Are the deadlines for your outsourced projects often not met? Are you unsure of the status of your project at any given time? Is the original budget of your study typically exceeded? 

If most of these questions have an affirmative response, chances are your outsourced program needs more effective project management. Project management helps prevent these problems by organizing and managing resources to ensure that project deliverables are completed on time, within budget, and that they are of high quality.  

Proactive project management is especially critical for outsourced biopharmaceutical projects, which often involve a small biotech company that may be dealing with multiple contractors. The nature of biopharmaceutical products, with their molecular and structural complexity, inherent instability, and sensitivity to manufacturing changes, can present numerous analytical challenges. Biopharmaceutical testing methods are often technique-dependent, highly product-specific, and sometimes not very robust and reproducible. Understanding and anticipating problems early can prevent major delays and budget overruns later.  

Smaller biotech companies may rely on a contract organization for regulatory and technical guidance—the contractor may  recommend the most efficient methods for supporting the company's analytical needs. This fosters a solid partnership, which, of course, is facilitated by effective project management. 

A biopharmaceutical study outsourced to an analytical contract laboratory may consist of multiple tasks, including method development and validation; method transfer; characterization of active pharmaceutical ingredient (API) and drug product (DP); stability and release testing; and testing support for formulation and process development. There are several uncertainties about analytical methods, formulation, the API and DP, and the manufacturing process. These unknowns create challenges in defining the contract laboratory's scope of work, timelines, budgets, and ability to meet original goals.  

The primary function of the project manager is to coordinate all project-related activities and to monitor progress of the agreed-upon work, timelines, and costs. Before initiating the study, the project manager works closely with the client to prepare a project plan outlining critical paths and milestones and determining the budget. Throughout the study, the project manager reports the status of each task, changes in scope, and potential risk of not meeting targeted timelines and budgets. This person often becomes the primary point of communication between the client and the contract laboratory, facilitating the flow of information between the two parties. The person in this position should proactively assess and evaluate resource allocation, execution of project tasks, and timelines for deliverables. He or she also drives implementation of contingency plans and problem solutions, and is empowered to motivate and influence the project team to achieve the program's overall goals.  The term "project manager" often becomes synonymous with project champion, project coordinator, project advocate, or project leader. 

Project management starts when a contract laboratory responds to a Request for Proposal (RFP) for a study to be outsourced. It is one of the most crucial steps in managing the relationship between the client and the contract laboratory, because  the project is defined, timelines and budgets are set, and the expectations of both parties are established. 

A contract laboratory pitfall is failing to carefully assess internal capacity or capability to perform the study before committing. The project must devote enough time and attention to the project definition stage to fully understand the scope and extent of the work. One or more project definition meetings (Table 1a) should take place to discuss the objectives of the study, background of the drug development program, technical information, specialized equipment or expertise needed, and other project requirements.  

Table 1a. Project management communication summary			

Also helpful is a checklist outlining key pieces of information needed to determine pricing, timing, and resource requirements. The contract laboratory's bid (proposal) should indicate explicitly what is, and is not, included in the fee, and assumptions should be stated clearly in the contract to clarify terms and conditions. For example, if a start date is agreed upon, one key assumption is, "initiation of the study is contingent upon receipt of samples and standards and approval of the protocol by the client." Assumptions are also essential to include in the bid when the responses to certain key questions in the project definition form are unavailable or not provided. Ideally, the project manager is engaged as early as possible in the bid preparation process, because the contract serves as the foundation for developing the project and resource plans.  

Assembling a project team for an outsourced biopharmaceutical study occurs early in the project, even before presenting a bid to the client. In order to commit to taking on a study, the contract laboratory must have formulated a resource plan. In determining the resource requirements for the study, the project manager, along with the operational leaders, should consider the following: 					

Experience, expertise, and training of the staff based on the techniques, methods, and compound(s) involved

Previous experience of the staff in working with the same client

Support functions such as quality assurance, technical writing, sample management, and stability storage

Availability of staff and equipment based on approximate time frame

Back-up staff in case of vacation, illness, or other unexpected events

It is in the best interests of the client and the contract laboratory to maintain a dedicated team for the project. This establishes "ownership" and accountability. It also promotes consistency in the results. Throughout the study, the project manager monitors the use of resources against project timelines, budgets, and study requirements, and recommends necessary adjustments to resources and timelines.  

Several avenues of communication should remain open during the lifetime of the program to guarantee an effective relationship between a contract laboratory and its client. Meetings, as summarized in Tables 1a and 1b, are essential to accomplish project management objectives. Aside from the project definition meeting, project initiation or kick-off meetings, both with the client and within the contract laboratory team, are critical tools for project management communication. Equally important during these meetings is establishing roles and responsibilities of project team members, lines of communication, guidelines for escalating issues when needed, and ways to handle investigations and deviations, as well as changes in project scope, timelines, and budgets.  

Table 1b. Project management communication summary			

Communication at the contract laboratory during the method transfer or method evaluation stage is crucial. Often, test methods for biopharmaceutical products are initially developed by the client or at a contract manufacturing facility. The sponsor should be certain to communicate all relevant information about the history of the methods, steps that are technique-specific, and other methods that were evaluated or that the sponsor attempted to develop (whether successful or not). Challenges in robustness and reproducibility of biopharmaceutical techniques are often encountered when methods are transferred from one laboratory to the other. Sharing relevant information through project management communication tools ensures seamless and efficient method transfer.  

To keep the communication lines open among all parties while the study is in progress, the project manager should provide status updates to the client on a regular basis, containing the following information:  					

Contract laboratories should make available a brief written summary report available before project update meetings or conference calls. These events are interactive, with ideas  exchanged and decisions made by the client and contract laboratory. They are especially useful for method development, transfer, and validation activities. For larger studies, a more formal review of the entire program, typically on a quarterly or biannual basis, is recommended. This enables both parties to take a step back and look at the "big picture" of which areas are working well and which need improvement. They can then evaluate performance metrics (such as turnaround time, timelines and budgets versus goals, and quality metrics), recommend systems and process improvements, and discuss the future of the program.  

After completing the outsourced study, assessments of the contract laboratory's overall performance and the interactions with client can take place as a "lessons learned" meeting. An evaluation of key performance measures in terms of technical skills, project management, quality, and communication is conducted. The outcome is often communicated to the upper management of both parties in an effort to improve performance of quality systems and processes in both organizations. This feedback helps clients understand what improvements can be made to manage their outsourcing partners more effectively. 

It is the project manager's responsibility to coordinate and drive these meetings, act as the meeting facilitator, prepare the meeting agenda, document and distribute meeting minutes, and follow up.  

