 18 months—it was actually completed almost five months ahead of schedule and came in under budget. 

Eighty years later, the Empire State Building is no longer the tallest building in the world, but it does remain a crowning achievement in architecture, an amazing accomplishment in the field of commercial construction, and a lasting lesson in project management. Indeed, it is a testament to successful project management, which requires disciplined planning and organization, and the ability to secure and manage resources to achieve specific goals. Contracted companies must be dependable, provide quality work, and adhere to a down-to-the-minute timetable. Effective logistics must be combined with a skilled, organized workforce.  

Image courtesy of Vetter Pharma International GmbH 

Constructing the Empire State Building was clearly fraught with risk. In today's high-cost, highly competitive drug development environment, where complex compounds require sophisticated technology and great expertise, small biotech companies find themselves particularly vulnerable to risk during early clinical phases, especially because most compounds fail to proceed to late stage development. Injectable products are often considered the most challenging and expensive drugs to develop, so the project management process is especially vital. 

Cost and time pressures can bring small biotech firms to the breaking point; having a skilled project management team in place as early as possible is crucial for survival. Clear and efficient processes, effective paths of communication, and close collaboration with technical experts during the early clinical phases should be given top priority. And in the event of something unexpected, the team must recalibrate the project plan to keep it on track.  

A small biotech company that understands the value of an integrated project-management strategy has taken a first big step in reducing a drug's time to clinic, optimizing costs, and increasing its return on investment. On the flip side, without careful project planning, the risks can quickly escalate from losing time and money to outright failure of the project resulting in serious damage to the reputation of the company or, in the worst-case scenario, complete business failure. 

A strategy planned in concert with a contract development and manufacturing organization (CDMO) is often the key to properly allocating resources, creating a top-notch project management team, satisfying regulatory authorities, and advancing the compound to later-phase development. 

The creation of an integrated project management team that will plan and form a development strategy is the strong foundation on which everything else will be built. The team's project manager has a responsibility to keep everyone's attention focused on project deliverables and deadlines and keep the project moving forward. Pulling together a group of individuals who are able and ready to solve problems from the lab to the filling line is key. By acquiring the most skilled, most experienced, and most qualified people, the project manager can often compensate for an overambitious schedule, too little money, or other project constraints.  

For smaller companies, a lack of staffing and expertise to accomplish the project target means asking a CDMO to designate a project manager and create the team. The team should possess a variety of skills, including experience in packaging development, process development, quality management, supply-chain management, and regulatory affairs. 

After creating the foundations of the project, communicating the blueprint effectively can avoid crises during later phases. For the contractors of the Empire State Building, enabling clear and consistent communication among 3400 workers across 60 different trades may have seemed almost impossible at first. But failure to do so would have resulted in catastrophe, if the building had exceeded its timeline and budget. Regular status checks, meetings, and reminders helped create a tangible picture of the finished deliverable for everyone, so that all effort focused in the same direction: up. Drug development projects should be no different. 

A skilled project manager has to coordinate communications and is responsible for ensuring that every step of the work plan is thoroughly documented and accessible to team members. Clear channels of communication help prevent misinformation from developing and spreading, reduce risk, and promote collaborative team relationships. Regular and orchestrated conference calls and team meetings, which are then well-documented and shared, help ensure project transparency and the free flow of accurate information.  

Biopharmaceutical companies of any size must define a clear decision-making process for the development project to run smoothly. Smaller firms are generally more nimble than larger organizations, but regardless of how fast or slow the process is, a common understanding of who has decision-making authority and what the turnaround times are prevents frustration. Such clear lines of authority become especially important when problems arise; quick decision-making reduces delays that can eat into precious funding.  

Just as poorly constructed buildings are more likely to topple, drug products have no room for error. Project managers, whether internal or CDMO based, should have the authority to acquire and coordinate resources, request and receive cooperation from team members, and make informed decisions. The project manager must be responsible for anticipating needs, overseeing costs, identifying and addressing issues that emerge, and realizing that the project is progressing as planned. 

The project manager should not just be a taskmaster; he or she should also be the chief motivator—keeping people energized and positive, especially when the pressure is on and people's nerves start to fray. A project manager who can create a trusting and collaborative environment is a major asset to the project.  

Many smaller biotech companies produce innovative science but may have limited experience with technical and regulatory issues. These organizations may wish to partner with a CDMO throughout the development process, starting at the preclinical stage or Phase I. 

Early-stage products often hit unexpected roadblocks so biotech companies should be prepared to respond quickly by analyzing the problem, developing a solution, and then swiftly updating project specifications—all while staying within timeline and budget. The depth of experience, capacity for innovation, and flexibility of an experienced CDMO can lend vital support. 

Smaller biotech companies typically lack the financial resources of larger companies, so the selection of the right CDMO can make the difference between the success or failure of not only the project underway but also the company itself. A high-quality CDMO can contribute critical consulting and production support to help manage the difficult procedures and decision-making inherent in early-phase development to keep the project on target. With a well-integrated project management team, a small company can maintain its milestone schedule and budget. 

