SPECIAL FEATURE- Analytical Testing of Biologics & Biosimilars

U.S. demand for biologics is expected to grow 6.5% per year to $102 billion in 2015, up from $74.3 billion in 2011, according to Freedonia Group. On a global scale, the biologic drug market will reach $178.4 billion in 2017, as stated in World Biological Drugs Market 2013-2023. According to the report, in 2012, biologics represented 15% of thea global pharmaceutical market, including seven of the top-10 products. Monoclonal antibodies (mAbs) made up 41% of the 2012 market, fusion proteins 8%, and cellular and regenerative medicines 1%. The remainder of biologics revenues came from a range of protein therapeutics, with insulin and other recombinant hormones the most significant agents.

Also on the horizon are biosimilars, known as follow-on biologics. A growing global market for biosimilars is gaining momentum in response to the expiration of patents for a number of key biologics and consumer demand to reduce treatment costs. Thus, according to Research and Markets, the global biosimilar market, valued at $2 billion in 2012 is projected to reach $19.4 billion by 2018.

Contract manufacturers who can bring biologics and biosimilars to market fast and less expensively will be in great demand. Over the past several years, studies conducted by BioPlan Associates have shown that an increasing number of biomanufacturers, up to 70%, are outsourcing at least some of their bioprocessing activities. BioPlan tested 24 areas of bioprocess outsourcing in its 2013 global study of biomanufacturing. Results from the study indicate that the most commonly outsourced activity is analytical testing because of the need for highly specialized staff and equipment required to perform assays as well as regulatory agencies wanting more characterization and other data about products. On average, facilities outsource 32% of their analytical testing/bioassays (up from 28%) meaning that close to one-third of analytical testing is estimated to be outsourced by the industry.

Analytical testing provides quality, actionable chemical information that ferrets out process impurities, contaminants, and degradants. Several contract providers in this market recently sat down with Drug Development & Delivery Magazine to discuss the importance of outsourcing analytical testing in the biologic/biosimilar space, the associated challenges, and how to ensure the products get to market safely and quickly. Participants in this discussion are: Wayland Rushing, PhD, Senior Scientific Advisor, ABC Labs; James Hurst, Head of Analytical Development at Almac; Shri Thanedar, PhD, CEO and Andrew Kolbert, PhD, Vice President of Technology, Avomeen; Tammy Thompson-Madsen, Pharmaceutical Scientist, BioConvergence; Adam Lambert PhD, Director, Preformulation and Analytical Chemistry, CoreRx, Inc.; Michael J. McDowell, Vice President, Business Development and Project Management, Eurofins Lancaster Laboratories, Inc.; Assad J. Kazeminy, PhD, President and Founder, Irvine Pharmaceutical Services, Inc.; Erik Foehr, PhD, Vice President, Analytical Services for Pacific BioLabs; and Paul Skultety, PhD, Vice President, Pharmaceutical Development Services & Project Management, Xcelience.

Q: What do you consider to be the biggest trend in the analytical testing market?
 

Mr. McDowell: In addition to the ongoing shift in development pipelines from synthetic small molecules to biologics, there is much more diversity in the type of biologic or modality being tested. For example, we are currently supporting monoclonal antibodies, including biosimilars, bi-specific antibodies, fusion proteins, synthetic peptides, therapeutic enzymes, vaccines, gene  therapy, and cell therapy products. This continuing trend toward greater diversity requires a broader set of expertise and equipment to evaluate the quality attributes of the drug.

Dr. Kolbert: The biggest trend in the analytical testing market is who is requesting the testing. Development of methods for assay and release testing is no longer restricted to pharmaceutical companies. Manufacturers of nutraceuticals and supplements are getting pressure from the FDA to qualify their raw materials and provide some level of release testing for their final products. In terms of GMP compliance requirements, we are seeing a much more sophisticated nutraceutical industry that is starting to behave more like pharma. 

Dr. Lambert: Implementation of Quality–by-Design (QbD), and its wider acceptance in the industry is creating a need for more sophisticated means of analysis. At this point, QbD is having a major impact on the work we are performing in the CoreRx analytical laboratories. The amount of work that goes into understanding the impact of different process unit operations on the quality of the finished dosage forms is substantial. Even for a simple direct blend and compression process, understanding the process design space and impact on product quality attributes can require a significant amount of sample analysis. Additionally, application of a QbD approach is leading to the identification of new analytical tools that will ultimately allow for the development of more robust processes. For example, in a granulation process, the characterization of specific granulation/blend attributes and process-related changes may link to the product performance or stability. In the past, these relationships might not have been established due to the approaches taken during the development of the process. Ultimately the application of QbD is leading to better defined manufacturing processes, and a better overall product for the consumer.