There are a number of commercially available or internally developed customized project management software applications that can be used to organize data for timelines, budgets, and project tasks. The effectiveness of such software depends on its flexibility and suitability to the program and both parties' needs.  

Key to the effectiveness of project management is proactively identifying potential impediments to completing the study in a timely and cost-effective manner. A simple technique to aid in this type of risk management is to ask the following sample questions:  					

Does the study involve an early phase of drug development?

Is method feasibility or transfer going to be conducted prior to sample analyses?

Does the laboratory have experience with a similar compound?

Is the client contact knowledgeable about the analytical portion of the study?

The next steps involve prioritizing the risks in order of probability and magnitude of impact on costs, quality, and timelines, and then formulating a risk management plan. The plan should list strategies to mitigate risks, persons responsible, and timetables for implementation, resources, assumptions made, and ways to measure effectiveness. 

Every outsourced project has its share of problems and issues. It is wise to devise a plan detailing when and how to escalate an issue to the next level supervisor,  technical expert, someone from upper management or quality assurance, or  client. Although there are no hard-and-fast rules, the following are some of the warning signs that someone of greater authority or experience should be consulted: 					

Articles

Are the deadlines for your outsourced projects often not met? Are you unsure of the status of your project at any given time? Is the original budget of your study typically exceeded?

The Importance of Project Management

Renting rather than owning can lead to a sense of insecurity. Those of us who have rented apartments or leased cars know the sense of impermanence, and lack of control, that comes with it. Business outsourcing is often just as unpredictable and the lack of control can be equally insecure. The good news is that as business models in biopharm evolve, companies that are at the extreme edge of outsourcing are showing remarkable success without ever owning a brick, and are accessing and controlling employees and resources far beyond the reach of what they would be able to acquire themselves.

Business models involving high degrees of outsourcing have been evolving rapidly in the biopharm space. During the nineties, the biopharmaceutical industry responded to business pressures through the fully integrated pharma company (FIPCO) structure. However, it became apparent that large integration, infrastructure, and coordination costs are associated with having functions housed in one company, and the FIPCOs found themselves to be inflexible—unable to adapt to the emergence of new technologies. The pendulum quickly swung the other way and many adopted a network structure, shifting the biopharm value chain as companies leveraged partnerships, alliances, and outsourcing. Soon outsourcing drug discovery and development became the new pathway to optimize resources and accelerate the development process. Partnering with a surging number of CROs, CMOs, CSOs, and other niche providers, biopharm companies in 2007 will have an estimated spend of more than $7 billion on international clinical trial outsourcing alone.  

During the time period of shifting models and uncertainty, one very small company kept a laser focus on its virtual model and thrived. Endo Pharmaceuticals, Inc. of Chadds Ford, PA,  is a semi-virtual CNS and supportive care oncology therapeutics company that in-licenses products (as the substitute for the "R" function in its R&D).  The company always stayed close to its core tenet. That tenet was never to operate or own something that could be performed just as well by someone else. Following that mantra enabled this company to grow in 10 short years from approximately $80 million in sales and $300 million in enterprise value, as of its birth in a management buy-out in 1997, to $909 million in net sales and over $4 billion in market value (at year-end 2006). All this while, Endo did not stray from its outsourcing model, maintaining only a small core group of employees responsible for strategic alliance management, regulatory strategy, clinical supervision, and financial control.  

Outsourcing all noncore business functions, including manufacturing, clinical drug development, and distribution, Endo Pharmaceuticals now boasts of annual commercial revenues per non-field sales employee exceeding $2 million. Its core corporate employees work and operate out of a leased corporate office complex that the landlord has expanded, building by building, as the company has prospered. 

Today, 100% of the company revenue is alliance-dependent. John Buckingham, Endo's senior VP of alliance management, elaborating on the semi-virtual model says, "Companies that pursue a business alliance model are better suited to address current biopharm market opportunities because of the flexibility that it affords. The alliance model is not just for companies that have no options, and many biopharm executives wrongly perceive alliances in that way. The notion that when a company is small, it is making significant compromises by partnering, or that a company should get into partnerships only to survive, could not be further from the truth."  

Endo firmly believes that alliances are not a desperate last option, but rather a great first option and a good model to follow, no matter what the company's size or stage of development is. It's the exact opposite approach taken in the fully integrated pharma company model, or what others have called the smokestack mentality of wanting to have absolute control over everything, from discovery to distribution. Buckingham goes on to describe the Endo approach, "We are going to go out there and partner with the best people and the best companies in the industry. We will pay for access to expertise and resources as they are needed, but we will not pay for them when we do not need them. While we have core competencies in business strategy, product development, finance, legal affairs, and commercialization, outside of our full-time sales force, the only significant infrastructure that Endo has developed is an infrastructure for accessing external technology, which is second to none." 

In the model adopted by Endo, every link on the value-added chain can be open to the outside world (see Figure 1). The company determined early on that to be successful in the tough world of lower-cost marketing and sales programs in the smaller markets that are treated by narrow specialties of physicians, it would have to employ a full-time, dedicated sales force as a core capability. But in all other areas, Endo's employees would become project management specialists, managing the drug development, manufacturing, and distribution process through the use of multiple, specialized outsourcing service providers.  

Figure 1.  In the virtual-company model every link on the value-added chain can be open to the outside world. Adapted from Dr. Gene Slowinskis book, Reinventing Corporate Growth, 2005.			

Building Your Own Specialized Outsource Partner

For distribution, Endo doesn't own a single warehouse or shipping pallet, or employ any customer service telephone representatives. It relies completely on UPS Supply Chain Solutions to distribute its new and existing products to market. Unfortunately for Endo, it wasn't able to just step into a smoothly running turnkey operation. In 1997, few specialized outsourcing service providers in the distribution area were equipped to grow the shipment volume of highly regulated opioid pain therapies that the company began operations with after its management buyout.  

Daniel J. Carbery, an executive who came on board at Endo in its early days and who is now the senior VP of operations, stepped up to the challenge. He developed a supply chain that had incredible restrictions because of its special governmental requirements for close monitoring of narcotic drugs all along the supply chain. At the same time, Carbery had to figure out a way for Endo not to stray from its semi-virtual model. The new company needed a way to track orders, monitor outgoing shipments, and get paid for its products. It also needed real-time contact with its customers in the retail pharmacy, wholesaler, and physician market spaces. For some of its products, Endo needed a flexible storage and transportation system that could house and ship injectables in a cold chain environment. "We knew what we wanted, but there were no companies with both full-service systems and adequate flexibility available," says Carbery. "So, we worked with UPS Supply Chain Solutions to create a flexible, scalable, and highly integrated distribution system," recalls Carbery. "We couldn't afford to internalize or recreate such an operation on our own. And the reality is that we didn't want to." 