The Empire State Building is a great example of a successful project. And while biotech project management is not entirely analogous to the creation of an iconic architectural masterpiece, it does share complexity and the need for highly skilled individuals. 

A well-integrated project management plan and rigorous execution can provide a blueprint for current and future projects. The following steps are essential for success:  

Develop a plan tailored to the size and scope of each project, taking into account its unique challenges and the strengths and limitations of your team.

Create well-defined decision-making processes—and use them.

Consistently evaluate project progress and keep the team focused on objectives and goals. 

Take a hands-on approach throughout the project to support the team in meeting its daily schedule.

Maintain clear channels of communication and documentation to maintain transparency, keep everyone on the same page, and engender trust. 

Anticipate and respond quickly to emerging problems and changing circumstances.

The Empire State Building celebrated its symbolic opening on March 1, 1931, when then-President Herbert Hoover pulled a switch from his office in Washington, DC, to illuminate the building for the first time. That date in history will always remain the day the most iconic building of New York was completed. Where the right plan and the right team move forward, success and celebration will follow. 

is managing director at Vetter Pharma International Gmbh, tel. +49 751.3700.3729, 

An architectural wonder teaches the biopharmaceutical industry a valuable lesson in project management.

Empire State Drug Development

Biological applications within the pharmaceutical industry have proven to be one of the primary technological development areas of the 21st century. Productivity in biological R&D has surpassed returns from conventional small-molecule pharmaceuticals, and the number of biologic license applications (BLAs) has been rising. Increased capital and labor resource allocation towards biologically-derived pharmaceuticals and biocatalysts has buoyed the biopharmaceutical research market as the new frontier in innovative drugs. More specifically, the industry's trajectory towards pharmacogenetics has the potential to provide access to more powerful personalized medicines. Not only will pharmocogenetics remove guesswork from the drug selection process, it will also speed recovery time and increase safety by significantly reducing the likelihood of adverse reactions. Moreover, advance knowledge of susceptibility to particular diseases will allow for careful monitoring so that treatments can be introduced at the most appropriate stage to maximize their effect. 

Some well-known large capitalization pharmaceutical companies have recently made significant investments in biotechnology through acquisitions, in-licensing, or partnership deals with emerging biotech firms. With conventional R&D yielding below-par returns and the industry's vulnerability to generic competition, the development of large-molecule biologics is an attractive option for many pharmaceutical companies. Sanofi-Aventis' $20-billion acquisition of Genzyme, completed in April 2011, was a clear play for positioning within the biotherapeutics market. Also noteworthy are Roche's $47-billion acquisition of the remaining stock in US biotech Genentech that it did not already own, and Pfizer's $68-billion merger with Wyeth Pharmaceuticals, which had one of the strongest biotechnology pipelines among large pharmaceutical players.  

According to S&P industry data, biotechnology products are expected to account for 48% of the top 100 drugs of 2016. Of the 25 drugs approved by FDA through August 2011, 21 were new molecular entities (NMEs). According to the Pharmaceutical Research and Manufacturers of America (PhRMA), biopharmaceutical companies are currently working on 887 cancer medicines, all of which are either in clinical trials or under review by FDA. The total includes 98 being developed for lung cancer, 91 for breast cancer, 80 for prostrate cancer, and 55 for colorectal cancer. Biologic-based products accounted for 12 of the 27 new pharmaceuticals and biologics approved by FDA in 2010. A move away from vaccines in favor of products such as monoclonal antibodies (mAbs) was the norm until 2007. However, since then, vaccine development has seen a reinvigoration. For example, in 2008, the number of candidate vaccines in development rose to 223 from just 62 in 2006. MAbs, which had been by far the biggest pipeline category, were overtaken, despite the rise of investigational drugs from 160 to 192 over the same period. 

Much of the motivation for biomanufacturing research has been based on the belief that it is significantly different from traditional manufacturing and therefore requires different resources and approaches for both engineers and management. In many cases, the underlying technology required to support production at scale did not even exist five years ago. In fact, the manufacturing infrastructure needed to support this market is enormous. While the foundation of the needed capacity is in place for some segments, the capital expenses and development necessary to support a $600 billion per year market requires much planning and a comprehensive technology map for execution. The key differences between conventional small-molecule manufacturing and biomanufacturing include: 

The transfer of products from the prototype stage to production is a significant task in the developmentof  biotechnology and biomedical products because of the complexity of the products and the regulations established by government agencies such as FDA. Scalability comprises a large part of the difficulty as well. A test tube of organisms will often react differently than a vat of organisms.  

Biotechnology products comprise complex technology that may not yet exist at the time of product conception and design. Managing the creation of the technology for concurrent design and manufacturing as required for product advancement, and applying it to products are extremely difficult, but is usually required in biomanufacturing. This provides significant challenges to companies because they are often required to invent or acquire untested, leading-edge technology as they develop new products. Development risk of products in biotechnology is generally high because of the leading-edge nature of the products and their cost of introduction.  