Dr. Skultety: The most noticeable trend is that we must continually find ways to do things faster. Greater efficiency in formulation development work has compressed the timelines for the analytical work. We need to get methods developed quicker so we can initiate the stability on the finished product as soon as possible after manufacture is completed. This allows for filing the IND sooner, which in turn can get the clinical study started sooner.

Q: What are the biggest challenges associated with analytical testing of small molecules and biologics?

 Dr. Kazeminy: Some of the biggest challenges associated with analytical testing are timing, customization, and managing remediation of client programs. Our procedures, while compliant, are meant to serve a broad range of customer needs. Clients prefer to have services that are an extension to their own lab and manufacturing procedures. This certainly can be accomplished, but may add time and costs to a program.

Dr. Skultety: The biggest challenge we have seen over the past couple of years is development of appropriate dissolution methods. As the majority of the compounds are only very slightly soluble, it becomes more difficult to develop a method with the appropriate dissolution media that can be discriminating. Another challenge is dealing with the changes in the active ingredient from the early lots to the GMP material. In a number of cases, changes such as new impurities will show up and have to be dealt with as the GMP material is evaluated.

Mr. McDowell: We do not see the level of familiarity and experience with the outsourced molecule from the sponsor that we did in the past. Companies are insourcing more development candidates and outsourcing earlier in the process. When a problem arises during the method establishment phase, the client is less often in a position to help the contract laboratory troubleshoot the method. We have seen that method development expertise is the key component to executing effectively on method transfers and keeping the overall program on schedule.

Mr. Hurst: As a CDMO, the biggest trends we have seen over the last few years are towards more pediatric development and also potent molecule development. These bring with them challenges for the analytical groups that support the product development projects in that they raise new containment challenges as well as the obvious technical challenges of reliably detecting/analyzing increasingly low doses in the associated drug products.

Ms. Thompson-Madsen: In the most general terms, every active pharmaceutical ingredient (API) and presentation is unique, and must be approached on a case-by-case basis. The challenge of testing is to provide an accurate view of a sample at a particular time without bias. Small molecules may be prone to solubility issues, moisture instability or light degradation. Biologics may aggregate, be thermally sensitive, and are generally more complex. It is important to understand each material so it can be properly characterized and not create additional issues with improper sample handling techniques.

Dr. Lambert: Issues ranging from molecule solubility to chemical stability of samples are always possibilities when analyzing small molecule drugs. Most small molecule drugs have their own peculiarities. Even with well-established, validated analytical methods, issues in performing the analysis come up. All aspects of method validation (accuracy, precision, linearity specificity, etc.) can be problematic. The most challenging problems have centered on sensitivity of the analytical methods for detecting degradation products and separation of known impurities. Chemical similarities between the drug and degradation products can often be problematic. Similarities between two or more degradation products can also create difficulties in analysis. For biologics, tying back the analytical results to the biology of the molecule can be one of the more challenging aspects of testing. For biologicals, potency and amount are not always the same, and physicochemical changes observed during the analysis of the molecule do not always impact the potency of the drug. Conversely, structural changes of the molecule, which affect potency, are not always detectable during analysis. What this comes down to is identifying/justifying realistic ranges of analytical results that are meaningful to the drug product being developed. For example, there was a biological product that we developed for a client where large variations in a chromatographic assay were observed, while a protein specific activity assay indicated that no changes were occurring. We were tasked to identity the root cause of the changes and determine which of the two tests was predictive of product stability. Results from this investigation led to the development of a third method for analysis.

Dr. Foehr: Small molecules and biologics have become more complex to study because they are now modified in some way or formulated/delivered in unique ways. Thus, we see a trend of analytical testing of medical devices and combination drug/delivery devices increasing. Pharmaceuticals and medical devices have become increasingly complex. Combination products, delivery devices, and reformulated or re-engineered drugs are more common. These complex products require novel techniques and instrumentation to characterize. For instance, temperature-sensitive polymers can be analyzed using size exclusion chromatography with laser light scattering. Further, special care must be taken to separate and analyze the components in combination products. Sample preparation and extraction require experience and a solid background in chemistry. Multiple assays are required to fully characterize the complex pharmaceuticals.

Dr. Rushing: Small molecule challenges typically revolve around analytical detection and quantitation limits. For biologics, the challenges are more centered on the types of analytical techniques. In comparison to a small molecule (which may have 4-6 analytical methods), a biologic can have easily a dozen or more high-end methods for characterization. These methods are generally specialty methods (Amino acid analysis, Glycan analysis, etc.) requiring specialty instrumentation and technical knowledge. One area that transcends between the groups is leachables resulting from the DP container closure system or from the manufacturing process. This area is garnering a greater level of regulatory scrutiny and is generally not well understand by either pharma companies or the average CRO.