Everything in a semi-virtual company is tied to flexibility—the ability to rapidly scale up and down in response to changing business circumstances. Endo's complex supply chain is designed to suit its need to retain maximum scalability in the event of serendipitous in-licensing deals, which can suddenly drop the company into new markets with new product introductions. Carbery describes his semi-fixed system arrangement with UPS that assures scalability, "You've heard of playing in the same sandbox as someone else? We rent our own 'sandbox' from UPS. It's a dedicated space where our product orders are fulfilled, products are picked, packed, and labeled, and all documents are recorded." 

To make it all work, Carbery says he consciously has brought in a very different kind of operations employee group into Endo. He screened his hires to have an alliance-engaged mindset about making little differentiation between own-company employees (very few) and extended partner virtual employees (hundreds). His group speaks with UPS employees frequently and involves UPS in its preparations for new product introductions.   

One success story in this semi-virtual network partnership involved expert shuffling of product in a record short time during a recent licensing deal. According to Carbery, "We have six  branded products plus generics in the pipeline, and in past years have launched two on very short notice due to late stage in-license agreements. In 30 days, we not only owned the license to sell the drug, but also on the day the deal closed we had to start shipping, even though the product was still in somebody else's warehouse. Endo moved the product to its UPS-owned warehouse, conducted quality control checks, re-released it, and started shipping by 3 p.m. the same day. It's the rapid-response supply chain equivalent to buying a house and bringing your moving van along to the closing. The flexibility that our outsourcing partners give us to ramp up and down is incredible."  

Can a CRO be an Alliance Partner Rather Than a Supplier? 

In mid-2005, Endo began yet another outsourcing initiative that challenged the norms of the industry. Instead of building its own clinical operations infrastructure to meet the growing demands of its development pipeline, Endo decided to move in the other direction. It defined its core capabilities as designing clinical programs and studies and interpreting the resulting data. Endo then sought a well-qualified partner to perform all the necessary implementation work to place and conduct the studies and collect the resulting data. The result was an alliance relationship with PPD, Inc., a premier CRO. This was different from the typical industry approach of establishing a CRO relationship where the CRO is simply a preferred and qualified bidder. The company's goal was to find a forward-thinking CRO as an alliance partner becoming the only provider. 

Biopharm companies have many vendor relationships with CROs that seem to work, so why take it further and lock oneself into one CRO as an alliance partner? The answer is clear to any biopharm company that has used CRO services, and knows these services have almost become commoditized, limiting the relationship and the output to a one-time profit opportunity for the CRO. Roland Gerritsen van der Hoop, MD,  Endo's senior VP of R&D and regulatory affairs, explains, "We were looking for an extension of Endo, with a CRO providing dedicated resources that would be more efficient in training, and more Endo-aligned. Our goal in this initiative was to reduce planning and start-up time; we knew there could be closer involvement in our in-house budget process that would yield better planning for both. Also, a CRO as partner could produce better product development and lifecycle management plans, help prepare better evaluations for new in-licensing candidates, and even connect us more quickly to potential in-licensing opportunities."  

The result was the establishment of a mutually committed relationship with PPD for top-tier design and execution of clinical development programs. Although too early to tell, the relationship should at the very least soon produce some short-term benefits for Endo. Dr. Gerritsen van der Hoop continues, "For Endo this could mean no more involvement in day-to-day study activities, such as monitoring sites, compiling progress reports, or resolving queries. Instead, Endo's core development staff should potentially be freed to drive significant innovation for the company by focusing much more on interpreting data; thinking of, formulating, and programming additional in-depth analyses; improving study designs; providing input in discussion sections of reports or clinical sections of submissions; and contributing to acquiring technology for the company through due diligence assessments for in-licensing." 

There have been continual challenges associated with implementing a new and innovative approach, particularly with this preferred provider arrangement. Endo is a young, high-growth company. At least 40% of its employees have been at the company for fewer than three years. Many of them come fresh from a traditional environment where the CRO is treated as a supplier, not embraced as a partner. A change of perspective is ongoing in which Endo managers are retrained to hand off responsibility to the CRO so it can use its experience and best practices, rather than dictate to the CRO exactly how the clinical trial is to be conducted. This also requires a change in perspective on the CRO's side, so that it stands firm on its charge of steering the direction of the project, and insists, like a partner but unlike a supplier, that it knows what needs to be done and will implement its own industry-leading processes. Finally, a built-in small–versus–large organization culture clash exists that must be overcome. Endo is a small company, focused on a limited number of projects, while most CROs are large organizations with a pool of talented project managers that to some degree will be constantly circulating in and out of the projects to implement the clinical activities. These and other challenges may be quite difficult in the short run, but Endo sees it as an opportunity to build trust, and learn a lot about new models of partnership in the long run. 

Re-engineering the virtual outsourcing model has radically transformed Endo's product pipeline in less than 10 years, and produced a fifteen-fold increase in market value for the company since 1997. Numbers like these are the result of senior management sticking to its fundamental realization that no single firm has the resources to do everything. Endo's extreme version of semi-virtual partnering is catching its share of attention too. At the beginning of 2007, the company was recognized with an Honorable Mention award by the Association of Strategic Alliance Professionals (ASAP) Corporate Alliance Excellence Awards. Endo was cited for its role in changing the traditional model of the biopharm industry to one that is heavily reliant on effective alliance management practices at all points along the value chain. Perhaps this model shows just how an extreme outsourcing structure can continue to produce results over the long term. More importantly, it demonstrates that by not taking on layers of internal infrastructure, a company can maintain flexibility and ability to rapidly scale up and down to adapt to a changing scientific and commercial environment. 

 is senior director of alliance management at Endo Pharmaceuticals, Inc., Chadds Ford, PA, 610.558.9800, 

Partnering with a surging number of CROs, CMOs, CSOs, and other niche providers, biopharm companies in 2007 will have an estimated spend of more than $7 billion on international clinical trial outsourcing alone.

Outsourcing Virtually Everything: Making the Semi-Virtual Model Work

One result of the new European clinical trials directive

  has been more outsourcing of the manufacturing of clinical trial materials. These materials must meet current Good Manufacturing Practice (cGMP) requirements, which leads one to use the services of a contract manufacturing organization (CMO). Choosing the CMO who will become your partner for clinical trials manufacturing can be a time-consuming process. Finding a CMO with the appropriate combination of experience, reliability, reputation, and skilled staff, who can accommodate your manufacturing requirements in terms of scale, schedule, and cost, can be a daunting task. This article is a guide to smooth the road to the clinic.