Historically, traditional pharmaceutical companies have developed new chemical entities within their own drug discovery groups. In the case of biopharmaceuticals, much of the innovation that occurs is not related to the licensing of new drugs from biotechnology. To date, the traditional pharmaceutical companies have accounted for the introduction of 70% of the approved biopharmaceuticals; of which over 50% are originated externally. 

Trying to predict capacity requirements for opportunities presented by biomanufacturing is not simple. While the contract-manufacturing sector has strongly promoted the need for additional capacity, with many organizations investing in microbial and mammalian cell-culture capabilities, big pharmaceutical and biotechnology companies are also increasing capacity based on their product portfolios. These can be split in two main groups—those that focus on early-phase clinical supply and those that deal with large-scale capacity. A development group with access to a small-scale multiproduct production facility is required to support this type of function. For companies with limited product portfolios or those wholly focused on clinical supply, this function is often contracted out. There is a shortage of companies worldwide that can provide the necessary level of support. 

The goal of process optimization is to integrate process development with product development so that there are no surprises when the products are transferred to production. Within pharmaceutical R&D there is a strong correlation between highly effective process development capabilities and the profitability of the associated product and company. Companies with superior process development capabilities have strategic leverage in time-to-market and associated productivity.  

Because of the extensive regulatory requirements of drug introduction, it is desirable to delay process development as long as possible and then quickly develop it once approval looks likely. Some companies are much better at this task than others. The design of development processes for scale-up works reasonably well with chemical-process-based drugs. This is not always the case with biologics. The novel nature of each process requires significant learning and flexibility during implementation. Also the transfer of expertise acquired during development for application in new processes varies greatly from company to company. Some companies appear to have more structured knowledge that stems from their particular competencies. Understandably, different segments of the pharmaceutical market have differing approaches to biomanufacturing, although some similarities do exist when it comes to the desire to harmonize or standardize manufacturing across different therapeutic diseases and in the categories of biotherapeutics (i.e., hormones, mAbs, enzymes, or proteins). 

Based on data from its Q4 Pharmaceutical and Biotechnology Outsourcing survey, which included 2619 individuals in outsourcing-facing roles, Nice Insight found distinct differences across customer groups with respect to biologic-based therapies. Seventy-six percent of respondents from both biotech companies and Big Pharma companies, each with an annual outsourcing spend in excess of $50 million, indicated their business is actively engaged in the development of biotherapeutics (see Table I). These customer segments were second only to emerging biotech companies, in which 82% engage in the development of biologic-based therapies. Just over half of the respondents from specialty pharma companies stated their business develops biotherapeutics and only one-third of emerging pharma companies are developing biologic based therapeutics.  

Table I: 2012 trends towards biomanufacturing. Numbers 1â5 indicate the rank order of the relevance of the category of biologic based therapy within the development for each segment covered, with 1 being most relevant and 5 being the least.			

Big Pharma, biotech, and emerging pharma segments are in accordance, with monoclonal antibodies taking top priority,  whereas the specialty pharma and emerging biotech segments indicated protein-based therapeutics as their top priority.  Enzyme, hormone, and peptide-based therapeutics followed in sequence with respect to relevance across the segments. As mentioned above, standardization is an industry-wide goal when it comes to the development of biologic-based therapies. This was supported by Nice Insight's research, in which 82% of specialty pharma companies engaged in biotherapeutic development stated their organization was trying to standardize the process and 92% of Big Pharma companies stated the same.   

On average, the biotech and emerging biotech segments indicated that a slightly larger portion of their outsourcing budget was allocated to large molecule projects, spending 60% and 56% on biologic outsourcing, respectively. Big Pharma followed closely behind, allocating 53% of their budgets to biomanufacturing. Specialty pharma and emerging pharma were the only segments that had a slightly larger percentage of their budgets allocated to traditional, small-molecule projects, with 49% and 47% allocated to biologics. 

Trends in biomanufacturing are encouraging, as companies with superior process-design capabilities will be able to extract more profit from their operations and thus become more successful. Accordingly, these companies are likely to produce better products that are more aligned with customer needs. 

 is director of business intelligence at Nice Insight, That's Nice LLC, 

Growth in infrastructure and process-development capabilities will be required to support the biologics market.

Biotherapeutics Outpace Conventional Therapies

Outsourcing in the pharmaceutical industry, until recently, has been largely confined to commercial manufacturing, packaging, and support for clinical trials. The industry is rapidly changing; companies are facing rising costs, a fast evolving global market, and weak pipelines. Many companies are outsourcing activities that have historically been kept in house, freeing themselves to concentrate on their core competencies and become more agile in responding to changing conditions. These new outsourcing models include discovery and R&D, regulatory, chemistry and manufacturing controls (CMC) support, and back office sales and marketing activities—virtually no activity is out of bounds. Instead of building or acquiring specialized technologies and facilities, many companies are seeking access to them elsewhere.    

Smart outsourcing provides the following operational and business benefits:  					

Reduced operating costs and greater return on  investment (ROI)     

Shorter time to market through faster accesses to increased capacity, new technologies, specialized facilities, intellectual property (IP), and expertise  

More efficient use of critical internal resources (e.g., human and facilities)     

Avoidance of large expenditures to bring new or expanded capabilities in house as well as the cost of staffing those capabilities  

Increased velocity and flexibility in responding to rapidly changing global markets. 