Q: What advantages does an outsource provider offer to pharma with regard to analytical testing of small molecules and biologics?
 

Dr. Foehr: Start-ups may not have had the opportunity to learn from mistakes or successes of other innovators – contract labs share in the experience of a multitude of clients. Therefore, the experienced contract labs can be a tremendous resource to the pharmaceutical industry. As Big Pharma sheds R&D resources and virtual start-ups become the norm, in-house analytical experience and technical capabilities dry up. One of the last pools of experienced, well-resourced chemists is now found in the contract lab sector.

Dr. Thanedar: For a large pharma company, CROs tend to represent additional capacity in testing. Occasionally, in very specialized areas such as metals analysis and extractable and leachable studies, CROs may offer project-specific expertise. However, in most cases the additional capacity for short-term needs is the value offered. The value added to smaller pharma, biotechs, and virtuals is quite different. These companies often do not have the internal expertise to make the correct decisions regarding drug development, and require regulatory expertise and strategy development in addition to analytical testing. Virtuals may have no capability to even store their own reference standards and distribute them where needed and this sort of logistical support is expected of their CROs.

Dr. Skultety: Contract organizations have experience with a variety of active ingredients having a range of physical/chemical properties. The contract organization will develop a number of new methods each year and handle several method qualification/validations. Dealing with the larger volume of work, the contract organization becomes more efficient at getting the work initiated and completed in a timely manner. This broader exposure also allows for a better understanding of how to deal with a vast number of issues/problems that might arise when working with a new molecule.

Mr. McDowell: The main advantage is flexible capacity. Whether you are tactically outsourcing a test or strategically placing an entire development program, a contracting testing laboratory provides a flexible resource to help pharma keep fixed costs to a minimum. The robust outsource market over the past 10 years has resulted in service providers building capacity, expanding the breadth of their offerings, and gaining expertise needed to more effectively execute on complex programs. Outsourcing providers have also become more sophisticated in their delivery of services. Most offer on-site personnel at the client location and/or dedicated teams of employees in addition to the traditional fee for service model. This flexibility allows pharma to customize the service to fit each program requirement.

Mr. Hurst: An outsource partner can add real value in that their exposure to different projects and the knowledge they have gained from working with many different clients can help solve technical issues faster and speed up the development process. There are obviously strict confidentiality frameworks that an outsource partner works within, but once you have experienced a challenge you learn to approach similar challenges more efficiently the next time they occur.

Q: Looking at this past year, can you share an example of a successful small molecule or biologic analytical testing project?

Dr. Lambert: One that comes to mind (and the one I am most proud of) is actually a story with a not-so-happy ending. We were starting registration stability and we had completed the development and validation of a number of complicated chromatographic methods. The product was a drug-device combination project, so from an analytical perspective, there were a large number of complicated analyses that needed to be performed. One of the tests was evaluating the drug remaining in the device after delivery. Early on in the stability testing of the registration batches, a failure in this analysis identified a failure of one of the device components. This failure resulted in an incomplete dose being delivered from the device. We were able to quickly identify the root cause, and stop the stability studies before significant investments in analytical testing and manufacturing equipment were made. While it was disappointing to have the project end, it would have been far more disappointing (and expensive) for the client to have identified the problem after completion of the product registration and manufacturing scale-up.

Dr. Foehr: The use of cutting-edge technologies to solve analytical problems is especially rewarding. In the last year, Pacific BioLabs used Inductively Coupled Mass Spectrometry (ICP-MS) to measure low levels of specific elements. Trace metals are often used in manufacturing, combination drug-device products, and even as the active ingredient for medicinal purposes. ICP-MS is uniquely suited to detect trace elements in biological fluids and from process intermediates. We have supported clinical trials and new manufacturing processes using ICP-MS to measure trace elements.

Mr. McDowell: We were contracted to support all clinical stability and release testing on a biosimilar being developed to compete with the innovator product, Humira. The project required establishment of 15 methods, including a cell-based potency assay; ELISA binding assay; purity and impurities by SECHPLC, CE-SDS, and icIEF, just to name a few. All methods were fully validated in accordance with ICH guidance for both drug substance and drug product. The project was on a very tight timeline with no flexibility due to the scheduling of fill/finish activities at their CMO. All methods were fully validated and in a state of cGMP compliance within five months of project start. This timeline included the logistics of sourcing all study materials and review/approval of all protocols and reports. The methods were in place for testing of the drug substance upon release from one CMO, and the schedule was maintained for fill/finish activities on the drug product at the second CMO. We continue to support ongoing stability and release activities for this development candidate.