Few companies nowadays build their own cGMP manufacturing facilities for clinical trials materials because the cost of building and maintaining such a facility can be prohibitive. It is far easier (and cheaper) to outsource this element of therapeutic development. Not only does it avoid expensive outlays on special equipment and staff, but also it allows companies to benefit from the variety and range of experiences built up by CMOs.  

Working early with a CMO in the preclinical development phase can reap huge rewards. Close collaboration and consultation early on with an experienced manufacturing partner can actually help direct your efforts during preclinical development, and avoid unnecessary delays in progress to the clinical trials stage. 

The first critical step on the way to take a therapeutic candidate into clinical trials is to draw a road map. Even a simple Gantt chart will formulate a preliminary schedule for preparing cell and viral banks, followed by manufacture of the clinical trial material, leading to safety testing of that material, and ultimately, the delivery and administration of that material at the clinical trial site. 

Firm up the schedule by considering the critical milestones within the various activities outlined. For example, funding of the clinical trial may be provided in a phased manner, and may be contingent on the success of the previous milestone. In a typical contract, funding may be available for the initial cGMP manufacture of the cell and viral banks, but the funding for the activities that come later in the schedule may not be released until those banks are fully tested and released by the CMO. Therefore, establishing which parts of the manufacturing program are on the critical path is an important exercise and should be performed early in the planning stages. 

Work with your CMO to agree on the critical schedules and milestones. Make use of their project management skills, which will help both parties understand what must be done, and crucially, by what date to deliver material to the clinic. 

Explore the following factors with the CMO to ensure that all regulatory, quality, and logistical implications are considered in the manufacturing of clinical trail material: 					

Taking each of these factors in turn will be instructive. 

The size of the trial will have a bearing on the scale of manufacturing that will be required. This is probably the most important topic to discuss with your chosen CMO as early as possible in discussions about manufacturing. Consider the number of patients in the trial, the dose that each will receive (and how this dose is calculated), the number of doses that will be administered to each patient, and what overage needs to be built in (to allow for vial breakage during transit or in the hands of the clinician).  

Once the CMO knows how many doses it must deliver for the actual trial, the project manager can factor in how much additional material must be manufactured to allow for product testing requirements. When the total volume required has been determined, the CMO can advise on the most suitable manufacturing strategy to deliver the requisite amount. At this stage, you should also discuss the placebo requirements for the clinical trial (as these must also be made according to cGMP guidelines). 

Depending on which country (or countries) the clinical trial is due to take place in, there may be varying regulations surrounding the testing that must be performed on the clinical trial material. This can have a bearing on the manufacturing process. 

Certain tests may be performed on the final product in the form in which it would be delivered to the clinic (i.e., the final product containers). However, other tests will be required on the raw materials that go into the manufacture of the clinical trial material. The possible items are a long list: the cell bank, viral seed stock, viral bank, cell culture media, reagents, fetal bovine serum, downstream purification buffers, and formulation buffers.  

Some tests will also be performed on the bulk in-process material before its final processing and filling. This means that the scale of manufacturing must be sufficiently large to yield enough material for the clinical trial and also any attendant testing. 

Location can also have implications for the shipping logistics that will be involved in delivering material to the clinical trial site. These are good questions to consider: 					

Under what conditions will the material be stored? 

Will it be lyophilized and stable at room temperature? 

What validation will be required to prove that shipping and storage conditions are not having deleterious effects on the clinical trial material? 

What will be the ambient temperature conditions, depending on what country the trial is taking place in?

What distribution channels are available to ensure safe, efficient delivery of intact, functional clinical trial material?

Estimate the duration of the clinical trial so that you can develop the right kind of stability study. This study provides supporting data for the functionality of the clinical trial material over the length of time that the investigational medicinal drug product will be held in storage before administration to the patient.  

Schedule for Conducting the Clinical Trial

The target date for starting clinical testing is crucial. Work closely with the CMO to ensure you both agree on target date for delivering released product. You must also establish if the clinical trial date is a fixed date or if it is flexible. The start date may change if you need to wait until sufficient patient numbers are recruited into the trial, or if there is a delay in funding for the next milestone in the clinical development program. If the clinical trial date is not firmly fixed, you must consider the duration of the stability study that will be required to ensure that the latest possible date for patient administration will be covered by the supporting evidence. 

Another crucial element of the clinical trial design for you and your CMO to discuss is how the investigational medicinal drug product will be administered to the patient. Is the CMO expected to provide the clinical trial material in the final dosage form, or will they simply manufacture the product to the stage of bulk drug substance for delivery to another company, or back to the sponsor, for the final formulation and filling stage? 

Hold detailed discussions at this stage to determine the specification for the final product container, and how the CMO will ensure that the correct dose will be present in each container. For example, if a specific viral titer is to be delivered to each patient, how accurate will the volume be that is dispensed into each container, and has the extractable volume of the container been determined? If the clinical trial material is a liquid supplied in a glass vial, ask how much material will be left in the vial and in the holding volume in the syringe once the clinician has extracted the liquid from the vial. 

If the trial is to take the form of a prime and boost delivery, then take appropriate measures to ensure that the stability study covers this lag phase between the first and last doses. Obviously, the manufacturing scale will also have to be larger if more than one dose is required per patient. 

An area often overlooked in considering the final product container is the issue of filling validation. If the clinical trial material is to be supplied by the CMO in its final dosage form, then the CMO must undertake a filling validation to provide assurance that it is able to fill the requisite number of containers in an aseptic manner. The validation must also demonstrate that the correct volume of product is dispensed into each container, within an agreed and defined tolerance level.   

Conflicting Demands of Robustness and Speed

There are always lively discussions between process development professionals and those on the business side who are overseeing the clinical development. It is understandable that the sponsoring company will be anxious to deliver the clinical trial material to the clinic as fast as possible. Many biopharmaceutical companies' entire business model is based on speeding a therapeutic candidate into the clinic as quickly as possible to establish the safety of the product and to confirm proof of principle, with the intention of partnering with a larger pharmaceutical organization to take the candidate forward into later-phase clinical trials (and hopefully through to commercial manufacture). 

Compounding this need for speed is the fact that regulatory authorities do not insist on manufacturing early-phase clinical trial material using a fully validated manufacturing method. Everyone knows that validation will need to be performed for later-phase clinical trials (and certainly for commercial manufacture), but it can be tempting to avoid any extraneous expense and time in process development for a Phase 1 clinical trial.  

The antidote is to use the services of the Qualified Person (QP) within the CMO to prepare for a clinical trial. The QP will help ensure that compliance is built into the manufacturing process for clinical trial material and avoid any nasty surprises with the regulators. The QP can advise on whether the proposed manufacturing strategy and proposed design of the clinical trial will be likely to be acceptable to the regulatory authorities.  