To reap the full rewards of outsourcing over the long term and significantly enhance shareholder value, however, companies need to take a comprehensive approach. Companies that adopt a smart outsourcing strategy include:  					

Pursuing outsourcing in the context of an end-to-end, global supply chain strategy that is directly aligned with the company's strategic business goals

Managing outsourcing as part of a continuing, mutually beneficial, long-term strategic partnership

Assessing and effectively managing the increased risk that comes with more extensive and diverse outsourcing.  

Companies can use outside expertise to help carry out such an approach. This article outlines the benefits of using a third party in strategic outsourcing.   

Effective use of outside experts who have the requisite industry-specific technical, quality and compliance, operational, and business experience can provide an invaluable, independent source of perspective, methodologies, and tools to help ensure the best decisions are made each step of the way. Experts can help to tightly align outsourcing strategies with a company's strategic business and supply chain plans, re-affirm core competencies, and make informed recommendations regarding which current outsourcing needs represent the highest ROIs and competitive advantages going forward.   

The right consulting partner can give advice on how best to support these strategies with ongoing operational excellence and risk-management programs, as well as develop and maintain highly effective and mutually beneficial strategic relationships with prospective outsource providers. But whether a company engages external advisors or not, the company will need to be able to skillfully blend strategy, risk management, and a new mindset and approach to outsourcing partnerships to remain competitive in today's, and tomorrow's, rapidly changing and increasingly challenging global markets.    

The effective selection, qualification, and management of outsource partners begins with the way one thinks about those partners, no matter what the nature of the partnership (e.g., innovator

CMO or innovator-to-innovator). Short-term thinking about outsourcing as a stopgap measure or commodity solution to operational needs based largely on cost or capacity must be replaced by thoughtful and robust evaluations of both the current and future benefits of developing long-range strategic partnerships that deliver flexibility and value to both parties involved.  

Consider not only what outsource partners can provide in the near term, but also what they may be able to do as the relationship grows. Long-term strategic partnerships can have substantial benefits to each of the outsource partners in revenue, capacity planning, and potential access to new technologies and markets.  

For example, consider that two large pharmaceutical companies enter into mutually beneficial, long-term (>10 years) strategic relationships. These are innovator-to-innovator partnerships that are based on a progressive schedule of mutual exploration and cooperation. Among their short- and long-term goals are the use of each other's available capacity and specialized facilities, technical and scientific information-sharing, and potentially, the codevelopment of future products and technologies.  

Maintaining such long-term, strategic partnerships requires a significant shift in thinking and organizational culture on both sides—from a purely transactional relationship to one of shared planning, shared risk, and collaboration.    

This shift requires developing and nurturing a highly cooperative working relationship that incorporates trust, a shared vision, open communication, and a dedication to quality, timeliness, compliance, and continuous improvement.  

Selecting a strategic outsourcing partner goes far beyond a checklist of their capacity, capabilities, and cost. A company should thoroughly assess all of the risks associated with that partnership, develop the appropriate remediation plans and contingencies with the potential partner, and agree to jointly manage those risks to successful outcomes. Conducting a thorough and intelligent risk-based due diligence, performed as a shared exercise with the outsource partner, can identify key areas of uncertainty that need to be addressed. Due diligence can also help align each party's expectations with regard to their relative roles and responsibilities, accountability, and what success looks like for each of the parties involved. 

A number of alternative risk- assessment and risk-management methodologies and toolboxes exist. One should be selected that effectively identifies, prioritizes, and helps manage the risks that exist but that also provides an objective and quantifiable output that clearly supports the business case for that outsourcing decision.  

Key areas to be considered in these risk-based assessments are outlined in the sidebar (see "Due Diligence Checklist").  

At the conclusion of the assessment, both the company and potential outsource partner should have a comprehensive profile of the major risks of the overall outsourcing strategy, including those related to time, cost, and deliverables as well as the degree of regulatory, operational, and cultural risk.  

The prospective partners can then collaboratively determine the relative priorities of those risks to each party, how those risks will be mitigated, and the contingency plans that will need to be put in place. The time and cost of mitigating each risk and the ROI for doing this must also be carefully considered so that an informed business decision can be made about entering into the relationship.   

This risk-based assessment should not be a single undertaking. Conditions change and risks change with them. The evaluation should, therefore, be conducted periodically as a formal part of the business relationship process in order to continue to manage change and uncertainty, assure alignment of the partners with the goals and deliverables of the agreement, and to validate that the work or services being conducted continues to support the strategic supply chain and business strategy.   

Establishing and maintaining successful relationships

The success of strategic outsourcing relationships, both in the short and long term, depends upon effective planning and project management, appropriate metrics, successful knowledge transfer, ongoing open communication, and periodic reassessment to help assure the long-term viability and health of these critical business partnerships.   