Ms. Thompson-Madsen: In the past year, we undertook a client project with three distinct project phases involving testing (Unfortunately, the details can only be shared in the most general way). These projects were a progression of work that included determining the most stable form of the API, identifying preferred presentation forms (lyophilized versus liquid), and discovering the best excipients for solubility, tonicity, and stability. As a result of our partnership, the client was able to tap into the expertise needed to quickly progress into GMP manufacturingand clinical trials, for which we are now providing laboratory support.

Dr. Kazeminy: As a biologics example, a leading pharma company was in search of a company that had the range of capability and technical depth to manage multiple mAB, ADC, and peptides platform needs. Irvine adapted its facilities/systems to meet the needs of its client by providing hands-on project management and oversight of the client’s programs: method development, validation, transfer, stability, release, extractable and leachable studies, and raw material testing. We also established a dedicated cell-based assay lab to support client’s program needs and manage the client’s procurement process. As a small-molecule example, a start-up firm was in search of a single-solution provider to help in the development, manufacturing, and release testing of its Phase II and Phase II/III new chemical entity. Irvine guided the client through drug product formulation and process development projects from initial strategic planning to detailed technical execution. Within five months of project kick-off, Irvine helped transfer and qualify unique pieces of equipment; transfer and execute process validation batches; and manufacture clinical material and placebo. Irvine guided the development, transfer, and scale-up of the client’s complex small molecule NCE to full-scale manufacturing in time for, and in some cases exceeding, aggressive clinical trial timelines.

Q: Where do you see the analytical testing market in the next five years in terms of the level of sophistication outsourcing providers will bring to the testing of small molecules and biologics?

Dr. Skultety: One item will be the increased use of UPLCs. This use is still in its infancy; it is a good concept for some compounds and can decrease the testing run time significantly. As the use of QbD is expanded, this will change the way methods are developed and validated. The more this approach can be utilized, the easier it will be to get specifications approved by the FDA.

Ms. Thompson-Madsen: While instrumentation is getting easier to use, “true experts in the field” seem to be harder to find. Outsourcing may be a means to obtain the analytical expertise one may no longer have in house. Also, the products are gaining in diversity, which may require specialized methods to be developed and performed.

Dr. Foehr: The analytical testing market trend over the next five years will continue to favor experienced providers with the capabilities to leverage both analytical (or bioanalytical) testing capabilities and in-life services when supporting complex drug and device characterization. Regulatory pressures will drive more detailed chemical analysis of drugs, diagnostics, devices, cosmetics, e-cigarettes, and nutraceuticals. New innovative drugs and medical devices will require thorough toxicology, biocomparability, and chemical characterization. The convergence of the digital age with biochemical testing will present opportunities and challenges for analytical testing labs. The use of hand-held devices able to collect and transmit analytical data is on the way. Real-time analysis of clinical samples, or in-process manufacturing samples are just a couple ways the industry will be transformed. Ultimately, instrumentation will help push the limits of what is possible to measure, but experience and savvy implementation will continue to add to the sophistication of outsourcing providers.

Dr. Rushing: In the past, the typical type of work being outsourced was the routine “QC” testing. The analytical knowledge base and scientific expertise resided within the pharma companies. This has slowly evolved with the rise of “virtual” pharma companies relying more heavily on the services of the CROs to be their analytical knowledge base and scientific experts. This resulted in the CROs adding internal experts on drug development and high-end analytical capabilities. Large pharma is now starting to adapt similar outsourcing strategies as we have observed with the closing of internal laboratory capabilities by multiple large pharma in preference to oursourcing the work.

Mr. Hurst: There is definitely a trend towards large pharma looking to mimic the smaller pharma company approach by trying to fully utilize the knowledge and expertise outsource laboratories hold. They are increasingly looking for the contract laboratories to provide a value-added service of brains as well as brawn. I can only see this trend continuing as many of the larger companies continue to develop their virtual structures.

Dr. Thanedar: Testing of pharmaceuticals and the technology applied to drug development changes slowly, as the requirements are the same for everyone and the FDA is disinclined to require testing that uses cutting-edge instrumentation and techniques. Consequently, competitive advantage comes from providing a better client experience, some of which is affected by the application of improving technology. Increasingly, sophisticated customer relationship management programs allow CROs to keep track of client and project information and respond more quickly and effectively. Laboratory Information Systems allow clients to view data during a project through web-based portals. And client meetings and discussions are being held by Skype, Go-to-meeting, Live Meeting, and other interactive software. Finally, cloud-based storage allows the sharing of files as well as collaboration on documents. The most successful players in the CRO space will embrace these technologies.

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