Working with a QP will ensure that the trial design and manufacturing are appropriate for the stage that the therapeutic candidate has reached. The payoff is that you avoid any nightmare scenarios in which a sponsor has gone through cGMP manufacture of clinical trial material, but regulators have picked up some issue with regard to manufacturing, testing, or packaging that cannot be resolved. In the worst case, this could lead to the need to remanufacture the whole clinical trial investigational medicinal drug product, which would be a catastrophic waste of money and time.  

 is a commercial scientist at BioReliance, Ltd., Glasgow, UK, +44.(0).141.579.3265, 

Consider the number of patients, the dose each will receive (and how this dose is calculated), the number of doses per patient, and what overage is needed to allow for vial breakage.

Successful Steps for Outsourcing the Manufacture of Clinical Trials Materials

Sales of biopharmaceuticals are projected to grow at a rapid pace over the next few years. Biological products are expected to account for 60% of revenue growth for large pharmaceutical companies by 2010, with annual sales increasing by $26 billion, compared to a $13 billion increase for small molecules.

  Meeting the production capacity for this remarkable expansion, however, will have many companies, large and small, competing for solutions. Although several large drug companies have built up manufacturing capacity in anticipation of future growth, small- to mid-size biotechnology companies may be left exposed to fluctuations in demand, a shortfall of skilled labor, or a lack of flexibility in adapting to new technologies and regulatory demands. Smaller companies may simply remain behind the curve of anticipated demand. One solution lies in using outsourced expertise to rapidly adjust to changes in production requirements, to improve efficiencies, and ultimately to transfer this expertise in-house. In fact, a survey conducted in 2004 showed that 35% of companies with biologics outsourced at least some of their production, and the survey predicted that this number will increase to 47% by 2008.

  This article examines some of the emerging trends and strategies for meeting anticipated growth through outsourcing, particularly among smaller companies that focus their core competencies on discovery, and that lack their own infrastructure for product manufacturing and development. 

The areas of greatest need for outsourcing in the biopharmaceutical sector include drug substance and drug product manufacturing, preclinical biology, regulatory oversight, and first-in-human studies. The foremost challenge for emerging companies is drug substance and drug product manufacturing, followed by the rest of the critical path activities that lead to Phase 1 clinical development.  

Discovery-based organizations' core expertise is the ability to decipher biological pathways, to identify disease targets, and to develop novel drug candidates. These companies are able to make small quantities of their lead compounds; to take a drug into Phase 1 and Phase 2 clinical development, however, they must dramatically increase the scale of production under good manufacturing practice conditions. This step is extremely resource-intensive, and it is a step that most small companies cannot manage independently because it is a distraction from their core competencies.  

Emerging and mid-size companies have a number of choices when considering how to ramp up production of a drug candidate. Outsourcing to multiple vendors does not, by itself, protect these companies from wasteful and costly inefficiencies in development and manufacturing if the project is not managed properly by the skilled staff. To help smaller companies navigate these complexities, experienced consultants have taken an increasingly prominent role in shepherding biopharmaceutical or pharmaceutical products through the manufacturing and development processes, as well as in coordinating relationships among companies and their vendors. Consultants can help emerging companies realize greater efficiencies, speed development, and generate the quality of material needed for reliable preclinical and clinical safety and efficacy studies. Getting it right the first time adds long-term value to a project. 

Consultants can help biopharmaceutical companies and their boards understand the complexities of manufacturing systems, thereby minimizing mistakes that a company might make if it tries to do it alone. Biological manufacturing is an area where depth and breadth of expertise is commonly scarce at small companies. A company that deals directly with multiple vendors, without the benefit of a knowledgeable and experienced consultant, risks the expensive prospect of having to repeat its efforts as it endeavors to generate well-characterized biologics and meet regulatory requirements. Investing early and gaining access to consultants with hands-on drug development expertise is vital to achieving best practices on the first attempt. 

The greatest benefits of outsourcing as a whole are realized when a company takes a strategic rather than a tactical approach. Using a strategic approach, a company can team up with a vendor that provides a full suite of services—including manufacturing, preclinical, or clinical development—to develop integrated knowledge and technology around a product, and to eliminate the need to transfer this knowledge and technology among numerous vendors. By becoming involved early, a comprehensive drug development outsourcing firm can engage its scientists in preclinical safety and efficacy tests, and in formulation and manufacturing of the product, thus saving precious time and effort, and helping the company realize the synergies among each of these stages. Consultants can further streamline the process by identifying an appropriate vendor, solving problems, and managing timelines and budgets. 

A strategic outsourcing approach is particularly important for any project that requires substantial product knowledge and access to many chemical, biological, and clinical skills to drive the project through agreed-upon milestones. Small companies typically choose to deal with multiple vendors for development, manufacturing, preclinical, regulatory, logistics, and other services; this often leads to higher costs, mistakes, longer timelines, and higher risks. Companies should seek outsourcing partners that can provide a substantial number of development tasks internally, to reduce risk, time, and expenditure. 

Shared-Risk Relationships and Incentive-Based Relationships

One example of the strategic approach involves making outsourcing interaction either a shared-risk relationship or an incentive-based relationship. The outsourcing vendor presented with a lead compound must do the following: identify how best to formulate it, recognize the most stable form, determine how to scale up production, run preclinical and clinical programs, and guide development through to regulatory approval. The sponsoring company will commit this project to the outsourcing vendor as long as the compound remains viable. If the vendor can shepherd the novel compound through the development process to the agreed-upon accelerated milestones, it will be offered a reward. For example, if compressing the development timeline leads to $100 million in savings and recovered opportunity costs, the outsourcing vendor might be offered a bonus equivalent to 10% of that amount. Strategic outsourcing of this kind provides incentive for the vendor to identify efficiencies along the entire product development timeline. In other cases, the outsourcing firm may be responsible for all manufacturing and supply chain management of a sponsoring company's compound, ensuring that preclinical and clinical studies for various indications are adequately supplied, while avoiding oversupply.  

Strategic outsourcing exemplifies a "big picture" view of the outsourcing relationship. Rather than focusing on tactical requirements that may change with the ebb and flow of product development, the strategic relationship motivates the outsourcing vendor to realize efficiencies along a much larger segment of the research and development value chain. 

Perspectives on the value of strategic outsourcing can vary widely within a sponsoring company. Mid-level managers may have different concerns than executives have. For example, mid-level managers tend to outsource tactically; often, they do so because they are experiencing temporary shortfalls in capacity and need to augment their in-house efforts. These individuals may avoid long-term strategic approaches, especially if they perceive these approaches as threats to their roles in the company. A procurement person typically is driven to find the best price for a service and might not have a strategic view of the overall time- and cost-savings of outsourcing. A vice president of development, a CEO, or a CFO, on the other hand, often will have a better understanding of the objective of getting a compound through the approval process and to market as quickly and economically as possible. If an outsourcing vendor demonstrates a way to get the product to market six months faster, but with a 10% higher expense, the time saved probably more than compensates for the added upfront expense.  