Effective planning begins with the development and execution of the appropriate business and quality agreements that clearly define and specify the relative roles, relationships, specifications, and deliverables that are expected. These include the proper controls and contingencies that may be needed to address any unexpected situations that may arise.  Metrics must be established to serve as an early warning system for potential issues and to measure the relative success of the outcomes that are expected.  It is also highly recommended that companies establish dedicated resources to manage these relationships as they move to a broader and more strategic sourcing strategy. These dedicated resources should also monitor progress against plans, quality of the deliverables, costs, and other parameters that have been set forth in the business, technical, and quality agreements.   

The relationship begins in earnest with complete and reliable IP and knowledge transfer between the sponsor and the contract partner, including effective technical transfer if the outsourcing involves a process to be run or product to be made. Companies that intend to engage in outsourcing need to assure they have an effective information and technology transfer process in place that is formal, efficient, scientifically and technically sound, compliant, cost-effective, and reliable. This is a core competency that consistently produces maximum strategic impact. Too often, however, such transfers are treated as one-off events that are the responsibility of a single function, department, or site, rather than part of a comprehensive transfer framework supported by well-trained and experienced resources on both sides of the agreement. That framework should include the following: 									

An overall transfer program management process, including a governance structure, the establishment of executive sponsorship, and the clear delineation of roles and responsibilities, including those of support functions and transfers. In this way, the company can manage its outsourcing transfers as a portfolio and apply risk management techniques to the portfolio as a whole. 

Project-level management for each individual transfer, including a set of requirements, activities, decision points, milestones and best practices that help ensure predictable, on-time transfer that is able to be validated.  

Transfer strategy, including the means to fill any gaps in the organization or the receiving organization, an overall description of the transfer, and measures of success. 

When a process or product is being transferred, the organization must have the proper level of process understanding and control over that product or process so that it can provide clear, complete, and technically sound specifications to ensure successful transfer.  

Elements for achieving process understanding include employing QbD principles and techniques; identifying the appropriate critical-to-quality  attributes and associated critical process parameters to limit variability and maximize control; identifying drivers of variation and of interactions in critical processes; and understanding the right process-control strategies.  

When older or insufficiently developed processes with a high or uncertain level of variability must be transferred, improved control can usually be obtained retrospectively from conducting a highly structured, statistical analysis of the historic data associated with those processes. Such process capability and control evaluations, if implemented properly, can help achieve an improved level of understanding and control over these older and more variable processes in a relatively short period of time, often in just weeks. The risk of prolonged and costly transfer attempts, or even failure, is thereby, significantly reduced. Achieving process robustness is a critical success factor for right-first-time transfers to outsource partners, as well as successful validation and reliable operation of those transfers.  

Once the operational relationship is under way, the open and honest two-way communications, continued risk assessment, and cooperative problem solving upon which the partnership was first based must continue. This can't be emphasized strongly enough. Too often when outsource providers encounter technical problems or have quality or compliance issues, they tend to conceal those problems from the client while they attempt to resolve the issues on their own. Sooner or later, news of the problem comes to the attention of the client as a sudden and unexpected surprise, with potential negative impact on both the client and outsource partner. What otherwise may have been a minor problem potentially escalates into a major issue, which could have been more effectively managed if the outsource partner had communicated with the client and enlisted their help in a more timely and effective manner. Conversely, clients must keep the outsource provider fully informed of plans that will increase or reduce the volume and level of services that will be required so they can plan their resources and capacity accordingly. 

Finally, continue to assess the strategic outsourcing strategy at regular intervals to assure continued alignment with the strategic business goals of the company, the strategic supply chain strategy, as well as with changing patient needs and market conditions. Conduct a regular re-assessment of the performance history and potential risk at each of the partners along with a re-assessment of the entire outsourcing portfolio. This will help assure the continued success of those partnerships, the identification and remediation of any new risks that may arise, and also help to identify additional opportunities for strategic outsourcing as your company continues to evolve and grow.  

Questions to be asked during re-assessments include: 					

What are the highest-priority and highest-ROI opportunities for additional outsourcing that will support manufacture of our current products, introduction of future products, and overall strategic business plan?

Are there some outsourced projects that should be brought back in house?

Has there been a shift in any of our core competencies, technologies, or internal capacity to support our current and upcoming products?

Has there been a shift in our company's strategic business or supply chain plans as a result of changing competition, patient, or market conditions?

What are the relative priorities, timing, costs, risks, competitive advantages, and ROI of making a change in our current outsourcing strategy?  What if the change isn't made?

Outsourcing in the pharmaceutical industry, until recently, has been largely confined to commercial manufacturing, packaging, and support for clinical trials.

Smart Outsourcing: Strategic Alignment, Risk Management, and New Relationships

Pharmaceutical industry outsourcing, particularly for CROs and CMOs, has grown during the past 10 years, and indications are that it will continue to grow through the next decade. Entire new outsourcing industry sectors, such as high-throughput screening services, have become multibillion-dollar industries, and many functions formerly considered essential, such as in-house animal toxicology testing, now rarely exist within pharmaceutical companies. Pharmaceutical developers and manufacturers of all sizes, but particularly the largest international companies, now routinely outsource many tasks and functions formerly considered in-house core competencies. The underlying nature of the pharmaceutical industry has changed as cost management and process efficiencies become critical to survival. Outsourcing has become an industry norm, and now includes the full range of corporate activities—from screening and lead identification, to toxicology and other preclinical studies, clinical trials, marketing, and manufacturing at all scales.  

Outsourcing has proven effective at reducing operational and infrastructure costs. During this period, however, the pharmaceutical industry has seen a significant reduction in its R&D efforts and new product pipelines. This has caused many firms to implement further internal cutbacks and increase their outsourcing, as a way to reduce payroll and capital expenditures. This economics-driven increase in outsourcing has, in some ways, contributed to decreased long-term industry productivity. But even if outsourcing is ultimately proven not to be cost-effective in terms of supporting innovation and new product R&D, outsourcing will continue to experience growth. It is often the only option available to companies that must adapt to lower profits due to ailing R&D pipelines and products going off-patent.  

Although pharmaceutical outsourcing will continue to increase throughout the next decade, it is likely to do so at a lower rate than in the past. BioPlan Associates' annual biomanufacturing report shows that the top factors likely to create capacity (production) constraints are economics driven, including facility constraints, inability to hire experienced technical staff, and physical capacity of equipment. 

The study also evaluated 24 areas of outsourcing, with the primary outsourced activities include product characterization testing (70% of companies outsource at least some of this activity). Other tasks now routinely outsourced include validation services (69%), toxicity testing (65%), analytical testing (61%), and fill–finish operations (60%).   

Figure 1: Selected data: average change in biomanufacturers’ budgets 2009â2012. (FIGURE COURTESY OF THE AUTHOR)			

Currently, at about $25-billion annual revenue, pharmaceutical outsourcing will likely to grow at around 10% annually to over $40 billion per year in 5 years and about $60 billion in 10 years. The industry now appears to be slowly recovering and is starting to invest more in R&D. The recent BioPlan annual survey has also found that budgets for R&D and manufacturing are again rather uniformly increasing at a healthy rate; and many analysts project rosy futures for CROs and CMOs as industry R&D and manufacturing activity picks up.  

Much of the growth in outsourcing in the past decade, particularly the most dramatic and rapid growth, has taken place in developing countries, particularly China and India. Besides developing countries offering lower costs, these countries have their own rapidly growing domestic pharmaceutical markets and industries. Many of the largest global pharmaceutical companies invest billions in establishing their own R&D centers and outsourcing to CROs/CMOs in these countries. These actions provides access and a corporate presence in these rapidly growing markets.  

However, as the wage gap in these emerging economies narrow, labor and other outsourcing costs are increasing. In the future, we will see shifts in outsourcing to lesser-developed countries. At the same time, Chinese and Indian firms will shift to compete more on technology and quality, rather than on price.  

Throughout the next decade we will continue to see a shift towards developing biopharmaceuticals rather than drugs, with these products offering increased profits and protection against eventual generic-drug competition. Many profitable recombinant protein and antibody products are coming off-patent. Over the next decade, there will be a dramatic increase, likely a doubling, in the number of biopharmaceutical products as biosimilar, biobetter, and biogeneric versions of current products enter world markets. 

Much of the R&D and manufacturing of these new biosimilar products will be performed by CROs and CMOs that focus on productivity and cost-savings. Technological advances are making it easier and cost-effective to outsource manufacturing, including the use of disposable bioprocessing systems rather than more expensive fixed stainless-steel systems. Advances in screening and analytical testing are also driving outsourcing to firms providing these increasingly specialized and resource-intensive services. As documented in BioPlan's Top 1000 Global Biopharmaceutical Facilities Index (

), the increase in worldwide CMO and other bio/pharmaceutical outsourcing of the past decade will certainly continue through the next decade. 

articles address CMO and CRO perspectives, performance metrics, quality issues, and more. 

is president of BioPlan Associates, tel. 301.921.5979, 

New outsourcing industry sectors have become multibillion-dollar industries.

Biopharmaceutical Outsourcing Trends: The Next Decade

Investment in research and development largely by the pharmaceutical industry has resulted in a broad range of vaccines targeting more than 25 infectious diseases. During the past 30 years, advances in biotechnology, genetic technology, and information technology have resulted in acceleration in the pace of vaccine development. As a result, the vaccine industry has recently introduced a number of new vaccines, such as those against cervical cancer, meningococcal infection, potentially pandemic influenza, pneumococcal diseases, rotavirus diarrhea, and varicella zoster.  

The manufacturing processes for vaccines have also come a long way, from using heat-inactivated cells to using recombinant DNA technology-driven antigen production. For example, inactivated polio vaccine as developed by Salk has been changed and improved and is currently being produced in a Vero cell line. Additionally, there are a few other examples of expression systems that are specifically developed for use in vaccine production. These include the PER.C6 cell line, the associated AdVac/Virosome technology (Crucell/DSM), and the avian-derived cell lines from Vivalis and ProBioGen. Another expression technology with potential benefits is the Pfenex Expression Technology from Dow, which has been used to generate high levels of vaccine antigens. 