To ensure a successful outsourcing relationship with various interests within an organization, two or three external consultants might work closely with the company, perhaps joining the internal project team. Having an internal champion within the sponsoring company can be crucial to success. This champion can serve as a liaison among consultants, the vendor, and the company.  

The sponsoring company also must understand that although integrated services provided by a single outsourcing partner may be more expensive than services "cherry picked" from multiple vendors, the upfront investment will probably deliver greater returns downstream (for example, by bringing the product to Phase 1 and beyond more quickly and economically). In drug development, time is typically more important than money. Speed, flexibility, expertise, and innovation have their own currencies, and these must be weighed against costs.  

The trend in the industry today has been for pharmaceutical and biotechnology companies to consolidate outsourcing among fewer vendors—a trend that offers several key advantages. By consolidating outsourcing strategies around the full development of a compound, small- to mid-size biotechnology and small molecule companies can focus on their core competency: the discovery process. An experienced consultant, who can manage manufacturing through preclinical and clinical development using a limited number of external vendors, is able to build a repertoire of knowledge and experience around the compound. Even for a company with in-house manufacturing and supply chain capability, outsourcing the entire development of a compound enables a vendor to help the sponsoring company realize gains in efficiency, cost savings, and timeline management—greater gains than if the vendor had been assigned only pieces of the project. Working with fewer vendors also helps minimize the time-consuming task of transferring knowledge among multiple vendors. 

Continued consolidation of the pharmaceutical market will present challenges to contract service organizations. In recent years, the demand for manufacturing and development has fluctuated between feast and famine. Going forward, it is of paramount importance that each vendor develop a portfolio of projects to spread its own risk. In the past, vendor portfolio diversification was difficult to achieve. Now, however, the projected increase in the number of drugs moving toward commercialization suggests that the biopharmaceutical outsourcing market will stabilize and grow. Smart vendors that provide a suite of services, from manufacturing through clinical development, will survive consolidation, build a diverse portfolio of clients and projects, and establish a rich pool of knowledge and expertise.  

The value proposition of outsourcing has not only caught the attention of the pharmaceutical and biotechnology sector, but of the investment community as well. Investors have become more savvy about corporate evolution and about the role of outsourcing in leveraging and protecting core competencies. They recognize that as nascent companies, staffed with a handful of very bright discovery scientists, approach milestones requiring increased production of drugs and delivery of clinical results, the mere act of investing in internal development skills can be daunting and disruptive to an organization focused on new drug discovery. For emerging companies that need to respond rapidly to pipeline needs, to mitigate risk, and to focus on discovery, outsourcing development to consulting groups and service organizations has become a logical move.  

Many pharmaceutical and biological products originate from truly innovative discovery-focused companies with little internal development expertise. External consultants with broad hands-on drug development experience, and contract service organizations with full suites of drug development services, will play a central role in managing the projected expansion and commercialization of biopharmaceutical products over the next ten years. 

, is managing director at Aptuit Consulting, Lexington, MA, 978.456.9975, 

 1. Big pharma turns to biologics for growth to 2010. London: Datamonitor; 2006.  

 2. Langer ES, editor. Advances in large-scale biopharmaceutical manufacturing and scale-up production. Washington, DC: American Society for Microbiology and the Institute for Science and Technology Management; 2004.

The greatest benefits of outsourcing are realized when a company takes a strategic approach rather than a tactical approach.

Outsourcing: What is the Path Forward?

Contract manufacturing became popular in many industries during the 1990s as a way to meet rising costs and to retool. The pharmaceutical industry has been slow to adopt this practice because of its absolute need for secrecy. 

However, with fewer blockbuster drugs in the pipeline, companies are on the lookout for an enduring solution to meet market challenges. These include rising process costs resulting from stricter quality control criteria, evolving technologies, which are becoming more complex and costly, and the increasing stringency of regulatory standards. To maintain or expand market shares, pharmaceutical companies must devise new strategies to remain competitive.  

Finding a suitable contract manufacturer is one of the most viable options. It allows the pharmaceutical company to focus on research and development and marketing, while the contract manufacturer takes care of the manufacturing process, including validation, support for license application, and packaging. In addition, outsourcing can be scheduled into the strategic planning of a drug's lifecycle. Typically, a company contracts with a partner with the necessary facilities and experience during the early development phases. Finding the proper partner can be time-consuming, because it requires careful screening and assurance that the prospect has the right  know-how and experience: How long has a contract manufacturer been in the business? What kind of work has it  done? What kind of drugs? The more experience it has, the smoother the collaboration.  

The manufacturing processes involved in filling syringes, vials, and cartridges is one of the most complex and difficult procedures in the pharmaceutical world and exemplifies the requirements for a successful partnership. If a company intends to put a parenteral drug on the market, the entire manufacturing process becomes an excellent candidate for outsourcing. The process is costly, involves a wide range of procedures, and requires a company with a great deal of experience. Manufacturing parenterals involves such steps as matching the product's active substance with its mode of administration, process development, and transfer to commercial manufacturing. There are several keys to success in outsourcing: be sure to include requirements for future commercial manufacturing in the initial development phase; develop a precise project plan with a competent project management team; and adhere to a sound filing strategy to speed up time to market.  

Most pharmaceutical companies, but especially the smaller biotech firms that produce niche drugs, do not have the capacity or financial strength to maintain—much less build—capacities for manufacturing. This is especially true in light of today's regulatory constraints. The contract manufacturer will have to fulfill a number of important criteria, including extensive knowledge of aseptic filling from development to commercial manufacturing, knowledge of validation procedures, an excellent relationship with regulators, and even knowledge of marketing. 

Beyond these basic criteria, what else makes a good contract manufacturer? The facility itself must be state-of-the-art, so it can provide the highest quality work, which in turn facilitates validation. It needs laboratories and an elaborate concept for clean rooms. For example, up-to-date technology for performing aseptic filling, such as lines equipped with a restricted access barrier system, is an advantage for several reasons: it is the safest available and offers great flexibility in filling; it shows that the contract manufacturer is on the front lines of innovation in the business. The contract manufacturer must also have sufficient capacity so it can absorb a possible surge in demand, and it must have back-up capability, in case of a power failure or other possible events. Filling facilities must be equipped with an effective back-up power supply, a reliable supply of spare parts, in-house engineering capabilities, media supplies, and so on. A very conscientious contract manufacturer might even have more than one supplier, in case one cannot provide for some reason. Furthermore, having additional filling lines does not suffice for total reliability: Back-up filling lines must be at another location several miles away in the event of a catastrophic event.  

If a contractor has the capacity and safety through back-up systems, it is important to find out what additional  services and solutions are offered. The most efficient option is a program that starts with support in product development and considers the lifecycle management of the drug. The contract manufacturer will ideally offer various options in primary and secondary packaging, which can reduce time to market of a drug, removing some of the burden from the drug manufacturer. 

The available portfolio of solutions is critical. A contract manufacturer with a full range of products will possess the necessary flexibility to address the needs of the market. A basic portfolio should include single-chamber syringes, vials, and cartridges. Any additional, innovative products are a plus, such as tracking systems that allow a product to be traced from the filling line to the patient, and antitampering solutions. These are especially important in life-cycle management. If a lyophilized drug is to hit the market fast in a first cycle, it will probably be in a vial. For the second cycle—depending on the product—the drug company may opt for a more patient-friendly form like a dual-chamber syringe or cartridge. A viable contract manufacturer will have these capabilities on hand. Lifecycle management is an aspect that should not be underestimated: if planned early enough, it can mean the success of a drug against upcoming competition.  

Assuming a candidate company fulfills all of the "hard" criteria, there remains a number of other areas to consider: Know-how and experience in manufacturing must be just as up-to-date as the facilities, and well trained teams of scientists and engineers are a must. They ensure a competent and creative approach to solving problems. They also contribute to speeding up time-to-market. A well-versed team can work more efficiently; it has complete checklists for all processes and can organize each element so that no time is wasted. 

Another criterion for a good contract manufacturer is the company's market reach. How positioned is it internationally? The pharmaceutical industry in each country has its own regulatory systems and its own national specifications. But if a contract manufacturer has already filed for drugs sold globally, it is safe to assume that it has integrated its experience into its processes. Furthermore, it already will have established a solid working relationship with regulatory authorities. This can save a lot of time and effort when it comes to validation and seeking approvals.  

Having documented approvals by international regulatory agencies, such as the Food and Drug Administration (FDA), the European Agency for the Evaluation of Medicinal Products (EMEA), and other authorities is essential, especially if a drug company is trying to reach an international market. It is just one more element that can chip away at time to market, which can save a drug company a fair amount of money. 

The financial stability of a potential contract manufacturer is crucial, and somewhat related to the need for back-up. Manufacturing a drug is not a one-shot event, or a brief one. In the best-case scenario, a drug can take less than 12 months from first feasibility and process development to commercial manufacturing. In other words, a drug company is looking at a long-term relationship with the contract manufacturer. It should be able to show that it has independent financial staying power. A contract manufacturer with a history of organic, consistent growth generally proves to be a strong ally.  

Manufacturing drugs, especially new, innovative, "high-tech" substances, involves considerable risks, first and foremost, financial: Will the drug be a success? Establishing a productive and balanced relationship with a contract manufacturer means sharing possible risks. It involves regulating scenarios in the event of a boom, or, should the product encounter problems, slowing, or even halting, production. The contract manufacturer should have the experience, which reduces trial and error. Once the product is launched, the contractor is responsible for harmonizing production and demand.  

Adopting a sustainable outsourcing strategy can lead to a perfect win-win situation, but it also requires an investment from both parties. A contract manufacturer needs the experience to be flexible and innovative. Integrated management is required to make sure each project is being handled properly and that communication channels are open. Regular planning sessions must be held to ensure that each party is fully informed of any potential roadblocks. All processes carried out by each party must be carefully documented. One of the best ways to keep track of a project's progress is to jointly establish performance measures that can be easily quantified using objective data And because the pharmaceutical company will be sharing confidential data, the true core of any partnership is trust. 

Outsourcing is an important strategy in the pharmaceutical industry to meet the growing number of challenges. Because the outsourcing relationship is long-term, it influences future lifecycles of a drug and requires investments of time and money. It is a fundamental decision that must be made in the early phases of a drug's development, when there is time to find the right partner and develop a strong relationship. A good contract manufacturer provides the necessary support throughout all stages of a drug's development. It gives the pharmaceutical company the time and resources to focus on its core business—researching and developing lifesaving drugs and marketing them. 

 is a managing director at Vetter Pharma-Fertigung GmbH & Co. KG, Ravensburg, Germany, +49.751.3700.0. 

The contract manufacturer must have sufficient capacity so it can absorb possible surge in demand, and back-up capability in case of a power failure or other event.

Match.Contractmanufacturing: Finding The Perfect Match

A tremendous amount of analytical testing is required to support a biopharmaceutical product from discovery, development, and clinical trials, through manufacturing and marketing. Numerous methods are used to fully characterize large molecules because of their complexity—characterizing them is significantly more difficult than it is for small molecules. Biopharmaceuticals are produced via living systems, i.e., E. coli, yeast, or mammalian cells, which require additional testing matrices. Further, FDA requires orthogonal techniques when available to better reveal the structure and stability of a biopharmaceutical. Currently, more than half of the drug candidates in the discovery stage are biologics, including proteins, peptides, monoclonal antibodies, etc. As the overall number of these large molecules in the pipeline increases, many drug manufacturers may need to consider outsourcing portions of their analytical testing to fill voids in capacity or to meet timelines. This article describes some of the analytical methods used to support a typical biopharmaceutical product throughout its lifecycle from discovery and early development through stability and release testing. Table 1 lists some of the techniques commonly applied to biopharmaceuticals.

Biologics or biopharmaceuticals are inherently more complex than small-molecule drugs. For example, the cholesterol-lowering medicine simvastatin can be identified and fully characterized using a relatively small number of tests because of the drug's well-defined structure (C

) and associated molecular weight of 418.5722 daltons. However, biologics such as proteins can be thousands of times more massive (typical antibody molecular weight is ~150 kDa), with secondary and higher order structures. Additionally, there is the potential for molecular aggregation. The impact of the protein's structure on therapeutic efficacy and safety must be evaluated and the researcher must use various analytical tools to characterize these structures. For example, the primary structure of a protein is the specific amino acid sequence that makes up the peptide chains. This is typically determined using a technique such as high-performance liquid chromatography (HPLC).  

Table 1. Common analytical techniques used for biopharmaceuticals testing			

The folding of peptide chains into α-helices, β-sheets, and random coils in a protein defines its secondary structure. Fourier-transform infrared spectroscopy (FTIR) can be used to obtain secondary structure information by analyzing the amide bands. This can be used in conjunction with circular dichroism spectroscopy (CD). Therapeutic proteins and antibodies also are commonly glycosylated or PEGylated. This is the term used when proteins are modified or conjugated by attaching carbohydrates (glycosylated) or synthetic polyethylene glycol (PEG) to them. This results in different properties of the resulting product and greatly increases the challenge of fully characterizing the structure. Liquid chromatography or mass spectrometry (LC-MS) may be required to obtain a complete picture of the structure.  