What sets manufacturing of vaccines apart from that of other biopharmaceuticals is the risk and safety considerations related to working with pathogens and pathogenic antigens. While removal of host cell-related contaminants (e.g., host cell proteins, DNA) has to be demonstrated just as for other biotech therapeutics, removal or inactivation of adventitious viruses remains a significant challenge (1). Key questions for manufacturers remain. How does one ensure that the starting materials and final product are consistently safe and of high quality? Who can manufacture the amount of vaccine needed for clinical trials and, eventually, commercial production? 

This 27th article in the "Elements of Biopharmaceutical Production" series discusses the key technical, manufacturing, and regulatory considerations that need to be taken into account by the manufacturers today to make safe and efficacious vaccine products—whether manufactured in-house or outsourced. 

Producing a safe and effective vaccine requires about 12–15 years of research and is estimated to cost between $100 million and $1 billion, depending on the type of vaccine being developed. It is estimated that 60% of vaccine production costs are fixed, meaning that vaccine products require a sizable market to be profitable (2). As a result, many potentially vaccine-preventable diseases, such as those primarily affecting the developing world, are left without large-scale research interest from multinational vaccine manufacturers. Attempting to fill this void have been networks led by private philanthropies, governments, and public-private partnerships (1, 2). Despite the challenges mentioned above, vaccine production has considerable lure for manufacturers. The global vaccine market is expected to increase by more than 100%, from $24 billion in 2009 to $56 billion in 2016 (1). Multinational vaccine companies  historically have conducted much of the innovation, research, and development in the field of vaccine production. Many factors seem to discourage vaccine research and development, including liability concerns and price limits due to bulk purchasing. The vaccine industry is at present dominated by major players such as Merck, Sanofi-Aventis/Pasteur, GlaxoSmithKline, Novartis, and Pfizer (3). As illustrated in Figure 1, the number of biotech products including those that are in the pipeline indicates that there are more vaccines than recombinant proteins and monoclonal antibody products (4). The global vaccine market has experienced robust growth over the past few years, with economically emerging countries, such as India and China contributing effectively towards the industry's development. The governments in developing markets are spending significant amounts of money and resources for vaccine delivery and distribution. This spending, in turn, has led to the entry of more foreign vaccine players in these countries.  

Figure 1: Distribution of products in pipelines of major biopharma companies (adapted from reference 4). 

CHALLENGES IN PROCESS DEVELOPMENT AND MANUFACTURING

Process development is the technological foundation that underlies the manufacture of new vaccines and is central to successful commercialization. The key issue related to technology is the evolution and translation from a procedure used for making vaccines in a basic-research laboratory to a process that can be scaled up and run reproducibly in a manufacturing environment to make tens of millions of doses per year. Vaccine manufacture is broadly similar to other biotech manufacturing operations, but with some important differences. Purity is a particular challenge for vaccines, because some vaccine impurities have an immunomodulatory effect and can act like an adjuvant to the vaccine. Therefore, manufacturers have to scale up their production without losing the potency of the mixture of the vaccine and the impurity. Several new vaccine manufacturing platforms offer advantages including more effective vaccines, less costly vaccines, or more rapidly produced vaccines. At the same time, these manufacturing platforms raise new scientific and regulatory concerns that might potentially affect the vaccine's safety or efficacy. 

For example, novel cell substrates raise new questions about potential adventitious viral agents. Vaccines also differ from conventional drugs in that some vaccines are generally stockpiled and are not used continuously. Therefore, vaccine manufacturing needs to be flexible, rather than continuous. Meanwhile, cell banks required for vaccine manufacture may become depleted with time and a new working cell bank may be needed, but the cells may not grow and perform as they did 10 years ago. Growing expertise in cell-culture technology and bioprocessing is helping manufacturers to overcome these problems. 

Therefore, it should be possible to put many new vaccines into robust large-scale production during the next few years. The challenges of vaccine development are not limited to identification of suitable antigens, adjuvants, and delivery methods, but also include regulatory, technical, and manufacturing hurdles in translating a vaccine candidate into a commercial product. 

A variety of technologies have been used to develop successful vaccines. These technologies include live attenuated bacteria and viruses such as Bacillus Calmette-Guérin and measles, mumps, and rubella (MMR); inactivated bacteria and viruses such as whole cell pertussis; proteins such as diptheria and tetanus toxiods; polysaccharides such as PneumoVax (Merck & Co.); conjugated polysaccharides such as Prevnar (Pfizer), and virus-like particles (VLPs). This variety can be a challenge to the vaccine manufacturer with respect to standardization of facilities and equipment. Also, while manufacturing processes and practices have significantly advanced with time, certain critical vaccines are still manufactured by traditional methods because of lack of suitable technology or lack of incentive for developing improved technology. For example, influenza vaccines are manufactured by methods fundamentally unchanged over several decades. This has made the manufacturers susceptible to disruptions in the supply of suitable eggs and to virus strains that do not propagate in the allantoic fluids. Although demand for this vaccine has increased over time, the motivation to improve the process is neutralized by the seasonal nature of influenza and the variable risk associated with the antigenic drift and antigenic shift associated with the pathogen. At the other end of the spectrum is 

 serogroup B vaccine, wherein the natural antigenic elements of the bacteria elicit an autoimmune response. Many newer versions of this vaccine are presently undergoing advanced clinical trials (4).  