During the discovery phase, some unique analytical tools are used. DNA microarrays can be used to identify disease genes and show how they respond to drugs. The 3-D structure of proteins can be studied for binding sites using X-ray crystallography and NMR spectroscopy. Luminescence and fluorescence-based assays are developed to monitor specific aspects, such as binding, signaling, and other drug-receptor or enzyme interactions. Immunogenicity testing and G-protein coupled receptors (GPCR) assays may be carried out here.  

Validation Through the Product Lifecycle			

Based on the results of these studies, successful drug candidates may move into early development or preclinical activities, which emphasize safety and efficacy. Assays to support pharmacodynamics (PD), pharmacokinetics (PK), and toxicity with preclinical GLP animal studies are used.  

In conjunction with the more expensive and lengthy 

 test, such as cytochrome P-450 enzymes and Ames tests are increasingly being applied. P450 enzymes make up a superfamily of hemoproteins with highly diverse functions, including drug metabolism in humans; whereas, the Ames test can be used to determine mutagenic potential of drugs. The goal of these early development studies is to examine the drug in living systems before going to human clinical trials.  

As the drug candidate moves later into the process development phase, assays are needed to support formulation of drug product, including ingredients and excipients. Many excipients have associated methods described in the various compendia: United States Pharmacopoeia (USP), European Pharmacopoeia EP, British Pharmacopoeia (BP), and Japanese Pharmacopoeia (JP); while other will need new methods developed and validated or supplied by the vendor.  

The drug delivery system also has to be developed. Because of stability issues, biopharmaceuticals are typically not formulated as tablets, capsules, or the other more common vehicles used for small, stable, active pharmaceutical ingredients. An area of increasing concern and scrutiny for FDA is the potential adulteration of drug products by extractable and leachable compounds—contamination from the container, closure system, device, etc., that comes into contact with the drug formulation. 

Extractables are compounds that can be extracted from a component under exaggerated conditions such as in the presence of harsh solvents or at elevated temperatures. These compounds have the potential to contaminate the drug product. Leachables are compounds that leach into the drug product formulation from the component as a result of direct contact with the formulation under normal conditions. Leachables are typically a subset of extractables. Sources of these compounds include plastic components, elastomers, coatings, accelerants, antioxidants, inks, and vulcanizing agents. Phthalates are one specific example.  

These potential carcinogens are added to plastics to make them more flexible and can be found throughout the manufacturing process, as well as in packaging materials. Other examples are nitrosamines and polynuclear hydrocarbons (PAHs) which are classes of carcinogenic compounds found in rubber. Many drug products are distributed or administered in packages made of plastic and rubber components, and therefore, phthalates, PAHs, and nitrosamines could potentially come into contact with the drug product and be passed on to the patient.  

Evaluation of extractables and leachables can be an arduous task. Studies must be properly designed, and a wide array of potential contaminants must be screened for using approaches like those described in Table 2.  

Table 2. Testing must be conducted to identify extractables and leachables that may contaminate the drug product.			

Extractables and leachables issues should be addressed early in the process to avoid regulatory delays for the drug manufacturer. The development of unique packaging and delivery systems required for biopharmaceuticals has intensified this issue due to the growing possibilities of "foreign" materials coming into contact with drug products. 

Material will initially be produced on the laboratory scale. As more material is needed for clinical trials, the manufacturing moves to pilot scale. Successful drugs will then progress to a large-scale commercial production environment, and all aspects of this environment must be validated, including water, air, and cleanliness of equipment. 

GMP regulations require the testing of water for injection (WFI) and purified water (PW). An example of the battery of test performed is shown in Table 3.  

Table 3. GMP regulations require testing of water for injection (WFI) for common contaminants.			

During these various phases, cell line selections, cell culture processing, harvesting, and purification are all studied and optimized. GMP regulations require that these processes be validated. Therefore, assays must be developed and large amounts of data must be collected on critical parameters such as purity, contamination, degradation, etc.  

Cleaning validations may also be carried out on equipment, surfaces, etc., to check for residual detergents, product, or microorganisms. In many cases, a simple, nonspecific assay such as total organic carbon (TOC) can be used. However, in other situations, specific analyses (one that can determine the concentration of a specific chemical) are performed using HPLC. Moreover, an increasing number of applications that use single-use or disposables, such as filters, tubing, and bags for biopharmaceuticals can introduce unwanted extractables into the final product. The qualification and quality control of all components coming into contact with the drug formulation has become an integral part of any FDA application process. 

Process validation is a legal requirement in the industry to demonstrate through appropriate testing and documentation that the finished biopharmaceutical produced by a specified process meets all release requirements for quality. Successful process validation requires thorough process development, identification of controlled and critical parameters, and establishment of specifications throughout the process. A minimum of three consecutive lots of product meeting the established quality specifications is necessary to validate a process. Many of the tests described here are used during process validation. These validations may entail collection and testing of large volumes of samples.  

Once the drug is approved there will be ongoing testing to support stability and release of the product. This typically covers critical parameters such as characterization, identity, concentration, purity, excipient testing, potency, sterility, and safety. An example of a specific testing matrix is shown in Table 4.  

Table 4. Ongoing stability and release tests like these are conducted after drug approval.			

In conclusion, an enormous amount of analytical testing is required to support a biopharmaceutical product throughout its lifecycle, from discovery and early development through stability and release testing. Due to their complexity, an extensive number of methods are required to fully characterize them. Many biopharmaceutical organizations may need to consider outsourcing portions of their analytical testing to remain competitive. 

, is the director of Method Development and Validation and Biopharmaceutical Services at Lancaster Laboratories, Lancaster, PA, 717.656.2300, 

A tremendous amount of analytical testing is required to support a biopharmaceutical product from discovery, development, and clinical trials, through manufacturing and marketing. Numerous methods are used to fully characterize large molecules because of their complexity-characterizing them is significantly more difficult than it is for small molecules. Biopharmaceuticals are produced via living systems, i.e., E. coli, yeast, or mammalian cells, which require additional testing matrices.

BioPharm International-04-02-2007

The Importance of Project Management

Outsourcing Virtually Everything: Making the Semi-Virtual Model Work

Successful Steps for Outsourcing the Manufacture of Clinical Trials Materials

Outsourcing: What is the Path Forward?

Match.Contractmanufacturing: Finding The Perfect Match

Analytical Testing to Support Biopharmaceutical Products