Compliance with the principles and guidelines of cGMP is a statutory requirement that applies to all pharmaceutical products including vaccines. In recent years, a number of novel tools and trends have been pursued in pharmaceutical manufacturing. These include novel ways of managing the manufacturing operations, such as operational excellence initiatives including lean manufacturing, total quality management, quality risk management, Six Sigma, and process and analytical technology. 

Vaccines are complex and diverse biomolecules ranging from recombinant subunit antigens to live organisms. Therefore, their manufacturing has traditionally been relatively inefficient and technically challenging. As a result, a range of purification technologies and specialized development approaches are required to manufacture sufficient quantities of these products. To date, production of viruses and VLPs is primarily performed by density-gradient centrifugation, a labor-intensive process that is not readily scalable. An alternative strategy is to apply column chromatography. However, the problem with conventional porous chromatography resins is low binding efficiency due to the large size of viruses and low flow rate. With the adoption of membranes and monolithic columns, purification of recombinant vaccines is easier because of low steric restriction to the active binding channels (5). These formats also offer higher flow rates, resulting in smaller columns and shorter cycle times.  

With advances in technology, vaccine manufacturers have access to a greater range of choices. For instance, traditional vaccines, which are often made through inactivation or crude fractionation of an infectious agent, are now being supplemented by vaccines based on pure proteins, engineered virus particles, DNA, or even cells. The latter may offer significant advantages in terms of safety and the ability to generate the required immune response. However, there are challenges in implementing such technologies as they require more sophisticated and expensive manufacturing technology, which could limit their broad availability and implementation (6).  

CHALLENGES IN ANALYTICAL CHARACTERIZATION

Development of safe, effective and affordable vaccines requires that along with the use of suitable manufacturing approaches there is effective testing of manufacturing intermediates and an application of modern characterization approaches (see Table I). The difficulty of characterizing complex biological products such as vaccines makes it especially challenging to ensure that they can be manufactured in a consistent, reproducible, and commercially viable manner with assurance of safety, quality, and efficacy. The risk of manufacturing inconsistencies is especially high for novel products, because traditional testing technologies might not be able to identify subtle and unanticipated variability (7).  

Table I: Advantages and disadvantages of approaches used in vaccine characterization.  CD is circular dichroism, and FTIR is Fourier transform infrared spectroscopy.  

Analytical testing of vaccines, just as any other pharmaceutical product, provides evidence that the vaccine and its intermediates meet the specifications defined within the license application. Safety, efficacy, and potency tests associated with a licensed vaccine are maintained within the approved filing and published in 21 

 Part 610 in the US. In addition, several pharmacopeias (e.g., the Indian Pharmacopeia, British Pharmacopeia, US Pharmacopeia, and European Pharmacopeia) publish monographs for vaccines to provide standardized requirements for commercialization. Most countries require that vaccines be tested for both safety and efficacy by the manufacturer and a national testing laboratory (e.g., the FDA Center for Biologics Evaluation and Research in the US) before release and distribution.  

Because of their simple composition (i.e., a few well defined immunogenic molecules plus adjuvant), component vaccines are the most amenable to analytical characterization. Live or killed/attenuated vaccines usually are a complex mixture of immunogens since they are directly derived from organisms such as killed or attenuated virus, intact bacteria, or multiple bacterial components. For such vaccines, the biological matrix is rather complex, allowing more characterization to be focused on the adjuvant. Technological advances such as proteomics are likely to permit the characterization of the biological components of such vaccines going forward. In the case of live and attenuated vaccine material, for example Bacillus Calmette-Guerin vaccine and oral polio vaccine, the efficacy of each vaccine batch is related to the number of live particles determined either by counting or by titration, that is, entirely 

 testing is only carried out for a new seed strain. Unlike live vaccines that are quantified by 

 potency test is required for each batch of inactivated vaccines, although some exceptions do remain (8).  

Classical methods for characterization of vaccines

These methods rely on the study of physical-chemical parameters such as differential scanning calorimetry (DSC), thermo-gravimetric analysis (TGA), pH, protein content determination, elemental composition, and studying the effects of stress such as freeze-thaw and agitation (9). TGA and DSC can be used to assess a change in the denaturing point of the protein or polynucleotide present. Appearance and pH can be used to monitor changes in composition or the impact of stress as observed by clumping or discoloration. Particle size analysis and particle size distribution can provide further insight into clumping and exposure to stressful conditions which can significantly affect the safety and efficacy of the vaccine. However, these methods are unable to determine small changes or relate the change in any of the measured parameters to an effect on potency and safety of the vaccine. 

Challenges of vaccine development include regulatory, technical, and manufacturing hurdles in translating a vaccine candidate into a commercial product.

BioPharm International-03-02-2012